Presentation on theme: "Clostridium difficile Infection"— Presentation transcript:
1 Clostridium difficile Infection Michael J. Tan, MD, FACP, FIDSAAssociate Professor of Internal MedicineNortheastern Ohio Universities College of MedicineSumma Health SystemAkron, Ohio
2 ObjectivesReview common challenging aspects treating diarrhea in the era of epidemic Clostridium difficile infection:Treatment/ManagementDiagnosisNew and emerging therapies
3 In a patient with liquid stool, which of the following would be most suggestive of non-C. difficile diarrheaA. Negative stool C difficle toxins x3B. Single negative C difficile common antigenC. Single Positive C difficile Common antigen with negative C difficile toxinD. Negative fecal leukocytesE. Negative stool lactoferrin
4 History1893 Pseudomembranous colitis first described as “Diphtheritic colitis”. Finney Bull Johns Hopkins Hosp1935 Bacillus difficilis isolated from feces of newborns. Hall & O’Toole Am J Dis Child1950s+ Colitis was attributed to staphylococcus aureus.1960 Doubt cast on above…S. aureus not always found. Dearing Gastroenterology1974 Clindamycin-associated colitis. Tedesco. Ann Intern Med1977 Undescribed toxin in pseudomembranous colitis. Larson. Br Med J1977 Antibiotic-induced colitis. Implication of a toxin neutralized by Clostridium sordellii antitoxin. Rifkin. LancetClindamycin associated colitis in hamsters: protection with vancomycin. Bartlett. Gastroenterology1978 Identification of Clostridium difficile as a cause of pseudomembranous colitis. George. Br Med J2000s S aureus may cause disease like C. difficile.
5 CaseA 70 year old female is admitted to your service with liquid stool seven times a day. You are seeing her for the first time, and she has no orders entered yet.Which of the following is the most appropriate next step?A. Start on oral vancomycin 125mg PO q6hB. Start on oral metronidazole 500mg PO q8hC. C difficile Common AntigenD. Take more historyE. Call ID
6 HistoryShe was recently treated with a course of amox/clav x 7 days for “bronchitis”She just finished her last dose the morning of admissionShe usually has one soft stool dailyOn amox/clav she went 3-4x/day mushyNow stool is 7x/day mostly liquidShe has some abdominal discomfortShe’s still tolerating PWBC is 16kCrt 1.6
7 What to do now? A. Start metronidazole 500mg PO q8h B. Start metronidazole 500mg IV q6h and Vancomycin 125mg PO q6hC. Start vancomycin 125mg PO q6h and order C difficile assayD. Order C difficile assay, await result before startingE. Start a bulk-forming agent
8 What is this common antigen test? Toxin test as a test of cure? Sensitivity of Toxin EIA 70-80%Common antigen very sensitive, but can’t differentiate between toxin producing and non-toxin producingIf a Common Antigen is negative, negative predictive value about >98%, probably NOT CDI.Screen with common antigen. Use toxin to confirm.Negative toxin won’t rule out CDI.
9 Diagnostic Aids Toxin Assay Toxin A/B – Both Antigen detection Fast, but less sensitive than stool cultureAntigen detectionNeed to combine with toxin assayStool culturesSlow and labor intensive but sensitiveGrowth may not be toxigenic strainPCRMay be gaining favor for detection of toxigenic C. difficileWill need high sensitivity and specificityColonoscopy with biopsyAbdominal CT ScanClinical suspicionHistory/epidemiologyLactoferrin?
10 Testing methods Classically C. difficile A/B toxin testing Sensitivity is about 80% (70%-90%)Culture is gold standardSlow and labor intensiveIDSA doesn’t make a firm recommendation on which approach to use.
11 Two-Step testing approach Test with Common AgIf (-) extremely unlikely C DiffIf (+) test for cytotoxinIf Cytotoxin (+) C DifIf Cytotoxin (-) clinical judgementCytotoxin testing not widely availableTwo step common Ag + Toxin A/B
12 Testing principles-Update Common AntigenDo only once, repeat only if stools change+ Common, - toxin, same boat as before; clinical judgment should be exercisedToxinIf the first one is negative, it’s still not likely to be CDAD. Don’t go beyond two.Don’t test formed stools. Test only if liquid.Still NOT recommended as test of cure. Risk of asymptomatic colonization.
