การติดเชื้อดื้อยา C.difficile cre vre ภัยเงียบในโรงพยาบาล

การติดเชือดือยา Clostridium difficile

CRE และ VRE: ภยัเงียบในโรงพยาบาล

ผู้ช่วยศาสตราจารย ์นายแพทย ์ธนา ขอเจริญพร

หน่วยโรคติดเชือ ภาควิชาอายรุศาสตร์

คณะแพทยศาสตร ์มหาวิทยาลยัธรรมศาสตร์

TopicsOrganisms• Clostridium difficile• Carbapenem-resistant Enterobacteriaceae

(CRE)• Vancomycin-resistant enterococci (VRE)

Contents• Epidemiology• Transmission• Infection control issues

Clostridium difficile infection

Clostridium difficile infection (CDI)

• Gram-positive anaerobic bacilli bacteria• Colonization in healthy persons• Overgrowth causes infection.

Definition of CDI• Presence of diarrhea, defined as passage of 3 or more

unformed stools in 24 consecutive hours AND• A stool test result positive for

• Toxigenic C. difficile or its toxins OR• Colonoscopic or histopathologic findings

demonstrating pseudomembranous colitis

Clostridium difficile infection (CDI)For better comparability between healthcare facility:Standardized case definitions for surveillance• Healthcare facility (HCF)-onset, HCF-associated CDI• Community-onset, HCF-associated CDI• Community-associated CDI

Clostridium difficile infection (CDI)Epidemiology• Unknown data in Thailand• In Canada, 3.8 to 9.5 cases per 10,000 patient-days, or

3.4 to 8.4 cases per 1,000 admissions in acute care hospitals

• Emergence of more severe disease in the past decade• NAP1/BI/027 strain

• North American Pulse field gel electrophoresis type 1• BI pattern (restriction endonuclease analysis)• 027(PCR ribotype designation)


How can C. difficile spread from person to person?

• Its vegetative state (spore)• Fecal oral route within healthcare facilities• Environmental contamination (esp. rectal thermometer,

bed pan)


Risk factors for CDI

• Advanced age• Duration of hospitalization• Antimicrobial use (long-term use, multiple agents, braod

spectrum)• Cancer chemotherapy (neutropenia)• Gastrointestinal surgery• Manipulation of the gastrointestinal tract, including tube

feeding• Use of proton pump inhibitor

Clostridium difficile infection (CDI)Clinical manifestations• Asymptomatic carriage to septic shock• Incubation period 2-3 days• Diarrhea (sometime mucous or bloody stool)• Fever• Abdominal cramping• Leukocytosis

Other findings• Bacteremia (rare)• Arthritis (rare)• Ileitis (rare)

Clostridium difficile infection (CDI)Complications• Colonic ileus• Toxic megacolon• Perforation with peritonitis• Hypoalbuminemia• Severe sepsis and septic shock• Multi-organ failure

Clostridium difficile infection (CDI)What is the best testing strategy to diagnose CDI?

• Testing for C. difficile or its toxins should be performed only on diarrheal (unformed) stool.

• Testing of stool from asymptomatic patients is not clinically useful, including use as a test of cure.

• Stool culture is the most sensitive test and is essential for epidemiological studies.

• Stool culture is not clinically practical because of its slow turnaround time.

SHEA and IDSA guidelines 2010

Clostridium difficile infection (CDI)What is the best testing strategy to diagnose CDI?

• Enzyme immunoassay (EIA) testing for C. difficile toxin A and B is rapid but is less sensitive.

• EIA detection of glutamate dehydrogenase (GDH) as initial screening and then uses the cell cytotoxicity assay or toxigenic culture as the confirmatory test

• Repeat testing during the same episode of diarrhea is of limited value

• Empiric therapy assess the response


Clostridium difficile infection (CDI)Infection Control measures

• Contact isolation during the diarrheal duration• Single room, if not possible cohorting

• Healthcare workers and visitors must use gloves and gowns on entry to a room of a patient with CDI.

• Routine identification of asymptomatic carriers for infection control purposes is not recommended.



• Hand hygiene• C. difficile, in its spore form, is highly resistant to

alcohol.• Wash hand with soap or antimicrobial soap and

water• The effectiveness of soap vs. antimicrobial soap is

inconclusive.• Physical removal is essential.



