Transcript Stool Wars: Attack of the Phantom Menace

Clostridium difficile:
Shifting Sands of a Pesky Pathogen
Bob Fader, Ph.D. D (ABMM)
Section Chief, Microbiology
Scott & White Memorial Hospital
Temple, TX
[email protected]
Objectives
• Identify the reasons for the increase and
severity of Clostridium difficile diarrhea
• List the methods of lab testing for C.
difficile and discuss the pros and cons of
each method
• Describe treatment modalities for C.
difficile disease
• Discuss Infection Control processes
required for containment of C. difficile in
the health care setting
Clostridium difficile – The Basics
• Anaerobic Gram positive bacillus
• Spore-former
• Normal bowel flora
in 2 - 5% of population
– Up to 20% in LTC facilities
• Infection most often associated with
prior antibiotic therapy
• Originally strictly a hospital-acquired
infection but now can also be seen in
outpatients as well
C. difficile – Advanced Info
• C. difficile diarrhea is a toxin-mediated
disease
• Large increase in number and severity
of cases seen since 2004
• Largely due to strain with deletion in
regulatory gene for toxin production
– Results in 20-fold increase in toxin
production
• Increasing number of strains also
resistant to the fluoroquinolones
APIC C. difficile Survey
National Prevalence Study of Clostridium difficile
in U.S. Healthcare Facilities
• Health care institutions requested to collect data
on C. difficile on any one day (May-August 2008)
• 648 facilities
• 13 of every 1000 pts either infected or colonized
• 6.5 - 20 times higher than previous estimates
So what happened?
• Appearance of a new strain of C. difficile in
hospitals in Quebec
• Quickly spread south to the U.S. and over
to Europe
• Strain is known as NAP1 (toxinotype III)
Spread of NAP1 strain of C. difficile
Deaths in the UK caused by
C. difficile
C. difficile Epidemiology
Normal colon
Pseudo
membranous
colitis
C. difficile Toxin Genes
Increased Toxin A Production in vitro
In vitro production of toxins A
and B by C. difficile isolates.
Median concentration and IQRs
are shown. C. difficile strains
included 25 toxinotype 0 and 15
NAP1/027 strains (toxinotype III)
from various locations.
From Warny M, et al. Lancet. 2005;366:1079-1084.
Increased Toxin B Production in vitro
In vitro production of toxins A
and B by C. difficile isolates.
Median concentration and IQRs
are shown. C. difficile strains
included 25 toxinotype 0 and 15
NAP1/027 strains (toxinotype III)
from various locations.
From Warny M, et al. Lancet. 2005;366:1079-1084.
Comparison of Molecular Characteristics of
2 C. difficile Isolates with Historical Standard-Type
Strains and a Recently Recognized Epidemic Strain,
by Selected Characteristics, OH and PA, 2005
Standard
Strain
Epidemic
Strain
Ohio
Strain
Pennsylvania
Strain
0
III
IX
XIV/XV
< 80% related
to NAP1†
NAP1
85% related
to NAP1
64% related to
NAP1
Binary toxin
_
+
+
+
18 bp deletion in
tcdC
_
+
_
+
Characteristic
Toxinotype
PFGE* pattern
*Pulsed-field gel electrophoresis.
† North American pulsed-field type 1.
McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP, Johnson S, Gerding
DN. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-2441.
CDC. MMWR. 2005;54:1201-1205.
Resistance of Current (after 2000) BI/NAP1
Isolates to Clindamycin and Fluoroquinolones
Compared with Current Non-BI/NAP1 Isolates
and Historic (before 2001) BI/NAP1 Isolates
No. (%)
Intermediate
or
Resistant to:
Current
BI/NAP1
Isolates
n=24 (%)
Current
nonBI/NAP1
Isolates
n=24 (%)
P-Value for
BI/NAP1
vs. NonBI/NAP1
Isolates
Historic
BI/NAP1
Isolates
n=14 (%)
P-Value for
Current vs.
Historic
BI/NAP1
Isolates
Clindamycin
19 (79)
19 (79)
1.0
10 (71)
0.7
Levofloxacin
24 (100)
23 (96)
1.0
14 (100)
1.0
Gatifloxacin
24 (100)
10 (42)
<0.001
0
<0.001
Moxifloxacin
24 (100)
10 (42)
<0.001
0
<0.001
From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.
