Prevention and Treatment of Opportunistic Infections in IBD

Mark T. Osterman, MD MSCEAssistant Professor of Medicine

University of Pennsylvania

Case #1• 64 year-old man

• UC pancolon Dx’d age 50

• Started Pred / Pentasa without benefit

• Tried IFX x5 doses without benefit

• Finally tried IV CsA with much benefit

• Transitioned to AZA

• Stopped AZA on own after 2y during which he took Colazal 6.75 g/d

• Remained on this for 5y

History

• Then had flare so started Pred 40 mg/d without benefit

• Referred to me and I admitted him

–Looked and felt poorly

–15 loose BM/d

–Moderate L mid abd pain

Subsequent Course• Treated with PO Vanc 125 mg QID

• Tapered Pred

• Improved quickly and went home after 5d

• Completed 14d of Vanc

• Admitted 2mo later with same symptoms as initially

• C. diff negative

• Stool Cx negative

Colonoscopy

Subsequent Course

• Started IV steroids without benefit x 3d

• Started IV CsA with much benefit after 2d

• Went home after 7d of IV CsA on PO CsA and AZA

• Admitted 2mo later with same symptoms and T102

• C. diff positive

Subsequent Course

• Held CsA / AZA

• Started PO Vanc 500 mg QID + IV MTZ 500 mg Q8h with benefit

• Restarted CsA / AZA after 1wk

• Started Vanc pulse after 2wk: 500 mg Q3d x 10 doses

• Doing well since

Clostridium Difficile Infection (CDI)

Burden of CDI in IBD

1Rodemann JF et al, Clin Gastroenterol Hepatol 20072Issa M et al, Clin Gastroenterol Hepatol 20073Anathakrishnan AN et al, Gut 2008

Author Years Population Rate of CDI

Rodemann1 1998-2004 Referral center UC: 1.8 → 5.8%CD: 1.0 → 2.2%

Issa2 2004-2005 Referral center All IBD: 1.8 → 4.6%

Ananthakrishnan3 1998-2004 NIS discharge database

UC: 2.4 → 3.9%CD: 0.8 → 1.2%

Nguyen4 1998-2004 NIS discharge database

UC: 2.7 → 5.1%CD: 0.9 → 1.1%

Ricciardi5 1993-2003 NIS discharge database

UC: 1.7 → 3.6%CD: 0.9 → 1.3%

Ananthakrishnan6 1998-2007 NIS discharge database

UC: 2.4 → 5.3%CD: 0.8 → 1.5%

4Nguyen GC et al, Am J Gastroenterol 20085Ricciardi R et al, Dis Colon Rectum 20096Anathakrishnan AN et al, Inflamm Bowel Dis 2011

Clinical Outcome in IBD

1Issa M et al, Clin Gastroenterol Hepatol 20072Anathakrishnan AN et al, Gut 20083Nguyen GC et al, Am J Gastroenterol 20084Ricciardi R et al, Dis Colon Rectum 2009

Issa1 63% required hospitalization, 20% had colectomy

Ananthakrishnan2 ↑ mortality (OR 4.7 [2.9-7.9]), hospital stay (OR 3), charges ($11.4K), TPN use (OR 1.9) vs. IBD

Nguyen3 ↑ mortality vs. UC: OR 3.8 (2.8-5.1)↑ hospital stay/charges (46/46%, 65/63%) vs. UC/CD

Ricciardi4 ↑ mortality over time in UC: 5.3% → 8.5%Operative mortality 26% in UC

Ananthakrishnan5 Mortality vs. IBD: OR 2.4 (1.5-3.7) → 3.4 (2.7-4.3)Colectomy vs. IBD: OR 1.4 (0.8-2.4) → 2.5 (1.9-3.3)

Jodorkovsky6 2-fold ↑ hospitalization and colectomy at 1y vs. UC

Jen7 ↑ in-hospital mortality vs. IBD: OR 6.3 (5.7-7.0)↑ hospital stay vs. IBD: 28 days

5Anathakrishnan AN et al, Inflamm Bowel Dis 20116Jodorkovsky D et al, Dig Dis Sci 20107Jen M-H et al, Aliment Pharmacol Ther 2011

Risk Factors: Gen Population• Exposure (hospital, retirement home)

• Duration of hospitalization

• Increasing age (especially >65)

• Comorbidities (number, severity)