13 Is metronidazole still effective? Metronidazole is still acceptable as first line therapy for MILD diseaseMetronidazole 500mg PO q8h or 500mg IV q6hVancomycin preferred for anything other than mild diseaseNo data to show that 250mg or 500mg of vancomycin better than 125mg PO q6h.May have better toxin clearing, but no evidence of morbidity or mortality improvement.
14 Vancomycin or metronidazole? If Severe, vancomycinAge > 65Multiple comorbid conditionsAbdominal symptoms, peritonitis, radiographic findingsLeukocytosis >15kSepsis syndrome(Pretty much anyone who can get admitted)If Unable to PO, metronidazole 500mg IV q6hNo proven benefit of vancomycin PO + metronidazole IV/PO
15 Treatment Stop antibiotics if possible For first time positive of mild diseaseMetronidazole 500mg PO q8hMetronidazole 500mg IV q6hr if unable to POAlternative Vancomycin 125mg PO q6hTreatment generally 10-14dSevere DiseaseVancomycin 125mg PO q6hGenerallyNo benefit of combining metronidazole and vancomycinNo benefit of 250mg or 500mg of Vanc PO vs. 125mg
16 Case Vancomycin 125mg PO q6h started on hospital day #1 Day 2-3, WBC improves, creatinine improvesDay 3-4, little stoolDay 5: Big loose, semi-formed BM, creat and WBC stableWhich of the following is reasonable?A. Increase vancomycin to 250mg PO q6hB. Recheck stool C difficile assayC. This happens…continue therapy as current.D. Add lactobacillus and saccharomycesE. ID Consult
17 Epidemic strainNot generally more resistant to vancomycin or metronidazoleBaines: JAC 2008 Aug 7, Emergence of reduced susceptibility to metronidazole in C difficile.Interestingly for 001 ribotype England, NOT 027!!Can be more difficult to treatCan take longer to respond to therapy
18 Response to treatmentEpidemic strain C Diff may take longer to respond to therapyPatients should be given 3-5 days on therapy with no improvement before being considered a treatment failureAny improvement in stool frequency, consistency, leukocytosis or abdominal pain is improvementNot uncommon for patients to improve to not having any stool, but then have a huge stool around this time
19 Epidemiology 10-20% of inpatients on antibiotics develop diarrhea 20% of these from C. diff. Bartlett NEJM 2002, Cleary Dis Colon Rectum 1998Mortality 6-30% when pseudomembranous colitis is present1% of hospitalized patients develop CDAD20% of cases are community acquired Buchner Am J Gastro2001, Dallal Annals Surgery
20 Epidemiology CDAD continues to rise Discharge data: hospitalizations affected by CDAD 2005Rate is doubled that of 2000Disproportionately affects patients over 65Attributable mortality direct and indirect up 7%/17%Classic attributable mortality <1%CostHospital costs (1990s) $2000-$5000Mean lifetime cost $11000
21 Epidemiology Higher readmission rates Higher rates of patients to LTAC Number and rate increased 5-fold on death certificates between 1999 and 2004Previously low-risk patients are at riskPregnant and community onset patients are increasingly common, including lack of antibioticsMore than half the states have Epidemic strain
22 States with BI/NAP1/027 strain of C. difficile (N=40), October, 2008 DCHIPRAKCDC
23 Epidemiology Dubberke E., et al, Arch Intern Med. 2007;167:1092-1097 Wards with more CDAD patients had higher risk of patients developing CDADAssociation almost as strong as antibiotic use
25 CaseYou made no change to her therapy. Day 6-7, stools back to 1-3x/day, soft but “not perfect”. Feels better, hoping for discharge.What next?A. Plan discharge and finish14 day course of vancomycin 125mg POB. Recheck C difficle assaysC. Add lactobacillus and/or saccharomyces therapyD. Stop PO Vancomycin and DischargeE. Consult ID. She still has diarrhea.
