1. Carbapenem-Resistant Enterobacteriaceae (CRE)
Dr Cheng Wing Ho Stephen
ICU, Pamela Youde Nethersole Eastern Hospital
Friday Meeting Jan 21, 2011
Carbapenem-Resistant Enterobacteriaceae (CRE)

2. Overview What is CRE? Mechanism of resistance International cases
3 recent cases in Hong Kong
Possible treatment options
HA / CDC guidelines on infection control

3. Background Enterobacteriaceae Gram -ve bacilli Facultative anaerobes
Gut flora, or found in soil / water
Common causative agents of UTI, pneumonia
Examples:
E. coli, Klebsiella, Salmonella, Shigella, Proteus

4. Background Treatment options Extended-spectrum-β-lactamase strains
Penicillin (e.g. ampicillin, amoxicillin, piperacillin)
Cephalosporin (e.g. cefuroxime, ceftriaxone)
(combined with β-lactamase inhibitor)
 Augmentin, Tazocin, Sulperazone
Carbapenem (e.g. imipenem, ertepenem, meropenem)
Quinolone (eg. ciprofloxacin, levofloxacin)
Extended-spectrum-β-lactamase strains
only sensitive to carbapenem group and limited penicillin/cephalosporin coupled with β-lactamase inhibitors

5. What is CRE?
Enterobacteriaceae strains resistant to carbapenem have emerged in the past decade
Wide-spread outbreaks have been reported in recent years
No reliable treatment options
Huge reservoir of carriers in healthy population
Easy species-to-species spread
Potential devastating health consequences

6. Mechanism of resistance
Carbapenemase
b-lactamase
hydrolyzing agent
4 classes (A-D): serine vs zinc
produced by ‘Superbugs’
Klebsiella Pneumoniae Carbapenemase (KPC)
Verona integron-encoded metallo-β-lactamase (VIM)
Oxallinase group β-lactamase (OXA)
SME, IMI, NMC and CcrA (little clinical significance)

7. Carbapenemase expression in bacteria
Enzyme
Bacteria
KPC
Enterobacteriaceae
VIM
Pseudomonas
OXA
Acinetobacter
SME
Serratia

8. Carbapenemase Klebsiella Pneumoniae Carbapenemase (KPC)
first detected in 1996
most commonly expressed in K. pneumonia
also reported in Citrobacter, Enterobacter , E. coli, Salmonella, Serratia
class A b-lactamase
causes resistance to all b-lactams including extended-spectrum cephalosporins and carbapenems

9. Carbapenemase Klebsiella Pneumoniae Carbapenemase (KPC)
encoding gene blaKPC carried on plasmids
reported to be found on plasmids with
normal spectrum b-lactamases
extended spectrum b-lactamases
aminoglycoside resistance
fluoroquinolone resistance
 leads to extensive-drug resistance (XDR)
virulence factors on plasmids
easy transmission of self-reproducing plasmid between species

10. Statistical data on KPC
European Antimicrobial Resistance Surveillance System (EARSS)
CRKP in 0.3% of blood isolates prior to 2006
following an outbreak in 2006 in Israel
 11% in 2006, 22% in 2007
mortality associated with CRKP isolation up to 44%
standardized morality rate ~8 deaths per 100,000
compared to 6 deaths per 100,000 of MRSA (2005)
Predictors of CRKP acquisition among hospitalized adults and effect of acquisition on mortality. Antimicrob Agents Chemother. 2008;52(3):

11. A new carbapenemase New Delhi metallo-b-lactamase (NDM-1)
class B b-lactamase
plasmid carrying encoding gene blaNDM
first detected in 2009 from an isolate of K. pneumoniae
Swedish patient with antibiotic-resistant infection acquired and unsuccessfully treated in New Delhi, India
novel gene identified in Sweden

12. 14 out of 24 patients come from ICU
A new carbapenemase
New Delhi metallo-b-lactamase (NDM-1)
over a 3-month period in Mumbai, India, 24 cases of carbapenam resistant isolates were identified
22 carry the NDM-1 gene
K. pneumoniae (10)
E. coli (9)
14 samples from ICU
Carbapenem-resistance 0%  8%
in 3 years
14 out of 24 patients come from ICU
“New Delhi Metallo-β lactamase (NDM-1) in Enterobacteriaceae: Treatment options with Carbapenems Compromised”. Journal of Association of Physicians of India 58: 147–150, March 2010

