choosing antibiotics in mdro infections in nicu · hypomagnesemia, hyponatremia and hypokalemia,...
TRANSCRIPT
Choosing antibiotics in MDRO infections in NICU
Dr Sachin ShahMD (Pediatrics) DM (Neonatology)
Fellowship in Neonatology (Australia and Canada)
Fellowship in Pediatric critical care (Canada)
Director
Neonatal and Pediatric Intensive care services
Case based approach
MDR organisms
Newer antibiotics
Rationale approach
MDRO ndash Organisms resistant to one or
more classes of antibiotics
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
Primi 35 years old IVF pregnancy Twins
DCDA
Leaking started at 24 weeks Cervical stitch
insitu on and off leak Managed
conservatively
At 25 weeks developed fever
Received IV piperacillin tazobactum
Emergency LSCS at 25+2 weeks in vo
suspected chorioamnionitis
Twin 1 ndash intact membranes
Twin 2 ndash ruptured sac
Both cried at birth and stabilised on CPAP
BW 700 gms and 720 gms
Antibiotic options
Twin 1
Twin 2
Same or different
1st line 2nd line 3rd line
Wait for maternal cs
Depending on clinical scenario and lab
work
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Case based approach
MDR organisms
Newer antibiotics
Rationale approach
MDRO ndash Organisms resistant to one or
more classes of antibiotics
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
Primi 35 years old IVF pregnancy Twins
DCDA
Leaking started at 24 weeks Cervical stitch
insitu on and off leak Managed
conservatively
At 25 weeks developed fever
Received IV piperacillin tazobactum
Emergency LSCS at 25+2 weeks in vo
suspected chorioamnionitis
Twin 1 ndash intact membranes
Twin 2 ndash ruptured sac
Both cried at birth and stabilised on CPAP
BW 700 gms and 720 gms
Antibiotic options
Twin 1
Twin 2
Same or different
1st line 2nd line 3rd line
Wait for maternal cs
Depending on clinical scenario and lab
work
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
MDRO ndash Organisms resistant to one or
more classes of antibiotics
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
Primi 35 years old IVF pregnancy Twins
DCDA
Leaking started at 24 weeks Cervical stitch
insitu on and off leak Managed
conservatively
At 25 weeks developed fever
Received IV piperacillin tazobactum
Emergency LSCS at 25+2 weeks in vo
suspected chorioamnionitis
Twin 1 ndash intact membranes
Twin 2 ndash ruptured sac
Both cried at birth and stabilised on CPAP
BW 700 gms and 720 gms
Antibiotic options
Twin 1
Twin 2
Same or different
1st line 2nd line 3rd line
Wait for maternal cs
Depending on clinical scenario and lab
work
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
Primi 35 years old IVF pregnancy Twins
DCDA
Leaking started at 24 weeks Cervical stitch
insitu on and off leak Managed
conservatively
At 25 weeks developed fever
Received IV piperacillin tazobactum
Emergency LSCS at 25+2 weeks in vo
suspected chorioamnionitis
Twin 1 ndash intact membranes
Twin 2 ndash ruptured sac
Both cried at birth and stabilised on CPAP
BW 700 gms and 720 gms
Antibiotic options
Twin 1
Twin 2
Same or different
1st line 2nd line 3rd line
Wait for maternal cs
Depending on clinical scenario and lab
work
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Case
Primi 35 years old IVF pregnancy Twins
DCDA
Leaking started at 24 weeks Cervical stitch
insitu on and off leak Managed
conservatively
At 25 weeks developed fever
Received IV piperacillin tazobactum
Emergency LSCS at 25+2 weeks in vo
suspected chorioamnionitis
Twin 1 ndash intact membranes
Twin 2 ndash ruptured sac
Both cried at birth and stabilised on CPAP
BW 700 gms and 720 gms
Antibiotic options
Twin 1
Twin 2
Same or different
1st line 2nd line 3rd line
Wait for maternal cs
Depending on clinical scenario and lab
work
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Emergency LSCS at 25+2 weeks in vo
suspected chorioamnionitis
Twin 1 ndash intact membranes
Twin 2 ndash ruptured sac
Both cried at birth and stabilised on CPAP
BW 700 gms and 720 gms
Antibiotic options
Twin 1
Twin 2
Same or different
1st line 2nd line 3rd line
Wait for maternal cs
Depending on clinical scenario and lab
work
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Antibiotic options
Twin 1
Twin 2
Same or different
1st line 2nd line 3rd line
Wait for maternal cs
Depending on clinical scenario and lab
work
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Clinical course
Twin 1 ndash CPAP 30 FiO2 Mild RDS
