Determination of the Dynamically Linked Indices of Fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model

Abstract

Fosfomycin is the only expoxide antimicrobial and is currently under development in the United States as an intravenously administered product. We were interested in identifying the exposure indices most closely linked to its ability to kill bacterial cells and to suppress amplification of less susceptible subpopulations. We employed the hollow fiber infection model for this investigation and studied wild-type strain Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened the study duration to 24 h but sampled the system more intensively. Doses of 12 and 18 g/day and schedules of daily administration, administration every 8 h, and administration by continuous infusion for each daily dose were studied. We measured fosfomycin concentrations (by liquid chromatography-tandem mass spectrometry), the total bacterial burden, and the burden of less susceptible isolates. We applied a mathematical model to all the data simultaneously. There was a rapid emergence of resistance with all doses and schedules. Prior to resistance emergence, an initial kill of 2 to 3 log₁₀(CFU/ml) was observed. The model demonstrated that the area under the concentration-time curve/MIC ratio was linked to total bacterial kill, while the time that the concentration remained above the MIC (or, equivalently, the minimum concentration/MIC ratio) was linked to resistance suppression. These findings were also seen in other investigations with Enterobacteriaceae (in vitro systems) and P. aeruginosa (murine system). We conclude that for serious infections with high bacterial burdens, fosfomycin may be of value as a new therapeutic and may be optimized by administering the agent as a continuous or prolonged infusion or by use of a short dosing interval. For indications such as ventilator-associated bacterial pneumonia, it may be prudent to administer fosfomycin as part of a combination regimen.

Keywords: Pseudomonas aeruginosa; fosfomycin; hollow fiber infection model; pharmacodynamics.

FIG 1

Fosfomycin (FOS) concentration-time profiles for 12 g and 18 g per day with each daily dose administered once daily every 24 h [Q24h], every 8 h (Q8h), and by continuous infusion (CI) after a loading dose.

FIG 2

Bacterial cell kill and resistance emergence with different fractionated schedules of administration of 12 and 18 g of fosfomycin per day.

FIG 3

Pre-Bayesian (population) predicted-observed plots for fosfomycin concentrations, total population bacterial burden, and resistant bacterial burden.

FIG 4

Bayesian (individual) predicted-observed plots for fosfomycin concentrations, total population bacterial burden, and resistant bacterial burden.

FIG 5

Total colony counts of P. aeruginosa in the hollow fiber infection model at hours 0, 2, and 4 as a function of the dose fractionation regimen.