Abstract
Resistance to colistin is increasingly reported in Klebsiella pneumoniae clinical isolates. The aim of this study was to analyze the molecular epidemiology and virulence profiles of 25 colistin-resistant K. pneumoniae blood isolates from the Hospital Agency “Ospedale dei Colli,” Naples, Italy, during 2015 and 2016. Colistin MIC values of isolates ranged from 4 to 256 mg/L. The inactivation of the mgrB gene, encoding a negative regulator of the PhoQ/PhoP signaling system, was the most frequent mechanism of colistin resistance found in 22 out of 25 isolates. Of these, 10 isolates assigned to ST512 and PFGE types A and A4 showed identical frameshift mutation and premature termination of mgrB gene; 4 isolates assigned to ST258 and PFGE types A1 showed non-sense, frameshift mutation, and premature termination; 3 and 1 isolates assigned to ST258 and PFGE A2 and ST512 and PFGE A3, respectively, had insertional inactivation of mgrB gene due to IS5-like mobile element; 2 isolates assigned to ST101 and 1 to ST392 had missense mutations in the mgrB gene, 1 isolate assigned to ST45 showed insertional inactivation of mgrB gene due to IS903-like mobile element. phoQ missense mutations were found in 2 isolates assigned to ST629 and ST101, respectively, which also showed a missense mutation in pmrA gene. The mcr-1-2-3-4 genes were not detected in any isolate. Colistin-resistant K. pneumoniae isolates showed variable virulence profiles in Galleria mellonella infection assays, with the infectivity of two isolates assigned to ST45 and ST629 being significantly higher than that of all other strains (P < 0.001). Interestingly, colistin MIC values proved to make a significant contribution at predicting lethal doses values (LD50 and LD90) of studied isolates in G. mellonella. Our data show that MgrB inactivation is a common mechanism of colistin resistance among K. pneumoniae in our clinical setting. The presence of identical mutations/insertions in isolates of the same ST and PFGE profile suggests the occurrence of clonal expansion and cross-transmission. Although virulence profiles differ among isolates irrespective of their genotypes, our results suggest that high colistin MIC could predict lower infectivity capability of the isolates.
Highlights
The occurrence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) Klebsiella pneumoniae infections (BialekDavenet et al, 2014; Bradford et al, 2015; Holt et al, 2015; Pitout et al, 2015; Cerqueira et al, 2017; Logan and Weinstein, 2017; Otter et al, 2017) has favored the use of colistin-based regimens as the most frequent therapeutic options (van Duin et al, 2013)
An increase of colistin-resistant K. pneumoniae clinical isolates was observed in the Hospital Agency (HA) “Ospedale dei Colli” during 2015 and 2016 with a prevalence of colistin-resistant K. pneumoniae isolates over total K. pneumoniae isolates of 0.15
Our data demonstrate the cross transmission and clonal expansion of 4 epidemic genotypes in different patients and wards: ST512/A genotype was isolated in M-intensive care units (ICU) and IDD wards of “D. Cotugno” hospital, ST258/A1 and ST258/A2 genotypes were isolated in CR-ICU, R-ICU and R-ICU wards of “V. Monaldi” hospital and M-ICU of “D. Cotugno,” ST629/D genotype in M-ICU ward of “D. Cotugno” hospital and CSICU ward of “V. Monaldi” hospital
Summary
The occurrence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) Klebsiella pneumoniae infections (BialekDavenet et al, 2014; Bradford et al, 2015; Holt et al, 2015; Pitout et al, 2015; Cerqueira et al, 2017; Logan and Weinstein, 2017; Otter et al, 2017) has favored the use of colistin-based regimens as the most frequent therapeutic options (van Duin et al, 2013). Molecular mechanisms responsible for colistin resistance rely on mutations in the genes of two component transcriptional regulatory systems PhoPQ and PmrAB, which regulate the expression of pmrC gene that codes for the addition of phosphoethanolamine and pmrHFIJKLM operon genes that encode biosynthesis and lipid A transfer of 4-amino-4-deoxyL-arabinose (Cheng et al, 2015, 2016; Jayol et al, 2015; Wright et al, 2015; Novovicet al., 2017; Poirel et al, 2017; Pragasam et al, 2017). The acquisition of plasmid-borne mcr 1.2 gene encoding a membrane-anchored enzyme which adds phosphoethanolamine to lipid A has been recently reported in K. pneumoniae (Di Pilato et al, 2016)
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