Dataset Information

Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella pneumoniae in vitro.

ABSTRACT: The purpose of this study was to investigate the synergistic and bactericidal effects of combinations of colistin with meropenem or amikacin in vitro and provide laboratory data needed for development of therapeutic strategies for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection. We found that minimum inhibitory concentration (MIC) of colistin, meropenem and amikacin were 2~32, 4~256, and 1~16384 ?g/ml, respectively. The minimum bactericidal concentration of the antibiotics was either 1× or 2×MIC. Treatments of 6 CRKP isolates at 1 ?g/ml colistin completely killed 2 of them and suppressed 4 others growth. 4 CRKP isolates at 16 ?g/ml meropenem or amikacin completely killed and suppressed 2 others growth. 2 CRKP isolates showed synergic effects in all colistin combination and 3 CRKP isolates showed synergic effects in part of colistin combination. Our data suggest that colistin in combination with either meropenem or amikacin could be a valid therapeutic option against colistin-resistant CRKP isolates. Moreover, the combination of colistin-amikacin is less expensive to treat CRKP infections in Eastern Heilongjiang Province.

SUBMITTER: Yu L

PROVIDER: S-EPMC6916149 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella pneumoniae in vitro.

Yu Lan L Zhang Jisheng J Fu Yanjun Y Zhao Yongxin Y Wang Yong Y Zhao Jing J Guo Yuhang Y Li Chunjiang C Zhang Xiaoli X

Frontiers in cellular and infection microbiology 20191210

The purpose of this study was to investigate the synergistic and bactericidal effects of combinations of colistin with meropenem or amikacin in vitro and provide laboratory data needed for development of therapeutic strategies for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection. We found that minimum inhibitory concentration (MIC) of colistin, meropenem and amikacin were 2~32, 4~256, and 1~16384 μg/ml, respectively. The minimum bactericidal concentratio ...[more]

PMID: 31921701

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Project description:Carbapenem-resistant Enterobacteriaceae (CRE) are resistant to most antibiotics, making CRE infections extremely difficult to treat with available agents. Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) are predominant carbapenemases in CRE in the United States. Nacubactam is a bridged diazabicyclooctane (DBO) β-lactamase inhibitor that inactivates class A and C β-lactamases and exhibits intrinsic antibiotic and β-lactam "enhancer" activity against Enterobacteriaceae In this study, we examined a collection of meropenem-resistant K. pneumoniae isolates carrying blaKPC-2 or blaKPC-3; meropenem-nacubactam restored susceptibility. Upon testing isogenic Escherichia coli strains producing KPC-2 variants with single-residue substitutions at important Ambler class A positions (K73, S130, R164, E166, N170, D179, K234, E276, etc.), the K234R variant increased the meropenem-nacubactam MIC compared to that for the strain producing KPC-2, without increasing the meropenem MIC. Correspondingly, nacubactam inhibited KPC-2 (apparent Ki [Ki app] = 31 ± 3 μM) more efficiently than the K234R variant (Ki app = 270 ± 27 μM) and displayed a faster acylation rate (k2/K), which was 5,815 ± 582 M-1 s-1 for KPC-2 versus 247 ± 25 M-1 s-1 for the K234R variant. Unlike avibactam, timed mass spectrometry revealed an intact sulfate on nacubactam and a novel peak (+337 Da) with the K234R variant. Molecular modeling of the K234R variant showed significant catalytic residue (i.e., S70, K73, and S130) rearrangements that likely interfere with nacubactam binding and acylation. Nacubactam's aminoethoxy tail formed unproductive interactions with the K234R variant's active site. Molecular modeling and docking observations were consistent with the results of biochemical analyses. Overall, the meropenem-nacubactam combination is effective against carbapenem-resistant K. pneumoniae Moreover, our data suggest that β-lactamase inhibition by nacubactam proceeds through an alternative mechanism compared to that for avibactam.

