Infect Chemother.  2020 Dec;52(4):516-529. 10.3947/ic.2020.52.4.516.

Fosfomycin Dosing Regimens based on Monte Carlo Simulation for Treated Carbapenem-Resistant Enterobacteriaceae Infection

Affiliations
  • 1Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
  • 2Division of Pharmaceutical care, Department of Pharmacy, Phrae Hospital, Phrae, Thailand
  • 3Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
  • 4Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
  • 5Pharmaceutical Initiative for Resistant Bacteria and Infectious Diseases Working Group (PIRBIG), Nakorn Pathom, Thailand
  • 6Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakorn Pathom, Thailand
  • 7College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
  • 8Division of Infectious Disease, Department of Medicine, Phrae Hospital, Phrae, Thailand
  • 9Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
  • 10Biofunctional Molecule Exploratory Research Group, Biomedicine Research Advancement Centre, School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, Malaysia
  • 11Novel Bacteria and Drug Discovery Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, Malaysia

Abstract

Background
Infections by Carbapenem-Resistant Enterobacteriaceae (CRE) remain a leading cause of death in critically ill patients. Fosfomycin has been regarded as an alternative therapy for treatment of infections caused by CRE organisms. The purpose of this study is to evaluate clinical outcomes amongst patients with CRE infection who are receiving a fosfomycin dosing regimen using a Monte Carlo simulation and fosfomycin minimum inhibitory concentration (MIC).
Materials and Methods
Fosfomycin MIC was defined by the E-test method. We used Fosfomycin pharmacokinetic parameters from a previously published study. The percent of the time period in which the drug concentration exceeded the MIC, or %T>MIC, used in this study were determined to be 70% of T>MIC and 100% of T>MIC, respectively. All dosing regimens were estimated for the probability of target attainment using a Monte Carlo simulation.
Results
In this study, we found the MIC's of fosfomycin against CRE isolates ranged from 8 mg/L to 96 mg/L. The total daily dose of fosfomycin ranged from 16 - 24 g and was administered utilizing various fosfomycin dosing regimens to achieve the pharmacokinetic/ pharmacodynamic (PK/PD) target in pathogens with a MIC of 32 mg/L for 70%T>MIC and a MIC of 12 mg/L for 100%T>MIC, respectively. For the twelve patients who received the recommended fosfomycin dosing regimen, eleven achieved bacterial eradication for a microbiological cure rate of 91%; and of those patients achieving eradication, two died despite having negative cultures for CRE; the one remaining patient had bacterial persistence. The most commonly observed adverse drug reactions were hypernatremia (3 cases) and hypokalemia (3 cases) and acute kidney injury (3 cases).
Conclusion
Our findings suggest fosfomycin has tended to good efficacy when using dosing regimens that achieve the PK/PD target. Nonetheless, further validation of these regimens in larger populations is needed.

Keyword

Fosfomycin; Monte Carlo; Carbapenem-Resistant Enterobacteriaceae; Microbial sensitivity tests
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