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Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii.

ABSTRACT: Polymyxins are last-resort antibiotics for treating infections of Gram-negative bacteria. The recent emergence of polymyxin-resistant bacteria, however, urgently demands clinical optimisation of polymyxin use to minimise further evolution of resistance. In this study we developed a novel combination therapy using minimal concentrations of polymyxin B. After large-scale screening of Streptomyces secondary metabolites, we identified a reliable polymixin synergist and confirmed as netropsin using high-pressure liquid chromatography, nuclear magnetic resonance, and mass spectrometry followed by in vitro assays using various Gram-negative pathogenic bacteria. To evaluate the effectiveness of combining polymixin B and netropsin in vivo, we performed survival analysis on greater wax moth Galleria mellonella infected with colistin-resistant clinical Acinetobacter baumannii isolates as well as Escherichia coli, Shigella flexineri, Salmonella typhimuruim, and Pseudomonas aeruginosa. The survival of infected G. mellonella was significantly higher when treated with polymyxin B and netropsin in combination than when treated with polymyxin B or netropsin alone. We propose a netropsin combination therapy that minimises the use of polymyxin B when treating infections with multidrug resistant Gram-negative bacteria.

SUBMITTER: Chung JH

PROVIDER: S-EPMC4910107 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii.

Chung Joon-Hui JH Bhat Abhayprasad A Kim Chang-Jin CJ Yong Dongeun D Ryu Choong-Min CM

Scientific reports 20160616

Polymyxins are last-resort antibiotics for treating infections of Gram-negative bacteria. The recent emergence of polymyxin-resistant bacteria, however, urgently demands clinical optimisation of polymyxin use to minimise further evolution of resistance. In this study we developed a novel combination therapy using minimal concentrations of polymyxin B. After large-scale screening of Streptomyces secondary metabolites, we identified a reliable polymixin synergist and confirmed as netropsin using h ...[more]

PMID: 27306928

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Project description:BackgroundInfections sustained by multidrug-resistant (MDR) and pan-resistant Acinetobacter baumannii have become a challenging problem in Intensive Care Units. Tigecycline provided new hope for the treatment of MDR A. baumannii infections, but isolates showing reduced susceptibility have emerged in many countries, further limiting the therapeutic options. Empirical combination therapy has become a common practice to treat patients infected with MDR A. baumannii, in spite of the limited microbiological and clinical evidence supporting its efficacy. Here, the in vitro interaction of tigecycline with seven commonly used anti-Acinetobacter drugs has been assessed.MethodsTwenty-two MDR A. baumannii isolates from Intensive Care Unit (ICU) patients and two reference strains for the European clonal lineages I and II (including 3, 15 and 6 isolates that were resistant, intermediate and susceptible to tigecycline, respectively) were tested. Antimicrobial agents were: tigecycline, levofloxacin, piperacillin-tazobactam, amikacin, imipenem, rifampicin, ampicillin-sulbactam, and colistin. MICs were determined by the broth microdilution method. Antibiotic interactions were determined by chequerboard and time-kill assays. Only antibiotic combinations showing synergism or antagonism in both chequerboard and time-kill assays were accepted as authentic synergistic or antagonistic interactions, respectively.ResultsConsidering all antimicrobials in combination with tigecycline, chequerboard analysis showed 5.9% synergy, 85.7% indifference, and 8.3% antagonism. Tigecycline showed synergism with levofloxacin (4 strains; 16.6%), amikacin (2 strains; 8.3%), imipenem (2 strains; 8.3%) and colistin (2 strains; 8.3%). Antagonism was observed for the tigecycline/piperacillin-tazobactam combination (8 strains; 33.3%). Synergism was detected only among tigecycline non-susceptible strains. Time-kill assays confirmed the synergistic interaction between tigecycline and levofloxacin, amikacin, imipenem and colistin for 5 of 7 selected isolates. No antagonism was confirmed by time-kill assays.ConclusionThis study demonstrates the in vitro synergistic activity of tigecycline in combination with colistin, levofloxacin, amikacin and imipenem against five tigecycline non-susceptible A. baumannii strains, opening the way to a more rationale clinical assessment of novel combination therapies to combat infections caused by MDR and pan-resistant A. baumannii.

Project description:Polymyxins are currently used as the last-resort antibiotics against multidrug-resistant Acinetobacter baumannii. As resistance to polymyxins emerges in A. baumannii with monotherapy, combination therapy is often the only remaining treatment option. A novel approach is to employ the combination of polymyxin B with non-antibiotic drugs. In the present study, we employed metabolomics to investigate the synergistic mechanism of polymyxin B in combination with the antineoplastic drug mitotane against polymyxin-susceptible and -resistant A. baumannii. The metabolomes of four A. baumannii strains were analyzed following treatment with polymyxin B, mitotane and the combination. Polymyxin B monotherapy induced significant perturbation in glycerophospholipid (GPL) metabolism and histidine degradation pathways in polymyxin-susceptible strains, and minimal perturbation in polymyxin-resistant strains. Mitotane monotherapy induced minimal perturbation in the polymyxin-susceptible strains, but caused significant perturbation in GPL metabolism, pentose phosphate pathway and histidine degradation in the LPS-deficient polymyxin-resistant strain (FADDI-AB065). The polymyxin B - mitotane combination induced significant perturbation in all strains except the lipid A modified polymyxin-resistant FADDI-AB225 strain. For the polymyxin-susceptible strains, the combination therapy significantly perturbed GPL metabolism, pentose phosphate pathway, citric acid cycle, pyrimidine ribonucleotide biogenesis, guanine ribonucleotide biogenesis, and histidine degradation. Against FADDI-AB065, the combination significantly perturbed GPL metabolism, pentose phosphate pathway, citric acid cycle, and pyrimidine ribonucleotide biogenesis. Overall, these novel findings demonstrate that the disruption of the citric acid cycle and inhibition of nucleotide biogenesis are the key metabolic features associated with synergistic bacterial killing by the combination against polymyxin-susceptible and -resistant A. baumannii.

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Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii.

Publications

Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii.

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