Dataset Information

In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant Klebsiella pneumoniae.

ABSTRACT: Objectives:Colistin is still a "last-resort" antibiotic used to manage human infections due to multidrug-resistant (MDR) Klebsiella pneumoniae. However, colistin-resistant K. pneumoniae (CR-Kp) isolates emerged a decade ago and had a worldwide distribution. The purpose of this study was to evaluate the genetic data of CR-Kp and identify the antibacterial activity of fosfomycin (FM) alone and in combination with amikacin (AMK) or colistin (COL) against CR-Kp in vitro. Methods:Three clinical CR-Kp isolates from three patients were collected. Whole-genome sequencing and bioinformatics analysis were performed. The Pharmacokinetics Auto Simulation System 400, by simulating human pharmacokinetics in vitro, was employed to simulate FM, AMK, and COL alone and in combination. Different pharmacodynamic parameters were calculated for determining the antimicrobial effect. Results:Whole-genome sequencing revealed that none of the three isolates contain mcr gene and that no insertion was found in pmrAB, phoPQ, or mgrB genes. We found the antibacterial activity of AMK alone was more efficient than FM or COL against CR-Kp. The area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was higher than 170 LogCFU/mL·h-1. In addition, the area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with COL (75,000 IU/kg every12 hours) was higher than that of monotherapies (>100 LogCFU/mL·h-1 vs <80 LogCFU/mL·h-1). Conclusion:FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was effective at maximizing bacterial killing against CR-Kp.

SUBMITTER: Yu W

PROVIDER: S-EPMC5926077 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant <i>Klebsiella pneumoniae</i>.

Yu Wei W Luo Qixia Q Shi Qingyi Q Huang Chen C Yu Xiao X Niu Tianshui T Zhou Kai K Zhang Jiajie J Xiao Yonghong Y

Infection and drug resistance 20180424

<h4>Objectives</h4>Colistin is still a "last-resort" antibiotic used to manage human infections due to multidrug-resistant (MDR) <i>Klebsiella pneumoniae</i>. However, colistin-resistant <i>K. pneumoniae</i> (CR-Kp) isolates emerged a decade ago and had a worldwide distribution. The purpose of this study was to evaluate the genetic data of CR-Kp and identify the antibacterial activity of fosfomycin (FM) alone and in combination with amikacin (AMK) or colistin (COL) against CR-Kp in vitro.<h4>Met ...[more]

PMID: 29731646

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Project description:Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial and community-acquired infections. Klebsiella has developed resistance against antimicrobials including the last resort class; carbapenem. Currently, treatment options for carbapenem-resistant-Klebsiella (CRK) are very limited. This study aims to restore carbapenem effectiveness against CRK using celastrol and thymol. Clinical Klebsiella isolates were identified using biochemical and molecular methods. Antimicrobial susceptibility was determined using disk-diffusion method. Carbapenemase-production was tested phenotypically and genotypically. Celastrol and thymol-MICs were determined and the carbapenemase-inhibitory effect of sub-MICs was investigated. Among 85 clinical Klebsiella isolates, 72 were multi-drug-resistant and 43 were meropenem-resistant. Phenotypically, 39 isolates were carbapenemase-producer. Genotypically, blaNDM1 was detected in 35 isolates, blaVIM in 17 isolates, blaOXA in 18 isolates, and blaKPC was detected only in 6 isolates. Celastrol showed significant inhibitory effect against carbapenemase-hydrolytic activity. Meropenem-MIC did not decrease in presence of celastrol, only 2-fold decrease was observed with thymol, while 4-64 fold decrease was observed when meropenem was combined with both celastrol and thymol. Furthermore, thymol increased CRK cell wall-permeability. Molecular docking revealed that celastrol is superior to thymol for binding to KPC and VIM-carbapenemase. Our study showed that celastrol is a promising inhibitor of multiple carbapenemases. While meropenem-MIC were not affected by celastrol alone and decreased by only 2-folds with thymol, it decreased by 4-64 folds in presence of both celastrol and thymol. Thymol increases the permeability of CRK-envelope to celastrol. The triple combination (meropenem/celastrol/thymol) could be useful for developing more safe and effective analogues to restore the activity of meropenem and other β-lactams.

Dataset Information

In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant Klebsiella pneumoniae.

Publications

In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant <i>Klebsiella pneumoniae</i>.

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