Comparison of Five β‐Lactam Antibiotics Against Common Nosocomial Pathogens Using the Time Above MIC at Different Creatinine Clearances

Study Objective. To compare the time above the minimum inhibitory concentration (T>MIC) for five parenteral β‐lactam antibiotics against common nosocomial bacterial pathogens at different creatinine clearances (Clcr). Interventions. Serum concentration‐time profiles were simulated for cefepime, ceftazidime, piperacillin, piperacillin‐tazobactam, and imipenem at Clcr ranging from 120‐30 ml/minute. The MIC data for 90% of organisms (MIC90) were collected for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Pseudomonas aeruginosa, and oxacillin‐susceptible Staphylococcus aureus, and a weighted geometric mean MIC90 was calculated. The T>MIC was calculated as percentage of the dosing interval in which free concentrations exceeded the weighted geometric mean MIC90. A T>MIC of 70% or greater was considered desirable for all organisms except S. aureus (≥ 50%). Measurements and Main Results. Cefepime 2 g every 12 hours (Clcr ≥ 70 ml/min) and every 24 hours (Clcr ≤ 60 ml/min) achieved desirable T>MIC for all Enterobacteriaceae and S. aureus at every Clcr. Imipenem 0.5 g achieved desirable T>MIC for E. coli, K. pneumoniae, C. freundii, and S. aureus at every Clcr. However, imipenem T>MIC was less than 70% for the following regimens and organisms: S. marcescens 0.5 g every 6 hours (Clcr ≥ 90 ml/min), E. aerogenes 0.5 g every 6 hours (Clcr ≥ 80 ml/min), E. cloacae 0.5 g every 6 hours (Clcr ≥ 100 ml/min), S. marcescens 0.5 g every 8 hours (Clcr 60–70 ml/min), E. cloacae 0.5 g every 8 hours (Clcr 60–70 ml/min), and E. aerogenes 0.5 g every 8 hours (Clcr 50–70 ml/min). Ceftazidime 2 g every 8 hours (Clcr 60–100 ml/min) and every 12 hours (Clcr 40–50 ml/min) achieved desirable T>MIC for E. coli, K. pneumoniae, S. marcescens, and S. aureus only. At every dose and Clcr, piperacillin‐tazobactam achieved desirable T>MIC for S. aureus but not for any Enterobacteriaceae at Clcr > 50 ml/minute. Piperacillin did not achieve desirable T>MIC for any organism, and none of the β‐lactams attained a T>MIC of 70% or above for P. aeruginosa at any Clcr. Conclusion. At every Clcr, cefepime achieved a desirable T>MIC for more nosocomial pathogens than any other β‐lactam evaluated. Based on pharmacodynamic data, cefepime is an appropriate empiric choice for treatment of nosocomial infections. However, when P. aeruginosa is a potential pathogen, empiric combination therapy should be considered.