Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: a report from the OPTAMA Program.
OBJECTIVE
To compare the probability of achieving specific pharmacodynamic exposures of commonly used intravenous antibiotics for the empirical treatment of nosocomial pneumonia against those pathogens most commonly implicated in the disease.


METHODS
Ten thousand-subject Monte Carlo simulation.


METHODS
Research center.


METHODS
None.


METHODS
Pharmacodynamic analysis was conducted for the following antimicrobials at standard doses: meropenem, imipenem-cilastatin, ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin. Prevalence of causative pathogens was based on the 2000 SENTRY Antimicrobial Surveillance Study, and minimum inhibitory concentration (MIC) values were obtained using the 2003 US MYSTIC database. The probabilities of each drug and dosing regimen in achieving pharmacodynamic targets were calculated. Bactericidal targets were defined as 40% T>MIC for the carbapenems, 50% T>MIC for other beta-lactams, and an area under the curve (AUC)/MIC ratio of 125 for ciprofloxacin. A sensitivity analysis was performed using two alternate models to determine the impact of varying pathogen prevalence on target attainment.


RESULTS
Meropenem and imipenem provided high probabilities of achieving their bactericidal target of 40% T>MIC, with target attainments of 98% for all regimens. At the bactericidal end point of 50% T>MIC, cefepime 2 g every 8 hrs displayed the highest target attainment at 99.9%, followed by cefepime 2 g every 12 hrs, ceftazidime 2 g every 8 hrs, piperacillin/tazobactam 4.5 g every 6 hrs and 3.375 g every 6 hrs, cefepime 1 g every 12 hrs, and ceftazidime 1 g every 8 hrs with target attainments of 95.0%, 92.5%, 92.3%, 91.3%, 90.3%, and 67.9%, respectively. Ciprofloxacin presented the lowest probability of achieving its bactericidal target of an AUC/MIC ratio of 125, with target attainments of 54.7% and 12.0% when given as 400 mg every 8 hrs and 400 mg every 12 hrs, respectively.


CONCLUSIONS
Meropenem, imipenem, cefepime, ceftazidime (2 g every 8 hrs), and piperacillin/tazobactam have high probabilities of achieving adequate pharmacodynamic exposures when given for the empirical treatment of nosocomial pneumonia in the absence of methicillin-resistant S. aureus. Ceftazidime 1g every 8 hrs and ciprofloxacin produce low target attainment rates and will not likely result in high clinical success rates when given as monotherapy.
Sun
Heather K
HK
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Kuti
Joseph L
JL
Nicolau
David P
DP
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000077723:Cefepime; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D003428:Cross Infection / Q000382:microbiology*; D004305:Dose-Response Relationship, Drug; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D015378:Imipenem / Q000494:pharmacology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010878:Piperacillin / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D018410:Pneumonia, Bacterial / Q000382:microbiology*; D013845:Thienamycins / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D013845:Thienamycins; D000077725:Piperacillin, Tazobactam Drug Combination; D002939:Ciprofloxacin; D015378:Imipenem; D000077723:Cefepime; D010397:Penicillanic Acid; D002442:Ceftazidime; D000077731:Meropenem; D010878:Piperacillin