Using PK/PD Principles in Using PK/PD Principles in Antibiotic PrescribingAntibiotic PrescribingSAHD May 20, 2011SAHD May 20, 2011
Peter Gayo MunthaliPeter Gayo MunthaliConsultant MicrobiologistConsultant Microbiologist
UHCWUHCWHonorary Associate Clinical ProfessorHonorary Associate Clinical Professor
University of WarwickUniversity of Warwick
ObjectivesObjectivesBy the end of this session you should be able to:1. Appreciate the importance of prescribing antibiotics in a timely
manner2. Understand the right dosing for major classes of antibiotics 3. Select antibiotics according to the site of infection 4. Safely prescribe Gentamicin and Vancomycin,be able to
monitor levels logically and interpret them5. Select safe antibiotics for use in renal and hepatic failure6. Understand the consideration of antibiotic interactions with
other drugs
There are Three in this RelationshipThere are Three in this Relationship
Drug
Bacteria
Resistance
Pharmacodynam
ics
(PD)Infection
Host defence
Toxici
ty
Pharm
acok
inet
ics
(PK)
Host
Improving the probability of Improving the probability of positive outcomespositive outcomes
• Window of opportunity– Early recognition and treatment of infection
– Selection of appropriate antibiotic(e.g. through in vitro susceptibility determination)
– Optimization of DOSE using Pharmacodynamic principles
– Use optimized dosing that would allow for the minimization of selecting further resistance
Early recognition of infection Early recognition of infection (Sepsis)(Sepsis)
• Systemic inflammatory response syndrome (SIRS)Systemic inflammatory response syndrome (SIRS)Systemic activation of the immune responseSystemic activation of the immune response 2 of the following in response to an insult:2 of the following in response to an insult:
• T > 38 .C or < 36.CT > 38 .C or < 36.C• HR > 90 bpmHR > 90 bpm• RR > 20 bpm or PaCO2 < 32 mmHgRR > 20 bpm or PaCO2 < 32 mmHg• WBC > 12 000 cells/mm3 , < 4 000 cells/mm3 or >10 % bandsWBC > 12 000 cells/mm3 , < 4 000 cells/mm3 or >10 % bands
• SepsisSepsisThe systemic response to infectionThe systemic response to infectionSIRS + suspected or confirmed infectionSIRS + suspected or confirmed infection
(Bone et al Crit Care med 1989.;17 :389) (Bone et al Crit Care med 1989.;17 :389)
SepsisSepsis• Severe sepsis
– Sepsis + organ dysfunction, hypoperfusion or hypotension
• Septic shock– Severe sepsis +
• unresponsive to fluid resuscitation • need for vasopressor agents
• Multiple organ dysfunction syndrome– Organ dysfunction – Homeostasis cannot be maintained without intervention
Severe Sepsis BundlesSevere Sepsis BundlesSepsis Resuscitation Bundle(To be completed as soon as possible and scored over first 6
hours)1. Serum lactate measured2. Blood culture obtained prior to antibiotic administration3. From presentation, broad spectrum antibiotics administered
within 3 hours for ED admission and 1 hour for non-ED ICU admission
4. In the event of hypotension and /or lactate >4mmol/l (36mg/dl):
a. Deliver an initial minimum of 20ml/Kg of crystalloid (or colloid equivalent)
b. Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure >65mmHg
5. In the event of persistent hypotension despite fluid resuscitation (septic shock) and /or lactate >4mmmol/L (36mg/dl):
a. Achieve central venous pressure (CVP) of >8mmHgb. Achieve central venous oxygen saturation (ScvO2) of > 70%
Early treatment of infectionEarly treatment of infection prospective observational study on 101 consecutive adult patients with
severe sepsis or septic shock
• The rate of compliance with the 6-hour sepsis bundle was 52%.
• non-compliant group had a more than twofold increase in hospital
mortality
– (49% versus 23%, RR 2.12 (95% CI 1.20 to 3.76), P = 0.01)
– similar age and severity of sepsis both groups
• Compliance with the 24-hour sepsis bundle in only 30% (21/69).
