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

The intravenous (IV) formulation of fosfomycin has been re-introduced lately in clinical practice mainly to overcome treatment failures against multi drug-resistant (MDR), bacterial strains. However, appropriate dosing schedules of the IV formulation of the drug have not yet been established. Areas covered: The mechanism of action and resistance development, commercial IV formulations, pharmacokinetic/pharmacodynamics (PK/PD) properties, IV dosing regimens commonly used for the treatment of MDR infections along with efficacy and safety issues were reviewed. Data regarding specific MDR pathogens with emphasis on daily doses and patients' outcomes, gaps in the current literature, as well as, in progress research agenda are presented. Expert opinion: The doses of fosfomycin IV range between 12-24 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) needs further evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) parameter associated with fosfomycin 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. Future research agenda should focus on these gaps of knowledge. RCTs and other comparative studies are needed to establish appropriate doses, intervals and combination selections. Four registered clinical trials are underway to address these issues in adult patients while a randomized interventional trial including a pharmacokinetic study in hospitalized neonates with clinical sepsis (Neofosfo trial) will be terminated soon