Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria

The alarming increase in drug resistance and decreased production of new antibiotics necessitate the evaluation of combinations of existing antibiotics. Fosfomycin shows no cross-resistance to other antibiotic classes. Thus, its combination with other antibiotics may potentially show synergy against resistant bacteria. To evaluate the available published evidence regarding the in vitro synergistic activity of fosfomycin with other antibiotic agents against Gram-positive and Gram-negative bacteria. PubMed and the Cochrane Library were searched. Forty-one studies, including 34 (82.9%) conducted/published before 2000, were eligible for inclusion. The relatively limited number of isolates examined and the considerable heterogeneity of the retrieved studies regarding the definitions of synergy and the methodologies used hamper conclusive remarks for specific combinations of fosfomycin with other antibiotics. Yet, in the 27 studies providing data for Gram-positive strains (16 for Staphylococcus aureus, 3 for coagulase-negative staphylococci, 5 for Streptococcus pneumoniae, and 3 for Enterococcus spp.), fosfomycin showed synergy against methicillin-resistant Staphylococcus aureus when combined with cefamandole, cephazolin, ceftriaxone, ciprofloxacin, imipenem, and rifampicin. Data regarding Gram-negative strains reported from 15 studies (12 exclusively for P. aeruginosa, 2 exclusively for Enterobacteriaceae, 1 for both, and 1 for Acinetobacter baumannii) suggested that fosfomycin showed an estimable synergistic effect with gentamicin, amikacin, ceftazidime, cefepime, ciprofloxacin, levofloxacin, and aztreonam against P. aeruginosa. The synergistic combination of fosfomycin with other antibiotics may be a useful alternative treatment option for Gram-negative and Gram-positive infections. Additional studies using more stringent definitions of synergy, and studies reporting on the clinical efficacy of fosfomycin combinations in the current era of high antimicrobial resistance are needed.