13. Latest situation
Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study
Lancet Infect Dis September ; 10(9): 597–602
UK (37) - all had travelled to India/Pakistan
Chennai (44), Haryana (26)
other sites in India and Pakistan (73)
K. pneumoniae (111)
E. coli (36)
Globally, estimated 250 identified isolates so far

14. Global spread of NDM-1 May 2010, first E.coli isolate in UK
Indian man received dialysis in India 18 months ago
June 2010, 3 Enterobacteriaciae strands in US
all received medical procedures in Indian hospitals previously
July 2010, 3 isolates of Acinetobacter baumannii in New Delhi, ICU
August 2010, first identified case in Ontario, Canada
September 2010, first case in Tokyo, Japan

15. First death case August 2010 Belgian man
road-traffic-accident in Pakistan
hospitalized for major leg injury
infected with an isolate of NDM-1
succumbed despite use of Colistin

16. CLSI guidelines for Laboratory workup for CRE
Enterobacteriaceae resistant or moderately resistant to Carbapenem
 PCR test for carbapenemase gene
Isolates that are susceptible but with increased minimal inhibitory concentrations (MIC)
 Modified Hodge Test
If positive Modified Hodge Test
proceed to PCR test for gene identity
manage as CRE
test sample
-ve control
+ve control
Clinical and Laboratory Standards Institute performance standards for antimicrobial susceptibility testing

17. In Hong Kong Incidence of CRE in 2009 is about 0.05%
8 isolates carrying the metallo-b-lactamases (IMP type)
E. coli, Klebsiella spp. and Citrobacter freundii
Mostly colonizing flora
No cases of KPC isolates detected so far
2 cases of recently identified New Delhi metallo-b-lactamase isolate
An overview of surveillance of antimicrobialresistance by CHP in Hong Kong Communicable Diseases Watch 2010; Volume 7, Number 17. Aug 2010

18. The 2 NDM-1 cases in Hong Kong
Case 1 (October 2010)
66 year old Indian man
out-patient
followed up for hypertension, diabetes
treated for UTI that responded to ciprofloxacin
NDM-1 carrying E. coli detected in urine culture
history of spending 3 weeks in India in March 2010
no history of hospitilization in India
full recovery

19. The 2 NDM-1 cases in Hong Kong
Case 2 (December 2010)
54 year old Indian lady
treated for subdural hematoma in India from May to August 2010
attended and admitted to PMH on Dec 17 for respiratory distress
NDM-1 carrying E. coli detected in rectal swab
likely colonization due as no evidence of infection

20. Our recent CRE case in PYNEH
ICU in-patient in D10 (January 2010)
83 year old Chinese man
recent hospitilization in the Philippines
biliary papillomatosis
admitted for robotic assisted laparoscopic L hepatectomy, complicated with leakage
CRE was cultured from bile
only sensitive to Gentamicin (treated with Tazocin)
PCR test positive for VIM gene (class B)
patient discharged home
case reported and contact tracing underway

21. Possible treatment options
Antimicrobial
Interpretation
Amikacin I
Chloramphenicol R
Amox/clav
Ciprofloxacin
Ampicillin
Ertapenem
Aztreonam
Gentamicin
Cefazolin
Imipenem
Cefpodoxime
Meropenem
Cefotaxime
Pipercillin/Tazo
Cetotetan
Tobramycin
Cefoxitin
Trimeth/Sulfa
Ceftazidime
Polymyxin B
MIC >4μg/ml
Ceftriaxone
Colistin
Cefepime
Tigecycline S

22. Polymyxin Cyclic peptide with hydrophobic tail
Produced by Bacillus polymyxa
Selectively targets Gram-ve bacteria by disrupting both outer and inner membranes
Polymyxin B
Colistin (polymyxin E)
Only effectively via parenteral route
No guidelines for standard / optimum / max dose
Nephrotoxic and neurotoxic
Shown to be useful against MRAB, Pseudomonas

23. Tigecycline Glycylcyline, derivative of tetracycline
Protein synthesis inhibitor
Targets Gram+ve, Gram-ve bacteria, anaerobes
No activity against Pseudomonas, Proteus
Licensed for treating skin infection, intra-abdominal infections
100mg IV stat followed by 50mg Q8H
Side effects profile similar to tetracycline: GI upset, photosensitivity, teeth discoloration, fetal damage

