The Efficacy of Antibiotic Combination Therapies with Fosfomycin For Multi-Drug Resistant Gram-Negative Bacterial Infections

Background: Antimicrobial resistance in Gram-negative bacteria especially infections due to multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan drug-resistant (PDR) strains has narrowed therapeutic options. In the absence of many new agents, older antibiotics are being reconsidered in combination regimens. Fosfomycin, with a unique mechanism and broad spectrum, is a leading candidate in this context.Objective: To assess whether parenteral fosfomycin-based combinations influence mortality and morbidity in hospitalized adults with MDR/XDR/PDR Gramnegative infections.Methods: We conducted a retrospective study of adults treated between February 2019 and June 2020 in university hospital ICUs and wards. Patients received either combination therapy including IV fosfomycin (n=141) or combination therapy without fosfomycin (n=137). Demographic, clinical, laboratory and treatment data were extracted from the hospital information system.Results: Baseline age, sex, APACHE II and SOFA scores were similar between groups, whereas the fosfomycin group had a higher Charlson comorbidity index. No significant difference was observed in 28-day or 60-day mortality between fosfomycin and control groups (p=0.568 and p=0.094, respectively); point estimates favored the fosfomycin group (28-day mortality 41.1% vs 44.5%). Mortality correlated with higher illness severity and invasive device use in both groups. Ten patients receiving fosfomycin developed hypernatremia.Conclusion: In patients with high illness severity, comorbidity, and invasive device needs, fosfomycin-containing combinations, when used with suitable companion agents and accompanied by careful safety monitoring, constitute a rational treatment option against MDR/XDR/PDR Gram-negative infections. Pharmacokinetic (PK) and pharmacodynamic (PD) data and well-designed clinical studies are required to clarify clinical efficacy and safety.