Presentation on theme: "Tres Difficile Stephen M. Brecher PhD Director of Microbiology VA Boston Health Care System West Roxbury, Massachusetts."— Presentation transcript:
1 Tres DifficileStephen M. Brecher PhD Director of Microbiology VA Boston Health Care System West Roxbury, Massachusetts
2 The opinions expressed in this presentation are those of the presenter and do not necessarily represent the views of the Veterans Affairs Health-Care System
3 The Dominant SpeciesThe human body has 1013 human cells and a minimum of 1014 bacterial cells
4 Overview Case reports Historical perspective Organism & key properties Changing epidemiologyDiseaseDiagnosisTreatmentInfection control
5 Case Study 160 yo male admitted to hospital for community acquired pneumonia, treated with levofloxacin and discharged7 days later, seen at another hospital because of pound weight gain over last few days (“my abdomen has never been so big”) and hypertension (213/106)Afebrile, WBC of 8.5, albumin 3.1, creatinine 0.9, no diarrhea notedAdmitted, treated for hypertension and ciprofloxacin given to complete treatment for CAP; discharged 3 days later
6 Case Study 1 (cont’d) Day 1 Presents to ER 3 days after discharge Fever (101), diarrhea, generally feeling ill, no abdominal painWBC 27.8K, albumin 2.9, creatinine 1.2Admitted with C. difficile colitis listed as a possible dx, but not treated (except for levofloxacin)Day 210 stools/day, altered mental statusC. difficile EIA positive; put on metronidazole 500 mg TID
7 Case Study 1 (cont’d) Day 3 Transferred to SICU, anuric, abdominal pain, distension, developed cardiac complications, ventilated, renal failure. Poor prognosis and colectomy ruled out following surgical consultOral and rectal vancomycin addedWBC > 30K, albumin 2.3, creatinine 3.1Day 4WBC 59.6K, toxic megacolonDay 5WBC 88K, made DNI/DNR, died
8 Historical Perspective In the 1960s it was noted that patients on antibiotics developed diarrhea1“staphylococcal colitis”Originally thought to be caused by S. aureus and treated with oral bacitracinStool cultures routinely ordered for S. aureusEarly 1970s, a new explanation“clindamycin colitis”Severe diarrhea, pseudomembranous colitis, and occasional deaths documented in patients on clindamycin1. Gorbach SL. NEJM. 1999;341:
9 “Antibiotic Associated Pseudomembranous Colitis Due to Toxin-Producing Bacteria” Bartlett and co-workers1 demonstrated cytotoxicity in tissue culture and enterocolitis in hamsters from stool isolates from patients with pseudomembranous colitisIsolate was C. difficileBacillus difficilis (now confirmed as C. difficile) was cultured from healthy neonates (with difficulty, hence the name) in 193521. Bartlett JG, et al. NEJM. 1978;298:2. Hall JC and O’Toole E. Am J Dis Child. 1935;49:
10 Quiz TimeQ. Why did it take so long to associate the organism C. difficile with the disease?A. Organism was (is) found in healthy infantsQ. Why do antibiotics sometimes cause diarrhea (unrelated to C. difficile)?A. Disrupt the intestinal flora which plays a major role in digestion of food
11 Clostridium difficile Gram-positive, anaerobic, spore-forming bacillusVegetative cells die quickly in an aerobic environmentSpores are a survival form and live for a very long time in the environmentGrows on selective media in 2 days and smells like horse manure (p-cresol)
12 Importance of SporesResistant to heat, drying, pressure, and many disinfectantsResistant to all antibiotics because antibiotics only kill or inhibit actively growing bacteriaSpores survive well in hospital environmentSpores are not a reproductive form, they represent a survival strategy
13 Source of InfectionsSpores in hospital, nursing home, or long-term care environment associated with ill patientsLarge numbers of spores on beds, bed-rails, chairs, curtains, medical instruments, ceiling, etc.Asymptomatic carriers in those same environmentsLow risk compared to patients with active diseaseFalse negative lab tests (low sensitivity)Unknown in community based infections, but food has been implicated11. Jhung MA, et al. Emerg Infect Dis. 2008;14:
14 Risk Factors for Infection Hospitalization or long-term care facilityAntibiotics (some more than others)Increasing age (>65, >>80)Co-morbiditySurgery? Proton-pump inhibitorsCommunity-associated casesPeri-partumClose contact of CDI (C. difficile infection) caseFood
15 Case Study 231 yo pregnant female (14 weeks, twins) seen at a local ER with history of3 weeks intermittent diarrhea3 days cramping and watery diarrheaStool + for C. difficile toxinReceived T/S for UTI 3 months prior to ER visitAdmitted, treated with metronidazole and dischargedReadmitted next day with severe colitisTreated in hospital for 18 days with metronidazole, oral vancomycin and cholestyramine, discharged
16 Case Study 2 (cont’d) Readmitted 4 days later Diarrhea and hypotension Spontaneously aborted her fetusesSubtotal colectomy, aggressive therapyDied on 3rd dayPost-mortem showed toxic megacolon with evidence of pseudomembranous colitisMMWR 54:(47);
17 What Can We Learn From Case 2? We know nearly nothing about community based CDITesting for C. difficile is now both an in-patient and out-patient testRisk factors other than colonic imbalance mediated by antibiotics must be considered
18 Role of AntibioticsAll antibiotics (including metronidazole and vancomycin) are associated with CDIHigh-risk groupClindamycinCephalosporins/penicillins/beta-lactamsFluoroquinolonesAlteration of normal colonic flora thought to favor growth of C. difficileAntibiotics do not know they are suppose to kill/inhibit only the “bad guys”
19 Pathogenesis Historical Perspective Most CDI were mildDiarrhea was main symptomPseudomembranous colitis and toxic megacolon were rareDiscontinuing antibiotics worked in many casesHigh response rate to metronidazole and vancomycin
20 Incidence of CDI United States United Kingdom CDI is not a reportable disease so exact number of cases and deaths remain unknownBased on discharge diagnoses, CDI cases have tripled over last 5 yearsUnited KingdomDeaths in UK ~ 9,000/yearCDI = C. difficile infection.
