Pharmacodynamics: Integrating Concerns about Resistance and Efficacy in the Practical Care of Patients William A. Craig, MD University of Wisconsin and Wm S. Middleton Memorial VA Hospital Madison, WI USA
Pharmacology of Antimicrobials Pharmacologic Time Course of and toxicologic Drug Levels in effects Tissues & Fluids Time Course Dosing of Drug Levels Regimen in Serum Time Course of Time Course of Absorption Drug Levels at Antimicrobial Distribution Site of Infection Activity Elimination Pharmacodynamics (PD ) Pharmacokinetics (PK)
Measures of Antimicrobial Activity Potency - MIC - MBC Time Course of Activity - Rate of killing and impact of increasing concentrations (concentration-dependent versus time-dependent killing) - Persistent effects (postantibiotic effect, postantibiotic sub-MIC effect, postantibiotic leukocyte effect, postantimicrobial effect)
Bactericidal Activity of Tobramycin and Ticarcillin against Pseudomonas aeruginosa Log CFU per Thighog 9 Tobramycin Ticarcillin 8 7 6 5 4 0 2 4 6 8 12 0 2 4 4 mg/kg Time (hours) 300 mg/kg 12 mg/kg 800 mg/kg 20 mg/kg 2400 mg/kg Vogelman et al. J Infect Dis 157, 1988
1st Pattern of Antimicrobial Activity • Concentration-dependent killing and prolonged persistent effects • Seen with quinolones, aminoglycosides, ketolides, and daptomycin • Goal of dosing regimen: maximize concentrations – amount of drug and peak level are important
2nd Pattern of Antimicrobial Activity • Time-dependent killing and minimal or no persistent effects (except with staphylococci) • Seen with all beta-lactams • Goal of dosing regimen: optimize duration of exposure; maximum killing when levels constantly above 4-5 times MIC
3rd Pattern of Antimicrobial Activity • Time-dependent killing and moderate to prolonged persistent effects • Seen with macrolides, azithromycin, clindamycin, tetracyclines, glycylcyclines, streptogramins, glycopeptides, oxazolidinones, deformylase inhibitors • Goal of dosing regimen: optimize amount of drug; maximum killing when T>MIC 100%
Major Goal of Pharmacodynamics Establish the PK/PD TARGET required for effective antimicrobial therapy - identify which PK/PD indice (T>MIC, AUC/MIC, peak/MIC) best predicts in vivo antimicrobial activity - determine the magnitude of the PK/PD parameter required for in vivo efficacy and to prevent resistance
Neutropenic Mouse Thigh-Infection Model 1. Neutropenia induced by 2 2. Bacteria injected into injections of cyclophosphamide thighs on day 0 (10 6-7) on days -4 and -1 4. Thighs removed, 3. Treatment (usually given SQ) homogenized, serially started 2 hr after infection and diluted and plated for continued for 1-5 days CFU determinations
Correlation of PK/PD Parameters with Efficacy Levofloxacin against Streptococcus pneumoniae in Thighs of Neutropenic Mice 10 Log 10 CFU / Thigh at 24 Hrs 8 6 4 2 0 10 100 1000 1 10 100 1000 0 25 50 75 100 24-Hr AUC/MIC Peak/MIC Time Above MIC Andes & Craig, Int J Antimicrob Agents, 2002
Relationship Between PK/PD Parameters and Efficacy for Cefpirome against Klebsiella pneumoniae in Lungs of Neutropenic Mice 10 Log 10 CFU/Thigh at 24 Hrs 9 8 7 6 5 4 3 2 10 100 1000 1 10 100 1000 0 25 50 75 100 24-Hr AUC/MIC Peak/MIC Time Above MIC Craig Antimicrobial Pharmacodynamics in Theory and Practive 2002
Factors That Affect the Magnitude of PK/PD Parameters - dosing regimen - drug class - protein binding - infecting pathogen - presence or absence of neutrophils - site of infection
24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Fluoroquinolones with S. pneumoniae ATCC 10813 160 24-Hr AUC/MIC 120 Total 80 Free 40 0 Gati Sita Moxi Gemi Garen Levo Cipro Andes & Craig 40th and 41st ICAAC, 2000 and 2001
Time Above MIC Required for a Static Effect with 4 Cephalosporins Time Above MIC (% of Dosing Interval) Drug GNB S. pneumoniae S.aureus Ceftazidime 36 (27-42) 39 (35-42) 22 (19-24) Cefpirome 35 (29-40) 37 (33-39) 22 (20-25) Cefotaxime 38 (36-40) 38 (36-40) 24 (20-28) Ceftriaxone 38 (34-42) 39 (37-41) 24 (21-27) Craig Diagn Microbiol Infect Dis 22:89, 1995
T>MIC for Free Drug for Static Doses with Cephalosporins, Penicillins and Carbapenems against Multiple Strains of S. pneumoniae with Various Penicillin MICs 50 40 T>MIC (%) 30 Cephalosporins 20 Penicillins 10 Carbapenems 0 0.008 0.03 0.12 0.5 2 8 MIC (mg/L)
