Molecular Epidemiology and Mechanisms of Tigecycline Resistance in Clinical Isolates of Acinetobacter baumannii from a Chinese University Hospital
01 Jan 2014-Antimicrobial Agents and Chemotherapy (American Society for Microbiology)-Vol. 58, Iss: 1, pp 297-303
TL;DR: This study showed that the active efflux pump AdeABC appeared to play important roles in the tigecycline resistance of A. baumannii, and phenyl-arginine-β-naphthylamide (PAβN) and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could partially reverse the resistance pattern of tigECYcline.
Abstract: For its remarkable ability to acquire antibiotic resistance and to survive in nosocomial environments, Acinetobacter baumannii has become a significant nosocomial infectious agent worldwide. Tigecycline is one of the few therapeutic options to treat infections caused by A. baumannii isolates. However, tigecycline resistance has been increasingly reported. Our aim was to assess the prevalence and characteristics of efflux-based tigecycline resistance in clinical isolates of A. baumannii collected from a hospital in China. A total of 74 A. baumannii isolates including 64 tigecycline non-susceptible A. baumannii (TNAB) and 10 tigecycline susceptible A. baumannii (TSAB) isolates were analyzed. The majority of them were detected to be positive for adeABC , adeRS , adeIJK and abeM, while the adeE gene was found in only one TSAB isolate. Compared with TSAB isolates, the mean expression level of adeB , adeJ, adeG and abeM in TNAB isolates were observed to increase by 29-, 3-, 0.7- and 1-fold, respectively. The efflux pump inhibitors (EPIs) PAβN and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could partially reverse the resistance pattern of tigecycline. Moreover, tetX1 gene was detected in 12 (18.8%) TNAB isolates. To our knowledge, this is the first report that tetX1 gene was detected in the A. baumannii isolates. ST208 and ST191 which both clustered into clonal complex 92 (CC92) were the predominant sequence types (STs). This study showed that active efflux pump AdeABC appeared to play important roles in the tigecycline resistance of A. baumannii. The dissemination of TNAB isolates in our hospital is mainly attributable to the spread of CC92.
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TL;DR: This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps, with particular focus on AcrAB-TolC and Mex pumps.
Abstract: 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.
1,016 citations
TL;DR: Current studies on the virulence factors that contribute to A. baumannii pathogenesis are summarized and Mechanisms of antibiotic resistance of this organism, including acquirement of β-lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites are discussed.
Abstract: Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of -lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized.
572 citations
Cites background from "Molecular Epidemiology and Mechanis..."
...…| www.frontiersin.org 11 March 2017 | Volume 7 | Article 55 efflux pump inhibitors, such as 1-(1-naphthylmethyl)-piperazine and carbonyl cyanide 3-chlorophenyl-hydrazone, supports the importance of efflux pumps in A. baumannii antibiotic resistance (Pannek et al., 2006; Deng et al., 2014)....
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TL;DR: This Review highlights seminal work in the resistome field, discusses recent advances in the studies of resistomes, and proposes a resistome paradigm that can pave the way for the improved proactive identification and mitigation of emerging antibiotic resistance threats.
Abstract: Antibiotic resistance is a natural feature of diverse microbial ecosystems. Although recent studies of the antibiotic resistome have highlighted barriers to the horizontal transfer of antibiotic resistance genes between habitats, the rapid global spread of genes that confer resistance to carbapenem, colistin and quinolone antibiotics illustrates the dire clinical and societal consequences of such events. Over time, the study of antibiotic resistance has grown from focusing on single pathogenic organisms in axenic culture to studying antibiotic resistance in pathogenic, commensal and environmental bacteria at the level of microbial communities. As the study of antibiotic resistance advances, it is important to incorporate this comprehensive approach to better inform global antibiotic resistance surveillance and antibiotic development. It is increasingly becoming apparent that although not all resistance genes are likely to geographically and phylogenetically disseminate, the threat presented by those that are is serious and warrants an interdisciplinary research focus. In this Review, we highlight seminal work in the resistome field, discuss recent advances in the studies of resistomes, and propose a resistome paradigm that can pave the way for the improved proactive identification and mitigation of emerging antibiotic resistance threats.
390 citations
TL;DR: The findings suggest that both the surveillance of tet(X) variants in clinical and animal sectors and the use of tetracyclines in food production require urgent global attention.