21 PathogenesisToxigenic strains produce 2 large protein exotoxins that are associated with virulenceToxins A and BMutants strains that do not make toxins A and B are not virulentSome strains make a third toxin known as Binary ToxinBy itself, not pathogenicMay act synergistically with toxins A and B in severe colitisMore common in animal strains
22 Pathogenesis of CDI Asymptomatic C. difficile colonization AntimicrobialC. difficile exposureSlide 22Originally, it was thought that the administration of antimicrobial therapy following asymptomatic colonization resulted in C. difficile-associated diarrhea. However, later findings suggested that patients who are colonized with C. difficile are at a reduced risk of developing active infection.1 Those data led to the revised hypothesis of C. difficile pathogenesis, as shown in this slide.After hospitalization or admission to a long-term healthcare facility, patients are at an increased risk of exposure to C. difficile. The administration of antimicrobials or other agents that may alter the colonic flora (eg, chemotherapy) render the patient susceptible and lead to the development of C. difficile disease, asymptomatic C. difficile colonization, or nothing. The incubation period after exposure in a susceptible patient is less than 1 week.1Do not exclude the diagnosis of C. difficile in patients who have received other agents that can potentially alter the colonic flora. (This is the exception; the vast majority of patients with CDI will have received antimicrobials.)Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis. 1998;26:C. difficile infectionHospitalizationFrom Johnson S, Gerding DN. Clin Infect Dis. 1998;26: ; with permission.22
23 Pathogenesis Changing Epidemiology Increasing morbidity and mortality noted beginning in 2000Outbreaks in US & Canada (>200 deaths)Was this due to poor infection control, emergence of antibiotic resistance, or something else?A new, hypervirulent strain was detected
24 Epidemic Strain Strain typed BI/NAP1/0271,2 Is highly resistant to fluoroquinolones2,4Binary toxin genes are presentProduces large quantities of toxins A and B1,3Has a tcdC gene deletion1Slide 24The CDC has reported a new strain of C. difficile.3 Various methods of classification exist for the epidemic strain. The epidemic strain is characterized as toxinotype III, North American pulsed-field gel electrophoresis (PFGE) type 1, and polymerase chain reaction (PCR)-ribotype 027 (NAP1/027).1 In Quebec, the strain is classified as Pulsovar A and was determined to be identical to NAP1.2This new strain produces both toxin A and toxin B and they are not “missed” by laboratories that use toxin A immunoassays. This strain has caused multiple recent outbreaks of C. difficile infection across the United States and in Montreal, Canada, and the United Kingdom. Other features of the new strain include high-level resistance to fluoroquinolones, which may be related to increased virulence.2,4 The epidemic strain also produces binary toxin. However, the significance of binary toxin is unknown at this time. This strain appears to produce greater amounts of toxins A and B and has a deletion in the tcdC gene, which potentially downregulates toxin production.1This slide shows the polymorphisms and deletions in the tcdC variants that have been identified in toxinotype III strains (the tcdC protein may downregulate the production of toxins A and B), which may result in a decreased ability to regulate toxin production, causing dramatically increased amounts of toxins A and B. This association requires further verification.4-6Warny M, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet. 2005;366:Hubert B, et al. A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Quebec. Clin Infect Dis. 2007;44:CDC. Frequently asked questions about a new strain of Clostridium difficile. Fact Sheet, July 2005.McDonald LC, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:Spigaglia P, Mastrantonio P. Molecular analysis of the pathogenicity locus and polymorphism in the putative negative regulator of toxin production (TcdC) among Clostridium difficile clinical isolates. J Clin Microbiol. 2002;40:Rupnik M, et al. Revised nomenclature of Clostridium difficile toxins and associated genes. J Med Microbiol. 2005;54:Warny M, et al. Lancet. 2005;366:Hubert B, et al. Clin Infect Dis. 2007;44:CDC Fact Sheet. July 2005.McDonald LC, et al. N Engl J Med. 2005;353:Adapted from McDonald LC, et al. N Engl J Med. 2005;353: ; with permission.24
25 In Vitro Production of Toxins in Epidemic Strain Slide 25The figure depicts the in vitro production of toxins A and B by C. difficile isolates of toxinotype 0 (red line) and toxinotype III (blue line).These data are based on observations published recently by Warny and colleagues using isolates from 124 patients with CDAD in Quebec, Canada. Additional isolates from recent outbreaks were obtained from the US Centers for Disease Control and Prevention, Montreal, and the United Kingdom.As shown, the peak concentration of toxin A was 16 times higher in the toxinotype III strain than in type 0 strains, and the concentration of toxin B was 23 times higher. Furthermore, control strains (type 0) produced toxin during the stationary phase, whereas type III strains produced toxin during the log and stationary phases.1Warny M, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet. 2005;366:From Warny M, et al. Lancet. 2005;366: , with permission.