T>MIC for ß-Lactams Versus Mortality in Animal Models: Literature Review with Pneumococci(%) 100 Cephalosporins Penicillins 80 Mortality 60 40 20 0 0 20 40 60 80 100 Time Above MIC (% of Interval) Craig Antimicrobial Pharmacodynamics in Theory and Practive 2002
Relationship Between T>MIC and Bacterial Eradication with Beta-Lactams in Otitis Media (Circles) and Maxillary Sinusitis (Squares) • Bacteriologic cure for beta- 100 lactams with S. pneumoniae Bacterial Eradication (percent) and H. influenzae from double-tap studies in acute 80 otitis media and acute maxillary sinusitis 60 • Time above MIC calculated from serum levels and MICs 40 PSSP PISP-PRSP Craig & Andes, Pediatr Infect Dis J H. influenza 20 15:255, 1996; Dagan et al JAC 47:129, 2001; Dagan et al Pediatr Infect Dis J 20:829, 2001 0 0 20 40 60 80 100 Time Above MIC (percent)
Comparison of the Relationships Between Efficacy and 24-Hr AUC/MIC for Fluoroquinolones in Animal Models and Infected Patients Animals - Literature Review Seriously ill patients + Ciprofloxacin 100 100 Clinical 80 Mortality (%) 80 Microbiologic Efficacy 60 60 40 40 20 20 0 0 0-62.5 62.5-125 125-250 250-500 >500 2.5 10 25 100 250 1000 24-H r AU C /M IC 24-Hr AUC/MIC Andes, Craig Int J Antimicrob Agents, 2002Forrest et al. AAC 37:1073, 1993
Comparison of the Relationships Between 24-Hr AUC/MIC and Efficacy against Pneumococci for Fluoroquinolones in Animals and Patients Animals - Literature Review Patients with CAP and AECB 100 • 58 patients enrolled in a comparative trial of 80 Mortality (%) levofloxacin vs gatifloxacin • Free-drug 24-hr AUC/MIC 60 <33.7 , the probability of a 40 microbiologic cure was 64% 20 • Free-drug 24-hr AUC/MIC >33.7 , the probability of a 0 microbiologic cure was 1 2.5 10 25 100 250 1000 100% 24-H r AUC /M IC Andes, Craig Int J Antimicrob Agents, 2002 Ambrose et al AAC 45:2793, 2001
Uses of Pharmacodynamic Studies • Drug development - new formulations active against organisms with high MICS (e.g. high dose amoxicillin/clavunate) - dosage regimens for phase II and III clinical trials - drug selection for clinical studies • Optimize dosing regimens - longer infusions and continuous infusion of beta-lactams - once-daily dosing of aminoglycosides
Uses of Pharmacodynamic Studies • Guidelines for antimicrobial usage • Reduction of emergence of resistance • Modifications of susceptibility and resistance breakpoints - parenteral cephalosporins for S. pneumoniae - fluoroquinolones for S. aureus • Identify problem drug-organism combinations with specific MICs
Fluoroquinolone AUC/MIC 90 Ratios for S. pneumoniae 200 Total 150 Unbound AUC/MIC ratio 100 100 50 33 33 0 Cipro 500 Cipro 750 Levo 500 Levo 750 Moxi 400 Gati 400 BID BID QD QD QD QD Jacobs MR. Clin Microbiol Infect . 2001;7:589-596.
PK/PD Parameters versus Emergence of Resistance for Fluoroquinolones Resistance Developed 24-Hr AUC/MIC P. aeruginosa Other GNB <100 - Monotherapy 80% 100% >100 – Monotherapy 33% 10% Combinations 11% 0% 25% 12% Thomas et al. AAC 42:521, 1998
Magnitude of PK/PD Parameters for Common Drugs Used Against Pseudomonas aeruginosa Drug Dose MICs Peak/MIC AUC/MIC Ciprofloxacin 400mg q8 0.25-1 20/4 144/36 Levofloxacin 750mg q24 0.5-4 12/3 125/31 Tobramycin 7 mg/kg q24 1-4 24/6 84/21
Monte Carlo Simulation PK Variation PK Variation in Simulate In Normal 10,000 Patients Volunteers or Patients Determine Percentage of Patients that would meet the PK/PD Target required for efficacy Drusano et al
Monte Carlo Simulation: Cefotaxime Percent of 10,000 Patients Attaining Indicated PK/PD Exposure Target T>MIC with 1g every 8 hr MIC 30% 40% 50% 60% 70% 0.5 100 99 97 89 73 1 99 98 89 71 49 2 98 91 67 41 22 4 92 62 29 11 4 8 58 15 3 0 0 16 12 0 0 0 0 Ambrose & Dudley, ICAAC 2002
Clinical Outcome in 42 Patients with ESBL-Producing Klebsiella/E. coli Bacteremia and Treated with Cephalosporin Monotherapy MIC MIC MIC MIC Outcome <1 ų g/L 2 ų g/L 4 ų g/L 8 ų g/L Success 13 (81%) 4 (67%) 3 (27%) 1 (11%) Failure 3 (19%) 2 (33%) 8 (73%) 8 (89%) Paterson et al J Clin Micro 39:2206, 2001; Kim et al AAC 46:1481, 2002; Wong-Beringer et al Clin Infect Dis 34:135, 2002; Kang et al AAC In press 2004; Bhavani et al 44 rd ICAAC, Abstract K-1588, 2004
Monte Carlo Simulation: Meropenem Percent of 10,000 Patients Attaining Indicated PK/PD Exposure Target T>MIC of 40% with doses of: MIC 0.5g q8 (1h inf) 0.5g q8 (3h inf) 0.5 95 100 1 90 100 2 65 99 4 32 80 8 4 14 16 0 1 Lomaestro & Drusano AAC 2004
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