m.d., m.sc.(canada), fimsa, senior consultant physician & cardio-metabolic specialist

M.D., M.Sc.(Canada), FIMSA,

Senior Consultant Physician &

Cardio-Metabolic Specialist

Published Online - August 11, 2010

Grundmann H et al. Lancet 2006;368:874.

Bars represent number of new antimicrobial agents approved by the FDA during that period

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1983-87 1988-92 1993-97 1998-02 2003-05 2008

•Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286;•New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912

Resistan

ce

Inactive

– Lactam Ring - Lactamase

Active

Penicillinase

Gene for - LactamasePlasmid

This organism can freely grow

in the presence of Penicillin

Genomic islands

Prophages

ConjugativeTransposons (gram +ve)

Super Integrons(Mainly Protobacteria)

IntegronsTransposons

Insertion Sequences

Minimal species

Genomic backbone

e.g. Escherichia Coli

Common: 4.1 Mb

K12 Islands: 0.53 Mb

0157:H7 Islands: 1.34 Mb

Inappropriate empiric antibiotic therapy can lead to increases in:

– mortality– morbidity– length of hospital stay– cost burden– resistance selection

A number of studies have demonstrated the benefits of early use of appropriate empiric antibiotic therapy for patients with nosocomial infections

Inappropriate antibiotic therapy can be defined as one or more of the following:

– ineffective empiric treatment of bacterial infection at the time of its identification

– the wrong choice, dose or duration of Rx.

– use of an antibiotic to which the pathogen is resistant

Antibiotic resistance either arises as a result of innate consequences or is acquired from other sourcesBacteria acquire resistance by:•Mutation: spontaneous single or multiple changes in bacterial DNA•Addition of new DNA: usually via plasmids, which can transfer genes from one bacterium to another•Transposons: short, specialised sequences of DNA that can insert into plasmids or bacterial chromosomes

Structurally modified antibiotic target site, resulting in:

– Reduced antibiotic binding

– Formation of a new metabolic pathway preventing metabolism of the antibiotic

Interior of organism

Cell wall

Target siteBinding

Antibiotic

Antibiotics normally bind to specific binding proteins on the bacterial

cell surface


Cell wall

Modified target site

Antibiotic

Changed site: blocked binding

Antibiotics are no longer able to bind to modified binding proteins on the bacterial

cell surface

Altered uptake of antibiotics, resulting in:

• Decreased permeability

• Increased efflux


Cell wall

Porin channel

into organism

Antibiotic

Antibiotics normally enter bacterial cells via porin channels in the cell wall


Cell wall

New porin channel

into organism

Antibiotic

New porin channels in the bacterial cell wall do not allow antibiotics to enter the cells


Cell wall

Porin channel

through cell wall

Antibiotic

Entering Entering

Antibiotics enter bacterial cells via porin channels in

the cell wall


Cell wall

Porin channel

through cell wall

Antibiotic

Entering Exiting

Active pump

Once antibiotics enter bacterial cells, they are immediately excluded from the cells

via active pumps

Antibiotic inactivation

• Bacteria acquire genes encoding enzymes that inactivate antibiotics

Examples include:-Lactamases

• Aminoglycoside-modifying enzymes

• Chloramphenicol acetyl transferase


Cell wall

Antibiotic

Target siteBindingEnzyme

Inactivating enzymes target antibiotics


Cell wall

Antibiotic

Target siteBindingEnzyme

Enzymebinding

Enzymes bind to antibiotic molecules


Cell wall

Antibiotic

Target siteEnzyme

Antibioticdestroyed

Antibiotic altered,

binding prevented

Enzymes destroy antibiotics or prevent binding to target sites

+–Quinolones–++Trimethoprim–++Sulphonamide

++Macrolide+–Chloramphenicol

+–Tetracycline+++–Aminoglycoside

+Glycopeptide++++-lactam

Modified target Altered uptake Drug inactivation

Three mechanisms of -lactam antibiotic resistance are recognised:

• Reduced permeability

• Inactivation with -lactamase enzymes

• Altered penicillin-binding proteins (PBPs)

AmpC and Extended-Spectrum -lactamase (ESBL) production are the most important mechanisms of -lactam resistance in nosocomial infections

The antimicrobial and clinical features of these resistance mechanisms are highlighted in the following slides

Worldwide problem:• Incidence increased from 17% to 23%

between 1991 and 2001 in UK

Very common in Gram-negative bacilli

AmpC gene is usually sited on chromosomes, but can be present on plasmids

Enzyme production is either constitutive (occurring all the time) or inducible (only occurring in the presence of the antibiotic) Pfaller et al. Int J Antimicrob Agents 2002;19:383–388;

Sader et al. Braz J Infect Dis 1999;3:97–110; Livermore et al. Int J Antimicrob Agents 2003;22:14−27

An increasing global problem

Found in a small, expanding group ofGram-negative bacilli, most commonly the Entero-bacteriaceae spp.