26 Not So Fast2 recent papers questioned whether this strain is more virulentNAP-1 strain was detected around 25% of time in their hospital (BID in Boston) but was not associated with increased severity of disease (non-epidemic setting)118 and 39 bp deletion containing strains were not associated with increased severity of CDI at the Mayo Clinic2Age >65 and prior NH stay implicated1. Cloud, J. et al Cl Gastro and Hept. 7:2. Verdoorn, B. P. et al. Diag Micro and ID /j.diagmicrobio
27 Should You Treat the Patient or Treat the Strain? Routine diagnostics laboratory tests do not provide strain typeRoutine tests not always reliableAlways treat the patient based symptoms, history, risk factors and markers of severe disease
28 Symptoms of CDI Asymptomatic colonization Diarrhea mild moderate severeAbdominal pain and distensionFeverPseudomembranous colitisToxic megacolonPerforated colon sepsis death
29 Markers of Severe Disease LeukocytosisProminent feature of severe diseaseRapidly elevating WBCUp to >100 K>10 BM/dayAlbumin < 2.5Creatinine 2x baselineHypertensionPseudomembranous colitisToxic megacolonSevere distension and abdominal pain
30 Laboratory Diagnosis of C. difficile Infection (CDI)
31 Which Test Should I Use? Considerations AccuracyTime to detectionPrevalence in your populationScreening tests followed by confirmatory testsIn a low prevalence population, a screening test with a high sensitivity is useful (no/few false negatives)CostEase of useAt this time, there is no perfect test for the diagnosis of CDI
32 What Should I do First? Make some rules Rule 1: Accept only liquid stools or soft stoolsWhy? Any Exceptions?Rule 2: Limit repeat testing once a patient is positiveWhy? Any exceptions
33 The Specimen Fresh is best (test within 2 hours) Liquid or loose, not solidIf unable to test within 2 hours, refrigerate at 4°C for up to 3 daysFreeze at -70°C (not -20°C) if testing will be delayedSpecimen quality will influence test resultsIn: Manual Clin Micro. 9th ed. 2007;p. 897.
34 Laboratory Diagnosis of CDI Enzyme Immunoassay (EIA)Glutamate Dehydrogenase (GDH)Cell Culture Neutralization Assay (CCNA)Laboratory DiagnosisToxigenic Culture (Culture and CCNA)Stool CultureMolecular Based (PCR Or LAMP)
35 Conflicting Results with EIA Recently Published EIA Papers(1-6)ParameterRangeSensitivity32 – 98.7%Specificity92 – 100%PPV76.4 – 96%NPV88 – 100%Stamper PD, et al. J Clin Microbiol. 2009;47:Musher DM, et al. J Clin Microbiol. 2007;45:Sloan LM, et al. J Clin Microbiol. 2008;46:Gilligan PH. J Clin Microbiol. 2008;46:Ticehurst JR. J Clin Microbiol. 2006;44:Nice review by Planche T, et al
36 EIA Testing Advantages Rapid Inexpensive Relatively easy No costly equipmentBatch or single test formatsDisadvantagesGreat variations in published sensitivity and specificityTechnologist errorContamination
37 Two-Step Tests1-3 Screening Tests Glutamate dehydrogenase (GDH) Detects nearly all true positives as well as false positivesLow PPVHigh sensitivityVery few false negativesWorks best in a low-prevalence populationEIA: Is it accurate enough to use as a screening test? Confirmatory test?Confirmatory TestsCCNAAdd 1-2 daysCX followed by CCNAAdd 3-4 daysPCRPossibility of false positives due to colonizationGilligan PH. J Clin Microbiol. 2008;46:Ticehurst JR. J Clin Microbiol. 2006;44:Planche T, et al
38 Most Recent StudiesCdiff Quik Chek Complete (GDH and EIA on one test card)1Both + = +Both - = -13.2% discrepant, re-test. Use PCRPCR had very high S,S, PPV and NPV2PCR resolved low false positive EIA3Quinn, C. D J Clin Microbiol. 48:Novak-Weekley, S. et al J. Clin Microbiol.doi: /JCMBrecher, S. et al ICAAC Abstract D-1422
39 Molecular-Based Assays Polymerase Chain Reaction (PCR)3 FDA Approved test kits2 of them are less expensive but more labor intensive1 is easy enough to do that even I can do it, but is expensiveI recently switched from an EIA to the expensive PCRThe cost of a misdiagnosed patient is too great, especially for our Veterans
41 Treatment of Mild to Moderate Disease Stop antibiotic(s) if medically reasonableMetronidazoleOral or IV, 500 mg TID for days is standard therapy5–20% failure rate20% relapse rateCan use a full 2nd course for failure/relapse but beyond 2 courses, switch to vancomycinFailures not due to metronidazole resistance
42 Initial Treatment Options for CDI Historical response (96%) and relapse rates (20%) similar between metronidazole and vancomycin1More recently, efficacy of metronidazole for severe disease called into question2-4Recent prospective trials report vancomycin to be superior to metronidazole in severe CDI5-7Slide 42Historically, small clinical trials have demonstrated similar response (96%) and relapse rates (20%) between metronidazole and vancomycin.1However, the efficacy of metronidazole has recently been called into question; several observational studies have demonstrated both increased failure and recurrence rates of metronidazole when compared with treatment periods prior to the yearIn addition, recent prospective trials have reported vancomycin to be superior to metronidazole in the setting of severe disease.5-7Aslam S, et al. Lancet Infect Dis. 2005;5:Fernandez A, et al. J Clin Gastroenterol. 2004;38:Gerding DN. Clin Infect Dis. 2005;40:Musher DM, et al. Clin Infect Dis. 2005;40:Lahue BJ, Davidson DM. The 17th European Congress of Clinical Microbiology and Infectious Diseases, March 31 to April 4, 2007; Munich, Germany. Abstract 1732_215.Zar FA, et al. Clin Infect Dis 2007;45:Louie T, et al. The 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2007; Chicago, Illinois. Abstract k-425-a.1. Aslam S, et al. Lancet Infect Dis. 2005;5:2. Fernandez A, et al. J Clin Gastroenterol. 2004;38:3. Gerding DN. Clin Infect Dis. 2005;40:4. Musher DM, et al. Clin Infect Dis. 2005;40:5. Lahue BJ, Davidson DM. The 17th ECCMID Meeting, March 31 to April 4, 2007; Munich, Germany. Abstract 1732_215.6. Zar FA, et al. Clin Infect Dis 2007;45:7. Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a.
