Cluster-dependent colistin hetero-resistance in<i>Enterobacter cloacae</i>complex

Guérin, François; Isnard, Christophe; Sinel, Clara; Morand, P; Dhalluin, Anne; Cattoir, Vincent; Giard, Jean‐Christophe

doi:10.1093/jac/dkw260

Cited by 78 publications

(84 citation statements)

References 21 publications

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“…Performing a population analysis may not be practical for many laboratories. Heteroresistance to colistin among strains of the Enterobacter cloacae complex is hsp60 genetic cluster dependent (11). There are 12 clusters (C-I to C-XII) of which the species name could be assigned confidently to specific clusters.…”

Section: Discussionmentioning

confidence: 99%

Colistin and Polymyxin B Susceptibility Testing for Carbapenem-Resistant and mcr -Positive Enterobacteriaceae: Comparison of Sensititre, MicroScan, Vitek 2, and Etest with Broth Microdilution

et al. 2017

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Colistin and polymyxin B remain part of the last line of antibiotics for multidrug-resistant Gram-negative bacteria, such as carbapenem-resistant Enterobacteriaceae. Current joint EUCAST-CLSI recommendations are for broth microdilution (BMD) to be performed for MIC testing of colistin. Commercial susceptibility testing methods were evaluated and compared against the reference BMD, using a susceptibility breakpoint of Յ2 mg/liter for both colistin and polymyxin B. Seventy-six Enterobacteriaceae were included, of which 21 were mcr-1 positive (18 Escherichia coli isolates, 2 Klebsiella pneumoniae isolates, and 1 Enterobacter aerogenes isolate). Rates of essential agreement (EA) of colistin test results between BMD and Vitek 2, Sensititre, and Etest were 93.4%, 89.5%, and 75.0%, respectively. Rates of EA of polymyxin B test results between BMD and Vitek 2, Sensititre, and Etest were 96.1%, 96.1%, and 48.7%, respectively. A positive MIC correlation with a categorical agreement of Ͼ90% was achieved for Sensititre (colistin Spearman's ϭ 0.863, and polymyxin B Spearman's ϭ 0.877) and Vitek 2 (polymyxin B [only] Spearman's ϭ 0.8917). Although a positive MIC correlation (Spearman's ϭ 0.873) with the reference method was achieved for colistin testing with Vitek 2, categorical agreement was Ͻ90%, with very major error rates of 36%. Correlation with the Etest MIC was lower, with very major error rates of 12% (colistin) and 26.1% (polymyxin B). MicroScan (colistin) categorical agreement was 88.2%, with a very major error rate of 4%. Colistin MICs for 15 of the 21 mcr-1-positive isolates were Ͼ2 mg/liter, and polymyxin MICs for 17 of them were Ͼ2 mg/liter by broth microdilution. The use of a lower breakpoint of Յ1 mg/liter further improves detection of mcr-1 for all testing methods. However, further data on the correlation between MICs and clinical outcome are required to determine the most suitable breakpoint to guide clinical management.KEYWORDS colistin, polymyxin B, susceptibility testing, mcr-1 M ultidrug-resistant organisms (MDROs) represent a progressive burden on health care systems globally. Carbapenem-resistant Enterobacteriaceae (CRE) are now reported worldwide. CRE infections are difficult to treat, and there are limited options available. The polymyxins (colistin and polymyxin B) are antibiotics which are used for treating infections with CRE. Polymyxins initially fell out of favor among clinicians due to concerns over high rates of nephrotoxicity and neurotoxicity (1). In recent years, the use of polymyxins has been on the rise, with increasing rates of CRE infection.

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Section: Discussionmentioning

confidence: 99%

Colistin and Polymyxin B Susceptibility Testing for Carbapenem-Resistant and mcr -Positive Enterobacteriaceae: Comparison of Sensititre, MicroScan, Vitek 2, and Etest with Broth Microdilution

et al. 2017

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“…Moreover, colistin heteroresistance in E. cloacae 146 was induced by innate immune defenses within a murine infection model to lead to treatment 147 failure (40). Transcriptional analysis of susceptible and resistant populations suggested that pEtN 148 and L-Ara4N lipid A modifications contribute to heteroresistance (40) and PhoPQ contributed to 149 regulation (35,40), as described in other Enterobacteriaceae (5). However, it was not established 150 that the lipid A modifications actually occur, nor has PhoPQ-dependent, PmrAB-independent 151 regulation of colistin heteroresistance been fully described in E. cloacae or other ECC isolates.…”

Section: Introductionmentioning

confidence: 93%

“…infections have increasingly emerged in nosocomial settings and are problematic because they 135 encode multidrug resistance (MDR) mechanisms, which limits treatment options (33, [35][36][37]. 136…”

Section: Introductionmentioning

confidence: 99%

“…Alternative last-line therapeutics used to treat MDR Gram-negative infections include the 137 CAMP, colistin (polymyxin E), which binds the lipid A portion of LPS to perturb the outer 138 membrane and lyse the bacterial cell. Despite the success of colistin treatment as a last-line 139 therapeutic to combat Gram-negative infections (38, 39), many ECC clusters demonstrated 140 heteroresistance, where a subset of the clonal population is colistin resistant (35,(40)(41)(42). We do 141 not fully understand the underlying molecular mechanism(s) that regulate colistin 142 heteroresistance in ECC; further characterization will advance our understanding of 143 antimicrobial resistance and could help improve treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

