C-Diff

1. C-Diff

2. Which type of Clostridium difficile infection (CDI) is the most common? A) Health care facility (HCF)-onset B) Community-onset, HCF-associated C) Community-associated D) Indeterminate origin

3. Answer • B) Community-onset, HCF-associated

4. Historical background • Clostridium difficile first described in 1935 • emergence of clindamycin-associated colitis (condition due to toxin-producing clostridia) seen in 1970s • for many years thereafter, C difficile infection (CDI) thought easily treatable with metronidazole • however, outbreaks of virulent epidemic strain associated with high morbidity and mortality reported in last decade Types of • CDI: health care facility (HCF)-onset—develops >48 hr after admission to HCF • community-onset but HCF-associated— constitutes majority of cases; symptom onset occurs briefly after discharge from HCF • community-associated—rare; no history of discharge from HCF in preceding 12 wk (if discharge within 4-12 wk • CDI categorized as of indeterminate origin

5. All the following antimicrobial agents are frequent inducers of CDI, except: A) Ampicillin B) Clindamycin C) Macrolides D) Third-generation cephalosporins

6. Answer • C) Macrolides

7. Prevalence • has risen dramatically since 1990s; highest in patients 65 yr of age (800 cases per 100,000, vs 140 cases per 100,000 in overall population) • infection emerging in populations previously thought to be at low risk • Factors contributing to resurgence of C difficile–associated diarrhea (CDAD): virulence of C difficile strains • Resistance to antimicrobial agents • increasing numbers of elderly and immunocompromised people • possibly, increased use of alcoholbased handrubs for hygiene in HCFs Proportion of population with positive toxin assay for C difficile • healthy neonates — vast majority (but generally asymptomatic colonization); healthy adults — only 1% to 2% • hospitalized patients— 8% to 18%; patients with antibioticassociated diarrhea (AAD)—10% to 25%; • patients with pseudomembranous colitis (PMC)—95% to 100

8. Risk factors for CDAD • >65 yr of age • antimicrobial exposure • gastrointestinal (GI) surgery • tube feeding • use of proton pump • inhibitors and histamine-2 receptor antagonists • Comorbidities (especially organ transplantation and renal failure) • use of cancer chemotherapeutic agents • length of stay in hospital single greatest risk factor for exposure to C difficile • Antimicrobial agents that induce CDI: frequent inducers— ampicillin • third-generation cephalosporin • Clindamycin • Fluoroquinolones • infrequent inducers—macrolides and sulfonamides • rare inducers —consider switching to this category in cases in which anti-infective agent cannot be entirely eliminate

9. C difficile colonization is associated with an increased risk for recurrent C difficile-associated diarrhea (CDAD). A) True B) False

10. Answer •  B) False

11. Pathogenesis of CDAD • disruption of normal enteric flora • acquisition of toxigenic C difficile • once infection acquired, 50% of patients mount protective serum antibody response (which results in asymptomatic colonization [carrier state]), and 50% unable to mount protective antibody response (develop CDAD) • 60% to 90% of patients with CDAD recover without recurrence • recurrence may occur when comorbidity or trigger responsible for infection persists • Risk for CDAD after colonization: C difficile colonization paradoxically associated with reduced risk • IgG levels and CDAD: patients colonized with C difficile who have high levels of IgG antibody against toxin A less likely to develop mild or severe CDAD • Mechanism of CDAD: presence of toxin in intestine induces array of inflammatory cascade reactions that result in multiple disruptions of epithelial barrier, neutrophil infiltration, and, subsequently, PMC • New epidemic strain (B1/NAP1) of C difficile: contains additional toxin (“binary toxin”) • deletions in negative regulatory genes allow increased production of toxins A and B (produces 16-23 times more toxin than nonepidemic strain) • has greater propensity for resistance to fluoroquinolones • associated with higher incidence of sepsis, leukemoid reactions, colectomies, and death

12. Which of the following agents should not be used to treat CDAD? A) Metronidazole B) Vancomycin C) Probiotics D) Atropine

13. Answer •  D) Atropine

14. Treatment of CDAD • 25% of patients improve without need for further therapy after change in or complete discontinuation (if possible) of triggering antibiotic • older randomized trial showed similar treatment success and relapse rates with metronidazole and oral vancomycin • more recent study showed that vancomycin appears to be more effective than metronidazole against B1/NAP1 strain (for moderate to severe CDI) • atropine and similar antimotility agents should be avoided • probiotics —trials of many probiotics showed high efficacy for prevention of AAD, but most effective probiotic undetermined due to high heterogeneity • Fulminant colitis: x-ray of abdomen recommended in patients with moderate to severe CDI to rule out impending or present toxic megacolon • positive finding indicates need for immediate subtotal colectom

