Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality

Abstract

Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide.

Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling.

Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp.

Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.

Keywords: Klebsiella pneumoniae; carbapenem-resistant Enterobacteriaceae; colistin; mortality; ST258.

Figure 1.

The numbers of isolates that correspond to each minimum inhibitory concentration (MIC) value for the MIC as reported by the clinical microbiology laboratories (“clinical colistin MIC”) and the centralized research laboratory (“research colistin MIC”), as well as the polymyxin B MIC are shown.

Figure 2.

The percentages of susceptible and intermediate isolates for each drug are shown separately for colistin-resistant (ColR) and colistin-susceptible (ColS) carbapenem-resistant Klebsiella pneumoniae (CRKp). Underneath each bar is the number of CRKp tested for each drug in the ColR and ColS groups. The black and white bars represent the percentage of susceptible/tested CRKp isolates in the ColR and ColS groups, respectively. The dark-gray and light-gray bars on top of the black and white bars represent the percentage of intermediate/tested CRKp isolates in the ColR and ColS groups, respectively. Abbreviation: TMP/SMX, trimethoprim/sulfamethoxazole.

Figure 3.

Repetitive extragenic palindromic–polymerase chain reaction (rep-PCR) dendrogram of colistin-resistant carbapenem-resistant Klebsiella pneumoniae isolates. A ≥95% similarity cutoff (gray line) was used to consider isolates of the same rep-PCR type. Colored boxes next to each strain represent the various hospitals from which isolates were recovered. Abbreviation: KPC, klebsiella pneumoniae carbapenemase.

Figure 4.

Kaplan-Meier curve showing the 30-day in-hospital survival for patients with colistin-resistant carbapenem-resistant Klebsiella pneumoniae (CRKp) as compared to colistin-susceptible CRKp. Patients were censored at the time of hospital discharge.