Activities of Fosfomycin, Tigecycline, Colistin, and Gentamicin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Foreign-Body Infection Model

Abstract

Limited antimicrobial agents are available for the treatment of implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli. We compared the activities of fosfomycin, tigecycline, colistin, and gentamicin (alone and in combination) against a CTX-M15-producing strain of Escherichia coli (Bj HDE-1) in vitro and in a foreign-body infection model. The MIC and the minimal bactericidal concentration in logarithmic phase (MBC log ) and stationary phase (MBC stat ) were 0.12, 0.12, and 8 g/ml for fosfomycin, 0.25, 32, and 32 g/ml for tigecycline, 0.25, 0.5, and 2 g/ml for colistin, and 2, 8, and 16 g/ml for gentamicin, respectively. In time-kill studies, colistin showed concentration-dependent activity, but regrowth occurred after 24 h. Fosfomycin demonstrated rapid bactericidal activity at the MIC, and no regrowth occurred. Synergistic activity between fosfomycin and colistin in vitro was observed, with no detectable bacterial counts after 6 h. In animal studies, fosfomycin reduced planktonic counts by 4 log 10 CFU/ml, whereas in combination with colistin, tigecycline, or gentamicin, it reduced counts by >6 log 10 CFU/ml. Fosfomycin was the only single agent which was able to eradicate E. coli biofilms (cure rate, 17% of implanted, infected cages). In combination, colistin plus tigecycline (50%) and fosfomycin plus gentamicin (42%) cured significantly more infected cages than colistin plus gentamicin (33%) or fosfomycin plus tigecycline (25%) (P < 0.05). The combination of fosfomycin plus colistin showed the highest cure rate (67%), which was significantly better than that of fosfomycin alone (P < 0.05). In conclusion, the combination of fosfomycin plus colistin is a promising treatment option for implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli.

Efficacy of Fosfomycin Compared to Vancomycin in Treatment of Implant-Associated Chronic Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rats

“…However, the clinical relevance of developing resistance has been recently questioned (6,7). Further, recent data from preclinical studies have shown that FOF is effective for the treatment of biofilm-associated infections when combined with other classes of antibiotics (8)(9)(10). However, data on the efficacy of FOF monotherapy for the treatment of implant-associated infections in osseous tissue are limited.…”

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

“…Furthermore, fosfomycin and daptomycin are currently being investigated and might be promising candidates in the fight against foreign-body-related infections (219)(220)(221). In the case of prosthetic joint-related infection (PJI), in vivo models led to the demonstration that fluoroquinolones exhibited more penetration into the site of infection (222).…”

Fosfomycin

“…Several experimental studies (in vitro and biofilm infection models) showed that fosfomycin, alone or in combination with other antibiotics, not only reduced or eradicated clinically significant bacteria from biofilms (26)(27)(28)(29)(30) but also resulted in modifications of the biofilm structure. In a rat cellulose-pouch methicillin-resistant Staphylococcus aureus (MRSA) biofilm model, combination therapy with vancomycin and fosfomycin resulted in the disappearance of biofilm-like structures (31).…”

“…However, antagonism between colistin and fosfomycin against OXA-48-producing K. pneumoniae isolates was reported (checkerboards were used) (156). Regarding E. coli, the data refer to ESBL-producing strains; synergy was reported with carbapenems (by checkerboards, timekill assays, and Etest), aztreonam (by checkerboards and time-kill assays), colistin (by time-kill assay and Etest), netilmicin (by Etest), and tigecycline (by time-kill assays and Etest) (28,59,152,153,157). In addition, synergy was reported with cefoxitin (by time-kill assays) at concentrations equal to the MIC of the isolate but not at higher concentrations (157).…”