MgrB Inactivation Is a Common Mechanism of Colistin Resistance in KPC-Producing Klebsiella pneumoniae of Clinical Origin

Cannatelli, Antonio; Giani, Tommaso; D’Andrea, Marco Maria; Pilato, Vincenzo Di; Arena, Fabio; Conte, Viola; Tryfinopoulou, Kyriaki; Vatopoulos, Alkiviadis; Rossolini, Gian María

doi:10.1128/aac.03110-14

Cited by 315 publications

(324 citation statements)

References 20 publications

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“…1). As in previous studies (18,20,21,32,33), the mgrB region of these 8 strains was interrupted by IS10R and IS5-like elements. To demonstrate an effect on mgrB expression after IS element insertion in the promoter, the expression of mgrB mRNA was quantified by RT-qPCR, and the expression of mgrB was significantly reduced in those 5 strains (Table 1).…”

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confidence: 52%

“…Modification of Ara4N is achieved by the pmrHFIJKLM operon (13), and the two-component systems PhoPQ and PmrAB with connector PmrD are involved in the regulation of the pmrHFIJKLM operon (16,17). Moreover, MgrB is a negative regulator that influences PhoQ-PhoP phosphorylation (18)(19)(20). In this study, we analyzed capsular type and multilocus sequence type (MLST) distribution of colistin-resistant K. pneumoniae in Taiwan and attempted to define the mechanisms of resistance to colistin.…”

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confidence: 99%

“…Recent studies have demonstrated that the insertion sequence (IS) into mgrB disinhibits PhoQ phosphorylation, resulting in increased expression of pmrHFIJKLM mRNA and leading to reduced susceptibility to colistin in K. pneumoniae (18,19). Therefore, we used PCR to examine whether the mgrB gene in our colistin-resistant strains was interrupted by IS elements.…”

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confidence: 99%

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Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Cheng

Lin

Pan

et al. 2015

Antimicrob Agents Chemother

143

103

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Colistin is one of the antibiotics of last resort for the treatment of carbapenem-resistant Klebsiella pneumoniae infection. This study showed that capsular type K64 (50%) and ST11 (53.9%) are the prevalent capsular and sequence types in the colistin-resistant strains in Taiwan. The interruption of transcripts (38.5%) and amino acid mutation (15.4%) in mgrB are the major mechanisms contributing to colistin resistance. In addition, novel single amino acid changes in MgrB (Stop48Tyr) and PhoQ (Leu26Pro) were observed to contribute to colistin resistance. Klebsiella pneumoniae is an important human pathogen that causes several hospital-acquired and community-acquired diseases (1, 2). Although carbapenem is generally used to treat infections caused by extended-spectrum ␤-lactamase (ESBL)-carrying K. pneumoniae (3), K. pneumoniae strains carrying carbapenemases or ESBL strains combined with the loss of porins can result in carbapenem-resistant K. pneumoniae (CRKP) (4-6). To eradicate CRKP, colistin and tigecycline are typically used to treat patients (7). Unfortunately, resistance to colistin and tigecycline has also been reported, with a 17% resistance rate of CRKP to colistin in Taiwan (8). A surveillance study also revealed that 43% of carbapenemase-producing K. pneumoniae isolates were resistant to colistin in Italy (9).Colistin, also called polymyxin E, is a cationic antimicrobial peptide that targets bacterial lipopolysaccharide (LPS), causing cell membrane leakage (10). Previous studies have demonstrated that the modification of lipid A with 4-amino-4-deoxy-L-arabinose (Ara4N) and phosphoethanolamine neutralizes the negative charge and reduces susceptibility to colistin in Enterobacteriaceae (11)(12)(13)(14)(15). Modification of Ara4N is achieved by the pmrHFIJKLM operon (13), and the two-component systems PhoPQ and PmrAB with connector PmrD are involved in the regulation of the pmrHFIJKLM operon (16,17). Moreover, MgrB is a negative regulator that influences PhoQ-PhoP phosphorylation (18)(19)(20). In this study, we analyzed capsular type and multilocus sequence type (MLST) distribution of colistin-resistant K. pneumoniae in Taiwan and attempted to define the mechanisms of resistance to colistin.Colistin-resistant K. pneumoniae strains were retrospectively collected from patients in the Taipei Veterans General Hospital (VGH) from February to August 2013. All 26 strains were clinical isolates and were isolated from different patients. Among the 26 clinical isolates, the Col14 and Col40 strains were CRKP, and only the Col14 strain harbored the carbapenemase KPC. Colistin was used to treat infections in 16 of the 26 patients prior to the isolation of strains, and the other patients did not receive colistin in the VGH (Table 1). However, we could not trace the colistin usage of these patients in other hospitals. Previous studies also showed that some colistin-resistant strains are isolated from healthy individuals (21). Resistance to colistin in strains that were not exposed to colistin might be due to spontaneous...

