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Volume 5 No 24; 1 June 2011

Carbapenemase-producing Enterobacteriaceae in the UK, 2003-2011

Carbapenem antibiotics are key drugs against otherwise multi-resistant gram-negative rods. Consequently, bacteria with acquired carbapenem resistance are a global public health concern. The Antibiotic Resistance Monitoring and Reference Laboratory (armrl@hpa.org.uk) continues to receive increasing numbers of Enterobacteriaceae that are resistant to one or more carbapenems. Most are confirmed by molecular methods to produce a carbapenem-hydrolyzing ß-lactamase ('carbapenemase'). More detail on carbapenemase types, detection, prevention of spread and treatment of infected cases is given in recent ARHAI-HPA guidance [1].

The UK's first known carbapenemase-positive enterobacterial isolate was detected in 2003 and, until 2007, ARMRL confirmed fewer than five cases per year. In stark contrast, there have been marked year-on-year increases since 2008 (table 1), and to week 22 of 2011 a total of 657 carbapenemase-positive Enterobacteriaceae have been referred by 90 UK laboratories. Multiple isolates, in some cases belonging to different bacterial species, have been received from some patients; some isolates were causing severe infections, including fatal septicaemias, others were from faecal surveillance cultures. During this 8.5-year period, 71 UK laboratories referred 1-4 positive isolates, nine referred 5-9 isolates and 10 referred 10 isolates or more.

These UK isolates produced diverse enzymes: KPC-, OXA-48- and IMI- type non-metallo-carbapenemases; or NDM-, VIM- and IMP- type metallo-carbapenemases (MBLs). One isolate produced both KPC and VIM enzymes (table 1).

Table 1. Carbapenemase producers by year and numbers of affected UK laboratories
Year Carbapenemase type Total
Non-metallo
Mixed
Metallo

IMI

KPC

OXA-48

KPC+VIM

IMP

NDM

VIM

2003

1

1

1

3

2004

3

3

2005

2006

3

1

4

2007

1

1

2

2008

5

9

1

5

2

22

2009

13

15

9

32

4

73

2010

2

231

20

9

45

26

333

Q1-2, 2011

130

12

1

27

47

217

Total

2

384

57

1

23

109

81

657

No. of UK labs

2

31

22

1

11

42

19

90

The vast majority of carbapenemase producers (80%; table 2) were Klebsiella spp. (mainly K. pneumoniae), followed by E. coli and Enterobacter spp. (each 9%). These various carbapenemases are all encoded by genes that are usually located on horizontally-transmissible plasmids, allowing them to spread between strains, species and genera, as evidenced by small numbers of isolates belonging to other genera (collectively totalling c. 2%).

Table 2. Enterobacteriaceae producing carbapenemases in the UK
Genus Carbapenemase type Total (%)

IMI

IMP

KPC

KPC+VIM

NDM OXA-48 VIM

Citrobacter spp.

1

3

1

5 (1)

Enterobacter spp.

2

8

29

11

1

7

58 (9)

Escherichia coli

2

26

22

10

1

61 (9)

Klebsiella spp.

13

325

1

71

46

71

527 (80)

Morganella morganii

1

1 (0.2)

Providencia stuartii

1

1 (0.2)

Raoultella spp.

2

1

3 (0.5)

Serratia spp.

1

1 (0.2)

Total

2

23

384

1

109

57

81

657 (100)

 

The dominant carbapenemases detected among referred Enterobacteriaceae were KPC enzymes, which are prevalent in the USA, Greece, and Israel and scattered elsewhere [2]. Early UK isolates with KPC were often linked with overseas travel, but this is now less pronounced and there has been spread within some UK hospitals; specifically the large numbers of KPC-positive isolates reflect an ongoing problem in NW England, which involves the transmission of plasmids encoding KPC enzymes between different bacterial strains, principally of K. pneumoniae, but with spread also to E. coli and Enterobacter spp. Many of these isolates are from faecal screens rather than infections.

Although less numerous than KPC producers, Enterobacteriaceae with the recently-described NDM metallo-carbapenemase have wider UK scatter; NDM-positive isolates have been received from 42 laboratories since the enzyme was first detected in 2008. The UK has recorded more NDM cases than any other European country [3]. This type of carbapenemase has been associated with patients with a history of hospitalization or travel to the Indian subcontinent [4], where the resistant bacteria have been detected in seepage or communal tap waters [5]. A minority of NDM cases in other European countries, though not yet in the UK, have epidemiological links with the Balkans, which may represent a second reservoir [6].

