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Clostridium difficile enterocolitis; C difficile-associated diarrhea (CDAD, CDD)

Etiology: 1) antibiotics* (within past 6 weeks) a) odds ratio (OR) after any antibiotic (OR=3.56-6.91) b) clindamycin (OR=16.8-20.4) [41] highest risk (OR=25.4) [95] c) cephalosporins/monobactams/carbapenems (OR=4.47-5.68) [41] - cefdinir (OR=11.0), cefuroxime (OR=9.6), cefpodoxime (OR=9.2) [95] d) fluoroquinolones (OR=5.50-5.65) [41]; ciprofloxacin (OR=6.8) [95] e) penicillins (OR=2.71-3.25); - amoxicillin (OR=2.0), amoxicillin-clavulanate (OR=8.5) f) macrolides (OR= 2.55-2.65) g) trimethoprim/sulfamethoxazole (OR=1.81-1.84) h) tetracyclines not associated with increase risk of C difficile colitis (OR=0.91-0.92) [41] i) receipt of antibiotic by prior occupant to hospital bed increases risk for C difficile colitis (RR=1.22) [67] 2) C difficile colitis may occur without recent antibiotic exposure in patients with inflammatory bowel disease [3] 3) gastric acid suppression increases risk [29,73] a) proton pump inhibitors (PPI) [9,11,14,73] - PPI may alter specific bacteria that increase risk of C difficile colitis [58] b) histamine H2 receptor antagonists [29] 4) tube feeding increases risk [3] 5) recent abdominal surgery 6) use of glucocorticoids [29] 7) hospitalization increases risk [29] - even without antibiotic use, patients hospitalized in a region with high antibiotic use are at increased risk for C difficile colitis [65] 8) age >= 80 increases risk [29] 9) severity of C difficile infection increased by a) gastric acid suppression [29] b) use of glucocorticoids [9] 10) obesity may increase risk [42] 11) dietary trehalose may select for emergence of 2 virulant epidemic strains of C difficile [75] * also, prolonged or multiple antibiotics Epidemiology: 1) most common cause of nosocomial diarrhea - contamination of the hospital environment with C difficile spores [26] - prescribing antibiotics to hospitalized patients increases risk for C difficile colitis in next bed occupant [77] 2) most cases middle-age to older age 3) 18% risk of developing C difficile enterocolitis in patients admitted for infections requiring antibiotics [4] 4) prevalence of 0.7% in all hospitalized patients [4] 5) age >= 80 years associated with increased severity of infection & increased mortality [29] 6) 40-94% of cases in 2 studies community-acquired [30,56] - 61% of cases community-acquired [87] - community-acquired infection more common in women - reservoirs of C. difficile spores include: - pets, farm animals, prepared foods, newborn infants - exposure during diaper changes ? - 1/3 of cases occur without exposure to identified person infected with C difficile [44] - 39% of community-acquired cases not associated with antibiotic use - 1.5% of community acquired diarrhea (Salmonella more likely, 1.6%) 7) 95% of cases linked to healthcare exposures [31] 8) family members can acquire C difficile from recently discharged patients with asymptomatic carriage of C difficile [92] 9) BI strain of Clostridium difficile predisposes to relapse [35] 10) NAP1/027 strain can lead to severe infection [5] 11) 450,000 cases occurred in 2011 in the U.S. - ~29,000 deaths - incidence higher in women (RR=1.26), whites (RR=1.72), patients >= 65 years (RR=8.65) - ~2/3 of cases were healthcare-related - NAP1 strain more often in healthcare-related cases 12) multiply recurrent C difficile colitis increasing in U.S. [74] 13) see Clostridium difficile Pathology: 1) occurs as a result of synthesis of enterotoxin within the intestinal lumen by specific strains of C difficile 2) rarely, C difficile may directly invade the colonic mucosa 3) the distal colon is usually involved Clinical manifestations: 1) fever may exceed 40 C 2) watery diarrhea (bloody diarrhea uncommon) 3) abdominal pain, moderate to severe, may be distension* 4) diarrhea may be absent in patients with severe ileus or toxic megacolon 5) symptoms occur 1-10 weeks after antibiotic therapy * indicator of severe colitis Laboratory: 1) C difficile enterotoxin in stool (EIA) - good specificity, sensitivity 75-85% (single specimen) [3] - Clostridium difficile enterotoxin A in stool - Clostridium difficile enterotoxin B in stool - Clostridium difficile enterotoxin A+B in stool - Cepheid Xpert C. difficile/Epi assay 2) latex agglutination test - measures glutamate dehydrogenase activity which is produced by toxigenic & non toxigenic strains of C difficile & other bacteria - sensitive but not specific [3] - used in conjunction with C difficile enterotoxin in stool - positive concordant tests rule in C difficile colitis - negative concordant tests rule out C difficile colitis - discordant tests require rt-PCR for Clostridium difficile DNA [3] 3) Clostridium