43 Initial Treatment Options for CDI Metronidazole250 mg QID or500 mg TIDMay be administered PO or IVDevelopment of resistance rareHistorical first-line agentVancomycin125 mg QIDEffective in enteral (oral or rectal) form onlyTypically reserved for severe disease, those failing to respond to metronidazole, or cases in which metronidazole is contraindicatedSlide 43This table summarizes the most commonly employed initial treatment options for CDI. Metronidazole and vancomycin have been historically viewed as comparable with regard to efficacy and relapse rates. Given the higher cost of oral vancomycin and the concern for the development of vancomycin-resistant enterococci (VRE), metronidazole, administered orally or intravenously, has typically been the preferred initial agent of choice.Vancomycin has typically been reserved for patients with severe disease, intolerance to metronidazole, or those who failed to respond to metronidazole, or cases in which metronidazole is contraindicated (eg, pregnancy).Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Practice Guidelines. Am J Gastroenterol. 1997;92:Gerding DN, et al. Clostridium difficile-associated diarrhea and colitis. SHEA Position Paper. Infect Control Hosp Epidemiol. 1995;16:American Society of Health-System Pharmacists. Therapeutic Position Statement on the Preferential Use of Metronidazole for the Treatment of Clostridium difficile-Associated Disease. Am J Health-Syst Pharm. 1998;55:IV=intravenously; PO=orally.Fekety R. Am J Gastroenterol. 1997;92:Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:American Society of Health-System Pharmacists. Am J Health-Syst Pharm. 1998;55:
44 Metronidazole vs Vancomycin Zar et al1 classified patients as mild or severe CDIIn mild disease, vancomycin was slightly better than metronidazole (98% vs 90%)Not statistically significantIn severe disease, vancomycin was significantly better than metronidazole (97% cure vs 76% cure)1. Zar FA, et al. CID. 2007;45:
45 Clinical Success by Disease Severity: Tolevamer Phase III Results Defining CDI Disease SeverityMild CDI3–5 BM/dayWBC ≤15,000/mm3Mild abdominal pain due to CDIModerate CDI6–9 BM/dayWBC 15,001 to 20,000/mm3Moderate abdominal pain due to CDISevere CDI≥ 10 BM/dayWBC ≥20,001/mm3;Severe abdominal pain due to CDISlide 45This Phase III clinical trial compared tolevamer, a nonantibiotic binding resin with standard therapies, metronidazole, and vancomycin in mild, moderate, and severe CDI. The disease classifications were differentiated based on the following criteria:Mild CDI: 3-5 BM/day; WBC ≤15,000/mm3; with or without mild abdominal pain due to CDI.Moderate CDI: 6-9 BM/day; WBC 15,001 to 20,000/mm3; with or without moderate abdominal pain due to CDI.Severe CDI: ≥10 BM/day; WBC ≥20,001/mm3; severe abdominal pain due to CDI.Any one of the 3 defining characteristics could assign a patient to a category, with a default to the more severe category when symptoms overlapped.Louie T, et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhea (CDAD). The 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2007; Chicago, Illinois. Abstract k-425-a.Any one of the 3 defining characteristics assigns a patient to the more severe category.Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a.
46 Metronidazole vs Vancomycin vs Tolevamer Patients stratified as mild, moderate, or severeOriginal goal of study was to evaluate tolevamer as a treatment for CDIDrugMildModerateSevereTolevamer594637Metronidazole797665Vancomycin8580Louie et al. ICAAC AbstractK
47 C. difficile Infection: Case 3 79-year-old woman with multiple medical problems admitted to hospital for treatment of community-acquired pneumoniaResponds slowly to levofloxacin 750 mg dailyAfter 6 daysDevelops diarrhea (9 loose BMs)WBC count: 11,500/mm3Day 7–14 loose BMs, WBC count rises to 19,500/mm3Stool testing for C. difficile toxins A and B is requestedContinued antibiotic therapy for pneumonia is deemed necessaryHow would you manage her care?Await stool test results and monitor her progressEmpirically start metronidazole POEmpirically start metronidazole IVEmpirically start vancomycin POSlide 25This first case describes a 79-year-old woman with multiple medical problems. After being admitted to a hospital for treatment of community-acquired pneumonia, this woman slowly responds to levofloxacin 750 mg daily. After 6 days, she develops diarrhea (9 loose BMs), and her white blood cell count (WBC) is 11,500/mm3. By day 7, her diarrhea becomes more severe (7 to14 loose BMs) and her WBC rises to 19,500/mm3. Her stool is tested for C. difficile toxins A and B, but her antibiotic is continued as a medical necessity.How would you manage this patient?Await stool test results and monitor her progressEmpirically start metronidazole POEmpirically start metronidazole IVEmpirically start vancomycin POWe are going to review some treatment criteria for CDI before providing you with the correct answer.
48 C. difficile Infection: Case 3 79-year-old woman with multiple medical problems admitted to hospital for treatment of community-acquired pneumoniaResponds slowly to levofloxacin 750 mg dailyAfter 6 daysDevelops diarrhea (9 loose BMs)WBC count: 11,500/mm3Day 7–14 loose BMs, WBC count rises to 19,500/mm3Stool testing for C. difficile toxins A&B is requestedContinued antibiotic therapy for pneumonia is deemed necessaryHow would you manage her care?Await stool test results and monitor her progressEmpirically start metronidazole POEmpirically start metronidazole IVEmpirically start vancomycin POSlide 48This patient has multiple risk factors for CDI, including the use of a high-risk antimicrobial (levofloxacin), hospital admission and prolonged stay, advanced age, and multiple comorbidities. In this setting, the development of severe diarrhea should raise substantial concern for CDI. The finding of a markedly elevated WBC is consistent with CDI and should be considered another indicator of severe disease.A. Given a very high clinical suspicion for CDI, the patient’s age, comorbidities, and need for continued antibiotic therapy, conservative therapy is inappropriate.B. The high clinical suspicion for CDI and the presence of markers of severe disease (>10 BMs per day, WBC of >15,000/mm3) mean that metronidazole therapy is not optimal.C. Intravenous metronidazole can be an effective therapy for CDI, but there are no data to indicate that it is either superior or inferior to oral metronidazole therapy.D. Recent RCTs strongly indicate that oral vancomycin therapy is the treatment of choice for severe CDI. Where clinical suspicion is high and especially in severe disease (as in this case), prompt therapy is advised even before stool test results become available.