Hospital mortality was increased in the non-compliant group from 29%
to 50%,
– 76% increase in risk for death(RR 1.76 (95% CI 0.84 to 3.64), P =
0.16).
Critical Care 2005, 9:R764-R770
•2,000 consecutive patients admitted to surgical or medical ITU655 patients (33%) had either CA or HA infection 169 infected patients (25.8%) received inadequate antimicrobial treatment
•All Cause Hospital Mortality (All Cause Hospital Mortality (RR 4.26, 95% CI 3.52-5.15, p < 0.001)•Adequate antimicrobial treatment
•Mortality 12.2%•Inadequate antimicrobial treatment
•Mortality 52.1%
•Infection Related Mortality (Infection Related Mortality (RR 2.37, 95% CI 1.83-3.08, p < 0.001)
•Adequate antimicrobial treatment•Mortality 17.7%
•Inadequate antimicrobial treatment•Mortality 42.0%
•Most important independent determinant of hospital mortality was inadequate antibiotic treatment (OR 4.27, 95% CI 3.35-5.44, p < 0.001)
Role of Antibiotics (Kollef et al Chest 1999;115:462-474)
Timing of Antibiotics (Kumar A et al. Crit Care Med Kumar A et al. Crit Care Med
2006;34:1589–1596)2006;34:1589–1596)
•Retrospective, May 1999-June 2004, N=2731
•Outcome of antibiotic therapy after onset of recurrent or persistent hypotension
•Overall mortality 56.2%
•Survival decreased by 7.6% for each hour of delay
•Applied to all subgroups of infections regardless of the source of infection or causative pathogens
Key Message 1Key Message 1
• Diagnose sepsis early and give antibiotics promptly to reduce mortality from sepsis
PharmacodynamicsPharmacodynamics
Drug Absorption CurveDrug Absorption Curve
MIC CalculationMIC Calculation
MIC
Beta-LactamsBeta-Lactams
• The critical parameter is the time the antibiotic concentration remains above the MIC of the organism expressed as– T > MIC
BetaBeta-Lactams: -Lactams: Optimising ExposureOptimising Exposure
• The optimum level of exposure varies for different agents within the beta-lactam class
• Required %T>MIC for efficacy:– ~ 50%–70% for cephalosporins– ~ 50% for penicillins– ~ 40% for carbapenems
Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.
Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media
Craig et al, Ped Infect Dis 15: 255, 1996
Conventional (three-times daily regimen)Conventional (three-times daily regimen)
Nicolau DP et al. Antimicrob Agents Chemother. 1995;39:650–655
Once-daily vs. Conventional Once-daily vs. Conventional Three-times Daily Aminoglycoside Three-times Daily Aminoglycoside
RegimensRegimens
Once-daily vs. Conventional Once-daily vs. Conventional Three-times Daily Aminoglycoside Three-times Daily Aminoglycoside
RegimensRegimensConcentration (mg/L)Concentration (mg/L)
00
88
1414
44
66
1010
1212
Time (hours)00 1212 2424202044 88 1616
Once-daily regimenOnce-daily regimen
22MIC
Cmax:MIC modelFor optimal response,
Peak concentration: MIC ratio should be between 8-12.1
Aminoglycosides—Aminoglycosides—Relationship Between CRelationship Between Cmaxmax:MIC :MIC
Ratio and Clinical ResponseRatio and Clinical Response
55
6570
8389 92
0
10
20
30
40
50
60
70
80
90
100
2 4 6 8 10 12+
CCmaxmax:MIC:MIC
Clinical Clinical responseresponse
(%)(%)
Moore RD et al. J Infect Dis. 1987;155:93-99.
Key Message 2Key Message 2• Beta lactams need frequent dosing for
successful therapeutic outcome– Missing doses will lead to treatment failure
• Aminoglycosides should be given as a large single dose (except in infective endocarditis) for a successful therapeutic outcome– Multiple small doses will lead to treatment failure
and likely to lead to renal toxicity
PharmacokineticsPharmacokinetics
Where do bugs Hide?Where do bugs Hide?
