NDM-1 polymicrobial infections including Vibrio cholerae

e Doripenem and ertapenem have demonstrated efficacy against several NDM-1-producing isolates in vivo, despite having high MICs. In this study, we sought to further characterize the efficacy profiles of humanized regimens of standard (500 mg given every 8 h) and high-dose, prolonged infusion of doripenem (2 g given every 8 h, 4-h infusion) and 1 g of ertapenem given intravenously every 24 h and the comparator regimens of ceftazidime at 2 g given every 8 h (2-h infusion), levofloxacin at 500 mg every 24 h, and aztreonam at 2 g every 6 h (1-h infusion) against a wider range of isolates in a murine thigh infection model. An isogenic wild-type strain and NDM-1-producing Klebsiella pneumoniae and eight clinical NDM-1-producing members of the family Enterobacteriaceae were tested in immunocompetent-and neutropenic-mouse models. The wild-type strain was susceptible to all of the agents, while the isogenic NDM-1-producing strain was resistant to ceftazidime, doripenem, and ertapenem. Clinical NDM-1-producing strains were resistant to nearly all five of the agents (two were susceptible to levofloxacin). In immunocompetent mice, all of the agents produced >1-log 10 CFU reductions of the isogenic wild-type and NDM-1-producing strains after 24 h. Minimal efficacy of ceftazidime, aztreonam, and levofloxacin against the clinical NDM-1-producing strains was observed. However, despite in vitro resistance, >1-log 10 CFU reductions of six of eight clinical strains were achieved with high-dose, prolonged infusion of doripenem and ertapenem. Slight enhancements of doripenem activity over the standard doses were obtained with high-dose, prolonged infusion for three of the four isolates tested. Similar efficacy observations were noted in neutropenic mice. These data suggest that carbapenems are a viable treatment option for infections caused by NDM-1-producing Enterobacteriaceae. New Delhi metallo-␤-lactamase (NDM-1) is a novel carbapenemase that was first identified in a Klebsiella pneumoniae isolate in India in 2008 (1). Since then, it has disseminated at a high rate among Enterobacteriaceae isolates both within the Indian subcontinent and worldwide (2-4). The treatment options for infections caused by NDM-1-producing isolates are extremely limited, as these enzymes are known to hydrolyze penicillins, cephalosporins, and carbapenems while typically retaining susceptibility to only colistin and tigecycline (2), neither of which has been shown to be a dependable option on the basis of in vitro time-kill data and case reports (5-8). Aztreonam is not readily inactivated by metallo-␤-lactamases, including NDM-1, and may represent another potential option for therapy (1, 9). However, NDM-1-producing strains often coproduce other ␤-lactamases, such as CTX-M-and CMY-type enzymes, that possess the ability to hydrolyze aztreonam, further limiting the utility of all ␤-lactam antibiotics (1). Furthermore, in vivo efficacy data evaluating potential treatment options for NDM-1-producing isolates are sparse and clinical experience in treating inf...

Section: Discussionmentioning

confidence: 99%

In VivoEfficacy of Human Simulated Regimens of Carbapenems and Comparator Agents against NDM-1-Producing Enterobacteriaceae

Wiskirchen

Nordmann

Crandon

et al. 2014

“…Carbapenemase-mediated resistance in Vibrio spp. has been reported only in India, where clinical and environmental V. cholerae isolates carrying the NDM-1 metalloenzyme were described in several studies (4)(5)(6). We describe here an avian strain of V. cholerae that was isolated in southern France and that coharbors the bla VIM-1 and bla VIM-4 carbapenemase genes.…”

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confidence: 90%

“…This suggests that optimal transfer conditions would mainly occur in the environment rather than in the gut. The presence of metalloenzymes on different genetic locations (IncA/C and nontypeable plasmids [4,6], chromosome [5,6]) in V. cholerae is of concern because it indicates that they can spread easily on various mobile genetic elements.…”

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confidence: 99%

Non-O1/Non-O139 Vibrio cholerae Avian Isolate from France Cocarrying the bla _VIM-1 and bla _VIM-4 Genes

