Evaluation of dosing designs of carbapenems for severe respiratory infection using Monte Carlo simulation.

Abstract

Using the Monte Carlo simulation method, the influence of various doses and dosing frequencies of carbapenems on the antimicrobial activities against Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, which are the main causative organisms of respiratory infections, was studied with the aim of identifying optimized effectiveness. Based on pharmacokinetic (PK) parameters of individual carbapenems in healthy adults, data on changes in the respective blood concentrations in 2000 cases were simulated by applying a lognormal distribution to probability distributions of their volume of distributions and half-life periods. Based on minimum inhibitory concentration (MIC) distribution data of the individual carbapenems against these strains, MICs in the 2000 cases were also simulated. Using these data in blood concentrations and MICs, the probabilities of attaining various percentages of the dosing interval during which drug concentrations remain above MIC (T > MIC) were calculated at several dosing regimens. Considering the probabilities of attaining the bactericidal effect (50% T>MIC) and daily drug costs, imipenem (IPM) at 500 mg i.v. BID, panipenem (PAPM) at 500 mg i.v. BID, and biapenem (BIPM) at 300 mg i.v. BID against Streptococcus pneumoniae; meropenem (MEPM) at 500 mg i.v. BID or TID against Haemophilus influenzae infections; and MEPM at 500 or 1000 mg i.v. TID against Pseudomonas aeruginosa, each over 30 min, were determined as appropriate empirical treatments. Selecting carbapenems with superior antimicrobial activities and optimizing their dose regimens are important to improve the efficacy. Application of Monte Carlo simulation to MIC distributions allows determination of appropriate empiric therapy even if drug susceptibility of a causative organism in individual patients is unknown.

• Authors: Akira Watanabe, Shigeru Fujimura, Toshiaki Kikuchi, Kazunori Gomi, Katsuhiro Fuse, Toshihiro Nukiwa
• Journal: Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (J Infect Chemother) Vol. 13 Issue 5 Pg. 332-40 (Oct 2007) ISSN: 1341-321X [Print] Netherlands
• PMID: 17982723 (Publication Type: Journal Article)

Chemical References

• Carbapenems

Topics

• Carbapenems (administration & dosage, pharmacokinetics)
• Computer Simulation
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Dosage Calculations
• Haemophilus Infections (drug therapy)
• Haemophilus influenzae
• Humans
• Microbial Sensitivity Tests
• Monte Carlo Method
• Pneumonia, Pneumococcal (drug therapy)
• Pseudomonas Infections (drug therapy)
• Pseudomonas aeruginosa
• Respiratory Tract Infections (drug therapy, microbiology)
• Streptococcus pneumoniae