Pharmacodynamic evaluation of meropenem and cefotaxime for pediatric meningitis: a report from the OPTAMA program
Jennifer M Ellis1, Joseph L Kuti, David P Nicolau
1Department of Pharmacy Practice, University of Connecticut, School of Pharmacy, Storrs, USA.
Objective:
To determine the probability of meropenem (Merrem, AstraZeneca Pharmaceuticals L.P., Wilmington, DE, USA) and cefotaxime (Claforan, Aventis Pharmaceuticals Inc., Bridgewater, NJ, USA) achieving bactericidal exposures in the cerebrospinal fluid against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.
Methods:
A 5,000-patient Monte Carlo simulation in a population of 10-year-old children with meningitis was conducted. Pediatric pharmacokinetic data were derived from the literature. Pathogen minimum inhibitory concentrations (MICs) were obtained from common bacteria that had caused meningitis collected during pediatric clinical trials. Time above the MIC exposures in the cerebrospinal fluid was calculated. Bactericidal exposure or probability of target attainment was defined as 40% and 50% time above the MIC for meropenem and cefotaxime, respectively. High cumulative fractions of responses were defined as >90% probability of target attainment against the populations of bacteria.
Results:
Meropenem was calculated to achieve 94.7%, 94.3%, and 96.1% cumulative fractions of response against S. pneumoniae, H. influenzae, and N. meningitidis, respectively. Cefotaxime only achieved a high likelihood of bactericidal attainment against N. meningitidis (91.6%). Against S. pneumoniae and H. influenzae, cefotaxime was only calculated to achieve 84.3% and 84.8% cumulative fractions of response, respectively.
Conclusion:
In a simulated population of 10-year-old children, meropenem had a high likelihood of attaining bactericidal exposures in the cerebrospinal fluid. Cefotaxime had a >90% cumulative fraction of response against only N. meningitidis. Therefore, at the doses simulated, meropenem may be a more appropriate empiric choice for the treatment of bacterial meningitis in pediatric patients presumed to be caused by these pathogens until culture and susceptibility data are available.
Insights
Meropenem demonstrated a high probability of achieving bactericidal concentrations in cerebrospinal fluid for pediatric meningitis treatment. Cefotaxime was effective only against Neisseria meningitidis, suggesting meropenem as a potentially better empiric choice.
Area of Science:
- Pharmacology and Infectious Diseases
- Pediatric Clinical Research
- Antimicrobial Pharmacodynamics
Background:
- Bacterial meningitis remains a critical pediatric infection requiring effective antimicrobial therapy.
- Optimizing antibiotic exposure in cerebrospinal fluid (CSF) is crucial for successful treatment outcomes.
- Meropenem and cefotaxime are commonly considered antibiotics for empirical meningitis treatment.
Purpose of the Study:
- To evaluate the probability of meropenem and cefotaxime achieving bactericidal exposures in pediatric CSF.
- To compare the efficacy of meropenem versus cefotaxime against key meningitis pathogens: Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.
Main Methods:
- A Monte Carlo simulation involving 5,000 pediatric patients with meningitis was performed.
- Pharmacokinetic data from literature and pathogen MICs from clinical trials were utilized.
- Probability of target attainment (PTA) was calculated as time above the minimum inhibitory concentration (MIC) in CSF.
Main Results:
- Meropenem achieved high cumulative fractions of response (>90%) against all three pathogens.
- Cefotaxime demonstrated high PTA only against Neisseria meningitidis (91.6%).
- Cefotaxime showed lower PTA against Streptococcus pneumoniae (84.3%) and Haemophilus influenzae (84.8%).
Conclusions:
- Meropenem exhibited a high likelihood of achieving bactericidal CSF exposures in simulated pediatric meningitis cases.
- Cefotaxime's efficacy was limited to Neisseria meningitidis at the simulated doses.
- Meropenem may be a more suitable empiric antibiotic for pediatric bacterial meningitis caused by these pathogens pending susceptibility results.
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