Aberkane

Compain

Barraud

et al. 2015

We describe here a non-O1/non-O139 Vibrio cholerae isolate producing both VIM-1 and VIM-4 carbapenemases. It was isolated from a yellow-legged gull in southern France. The bla VIM genes were part of a class 1 integron structure located in an IncA/C plasmid. This study emphasizes the presence of carbapenemase genes in wildlife microbiota. Multidrug-resistant Vibrio cholerae strains have been increasingly reported worldwide (1). However, data on resistance to third-generation cephalosporins, mostly via genes encoding extended-spectrum ␤-lactamase (ESBL) (2, 3) or cephalosporinase determinants (4) are limited. Carbapenemase-mediated resistance in Vibrio spp. has been reported only in India, where clinical and environmental V. cholerae isolates carrying the NDM-1 metalloenzyme were described in several studies (4-6). We describe here an avian strain of V. cholerae that was isolated in southern France and that coharbors the bla VIM-1 and bla VIM-4 carbapenemase genes.In April 2013, 93 cloacal swab samples from juvenile unfledged yellow-legged gulls (Larus michahellis) breeding on the island of Carteau, Port-Saint-Louis, France, were screened for bacteria resistant to broad-spectrum ␤-lactam antibiotics. Briefly, swab samples were inoculated in Trypticase soy broth (Thermo Fisher Scientific) and grown at 37°C for 24 h. Samples were then subcultured in ESBL agar plates (bioMérieux, Marcy l'Etoile, France) and were examined after 24 and 48 h of incubation. Enterobacteriaceae resistant to multiple drugs via different resistance mechanisms (e.g., third-generation cephalosporin-resistant Escherichia coli and Proteus mirabilis harboring plasmid-mediated cephalosporinase genes or ESBL genes) were recovered (7; our unpublished data). In addition, a V. cholerae strain showing resistance to third-generation cephalosporins was detected. No other multidrug-resistant V. cholerae strain was recovered. Species identification was performed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (Bruker Daltonics, Bremen, Germany). Moreover, PCR analysis of the rfb gene cluster (8), the cholera toxin ctxA gene (9), and the colonization factor tcpA gene (9) revealed a nontoxigenic, non-O1/non-O139 isolate.Susceptibility testing was performed using the disk diffusion method on Mueller-Hinton agar and was interpreted according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints (version 5.0) (http://www.eucast .org/clinical_breakpoints/) (10). The strain was intermediate or resistant to most ␤-lactam antibiotics, except aztreonam. The MICs for amoxicillin, cefotaxime, ceftazidime, imipenem, ertapenem, doripenem, and meropenem were determined in the parental strain and the transconjugant with the Etest method (bioMérieux, Marcy l'Etoile, France) ( Table 1). Metallo-␤-lactamase production was observed by using the carbapenemase/metallo-␤-lactamase confirmative identification pack (Rosco Diagnostica NeoSensitabs, Eurobio, Courtaboeuf, France). Specifically, redu...

“…Though still relatively uncommon, the carbapenemase encoded by bla NDM has quickly established itself as one of the most important (4). First described in 2009 (5), the gene has since been identified in nearly every continent and has been detected in species as diverse as Acinetobacter baumannii and Vibrio cholerae (6)(7)(8). Furthermore, the gene has been associated with a diverse range of plasmids that often harbor multiple antibiotic resistance genes (9).…”

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confidence: 99%

Bacterial Peritonitis Due to Acinetobacter baumannii Sequence Type 25 with Plasmid-Borne New Delhi Metallo-β-Lactamase in Honduras

Waterman

McGann

Snesrud

et al. 2013

A carbapenem-resistant Acinetobacter baumannii strain was isolated from the peritoneal fluid of a patient with complicated intra-abdominal infection and evaluated at the Multidrug-resistant Organism Repository and Surveillance Network by wholegenome sequencing and real-time PCR. The isolate was sequence type 25 and susceptible to colistin and minocycline, with low MICs of tigecycline. bla NDM-1 was located on a plasmid with >99% homology to pNDM-BJ02. The isolate carried numerous other antibiotic resistance genes, including the 16S methylase gene, armA.