Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multidrug-resistant gram-negative organisms: a real-life experience

BACKGROUND We aim to investigate the efficacy of intravenous (IV) Fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) multidrug-resistant (MDR) gram negative bacteria (GNB) acute and subacute infections and risk factors associated with 90-day mortality. METHODS A retrospective, observational, monocentric study enrolled patients treated with IV Fosfomycin in combination regimens (>/= 72 h) for proven DTT-MDR-GNB based infection . Multivariate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving Fosfomycin was performed to control for confounding factors. RESULTS 70 patients were included: 54.3% carbapenem-resistant isolates, 31.4% resistant to ceftazidime/avibactam and 28.6% to ceftolozane/tazobactam. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), followed by osteomyelitis (17.1%) and intra-abdominal infections (IAI). All-cause 30 and 90-day mortality were 15.7% and 31.4% (18.9% and 50%, considering only DTT-MDR-GNB acute infections). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock, and the evidence of ceftolozane/tazobactam resistance., Resistance to ceftolozane/tazobactam was confirmed significant after adjustment by propensity score analysis (HR 5.84, 95%CI 1.65-20.68, p=0.006). CONCLUSIONS Fosfomycin seems a promising salvage, combination treatment in DTT- MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are urgently required to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of difficult to treat GNB infections.