15. Approximately _______ of patients with CDAD relapse within 30 days after cessation of therapy. A) 20% B) 33% C) 40% D) 50%

16. Answer • A) 20%

17. Recurrent CDAD • 20% of patients relapse within 30 days after cessation of therapy (>50% experience further relapses) • Underlying mechanism lack of host immune response to toxin A • Prophylactic metronidazole or oral vancomycin for patients with ongoing antibiotic use not currently recommended • treatment—age, comorbidities, and immune status need to be considered • use vancomycin for initial recurrence (use metronidazole only for mild cases) • for subsequent recurrences, treat with tapered or pulsed vancomycin for 6 wk (consider use of rifaximin after completion of vancomycin and intravenous immunoglobulin [IVIG]) • Saccharomyces boulardii as probiotic: has little effect on initial episode of CDI treated with vancomycin or metronidazole, but appears to reduce rate of recurrence • not approved by Food and Drug Administration (FDA) for this purpose • Lactobacillus casei as probiotic: recent randomized trial showed lower incidence of AAD and 0% C difficile toxin in patients who consumed probiotic drink containing L casei (DanActive) than in placebo group • L casei only probiotic proven effective in primary prevention of CD

18. New treatments for C difficile • in development—monoclonal antibodies to toxins A and B • fidaxomycin (currently in phase III trials) • currently available for other indications— IVIG for cases of severe refractory recurrent CDI (efficacy unclear) • Fecal transplantation: emerging body of literature suggests efficacy in treatment of recurrent C difficile colitis • donor stool must be tested for viral and other enteric pathogens and parasites • best donor close family member • efficacy in treating or preventing CDI not yet studied in randomized trials • Animals as source of C difficile: strains in animals generally different from those in humans, but potential for transmission exists

19. Questions and Answers • Outpatient management of patient with relapse of C difficile enteritis shortly after course of oral metronidazole • if recurrence mild, second course of metronidazole reasonable • oral vancomycin recommended in most cases • Dosing of vancomycin for outpatient treatment of CDI: 2010 guidelines from Infectious Diseases Society of America (IDSA) recommend 125 mg oral vancomycin qid (however, most practitioners use 250 mg qid) • Number of stool samples needed to diagnose CDI: depends on diagnostic test used • polymerase chain reaction extremely sensitive for C difficile (requires only one sample) if enzyme immunoassay negative but result questionable, retest (speaker recommends different test rather than second sample with same test) • Test of cure: almost never required because patients carry toxigenic C difficile well after symptoms resolve • retesting recommended in patients with recurrence, because episode may be caused by antibiotic and not by C difficile • Helping patients tolerate metronidazole: probiotics may help mitigate nausea and other adverse effects • limit duration of therapy (10-14 days recommended

20. Questions and Answers • Once-daily metronidazole for treatment of CDI: not recommended on basis of current data, but speaker suspects it would be appropriate In-hospital testing for colonization of C difficile • Current guidelines do not recommend routine testing in patients, mainly because identification and isolation of asymptomatic carriers not shown to reduce transmission • Test for specific type of C difficile in colonized patients: most tests confined to semiformed, loose, or watery stools, so laboratory often automatically rejects samples from patients with asymptomatic colonization (because they have formed stool) • instrument that distinguishes between epidemic and nonepidemic strains exists, but used only in research (not clinically available) • Dose of clindamycin and risk of developing CDI: no dose-dependent effect • lowest dose possible (150 or 300 mg) recommended for treating skin and soft tissue infections; if higher dose indicated, IV rather than oral route advised • avoid use of clindamycin in patients with history of CDI • Ground or tap water as source of community-associated CDI: anti-infectives ubiquitous in ground and tap water • Rates of community-associated CDI low because both anti-infective agent and exposure to C difficile required for infection

21. Fidaxomicin for treatment of CDI • recent trial found lower rates of relapse in patients without B1/NAP1 strain to be main advantage of oral fidaxomicin (vs vancomycin) for treatment of CDI • first in new class of macrocyclic antibiotics that inhibit RNA polymerase • has narrow spectrum of activity • achieves high stool levels • approval by FDA expected soon

