Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance

J Antimicrob Chemother. 2016 Aug;71(8):2218-29. doi: 10.1093/jac/dkw115. Epub 2016 Apr 26.


Objectives: Fosfomycin resistance occurs rapidly with monotherapy. This study systematically investigated bacterial killing and emergence of fosfomycin resistance with fosfomycin combinations against Pseudomonas aeruginosa.

Methods: Four clinical isolates and a reference strain of P. aeruginosa were employed. Combinations of fosfomycin plus polymyxin B, tobramycin or ciprofloxacin were examined over 24 h using time-kill studies (inocula ∼10(6) cfu/mL) incorporating clinically relevant concentrations (fosfomycin, 30, 150 or 300 mg/L; polymyxin B, 0.5, 1 or 2 mg/L; tobramycin, 0.5, 1.5 or 4 mg/L; ciprofloxacin, 0.5, 1 or 2.5 mg/L). Microbiological response was examined by log changes and population analysis profiles.

Results: Against susceptible isolates, monotherapy produced varying degrees of initial killing followed by rapid regrowth. Fosfomycin plus polymyxin B or tobramycin produced greater initial killing (up to ∼4 log10 cfu/mL) with many concentrations compared with monotherapy against fosfomycin-susceptible (FOF(S)) isolates. With these combinations, synergy or additivity was observed in 54 (67%) and 49 (60%) of 81 cases (nine combinations across three isolates at three timepoints) for polymyxin B and tobramycin, respectively. Substantial improvements in killing were absent against fosfomycin-resistant (FOF(R)) isolates. For fosfomycin/ciprofloxacin combinations, synergy or additivity was observed against FOF(R) isolates in 33 of 54 (61%) cases (nine combinations across two isolates at three timepoints), while improvements in killing were largely absent against FOF(S) isolates. No combination prevented emergence of fosfomycin resistance.

Conclusions: Against P. aeruginosa, fosfomycin in combination with polymyxin B or tobramycin (FOF(S) isolates) or ciprofloxacin (FOF(R) isolates) increased bacterial killing, but did not suppress emergence of fosfomycin resistance.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Ciprofloxacin / pharmacology*
  • Drug Interactions*
  • Drug Resistance, Bacterial
  • Fosfomycin / pharmacology*
  • Humans
  • Microbial Viability / drug effects
  • Polymyxin B / pharmacology*
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / isolation & purification
  • Pseudomonas aeruginosa / physiology
  • Tobramycin / pharmacology*


  • Anti-Bacterial Agents
  • Fosfomycin
  • Ciprofloxacin
  • Polymyxin B
  • Tobramycin