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Part I: Antibiotic resistance - Local scenario

1.5 Carbapenem-resistant Enterobacteriaceae (CRE)

Enterobacteriaceae can acquire resistance to carbapenem through production of carbapenemase (Table 1.8), modification of outer membrane permeability and efflux pump (56).

  1. Carbapenemase, KPC-producing Klebsiella pneumoniae was first discovered from a clinical isolate through the Intensive Care Antimicrobial Resistance Epidemiology (ICARE) surveillance in North Carolina in 1996 (57–58) and followed by a substantial spread in New York (59), Israel (60) and Greece (61). Enterobacteriaceae producing KPC has also been described in South America (Colombia, Brazil and Argentina) (62–64) and China (65–66). Other than K. pneumoniae, the KPC-enzyme has also been described in many other Enterobacteriaceae species (58). Infection caused by carbapenem-resistant organisms increases the risk of complications and mortality (67).
  2. New Delhi metallo-ß-lactamase 1 (NDM-1) was first described in 2009 in a Swedish patient of Indian origin. He was hospitalised in India and acquired urinary tract infection caused by a carbapenem-resistant K. pneumoniae (68). Like other metallo-ß-lactamases, the enzyme NDM-1 can hydrolyse all ß-lactams except aztreonam. Resistance to aztreonam is usually due to the coexisting ESBL or AmpC ß–lactamase. Majority of the NDM-1 producing organisms harbour other resistance mechanisms, rendering them resistant to almost all classes of antibiotics with the possible exception of colistin (69–70).
  3. NDM-1 producing Enterobacteriaceae has spread across Europe. In a recent survey conducted in 29 European countries, cases were reported in 13 countries (69). Majority of the cases had a history of travel to the Indian subcontinent. Many countries have developed their own national guidelines to deal with the problem of NDM-1 (69).
  4. The first NDM-1 producing E. coli in HK was isolated in October 2009 from a patient with urinary tract infection with travel history to India (71). Several cases of IMP-4 were found in hospitalised patients since mid-2009 in HK (Figure 1.3) (72). The first KPC-2 producing K. pneumoniae was described in February 2011 (73).
  5. The spread of NDM-1 is probably due to the huge selection pressure created by widespread non-prescription use of antibiotics in India (74) and involvement of promiscuous mobile elements in the gene’s dissemination (75).
  6. A local review of the NDM detected from 2009–2014 was performed by the CHP. From 2009–2013, there was a gradual rise of NDM cases detected, ranging from 1 to 19 patients, but there were no local cases of NDM detected during this period. Twelve local cases of NDM was first detected in 2014, where four patients had signs of infection. Majority of the imported NDM cases were from China, followed by India and other South East Asian countries (76).
  7. A local study in 2016 investigated the clonality and mechanism of resistance of 92 strains of CRE isolated between 2010 and 2012. Only 10% were genotypic carbapenemase-producing Enterobacteriaceae (CPE) confirmed by polymerase chain reaction (PCR). Porin loss combined with AmpC and/or CTX-M type ESBL was the major mechanism of resistance of the CRE isolated (77).
  8. Plasmid-mediated colistin resistance by mcr-1, a gene that can be transferred horizontally among bacteria has been first described in China in both food animals and human (78). HK has also detected CPE with mcr-1 recently (79). The coexistence of mcr-1 with carbapenemase (e.g. NDM, KPC) has been described in China (80–82), South America (83), Singapore (84), Germany (85).


Figure 1.3 Number of carbapenemase-producing Enterobacteriaceae confirmed at the Public Health Laboratory Services Branch, CHP, 2009 to 2016. A HK wide surveillance was implemented since the last quarter of 2010.


Table 1.8 Different classes of carbapenemase

  Class A Metallo-ß-lactamase OXA carbapenemase
Molecular class Class A Class B Class D
Functional class 2f 3 2d
Gene location Usually transposon Usually plasmid Usually plasmid
Examples KPC1
OXA-23, 24, 51, 58
(types in Acinetobacter spp.)2
OXA-48, 181, 232
(types in Enterobacteriaceae)1
Found in Enterobacteriaceae Non-fermenters and Enterobacteriaceae Non-fermenters and Enterobacteriaceae
Inhibited by Clavulanate and tazobactam EDTA No effective inhibitor
Active site Serine Zinc ion Serine
Carbapenem Hydrolysed Hydrolysed Hydrolysed
Aztreonam Hydrolysed Not hydrolysed Not hydrolysed
Early ß-lactam Hydrolysed Hydrolysed Hydrolysed
Extended spectrum cephalosporin Hydrolysed (except SME) Hydrolysed Hydrolysed poorly



  1. 1Seen in HK
  2. 2Common in HK