Usually associated with large plasmids

Enzymes are commonly mutants of TEM- and SHV-type -lactamases

Jones et al. Int J Antimicrob Agents 2002;20:426–431; Sader et al. Diagn Microbiol Infect Dis 2002;44:273–280

Inhibited by -lactamase inhibitors

Usually confer resistance to:

• 1, 2 and 3rd generation Cephalosporins eg. Ceftazidime

• Monobactams eg. Aztreonam

• Carboxypenicillins eg. Carbenicillin

Varied susceptibility to Piperacillin / Tazobactam

Typically susceptible to Carbapenems and Cephamycins

Often non-susceptible to fourth generation Cephalosporins

Introduction of methicillin in 1959 was followed rapidly by reports of MRSA isolates

Recognized hospital pathogen since the 1960s

Major cause of nosocomial infections worldwide

• Contributes to 50% of infectious morbidity in ICUs

• Surveillance studies suggest prevalence has increased worldwide, reaching 25–50% in 1997

Jones. Chest 2001;119:397S–404S

MRSA in hospitals leads to an associated rise in incidence in the community

Community-acquired MRSA strains may be distinct from those in hospitals

In a hospital-based study, >40% of MRSA infections were acquired prior to admission

Risk factors for community acquisition included:

• Recent hospitalization; Previous antibiotic therapy

• Residence in a long-term care facility; Intravenous drug use•Hiramatsu et al. Curr Opin Infect Dis 2002;15:407–413•Layton et al. Infect Control Hosp Epidemiol 1995;16:12–17; Naimi et al. 2003;290:2976−2984

• Mechanism involves altered target site

– new penicillin-binding protein — PBP 2' (PBP 2a)

– encoded by chromosomally located mecA gene

• Confers resistance to all -lactams

• Gene carried on a mobile genetic element — staphylococcal cassette chromosome mec (SCCmec)

• Laboratory detection requires care

• Not all mecA-positive clones are resistant to methicillin

•Hiramatsu et al. Trends Microbiol 2001;9:486–493

•Berger-Bachi & Rohrer. Arch Microbiol 2002;178:165–171

• Cross-resistance common with many other antibiotics

• Ciprofloxacin resistance is a worldwide problem in MRSA:

– involves ≥2 resistance mutations

– usually involves parC and gyrA genes

– renders organism highly resistant to ciprofloxacin, with cross-resistance to other quinolones

• Intermediate resistance to glycopeptides first reported in 1997

•Hiramatsu et al. J Antimicrob Chemother 1997;40:135–136

•Hooper. Lancet Infect Dis 2002;2:530–538

• Vancomycin-resistant enterococci (VRE)

• Vancomycin-resistant S. aureus (VRSA)

• Resistance most common in organisms associated with nosocomial infections

– Pseudomonas aeruginosa

– Acinetobacter spp.

– also increasing among ESBL-producing strains

• Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance programme (1997―2000)

– 13.4% of Gram-negative strains resistant to ciprofloxacin

– P. aeruginosa and Acinetobacter baumannii are the most prevalent resistant strains

– increasing prevalence of resistance during surveillance period

•Masterton. J Antimicrob Chemother 2002;49:218–220 Thomson. J Antimicrob Chemother 1999;43(Suppl. A):31–40

MRSA

• S. aureus occurred in 22.9% of pneumonias in hospitalised patients in USA and Canada (1997 SENTRY data)

Enterococcus spp. resistance

• has developed rapidly, especially among VRE

Streptococcus pneumoniae resistance

• emerging in many countries, including community-acquired resistance

• Hong Kong (12.1%), Spain (5.3%) and USA (<1%)

• marked cross-resistance with other frequently used antibiotics

•Hooper. Lancet Infect Dis 2002;2:530–538

Antibiotic resistance in the hospital setting is increasing at an alarming rateand is likely to have an important impact on infection management

Steps must be taken now to control the increase in antibiotic resistance

•Cosgrove et al. Arch Intern Med 2002;162:185–190

The Academy for Infection Management supports the concept of using appropriate antibiotics early in nosocomial infections and proposes:

• selecting the most appropriate antibiotic based on the patient, risk factors, suspected infection and resistance

• administering antibiotics at the right dose for the appropriate duration

• changing antibiotic dosage or therapy based on resistance and pathogen information

• recognising that prior antimicrobial administration is a risk factor for the presence of resistant pathogens

• knowing the unit’s antimicrobial resistance profile and choosing antibiotics accordingly

Hand washing plays an important role in nosocomial pneumonias

Wash hands before and after suctioning, touching ventilator equipment, and/or coming into contact with respiratory secretions.