• Environmental cleaning• Identification and removal of contaminated

environmental sources• Use of chlorine-containing cleaning agents (with at

least 1,000 ppm available chlorine) or or other sporicidal agents

• Routine environmental screening for C. difficile is not recommended.



• Antimicrobial use restriction• Minimize the frequency and duration of antimicrobial

therapy and the number of antimicrobial agents prescribed

• Antimicrobial stewardship program


Clostridium difficile infection (CDI)Treatment

• Discontinue unnecessary antimicrobial therapy• Medications

• Metronidazole (oral or IV)• Vancomycin (oral or intra-colonic)• Fidaxomicin

• Fecal transplantation• Surgery (severe and intractable cases)

Carbapenem-resistant Enterobacteriaceae (CRE)


• Super bugs• Resistant to carbapenems (broad-spectrum antibiotics)

• Ertapenem• Imipenem• Meropenem• Doripenem

• Enterobacteriaceae (Gut pathogens)• Escherichia coli• Klebsiella pneumoniae• Proteus mirabilis• Enterobacter spp.• Others

Carbapenem-resistant EnterobacteriaceaeMechanisms of resistance

Carbapenemase (Ambler molecular classification)• Class A beta-lactamases

• KPC (Klebsiella pneumoniae carbapenemase)• NMC (non-metalloenzyme carbapenemase)

• Class B beta-lactamases• Metallo-beta-lactamases• IMP, VIM, GIM, SPM, SIM• NDM-1

• Class D beta-lactamases• OXA-types• OXA-23, OXA-48, OXA-51, OXA-58

Carbapenem-resistant EnterobacteriaceaeMechanisms of resistance

The combination of extended-spectrum beta-lactamase production or ampC production and porin loss

• Class A Beta-lactamases• Epicenter in New York city (US), now most stated

have reported it.• Greece, Israel, South America, China• Documented transfers from endemic areas to

Europe and Australia• Thailand (?rate)

Klebsiella pneumoniae carbapenemase (KPC)

• Class B Beta-lactamases• Widely disseminated across the Indian subcontinent• Most common enzyme produced by carbapenemase-

resistant Klebsiella pneumoniae in India (5-10% of healthcare-associated gram-negative infections)

• Cases included those who have traveled and undergone procedures in India and Pakistan

New Delhi Metallo-Betalactamase-1 (NDM-1)

Kumarasamy K et al. Lancet Infect Dis 2010;10:597.

Deshpande P et al. Clin Infect Dis 2010;15:1222.


Epidemiology

Carbapenem-resistant EnterobacteriaceaeRisk factors

Apisarnthanrak A, Hsu LY, Khawcharoenporn T et al. Expert Rev Anti Infect Ther 2013; 11: 147–157.


Clinical manifestations• Urinary tract infection• Pneumonia• Bloodstream infection• Gastrointestinal infection including hepatobiliary tract

infection• Surgical site infection• Others


Diagnosis• General drug susceptibility testing (resistant to at least

one of the carbepenems)• Carba NP• Metallo-β-lactamase testing• Polymerase chain reaction (PCR)


Infection control measures• Contact isolation (strict isolation)• Performing hand hygiene before donning a gown and

gloves• Donning gown and gloves before entering the affected

patient’s room


Infection control measures• Removing the gown and gloves and performing hand

hygiene prior to exiting the affected patient’s room• Surveillance cultures• Empiric contact isolation• Laboratory notification


Infection control measures• Removal of unnecessary devices• Inter-facility communication• Antimicrobial stewardship (esp., carbapenem use)• Environmental cleaning• Patient and staff cohorting (outbreak setting, high local

prevalence)• Screening of contacts of CRE patients• Chlorhexidine bathing• When to discontinue contact isolation

Carbapenem-resistant EnterobacteriaceaeTreatment options

• Additional antibiotic susceptibility testing required:• Tigecycline• Colistin• Fosfomycin

