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Effectiveness of a double-carbapenem combinations against carbapenem-resistant Gram-negative bacteria.

ABSTRACT: The emergence of carbapenem-resistant organisms posed considerable threat to global health while only limited treatment options are available and led to efforts to discover a novel way to treat them. To evaluate in vitro synergistic activity of meropenem plus ertapenem, a total of 203 carbapenem-resistant strains, collected from 12 provinces and municipalities in China, were examined with a dual carbapenem combination therapy. The statistical software R was used for analysis. Two hundred and one (201) of carbapenem-resistant strains mainly produced four types of carbapenemase: KPC-2 (n = 142, 69.95%), OXA-232 (n = 7, 3.45%), NDM (n = 38, 18.72%; 36 NDM-1, 1 NDM-4, 1 NDM-5), and IMP (n = 15, 7.39%; 1 IMP-26, 10 IMP-30, 4 IMP-4). Fifty-one out of two hundred and three (51/203 or 25.12%) of the examined strains showed a synergistic effect for the meropenem plus ertapenem combination throughout the checkerboard method, while only three isolates showed potential clinically relevant synergy (3/203, 1.48%). An additive effect was observed in 55/203 (27.09%) of the examined strains. Ninety-seven of the examined isolates (47.78%) showed fractional inhibitory concentration (FIC) greater or equal to 2 (indicating antagonism). The synergistic activity of meropenem plus ertapenem combination suggests this combination can be a possible way to treat the infection caused by the carbapenem-resistant organisms, especially for IMP or NDM producer with a lesser minimum inhibitory concentration (MIC) and the infected individual who was not recommended to use colistin or tigecycline.

SUBMITTER: Lu J

PROVIDER: S-EPMC9257860 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. METHODS:This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. RESULTS:Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. CONCLUSION:The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.

Project description:BackgroundCarbapenem-resistant Gram-negative bacteria are a major clinical concern as they cause virtually untreatable infections since carbapenems are among the last-resort antimicrobial agents. β-Lactamases implicated in carbapenem resistance include KPC, NDM, and OXA-type carbapenemases. Antimicrobial combination therapy is the current treatment approach against carbapenem resistance in order to limit the excessive use of colistin; however, its advantages over monotherapy remain debatable. An alternative treatment strategy would be the use of carbapenem/β-lactamase inhibitor (βLI) combinations. In this study, we assessed the in vitro and in vivo phenotypic and molecular efficacies of three βLIs when combined with different carbapenems against carbapenem-resistant Gram-negative clinical isolates. The chosen βLIs were (1) Avibactam, against OXA-type carbapenemases, (2) calcium-EDTA, against NDM-1, and (3) Relebactam, against KPC-2.MethodsSix Acinetobacter baumannii clinical isolates were screened for bla OXA-23-like, bla OXA-24/40, bla OXA-51-like, bla OXA-58, and bla OXA-143-like, and eight Enterobacteriaceae clinical isolates were screened for bla OXA-48, bla NDM-1, and bla KPC-2. The minimal inhibitory concentrations of Imipenem (IPM), Ertapenem (ETP), and Meropenem (MEM) with corresponding βLIs for each isolate were determined. The efficacy of the most suitable in vitro treatment option against each of bla OXA-48, bla NDM-1, and bla KPC-2 was assessed via survival studies in a BALB/c murine infection model. Finally, RT-qPCR was performed to assess the molecular response of the genes of resistance to the carbapenem/βLI combinations used under both in vitro and in vivo settings.ResultsCombining MEM, IPM, and ETP with the corresponding βLIs restored the isolates' susceptibilities to those antimicrobial agents in 66.7%, 57.1%, and 30.8% of the samples, respectively. Survival studies in mice revealed 100% survival rates when MEM was combined with either Avibactam or Relebactam against bla OXA-48 and bla KPC-2, respectively. RT-qPCR demonstrated the consistent overexpression of bla OXA-48 upon treatment, without hindering Avibactam's activity, while bla NDM-1 and bla KPC-2 experienced variable expression levels upon treatment under in vitro and in vivo settings despite their effective phenotypic results.ConclusionNew carbapenem/βLI combinations may be viable alternatives to antimicrobial combination therapy as they displayed high efficacy in vitro and in vivo. Meropenem/Avibactam and Meropenem/Relebactam should be tested on larger sample sizes with different carbapenemases before progressing further in its preclinical development.

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Effectiveness of a double-carbapenem combinations against carbapenem-resistant Gram-negative bacteria.

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