Use a continuous subglottic suction ET tube for intubations expected to be > 24 hours

Keep the HOB elevated to at least 30 degrees unless medically contraindicated

• Various Antibiotic Classes

• Mechanisms of action of Anti Bacterials

• Mechanisms of Bacterial Resistance

• Animation on Drug Resistance

Lactamases – Drug Resistance

• NDM1 – Superbug – Concerns

• Other Superbugs – Global Issues

• How to prevent Drug Resistance

• Where we are heading in future

• The Antimicrobial Availability Task Force of the IDSA1 identified as particularly problematic pathogens

– A. baumannii and P. aeruginosa

– ESBL-producing Enterobacteriaceae

– MRSA

– Vancomycin-resistant enterococcus

• Declining research investments in antimicrobial development2

•1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68.

• The rapid and disturbing spread of:

– extended-spectrum ß-lactamases

– AmpC enzymes

– carbapenem resistance

• metallo-β-lactamases

• KPC and OXA-48 β-lactamases

– quinolone resistance

• β-lactamases capable of conferring bacterial resistance to

– the penicillins

– first-, second-, and third-generation cephalosporins

– aztreonam

– (but not the cephamycins or carbapenems)

• These enzymes are derived from group 2b β-lactamases (TEM-1, TEM-2, and SHV-1)

– differ from their progenitors by as few as one AA

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Switzer Sweden Spain Ireland Germany UK France Italy Israel Turkey Greece Poland

Country

E. coli and Klebsiella ESBL Phenotype Rates by Country (SENTRY Program)

Klebsiella E. coli

• Until 2000, most ESBL producers were hospital Klebsiella spp. with TEM and SHV mutant β-lactamases

• Now, the dominant ESBLs across most of Europe and Asia are CTX-M enzymes, which originated as genetic escapes from Kluyvera spp

• Currently recognized as the most widespread and threatening mechanism of antibiotic resistance, both in clinical and community settings

– 80% of ESBL-positive E. coli from bacteraemias in the UK and Ireland are resistant to fluoroquinolones

– 40% are resistant to gentamicin

Livermore, DM J. Antimicrob. Chemother 2009

• Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems

• Resilient against inhibition by all commercially viable ß-lactamase inhibitors

– Subgroup 2df: OXA (23 and 48) carbapenemases

– Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC

– Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems

• IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae

• KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumoniae

• Substrate hydrolysis spectrum includes cephalosporins and carbapenems

•Nordmann P et al. LID 2009

• Once expressed at high levels, confer resistance to many β-lactam antimicrobials (excluding cefepime and carbapenems)

• In E. coli, constitutive over expression of AmpC β-lactamases can occur because

– of mutations in the promoter and/or attenuator region (AmpC hyperproducers)

– the acquisition of a transferable ampC gene on a plasmid or other transferable elements (plasmid-mediated AmpC β-lactamases)

Genetic group Geographic origin Characterized enzymes

imp Japan IMP-1 through IMI-13a IMP-14, and IMP-16a

vim Italy VIM-1 through VIM-7a

spm Brazil SPM-1a

gim Germany GIM-1a

vim USA VIM-7a,b sim Korea SIM-1

– Ceftaroline

– Ceftobiprole

• Oral penem

– Faropenem

•Hebeisen P et al. Antimicrob Agents Chemother. 2001. Sader HS et al. Antimicrob Agents Chemother. 2005. Granizo JJ et al. Clin Ther. 2006. Schurek KN et al. Expert Rev Anti Infect Ther. 2007.

Organism MIC90 (g/mL)

CTL CBP FAR

Pen-S 0.016 0.015 0.25

Pen-I 0.06 0.12 0.008

Pen-R 0.25 1 1

CTX-R* 0.5 1 ND‡

•Davies TA et al. ICAAC. 2005. Sahm DF et al. ICAAC. 2006. Van Bambeke F et al. Drugs. 2007.

McGee L et al; Morrissey I et al. ICAAC. 2007.