49 Treatment of Severe Disease Follow definition of severe disease>10 BM/day, high WBC, low albuminThis is a life-threatening infectionSurgical consultation recommended as patient may require a colectomyOral vancomycin drug of choiceDose varies based on severityCan add metronidazole (oral or IV)
50 Management of Severe CDI Early recognition is criticalInitiate therapy as soon as diagnosis is suspectedManage as for mild CDI plus:Oral vancomycin (125 mg QID for 10 to 14 days) as initial treatmentIf patient is unable to tolerate oral medication, consider intracolonic vancomycin instillation (by enema)0.5–1 g vancomycin (IV formulation) in 0.1 to 0.5 L of normal saline via rectal (or Foley) catheterClamp for 60 minutesRepeat every 4–12 hoursSlide 50Early recognition of severe C. difficile disease is critical, and therapy should be initiated as soon as the diagnosis is suspected. Patients should be assessed frequently to monitor for risk factors and markers of disease severity. Offending antibacterial agents should be discontinued if possible. Stool should be sent for testing and clinical course should be monitored.Based on recent prospective data, vancomycin is recommended as initial treatment for severe disease or in the otherwise critically ill because it has demonstrated superiority to metronidazole in this setting.2,3 In patients who are unable to tolerate oral medications, consider intracolonic vancomycin instillation by enema.4Patients with possible severe CDI should undergo a surgical consultation as soon as possible, in the event that the patient does not respond to medical treatment.Gerding DN, et al. Clostridium difficile-associated diarrhea and colitis. SHEA Position Paper. Infect Control Hosp Epidemiol. 1995;16:Zar FA, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:Louie T, Gerson M, Grimard D, et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhea (CDAD). The 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2007; Chicago, Illinois. Abstract K-425-a.Apisarnthanarak A, Raxavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis. 2002;35:Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:Zar FA, et al. Clin Infect Dis. 2007;45:Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a.Apisarnthanarak A, et al. Clin Infect Dis. 2002;35:
51 Management of Severe, Complicated CDI Potential role of intravenous immunoglobulin G (IVIG)1-6Antitoxin A IgG predicts clinical outcome of CDISerum antibodies to toxins A and B are prevalent in healthy populationsRecent studies in severe disease5,6Well tolerated in small numbers of patientsConflicting data regarding outcome improvement (mortality and need for colectomy)Often administered when surgery is considered imminentSlide 51Several case studies have described the use of intravenous immunoglobulin G (IVIG). The rationale for its use relates to the ability of antitoxin A IgG to predict the clinical outcome of infection with C. difficile and the presence of serum antibodies to toxins A and B in pooled sera from healthy donors.1-5(Note: When immunoglobulins are given, the dose is 300 to 400 mg/kg once, rather than over 5 days as for streptococcal necrotizing infections. Few data are available for the one-time treatment, which costs $2,000 compared with $10,000 for the 5-day treatment.)Most recent data report the administration of IVIG to 18 patients with severe CDI.6 There were no statistical differences in clinical outcomes as measured by all-cause mortality, colectomies, and length of stay. These data demonstrate that the use of IVIG in severe CDAD remains unsubstantiated. This study, although limited by a small sample size, does not support the use of IVIG at this dose for severe CDAD outside of a controlled trial.Salcedo J, et al. Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut. 1997;41:Beales ILP. Intravenous immunoglobulin for recurrent Clostridium difficile diarrhoea. Gut. 2002;51:456.Kyne L, et al. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000;342:Kyne L, et al. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet. 2001;357:McPherson S, et al. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis Colon Rectum. 2006;49:Juang P, et al. Clinical outcomes of intravenous immunoglobulin in severe Clostridium difficile-associated diarrhea. Am J Infect Control. 2007;35:1. Salcedo J, et al. Gut 1997;41:2. Beales ILP. Gut. 2002;51:456.3. Kyne L, et al. N Engl J Med. 2000;342:4. Kyne L, et al. Lancet. 2001;357:5. McPherson S, et al. Dis Colon Rectum. 2006;49:6. Juang P, et al. Am J Infect Control 2007;35:
52 Multiple Recurrent CDI Rates of recurrent CDI20% after first episode145% after first recurrence265% after two or more recurrences3Metronidazole or vancomycin resistance after treatment not reportedRepeated, prolonged courses of metronidazole not recommended (risk for peripheral neuropathy)Several empirical approaches have been advocated but most have no controlled dataSlide 52Unfortunately, up to 20% of patients treated for CDI will relapse after initial treatment.1 Recurrences have been reported in 45% of patients who have experienced a single recurrence.2 In addition, up to 65% of patients will experience two or more recurrences.3 Antibiotic resistance does not appear to be an issue in recurrent CDI.Several empirical approaches have been advocated but most have no controlled data.Aslam S, et al. Treatment of Clostridium difficile-associated disease: old therapies and new strategies. Lancet Infect Dis. 2005;5:McFarland LV, et al. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002:97:McFarland LV, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994;271:1. Aslam S, et al. Lancet Infect Dis. 2005;5:2. McFarland LV, et al. Am J Gastroenterol. 2002:97:3. McFarland LV, et al. JAMA. 1994;271:
53 Treatment of Recurrent CDI First recurrence can be treated in the same way as a first episode according to disease severity1Metronidazole should not be used beyond first recurrence or for >14 days2Concerns for hepatotoxicity and polyneuropathyFurther recurrences can be treated with oral vancomycin taper and/or pulse dosing2,3Slide 53Prior observations suggest that more than 90% of initial recurrences can be retreated with the same agent used for initial treatment because the first recurrence does not appear to be related to in vitro resistance.1 This practice continues to be effective with one exception. If, upon recurrence, the infection may then be classified as severe, oral vancomycin should be used to treat this recurrent episode.Metronidazole should not be utilized beyond treatment of the first recurrence and for durations exceeding 14 days due to the potential for toxicity, both hepatotoxicity and polyneuropathy.2For further recurrences, tapered or pulse dosing of vancomycin has been the most widely used regimen.2,3Gerding DN, et al. Clostridium difficile-associated diarrhea and colitis. SHEA Position Paper. Infect Control Hosp Epidemiol. 1995;16:McFarland LV, et al. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97:Tedesco FJ, et al. Approach to patients with multiple relapses of antibiotic-associated pseudomembraneous colitis. Am J Gastroenterol. 1985;80:1. Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:2. McFarland LV, et al. Am J Gastroenterol 2002;97:3. Tedesco FJ, et al. Am J Gastroenterol. 1985;80:
54 Other Treatments IVIG* Probiotics Nitazoximide Rifaximin Chasers Rifampin* Patients who produce antibody to toxins A and B usually do well so IVIG has been tried.