24. Other possible drugs NXL104 novel non-β-lactam β-lactamase inhibitor
use in combination with Ceftazidime
GSK (GlaxoSmithKline )
inhibits the enzyme topoisomerase
effective in clearing NDM-1
ACHN-490 and other Aminoglycosides
no activity against the NDM-1 isolates

25. HA guidelines on CRE
From data of other countries, KPC associated infections are mostly systemic infections
NDM-1 associated infections are usually UTI, pneumonia, and blood stream infection
Risk factors:
prolonged hospitalization
ICU stay
invasive devices
immunosuppression
prior use of multiple antibiotics
Infection Control Guideline on Carbapenem Resistant Enterobacteriaceae (CRE), Hospital Authority, 1 Dec 2010

27. Infection control strategies
1) Prudent antibiotic use
Antibiotic Stewardship Program (ASP) should be in place to give advice on and monitor the appropriate use of antimicrobials in patient care
2) Early detection of CRE
Active surveillance culture (ASC) - rectal swab/stool culture for patients hospitalized outside Hong Kong in the last 6 months
Screen carriage for same cubicle in-patients (>=2 days) of PCR +ve CRE, inform Infection Control Branch if discharged to elderly home, institutions
Infection Control Guideline on Carbapenem Resistant Enterobacteriaceae (CRE), Hospital Authority, 1 Dec 2010

28. Infection control strategies
3) Review of microbiology record of previous 6-12 months
detect unrecognized cases
if cases identified
point prevalence survey (a single round of active surveillance cultures) in high risk units
Example:
ICU
units where the identified case previously occupied
units exposed to broad-spectrum antimicrobials
4) Laboratory protocols for detecting CRE
Guidance for Control of Infections with Carbapenem-Resistant or Carbapenemase-Producing Enterobacteriaceae in Acute Care Facilities, March 2009

29. When CRE is confirmed... 1) Infection control measures:
Single room isolation
discontinue when infected site cleared or eradication of carriage in gut (culture negative for at least 2 consecutive stool/ rectal swabs collected at 48 hours interval)
Contact precautions
Hand hygiene
Dedicated equipments
Enhance / terminal environmental cleansing
Minimize patient transfer
Advice to visitors
Infection Control Guideline on Carbapenem Resistant Enterobacteriaceae (CRE), Hospital Authority, 1 Dec 2010

30. When CRE is confirmed... 2) Alert and reporting:
Inform the Chief Infection Control Officer’s Office (CICO Office) of any patient with PCR +ve CRE or when an outbreak of CRE is suspected
MHT positive cases should label in the CMS alert ‘Carbapenemase producing Enterobacteriaceae detected’
Revise CMS alert to ‘CRE PCR +ve’ if PCR tested positive
The alert should be removed when the patient has been eradicated of CRE
When CRE PCR +ve patient is re-admitted, infection control precautions should taken and ICT informed
Infection Control Guideline on Carbapenem Resistant Enterobacteriaceae (CRE), Hospital Authority, 1 Dec 2010

31. When CRE is confirmed... 3) Transfer / discharge issues
ICT involved in all inter-hospital or intra-hospital transfer of CRE +ve patient
Discharge to institutions / elderly home
should have 2 consecutive negative screening culture at 48 hours interval. ICB must be informed
asymptomatic prolonged CRE carriage (e.g. >=8 weeks) must be risk assessed jointly by the hospital ICT, CICO and ICB
Patients discharged home should be given education pamphlet on infection control precautions
Patients with CRE +ve confirmed after discharge should be contacted for information and education on infection control precautions
Infection Control Guideline on Carbapenem Resistant Enterobacteriaceae (CRE), Hospital Authority, 1 Dec 2010

33. Bring home message
Carbapenem-Resistant Enterobacteriaceae is an emerging threat to hospitalized patients
Global spread
High mortality
Treatment options are limited
Active surveillance should be performed for high risk patients with overseas hospitalization in past 6 months
Contact tracing / screening for confirmed cases
Importance of infection control measures
High vigilence in critically ill ICU patients

34. Thank you!
The End