Prevention and Treatment of Opportunistic Infections in IBD Mark T. Osterman, MD MSCE Assistant Professor of Medicine University of Pennsylvania
Jan 29, 2016
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