CBC ndash normal
Cs ndash awaited
Twin 2 - same as above
Routine preterm care given
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Motherrsquos HVS isolated Klebsiella
Blood cs of twin 2 also isolated Klebsiella
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
ESBL infections
ESBLs hydrolyze broad range of beta
lactams including penicillin cephalosporins
but not carbapenems
GNB ndash Ecoli Klebsiella Proteus etc
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Beta lactam ndash Beta lactamase
inhibitor in ESBL infections
BL-BLI combination generally have in vitro
activity against organisms possessing a single
ESBL
Many organisms now produce multiple
ESBLs simultaneously
Reduces the effectiveness of the BL-BLI
resulting in in vitro resistance
Therapeutic failure with BL-BLIs may occur
in high-inoculum infections
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Small observational studies of neonates
infected with ESBL-producing organisms
found no difference in outcomes of neonates
receiving BL-BLIs or carbapenems
These studies had insufficient power to detect
a difference if one exists
BL-BLI is a reasonable treatment option for
ESBL-producing GNB from a urinary source
when appropriate dosing is used
bullPillay T et al Piperacillintazobactam in the treatment of Klebsiella pneumoniae
infections in neonates Am J Perinatol 1998 1547ndash51
bullVelaphi S et al Mortality rate in neonates infected with extended-spectrum beta
lactamase-producing Klebsiella species and selective empirical use of meropenem
Ann Trop Paediatr 200929101ndash10
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Fluroquinolones
Excellent tissue penetration
Useful as combination therapy
Ciprofloxacin
Single report of use in neonates
Children 20-30 mgkgday in 2 divided
doses
Prolongs QT interval
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Carbapenems
Drug of choice
Meropenem or Imipenem- Cilastatin
Ertapenem ndash UTI or SSTI
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Meropenem is the preferred carbapenem in
newborn infants as the safety profiles of
other carbapenems have not been
established in neonates
Gentamicin resistance is common
Amikacin or netilmicin which are resistant
to the aminoglycoside-modifying enzymes
of the bacteria can be used in patients who
are infected with a gentamicin-resistant
pathogen
Hoban DJ et al In vitro activity of three carbapenem antibiotics Comparative
studies with biapenem (L-627) imipenem and meropenem against aerobic pathogens
isolated worldwide Diagn Microbiol Infect Dis 1993 17299
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
ESBLs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
MDRO infection is associated with
Increased mortality
Increased morbidity
Increased length of stay
Increased cost of care
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Biggest problem today
Development of MDRO has outpaced
development of newer antibiotics
Very few antibiotics in pipeline
Acquired from community also
Maintain a balance between appropriate
initial antibiotic coverage and prevention of
resistance
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Pharmacokinetic and
pharmacodynamic aspects
Concentration dependent killing ndash higher
concentration (high peak)ndash better
eradication of bacteria
Aminoglycosides fluroquinolones colistin
Maximal efficacy seen with larger doses
given less frequently
Doses limited by toxicity
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Concentration independent killing
Maximum efficacy achieved with
maintaining drug concentration above the
pathogensrsquo minimum inhibitory
concentration (MIC)
More frequent administration to keep conc
above MIC for atleast 50-70 of the dosing
interval
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Rising MICs for most pathogens
Doses in NICU may be higher than that in
community
Cephalosporins carbapenems penicillins
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Case 2
3 weeks old baby transferred to Surya
Born at 31 weeks BW 1400 grams
CIAB had mild RD at birth and given
CPAP
Weaned off CPAP on day 5
Developed feeding intolerance and bilious
aspirates
Low platelets Given RDP
Meropenemamikacin given
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Settled clinically for few days
But not tolerating feeds
3 weeks ndash Abdominal distension with
