ABSTRACT
To the best of our knowledge, to date, no study has investigated the optimal dosage regimens of either colistin or sitafloxacin against drug-resistant Acinetobacter baumannii (A. baumannii) infections by using specific parameters. In the current study, we aimed to explore the optimal dosage regimens of colistin and sitafloxacin, either in monotherapy or in combination therapy, for the treatment of carbapenem-, multidrug-, and colistin-resistant A. baumannii infections. A Monte Carlo simulation was applied to determine the dosage regimen that could achieve the optimal probability of target attainment (PTA) and cumulative fraction of response (CFR) (≥90%) based on the specific parameters of each agent and the minimal inhibitory concentration (MIC) of the clinical isolates. This study explored the dosage regimen of 90, 50, 30, and 10 mL/min for patients with creatinine clearance (CrCL). We also explored the dosage regimen for each patient with CrCL using combination therapy because there is a higher possibility of reaching the desired PTA or CFR. Focusing on the MIC90 of each agent in combination therapy, the dosage regimen for colistin was a loading dose of 300 mg followed by a maintenance dose ranging from 50 mg every 48 h to 225 mg every 12 h and the dosage regimen for sitafloxacin was 325 mg every 48 h to 750 mg every 12 h. We concluded that a lower-than-usual dose of colistin based on specific pharmacokinetic data in combination with a higher-than-usual dose of sitafloxacin could be an option for the treatment of carbapenem-, multidrug-, and colistin-resistant. A. baumannii. The lower dose of colistin might show a low probability of adverse reaction, while the high dose of sitafloxacin should be considered. In the current study, we attempted to find if there is a strong possibility of drug selection against crucial drug-resistant pathogen infections in a situation where there is a lack of new antibiotics. However, further study is needed to confirm the results of this simulation study.
ABSTRACT
The purpose was to explore the optimal dosage regimen of colistin using Monte Carlo simulations, for the treatment of carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant Escherichia coli based on PK/PD targets in critically ill patients. A total of 116 carbapenem-resistant K. pneumoniae and E. coli were obtained from various clinical specimens at Siriraj Hospital in Bangkok, Thailand. Minimum inhibitory concentrations (MICs) of colistin were determined by broth microdilution method. Monte Carlo simulation was used to calculate the cumulative fraction of response (CFR) for European Medicine Agency (EMA), US-Food and Drug Administration (FDA), Nation et al., Siriraj Hospital and our study regimens. The targeted CFR was 90%. For colistin-susceptible K. pneumoniae, all of the dosage regimens achieved ≥90% CFR in patients with creatinine clearance <80 mL/min except the FDA-approved regimens for patients with creatinine clearance 51-79 and 11-29 mL/min, respectively. While, patients with creatinine clearance ≥80 mL/min, CFR ≥90% was observed in Siriraj Hospital and our study regimen. For colistin-susceptible E. coli, all of the dosage regimens achieved ≥90% CFR regardless of renal function. In contrast, the currently approved regimens achieved CFR target in only 10-50% for colistin-resistant isolates subgroup. These results suggest that currently approved regimens still recommended for colistin-susceptible CRE. For colistin-resistant CRE, alternative approaches such as high dose or combination therapy should be considered.