• Given limited clinical data, combination therapy with at least two active agents are suggested.• Higher mortality in severe cases receiving

monotherapy• Emergence of resistance during monotherapy

Carbapenem-resistant EnterobacteriaceaeAvailable options

Preferred• Tigecyline + colistin

Alternatives• Tigecycline + prolonged infusion carbapenem or

rifampicin• Colistin + prolonged infusion carbapenem or

rifampicin• Tigecyline + colistin + prolonged infusion

carbapenem• Fosfomycin or aminoglycosides (if susceptible for

urinary tract infection)

Vancomycin-resistant Enterococci (VRE)

Vancomycin-resistant enterococci (VRE)

• Gram-positive cocci in chain• Super bugs• Resistant to vancomycin• Also resistant to

• Penicillin• Ampicillin• Piperacillin-tazobacam• Imipenem


Mechanism of resistance• High-level resistance to vancomycin is encoded by

different clusters of genes (e.g., vanA, vanB, and vanDgenes)

• Changing the binding site of bacteria cell wall precursor


Epidemiology• First described in Europe in 1980s• In the US, vancomycin resistance was found in 60% of

E. faecium isolates and 2 % of E. faecalis isolates• Data from the NHSN: vancomycin resistance was found

in 80%of E. faecium and 6.9% of E. faecalis in 2006 and 2007

• VRE was associated with mortality among all enterococcal bloodstream infections.

The National Antimicrobial Resistance Surveillance Thailand (NARST) Program

Enterococcus isolates (2014)• E. faecalis (45.5%), E. faecium (22.4%)

Antibiotic Resistance rate (%)E. faecalis E. faecium

Ampicillin 3.7 92.2High-level gentamicin 57.5 53.3Vancomycin 0.5* 8.4*

http://narst.dmsc.moph.go.th/antibiograms/2014/2014all.pdf.


Transmission• GI colonization as an important source• By direct contact (e.g., the hands of healthcare

workers) and indirectly from environmental surfaces


Risk factors for infections with VRE• Previous antimicrobial therapy

• Vancomycin• Cephlosporins• Multiple broad spectrum antibiotic use increases colonization

with VRE.• Patient characteristics

• Hospitalization longer than 72 hrs• Significant underlying medical conditions

• On HD• Cancer• Transplant recipient• Requirement for ICU• Invasive devices


Risk factors for infections with VRE• Colonization pressure• Exposure to contaminated surfaces

• Staying in the room with inadequate cleaning• Shared rectal thermometer• Hands of healthcare workers

• Residence in long-term care facilities


Clinical manifestations• Urinary tract infection• Bloodstream infection• GI infection• Device-associated infection


Diagnosis• Routine bacterial culture and susceptibility testing

(may be fastidious)• Identification of vancomycin resistance

• MIC determination for screening• PCR for vancomycin-resistant gene identification


Infection control measures• Hand hygiene• Contact precautions• Cohorting of colonized patients (area or unit closure

may be necessary for an outbreak)• Surveillance cultures (rectal swab culture)

Vancomycin-resistant enterococci (VRE)• The optimal treatment for VRE is uncertain.

Birmingham MC et al. Clin Infect Dis 2003;36:159.Cubicin. http://www.rxlist.com/cubicin-drug.htm

Tygacil. http://www.rxlist.com/tygacil-drug.htm

Antibiotics Approved indications CommentsLinezolid Infections ± bacteremia Bacteriostatic, cost,

side effectsDaptomycin Off-label use (SSTI,

bacteremia, UTI, IAI)?Lt. side IE, dose adjust with type of infection, CK

Tigecycline Off-label use (SSTI, IAI, ?PNA)

Serum conc, notfirst line


Teicoplanin. http://www.sanofi-aventis.co.uk/products/Targocid_SPC.pdf Tripodi MF et al. Eur J Clin Microbiol Infect Dis 1998;17:734.

Stevens MP et al. Clin Infect Dis 2005;41:1134.Schutt AC et al. Ann Pharmacother 2009;43:2108.

Antibiotics Approved indications CommentsTeicoplanin Not available in the US Van A and some

Van B mutation. S.E: low plt, neuro-nephrotoxicity

High dose ampicillin, Ampicillin ± FluoroquinolonesDaptomycin + Gentamicin ± AmipicillinDaptomycin + Gentamicin + RifampicinDaptomycin + Tigecycline

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การติดเชื้อดื้อยา C.difficile cre vre ภัยเงียบในโรงพยาบาล