•*Multiple mutations in PBP1a, 2b, and 2x. ‡ MIC90 of 2 mg/L vs. cefuroxime-resistant strain

ABx Route In vivo Efficacy Cross-Resistance

Limitations

CTL IV Good lung penetration in rabbit model

None - all active

against MDR

strains

Presumed or reported cross-hypersensitivity to -lactamsCBP IV Equal to CTX in

murine model

FAR PO Eradication of S. pneumoniae; NI to AMX CLV, CPX

•Boswell FJ et al; Jones RN et al. J Antimicrob Chemother. 2002. Azoulay-Dupuis E et al. Antimicrob Agents Chemother. 2004.

Echols R et al; Kowalsky S et al; Lentnek A et al; Drehobl M et al. ICAAC. 2005. Jacqueline C et al; Young C et al; Rubino CM et al. ICAAC. 2006.

• Dalbavancin

– Once weekly IV dosing

• Oritavancin

• Telavancin

• Versus vancomycin:

– Additional mechanisms of action

– Renal and hepatic excretion

– No known nephrotoxicity or dose adjustments•Malabarba A et al. J Antimicrob Chemother. 2005

Organism MIC90 (g/mL)

VAN DAL*‡ ORI*‡ TEL*‡

Pen-S 0.5 0.03 0.004 0.03

Pen-NS 0.25-2 0.03 0.008 0.015

MDR ND ND 0.008 0.03

•Streit JM et al. Diag Micro Infect Dis. 2004. Lin G et al. ICAAC. 2005.

Thornsberry C et al. ICAAC. 2006. Draghi DC et al; Grover PK et al; Fritsche TR et al. ICAAC. 2007.

•*Rapidly bactericidal ‡ Also active against macrolide- and FQ-resistant strains

ABx Route In vivo Efficacy Cross-Resistance

AEs

DAL IV Animal model of PCN-resistant NBPP

Partial with vancomycin;

clinical significance

unclear

Redman syndrome with TEL;

Rare in platelets

ORI IV High AUC:MIC ratios in ELF and plasma in murine NBPP

TEL IV Good penetration into ELF and AMs in human volunteers; Phase III trial pending

•Gotfried M et al. ICAAC. 2005. Lehoux D et al. ICAAC. 2007.

• Garenoxacin (PO/IV)

– Bactericidal

– MIC90 = 0.06 g/mL for penicillin-, macrolide-, and 6 drug- resistant S. pneumoniae

– MIC90 = 1 g/mL for CIP- and LEV- resistant S. pneumoniae

– More potent than MOX

•Wu P et al. Antimicrob Agents Chemother. 2001. Jones RN et al. Diag Micro Infect Dis. 2007.

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• a group of polypeptide antibiotics that consists of 5 chemically different compounds (polymyxins A-E), were discovered in 1947

• Only polymyxin B and polymyxin E (colistin) have been used in clinical practice

• the primary route of excretion is renal

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• The target of antimicrobial activity of colistin is the bacterial cell membrane

• Colistin has also potent anti-endotoxin activity

– The endotoxin of G-N bacteria is the lipid A portion of LPS molecules, and colistin binds and neutralizes LPS

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• Active:

– Acinetobacter species,

– Pseudomonas aeruginosa,

– Enterobacteriaciae

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• 160 mg (2 million IU) ever 8 h

• 240 mg (3 million IU) every 8 h for life-threatening infections

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• Dose adjustment for renal failure

• Adverse effects:

– nephrotoxicity (acute tubular necrosis)

– neurotoxicity (dizziness, weakness, facial paresthesia, vertigo, visual disturbances, confusion, ataxia, and neuromuscular blockade, which can lead to respiratory failure or apnea)

June 30, 2008 -- Health Canada has authorised the marketing of ceftobiprole medocaril for injection (Zeftera and marketed by Janssen Ortho) for the treatment of complicated skin and soft tissue infections including diabetic

foot infections

On September 24, 2007, Health Canada approved daptomycin intravenous infusion (Cubicin, Cubist

Pharmaceuticals, Inc, and marketed by Oryx Pharmaceuticals, Inc) for the treatment of complicated

skin and skin structure infections caused by certain gram-positive infections and for bloodstream

infections, including right-sided infective endocarditis, caused by S. aureus.

• Irreversibly binds to cell membrane of Gram-positive bacteria

– Calcium-dependent membrane insertion of molecule

• Rapidly depolarizes the cell membrane

– Efflux of potassium

– Destroys ion-concentrationgradient

• Mechanism of action of Anti bacterials

• Mechanism of Bacterial Resistance

– Second level

• Third level

– Fourth level

• Fifth level

m.d., m.sc.(canada), fimsa, senior consultant physician & cardio-metabolic specialist

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