Abstract
ABSTRACTWe assessed the prevalence of polymyxin B (PMB)- and tigecycline (TGC)-heteroresistant Klebsiella pneumoniae isolates and investigated the combined effect of PMB and TGC against dual-heteroresistant K. pneumoniae. Ninety-five nonduplicated carbapenem-resistant K. pneumoniae (CRKP) clinical isolates were collected from a tertiary-care teaching hospital in China. PCR was used to detect the resistant genes among the CRKP isolates. Population analysis profiling (PAP) was carried out to evaluate the existence of heteroresistance. A time-kill assay of PMB combined with TGC was conducted against heteroresistant K. pneumoniae strains. Real-time PCR was performed to determine the pmrA, phoP, and acrB expression levels. Among them, 74 isolates (77.9%) were susceptible to TGC, and 90 isolates (94.7%) were susceptible to PMB. In addition, of the TGC-susceptible isolates, 49 strains (66.2%) exhibited heteroresistant phenotypes. All of the PMB-susceptible isolates showed heteroresistant phenotypes. Forty-six isolates (48.4%) were heteroresistant to both TGC and PMB. All of the isolates carried the blaKPC gene, and one strain carried both blaKPC and blaNDM genes. The time-kill assay revealed in four isolates that early bactericidal activity could be triggered by the combination of PMB and TGC, and there was no regrowth, even at a relatively lower concentration (0.125 mg/liter PMB with 1 mg/liter TGC). Upregulated expression of pmrA, phoP, and acrB indicated that heteroresistance could be related to two-component systems and the AcrAB-TolC efflux pump. The combination of PMB and TGC may be a treatment strategy for those infected with CRKP heteroresistant to PMB and/or TGC.IMPORTANCE Tigecycline and colistin are two of the last treatment options remaining for carbapenem-resistant Enterobacteriaceae. Unfortunately, tigecycline resistance and colistin heteroresistance are also increasing rapidly. In the current study, we identified a high prevalence of heteroresistance to both PMB and TGC among clinical isolates of carbapenem-resistant K. pneumoniae (CRKP). The resistant subpopulations could survive pressure from TGC or PMB but were killed by the combination at a relatively low dose. It is proposed that the combination of PMB and TGC may be a treatment strategy for patients who are infected with CRKP heteroresistant to PMB or TGC.
Highlights
We assessed the prevalence of polymyxin B (PMB)- and tigecycline (TGC)heteroresistant Klebsiella pneumoniae isolates and investigated the combined effect of PMB and TGC against dual-heteroresistant K. pneumoniae
carbapenem-resistant K. pneumoniae (CRKP) clinical isolates we obtained for this study had resistant phenotypes to almost all antibacterial agents, except TGC and PMB
PMB and TGC are regarded as last-resort antibiotics to cure CRKP, it has been reported that resistance or heteroresistance to them can lead to treatment failure [25,26,27]
Summary
We assessed the prevalence of polymyxin B (PMB)- and tigecycline (TGC)heteroresistant Klebsiella pneumoniae isolates and investigated the combined effect of PMB and TGC against dual-heteroresistant K. pneumoniae. We identified a high prevalence of heteroresistance to both PMB and TGC among clinical isolates of carbapenem-resistant K. pneumoniae (CRKP). Tigecycline (TGC) seem to be used as the last-resort options to cure CRKP infection, but clinicians still need to consider several factors, such as nephrotoxicity, available plasma concentrations in vivo, and increasing resistance during the treatment [11,12,13]. Heteroresistance is defined as the presence of several subpopulations existing in a clinical isolate which show various levels of resistance compared with the respective parental population [13, 16] This unique phenotype lacks a conventional detection method and may be misclassified as susceptible by the routine antibiotic susceptibility testing method [19]. There is an urgent need to explore alternative antimicrobial therapies aimed at eliminating the regrowth of resistant subpopulations in heteroresistant strains
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