title: The combination of meropenem and levofloxacin is synergistic with respect to both Pseudomonas aeruginosa kill rate and resistance suppression.
abstract: New approaches are needed for the treatment of Pseudomonas aeruginosa infections. All available single agents are suboptimal, especially for resistance suppression. Classical beta-lactam/aminoglycoside combinations are not used often enough at least in part because of concern for nephrotoxicity. We evaluated the combination of meropenem and levofloxacin against the P. aeruginosa PAO1 wild type and its isogenic MexAB pump-overexpressed mutant. The drugs were studied using an in vitro hollow-fiber pharmacodynamic infection model. There were 16 different regimens evaluated for both isolates. Both total population and resistant subpopulations were quantified. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The impact of monotherapy versus that of combination therapy for attainment of a 3-log cell kill and for resistance suppression was examined using Kaplan-Meier analysis. Drug exposures were calculated by fitting the concentration-time data using the ADAPT II package of programs. For both isolates, monotherapy allowed resistance emergence with all but the largest exposure or with all exposures. In contrast, there was no resistance emergence with any combination regimen. Kaplan-Meier analysis showed significant differences in time to attainment of a 3-log cell kill as well as time to resistance emergence for monotherapy and combination therapy for both isolates, in favor of the combination regimens. Determination of the pharmacodynamic indices associated with resistance suppression demonstrated a 2- to 3-fold reduction with the use of combinations. Combination therapy with meropenem and levofloxacin provides a significantly faster time to attain a 3-log cell kill and significantly better resistance suppression than does either monotherapy. This combination should be evaluated in a clinical trial.
authors.affiliation: Ordway Research Institute, Albany, NY 12208, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.forename: Caroline
authors.initials: C
authors.lastname: Grasso
authors.forename: Nadzeya
authors.initials: N
authors.lastname: Bahniuk
authors.forename: Brian
authors.initials: B
authors.lastname: Van Scoy
authors.forename: David L
authors.initials: DL
authors.lastname: Brown
authors.forename: Robert
authors.initials: R
authors.lastname: Kulawy
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005798:Genes, Bacterial; D006801:Humans; D066298:In Vitro Techniques; D064704:Levofloxacin; D026901:Membrane Transport Proteins / Q000235:genetics; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015242:Ofloxacin / Q000008:administration & dosage* / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D013845:Thienamycins / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; D013845:Thienamycins; D064704:Levofloxacin; D015242:Ofloxacin; D000077731:Meropenem