Abstract: Tigecycline is a last-resort antibiotic that is used to treat severe infections caused by extensively drug-resistant bacteria. tet(X) has been shown to encode a flavin-dependent monooxygenase that modifies tigecycline1,2. Here, we report two unique mobile tigecycline-resistance genes, tet(X3) and tet(X4), in numerous Enterobacteriaceae and Acinetobacter that were isolated from animals, meat for consumption and humans. Tet(X3) and Tet(X4) inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline. Both tet(X3) and tet(X4) increase (by 64-128-fold) the tigecycline minimal inhibitory concentration values for Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. In addition, both Tet(X3) (A. baumannii) and Tet(X4) (E. coli) significantly compromise tigecycline in in vivo infection models. Both tet(X3) and tet(X4) are adjacent to insertion sequence ISVsa3 on their respective conjugative plasmids and confer a mild fitness cost (relative fitness of >0.704). Database mining and retrospective screening analyses confirm that tet(X3) and tet(X4) are globally present in clinical bacteria-even in the same bacteria as blaNDM-1, resulting in resistance to both tigecycline and carbapenems. Our findings suggest that both the surveillance of tet(X) variants in clinical and animal sectors and the use of tetracyclines in food production require urgent global attention.
367 citations
TL;DR: The full potential of the tetracyclines class can be explored for use against current and emerging multidrug-resistant (MDR) pathogens, including carbapenem-resistant Enterobacteriaceae, MDR Acinetobacter species, and Pseudomonas aeruginosa.
Abstract: Tetracyclines possess many properties considered ideal for antibiotic drugs, including activity against Gram-positive and -negative pathogens, proven clinical safety, acceptable tolerability, and the availability of intravenous (IV) and oral formulations for most members of the class. As with all antibiotic classes, the antimicrobial activities of tetracyclines are subject to both class-specific and intrinsic antibiotic-resistance mechanisms. Since the discovery of the first tetracyclines more than 60 years ago, ongoing optimization of the core scaffold has produced tetracyclines in clinical use and development that are capable of thwarting many of these resistance mechanisms. New chemistry approaches have enabled the creation of synthetic derivatives with improved in vitro potency and in vivo efficacy, ensuring that the full potential of the class can be explored for use against current and emerging multidrug-resistant (MDR) pathogens, including carbapenem-resistant Enterobacteriaceae, MDR Acinetobacter species, and Pseudomonas aeruginosa.
347 citations
Cites background from "Molecular Epidemiology and Mechanis..."
...…and transposons, recent reports of tet(X) in Enterobacteriaceae and Pseudomonadaceae hospital urinary tract infection (UTI) isolates in Sierra Leone, and tet(X) in A. baumannii in a Chinese hospital, are of concern with regard to the spread of this mechanism (Leski et al. 2013; Deng et al. 2014)....
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...baumannii in a Chinese hospital, are of concern with regard to the spread of this mechanism (Leski et al. 2013; Deng et al. 2014)....
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References
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01 Jan 2001
TL;DR: The supplemental information presented in this document is intended for use with the antimicrobial susceptibility testing procedures published in the following Clinical and Laboratory Standards Institute (CLSI)–approved standards.
Abstract: The supplemental information presented in this document is intended for use with the antimicrobial susceptibility testing procedures published in the following Clinical and Laboratory Standards Institute (CLSI)–approved standards: M02-A12—Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Twelfth Edition; M07-A10—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Tenth Edition; and M11-A8—Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard— Eighth Edition. The standards contain information about both disk (M02) and dilution (M07 and M11) test procedures for aerobic and anaerobic bacteria. Clinicians depend heavily on information from the microbiology laboratory for treatment of their seriously ill patients. The clinical importance of antimicrobial susceptibility test results demands that these tests be performed under optimal conditions and that laboratories have the capability to provide results for the newest antimicrobial agents. The tabular information presented here represents the most current information for drug selection, interpretation, and QC using the procedures standardized in the most current editions of M02, M07, and M11. Users should replace the tables published earlier with these new tables. (Changes in the tables since the previous edition appear in boldface type.) Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing. 26th ed. CLSI supplement M100S (ISBN 1-56238-923-8 [Print]; ISBN 1-56238924-6 [Electronic]). Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2016. The data in the interpretive tables in this supplement are valid only if the methodologies in M02-A12—Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Twelfth Edition; M07-A10—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Tenth Edition; and M11-A8—Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard— Eighth Edition are followed.
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TL;DR: This research presents a novel, scalable and scalable approach that allows for real-time assessment of the severity of the infection and its impact on patients’ health.
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TL;DR: In this paper, the NHSN criteria for all healthcare-associated infections (HAIs) are presented, including those for the "Big Four" (surgical site infection [SSI], pneumonia [PNEU], bloodstream infection [BSI] and urinary tract infection [UTI]).
4,927 citations
Journal Article•
TL;DR: In this article, the NHSN criteria for all healthcare-associated infections (HAIs) are presented, including those for the "Big Four" (surgical site infection [SSI], pneumonia [PNEU], bloodstream infection [BSI] and urinary tract infection [UTI]).
4,849 citations