perforation and shifted
Blood cs - Enterobacter
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Options
Supportive care continued
Antibiotics
Ventilation Drain done
Exploratory laparotomy ndash Distal ileostomy
done after 48 hours
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Carbapenem resistant GNBs
Carbapenem resistant enterobacter (CRE)
Carbapenem resistant acinetobacter
Carbapenem resistant pseudomonas
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
CRE ndash some caveats
Carbapenemase production does not always
translate to clinical failure with carbapenems
Therapeutic efficacy has been reported at
approximately 70 for MICs of 4 μgmL
(reported as resistant according to current CLSI
guidelines) no different from MICs le2 μgmL
Mainstay of treatment for CRE is combination
therapy
More efficacious than monotherapy
Tzouvelekis LS et al Carbapenemases in Klebsiella pneumoniae and other
Enterobacteriaceae an evolving crisis of global dimensions Clin Microbiol Rev
2012 25682ndash707
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Prolonged infusion carbapenem
therapy
Bacterial killing is enhanced when the non protein
bound lactam concentration exceeds the MIC ( fT
gtMIC) of the organism at least 40 of the time
for carbapenems
Intermittent dosing can lead to precipitous drops
in serum drug concentrations as meropenem is
rapidly cleared through the kidneys
Prolonging the infusion leads to a higher
probability of achieving target fTgtMIC
Tamma PD Jenh AM Milstone AM Prolonged beta-lactam infusion for gram-negative
Infections Pediatr Infect Dis J 201130336ndash7
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Meropenem dose of 40 mgkgdose
intravenously every 8 hours reliably
achieves this target for MICs le2 μgmL
For MICs of 4ndash8 μgmL a prolonged
infusion of meropenem over 3 hours can be
used for target attainment
Courter JD et al Optimizing bactericidal exposure for beta-lactams using prolonged
and continuous infusions in the pediatric population Pediatr Blood Cancer 2009
53379ndash85
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Polymixins
Polymixin B and Polymixin E (Colistin)
Similar profile
Polymyxin B does not have a prodrug Given in the
form of its active microbiological agent
Adult data suggest that nephrotoxicity is less
concerning with this agent compared with colistin as
urinary excretion is minimal
Pharmacokinetic studies have not been conducted in
children and limited clinical experience in pediatrics
population is limited
Dara JS CL et al Microbiological and genetic characterization of carbapenem-resistant
Klebsiella pneumoniae isolated from pediatric patients J Ped Infect Dis 2013 11ndash5
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Colistin
Colistin is administered parenterally in the
form of its inactive prodrug colistimethate
sodium (CMS) which is slowly and
incompletely converted to colistin (~20
conversion in vivo by enzymatic hydrolysis)
Bactericidal concentration dependent kiling
Kassamali Z et al Clin Infect Dis 201357877ndash83
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
CMS is cleared by kidney
Conversion of CMS to colistin is slow and
unpredictable
Even after administering a loading dose
several hours of delay occurs before
achievement of the maximum serum
concentration of colistin
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Colistin
Rapid clearance of CMS may reduce the
systemic availability of colistin to levels
insufficient to overcome infections
The utility of a loading dose has not yet
been evaluated in children
Seems logical approach
Suggested intravenous loading dose of
50000unitskg
25000-40000unitskg 8 hourly
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Hypomagnesemia hyponatremia and
hypokalemia have also been reported in
neonates receiving colistin therapy
Thomas R et al The use of polymyxins to treat carbapenem resistant infections in neonates and
children Expert Opinion on Pharmacotherapy 2018DOI 1010801465656620181559817
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Tigecycline Broad-spectrum bacteriostatic agent
Minocycline derivative
Tigecycline monotherapy was associated with
increased mortality compared with other regimens in
meta-analysis of randomized trials
Possibly due to unfavorable pharmacokinetics
Serum concentrations peak at lt1 μgmL and
promptly decline due to rapid tissue distribution
