Determination of the dynamically-linked indices of fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model (HFIM) [PublishAheadOfPrint]

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 the 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 Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened study duration to 24 hours but sampled the system more intensively. Doses and schedules of 12 and 18 g/day and daily, 8 hourly administration and continuous infusion were studied at each daily dose. We measured fosfomycin concentrations (by LC/MS/MS), total bacterial burden and less-susceptible burden. We applied a mathematical model to all the data simultaneously. There was rapid emergence of resistance in all doses and schedules. Prior to the resistance emergence, an initial kill of 2-3 Log₁₀(CFU/ml) was observed. The model demonstrated that AUC/MIC Ratio was linked to total bacterial kill, while Time > MIC (equivalently C_min/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 high bacterial burden infections, 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 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.

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