• GI surgery

• NG feeding

• Immune suppression

• Ig deficiency McFarland LV et al, N Engl J Med 1989McFarland LV et al, J Infect Dis 1990Pepin J et al, CMAJ 2004Vesteinsdottir I et al, Eur J Clin Microbiol Infect Dis 2012Surawicz CM et al, Am J Gastroenterol 2013

Risk Factors: Gen Population• Abx

–Broad-spectrum, but every abx a/w CDI1

–Short / long exposure, single / multiple1

–Quinolones: up to 1/3 of cases today2

• PPIs

3Janarthanan S et al, Am J Gastroenterol 20124Kwok CS et al, Am J Gastroenterol 20125Deshpande A et al, Clin Gastroenterol Hepatol 2012

1Cohen SH et al, Infect Control Hosp Epidemiol 20102Pepin J et al, Clin Infect Dis 2005

Author #Studies #Patients Pooled Risk Ratio

Janarthanan3 23 300,000 1.7 (1.4 – 2.0)

Kwok4 39 300,000 1.7 (1.5 – 2.9)

Deshpande5 30 203,000 2.2 (1.8 – 2.6)

Risk Factors: IBD• UC (vs. CD)

• Colonic disease1,2

• Extent of colonic disease (left-sided / extensive vs. distal)3

• Active disease (vs. remission)4

• Comorbidities2

• Hospitalization5,6 and abx use5,7 may be less of a factor than in gen population

1Issa M et al, Clin Gastroenterol Hepatol 20072Nguyen GC et al, Am J Gastroenterol 20083Powell N et al, Gut 20084Pascarella F et al, J Pediatr 2009

5Bossuyt P et al, J Crohns Coliits 20096Clayton EM et al, Am J Gastroenterol 20097Goodhand JR et al, Aliment Pharmacol Ther 2011

Risk Factors: IBD

• IBD meds–Maintenance IM + anti-TNF: OR 2.6 (1.3-

5.1)1

– IFX: no increased risk vs. IM2

–Corticosteroids vs. IM2

•Any: RR 3.4 (1.9-6.1)•Monotherapy: RR 2.7 (1.5-4.6)

1Issa M et al, Clin Gastroenterol Hepatol 20072Schneeweiss S et al, Aliment Pharmacol Ther 2009

NAP1/BI/027• Likely in N. America/Europe since 1980s1

• Epidemic outbreaks: US/Quebec 2000s1-3

–High quinolone resistance–↑ use of quinolones–Severe, recurrent

• 16 and 23X more toxin A/B, binary toxin4

• Conflicting data on true severity5

• Severe disease seen with other strains5

• Multiple techniques to type C. diff6

1McDonald LC et al, N Engl J Med 20052Loo VG et al, N Engl J Med 20053Muto CA et al, Infect Control Hosp Epidemiol 2005

4Warny M et al, Lancet 20055Surawicz CM et al, Am J Gastroenterol 20136Cohen SH et al, Infect Control Hosp Epidemiol 2010

Diagnosis• Test liquid stool

• Do not retest for negative result– Retest positive in <5%– Chance for false positive

• Do not retest for cure– EIA and TC often positive 30d after symtoms

resolve

• Symptoms often identical to IBD

• Pseudomembranes often not presentCohen SH et al, Infect Control Hosp Epidemiol 2010Surawicz CM et al, Am J Gastroenterol 2013

Diagnosis

Deshpande A et al, Clin Infect Dis 2011Peterson LR et al, Am J Clin Pathol 2011Surawicz CM et al, Am J Gastroenterol 2013

Test Sens Spec Avail Cost ($) Utilization

Cx Low Mod Low 5-10 None (only toxigenic cause disease)

Toxigenic Cx

High High Low 10-30 Reference, limited useSlow (2-3 or 9d), costly

CCNA High High Low 15-25 Reference, limited useSlow (1-2d), costly

EIA for toxin A/B

75-95 83-98 High 5-15 Easy, quick, cheapMust detect both A/BSuboptimal sens

GDH 80-100 83-100 High 5-15 NPV 95-100, PPV 49-100Confirm: EIA or EIA+NAAT

NAATs 72-100 88-100 High 20-50 Most sens/specBest stand-alone test

Planche T et al, Lancet Infect Dis 2008Cohen SH et al, Infect Control Hosp Epidemiol 2010Shetty N et al, J Hosp Infect 2011

Treatment of Initial Episode

Cohen SH et al, Infect Control Hosp Epidemiol 2010Surawicz CM et al, Am J Gastroenterol 2013

