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Pharmacodynamics and the Dosing of Antibacterials William A. Craig, MD University of Wisconsin and Wm S. Middleton Memorial VA Hospital Madison, WI USA PRESENTATION OUTLINE • History of pharmacodynamics • Different patterns of antimicrobial activity • Pharmacodynamic target setting in animal models • Identify major factors that alter the pharmacodynamic target • Correlation between animal and human studies • Uses of pharmacodynamic modeling • Application to susceptibility breakpoints for gram-negative bacilli What is Pharmacodynamics ? • Relationship between concentration and pharmacologic and toxicologic effects of a drug • Relationship between measures of in vivo drug exposure and microbiologic (and clinical) efficacy Why Interest in Pharmacodynamics? • Always occurs when there is narrow difference between MICs and obtainable drug concentrations - early days of penicillin in 1940s (low doses used) - appearance of pseudomonas infections in 1960s and 1970s (high MICs) - appearance of resistant Streptococcus pneumoniae and other bacteria in 1990s Log CFU per Thighog Bactericidal Activity of Tobramycin and Ticarcillin against Pseudomonas aeruginosa 9 Tobramycin Ticarcillin 8 7 6 5 4 0 2 4 4 mg/kg 12 mg/kg 20 mg/kg 6 8 12 0 Time (hours) Vogelman et al. J Infect Dis 157, 1988 2 4 300 mg/kg 800 mg/kg 2400 mg/kg 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 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 (static effect, 1 or 2 log kill) Neutropenic Mouse Thigh-Infection Model 1. Neutropenia induced by 2 injections of cyclophosphamide on days -4 and -1 4. Thighs removed, homogenized, serially diluted and plated for CFU determinations 2. Bacteria injected into thighs on day 0 (106-7) 3. Treatment (usually given SQ) started 2 hr after infection and continued for 1-5 days Time Course of Antimicrobial Activity of Ciprofloxacin Against Klebsiella ATCC 43816 in Lungs of Neutropenic Mice Log10 CFU/Lung Death Death Death 10 Saline 0.29 q 6h 1.17 q 6h 4.69 q 6h 18.8 q 6h 75.0 q 6h 8 6 4 2 0 1 2 3 Days 4 5 Log10 CFU / Thigh at 24 Hrs Correlation of PK/PD Parameters with Efficacy Levofloxacin against Streptococcus pneumoniae in Thighs of Neutropenic Mice 10 8 6 4 2 0 10 100 1000 1 24-Hr AUC/MIC 10 100 Peak/MIC Andes & Craig, Int J Antimicrob Agents, 2002 1000 0 25 50 75 100 Time Above MIC Log10 CFU/Thigh at 24 Hrs Relationship Between PK/PD Parameters and Efficacy for Cefpirome against Klebsiella pneumoniae in Lungs of Neutropenic Mice 10 9 8 7 6 5 4 3 2 10 100 1000 24-Hr AUC/MIC 1 10 100 1000 Peak/MIC 0 25 50 75 100 Time Above MIC Craig Antimicrobial Pharmacodynamics in Theory and Practive 2002 Mathematical Analysis of DoseResponse Data from Animal Models after 24 Hours of Therapy 9 Log 10 CFUperThigat24Hrs Nonlinear regression and Hill equation to S t a t i c D o s e 8 estimate Emax (difference from 7 untreated control), P50 E m a x (dose giving 50% of 6 Emax) and slope (N) P 5 0 of the dose-response 5 1 L o g K i l l relationship N (Emax) Dose 1 0 3 0 1 0 0 3 0 0 CFU= D o s e ( m g / k g / 6 h r s ) DoseN + P50N Craig Diagn Microbiol Infect Dis 1995 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 Magnitude of PK/PD Parameters Does the magnitude of the parameter vary with: 1. different dosing regimens? NO, unless the clearance is too rapid in the animal model Static Dose (mg/kg/24 hrs) Impact of Dosing Interval on Static Dose for Amikacin against K. pneumoniae and E. coli in Mice with Normal and Impaired Renal Function 1000 K. pneumoniae E. coli Normal T1/2=17 min 100 K. pneumoniae E. coli Renal Impaired T1/2=104 min 10 1 3 6 12 24 Dosing Interval (Hours) Reddington and Craig, JAC 1995 Magnitude of PK/PD Parameters Does the magnitude of the parameter vary with: 1. different dosing regimens? NO 2. different drugs within the same class? NO, if free drug levels are used Protein binding is important !! 24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Fluoroquinolones with S. pneumoniae ATCC 10813 24-Hr AUC/MIC 160 120 Total Free 80 40 0 Gati Sita Moxi Gemi Garen Levo Cipro Andes & Craig 40th and 41st ICAAC, 2000 and 2001 Time Above MIC for Total and Free Drug for the Static Dose of Different Cephalosporins with Klebsiella pneumoniae ATCC 43816 70 60 50 40 Total Free 30 20 10 0 e e e e e id n m m m m c i i i o i o x p x n r id i e a a o z i f t p f r f a e o t e t f f e f C C e e e C C C C Craig Infect Dis Clin N Amer 2003 Magnitude of PK/PD Parameters Does the magnitude of the parameter vary with: 1. different dosing regimens? NO 2. different drugs within the same class? NO, if