Mechanisms of Tigecycline Resistance among Klebsiella pneumoniae Clinical Isolates

Sheng, Zhonghua; Hu, Fupin; Wang, Weixia; Guo, Qinglan; Chen, Zhijun; Xu, Xiaogang; Zhu, Demei; Wang, Minggui

doi:10.1128/aac.03808-14

Cited by 74 publications

(60 citation statements)

References 15 publications

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“…Recent studies have established that overexpression of AcrAB efflux pump plays a major role in tigecycline resistance in K. pneumoniae (23,30). Overexpression of OqxAB has contributed to tigecycline resistance in one study (12). The previous use of fluoroquinolones that are also effluxed through the AcrAB or OqxAB pump might result in overexpression of these efflux pumps and subsequently reduce susceptibility to tigecycline.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Juan

Huang²,

Lin

et al. 2016

Antimicrob Agents Chemother

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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.

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Section: Discussionmentioning

confidence: 99%

“…The RamA and AcrAB pathway and RarA, together with OqxAB pathways are implicated in tigecycline resistance in K. pneumoniae (12). Studies of tigecycline resistance mechanisms in K. pneumoniae usually include only a small number of isolates in the literature (12)(13)(14).…”

mentioning

confidence: 99%

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

Juan

Huang²,

Lin

et al. 2016

Antimicrob Agents Chemother

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“…Additionally, in vitro selection with cefoxitin and fluoroquinolones, starting from the drug-susceptible revertants of the clinical strains described above, resulted in AcrB overproduction caused mainly by mutations in ramR and in one case in soxR (299). A recent study linked ramR mutation-driven overexpression of AcrAB to tigecycline resistance in KPC-producing strains (300), although one study suggested that RamA-AcrB overexpression occurred only in about one-half of the tigecycline-resistant isolates (301).…”

Section: Klebsiella Pneumoniaementioning

confidence: 99%

“…Intriguingly, the genetic arrangement of rarA-oqxAB-oqxR is observed both in chromosomes and on a plasmid (790). Nearly all tested clinical tigecycline-nonsusceptible isolates (25 out of 26) from China contained mutations in ramR and/or acrR, with about onethird of the isolates carrying the simultaneous overexpression of ramA-acrB and rarA-oqxB (301). The expression of eefABC appears to be induced by an acidic or hyperosmolar environment but not by bile salts (793).…”

Section: K Pneumoniae Efflux Pumpsmentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…However, gene medicines (ribozymes, miRNA, antisense RNA) and DNA nanotechnology have been welcome to stop the horror of MDR bacterial pathogenesis. More sadly, bacteria have acquired promoter induction system by antibiotics and many transcription factor repressors (tetR, mtrR, acrR) have been found in conjugative plasmids [31]. Those TFs induced efflux pumps (mexAB, mtrCDF) and Beta-lactamases (blaNDM1, blaOXA23) could destroy antibiotics and such mechanisms remain elusive.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of AMR: Bacteria Won the Battle Against Antibiotics

Ak¹

2017

Insights Biomed

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Mechanisms of Tigecycline Resistance among Klebsiella pneumoniae Clinical Isolates

Cited by 74 publications

References 15 publications

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

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

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Mechanisms of AMR: Bacteria Won the Battle Against Antibiotics

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