Antimicrobial Pharmacodynamics

Antimicrobial Pharmacodynamics November 28, 2007 George P. Allen, Pharm.D. Assistant Professor, Pharmacy Practice OSU College of Pharmacy at OHSU

Objectives Become familiar with PD parameters what they tell us how to measure them Identify the PD parameter associated with efficacy and/or resistance prevention for a variety of antibiotics Identify dosing methods that may be used to optimize the PD of various antibiotics

Concentrations in Tissues & Body Fluids Pharmacologic and Toxicologic Effects Dosing Regimen Concentration in Serum Concentrations at Site of Infection Antimicrobial Effect Craig WA. Clin Infect Dis 1998;26:1-12.

Elements of PD Susceptibility data indicates potency, but not the time course of antibacterial activity Pharmacokinetic data indicates the time course of antibiotic concentrations, but not the killing activity of an antibiotic Integration of susceptibility results and PK data allows us to quantify antibiotic activity over time

Susceptibility Testing MIC (minimum inhibitory concentration) Measures lowest antimicrobial concentration that inhibits bacterial growth Expressed in a standard numerical scheme that incorporates doubling concentrations e.g., 0.25 mcg/ml, 0.5 mcg/ml, 1 mcg/ml, etc. MIC 90 versus MIC 50

MIC Analysis: Microdilution

MIC Analysis: Etest

Breakpoints Interpretive Standards for Pseudomonas aeruginosa Antimicrobial MIC (mcg/ml) Interpretive Standard S I R Piperacillin 32 32-64 128 Ceftazidime 8 16 32 Imipenem 4 8 16 Aztreonam 8 16 32 Gentamicin 4 8 16 Ciprofloxacin 1 2 4 Chloramphenicol 8 16 32

MICs for Fluoroquinolones Against Streptococcus pneumoniae 1994 2000 Fluoroquinolone Year MIC 90 % R Ciprofloxacin* Levofloxacin Gatifloxacin Moxifloxacin 1994-1995 2 n/a 1997-1998 2 n/a 1999-2000 2 n/a 1994-1995 1 0.3 1997-1998 1 0.5 1999-2000 1 0.7 1994-1995 0.5 0.2 1997-1998 0.5 0.4 1999-2000 0.25 0.4 1994-1995 0.25 0.1 1997-1998 0.25 0.4 1999-2000 0.125 0.3 *Breakpoint values have not been assigned for ciprofloxacin Brueggemann AB et al. Antimicrob Agents Chemother 2002;46:680-88.

In vitro Activity Against 8,352 Respiratory Isolates of Streptococcus pneumoniae SENTRY Program, 1997 1999 MIC (mg/l) Antibiotic % R MIC 50 MIC 90 Penicillin 0.03 2 14 Amoxicillin 0.06 2 3.2 Amoxicillin/clavulanate 0.25 2 2.8 Cefpodoxime 0.06 2 16.1 Erythromycin 0.25 4 17.7 Clindamycin 0.06 0.25 4.7 Tetracycline 2 16 12 TMP/SMX 0.5 4 19.8 Rifampin 1 1 0.3 Levofloxacin 1 2 0.4 Vancomycin 0.25 0.5 0 Hoban DJ et al. Clin Infect Dis 2001;32(Suppl 2):81-93.

Type: Gram Negative Susceptibility Organism: Klebsiella pneumoniae Antibiotic Result Ampicillin >=32 R Ampicillin/sulbactam >=32 R Cefazolin 32 R Ceftriaxone 4 R Ciprofloxacin 2 I Gentamicin >=16 R Levofloxacin 1 S Piperacillin 64 R Piperacillin/tazobactam Ticarcillin/clavulanate Tobramycin <=4 S 16 R >=16 R

What Do PD Studies Tell Us? 1. For a given antibiotic, the PD parameter that must be optimized in order to obtain the outcome of interest 2. The threshold or target value (of the above PD parameter) that must be attained in order to obtain the outcome of interest