26 CasePatient was discharged, and she finished 14 days of PO Vancomycin. After finishing the PO vancomycin, her stools returned to 1x/day, soft. Five days later you get a call…she has diarrhea. What next?A. Restart Vancomycin 125mg PO q6hB. Start Vancomycin 250mg PO q6hC. Start metronidazole 500mg PO q8hD. Get more historyE. Repeat C difficile assay
27 HistoryFurther history reveals that the patient is now having 3- 4BM/day, soft and mushy, not liquid like it was when she was admitted. Eating ok, no abdominal pain. Next?A. Restart the Vancomycin 125mg PO q6hB. Start Vancomycin 250mg PO q6hC. Probably not C difficile recurrence, watch the stool a little longerD. Recheck the C difficile assayE. Start a bulking agent.
28 Is this Recurrence or post-CDI irritable bowel? Get down to the nature of the stoolIs it…Liquid? Any form in it?>5x/dayLike it was before therapy? Better than it was before therapy but worse than baseline?Most stool that is better than it was before therapy, but worse than baseline is likely post-CDI IBSUsually does not require treatmentTreatment indicated, if it does go back to what it was before treatment
29 Reservoirs and Colonization McFarland NEJM 1989, JID 1990Asymptomatic colonization15-70% of neonates. (<=1 yr)< 5% of normal adults20% after 1 wk in hospital50% after >4 wks in hospital30% of newly colonized patients develop CDADThere is a greater chance of positive common antigen or positive toxin that is not representative or disease.Clinical presentation is key extremely important
30 CaseYou elected to observe the patient. Her stools calmed to a1-2x/day, soft and mushy, but 10 days after her last dose of PO Vanc, she has 6 stools in one day that are liquidy. She thinks she overdid the tacos, and she doesn’t call until day 12. Now her stools are 1-2/day again. What do you do?A. Restart the Vancomycin 125mg PO q6hB. Start Vancomycin 250mg PO q6hC. Probably not C difficile recurrence, watch the stool a little longerD. Recheck the C difficile assayE. Start a bulking agent.
31 CaseDay 15 post-therapy: On day 14 and 15, she’s been having 7-8 liquid stools per day. What now?A. Restart vancomycin 125mg PO q6h x 14 daysB. Restart vancomycin 250mg PO q6h x 14 daysC. Not likely a recurrence, watch a little longerD. Start a bulking agentE. Add probiotic therapy
32 How do I treat a recurrence? Is it really a recurrence?Recurrence usually in first 14 days after therapyRecurrence rate is about 20% of metronidazole or vancoSame course is usually indicated for first recurrenceMay advocate going to vancomycin if previously on metronidazoleSecond Recurrencedays?28 days?Taper?
33 Treatment Second Recurrence If continued response, same drug is appropriate—but would advocate using vancomycin insteadMany strategies14 days on 3 days off, 14 days onExtended duration, 28 daysChange medicationVancomycin TapersFlagyl absorption/transit failure with improved symptoms?
34 How do I treat a recurrence? Multiple recurrencesNo standard setMultiple drugsAsk a consultantVerify it’s actually CDIColonscopyRule out Inflammatory bowelS. aureusFungal overgrowth, bacterial overgrowth syndrome?Rule out other medication induced.Probiotics have a limited roleTherapy must be individualizedBinders, bulk-formers not of any benefitFecal transplant?
35 Follow-up studies in refractory patients Look for other causesCulture for S. aureusFungal Overgrowth/Overgrowth Syndrome?Get another colonoscopyInflammatory bowelIgG if possible IgG to toxin AOther historyColectomy/Bowel SurgeryMedications/ProbioticsWhat goes in affects what comes out
