management of c. difficile - picnet sli… · (5)thermal injury to >35% of body surface area...
TRANSCRIPT
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Management of C. difficile infection
Ted Steiner, M.D. Associate Professor
Associate Head, UBC Infectious Diseases April 11, 2013
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Ellington, Res&Staff Phys, ‘99.
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Admission to hospital
Admission to long-term care facility
Poor hand hygiene
Contact with a symptomatic CDI person
Age >65
Multiple comorbidities
Immunocompromised
Recent antibiotic exposure
Medications decreasing intestinal motility
Recent intestinal surgery
Some chemotherapies
CDI Risk Factors1
1. McFarland LV. Curr Opin Gastroenterol. 2009;25(1):24-35. 2. McFarland LV. J Med Microbiol. 2005;54(pt 2):101-111.
Almost all cases are associated with recent antibiotic use, which alters the normal gut microbiota, somehow enabling C difficile to proliferate and produce its toxins2
Patient Characteristics
Increased Exposure to C difficile
Disruption of Normal Gut Bacteria
3
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CDI Inpatient Cases in United States Increased Significantly From 20011
Total Number of Discharges1
(ICD-9-CM 008.45)
1. Elixhauser A, et al. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Health Care Policy and Research (US); 2006-2008 Apr. http://www.ncbi.nlm.nih.gov/books/NBK56038.
The number
of hospital discharges with CDI
more than doubled
from 2001 to 2005
4
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Marked Increase in CDI Rates and CDI-Related Mortality
New “hypervirulent” strain of C difficile (“NAP1/027/BI”) associated with higher CDI rates and severity1
Since 2003, CDI-related mortality rates as high as 14% have been seen in North America2
A Canadian study confirmed the bulk of mortality occurred in adults >60 years of age, especially those infected with NAP1 strain4
1. Kuijper EJ, et al. Clin Microbiol Infect. 2006;12(suppl 6):2-18. 2. Pépin J, et al. CMAJ. 2004;171(5):466-472. 3. Redelings MD, et al. Emerg Infect Dis. 2007;13(9):1417-1419. 4. Miller M, et al. Clin Infect Dis. 2010;50(2)194-201.
CDI mortality rates per million US population3
5
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CDI Incidence by Age
20.4/1,000 discharges
15.2/1,000 discharges
8.3/1,000 discharges
3.0/1,000 discharges
Source: AHRQ HCUP data.
CDI C
ases
/ 1
,000
Dis
char
ges
85+ 65-84 45-64 18-44 <18
Year 6
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Total Number of CDI Cases in US Hospitals
138,954
348,950
Including nursing homes and cases in the community, currently estimated at least 1 million cases per year in the United States 7
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CDI admission rates in the US
AHRQ-HCUP report #2012-01
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Effect of Strain Type and Age on CDI-Related Death
Miller M, et al. Clin Infect Dis. 2010;50(2):194-201.
Age (Years)
NS
NS
NS
P=0.02 P=0.07
P=0.005 NS
0
2
4
6
8
10
12
14
16
18
18–39 40–49 50–59 60–69 70–79 80–89 90+
CDI-
Rela
ted
Dea
th (%
)
NAP1/027 Non-NAP1
n=1,008
9
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C difficile Infection Rate per 1,000 Patient Admissions – CNISP
Public Health Agency of Canada | Agence de la santé publique du Canada.
*Based on 9 months of data 10
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Case Fatality Ratio for Patients With CDI by Age Group, 2010
0.8 0.3 0.9
0.81.1
3.5
0.0
1.0
2.0
3.0
4.0
5.0
<18 19-64 65+
Perc
ent o
f Cas
es
Age group, years
CDI contributed to death CDI cause of death
Public Health Agency of Canada | Agence de la santé publique du Canada. 11
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Public Health Agency of Canada | Agence de la santé publique du Canada.
Severe Outcomes Associated With C difficile Infection – CNISP
1.0
2.0
5.6
1.4
2.2
4.8
2.0
1.0
4.8
1.6
2.2
2.4
1.2
5.65.4
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Colectomy ICU admission Deaths: directly or indirectly associated with CDI2004/5 2007 2008 2009 2010
12
Perc
ent (
%)
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Diagnosis of CDI
• Toxin assay
• PCR
• Culture
• Endoscopy
• CT
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Assay
Comparison to toxigenic culture resultsa
Sensitivity (%) Specificity (%) PPV (%) NPV (%)
Premier toxins A and B
48 98 88 87
Xpect C. difficile A/B
48 84 46 85
Immunocard toxins A & B
48 99 91 87
Triage C. difficile panel (toxin A)
32 100 100 84
LC real-time PCR 86 97 90 96
Sloan L et al, J Clin Microbiol 2008, 46:1996
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IDSA/SHEA Guidelines: important “B” recommendations for diagnosis
• Test for CDI only in unformed stools (B-II)
• Toxigenic culture as gold standard for diagnosis (B-III)
• Toxin ELISAs lack sensitivity—favor two-step testing or PCR (B-II)
• Repeat testing during the same episode of diarrhea not recommended (B-II)
Ideal diagnostic method for routine clinical use still not standardized!