C. difficile-associated diseases
(CDAD)
•
•
•
•
•
•
Antibiotic-associated diarrhea
Pseudomembranous colitis
Toxic megacolon
Perforations of the colon
Sepsis
Death (rarely)
C. difficile Clinical Symptoms
•
•
•
•
•
Watery diarrhea
Fever
Loss of appetite
Nausea
Abdominal pain/tenderness
Risk factors for C. difficile
•
•
•
•
•
•
•
Prior antibiotic exposure
GI surgery/endoscopy
Long LOS in health care setting
Serious underlying illness
Immunocompromising conditions
Advanced age
Proton pump inhibitors?
Changes in age-specific C. difficile associated
disease 2000-2005
Zilberberg, M.D. et al. Increase in Adult Clostridium difficile-related
hospitalizations and case-fatality rate, United States, 2000-2005. Emerg
Infect Dis 2008 Vol 14 No 6
Stomach Acid-Suppressing Medications
and Community-Acquired CDAD, England
From Dial S, et al. JAMA. 2005;294:2989-2995.
Severe CDAD in Populations Previously
at Low Risk—Four States, 2005
• Recent reports to the Pennsylvania Department of
Health and CDC
– Young patients without serious underlying disease
– C. difficile toxin-positive by routine diagnostic testing
– Responded to CDAD-specific therapy
• Peripartum
– Within 4 weeks of delivery
– Reports from PA, NJ, OH, and NH
• Community-associated
– No hospital exposure in prior 3 months
– Reports from Philadelphia and 4 surrounding counties
CDC. MMWR. 2005;54:1201-1205.
Severe CDAD in Populations Previously
at Low Risk—Four States, 2005 (2)
Characteristic,
No. (%)
Community
(N=23)
Peripartum
(N=10)
Total
(N=33)
Aged < 18 years
11 (48)
0 (0)
11 (33)
Female
15 (65)
10 (100)
25 (76)
Antimicrobial exposure
15 (65)
9 (90)
24 (73)
Bloody diarrhea
6 (26)
2 (20)
8 (24)
Hospitalization
necessary
6 (26)
4 (40)
10 (24)
ER visit necessary
3 (13)
2 (20)
5 (15)
Relapse
8 (35)
5 (50)
13 (39)
CDC. MMWR. 2005;54:1201-1205.
Severe CDAD in Populations Previously
at Low Risk—Four States, 2005
• Transmission to close contacts in 4 cases
• 8 cases without antimicrobial exposure
– 5 children; 3 required hospitalization
– 3 had close contact with diarrheal illness
• Another 3 cases with < 3 doses of antimicrobials
• Clindamycin most common exposure (10 cases)
• Estimated minimum annual incidence of
community-associated disease
– 7.6 cases per 100,000 population
– 1 case per 5,000 outpatient antimicrobial prescriptions
CDC. MMWR. 2005;54:1201-1205.