Severity Criteria Treatment

Mild-moderate

DiarrheaOther Sx except below

PO MTZ 500 mg TID x10dStrength: A-I

Severe ↑ ageWBC >15, Cr >1.5X, alb <3Abdominal tenderness?IBD

PO Vanc 125 mg QID x10dStrength: B-I*

Severe and Complicated

ICUHypotensionT >38.5°CIleus, distentionWBC >35 or <2Lactate >2.2End organ failure

PO Vanc 500 mg QID + IV MTZ 500 mg TIDIleus/distention: PR Vanc 500 mg in 500 mL NS QID + IV MTZ 500 mg TIDSurgical consultStrength: C-III

0

20

40

60

80

100

MTZ Vanc

9098

76

97*

Res

po

nse

(%

)

Zar FA et al, Clin Infect Dis 2007

Severe CDI

Mild Severe

*p = 0.02

37/41 39/40 29/38 30/31

Severe CDI• Nonstandard dose of MTZ (250 mg QID)

• Nonvalidated definition of cure (negative follow-up toxin assay)

–MTZ known to be inferior to Vanc for microbiological endpoints

–Best outcomes: symptom resolution, recurrence, complications

• Definition of mild included many who would be considered severe today

Cohen SH et al, Infect Control Hosp Epidemiol 2010Surawicz CM et al, Am J Gastroenterol 2013

Fidaxomicin

0

20

40

60

80

100

Vanc Fidax

Cornely OA et al, Lancet Infect Dis 2012

0

20

40

60

80

100

Pat

ien

ts (

%)

Clinical Cure Recurrence

86

*p = 0.0002

n = 596RecurrenceClinical Cure

*p = 0.005

n = 509

Louie TJ et al, N Engl J Med 2011

Baseline Vanc Fidax

Prior 18% 17%

Severe 40% 39%

NAP1/BI/027 39% 38%

88 8887

25* 27*15 13

Baseline Vanc Fidax

Prior 14% 16%

Severe 24% 25%

NAP1/BI/027 33% 33%

Fidaxomicin

• Recurrence measured only up to d40– Need 90d to document strain recurrence

• Strain-specific effect implausible– No difference in MIC between NAP1 and non-

NAP1 strains– Vanc and Fidax have similar spectra of

activity against Gram-positive stool bacteria

• 1 Fidax patient with in vitro ↑ MIC– No in vitro resistance to Vanc in Vanc trials

Surawicz CM et al, Am J Gastroenterol 2013

Antibiotic Comparison

Cohen SH et al, Infect Control Hosp Epidemiol 2010Surawicz CM et al, Am J Gastroenterol 2013Louie TJ et al, N Engl J Med 2011

Abx Dose MIC (µg/mL)

Fecal Conc (µg/g)

Cost per Dose ($)

Cost per 10d ($)

MTZ 500 mg 2 9 0.73 22

Vanc 125 mg 2 64-880 17 680

IV Vanc 125 mg made PO

2.5-10 100-400

Fidax 200 mg 0.25 1225 140 2,800

IBD Meds and Clinical Outcome

Das R et al, Am J Gastroenterol 2010

Indication Grp 2 Grp 3

Resp 43% 43%

Rheum 15% 16%

Chemo 11% 3%

Endo 10% 6%

Neuro 6% 3%

Heme 4% 2%

Transplant 4% 13%

IBD 3% 6%

Other 2% 6%

Renal 2% 1%

Derm 1% 1%

IBD Meds and Clinical Outcome

• IS + abx vs. abx alone

• IS not randomly assigned

• 67% required treatment with IS + abx

• Death / colectomy / megacolon / perf / shock / resp failure: 12% vs. 0% (p=0.01)

– 2-3 IS: OR 17 (3.2-91) but small n

• No difference in CDI relapse, hospital stay, death/colecomy within 1 year

Ben-Horin S et al, Clin Gastroenterol Hepatol 2009

Recurrent CDI• <8 weeks after completion of treatment1

• 10-20%, but 40-65% after 1 recurrence1

• Same strain or different strain

• Risk factors– Continued non-CDI abx: OR 4.2 (2.1 – 8.6)2

– Older age: OR 1.6 (1.1 – 2.4)2

– Antacids: OR 2.2 (1.1 – 4.1)2

– Low level of anti-toxin IgG3

– Altered colon microbiota1Surawicz CM et al, Am J Gastroenterol 20132Garey KW et al, J Hosp Infect 20083Kyle L et at, Lancet 2001

