Management of C. difficile infection

Ted Steiner, M.D. Associate Professor

Associate Head, UBC Infectious Diseases April 11, 2013

Ellington, Res&Staff Phys, ‘99.

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

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

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

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

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

CDI admission rates in the US

AHRQ-HCUP report #2012-01

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

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

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

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 (

%)

Diagnosis of CDI

• Toxin assay

• PCR

• Culture

• Endoscopy

• CT

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

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!

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

Major treatment recommendations from SHEA guidelines

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

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

Reduced fecal bacterial diversity in recurrent CDAD

JY Chang et al, J. Infect. Dis. 2008, 197:435

Fidaxomicin

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%)

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

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)

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?

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

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

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

Gonzales et al, BMC Infect. Dis. 2010

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

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

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

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

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

Kwok et al, Am. J. Gastroenterol 2012; 107:1011–1019

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)

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

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)

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

What’s in the pipeline?

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

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

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

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)

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