Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms: A real-life experience

• Published in: International journal of antimicrobial agents 2024-05, Vol.63 (5), p.107134-107134, Article 107134
• Main Authors: Meschiari, Marianna, Faltoni, Matteo, Kaleci, Shaniko, Tassoni, Giovanni, Orlando, Gabriella, Franceschini, Erica, Burastero, Giulia, Bedini, Andrea, Serio, Lucia, Biagioni, Emanuela, Melegari, Gabriele, Venturelli, Claudia, Sarti, Mario, Bertellini, Elisabetta, Girardis, Massimo, Mussini, Cristina
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - therapeutic use; Ceftolozane/tazobactam resistance; Cephalosporins; Combination therapy strategy; Difficult-to-treat infections; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Fosfomycin - administration & dosage; Fosfomycin - therapeutic use; Gram-Negative Bacteria - drug effects; Gram-Negative Bacterial Infections - drug therapy; Gram-Negative Bacterial Infections - microbiology; Gram-Negative Bacterial Infections - mortality; Humans; Male; Middle Aged; Multi-drug-resistant Gram-negative infections; Pseudomonas aeruginosa - drug effects; Retrospective Studies; Risk Factors; Tazobactam - therapeutic use; Treatment Outcome
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2024.107134

•Fosfomycin in combination regimens represents a valid option for MDR-GNB difficult-to-treat infections characterized by poor penetration and incomplete source control.•Intravenous fosfomycin as salvage therapy was more often used for polymicrobial MDR-GN infections, mainly HAP-VAP due to carbapenem resistant P.aeruginosa.•The most frequent fosfomycin antibiotic partner was ceftazidime/avibactam, followed by meropenem, cefiderocol and ceftolazane/tazobactam.•Resistance to ceftolozane/tazobactam was an independent predictor of treatment failure. To investigate the efficacy of intravenous (IV) fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) acute and subacute infections with multi-drug-resistant (MDR) Gram-negative bacteria (GNB), and risk factors associated with 90-day mortality. A retrospective, observational, monocentric study enrolled patients treated with IV fosfomycin in combination regimens (≥72 h) for proven DTT-MDR-GNB infection. Multi-variate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving fosfomycin was performed to control for confounding factors. In total, 70 patients were included in this study: 54.3% had carbapenem-resistant isolates, 31.4% had ceftazidime/avibactam-resistant isolates and 28.6% had ceftolozane/tazobactam-resistant isolates. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), osteomyelitis (17.1%) and intra-abdominal infections. All-cause 30- and 90-day mortality were 15.7% and 31.4%, respectively (18.9% and 50% considering acute DTT-MDR-GNB infections alone). 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 ceftolozane/tazobactam resistance. The relationship between resistance to ceftolozane/tazobactam and 90-day mortality was confirmed to be significant after adjustment by propensity score analysis (hazard ratio 5.84, 95% confidence interval 1.65–20.68; P=0.006). Fosfomycin seems to be 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 needed urgently to demonstrate the superiority of fosfomycin in combination with other agents for the