22. Ceftaroline fosamil is the only β-lactam antibiotic active against: A) Extended-spectrum β-lactamase-producing gram-negative bacteria B) Pseudomonas aeruginosa C) Acinetobacter baumannii D) Methicillin-resistant Staphylococcus aureus

23. Answer •  D) Methicillin-resistant Staphylococcus aureus

24. Ceftaroline fosamil • fosamil part of prodrug (converted to active • form of ceftaroline in vivo) • like other Beta-lactam antibiotics, binds • to penicillin-binding proteins (PBPs) in cell membrane (unlike other Beta-lactam antibiotics, binds to and inhibits modified PBP 2a found in methicillin-resistant Staphylococcus aureus) • not active against extended-spectrum beta-lactamase-producing gram-negative bacteria and some other resistant organisms, such as Pseudomonas aeruginosa and Acinetobacter baumannii • approved by FDA for skin and soft tissue infections and community-acquired pneumonia • recent article found drug to be fairly effective against resistant S aureus organisms in vitro

25. The presence and degree of pyuria cannot be used to diagnose a catheter-associated urinary tract infection. A) True B) False

26. Answer • A) True

27. Catheter-associated urinary tract infection (CAUTI) • defined as 10 3 colony-forming units/mL in urine specimen from catheterized patient, plus compatible symptoms and no other identified source • presence and degree of pyuria cannot be used to diagnose UTI, although its absence in symptomatic patients suggests alternative source of symptoms • lack of alternative source key to diagnosis (if source not identified, initiation of treatment reasonable • antibiotic should be discontinued and patient reevaluated if no response seen within 72 hr) • Condom catheterization possible alternative to reduce catheter-associated bacteriuria (but data about effects on risk for UTI insufficient) • decreased recurrent bacteriuria and faster resolution of symptoms associated with replacement of catheters in place for 2 wk at time of treatment • data suggest 7 days of antimicrobial therapy sufficient for most patients; guidelines for management of CAUTI available on IDSA website

28.  Which of the following statements about the use of spinosad for treating head lice is incorrect? A) More effective than permethrin B) Combing of nits not required C) Two or more applications required for full efficacy D) Approved in January 2011 for individuals ≥4 yr of age

29. Answer • C) Two or more applications required for full efficacy

30. Head lice • difficult to eliminate • 6 to 12 million infestations annually in US • combined annual direct and indirect costs $1 billion • many lice resistant to permethrin (not ovicidal) • spinosad —produced by soil bacterium • appears nontoxic to mammals • more effective than permethrin in 2 combined phase III trials (85% lice-free [vs 44%] after treatment) • combing out nits not required • one application usually sufficient • approved by FDA in January 2011 for individuals 4 yr of age

31. In the United States, 60 cases of Cryptococcus _______ were reported in humans between 2004 and July 1, 2010. A) neoformans  B) laurentii  C) albidus  D) gattii

32. Answer •  D) gattii

33. Cryptococcus gattii • before 1999, thought to cause disease only in immunocompetent hosts in tropics and subtropics • identified in animals and humans on Vancouver Island in 1999 and on mainland of British Columbia in 2004 (several hundred cases) • 60 cases reported in humans (immunocompromised and nonimmunocompromised) from 2004 to July 1, 2010, in US • causes respiratory and central nervous system disease • consider in patient with symptoms consistent with chronic meningitis or respiratory syndrome and those without known immunocompromis

34. Prevention of SSIs in nasal carriers of S aureus • 800 patients undergoing surgery randomized to receive intranasal mupirocin plus chlorhexidine soap or placebo • results — rate of S aureus infection 3.4% in treatment group vs 7.7% in placebo group (relative risk, 0.42)

35. Treatment of influenza with oseltamivir is recommended in all the following groups, except: A) Patients <5 yr or ≥65 yr of age B) Healthy adolescents C) Individuals with chronic disease D) Pregnant or postpartum women

36. Answer • B) Healthy adolescents

37. Groups for whom treatment of influenza with oseltamivir recommended: • children 5 yr of age (especially 2 yr) • elderly (65 yr of age) • persons with chronic diseases • Patients with immunosuppression • pregnant or postpartum women • people with morbid obesity • Extensively drug-resistant tuberculosis (TB): defined as resistance to isoniazid plus rifampin plus fluoroquinolone plus injectable drug • automated molecular assay (Xpert MTB/RIF)—rapidly tests for Mycobacterium tuberculosis and resistance to rifampin in sputum samples • developed in public-private partnership; both sensitive and rapid

