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Experimental Therapeutics

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

G. L. Drusano, M. N. Neely, W. M. Yamada, Brandon Duncanson, David Brown, Michael Maynard, Michael Vicchiarelli, Arnold Louie
G. L. Drusano
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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M. N. Neely
Children’s Hospital of Los Angeles, Department of Pediatrics, Division of Infectious Diseases, University of Southern California, Los Angeles, California, USA
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W. M. Yamada
Children’s Hospital of Los Angeles, Department of Pediatrics, Division of Infectious Diseases, University of Southern California, Los Angeles, California, USA
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Brandon Duncanson
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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David Brown
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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Michael Maynard
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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Michael Vicchiarelli
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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Arnold Louie
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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DOI: 10.1128/AAC.01682-18
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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.

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The Combination of Fosfomycin plus Meropenem Is Synergistic for Pseudomonas aeruginosa PAO1 in a Hollow-Fiber Infection Model
G. L. Drusano, M. N. Neely, W. M. Yamada, Brandon Duncanson, David Brown, Michael Maynard, Michael Vicchiarelli, Arnold Louie
Antimicrobial Agents and Chemotherapy Nov 2018, 62 (12) e01682-18; DOI: 10.1128/AAC.01682-18

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The Combination of Fosfomycin plus Meropenem Is Synergistic for Pseudomonas aeruginosa PAO1 in a Hollow-Fiber Infection Model
G. L. Drusano, M. N. Neely, W. M. Yamada, Brandon Duncanson, David Brown, Michael Maynard, Michael Vicchiarelli, Arnold Louie
Antimicrobial Agents and Chemotherapy Nov 2018, 62 (12) e01682-18; DOI: 10.1128/AAC.01682-18
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KEYWORDS

Pseudomonas aeruginosa
fosfomycin
meropenem
pharmacodynamics

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