Concentration-Dependent Killing Killing activity increases with an increase in antibiotic concentration Maximal killing achieved at 8-10 x MIC, AUC/MIC=30, or AUC/MIC=125 Aminoglycosides, fluoroquinolones

Time-Dependent Killing Killing activity increases with an increase in time spent above the MIC Maximal killing achieved when T > MIC is 60-70% of dosing interval Penicillins, cephalosporins, macrolides

Concentration-Kill Relationship 8 Ciprofloxacin 8 Ticarcillin 7 7 1/4x MIC log 10 CFU/mL (Bacterial Count) 6 5 4 1/4x MIC 6 5 4 1x MIC 4x MIC 16x MIC 64x MIC 3 16x MIC 4x MIC 1x MIC 3 2 64x MIC 2 1 0 2 4 6 1 0 2 4 6 time (hr) Craig WA. Clin Infect Dis 1998;26:1-12.

Post-Antibiotic Effect (PAE) Describes persistent suppression of bacterial growth after antimicrobial exposure Implies that the effect is due to prior exposure rather than persistent inhibitory concentrations Usually measured in vitro Clinical significance is uncertain

Characteristics of PAE PAE is dependent on: Antibiotic Antibiotic concentration Duration of exposure Bacterial species: Gram + > Gram -

PD Parameters C max 1) C max /MIC 2) AUC/MIC 3) Time > MIC ABX Concentration AUC Time MIC C min Time Craig WA. Clin Infect Dis 1998;26:1-12.

Pattern of Activity Antibiotics Goal of Therapy PD Parameter Type 1 Concentrationdependent killing Prolonged persistent effects Aminoglycosides Fluoroquinolones Maximize concentrations C max /MIC AUC/MIC Type 2 Time-dependent killing Minimal persistent effects Beta-lactams Erythromycin Linezolid Maximize duration of exposure T>MIC Type 3 Time-dependent killing Moderate persistent effects Azithromycin Clindamycin Tetracyclines Maximize amount of drug AUC/MIC Gunderson BW et al. Pharmacotherapy 2001;21:302S-318S.

Evaluating Antimicrobial PD 1. Determine the PD parameter that correlates with the outcome of interest 2. Determine the value of that PD parameter that must be attained to ensure the outcome of interest

Step 1 Determine the PD parameter that correlates with the outcome of interest

Measuring PD Parameters In vitro models Animal models Human studies

Dose Fractionation Simulation of adequate number of unique PK profiles to allow statistically significant determination of PD Interval q4h q6h q8h q12h q24h Dose 100 mg 200 mg 300 mg 400 mg

In vitro Models

Typical Results: In vitro Models 12 11 10 9 Bacterial Count (CFU/mL) 8 7 6 5 Dose 1 Dose 2 Dose 3 Dose 4 4 3 Dose 5 0 4 8 12 16 20 24 28 32 36 40 44 48 time (hr)

Animal Models Rabbit Model of Endocarditis Mouse Thigh Infection Model

Typical Results: Animal Models 12 11 GC 10 9 Bacterial Count (CFU/thigh) or Mortality 8 7 6 5 Dose 1 Dose 2 Dose 3 Dose 4 4 3 Dose 5 0 4 8 12 16 20 24 28 32 36 40 44 48 time (hr)

Human Studies

Scenario #1 Craig WA. In: Antimicrobial Pharmacodynamics in Theory and Clinical Practice. 2001.

Scenario #2 Craig WA. In: Antimicrobial Pharmacodynamics in Theory and Clinical Practice. 2001.

Step 2 Determine the value of that PD parameter that must be attained to ensure the outcome of interest

Relationship Between 24-h AUC/MIC and Mortality in Animals for Fluoroquinolones against Gram (-) Bacilli Andes D et al. Int J Antimicrob Agents 2002;19:261-8.