“…Previous reports showed that colistin heteroresistance naturally occurs within clonal ECC 145 clusters, including E. cloacae (cluster XI) (35). Moreover, colistin heteroresistance in E. cloacae 146 was induced by innate immune defenses within a murine infection model to lead to treatment 147 failure (40).…”

Section: Introductionmentioning

confidence: 99%

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Colistin heteroresistance in Enterobacter cloacae is mediated by PmrAB-independent 4-amino-4-deoxy-L-arabinose addition to lipid A

Kang

Klein

Kazi

et al. 2019

Preprint

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word count: 221 26 Text word count (excluding references, table footnotes, and figure legends): 4,993 Abstract 43The Enterobacter cloacae complex (ECC) consists of closely-related, but genetically distinct 44 bacteria commonly associated with the human microbiota. ECC have been increasingly isolated 45 from healthcare-associated infections, demonstrating that these Enterobacteriaceae are emerging 46 nosocomial pathogens. ECC strains can rapidly acquire multidrug resistance to conventional 47 antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives 48 because they target the highly conserved lipid A component of the Gram-negative outer 49 membrane to lyse the bacterial cell. Many Gram-negative Enterobacteriaceae fortify their outer 50 membrane with cationic amine-containing moieties to protect from CAMP-inflicted lysis. The 51PmrAB two-component system (TCS) transcriptionally activates 4-amino-4-deoxy-L-arabinose 52 (L-Ara4N) biosynthesis to result in amine moiety addition to lipid A in many Enterobacteriaceae 53 such as E. coli and Salmonella. In contrast, PmrAB in E. cloacae is dispensable for CAMP 54 resistance. Instead, fitness against CAMPs presents as heteroresistance, or a subpopulation of 55 cells that exhibit clinically significant increases in resistance levels compared to the majority 56 population. We demonstrate that E. cloacae lipid A is modified with L-Ara4N to induce CAMP 57 heteroresistance and that the regulatory mechanism is independent of the PmrAB Ecl TCS. We 58show that the response regulator, PhoP Ecl , directly binds to the arnB Ecl promoter to induce 59 expression of L-Ara4N biosynthesis and PmrAB-independent addition to the lipid A 60 disaccharolipid. Therefore, we have identified a mechanism of ECC colistin heteroresistance that 61 directly involves the PhoPQ system. 62 63 64 65 Importance 66 Members of the Enterobacter cloacae complex (ECC) are Gram-negative nosocomial pathogens 67 that have emerged within healthcare facilities around the world. ECC infections are associated 68 with immunocompromised patients and infections are often life threatening. The cationic 69 antimicrobial peptide, colistin (polymyxin E), is a last-line treatment option to combat Gram-70 negative multidrug resistant infections. However, many ECC intrinsically encode a colistin 71 heteroresistance mechanism. Our analysis to characterize colistin heteroresistance in E. cloacae 72 revealed that 4-amino-4-deoxy-L-arabinose is conjugated to the lipid A disaccharolipid to protect 73 from colistin-mediated lysis. Additionally, this mechanism is directly regulated by the PhoPQ Ecl 74 two-component system. Elucidation of outer membrane antimicrobial resistance modifications 75 and their regulatory pathways in E. cloacae isolates will advance our understanding of CAMP 76 heteroresistance. 77 78 79 80 81 82 83 84 85 86 87 88 89Gram-negative bacteria assemble a highly conserved outer membrane (OM) barrier, which 90 restricts diffusion of toxins such as antibiotics into the cell. Glyceroph...

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Colistin Resistance in Aquaculture Environment: An Emerging Challenge

Dwivedi

Awasthi

2023

Macromolecular Symposia

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The emergence of colistin resistance is one of the most serious future issues since it is a last‐resort antibiotic used to treat infections caused by multidrug‐resistant (MDR) gram‐negative bacteria, particularly those resistant to carbapenems. The aquatic environment acts as a reservoir for the emergence and spread of colistin resistant pathogens. The emergence and transmission of a plasmid mediated mcr gene is one of the most important mechanism of colistin resistance in gram negative bacteria. Several mcr variants have been identified in zoonotic pathogens of aquatic origin that may easily transmit this gene to human pathogens. Currently, very few studies have been conducted to test colistin susceptibility in aquaculture associated bacteria. This may be attributed to a limited technical resource for screening colistin‐resistant microorganisms. As a result, to reduce the emergence and spread of colistin resistance in human and animal health, as well as in the environment, the One Health strategy and laboratory methodologies must be expanded.

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Cluster-dependent colistin hetero-resistance inEnterobacter cloacaecomplex

Cited by 78 publications

References 21 publications

Colistin and Polymyxin B Susceptibility Testing for Carbapenem-Resistant and mcr -Positive Enterobacteriaceae: Comparison of Sensititre, MicroScan, Vitek 2, and Etest with Broth Microdilution

Colistin and Polymyxin B Susceptibility Testing for Carbapenem-Resistant and mcr -Positive Enterobacteriaceae: Comparison of Sensititre, MicroScan, Vitek 2, and Etest with Broth Microdilution

Colistin heteroresistance in Enterobacter cloacae is mediated by PmrAB-independent 4-amino-4-deoxy-L-arabinose addition to lipid A

Colistin Resistance in Aquaculture Environment: An Emerging Challenge

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