Many carbapenemase-producing Enterobacteriaceae are resistant to multiple antibiotic classes, with only colistin remaining active against >90% of all producers (table 3). However, colistin resistance may occur, and is frequent in some isolates of the internationally-disseminated K. pneumoniae clone ST258 with KPC enzymes; colistin-resistant isolates of this clone have been referred from UK laboratories.

Table 3. Antibiotic susceptibilities of carbapenemase-producing Enterobacteriaceae from the UK
Antibiotic
% Susceptibility [a]
Metallo-enzyme Producers
(IMP, NDM or VIM)
Non-metallo-enzyme Producers
(KPC or OXA-48-like)

E. coli

Klebsiella

Enterobacter / Citrobacter

E. coli

Klebsiella

Enterobacter / Citrobacter

Imipenem

9%

1%

3%

10%

5%

18%

IPM+EDTA [b]

100%

99%

100%

27%

8%

27%

Meropenem

9%

5%

3%

47%

8%

27%

Ertapenem

0%

0%

0%

0%

0%

0%

Ampicillin

0%

0%

0%

0%

0%

0%

Co-amoxiclav

0%

0%

0%

0%

0%

0%

Piperacillin

0%

0%

3%

0%

0%

0%

PIP + tazobactam

4%

0%

7%

0%

0%

0%

Cefotaxime

0%

0%

0%

3%

2%

0%

Ceftazidime

0%

0%

0%

17%

6%

0%

Aztreonam

4%

18%

13%

13%

6%

0%

Ciprofloxacin

9%

10%

17%

53%
49%
50%

Gentamicin

0%

12%

27%

70%
65%
41%

Tobramycin

0%

1%

0%
50%
58%
50%

Amikacin

17%

32%

50%
90%
85%
91%

Colistin

100%
97%
93%
100%
92%
100%

Tigecycline

100%
47%
47%
100%
74%
68%
a. Susceptibility defined using BSAC v. 10.1 breakpoints [7].
b. Diagnostic test to distinguish metallo- from non-metallo- enzymes; not for therapeutic use.

Active vs. ≥90% producers

Active vs. >75-89% producers

Active vs. 50-74% producers

Active vs. <50% producers


It is important to note that carbapenemase-producing Klebsiella spp. more often express clearer resistance to carbapenems than carbapenemase producers of the other genera. A substantial minority of E. coli and Enterobacter spp. with KPC or OXA-48 enzymes remained apparently susceptible in vitro to meropenem and/or imipenem, though all were resistant to ertapenem (table 3).

Tigecycline remains active vs. carbapenemase-producing E. coli in vitro, but has poorer activity vs. other genera, and is not appropriate for UTIs or bloodstream infections; based on a smaller panel of tested isolates, fosfomycin showed similar behaviour and is suitable for urinary infections [8]. Some isolates, particularly from among the large cluster of KPC-positive K. pneumoniae in NW England, remain susceptible to aminoglycosides and ciprofloxacin. Of note, producers of OXA-48-like carbapenemases may remain susceptible to oxyimino-cephalosporins unless they have other co-resident mechanisms, such as ESBLs or AmpC enzymes. Therapy must be guided by the resistance profile of the causative isolate, which may remain susceptible to less commonly tested agents [8].

The HPA, together with the Government's ARHAI Committee, has issued "Advice on Carbapenemase Producers: recognition, infection control and treatment" [1].

UK laboratories are encouraged to send Enterobacteriaceae with reduced carbapenem susceptibility to ARMRL for investigation.

 

References

1. ARHAI-HPA. Advice on carbapenemase producers: recognition, infection control and treatment. 2011. HPA website: http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1294740725984.

2. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect. Dis. 2009; 9: 228-36.

3. Struelens MJ, Monnet DL, Magiorakos AP et al. New Delhi metallo-ß-lactamase 1-producing Enterobacteriaceae: emergence and response in Europe. Euro. Surveill 2010; 15.

4. Kumarasamy KK, Toleman MA, Walsh TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect. Dis. 2010; 10: 597-602.

5. Walsh TR, Weeks J, Livermore DM et al. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infect. Dis. 2011; 11: 355-62.

6. Livermore DM, Walsh TR, Toleman M et al . Balkan NDM-1: escape or transplant? Lancet Infect. Dis. 2011; 11: 164.

7. Andrews JM, BSAC Working Party On Susceptibility Testing. BSAC methods for antimicrobial susceptibility testing: Version 10.1, April 2011. BSAC website: http://www.bsac.org.uk/Susceptibility+Testing/GUIDELINES+Standardized+
Disc+Susceptibility+Testing+Method
.

8. Livermore DM, Warner M, Mushtaq S et al. What remains against carbapenem-resistant Enterobacteriaceae ? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline. Internat J of Antimicrob Agents 2011; 37: 415-9.