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Pre 2012: Drugs for C. difficile Drug Dosage Advantages Disadvantages
Vancomycin 125 mg p.o QID No drug is superior in initial cure; likely best drug for severe disease
Cost
Metronidazole 500 mg p.o. TID Cost Higher failure rate than Vancomycin; intolerance, equally prone to causing VRE
Rifaximin 200 mg p.o. TID Nonabsorbable; studied once in controlling relapses (“chaser”)
Small studies; evolving resistance in monotherapy
Nitazoxanide 500 mg p.o. BID Noninferior to MTZ and Vancomycin
Only small data sets so far
Fusidic acid 250 mg p.o TID Noninferior to MTZ in 1 trial
Minimal data; rapid resistance
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Major treatment recommendations from SHEA guidelines
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From Zar et al, CID 2007. One point each for age >60 years, temperature >38.3°C, albumin level <2.5 mg/dL, or peripheral WBC count >15,000 cells/mm3 within 48 h of enrollment. 2 points for pseudomembranes or ICU admission. Severe = ≥2 points
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CDI recurrences
• Multiple studies and case series have shown a recurrence rate of 25-30%
• Typically occur within 1 week, can be up to 30d
• Major risk factors: – Antibiotic use – PPIs > H2RA
• Minor associations: age, female sex, ? diverticulosis
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Reduced fecal bacterial diversity in recurrent CDAD
JY Chang et al, J. Infect. Dis. 2008, 197:435
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Fidaxomicin
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More good news about fidaxomicin
• Concomitant antibiotics delay response to vanc/fidax and increase risk of relapses
• Fidax superior to vanc in clinical cure (95% v 79%) in presence of concomitant antibiotics
• Lower relapse rate with fidax (17% vs 29%)
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The not-so-good news • Analysis of all subjects combined from the
Phase III Fidaxomicin vs. Vancomycin trials • Benefit of fidaxomicin highest in non-NAP1/BI
cases (16.6% vs 27.4%; p = .007) • Recurrence rate not significantly different in
NAP1/BI cases (23% vs 31%; p=0.2) • Studies not powered to answer this question • No significant benefit over vanco in patients
with relapsed disease (again, not powered).
Petrelli et al, CID, April 2012
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Current indications for fidaxomicin (from new BC guidelines)
• Severe CDI (by clinical definition) when vancomycin cannot be used (due to allergy, etc.)
• “Reasonable” for outpatient treatment of first episodes of CDI in patients who are willing to pay
• When available on hospital formularies, additional indications may be added (e.g. CDI in patients who need to remain on Abx)
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BC recommendations for recurrent disease
• First recurrence: treat as initial epidose
• Second recurrence: vancomycin 125 mg QID x 14 d – “Consider” taper
– refer to ID or GI for multiple recurrences
• What then?
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Biggest mistakes I see
• Overtreatment – Combination therapy – Elevated doses – Prolonged therapy – “step-up”
• Failure to consider alternative diagnoses • Retreatment on the basis of positive stool
assay • Continuation of unnecessary Abx and PPIs
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Overtreatment
• Combination therapy – Never proven beneficial in CDI – Rationale for IV MTZ as add-on is failure of
vancomycin to reach the colon (only in cases of severe ileus—even then not proven)
– NOT beneficial in recurrent disease – No other combinations proven effective in CDI
• Remember: goal is not to eradicate C. diff, just to
kill vegetative forms and allow the colonic mucosa to heal and commensals to repopulate
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Overtreatment (2)
• Elevated doses – SHEA/IDSA guidelines recommend 500 mg QID of
vanco for fulminant, potentially fatal disease • Grade IIIC recommendation—NO EVIDENCE
– Colonic levels of vancomycin are 100-1000X above the MIC even at 125 mg QID (typically < 1 µg/ml; stool concentrations reach 1000 µg/ml)
– Some commensals have higher MICs to vanco; hence high concentrations could be more destructive to the microbiota than 125 mg QID
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Gonzales et al, BMC Infect. Dis. 2010
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Overtreatment (3)
• Prolonged treatment – We often extend antibacterials for difficult-to-
eradicate infections (osteomyelitis, endocarditis) – This practice should not be applied to CDI
• Eradication is not the goal—spores are not killed by antibiotics
• Prolonging antibiotics simply delays reconstitution of normal commensals
– A vancomycin taper is the exception—here the goal is to keep C. diff replication/toxin production low enough to maintain health while commensals regrow
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Overtreatment (4)
“Step-up” treatment—using different drugs (fidaxomicin, rifaximin)
• I have seen this recommended in refractory, relapsing cases. Problems: – No clinical trial data for fidaxomicin on multiple
relapses • Theoretical benefit may be small once bacterial populations
are already damaged by repeated Abx – Very costly – Does it require a taper? Pulsed therapy? Etc.