55 Unproven Adjunctive Therapies for Recurrent CDI ProbioticsSaccharomyces boulardiiLactobacillus GGMay reduce the likelihood of further recurrences in some patients when added to and continued after treatment with metronidazole or vancomycin1-3RifampinEfficacy in one series (n=7) when added to vancomycin4NitazoxanideResponse demonstrated in patients (n=35) who failed prior metronidazole therapy5 and similar response and recurrence rates when compared with metronidazole for initial therapy (n=110)6Rifaximin “chaser”Effective when used for 14 days after vancomycin therapy (n=8)7Slide 55Adjunctive treatment with various unproven therapies has been utilized with some success.Probiotics are nonpathogenic organisms that have been used to repopulate the colonic microflora, and thus presumably restrict the growth of toxigenic C. difficile. In clinical trials evaluating such probiotics as Saccharomyces boulardii or Lactobacillus GG for the adjunctive treatment of CDI, the beneficial effect has been limited to a small number of patients when probiotics are added to and continued after treatment with metronidazole or vancomycin.1-3 Probiotics are generally safe and easy to administer; however, current data fail to provide sufficient evidence for their routine use in the treatment of patients with CDI.There have also been anecdotal reports of treatment success measured by resolution of symptoms with the use of vancomycin in combination with rifampin in one series of patients (n=7) with multiple relapses.4Nitazoxanide is a nitrothiazolide compound that is FDA-approved to treat diarrhea caused by Giardia lamblia and Cryptosporidium parvum; it also possesses in vitro activity against anaerobic bacterial enteric pathogens, including C. difficile. An open-label, compassionate use study using nitazoxanide for patients who failed to respond to metronidazole (n=35) demonstrated an initial response rate of 74%. However, one fifth of the patients later relapsed, demonstrating an overall success rate of 54%.5 Overall cure rate in this challenging population was 66%.A larger, prospective, randomized, double-blind study comparing nitazoxanide 500 mg orally twice daily (of 7 or 10 days’ duration) with metronidazole 250 mg orally four times daily for 10 days for treatment of CDI showed nitazoxanide to be noninferior to metronidazole. Per protocol results showed an 82.4% response rate (28 of 34) in the metronidazole arm compared with 89.5% (68 of 76) in the two nitazoxanide arms combined. No significant differences were observed with rate of recurrence among the groups either. (Sustained response rates at 31 days: metronidazole, 57.6%; 65.8% nitazoxanide 500 mg BID for 7 days; 74.3% nitazoxanide 500 mg BID for 10 days).6Recent data have also supported the potential role of rifaximin immediately following vancomycin in the setting of multiple recurrent disease.7McFarland LV, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994;271:McFarland LV. Alternative treatments for Clostridium difficile disease: what really works? J Med Microbiol. 2005;54:Surawicz CM, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 2000;31:Buggy BP, et al. Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin. J Clin Gastroenterol. 1987;9:Musher DM, et al. Clostridium difficile that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother. 2007;59:Musher DM, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. 2006;43:Johnson S, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:1. McFarland LV, et al. JAMA. 1994;271:2. McFarland LV. J Med Microbiol. 2005;54:3. Surawicz CM, et al. Clin Infect Dis. 2000;31:4. Buggy BP, et al. J Clin Gastroenterol. 1987;9:5. Musher DM, et al. J Antimicrob Chemother. 2007;59:6. Musher DM, et al. Clin Infect Dis. 2006;43:7. Johnson S, et al. Clin Infect Dis. 2007;44:55
56 Saccharomyces boulardii for CDI Prevention* Recurrent CDISlide 56 Despite numerous clinical trials, the ability of probiotics to prevent CDI remains controversial. Saccharomyces boulardii is one of the most studied probiotics in CDI. The results of two separate studies using S. boulardii are summarized in this figure. Both compared S. boulardii 500 mg twice daily to placebo in a double-blind randomized placebo-controlled study design. S. boulardii or placebo were administered during and after antimicrobial therapy (vancomycin or metronidazole) to patients with CDI. The endpoint of both studies was the development of recurrent CDI.In the first study, patients with a first episode of CDI had similar recurrence rates in the placebo (24%) and S. boulardii groups (19%, P>0.05). Conversely, again in the first study, patients with a history of recurrent CDI had significantly higher further recurrence rates in the placebo (65%) compared with the S. boulardii group (35%, P=0.04).A second study aimed to confirm the finding that S. boulardii provides protection against recurrent CDI in high-risk patients. However, in this second larger study, patients with a prior history of recurrent CDI had similar recurrence rates in the placebo (47%) compared with the S. boulardii group (44%, P>0.05).The inconclusive and often contradictory findings in these and other studies of probiotics in CDI prevention have led many experts to conclude that the beneficial effects, if any, of these agents are marginal and that their protective effects cannot be relied upon with confidence.McFarland LV, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994;271:Surawicz CM, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 2000;31:P=0.04*Metronidazole or vancomycin for 10–14 days plus placebo or S. boulardii 1 g daily × 4 weeks.1. McFarland. JAMA. 1994;271:2. Surawicz et al. Clin Infect Dis. 2000;31:
57 Recurrent CDI: Rifaximin Chaser Eight women with multiple recurrencesRifaximin 400 mg BID for 2 weeks immediately after completing last course of vancomycinSeven of eight patients had no further diarrhea recurrenceSingle case of rifaximin resistance (identified after therapy) with recurrent CDI after a second course of rifaxminEffective in interrupting recurrent episodes but resistance may become an issueSlide 57Rifaximin is a poorly absorbed rifamycin derivative approved for treatment of traveler’s diarrhea in the United States. It is highly active against C. difficile in vitro and has been used off-label for treatment of CDI. Recent reports describe the use of a “rifaximin chaser” for multiple relapse disease in a small number of women.A 2-week course of rifaximin was used as a follow-up or “chaser” immediately following vancomycin therapy. The regimen was effective in interrupting recurrent episodes, although resistance was observed in a single case after a second course of rifaximin was administered. The sequential administration of vancomycin followed by rifaximin may prove to be important and may influence the development of resistance.Johnson S, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:Johnson S, et al. Clin Infect Dis. 2007;44:
58 Recurrent CDI: Fecal Transplantation Rationale: restoration of bacterial homeostasisPreparation of donor specimenFresh (<6 hours)~30 g or ~2 cm3 volumeAdd 50 mL 0.9% normal saline, and homogenize with blenderFilter suspension twice with paper coffee filterDelivered by nasogastric tube following vancomycinResults1 of 16 survivors had a single subsequent recurrenceSlide 58Fecal transplantation has also been described in patients with multiple recurrent CDI, indicative of the desperate nature of these patients and the indignities they are willing to undergo. The protocol, which reads like a kitchen recipe, states that the donor specimen should be fresh and approximately 30 g or 2 cm3 in volume. The specimen should be homogenized with 50 mL of normal saline and filtered with a paper coffee filter, twice.The transplant stool specimen is drawn into a syringe and instilled by way of a nasogastric tube placed in the patient’s stomach. Then the tube is flushed with saline and removed.1Results thus far report that 1 of 16 survivors had a single subsequent episode following the procedure.Aas J, et al. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003;36:Aas J, et al. Clin Infect Dis. 2003;36:
59 Infection Control Wash hands with warm soap and water Mechanical removal of sporesAlcohol does not kill sporesStool is pre-treated with alcohol when growing C. difficileContact and barrier precautionsPrivate roomAntibiotic stewardship
60 Efficacy of Hand Hygiene Methods for Removal of C Efficacy of Hand Hygiene Methods for Removal of C. difficile Contamination from HandsDecrease in colony countsWWS = warm water and soapCWS = cold water and soapWWA = warm water and antibacterialAHW = alcohol hand wipeAHR = alcohol hand rubcompared with no wash2.521.51Decrease in colony counts1.81.8(log CFU/mL)1.40.5******Slide 60The efficacy of various hand hygiene methods for removal of C. difficile on the hands of experimentally inoculated volunteers was investigated, and the results are shown above. Ten volunteers were randomly allocated to the interventions, and analysis involved the measure of colony counts after the intervention.The authors concluded that plain soap and water was superior to alcohol hand rubs but that alcohol and hand wipes may help displace spores off “touch” surfaces of hands and may be better than not washing at all.Oughton M, et al. Alcohol rub and antiseptic hand wipes are inferior to soap and water for removal of C. difficile by handwashing. The 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherap, September 17-20, 2007; Chicago, IL.0.6-0.1-0.5-1WWSCWSWWAAHWAHRHand hygiene methodCFU = colony forming units* Different from AHR (P<0.05).** Different from AHR and AHW (P<0.05)Oughton M, et al. The 47th Annual ICAAC Meeting, 2007.
61 Alcohol Gels and Hand Hygiene Alcohol-based gels appear to be less able to remove C. difficile sporesHowever, in general they:Provide an excellent method of hand hygiene effective against many common nosocomial pathogensAre convenient thereby increasing complianceHave not been implicated in CDI outbreaksIn the setting of a CDI outbreak or increased rates, visitors and healthcare workers should wash hands with soap and water after caring for patients with C. difficileSlide 61It continues to be acknowledged that alcohol-based hand gels appear less able to remove C. difficile spores from the hands of healthcare workers (HCWs) and those who come in contact with patients with C. difficile infection.However, these gels offer several advantages. They provide an excellent method of hand hygiene effective against many common nosocomial pathogens. Furthermore, they are convenient, thereby increasing compliance with frequent hand hygiene. Finally, despite the theoretical concerns mentioned above, they have not been implicated in CDI outbreaks.Thus, their general use is encouraged. However, in the setting of an outbreak or increased rates, visitors and healthcare workers should wash their hands with soap and water after caring for patients with C. difficile infection.CDC. Fact Sheet, August 2004 (updated 7/22/05).Oughton M, Loo V, Fenn S, et al. Alcohol rub and antiseptic hand wipes are inferior to soap and water for removal of C. difficile by handwashing. The 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2007; Chicago, Illinois.CDC. Fact Sheet, August 2004 (updated 7/22/05).Oughton M, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL.
