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

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

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

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

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

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)

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

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

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

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):1028-1033

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

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

Latest situation Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study Lancet Infect Dis. 2010 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 http://www.ndm1bacteria.com

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

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

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. 2009 performance standards for antimicrobial susceptibility testing. 2009.

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

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

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

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

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

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

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

Other possible drugs NXL104 novel non-β-lactam β-lactamase inhibitor use in combination with Ceftazidime GSK 299423 (GlaxoSmithKline 299423) inhibits the enzyme topoisomerase effective in clearing NDM-1 ACHN-490 and other Aminoglycosides no activity against the NDM-1 isolates

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

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

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

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

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

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

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

Thank you! The End