free drug levels are used 3. different organisms ? Similar for most organisms in neutropenic mice; less T>MIC with staphylococci with ß-lactams 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 Magnitude of PK/PD Parameters Does the magnitude of the parameter vary with: 4. resistant organisms No T>MIC for Free Drug for Static Doses with Cephalosporins, Penicillins and Carbapenems against Multiple Strains of S. pneumoniae with Various Penicillin MICs T>MIC (%) 50 40 30 Cephalosporins Penicillins Carbapenems 20 10 0 0.008 0.03 0.12 0.5 2 MIC (mg/L) 8 Free Drug AUC/MIC 24-Hr AUC/MIC of Gemifloxacin (Free Drug) for the Static Doses with 61 Strains of S. pneumoniae in Thighs of Neutropenic Mice 80 40 20 10 Wild type mutants 5 2.5 Efflux 0.008 0.03 0.12 0.5 MIC (mg/L) 2 Magnitude of PK/PD Parameters Does the magnitude of the parameter vary with: 4. resistant organisms NO 5. different sites of infection (e.g. blood, lung, peritoneum, soft tissue)? NO for most drugs; vancomycin less potent in lung infection than thigh Factors That Do Not Affect the Magnitude of PK/PD Parameters - resistant organisms - animal species Can values obtained in animals be predictive of efficacy in humans ? T>MIC for ß-Lactams Versus Mortality in Animal Models: Literature Review Mortality (%) 100 Cephalosporins Penicillins 80 60 40 20 0 0 20 40 60 80 100 Time Above MIC (% of Interval) Craig Antimicrobial Pharmacodynamics in Theory and Practive 2002 Double Typanocentesis Studies in Acute Otitis Media First tap to identify the causative pathogen Second tap at 3-5 days to determine if organisms had been eradicated Techniques first performed by Howie. Most recent studies with resistant organisms performed by Dagan. Time above MIC calculated from serum levels and MICs Craig & Andes, Pediatr Infect Dis J 15:255, 1996; Multiple studies by Dagan et al Bacterial Eradication (%) Relationship Between T>MIC and Bacterial Eradication with ß-Lactams in Acute Otitis Media 100 80 60 40 PSSP PISP-PRSP H. flu Best Fit 20 0 0 20 40 60 80 Time Above MIC (%) Craig Infect Dis Clin N Amer 2003 100 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 organisms • Modifications of susceptibility and resistance breakpoints - oral ß-lactams for S. pneumoniae - parenteral cephalosporins for S. pneumoniae - fluoroquinolones for S. aureus ESBLs and Clinical Failures • Emergence of Enterobacteriaceae with increased MICs due to novel ß-lactamases (ESBLs) • Associated with clinical failures and existing breakpoints fail to detect all these enzymes • Development by NCCLS of reference methods for screening and confirmation of ESBLs in some Enterobacteriaceae; does not work for all Enterobacteriaceae. • Elevated MICs in may also arise from mechanisms not targeted by the current ESBL test Pharmacodynamic Studies of ExtendedSpectrum Cephalosporins against Enterobacteriaceae with and without ESBLs in Thighs of Neutropenic Mice Drugs: Cefotaxime, Ceftriaxone, Ceftazidime and Cefepime ESBLs: TEM-3, TEM-7, TEM-10, TEM-12, TEM-26, SHV-2, SHV-4, SHV-5, SHV-7, CTX-M2, CTX-M3 alone or in combination with OXA-1, OXA-2, TEM-1, and/or AMP-C Non-ESBLs: TEM-1, TEM-1 and OXA-1, AMP-C, wild-type High inocula – 107-8 Change in Log10 CFU/Thigh over 24 Hours Activity of 4 Cephalosporins against Various Enterobacteriacea with and without ESBLs in Murine Thigh-Infection Model 3 ESBLs 3 Non-ESBLs 2 2 1 1 0 0 -1 -1 -2 -2 -3 -3 0 20 40 60 80 100 0 20 40 Time Above MIC (percent) 60 80 100 Monte Carlo Simulation PK Variation In Normal Volunteers or Patients Simulate PK Variation in 10,000 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 MIC 0.5 1 2 4 8 16 30% 100 100 99 98 92 65 T>MIC with 2g every 8 hr 40% 50% 60% 70% 100 99 96 88 99 97 89 73 98 89 71 49 91 67 41 22 62 29 11 4 15 3 0 0 Ambrose & Dudley, ICAAC 2002 Clinical Outcome in 42 Patients with ESBL-Producing Klebsiella/E. coli Bacteremia and Treated with Cephalosporin Monotherapy Outcome MIC <1 ųg/L MIC 2 ųg/L MIC 4 ųg/L MIC 8 ųg/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 44rd ICAAC, Abstract K-1588, 2004 Distribution of Enterobacteriacea with MICs of 4 and 8 mg/L Total 0f 11, 913 Isolates from ICU Patients Total Strains E. coli Kleb spp Other Ceftazidime 464 89 (19%) 158 (34%) 217 (47%) Ceftriaxone 532 46 (9%) 169 (32%) 317 (59%) 2002-2003 Sentry Program Jones, R Acknowledgements Pharmacodyamics Andes DR Bundtzen R Ebert S Fantin B Gerber A Gudmundsson S Kiem S Leggett J MacDonald Mouton J Redington J Totska K Turnidge J Van Ogtrop M Vogelman B Walker R Watanabe Y Otitis Dagan R ESBLs Ambrose P Dudley M Jones R It all started with a mouse. -Walt Disney