Project description:The emergence and dissemination of carbapenemases, bacterial enzymes able to inactivate most β-lactam antibiotics, in Enterobacteriaceae is of increasing concern. The concurrent spread of resistance against colistin, an antibiotic of last resort, further compounds this challenge further. Whole-genome sequencing (WGS) can play a significant role in the rapid and accurate detection/characterization of existing and emergent resistance determinants, an essential aspect of public health surveillance and response activities to combat the spread of antimicrobial resistant bacteria. In the current study, WGS data was used to characterize the genomic content of antimicrobial resistance genes, including those encoding carbapenemases, in 10 multidrug-resistant Klebsiella pneumoniae isolates from Pakistan. These clinical isolates represented five sequence types: ST11 (n = 3 isolates), ST14 (n = 3), ST15 (n = 1), ST101 (n = 2), and ST307 (n = 1). Resistance profiles against 25 clinically-relevant antimicrobials were determined by broth microdilution; resistant phenotypes were observed for at least 15 of the 25 antibiotics tested in all isolates except one. Specifically, 8/10 isolates were carbapenem-resistant and 7/10 isolates were colistin-resistant. The blaNDM-1 and blaOXA-48 carbapenemase genes were present in 7/10 and 5/10 isolates, respectively; including 2 isolates carrying both genes. No plasmid-mediated determinants for colistin resistance (e.g. mcr) were detected, but disruptions and mutations in chromosomal loci (i.e. mgrB and pmrB) previously reported to confer colistin resistance were observed. A blaOXA-48-carrying IncL/M-type plasmid was found in all blaOXA-48-positive isolates. The application of WGS to molecular epidemiology and surveillance studies, as exemplified here, will provide both a more complete understanding of the global distribution of MDR isolates and a robust surveillance tool useful for detecting emerging threats to public health.

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Project description:Colistin is one of the last-resort options for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections if novel antibiotics are unavailable, where the development of colistin resistance during treatment represents a major challenge for clinicians. We aimed to investigate the risk factors associated with the development of colistin resistance in patients with CRKP infections following colistin treatment. We conducted a retrospective case-control study of patients with CRKP strains available before and after colistin treatment at a medical center in Taiwan, between October 2016 and November 2020. Cases (n = 35) included patients with an initial colistin-susceptible CRKP (ColS-CRKP) strain and a subsequent colistin-resistant CRKP (ColR-CRKP) strain. Controls (n = 18) included patients with ColS-CRKP as both the initial and subsequent strains. The 30-day mortality rate after the subsequent CRKP isolation was not different between cases and controls (12/35 [34%] versus 5/18 [28%] [P = 0.631]). blaKPC (n = 38) and blaOXA-48 (n = 11) accounted for the major mechanisms of carbapenem resistance. Alterations in mgrB were found in 18/35 (51%) ColR-CRKP strains, and mcr-1 was not detected in any of the strains. More patients received combination therapy in the control group than in the case group (17/18 versus 21/35 [P = 0.008]). The logistic regression model indicated that combination therapy with tigecycline was protective against the acquisition of colistin resistance (odds ratio, 0.17; 95% confidence interval, 0.05 to 0.62 [P = 0.008]). We observed that the inclusion of tigecycline in colistin treatment mitigated the risk of acquiring colistin resistance. These results offer insight into using the combination of tigecycline and colistin for the treatment of CRKP infections in antimicrobial stewardship. IMPORTANCE Treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is challenging due to the limited options of antibiotics. Colistin is one of the last-resort antibiotics if novel antimicrobial agents are not available. It is crucial to identify modifiable clinical factors associated with the emergence of resistance during colistin treatment. Here, we found that the addition of tigecycline to colistin treatment prevented the acquisition of colistin resistance. Colistin-tigecycline combination therapy is therefore considered a hopeful option in antimicrobial stewardship to treat CRKP infections.

Dataset Information

Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella pneumoniae in vitro.

Publications

Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant <i>Klebsiella pneumoniae in vitro</i>.

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