CytosolListeria monocytogenesShigella flexeneriRickettsia spp
ER
Legionella pneumophila
Mycobacterium spp
Endosomes
Lysosomes
Legionella pneumophilaCoxiella brunetiStaphylococcus aureus
Phagosomes
Brucella sppSalmonella sppFrancisella tularensis
Inclusions
Chlamydia spp
Early Endosomes
Nucleus
Use of Pharmacokinetics in Treatment
Aminoglycosides
Good
Circulating organisms
Poor
Soft tissue
Bone and joints
Abscesses
Lungs
CSF
Beta lactams
Good/variable (Dependant on individual antibiotic)
Soft tissue
Bone and joints
Lungs
CSF
Poor
Abscesses
Examples of good Tissue Penetrators
Tetracyclines
Macrolides
Quinolones
Clindamycin
Extra and Intracellular PharmacokineticsExtra and Intracellular PharmacokineticsAntibiotic Influx Efflux Accumulation Factor Accumulate
s
Beta lactams Fast Variable < 1 Cytosol
Erythromycin Fast Fast 4-10 Two Thirds
Lysosomes/one third cytosol
Clarithromycin Fast Fast 10-20
Azithromycin Fast Slow-v. slow 40-300
Telithromycin Fast to slow 15-50
Fluoroquinolones Fast-v.fast
Very fast 4-10 Cytosol
Aminoglycosides V.slow Very slow 2-4 (after several days) Lysosomes
Clindamycin Fast Fast 5-20 Unknown
Tetracyclines Fast ? 1-4 Unknown
Vancomycin slow ? 8 (after 24 hrs) Lysosomes (in kidneys)
Teicoplanin Fast ? 60 Unknown
Accumulation factor =Cellular conc /extracellular concV.fast < 3min, Fast 3-15min, slow 15min-3hrs, V.slow >3hrs
Infect Dis Clin N Am 17(2003) 615-634
Key Message 3Key Message 3
• When selecting an antibiotic consider the following;– Where is the infection?– Which antibiotics will reach the site of
infection
• Match the two and select your antibiotic
Antibiotics, Renal Function and Hepatic Antibiotics, Renal Function and Hepatic FunctionFunction
Renal FunctionEstimated Creatinine clearance (Cockcroft-Gault formula) 140-AgexMass (Kg) x ConstantSerum Creatinine in µmol/l
Constant 1.04 for Women, 1.23 for Men
Stage GFR(ml/min/1.73m²) Description I 90+ Normal
II 60-89 Mild reduction
IIIa 45-59 Moderate reduction
IIIb 30-44 Moderate reduction
IV 15-29 Severe reduction
V <15 Very severe (End-stage)
Effect of Creatinine Clearance on the Half Life of an Antibiotic with a Normal Half Life of 1 Hour
1 24
20
0
5
10
15
20
25
Normal 50% Normal 25% Normal 5% Normal
Creatinine Clearance
Hal
f Life
in H
ours
Excretion Less than 15% in urine and
Generally innocuous
Examples
•Macrolides (erythromycin)
•Sodium fusidate
•Clindamycin
Generally no dosage adjustment required
•Exception
•Chloramphenicol-not innocuous
Major Renal Excretion i.e. ≥ 50%
Generally innocuous
Examples
•Penicillins
•Cephalosporins
•Carbapenems
•Tetracyclines
Not Innocuous
Examples
•Aminoglycosides
•Polymyxin B, Colistin
•Vancomycin
•Amphotericin
Antibiotic Renal Handling
Excretion Less than 15% in urine and
Generally innocuousDose adjustment required only at moderate to severe renal impairment
Examples
Antibiotic Creatinine Clearance
Dose adjustment
Clindamycin Any None
Erythromycin Any None
Major Renal Excretion i.e. ≥ 50% Generally innocuous
Antibiotic Creatinine Clearance (CrCl)
Dose Adjustment
Amoxicillin >30 Nil
Co-amoxiclav >15 Nil
Tazocin >40 Nil
Ceftriaxone Any Nil
Meropenem >50 Nil
Doxycycline and Minocycline (All other tetracyclines to be avoided)
Any Nil
Major Renal Excretion i.e. ≥ 50% AND Poisonous
Antibiotic Creatinine Clearance (CrCl)
Dose Adjustment
Aminoglycosides (Gentamicin 5mg/Kg trough levels after 1st dose)
In all cases monitor levels
Reduced
Severe
<20
↑ dose interval
↑ dose interval and ↓dose
Avoid
Vancomycin (1g BD, trough levels before 4th Dose)
In all cases monitor levels
Reduced
Severe
Monitor Trough levels
Give only after trough levels known
