Impact of the New Delhi metallo-beta-lactamase on beta-lactam antibiotics

Abstract

Since the first New Delhi metallo-beta-lactamase (NDM) report in 2009, NDM has spread globally causing various types of infections. NDM-positive organisms produce in vitro resistance phenotypes to carbapenems and many other antimicrobials. It is thus surprising that the literature examining clinical experiences with NDM does not report corresponding poor clinical outcomes. There are many instances where good clinical outcomes are described, despite a mismatch between administered antimicrobials and resistant in vitro susceptibilities. Available in vitro data for either monotherapy or combination therapy does not provide an explanation for these observations. However, animal studies do begin to shed more light on this phenomenon. They imply that the in vivo expression of NDM may not confer clinical resistance to all cephalosporin and carbapenem antibiotics as predicted by in vitro testing but other resistance mechanisms need to be present to generate a resistant phenotype. As such, previously abandoned therapies, particularly carbapenems and beta-lactamase inhibitor combinations, may retain utility against infections caused by NDM producers.

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

“…Recently, Ghazi and colleagues (124) observed that despite a high MIC indicative of meropenem resistance due to Verona integrin-encoded metallo-betalactamase (VIM) in Enterobacteriaceae, treatment with this antibiotic resulted in unexpected bactericidal activity when used in a humanized high-dose regimen in a murine infection model. Additional examples with gram-negative bacteria harboring the New Delhi metallo-beta-lactamase (NDM) have also been published and supported by a review of the clinical literature surrounding successful treatment with carbapenems for NDM infections (125).…”

The rapid spread of carbapenem-resistant Enterobacteriaceae

“…NDM is endemic to parts of Asia and is responsible for sporadic outbreaks around the globe [Zmarlicka 2015]. As of August 2016 when we accessed the NCBI database, 16 variants of NDM were identified on a variety of plasmid types, corresponding to the high diversity of Enterobacteriaceae species shown to express it [NCBI 2016, Zmarlicka 2015].…”

“…As of August 2016 when we accessed the NCBI database, 16 variants of NDM were identified on a variety of plasmid types, corresponding to the high diversity of Enterobacteriaceae species shown to express it [NCBI 2016, Zmarlicka 2015]. A comprehensive study from 2012 to 2014 of 38,266 Enterobacteriaceae isolates collected from 40 countries spanning every inhabited continent found that global incidence of MBL presence is low (0.5%, 163/38,266), but dissemination is high (85%, 34/40 countries).…”

In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection

“…Meropenem was also more efficacious against UNT184-1 despite having the same MIC against both strains. A similar observation was made of increased in vivo susceptibility compared with in vitro activity against NDM-1-expressing isolates (21). A reason behind these differences may be reduced expression of activity of the enzyme in vivo due to metal ion availability, thus accounting for greater observed efficacy of certain treatments.…”