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confidence: 52%

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confidence: 99%

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Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Cheng

Lin

Pan

et al. 2015

Antimicrob Agents Chemother

143

103

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“…Other alterations, such as insertions or deletions of small nucleotide sequences in the mgrB gene, or even some complete deletions of the mgrB locus, have been reported (120,130,131). Insertional inactivation caused by diverse insertion sequences (IS), belonging to several families and inserted at different locations within the mgrB gene, is often responsible for acquired resistance to colistin in K. pneumoniae (105,117,120,(130)(131)(132) and Klebsiella oxytoca (133,134).…”

Section: Regulators Of the Pmrab And Phopq Two-component Systemsmentioning

confidence: 99%

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

2017

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SUMMARY Polymyxins are well-established antibiotics that have recently regained significant interest as a consequence of the increasing incidence of infections due to multidrug-resistant Gram-negative bacteria. Colistin and polymyxin B are being seriously reconsidered as last-resort antibiotics in many areas where multidrug resistance is observed in clinical medicine. In parallel, the heavy use of polymyxins in veterinary medicine is currently being reconsidered due to increased reports of polymyxin-resistant bacteria. Susceptibility testing is challenging with polymyxins, and currently available techniques are presented here. Genotypic and phenotypic methods that provide relevant information for diagnostic laboratories are presented. This review also presents recent works in relation to recently identified mechanisms of polymyxin resistance, including chromosomally encoded resistance traits as well as the recently identified plasmid-encoded polymyxin resistance determinant MCR-1. Epidemiological features summarizing the current knowledge in that field are presented.

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“…Due to this resistance spreading rapidly around the world, there has been a need for new therapeutic agents. Polymyxin and colistin were out of use since the early 1970s due to its side effects of neurotoxicity and nephrotoxicity, but colistin has become a preferred antimicrobial agent with increase of infections with resistant Enterobacteriaceae [10][11][12]. However, excessive use of colistin has led to resistance to this drug [13].…”

Section: Introductionmentioning

confidence: 99%

Colistin Resistance in Carbapenem-Resistant Klebsiella Pneumoniae Strains

Bhaskar

Mulki

Joshi

et al. 2017

Asian J Pharm Clin Res

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Objective: There is an increasing use of colistin consequent to increase in the infections caused by carbapenem-resistant Klebsiella pneumoniae. The present study was conducted to determine the minimum inhibitory concentration (MIC) of colistin and the resistance pattern of colistin in carbapenem-resistant K. pneumoniae (CRKP) strains in our intensive care unit (ICU).Methods: Antibiotic susceptibility testing for other antimicrobial agents was done by Kirby-Bauer disk diffusion method. MIC of colistin was determined by agar dilution method. The results of antibiotic susceptibility testing were interpreted as per Clinical Laboratory Standard Institute guidelines 2016 and MIC of colistin were interpreted as per European Committee on Antimicrobial susceptibility testing. The carbapenem resistance was phenotypically detected by modified hodge test and imipenem/imipenem ethylenediaminetetraacetic acid disk method.Results: Out of 518 K. pneumoniae, 329 were resistant to carbapenems, and 91 isolates showed resistance to colistin. The MIC of colistin ranged between 4 and >512 ug/ml and MIC 90 was 16 ug/L and MIC 50 was 4 ug/ml. A majority of the colistin-resistant isolates were found in multidisciplinary ICU (85/91). Conclusion:The emergence of colistin-resistant strains is a major problem due to limited treatment options for infections caused by CRKP carbapenemase producing K. pneumoniae. Colistin should not be used alone, combination therapy should be preferred.

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MgrB Inactivation Is a Common Mechanism of Colistin Resistance in KPC-Producing Klebsiella pneumoniae of Clinical Origin

Cited by 315 publications

References 20 publications

Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

Colistin Resistance in Carbapenem-Resistant Klebsiella Pneumoniae Strains

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