Intravenous fosfomycin for the treatment of multidrug-resistant pathogens: what is the evidence on dosing regimens?

ABSTRACT

Introduction: The intravenous (IV) formulation of fosfomycin has been re-introduced in clinical practice mainly to overcome treatment failures against multidrug-resistant (MDR) bacteria. Appropriate dosing schedules of the IV formulation have not yet been established.

Areas covered: The mechanism of action and resistance development, commercial IV formulations, pharmacokinetic/pharmacodynamic (PK/PD) properties, IV dosing regimens for the treatment of MDR infections along with efficacy and safety issues were reviewed. Data regarding specific MDR pathogens, daily doses and patients’ outcomes, gaps in the current literature, and in progress research agenda are presented.

Expert opinion: The doses of fosfomycin IV range between 12 and 24 grams/day depending on the severity of infection. The efficacy and safety of the commonly administered doses have been shown mainly in observational non-comparative trials. The optimal dose ensuring maximal efficacy with minimal toxicity along with the most appropriate co-administered antibiotic(s) need further evaluation. The pharmacokinetic/pharmacodynamic parameter associated with maximum efficacy has not yet been established, although, the ratio of the area under the concentration-time curve (AUC) for the free unbound fraction of fosfomycin versus the MIC (fAUC/MIC) may be linked to optimal treatment. RCTs and other comparative studies are underway to address gaps of knowledge in adult patients and neonates.

KEYWORDS:

• Fosfomycin
• intravenous
• multi-drug resistance
• dose
• treatment

Article highlights

• Literature has presented encouraging experience on the efficacy of fosfomycin against MDR pathogens, especially in critically ill patients.

• A wide range of doses have been used (between 12 and 24 g/day) with mild adverse events; however, careful monitoring for possible toxicity should always be implemented.

• Uncertainty for the prescribers regarding dosing remains since we prominent data or guidelines are lacking. Different sites of infections, diverse bacteria in association with heterogeneous patient populations and various dosing schedules preclude generalization of the current evidence without additional consideration.

• Combination to other antibiotics for the treatment of infections due to MDR pathogens is the gold standard, except in cases where fosfomycin monotherapy is the only existing option.

• According to available data, the most appropriate parameter for the PK/PD profile of the drug has not been established. No well-defined parameter can safely predict drug efficacy or resistance development under treatment.

• Four trials on fosfomycin use in specific patient populations, for diverse sites of infection and various pathogens, are actually ongoing.

• Future research agenda should further focus on these gaps of knowledge. RCTs and other comparative studies are needed to define appropriate doses, intervals, and combination options.

Declaration of interest

G Dimopoulos has received lecturers fees from Infectopharm. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.