Pharmacodynamics of Fosfomycin Against ESBL- And/or Carbapenemase-producing Enterobacteriaceae

Background: The increase in antibiotic resistance in Gram-negative bacteria and the limited therapeutic options due to the shortage of new antibiotics have increased the interest of the 'old' antibiotic fosfomycin in the treatment of infections. However, there are contradictory reports on the pharmacodynamics of and emergence of resistance to fosfomycin.

Methods: Time-kill assays were performed with 11 ESBL-positive and 3 ESBL-negative strains, exposing the bacteria to 2-fold static concentrations from 0.125× to 32× MIC. The sigmoid maximum effect (Emax) model was fitted to the time-kill curve data. Amplification of resistance over time was evaluated under various conditions of selective pressure by plating on 16× MIC plates.

Results: Fosfomycin was bactericidal for all strains within 8 h. Using the Emax model, no significant differences between strains were observed for the pharmacodynamic parameters. However, the large variation in Hill slope factors for Escherichia coli of 0.87 up to 4.02 indicates that the killing behaviour appears to be more time dependent for some strains but concentration dependent for others. In the fosfomycin-exposed cultures under low and high selective pressure (≥2× MIC) the median resistance proportions between the resistant and total population increased from ≤2 × 10-6 (T = 0 h) to 0.652-0.899 (T = 24 h). Resistance appeared stable after repeated subculturing.

Conclusions: Killing behaviour of fosfomycin does not only differ between species but also within species and may have an impact on the design of optimal dosing regimens. Although fosfomycin was bactericidal against all strains (re)growth of resistant subpopulations occurred relatively fast. This may limit the use of fosfomycin as a single drug therapy.