38. Choose the incorrect statement about stroke. A) Focal neurologic deficit with presumed vascular onset B) Duration >24 hr C) Typically diagnosed by computed tomography (CT) D) Transesophageal echocardiography helpful in identifying cause

39. Answer •  C) Typically diagnosed by computed tomography (CT)

40. Stroke • defined as focal neurologic deficit with presumed vascular onset • duration >24 hr • if less than 24 hr, called transient ischemic attack (TIA) • however, most TIAs last 15 min) • computed tomography (CT) not very useful but diffusionweighted magnetic resonance imaging (MRI) extremely helpful in establishing diagnosis

41. It is estimated that control of hypertension in patients would reduce the incidence of stroke in the United States by: A) 50% B) 40% C) 33% D) 20%

42. Answer •  A) 50%

43. Indistinct symptoms that may suggest stroke: loss of consciousness • headache; march of symptoms from one body part to another • positive neurologic findings • Transesophageal echocardiography (TEE) superior to transthoracic echocardiography (TTE) in identifying causes of • stroke (eg, left ventricular thrombus; valvular disease; patent foramen ovale plaque in aortic arch) • Ischemic penumbra (IP): relatively hypoperfused area of brain (between normal tissue and tissue of infarct) at risk for infarction but not irreversibly damaged • target for acute intervention (salvaging IP one of goals of treatment) • Resurgence in stroke mortality rate: annual death rate declined over last 20 yr, but expected to double over next 30 yr • Risk factors for stroke: controllable—hypertension (HTN) • Hyperlipidemia • diabetes mellitus (DM) • smoking • noncontrollable — ethnicitysex • nationality • Guidelines for stroke prevention: treat HTN, cholesterol, and DM; smoking cessation • discontinue heavy alcohol use • weight reduction • moderate-intensity exercise for 30 min most • days of week • estimated that control of HTN in patients would reduce incidence of stroke in United States by 50

44. Aggressive statin therapy should be avoided in patients after a stroke or transient ischemic attach (TIA). A) True B) False

45. Answer •  B) False

46. Stroke Prevention by Aggressive Reduction in Cholesterol • Levels (SPARCL) study: 5000 patients with recent history of stroke or TIA and hyperlipidemia randomized to 80 mg atorvastatin vs placebo • results — aggressive antihyperlipidemic therapy reduced incidence of fatal or nonfatal stroke by 16% and need for revascularization surgery in heart and neck by almost 50% • implications — aggressive statin therapy should be strongly considered in patients after stroke or TIA • most effective agent and dosage unclear • Management of DM and stroke prevention: results of several recent trials suggest more aggressive control of type 1 and type 2 DM does not reduce risk for stroke • Stroke risk in smokers: smoking 2 packs of cigarettes daily associated with 2-fold risk for stroke • if smoking stopped, risk reverts to baseline within 5 yr

47. Screening asymptomatic patients for carotid disease: in United States, 66% of adults >40 yr of age have some carotid plaque (and 10% of men >65 yr of age have moderate to high-grade asymptomatic stenosis) • presence of plaque clear marker of risk for stroke • consider noninvasive screening for all patients at increased risk

48. All the following antiplatelet agents are approved for use in the prevention of recurrent stroke, except: A) Aspirin (ASA) B) Clopidogrel C) Ticlopidine D) Cilostazol

49. Answer •  D) Cilostazol

50. Antiplatelet therapy • antiplatelet agents approved for use in prevention of recurrent stroke include aspirin (ASA), clopidogrel, ASA plus dipyridamole, and ticlopidine • no good evidence antiplatelet therapy reduces risk for stroke in asymptomatic patients • possibly small benefit in older women and men with substantial atherosclerotic risk (however, substantial increase in risk for hemorrhagic stroke) • in symptomatic patients, antiplatelet agents reduce risk for stroke by 25% • ASA good for almost all patients • little reason to use dipyridamole • clopidogrel probably no better than ASA, except in patients with gastrointestinal (GI) intolerance, allergy to ASA, stents, or history of TIA or stroke while on ASA • combination of clopidogrel and ASA may be beneficial in patients with atrial fibrillation (AF) who cannot tolerate warfarin (consider dabigatran) • many new anticoagulant agents in development or have just become available for clinical use