Dataset Information

Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Sulbactam against Extensively Drug-Resistant Acinetobacter baumannii in a Murine Thigh-Infection Model.

ABSTRACT: Few effective therapeutic options are available for treating severe infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-AB). Using a murine thigh-infection model, we examined the in vivo efficacy of colistin in combination with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin, or sulbactam against 12 XDR-AB strains. Colistin, tigecycline, rifampin, and sulbactam monotherapy significantly decreased bacterial counts in murine thigh infections compared with those observed in control mice receiving no treatment. Colistin was the most effective agent tested, displaying bactericidal activity against 91.7% of strains at 48 h post-treatment. With strains showing a relatively low minimum inhibitory concentration (MIC) for meropenem (MIC ? 32 mg/L), combination therapy with colistin plus meropenem caused synergistic inhibition at both 24 h and 48 h post-treatment. However, when the meropenem MIC was ?64 mg/L, meropenem did not significantly alter the efficacy of colistin. The addition of rifampin and fusidic acid significantly improved the efficacy of colistin, showing a synergistic effect in 100% and 58.3% of strains after 24 h of treatment, respectively, while the addition of tigecycline, fosfomycin, or sulbactam did not show obvious synergistic activity. No clear differences in activities were observed between colistin-rifampin and colistin-fusidic acid combination therapy with most strains. Overall, our in vivo study showed that administering colistin in combination with rifampin or fusidic acid is more efficacious in treating XDR-AB infections than other combinations. The colistin-meropenem combination may be another appropriate option if the MIC is ?32 mg/L. Further clinical studies are urgently needed to confirm the relevance of these findings.

SUBMITTER: Fan B

PROVIDER: S-EPMC4912081 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Sulbactam against Extensively Drug-Resistant Acinetobacter baumannii in a Murine Thigh-Infection Model.

Fan Bing B Guan Jie J Wang Xiumei X Cong Yulong Y

PloS one 20160617 6

Few effective therapeutic options are available for treating severe infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-AB). Using a murine thigh-infection model, we examined the in vivo efficacy of colistin in combination with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin, or sulbactam against 12 XDR-AB strains. Colistin, tigecycline, rifampin, and sulbactam monotherapy significantly decreased bacterial counts in murine thigh infections compared with those ...[more]

PMID: 27315107

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Project description:Background:We retrospectively analyzed the effect of tigecycline and cefoperazone/sulbactam therapies on the prognosis of patients with carbapenem-resistant Acinetobacter baumannii bloodstream infection (CRAB-BSI). Methods:CRAB-BSI patients receiving tigecycline therapy or cefoperazone/sulbactam therapy between January 2012 and December 2017 was enrolled, and strict exclusion criteria were followed. The 28-day mortality of patients was analyzed. The impact of cefoperazone/sulbactam therapy on prognosis was evaluated using Cox multivariate regression analysis. The 28-day mortality of patients receiving cefoperazone/sulbactam monotherapy and cefoperazone/sulbactam-based combination therapy was also compared. Results:Three hundred forty eight patients with CRAB-BSI were enrolled in the study. Two hundred ten patients were included after applying the exclusion criteria. Of these, 135 patients received tigecycline therapy and 75 patients received cefoperazone/sulbactam therapy. The 28-day mortality of patients in the latter group was, significantly lower than that of the tigecycline group [29.3% vs. 51.9%; P = 0.001]. Cox multivariate regression analysis revealed that cefoperazone/sulbactam therapy exerted a protective effect on the prognosis of patients [hazard ratio 0.566, 95% confidence interval (0.342-0.940); P = 0.028]. Kaplan-Meier survival curve analysis indicated that the 28-day mortality of patients receiving cefoperazone/sulbactam therapy was lower than that of patients receiving cefoperazone/sulbactam monotherapy, but the difference was not significant (22.2% vs. 40%; P = 0.074). However, the mortality of patients receiving cefoperazone/sulbactam with imipenem/cilastatin was significantly lower than that of patients receiving cefoperazone/sulbactam monotherapy (P = 0.048). Conclusions:Patients treated with cefoperazone/sulbactam therapy had a better clinical outcome. The mortality of patients receiving cefoperazone/sulbactam with imipenem/cilastatin seems to be the lowest.

Project description:Nosocomial infections with Acinetobacter baumannii are a global problem in intensive care units with high mortality rates. Increasing resistance to first- and second-line antibiotics has forced the use of colistin as last-resort treatment, and increasing development of colistin resistance in A. baumannii has been reported. We evaluated the transcriptional regulator PmrA as potential drug target to restore colistin efficacy in A. baumannii Deletion of pmrA restored colistin susceptibility in 10 of the 12 extensively drug-resistant A. baumannii clinical isolates studied, indicating the importance of PmrA in the drug resistance phenotype. However, two strains remained highly resistant, indicating that PmrA-mediated overexpression of the phosphoethanolamine (PetN) transferase PmrC is not the exclusive colistin resistance mechanism in A. baumannii A detailed genetic characterization revealed a new colistin resistance mechanism mediated by genetic integration of the insertion element ISAbaI upstream of the PmrC homolog EptA (93% identity), leading to its overexpression. We found that eptA was ubiquitously present in clinical strains belonging to the international clone 2, and ISAbaI integration upstream of eptA was required to mediate the colistin-resistant phenotype. In addition, we found a duplicated ISAbaI-eptA cassette in one isolate, indicating that this colistin resistance determinant may be embedded in a mobile genetic element. Our data disprove PmrA as a drug target for adjuvant therapy but highlight the importance of PetN transferase-mediated colistin resistance in clinical strains. We suggest that direct targeting of the homologous PetN transferases PmrC/EptA may have the potential to overcome colistin resistance in A. baumanniiIMPORTANCE The discovery of antibiotics revolutionized modern medicine and enabled us to cure previously deadly bacterial infections. However, a progressive increase in antibiotic resistance rates is a major and global threat for our health care system. Colistin represents one of our last-resort antibiotics that is still active against most Gram-negative bacterial pathogens, but increasing resistance is reported worldwide, in particular due to the plasmid-encoded protein MCR-1 present in pathogens such as Escherichia coli and Klebsiella pneumoniae Here, we showed that colistin resistance in A. baumannii, a top-priority pathogen causing deadly nosocomial infections, is mediated through different avenues that result in increased activity of homologous phosphoethanolamine (PetN) transferases. Considering that MCR-1 is also a PetN transferase, our findings indicate that PetN transferases might be the Achilles heel of superbugs and that direct targeting of them may have the potential to preserve the activity of polymyxin antibiotics.

Dataset Information

Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Sulbactam against Extensively Drug-Resistant Acinetobacter baumannii in a Murine Thigh-Infection Model.

Publications

Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Sulbactam against Extensively Drug-Resistant Acinetobacter baumannii in a Murine Thigh-Infection Model.

Similar Datasets

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