• Rifaximin data limited to case series; only in US
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Is it really a CDI relapse?
• A positive toxin, PCR, or antigen assay after treatment is common—cannot be used to rule in disease (but can help to rule out)
• Other conditions can cause diarrhea after recurrent CDI – Post-infectious IBS – Microscopic colitis – Lactose intolerance – New enteric infections
• I have a low threshold to refer to GI for endoscopy
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Continuation of unnecessary abx or PPIs
• Many patients receive Abx for soft indications – Bronchitis/COPD flare – Asymptomatic bacteriuria (even symptomatic bacteruria)
• There is no evidence to support “prophylactic” vancomycin or MTZ in patients with a history of CDI who get placed on other Abx – Is likely to cause greater disturbance in the microbiome – Can provide a false sense of security – Most patients with prior CDI will NOT relapse when given
additional Abx
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Howell, M. D. et al. Arch Intern Med 2010;170:784-790.
Rates of Clostridium difficile infection stratified by the type of antibiotics and acid-suppressive therapy
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Kwok et al, Am. J. Gastroenterol 2012; 107:1011–1019
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Are PPIs overprescribed in hospital?
• Rashid et al, ISRN Gastroenterol. 2012
• Retrospective analysis from single teaching hospital
• 70% of patients with CDI had an inappropriate PPI indication (86% on medical, 14% on surgical)
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FDA indications for PPIs
• Healing of erosive esophagitis • Maintenance of healing of erosive esophagitis • Symptomatic gastroesophageal reflux disease • Helicobacter pylori eradication in combination with antibiotics • Short-term treatment of active gastric ulcer • Short-term treatment of active duodenal ulcer • Maintenance of healed duodenal ulcer • Healing of NSAID-Associated gastric ulcer • Risk reduction of NSAID-associated gastric ulcer • Risk reduction of upper gastrointestinal bleeding in critically Ill
patients • Pathological hypersecretory conditions including Zollinger-Ellison
syndrome
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American Society of Health-System Pharmacists therapeutic guidelines on stress ulcer prophylaxis Intensive care unit (ICU) patient plus one of the following: (1)Coagulopathy (i.e., platelet count of <50,000 mm3, international normalized ratio (INR) >1.5, or an activated partial thromboplastin time (aPTT) >2 times control) (2) Mechanical ventilation for >48 hours (3)History of gastrointestinal ulceration or bleeding within one year of admission (4)Glasgow coma score of ≤10 (5)Thermal injury to >35% of body surface area (6)Partial hepatectomy (7)Multiple trauma (injury severity score of ≥16) (8)Transplantation perioperatively in the ICU (9)Spinal cord injury (10) Hepatic failure (11) Two or more of the following risk factors: sepsis, ICU stay of greater than one week, occult bleeding lasting at least six days, and high-dose corticosteroids (>250 mg/day of hydrocortisone)
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Probiotics
• Not recommended in IDSA guidelines (C-III)
• Based on limited data and risk of bloodstream infection
• Some experts still use Saccharomyces boulardii (Florastor) in relapsing patients undergoing stool transplant
• My experience—they just don’t work
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What’s in the pipeline?
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Novel anti-C. diff drugs
• Phase III – Surotomycin (CB-183,315, Cubist)—lipopeptide – MK3415, 3415A (Merck)—antitoxin mAbs
• Phase II
– LFF571 (Novartis)—semisynthetic thiopeptide – GT160-246 (Genzyme)—anionic polymer – Cadazolid (ACT-179811, Actelion)—oxazolidinone – VP 20621 (ViroPharma)—nontoxigenic C. diff
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Anti-toxin therapy
• Humanized mAbs against TxA and TxB
• Given IV as single dose
• Phase II trial: 70% reduction in recurrence rate vs placebo (p=0.0004)
• Trend towards less severe disease after treatment (p =0.06)
• Phase III trials underway
Lowy et al, DDW 2009, 751b
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Ongoing Canadian studies of stool transplantation
• UHN (Toronto, S. Hota)—non-blinded RCT of vancomycin taper vs. fresh donor stool enema
• McMaster (C. Lee)—Double-blinded RCT of fresh vs. frozen stool from standarized donor
• Queen’s (E. Petrof)—synthetic stool (polymicrobioal cultures)—not currently enrolling
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Problems with fecal replacement therapy
1. No consensus on best methods (Donor, route, frequency, drug treatment)
2. Standardization of procedure
3. Liability (no adverse outcomes reported)
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Conclusions
• CDI infection rates remain high and relapses are common
• Metronidazole and vancomycin remain treatments of choice – Newer drugs may prove superior – Fidaxomicin an attractive option in initial episodes if
cost is not a concern
• Recurrences should be managed by an experienced provider to avoid mistreatment and overtreatment