36 What preventive measures can be taken? Prophylactic CDI therapies?Prophylactic probiotics?
37 Probiotics and Prophylaxis There are no good randomized clinical trials that suggest probiotics have any beneficial effectThere are many cases of lactobacillus bacteremia and saccharomyces fungemia“Prophylaxis” with these agents has not demonstrated fewer CDAD cases“Prophylaxis” with metronidazole or vancomycin has not been shown to be effectiveA recent meta analysis of studies suggests some benefit of Lactobacillus rhamnosus for AAD but not CDAD and Saccharomyces boulardii for CDAD recurrences. (Am J Gastroenterol.101 (4):812–822 (2006) McFarland LV Meta-Analysis of Probiotics for the Prevention of Antibiotic Associated Diarrhea and the Treatment of Clostridium difficile Disease)BMJ 335:80 (2007) Hickson et al, Efficacy with a Lactobacillus preparation for prevention of diarrhea. Does have methodological flawsKale-Pradhan et al, Pharmacotherapy 2010;30(2); Role of Lactobacillus in the Prevention of Antibiotic-Associated Diarrhea: A meta-analysis. Data heavy from one particular paper; suspect at bestOther probiotic preps are under investigation
38 What about these?Probiotics – NOT definitively helpful. Have been documented cases of lactobacillus bacteremia and Saccharomyces fungemiaLactobacillusSaccharomycesAcidophilusBacitracin – as effective as vancomycin, but higher residual toxin without more evidence of recurrent colitisCholestyramine – NOT demonstrated to be helpful. Runs risk of binding other agents
39 Is there going to be anything that works better? Yes and No
40 Therapeutics Accepted Controversial Some studied success MetronidazoleVancomycin POSome studied successNitazoxanideRifaximinTinidazoleBacitracinRamoplaninControversialProbioticsCholestyramineIVIGVancomycin retention enemaStool transplantResearch compoundsTolevamer (failed)MBL-monoclonal Ab. A & BOPT-80 (Fidaxomicin)Lipoglycopeptide?Vaccine?
41 MDX-066 (CDA-1) and MDX-1388 (CDB-1) Phase II CompletedHuman antibody-based monoclonal antibodies to neutralize CDTA/CDTB11/3/2008Standard of care (metro vs. vanco) + MAb vs. placebo one time infusion.Placebo recurrence rate 20%, consistent with literatureMAb recurrence rate reduced 70% compared with placeboMedarex/Massachusetts Biologic Laboratories Press Release, 11/3/2008
42 OPT-80-fidaxomicin One of Two Phase 3 trials completed Newest data 10 days OPT-80 vs. vancomycin POSimilar Cure rates compared with vancomycin 92.1% vs 89.9%Lower recurrence rates compared with vancomycin, 13.3% vs 24%Global Cure rates higher compared with vancomycin, 77.7% vs %Second Phase 3 trial just finishedNewest dataAs above, but recurrence rate similar to vancomycin when dealing with epidemic strainSecond Phase 3 complete with similar results; Epidemic strain data still pending.Optimer Pharmaceuticals Press Release 11/10/2008
43 Outpatient Diarrhea Get a full history Get down to the poop Medication historyAbx associated diarrhea medicationsOther laxatives/catharticsOTC/Natural remediesTravel HistoryActivitiesDining HistorySick ContactsDuration/Recurrence
44 Outpatient diarrhea Stool Ova and Parasite Stool culture GiardiaStool cultureSalmonella, Shigella, Yersinia, CampyImmunecompromisedModified Acid-fast stains for “-sporidosis”C Difficile assays
45 Outpatient Diarrhea Base CDI therapy on index of suspicion Base any diarrhea therapy on index of suspicionNon-toxic and controllable stools?It’s ok to observe without therapy!
46 Inpatient Diarrhea Get a full history Get down to the poop Start prior to or after admission?Get down to the poopMedication historyAbx associated diarrhea medicationsOther laxatives/cathartics/tube feedsOTC/Natural remediesDuration/RecurrenceSome of the outpatient questions apply too
47 Inpatient diarrhea Stool Ova and Parasite Stool culture Generally don’t check unless admitted <48h and diarrhea started prior to admitStool cultureSalmonella, Shigella, Yersinia, CampyImmunecompromisedModified Acid-fast stains for “-sporidosis”C Difficile assaysFecal WBC, lactoferrin?
48 Inpatient Diarrhea Base CDI therapy on index of suspicion Base any diarrhea therapy on index of suspicionDoesn’t sound quite like CDI, and the stool is controllable, and the patient is “stable?”It’s ok to observe without therapy!Have a threshold to start.
49 Is it ok to use a bulk-former? Generally bulk-formers of little benefitIf fairly certain CDI is not active, ie Post-CDI irritable bowelProbably ok to use bulk-formerProbably ok to use gut slowing agentBut monitor closely for recurrence or worsening
50 Summary Test stool where suspicion is high Do not treat asymptomatic diseaseEpidemic strains appear to produce more toxinEpidemic strains are more virulent, but not resistantSingle recurrence does not indicate resistanceVancomycin PO is preferred for severe diseaseMetronidazole is still first line for mild diseaseSurgical intervention indicated for severe cases/megacolon/obstructionPursue other causes if CDAD evaluation continues to be negative