Worldwide dissemination of the NDM-type carbapenemases in Gram-negative bacteria

Abstract

The emergence of one of the most recently described carbapenemases, namely, the New Delhi metallo-lactamase (NDM-1), constitutes a critical and growingly important medical issue. This resistance trait compromises the efficacy of almost all lactams (except aztreonam), including the last resort carbapenems. Therapeutical options may remain limited mostly to colistin, tigecycline, and fosfomycin. The main known reservoir of NDM producers is the Indian subcontinent whereas a secondary reservoir seems to have established the Balkans regions and the Middle East. Although the spread of bla NDM-like genes (several variants) is derived mostly by conjugative plasmids in Enterobacteriaceae, this carbapenemase has also been identified in P. aeruginosa and Acinetobacter spp. Acinetobacter sp. may play a pivotal role for spreading bla NDM genes for its natural reservoir to Enterobacteriaceae. Rapid diagnostic techniques (Carba NP test) and screening of carriers are the cornerstone to try to contain this outbreak which threatens the efficacy of the modern medicine.

Figure 1

Antibiogram of a NDM-1-producing K. pneumoniae isolate. The bla _NDM-1 gene was located onto a IncHIIB plasmid of ca. ~200 kb in that strain that also harbored two additional β-lactamase genes (bla _CTX-M-15, bla _SHV-12, bla _OXA-1) and an aminoglycoside methylase (armA) responsible for high-level resistance to all aminoglycosides. PTZ, piperacillin + tazobactam; PIP, piperacillin; TIC, ticarcillin; AMX, amoxicillin; ETP, ertapenem; TCC, ticarcillin + clavulanic acid; CAZ, ceftazidime; CF, cefalotin; FOX, cefoxitin; IMP, imipenem; AMC, amoxicillin + clavulanic acid; CTX, cefotaxime; CMX, cefuroxime; MEM, meropenem; ATM, aztreonam; FEP, cefepime; FT, nitrofurantoin; NOR, norfloxacin; OFX, ofloxacin; CIP, ciprofloxacin; FOS, fosfomycin; TGC, tigecycline; TE, tetracycline; CS, colistin; SSS, sulfonamide; SXT, sulfamethoxazole + trimethoprim; C, chloramphenicol; NET, netilmicin; GM, gentamicin; AN, amikacin; TM, tobramycin; RA, rifampicin.

Figure 2

Geographical distribution of NDM producers.

Figure 3

Schematic representation of bla _NDM-associated genetic structures identified among Gram-negative clinical isolates. (a) Structure found in A. baumannii, where the bla _NDM gene is part of the composite transposon Tn125. (b) Structures found in Enterobacteriaceae and P. aeruginosa where ISAba125 is presented as full or truncated element with ble _MBL gene (bleomycin resistance encoding gene) also being present as full or truncated gene. Genes and their corresponding transcription orientations are represented by horizontal arrows. oriIS of ISCR21 is indicated by a circle. The bla _NDM promoter is indicated (P). IS, insertion sequence; gene names are abbreviated according to their corresponding proteins: ble _MBL, bleomycin resistance gene; Δiso for truncated phosphoribosylanthranilate isomerase; Δpac for truncated phospholipid acetyltransferase.

Figure 4

Alignment of the amino acid sequences of the eight reported NDM variants. Conserved residues of the active site of metallo-β-lactamases are highlighted in gray. The bolded leucine in position 154 has been described to be responsible to an increased carbapenem hydrolysis.

Figure 5

Principle (a) and interpretation (b) of the Carba NP test recently developed for the rapid identification of carbapenemase producers among Enterobacteriaceae and Pseudomonas spp.