Comparison of pharmacodynamic target attainment between healthy subjects and patients for ceftazidime and meropenem.
OBJECTIVE
To compare the pharmacodynamics of two beta-lactams--ceftazidime and meropenem--in healthy subjects versus patients.


METHODS
Monte Carlo simulation based on published pharmacokinetic studies.


METHODS
One hundred and ninety-seven participants (75 healthy volunteers and 122 patients) from published pharmacokinetic studies of ceftazidime or meropenem.


RESULTS
Data on total body clearance and volume of distribution for ceftazidime and meropenem in healthy subjects and patients were obtained from published studies. Monte Carlo simulations were performed based on the pharmacokinetics from each study for ceftazidime 1000 mg every 8 hours and meropenem 1000 mg every 8 hours against isolates of Escherichia coli , Klebsiella pneumoniae , Acinetobacter baumannii , and Pseudomonas aeruginosa collected from North and South America. We calculated the likelihood of obtaining bactericidal exposures (50% time above the minimum inhibitory concentration [MIC] for ceftazidime and 40% time above the MIC for meropenem) for each combination of pharmacokinetic study data and MIC distribution. Linear regression was used to compare target attainments for healthy subjects versus patients. Only three drug-pathogen combinations differed in target attainment between healthy subjects and patients: ceftazidime against P. aeruginosa in North America and meropenem against E. coli and P. aeruginosa in South America. The regression line of target attainment for patients versus healthy subjects had a slope of 1.04 (95% confidence interval [CI] 0.983-1.093) and a y intercept of -3.73 (95% CI -8.265-0.827, r2 = 0.992). The beta values for slope and intercept did not differ to a statistically significant extent between the regression line and the line of identity (p=0.264).


CONCLUSIONS
The pharmacodynamic target attainment calculated with healthy subject pharmacokinetic data was predictive of patient target target attainment for ceftazidime and meropenem.
Kuti
Joseph L
JL
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
Horowitz
Sheryl
S
Nightingale
Charles H
CH
Nicolau
David P
DP
D040981:Acinetobacter baumannii / Q000187:drug effects / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000302:isolation & purification; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006207:Half-Life; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000302:isolation & purification; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D009656:North America; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D012016:Reference Values; D013020:South America; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D002442:Ceftazidime; D000077731:Meropenem