Relationship Between 24-h AUC/MIC and Mortality in Animals for Fluoroquinolones against S. pneumoniae Andes D et al. Int J Antimicrob Agents 2002;19:261-8.

Relationship Between Time > MIC and Mortality in Animal Models of S. pneumoniae with β-lactams Craig WA. Clin Infect Dis 1998;26:1-10.

Relationship Between Time > MIC and Bacterial Eradication in Otitis Media and Maxillary Sinusitis Craig WA. Clin Infect Dis 1998;26:1-12.

% Patients with Positive Clinical and Microbiologic Outcome (74 patients treated with ciprofloxacin 200-400 mg IV q8h) 100 Eradication Cure 80 60 % 40 20 0 AUC/MIC < 125 AUC/MIC > 125 Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-81.

Unresolved Issues Endpoint targeted Site of infection Effect of protein binding Immune status Organism Combination therapy

PD Parameters and Resistance Comparatively little research performed Resistance is difficult to obtain in a randomized clinical trial Prevention of resistance may be more important than maximization of killing

Application of PD 1. How effective will a specific dose of an antibiotic be in a given patient? 2. What is the highest MIC that will allow attainment of the PD goal? 3. Can we increase the dose of an antimicrobial to achieve the PD goal? 4. Of available options for a given infection, will a particular agent be able to attain the PD goal?

Beta-lactams

Beta-lactam PD Longer T > MIC improves efficacy 30-40% T > MIC for bacteriostatic effect 60-70% T > MIC for maximum killing

Should We Dose More Often? Beta-lactam Concentration MIC Time 24h

PD Profile of Piperacillin-Tazobactam MIC (mg/l) T>MIC (%) 4.5 gm q8h 3.375 gm q6h Pathogens 0.5 85.31 98 H. influenzae 1 77.11 94.09 Proteus spp. 2 68.12 86 MSSA E. coli S. pneumoniae 4 59.13 76.03 K. pneumoniae Enterobacter spp. Citrobacter spp. Serratia spp. 8 50.14 64.34 P. aeruginosa 16 41.14 52.65 n=12 Kim M-K et al. Pharmacotherapy 2002;22:569-77.

Continuous Infusion Dosing β-lactam Concentration MIC Time 24h

Likelihood of Achieving Pharmacodynamic Target (Monte Carlo Simulation in 1000 Patients) Cefepime Dose Cl Cr (ml/min) 2g q12h (30 min) (infusion time) 2g q8h (30 min) 2g q12h (6h) 4g q24h (24h) 120 4.5 21.4 18 64.5 90 13.2 41.4 36.6 72.4 60 38.5 68 63 81.4 Tam VH et al. Pharmacotherapy 20030;23:291-5.

PD of Cephalosporins in Otitis Media Caused by S. pneumoniae 100 Cefuroxime T>MIC (%) Bacteriologic Persistence % 80 60 40 20 Cefaclor 9 10 21 62 PSSP PISP PRSP Cefuroxime 75 35 0 Cefaclor 60 0 0 0 PSSP PISP/PRSP Dagan R et al. Lancet 2002;2:593-604.

Fluoroquinolones

Fluoroquinolone PD AUC/MIC determines efficacy C max /MIC determines resistance prevention? AUC/MIC > 125 for Gram - AUC/MIC > 30-40 for Gram +

FQ PD S. pneumoniae FQ MIC 90 C max C max /MIC AUC AUC/MIC Ciprofloxacin 2 3.1 1.5 40 20 Gatifloxacin 0.25 3.6 14.4 33 132 Levofloxacin 1 6.3 6.3 48 48 Moxifloxacin 0.125 4.5 36 48 400 Doern GV. Clin Infect Dis 2001;33 Suppl 3:187-92.

