Risk Factors, Outcomes, and Mechanisms of Tigecycline-Nonsusceptible Klebsiella pneumoniae Bacteremia

Abstract

A rise in tigecycline resistance in Klebsiella pneumoniae has been reported recently worldwide. We sought to identify risk factors, outcomes, and mechanisms for adult patients with tigecycline-nonsusceptible K. pneumoniae bacteremia in Taiwan. We conducted a matched case-control study (ratio of 1:1) in a medical center in Taiwan from January 2011 through June 2015. The cases were patients with tigecycline-nonsusceptible K. pneumoniae bacteremia, and the controls were patients with tigecyclinesusceptible K. pneumoniae bacteremia. Logistic regression was performed to evaluate the potential risk factors for tigecyclinenonsusceptible K. pneumoniae bacteremia. Quantitative reverse transcription-PCR was performed to analyze acrA, oqxA, ramA, rarA, and kpgA expression among these isolates. A total of 43 cases were matched with 43 controls. The 14-day mortality of patients with tigecycline-nonsusceptible K. pneumoniae bacteremia was 30.2%, and the 28-day mortality was 41.9%. The attributable mortalities of tigecycline-nonsusceptible K. pneumoniae at 14 and 28 days were 9.3 and 18.6%, respectively. Fluoroquinolone use within 30 days prior to bacteremia was the only independent risk factor for tigecycline-nonsusceptible K. pneumoniae bacteremia. The tigecycline-nonsusceptible K. pneumoniae bacteremia was mostly caused by overexpression of AcrAB and/or OqxAB efflux pumps, together with the upregulation of RamA and/or RarA, respectively. One isolate demonstrated isolated overexpression of kpgA. In conclusion, tigecycline-nonsusceptible K. pneumoniae bacteremia was associated with high mortality, and prior fluoroquinolone use was the independent risk factor for the acquisition of tigecycline-nonsusceptible K. pneumoniae. The overexpression of AcrAB and/or OqxAB contributes to tigecycline nonsusceptibility in K. pneumoniae.

Tigecycline resistance among carbapenem-resistant Klebsiella Pneumoniae: Clinical characteristics and expression levels of efflux pump genes

“…A literature review showed that reported mechanisms in tigecycline resistance of K . pneumoniae include overexpression of ramA and acrAB [9, 31, 32], deletions, insertions and point mutations in ramR [33, 34], overexpression of rarA and oqxB [9, 32, 35], a point mutation in the repressor oqxR and overexpression of the OqxAB efflux pump [13], IS 5 element integration in a putative efflux pump, KpgABC [23], overexpression of marA and acrAB , and structural alteration of the ribosomal protein S10 [34]. The detailed role of each mechanism in conferring tigecycline resistance requires further investigation.…”

The role of RND-type efflux pumps in multidrug-resistant mutants of Klebsiella pneumoniae

“…The first report of oqxAB was from a plasmid in E. coli in 2004 35 . An ortholog of oqxAB was not found in the E. coli genome, but was found in the K. pneumoniae genome 36 . Several transcriptional regulator genes were located in the flanking regions of oqxAB in the K. pneumoniae genome, and it was also reported that both rarA, located upstream of oqxAB, and oqxR, downstream of oqxAB, were regulator genes of oqxAB 5,37 .…”

CusS-CusR Two-Component System Mediates Tigecycline Resistance in Carbapenem-Resistant Klebsiella pneumoniae

“…Thus, we also detected acrE and acrF, but no increase in expression was observed. Juan et al (2016) evaluated 43 strains each of tigecycline-non-susceptible KP and tigecycline-susceptible KP, and found that the overexpression of OqxAB efflux pumps was a major cause of tigecycline-non-susceptible KP resistance to tigecycline. However, the evolved strains in this study did not show an increase in their expression.…”