Recurrent CDI: Treatment

Cohen SH et al, Infect Control Hosp Epidemiol 2010Surawicz CM et al, Am J Gastroenterol 2013

Recurrence # Treatment

1 Same as initialStrength: A-II

2 PO Vanc 125 mg QID x 10d followed by pulse* + taper 125 mg Q3d x 10 doses

Strength: B-III?Fidax

>3 FMT Strength: B-II

FMT• Indication– >3 recurrences– Consider for initial episode• Moderate: no response to Vanc after 1wk• Severe: no response after 2d

• Donor exclusion– ID: HIV, hepatitis, infx, high-risk behaviors– GI: IBD, IBS, chronic constipation / diarrhea,

CA / polyposis–Meds: immunosuppressants, recent abx

Bakken JS et al, Clin Gastroenterol Hepatol 2011

FMT• Donor testing– FDA guidelines for cells / tissue / products• Stool: CDI, Crypto/Giardia, Iso/Cyclospora,

O&P, Hp (if using UGI route)• Blood: HIV, hepatitis, syphilis

• Stool preparation / administration– Use within 6h but up to 24h– Dilute w/ NS / H2O / 4% milk, then blend / filter

– Route: N-GDJ-T, EGD, colonoscope (ileum and/or R colon or throughout), enema, pill

– Volume: UGI 25-50 mL, colon 250-500 mLBakken JS et al, Clin Gastroenterol Hepatol 2011

FMT• Nonrandomized outcomes– Short-term• Cure rate: 1° 89-94%, 2° 94-100%1-3

• Time to Sx resolution (mean): diarrhea 5d, pain 10d2

• Effective for NAP13

– Long-term (up to 68 mo)2

• 2/77 had improvement in pre-existing disease: arthritis and allergic sinusitis• 4/77 developed new disease: RA, Sjogren’s, ITP,

peripheral neuropathy• No death thought related to FMT

1Gough E et al, Clin Infect Dis 20112Brandt LJ et al, Am J Gastroenterol 20123Mattila E et al, Gastroenterology 2012

0

20

40

60

80

100

Vanc Vanc + prep Vanc + prep + FMT

4/13

31

Pat

ien

ts (

%)

van Nood E et al, N Engl J Med 2013

FMT

Cure Rate

*p <0.001

3/13 13/16

23

81*

FMT• Other findings1

– 3 non-responders to FMT had rpt FMT from different donor: 2 were cured

– 18 initial non-responders in other groups had off-protocol FMT: 11 cured after 1st FMT, 4 more after 2nd FMT

• NIH-funded blinded FMT RCT underway: donor vs. recipient stool via colonoscopy

1van Nood E et al, N Engl J Med 2013

8088

10094

Pat

ien

ts (

%)

1° Success

8/10 29/33 10/10 31/33

FMT for CDI in IBD

Hamilton MJ et al, Am J Gastroenterol 2012

2° Success

Probiotics• Prevention of abx-associated diarrhea1

–Meta-analysis: 25 studies, RR 0.43 (0.31-0.58)

• CDI recurrence prevention (with abx)2

Probiotic Duration /F/u (d)

RelapseProbiotic

RelapseControl

S. boulardii 28 / 56 15/57 (26%) 30/67 (45%)

S. boulardii 28 / 56 39/90 (43%) 37/78 (47%)

LGG 21 / 21 4/11 (36%) 5/14 (36%)

LGG 28 / 60 3/8 (38%) 1/7 (14%)

L. plantarum 38 / 70 4/11 (36%) 6/9 (67%)

1McFarland LV, Am J Gastroenterol 20062McFarland LV, Anaerobe 2009

Other Treatments for CDI• IV Tigecycline as rescue for severe

• Immunotherapy

– IVIG for severe or recurrent

–mAb to toxin A/B for recurrent: in phase III trials

–Vaccines (containing toxin A/B) for recurrent: in trials

• No convincing evidence for Rifaximin or Rifampin for recurrent CDI

Prevention• Infection control– Abx stewardship: can ↓ rate by 60%– Contact precautions: gloves, gown• Gloves (vinyl): can ↓ rate by >80%

– Isolation rooms– Disinfection of surfaces: EPA-approved agent– Hand hygiene (soap): ?chlorhexidine needed– Single-use disposable equipment– Hospital-based infection control program:

can ↓ rates by 33% during epidemicCohen SH et al, Infect Control Hosp Epidemiol 2010Surawicz CM et al, Am J Gastroenterol 2013

Prevention

Johnson S et al, Int J Infect Dis 2012