Identification of NDM-1-producing Enterobacteriaceae in Norway

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: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 63%

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

Wiskirchen

Nordmann

Crandon

et al. 2014

mentioning

confidence: 71%

“…Previous reports have described the concurrence of bla NDM-1 together with additional ESBLs, mainly CTX-M-15 (1,(16)(17)(18)(19), but this is the first time that they seem to be located on the same plasmid. Then again, this is also the first time that a bla NDM-1 gene has been found on such a large plasmid (NDM enzyme genes are typically found in plasmids ranging from 50 to 200 kb) (1,5,(16)(17)(18) and could reflect the formation of a cointegrate from two or more smaller plasmids carrying individual ␤-lactamase genes, such as bla CTX-M-15 or bla NDM-1 .…”

mentioning

confidence: 71%

First Description of an Escherichia coli Strain Producing NDM-1 Carbapenemase in Spain

Solé

Pitart

Roca

et al. 2011

A carbapenem-resistant Escherichia coli strain (DVR22) was recovered from a stool specimen from a patient with traveler's diarrhea who had traveled to India. Molecular screening led to the first identification of NDM-1 in Spain. The bla NDM-1 gene was located in a conjugative plasmid of ca. 300 kb that also contained the bla CTX-M-15 , bla TEM-1 , ⌬bla DHA-1 , and armA genes. In addition, bla NDM-1 was preceded by an ISAba125 insertion element only found in Acinetobacter spp.The emergence of carbapenem resistance among Enterobacteriaceae is a major cause of concern since carbapenems currently represent the treatment of choice for severe infections caused by multidrug-resistant strains producing extended-spectrum ␤-lactamases (ESBLs) (8).In addition to commonly known carbapenem-hydrolyzing enzymes in Enterobacteriaceae (IMP, VIM, KPC, and OXA-48), a novel class B metallo-␤-lactamase (NDM-1) has recently been described. This enzyme, first identified in Klebsiella pneumoniae and Escherichia coli clinical isolates recovered in Sweden from a traveler returning from India, confers resistance to all ␤-lactams except aztreonam (22). Since then, several reports have identified bla NDM genes worldwide that have typically been associated with multidrug-resistant strains (1,5,12,(16)(17)(18)23).A 40-year-old Spanish Caucasian male reported intermittent abdominal discomfort, fever, and bloody diarrhea about 5 days before returning from India. He visited a local dispensary in India where treatment with ofloxacin and ornidazole tablets (twice a day) was prescribed for 5 days. The patient reported to the Hospital Clinic of Barcelona 1 day after his return, still complaining of bloody diarrhea, although with fewer unformed stools. He was afebrile, without any sign of dehydration, and the rest of the physical examination was normal. The diarrhea resolved spontaneously over the next 9 days.A carbapenem-resistant E. coli (DVR22) strain was recovered from the stool samples of the patient, and after isolation and identification, antimicrobial susceptibility profiling analysis performed with both BD Phoenix (Becton Dickinson, Franklin Lakes, NJ) and Etest strips (AB bioMérieux, Solna, Sweden) indicated that strain DVR22 was resistant to all the antibiotics tested except tigecycline (MIC of 0.75 g/ml), fosfomycin (MIC of 32 g/ml), and colistin (MIC of 0.5 g/ml) (Table 1), presenting MICs of 8 g/ml and 16 g/ml for imipenem and meropenem, respectively, 24 g/ml for ertapenem, and 6 g/ml for doripenem (CLSI breakpoints from broth microdilution tests were used to classify the MICs obtained by Etest [7]). Screening for carbapenemase/MBL production yielded positive results when using either the cloverleaf test (modified Hodge test) or imipenem-EDTA Etest strips. PCR screening for ␤-lactamase genes followed by DNA sequencing using specific primers (NDM-1 F, 5Ј-CCAATATTATGCACC CGGTCG-3Ј, and NDM-1 R 5Ј-ATGCGGGCCGTATGAGT GATTG-3Ј) (2, 14, 21) identified the presence of bla NDM-1 , bla CTX-M-15 , bla TEM-1 , and a partial sequence of the bla DHA-...

“…NDM-1 was originally found in India (8) and has spread worldwide to countries including Australia (23), Belgium (2), Canada (16), China (6), Germany (22), Italy (17), Japan (37), Norway (26), Spain (27), Switzerland (24), the United Kingdom (15), and the United States (5). NDM-1 has a fold common to the other MBLs and shows the ability to hydrolyze most ␤-lactams (3).…”

mentioning

confidence: 99%

A Potential Substrate Binding Conformation of β-Lactams and Insight into the Broad Spectrum of NDM-1 Activity

Yuan

2012

New Delhi metallo-␤-lactamase 1 (NDM-1) is a key enzyme that the pathogen Klebsiella pneumonia uses to hydrolyze almost all ␤-lactam antibiotics. It is currently unclear why NDM-1 has a broad spectrum of activity. Docking of the representatives of the ␤-lactam families into the active site of NDM-1 is reported here. All the ␤-lactams naturally fit the NDM-1 pocket, implying that NDM-1 can accommodate the substrates without dramatic conformation changes. The docking reveals two major binding modes of the ␤-lactams, which we tentatively name the S (substrate) and I (inhibitor) conformers. In the S conformers of all the ␤-lactams, the amide oxygen and the carboxylic group conservatively interact with two zinc ions, while the substitutions on the fused rings show dramatic differences in their conformations and positions. Since the bridging hydroxide ion/water in the S conformer is at the position for the nucleophilic attack, the S conformation may simulate the true binding of a substrate to NDM-1. The I conformer either blocks or displaces the bridging hydroxide ion/water, such as in the case of aztreonam, and is thus inhibitory. The docking also suggests that substitutions on the ␤-lactam ring are required for ␤-lactams to bind in the S conformation, and therefore, small ␤-lactams such as clavulanic acid would be inhibitors of NDM-1. Finally, our docking shows that moxalactam uses its tyrosyl-carboxylic group to compete with the S conformer and would thus be a poor substrate of NDM-1.