C. difficile, CRE, VRE Hospital Infections

การติดเชือดือยา Clostridium difficile
CRE และ VRE: ภัยเงียบในโรงพยาบาล
ผู้ช่วยศาสตราจารย์ นายแพทย์ ธนา ขอเจริญพร
หน่วยโรคติดเชือ ภาควิชาอายุรศาสตร์
คณะแพทยศาสตร์ มหาวิทยาลัยธรรมศาสตร์

Topics
Organisms
• 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

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

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

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)

Complications
• Colonic ileus
• Toxic megacolon
• Perforation with peritonitis
• Hypoalbuminemia
• Severe sepsis and septic shock
• Multi-organ failure

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

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

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

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)

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 Enterobacteriaceae
Mechanisms 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

Mechanisms 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

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

• 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

• Removing the gown and gloves and performing hand
hygiene prior to exiting the affected patient’s room
• Surveillance cultures
• Empiric contact isolation
• Laboratory notification

• 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

Treatment 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

Available 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 vanD
genes)
• 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 92.2
High-level gentamicin 57.5 53.3
Vancomycin 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

• 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

• Hand hygiene
• Contact precautions
• Cohorting of colonized patients (area or unit closure
may be necessary for an outbreak)
• Surveillance cultures (rectal swab culture)

• 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 Comments
Linezolid Infections ± bacteremia Bacteriostatic, cost,
side effects
Daptomycin 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, not
first 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 Comments
Teicoplanin Not available in the US Van A and some
Van B mutation.
S.E: low plt, neuro-
nephrotoxicity
High dose ampicillin, Ampicillin ± Fluoroquinolones
Daptomycin + Gentamicin ± Amipicillin
Daptomycin + Gentamicin + Rifampicin
Daptomycin + Tigecycline

C. difficile, CRE, VRE Hospital Infections

C. difficile, CRE, VRE Hospital Infections

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C. difficile, CRE, VRE Hospital Infections