Amphotericin Reduced Avoid
Gentamicin monitoring 1Gentamicin monitoring 1
Hartford Nomogram
7 mg/Kg OD
•Precise Times of collection required
•Collection 6-12Hrs after dose
Gentamicin monitoring 2Gentamicin monitoring 2• Gentamicin 5-7mg/Kg OD
– Collect around 24Hrs post dose– Aiming for <1mg/l
• Checking if patient is clearing gentamicin
• High levels• Blood collected too early• Patient not clearing Gentamicin• Blood collected from lumen used to infuse
Gentamicin earlier on
Gentamicin monitoring 2Gentamicin monitoring 2
• Corrective measures– Re-check levels– Stop, look for alternative antibiotic– Omit dose and repeat levels after 12 Hrs
• Frequency– 2-3x/week after steady state
• More frequently if renal function changing or concurrent nephrotoxic drugs
Vancomycin trough level• Collect serum specimen 30 minutes or less before next dose
• Frequency of collection:
•First level at steady state (3rd - 5th dose)
•Subsequent levels once or twice/week
•More frequently if renal function changing or concurrent
nephrotoxic drugs
Vancomycin MonitoringGlycopeptide
•ONLY active against Gram-positive bacteria including MRSA
•IV only except for Clostridium Difficile associated diarrhoea when oral route is used (NOT absorbed from GI and not enough levels get into GI by IV route)
•1g BD IV standard dose
Therapy Trough Level (mg/L)
Dosing Interval Adjustment
Vancomycin <5 •On ≥q24h , decrease interval by 12 hours
•On q12h, consult microbiology/pharmacist
5-15 No change
15-20 Increase interval by 12 hours
>20 Consult microbiologist/pharmacist/Stop
Vancomycin with Aminoglycoside
<5 •On ≥q24h , decrease interval by 12 hours•On q12h, consult microbiology/pharmacist
5-10 No change
10-20 Increase interval by 12 hours
>20 Consult microbiologist/pharmacist/Stop
Hepatic failureHepatic failure
Antibiotic Handling Comments
Penicillins Kidneys Generally safe in liver failure, check individual drug for possible cholestatic jaundice
Tetracyclines Concentrated in the liver and excreted via bile and reabsorbed in the intestine. Eliminated in urine
Avoid or use with caution
Aminoglycosides Kidneys Safe
Macrolides Liver metabolism May worsen liver dysfunction, avoid
Chloramphenicol 85-95% conjugated in the liver
Avoid, increased probability of bone marrow toxicity
Glycopeptides Kidneys Safe
Co-trimoxazole Significant metabolism by liver
Avoid
Key Message 4&5Key Message 4&5• Aminoglycosides are toxic drugs and require
monitoring– Avoid use in renal failure but safe in liver failure– Avoid concomitant use with other renal toxic drugs – Check renal clearance, frequency according to renal function
• Vancomycin dosing should be BD dose and adjusted according to levels at steady state– Frequency of monitoring depends on renal function
• Beta lactams are the safest antibiotics in renal and hepatic failure– Adjustments to dose may still be required in severe failure
Antibiotic InteractionsAntibiotic Interactions
Antibiotic Interacting Drug
Comments
Penicillins MethotrexateAllopurinol
reduce excretion of MethotrexateIncreased risk of rash when given with
amoxicillin or Ampicillin
Tetracyclines RifampicinCarbamazepine,
barbiturates (Cytochrome P450 Inducers)
Plasma Doxycycline levels reducedAccelerates metabolism of
Doxycycline
Aminoglycosides Amphotericin, loop diuretics, Taccrolimus
Neostigmine
Increased nephrotoxicity /ototoxicityAntagonise effect
Macrolides Many Check BNF
Rifampicin (Cytochrome P450 Inducer)
Too many Check BNF
Key Message 6Key Message 6
• Always check the impact of an antibiotic on other drugs that a patient is on– Consult BNF
And So!And So!