62 Isolation and Barrier Precautions Patients with CDI and incontinence should be in private rooms or cohorted if private rooms are not availableContact precautions and isolationGloves and gowns required for direct contact and contact with environmentDiscontinuation of isolation when diarrhea resolvesDedicated equipment when possibleSlide 62Care for patients with CDI and fecal incontinence should be in private rooms as these are most likely to result in environmental contamination and person-to-person spread of toxinogenic C. difficile.1-3 A private room should be considered for all patients with CDI until diarrhea has resolved. Healthcare workers should use gloves for contact with patients with CDI and for contact with their body substances and their environment. Healthcare workers should also use gowns if soiling of clothing is likely. Patient care items, such as stethoscopes and blood pressure cuffs, should be dedicated and not shared with other patients without thorough decontamination.2CDC Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings, Available at:Gerding DN, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995;16:Simor AE, et al. Clostridium difficile in long-term care facilities for the elderly. SHEA Position Paper. The SHEA Long-Term-Care Committee. Infect Control Hosp Epidemiol. 2002;23:CDC Guideline for Isolation Precautions, 2007.Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:Simor AE, et al. Infect Control Hosp Epidemiol. 2002;23:
63 Environmental Disinfection Removal/thorough cleaning of environmental sources can decrease incidenceUse chlorine-containing agents (at least ppm available chlorine 10 minutes contact time) for environmental contamination, especially in outbreak areasFoggingSlide 63Removal of environmental sources can decrease the incidence of CDI. This is best shown by replacement of electronic thermometers.In addition, use of chlorine-containing agents (at least 5000 ppm available chlorine) should be used for environmental contamination in epidemic or endemic areas. The administration of this type of bleach solution has been observed to be the most effective method of environmental disinfection.2-4Poutanen SM, Simor AE. Clostridium difficile-associated diarrhea in adults. Can Med Assoc J. 2004;171:51-58.CDC. Frequently asked questions about a new strain of Clostridium difficile. Fact Sheet, July 2005.McMullen KM, et al. Use of hypochlorite solution to decrease rates of Clostridium difficile-associated diarrhea. Infect Control Hosp Epidemiol. 2007;28:Mayfield JL, et al. Environmental control to reduce transmission of Clostridium difficile. Clin Infect Dis. 2000;31:Fawley WN, Underwood S, Freeman J, et al. Efficacy of hospital cleaning agents and germicides against hospital epidemic Clostridium difficile strains. Infect Control Hosp Epidemiol. 2007;28:Poutanen SM, Simor AE. Can Med Assoc J. 2004;171:51-58.CDC. Fact Sheet, July 2005.McMullen KM, et al. Infect Control Hosp Epidemiol. 2007;28:Mayfield JL, et al. Clin Infect Dis. 2000;31:Fawley WN, et al. Infect Control Hosp Epidemiol. 2007;28:
64 Antimicrobial Use Restrictions Practice antimicrobial stewardshipDecrease duration of exposure and number of antimicrobial agentsBest evidence for controlling C. difficile demonstrated with restriction of cephalosporin or clindamycinRecent reports of fluoroquinolone restriction helping to control outbreaksSlide 64Because antimicrobial use has been recognized as an important risk factor for CDI, it seems prudent to practice antimicrobial stewardship by decreasing the duration of exposure and the number of antimicrobials administered to a patient.The best evidence for decreasing the rates of CDI has been observed with the restriction of cephalosporins, clindamycin and, more recently, fluoroquinolones. The judicious use of antibiotics is important because antibiotic restriction of particular agents in particular settings has been shown to decrease the rates of nosocomial C. difficile diarrhea.1-4 Targeting the use of high-risk agents to which the endemic strains of C. difficile are resistant may be especially valuable. McNulty C, et al. Successful control of Clostridium difficile infection in an elderly care unit through use of a restrictive antibiotic policy. J Antimicrob Chemother. 1997;40:Pear SM, et al. Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med. 1994;120:Climo MW, et al. Hospital-wide restriction of clindamycin: effect on the incidence of Clostridium difficile-associated diarrhea and cost. Ann Intern Med. 1998;128:Kallen AJ, Thompson A, Ristaino P, Chapman L, Nicholson A, Sim BT, Lessa F, Sharapov U, Fadden E, Boehler R, Gould C, Limbago B, Blythe D, McDonald LC. Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection at a community hospital. Infect Control Hosp Epidemiol. 2009;30:McNulty C, et al. J Antimicrob Chemother. 1997;40:Pear SM, et al. Ann Intern Med. 1994;120:Climo MW, et al. Ann Intern Med. 1998;128:Kallen AJ, et al. Infect Control Hosp Epidemiol. 2009;30:
65 Summary CDI is increasing in incidence, severity and poor outcomes Laboratory diagnosis is challengingCarefully evaluate what works best in your settingNo reasonable explanation for treatment failuresCommunity based infections are not well understoodImproved therapies are neededExtremely important to accurately detect and aggressively treat severe disease
66 Gitschier, J., Science, 1993 (261) p. 679 Y ChromosomeGitschier, J., Science, 1993 (261) p. 679Testis Determining Factor (TDF)Gadgetry (MAC- locus)Channel Flipping (FLP)Catching and Throwing (BLZ-1)Self-confidence (BLZ-2)(note: unlinked to ability)Ability to remember and tell jokes (GOT-1)Sports Page (BUD-E)Addiction to death & destructionmovies (MOV-E)Air Guitar (RIF)Ability to identify aircraft (DC10)Pre-adolescent fascination with Arachnidand Reptilia (MOM-4U)Spitting (P2E)Sitting on the john reading (SIT)Inability to express emotion over thephone (ME-2)Selective hearing loss (HUH?)Total lack of recall for dates (OOPS)