Antimicrobial Activity of Fosfomycin-Tobramycin Combination against Pseudomonas aeruginosa Isolates Assessed by Time-Kill Assays and Mutant Prevention Concentrations

Abstract

eThe antibacterial activity of fosfomycin-tobramycin combination was studied by time-kill assay in eight Pseudomonas aeruginosa clinical isolates belonging to the fosfomycin wild-type population (MIC ‫؍‬ 64 g/ml) but with different tobramycin susceptibilities (MIC range, 1 to 64 g/ml). The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined in five of these strains (tobramycin MIC range, 1 to 64 g/ml) in aerobic and anaerobic conditions simulating environments that are present in biofilm-mediated infections. Fosfomycin-tobramycin was synergistic and bactericidal for the isolates with mutations in the mexZ repressor gene, with a tobramycin MIC of 4 g/ml. This effect was not observed in strains displaying tobramycin MICs of 1 to 2 g/ml due to the strong bactericidal effect of tobramycin alone. Fosfomycin presented higher MPC values (range, 2,048 to >2,048 g/ml) in aerobic and anaerobic conditions than did tobramycin (range, 16 to 256 g/ml). Interestingly, the association rendered narrow or even null MSWs in the two conditions. However, for isolates with high-level tobramycin resistance that harbored aminoglycoside nucleotidyltransferases, time-kill assays showed no synergy, with wide MSWs in the two environments. glpT gene mutations responsible for fosfomycin resistance in P. aeruginosa were determined in fosfomycin-susceptible wild-type strains and mutant derivatives recovered from MPC studies. All mutant derivatives had changes in the GlpT amino acid sequence, which resulted in a truncated permease responsible for fosfomycin resistance. These results suggest that fosfomycin-tobramycin can be an alternative for infections due to P. aeruginosa since it has demonstrated synergistic and bactericidal activity in susceptible isolates and those with low-level tobramycin resistance. It also prevents the emergence of resistant mutants in either aerobic or anaerobic environments.

Review of the Guidelines of the Spanish Society of Chemotherapy on antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa

“…Ге терорезистентность часто встречается среди чувстви тельных штаммов, и по этой причине не рекомендуется применение монотерапии. Комбинации с тобрамици ном [220,221], амикацином [222,223], ципрофлок сацином [224,225] [230]. Авторы работы считают, что исходы терапии могут быть расценены как благоприятные.…”

fosI Is a New Integron-Associated Gene Cassette Encoding Reduced Susceptibility to Fosfomycin

“…In a recent publication, the in vitro activity of fosfomycin in combination with tobramycin and the mutant prevention concentration for multidrug-resistant P. aeruginosa strains was evaluated (23). The authors showed the occurrence of mutations in the permease gene glpT in all of the mutants with high fosfomycin MICs recovered during the study.…”

Potentiation of Aminoglycoside Activity in Pseudomonas aeruginosa by Targeting the AmgRS Envelope Stress-Responsive Two-Component System

“…Still, although a ␤-lactam-promoted increase in the uptake of the AG streptomycin has been seen in various bacteria (30-32), including P. aeruginosa (33), synergy between these agents in the absence of ␤-lactam-enhanced AG uptake has also been noted (32). Fosfomycin, another cell wall synthesis inhibitor, has also been shown to potentiate AG activity against including P. aeruginosa (34,35). Still, AGs are ototoxic (36) and nephrotoxic (37), which has hitherto limited their use in treating P. aeruginosa infections more generally.…”