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The Combination of Fosfomycin plus Meropenem Is Synergistic for Pseudomonas aeruginosa PAO1 in a Hollow-Fiber

G L Drusano¹, M N Neely², W M Yamada²

¹Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA gdrusano@ufl.edu.

Antimicrobial Agents and Chemotherapy

|September 26, 2018

Abstract:

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 of bacterial killing. 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 killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden Pseudomonas aeruginosa infections and requires further study.

Insights

Combination therapy with meropenem and fosfomycin effectively treats high-burden infections caused by Pseudomonas aeruginosa. This combination demonstrated significant bacterial killing and suppressed resistance emergence, outperforming single-agent treatments.

Area of Science:

Infectious Diseases
Pharmacology
Microbiology

Background:

Treating high-density bacterial infections, especially those caused by Pseudomonas aeruginosa, presents significant clinical challenges due to limited effective agents and pathogen resistance mechanisms.
Fosfomycin, an older antibiotic, has been re-evaluated for intravenous use, particularly for difficult-to-treat infections.
Combination chemotherapy is hypothesized to maximize the utility of fosfomycin in high-bacterial-burden scenarios.

Purpose of the Study:

To evaluate the efficacy of combining meropenem and fosfomycin against Pseudomonas aeruginosa in a high-bacterial-burden infection model.
To determine if combination therapy can overcome resistance mechanisms and suppress the emergence of resistance.
To assess the synergistic effects of meropenem and fosfomycin on bacterial killing and resistance suppression.

Main Methods:

Utilized the hollow-fiber infection model to study meropenem and fosfomycin in various monotherapy and combination regimens.
Employed a fully factorial study design with different doses of meropenem (1 and 2g 8-hourly) and fosfomycin (6 and 8g 8-hourly), including a no-treatment control.
Analyzed data using a high-dimensional model of 5 inhomogeneous differential equations to assess bacterial killing and resistance dynamics.

Main Results:

Combination therapy with meropenem and fosfomycin significantly outperformed all monotherapy regimens, achieving >6 log10 CFU/ml bacterial killing.
All combination regimens effectively countered the emergence of resistance, eliminating both meropenem and fosfomycin-resistant mutants.
Mathematical modeling indicated significant synergy between meropenem and fosfomycin for both bacterial cell killing and resistance suppression.

Conclusions:

Meropenem plus fosfomycin is a highly promising combination therapy for high-burden Pseudomonas aeruginosa infections.
The combination demonstrates superior efficacy in bacterial killing and preventing resistance compared to individual agents.
Further clinical studies are warranted to validate the use of meropenem and fosfomycin combination therapy.

Read full analysis

Keywords:

Pseudomonas aeruginosa fosfomycin meropenem pharmacodynamics

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