The combination of fosfomycin plus meropenem is synergistic for Pseudomonas aeruginosa PA01 in a Hollow Fiber Infection Model (HFIM). [Experimental Therapeutics]

Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. Pseudomonas aeruginosa is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries.

Fosfomycin is an agent discovered circa 40 years ago. Recently it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high bacterial burden infections.

We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the Hollow Fiber Infection Model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8 hourly) and two doses of fosfomycin alone (6 and 8 g 8 hourly) as well as all possible combinations plus a no-treatment control.

We used a high dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving > 6 Log₁₀(CFU/ml) bacterial kill. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell kill and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high burden Pseudomonas aeruginosa infections and requires further study.

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