Yahav D et al Efficacy and Safety of tigecyclinea systematic review and meta-analysis
J Antimicrob Chemother 2011 661963ndash71
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Tigecycline
Not effective against Pseudomonas Aeruginosa
and Proteus Mirabilis
Not FDA approved in children
European medicines agency (EMA)- age gt 8 years
Duration of therapy 5 -14 days
Suggested doses are 12 mgkg every 12 hours iv
to a maximum dose of 50 mg every 12 hours for
children aged 8 to 11 years and 50 mg every 12
hours for adolescents aged 12 to 17 years
Expert Rev Anti Infect Ther 2017 Jun15(6)605-612
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Tigecycline
Use in combination with other active agents may
be considered when alternative treatment options
are exhausted
Limited experience in Pediatrics
Tigecycline may cause permanent teeth
discoloration and enamel hypoplasia in children
aged lt8 years
Purdy J et al Pharmacokinetics and safety profile of tigecycline in children aged 8 to
11 years with selected serious infections a multicenter open-label ascending-dose
study Clin Ther 2012 34496ndash507e491
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
First line drugs Second line drugs
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Hsu AJ Tamma PD Treatment of multidrug resistant gram negative infections in
children Clinical infectious Diseases 2014581439-48
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Case
34 weeks 1400 grams BW 14 days old
Delivered by emergency LSCS in vo
maternal leak with severe oligohydramnios
Baby said to have cried at birth APGAR
not known
Baby was shifted to nicu for respiratory
distress was put on oxygen Given
ceftriaxone and amikacin PICC inserted
Developed abdominal distension with feed
intolerance and kept NBM PPN given
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Developed fever on day 3 of life
Septic work up repeated
iv antibiotics upgraded ndash Meropenem
tigecycline colistin clindamycin at various
stages received IVIg
CSF examination done PICC replaced
Baby had thrombocytopenia received RDP
and PCV
Baby shifted to Surya hospital on parental
request and retrieved by SMCH team for
further care on day 14
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Colistin carbapenem resistant
Klebsiella (C-C-RKp)
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Options
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Fosfomycin
Belongs to Epoxide class of antibiotics
Unrelated to any other class of Abs
Broad spectrum against Gram +ve and
Gram ndashve
Bactericidal
Expert Rev Anti Infect Ther 2017 Oct15(10)935-945
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Good tissue penetration
Usually used as combination therapy in
XDR patients who are very sick as a last
resort
Response rate in adult 50-90
Hpernatremia and hypokalemia ndash very
common
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Resistance can develop very fast esp
amongst Pseudomonas
Should be used with synergestic antibiotics
such as genta amikacin etc
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Dose
lt 40 weeks CGA ndash 50 mgkg BD
40-44 weeks ndash 200 mgkgday in 3 divided
doses
Frequent monitoring of SE is needed
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
In SMCH
Continued inj Meropenem
Fosfomycin
Blood culture grew Klebsiella- Pan Drug
resistant
The baby had persistent low borderline
platelets
CSF so meningitis
Repeat blood culture after 7 days was sterile
IV antibiotics were given for 3 weeks
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
All other organs normal
Baby discharged home after 3 weeks
Comments
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Infection control
Contact precautions
Hand hygiene
Minimizing the use of invasive devices
Antimicrobial stewardship
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Active surveillance
Screening high-risk patients to detect rectal
colonization has been suggested
Difficult to assess impact of surveillance
May be useful in the setting of outbreaks
due to carbapenemase-resistant organisms
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
Summary
Respect the threat of antimicrobial
resistance
MDRO are seen in NICU as well as in
community
Clinicians need to familiar with treatment
strategies for MDRO
Judicious and appropriate use of antibiotics
THANK YOU
THANK YOU