Necrotising Fascitis
Beta haemolytic Streptococcus group A
Patient•Severe sepsis with septic shock
•Acute renal failure
•On Gentamicin, Clindamycin,
•co-amoxiclav
Beta haemolytic Streptococcus group A isolated from tissue
Sensitive to:
Amoxicillin, meropenem, Clindamycin
Gentamicin, doxycycline, Vancomycin, Erythromycin, Gentamicin
What would you do?
a. Stop Gentamicin
b. Switch Co-amoxiclav to Benzylpenicillin
c. Continue with the same treatment
d. Add meropenem to the current treatment
What would you do?On 11/05/11 you are called by a nurse at 2300hrs to make a decision whether to give gentamicin or not since the level was not done that day.
Date Urea (mmol/L) (Normal Ref 2.5-7.8)
Creatinine µmol/L ( Normal Ref 50-90)
Gent Levels
09/05/11 6 99 <1
07/05/11 7 98 <1
04/05/11 8 102 <1
30/04/11 8 103 <1
Previous Renal Function and Gentamicin Levels
How do you proceed?How do you proceed?
a) Send urgent Gentamicin levels before giving it
b) Change to another antibiotic until you get levels back the following day
c) Omit Gentamicin dose
d) Give the Gentamicin and check levels the following day
What would you do?On 11/05/11 you are called by a nurse at 2300hrs to make a decision whether to give gentamicin or not since the level was not done that day.
Date Urea (mmol/L) (Normal Ref 2.5-7.8)
Creatinine µmol/L ( Normal Ref 50-90)
Gent Levels
09/05/11 15 110 Not done
07/05/11 9 90 <1
04/05/11 3 60 <1
31/04/11 2.7 53 <1
Previous Renal Function and Gentamicin Levels
How do you proceed?How do you proceed?
a. Send urgent Gentamicin levels before giving it
b. Change to another antibiotic until you get levels back the following day
c. Omit Gentamicin dose
d. Give the Gentamicin and check levels the following day
A 40 year old engineer comes in with SOB and fever of 40ºC. What is your diagnosis?
Which antibiotics would you use?
a. Benzylpenicillin
b. Amoxicillin
c. Erythromycin
d. Clarithromycin
Patient says she is allergic to Penicillin. What next?
Ask type of allergy
a. Pneumothorax
b. Community acquired pneumonia
c. Pulmonary embolus
It made my pint taste funny and my fish and chips were not the same. Which statements are correct?
a. Penicillin is safe
b. I would avoid the use of penicillin
It made me itchy all over and I had a rash. Which of these is correct ?
a. Amoxicillin can be given safely
b. Ertapenem can be given with caution
c. Doxycycline can be given safely
d. Ceftriaxone can be given safely
The laboratory phones and informs you that they have grown a pneumococcus
Sensitive to:
Gentamicin
Penicillin
Vancomycin
Chloramphenicol
Ciprofloxacin
Which antibiotics can be safely used to treat Chidongo who has severe penicillin allergy?
a) All of the above
b) Gentamicin
c) Vancomycin
d) Chloramphenicol
e) Ciprofloxacin
What would you do?What would you do?You are called at night to prescribe warfarin for a patient with PE.
Her INR has fallen below therapeutic range since Rifampicin was prescribed 5 days ago for Staphylococcus aureus bacteraemia
a. Reduce Rifampicin dose
b. Increase warfarin dose
c. Wait and see
d. Stop Rifampicin and replace it with something else
A patient on furosemide for CCF has been started on Gentamicin for UTI. Two days later her renal function has become severely deranged,
a. Stop furosemide
b. Stop Gentamicin
c. Stop Gentamicin and replace with another antibiotic