FQ Resistance in S. pneumoniae Reference Wortmann 1999 1 meningitis not reported 1/1 Empey 2001 1 CAP not reported 1/1 Urban 2001 2 CAP 1/2 2/2 Weiss 2001 16 HAP not reported 16/16 Kays 2002 1 CAP 1/1 1/1 Davidson 2002 4 CAP 4/4 4/4 Ross 2002 1 CAP 1/1 1/1 Anderson 2003 n 4 (10 episodes) Disease CAP Prior FQ 10/10 Resistance? 6/10

FQ PD P. aeruginosa 74 patients with severe infections Ciprofloxacin 200 mg - 400 mg IV q8h Patient-specific PD parameters and pathogen MICs used to correlate PD and outcome Outcomes measured: daily cultures, time to organism eradication Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-81.

FQ PD P. aeruginosa Factors Related to Positive Clinical and Microbiologic Outcome Univariate Analysis AUC/MIC > 125 MIC < 0.5 C max / MIC > 4 C min / MIC > 1 T > MIC > 33% Multivariate Analysis AUC/MIC > 125 Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-81.

FQ PD P. aeruginosa 100 Eradication Cure 80 60 % 40 20 0 AUC/MIC < 125 AUC/MIC > 125 Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-81.

FQ PD P. aeruginosa For susceptible bacteria (MIC < 0.125): standard FQ dosing likely to achieve AUC/MIC > 250 dose reduction a possibility? For less susceptible bacteria (MIC 0.25): more aggressive dosing may be required combination therapy? Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-81.

Aminoglycosides

Aminoglycoside PD Higher C max improves efficacy PAE allows longer dosing interval Lower C min lessens toxicity Longer dosing interval may limit development of bacterial resistance

Extended Interval Dosing C max 8-10x MIC AMG Concentration MIC Time 24h

Aminoglycoside Dosing Strategies Divided Daily Dosing Extended Interval 1.2 2.5 mg/kg q12-72h disease-targeted C max C max = ~ 6-10 mg/l C min < 1 mg/l 4-7 mg/kg q24h PD-targeted C max C max = ~ 12-20 mg/l C min ~ 0 mg/l

Limitations of Extended Interval Dosing Renal function must be good Cl Cr 50 ml/min usually required Appropriate patient populations Target concentrations still under debate Institution-specific nomograms

Extended-Interval AMG Dosing Protocols Calculate Cl Cr, IBW / ABW / dosing weight Determine target peak based on bacterium probably should also consider infection Dose: 4-7 mg/kg q24h 4-5 mg/kg = peak ~ 12-15 mg/l 6-7 mg/kg = peak ~ 16-20 mg/l TDM: peak? 8h concentration?

Meta-Analysis of 26 Studies of EIAD Difference in Clinical Response (± 95% CI) -40% -20% 0% 20% 40% 60% (sub-mean 1) Study (sub-mean 2) (mean) Boselli E et al. Crit Care Med 2003;31:2102-6.

Meta-Analysis of 26 Studies of EIAD Difference in Microbiologic Response (± 95% CI) -40% -20% 0% 20% 40% 60% (sub-mean 1) Study (sub-mean 2) (mean) Boselli E et al. Crit Care Med 2003;31:2102-6.

EIAD: Results Several thousand patients evaluated Few comparative trials published Trend towards increased efficacy Trend towards decreased nephrotoxicity Uncertain effect on ototoxicity

Clinician-Operated PD Programs

PD Optimization Programs 1. Empiric therapy (traditional approach) 2. Isolate pathogen, determine MIC 3. PK analysis 4. Adjust dose or interval using PD Scaglione F. Intl J Antimicrob Agents 2002;257:349-53.

Impact of a PD Intervention Program Focusing on Aminoglycosides, Fluoroquinolones, and Beta-lactams in Patients with Severe Infection LOS a Failure Mortality PD Analyzed 11 days (7-16) 39/223 (17.5%) 11 (4.9%) PD Not Analyzed 16 days (9-23) 147/457 (31.9%) 46 (10.1%) a duration of hospitalization after infection identified n=680, October 2000 April 2001 Scaglione F. Intl J Antimicrob Agents 2002;257:349-53.