Laboratory Diagnosis of C. difficile
“A disease in search of a good
diagnostic test”
C. difficile - Lab Testing
General Caveats
• Lab testing should only be performed on
diarrheal stools (conform to the shape
of the container)
• One or two specimens collected on
consecutive days are sufficient for
diagnosis
• No more than one specimen per day
• Swab specimens are insufficient
• Once pt positive, no further testing for at
least 2 weeks **No “Test of Cure”**
C. difficile - Lab testing Options
• Culture on CCFA agar (Cycloserine
Cefoxitin Fructose agar)
– Most sensitive and specific
– If isolated still need to confirm
toxin production
– 72-96 hour turn-around-time
– Requires anaerobic culture
C. difficile – Lab Testing continued
• Latex agglutination –
– originally marketed as toxin assay
– now known to detect glutamate
dehydrogenase enzyme
– present in C. difficile but also in other
organisms (C. sordellii)
– Same day or next day results
– Need to confirm positives with toxin
assay
C. difficile – Lab Testing continued
• Enzyme immunoassays
– Detection of Toxin A only
• Will not detect ToxA negative/ToxB
positive strains
– Detection of Toxins A&B
• Better sensitivity than toxin A alone
– Microwell, lateral flow assay formats
– Same day or next day results
– Most popular (>90% of labs)
– Sensitivities – 65-85%
Microwell enzyme immunoassay
Lateral flow EIA
C. difficile – Lab Testing continued
• Cell culture Cytotoxicity Assay –
– Detects Toxin B (Cytotoxin) only
• Will not detect ToxA positive/ToxB
negative strains
– Considered the “gold standard” for
toxin testing
– Requires tissue culture capability
– Costly, slow, and time consuming
– 24-48 hour turn-around-time
C. difficile – Lab Testing continued
• Rapid enzyme EIA for glutamate
dehydrogenase enzyme
– Used as initial screen
– If negative you can report out as negative
• Positive rapid test requires confirmation by
cell culture cytotoxicity assay, EIA or PCR
• High specificity for negatives but still
cannot provide a rapid result for a positive
patient
C. difficile – Lab Testing continued
• Polymerase chain reaction
• BD GeneOhm Cdiff PCR assay has
recently been FDA approved
• Targets the Toxin B gene
• Fresh stool: Sensitivity 93.8%/Specificity 95.5%
• Frozen stool: Sensitivity 100%/Specificity 97.7%
• Evidence suggests a single negative is
enough to rule out infection
C. difficile – Lab Testing continued
• Polymerase chain
reaction for toxin A
and toxin B (S&W)
– Primers and probes for
Toxin A and B
– 146 specimens
– PCR picked up 7
additional positives
(37 vs 44)
Sens
EIA
PCR
84%
100%
Spec 97.7%
100%
PPV
94.9%
100%
NPV 92.2%
100%
Smith, D, Hocker, K, Fader, B, Luna, RA, Versalovic, J, Rao, A. Rapid PCR screening
strategy for hospital acquired infections including vancomycin-resistant Enterococci
and Clostridium difficile in adult patients. (ASM Annual meeting, 2008)
C. difficile Treatment
• Discontinue current antibiotics
– 23% cure rate
• Antibiotics – metronidazole
– oral vancomycin
– concern about selection of VRE
– 20% relapse rate
• Continue with metronidazole
• 2nd relapse – switch to vancomycin
C. difficile Treatment continued
• “Severe disease”
– Zar and CDC criteria
– Vancomycin shown superior to metronidazole
• Toxic megacolon – direct installation of
vancomycin + IV metronidazole
C. difficile Treatment continued
• Other antibiotics? (rifamixin, nitazoxinide)
• Toxin binding compound was in
development
– Recently stopped study
• Monoclonal antibodies
• Vaccine in development
• Probiotics – Saccharomyces boulardii and
Lactobacilli - questionable results
– usually in combination with antibiotics
Treatment – Stool Transplant
• Reserved for severe pseudomembranous colitis
and toxic megacolon
• Stool donated by healthy volunteer – usually
family member
– Fresh stool is homogenized, filtered through coffee
filter X2
• Administered by nasogastric tube or by enema
• Usually 5 treatments to help restore normal flora
Recurrent Clostridium difficile Colitis: Case Series Involving 18 Patients Treated with
Donor Stool Administered via a Nasogastric Tube. Johannes Aas, Charles E. Gessert,
and Johan S. Bakken; Clin. Infect. Dis. 2003. 36:580-585
Infection Control
Recommendations
• Conduct surveillance. Track positive
numbers and outcomes
• Emphasize early diagnosis and treatment
to physicians
• Enforce strict Infection Control policies
– Contact precautions
• Hand washing with soap and water as
opposed to alcohol-based hand rinse
when caring for C. diff positive pts
Infection Control
Recommendations
• Environmental cleaning and disinfection
strategy (need sporicidal agent)
– Terminal cleaning - Routine cleaning (SaniMaster 4) vs (Dispatch)
• SaniMaster 4 – ammonium chloride
• Dispatch – sodium hypochlorite
– Sani-wipes for equipment and other items
• Glo-Germ® to evaluate cleaning
Surveillance - Should we Screen?
• Is C. difficile the next organism for active
surveillance on inpatient admission?
• If so, should you also screen for
Vancomycin- Resistant Enterococcus
(VRE) with the same specimen?
• If nothing else, all positive C. difficile tests
from the laboratory should be reported to
Infection Control for tracking