difficile DNA - Clostridium difficile toxin genes in stool (PCR) - repeat testing within 7 days after collection of a PCR-negative stool is rarely useful [37] - positive concordant Clostridium difficile DNA & C difficile enterotoxin in stool (EIA) confirm difficile colitis [3] 4) Clostridium difficile culture from stool (not recommended) [3] a) anaerobic stool culture - 2-3 days - antibiotic sensitivity testing - epidemiologic studies b) cytotoxic effects of enterotoxin B - 75% sensitivity - for patients with a high pretest probability of C difficile colitis & a confirmed negative EIA test, order stool enterotoxin B testing rather than repeating an EIA [20] 5) complete blood count (CBC) to assess severity a) leukocytosis may reach 50,000 WBC/mm3 b) leukocytosis > 15,000 WBC/mm3 is a indicator of severe colitis [3] c) eosinophils in blood - eosinopenia, 0 eosinophils/uL (none), on admission associated with increased risk for mortality, colectomy, ICU admission, & vasopressor use [83] 6) serum creatinine > 50% increase above baseline - serum creatinine > 1.5 mg/dL [3] indicates severe colitis [3] 7) serum albumin < 2.5 g/dL is an indicator of severe colitis [3] 8) see ARUP consult [34] 9) hospitalized patients with diarrhea who test negative for C difficile colitis should be treated with antidiarrheal agents without further testing or treatment for C difficile [3] 10) documenting clearance of C difficile in follow-up of an initial positive test is of no benefit [3], unless patient is rechallenged with antibiotic therapy & develops similar symptoms* [93] * even if those symptoms would not otherwise suggest C difficile colitis Special laboratory: - flexible sigmoidoscopy vs colonoscopy a) may be indicated if patient has ileus & no stool is available, or b) when other colonic diseases are in the differential - ischemic colitis - inflammatory bowel disease c) ref [3] recommends flexible sigmoidoscopy d) visualization of pseudomembranes is an indicator of severe colitis Radiology: - computed tomography Differential diagnosis: 1) benign or simple antibiotic-associated diarrhea 2) diarrhea caused by other enteric pathogens 3) adverse reactions to non-antibiotic agents 4) ischemic colitis 5) inflammatory bowel disease 6) intra-abdominal sepsis Complications: 1) toxic megacolon* 2) colonic perforation* 3) ileus: 4) dehydration, hypovolemia, hypotension, shock* 5) hypoalbuminemia 6) reactive arthritis (1-4 weeks after onset) 7) promotes overgrowth of vancomycin-resistent enterococci (VRE) after treatment with either vancomycin or metronidazole [17] 8) relapse more common than reinfection - 88% of 2nd episode < 8 weeks after 1st = relapse - 65% of 2nd episode > 8 weeks after 1st = relapse [28] 9) opiates increase risk for severe disease, longer hospital stay, & higher hospital readmission rates [81] - > 75% of patients patients with C difficile colitis receive opioids when they are hospitalized [81] 10) mortality ~6% - risk factors - age >= 80 years - gastric acid suppression [29] - virulent NAP1/027 strain of C difficile * indicators of severe C difficile colitis Management: 1) stop offending agent(s) if possible a) continuation of offending antibiotics during therapy for C difficile-associated diarrhea reduces cure rate [27] b) fidaxomicin 200 mg BID may be more effective than vancomycin if offending antibiotics need to be continued for treatment of other infections [27,40] c) stop proton pump inhibitors (PPI) if possible - use OF PPI during treatment of C difficile colitis is associated with a 42% increased risk of recurrent infection [32] 2) assess severity a) leukocytosis > 15,000 WBC/mm3 b) serum creatinine > 50% increase above baseline (or > 1.5 mg/dL [3]) c) temperature > 38 C d) clinical or radiographic evidence of severe colitis 3) supportive therapy: a) hydration, oral preferred b) correction of electrolyte imbalance 4) infection control precautions a) contact isolation - treat in rooms separated from general population [47] - dedicated care teams [47] - contact isolation precautions applies to visitors [55] - maintain contact precautions for at least 48 hours after diarrhea resolves [76] b) maintain history of C difficile on medical record c) hand-washing d) alcohol-based disinfectants not effective [3,47] e) environmental cleaning with sodium hypochlorite (bleach) 5) avoid anti peristaltic agents 5) anti-diarrheal agents a) bismuth subsalicylate (Pepto-Bismol) 1] 60 mL every 4 hours x 4 doses, then 2] 30 mL every 4-6 hours PRN b) cholestyramine may abdorb enterotoxin 6) metronidazole (Flagyl) 500 mg PO TID for 10-14 days [22] a) MKSAP19 no longer recommends metronidazole except for adjunctive intravenous therapy in conjunction with vancomycin for severe colitis [3] b) formerly drug of choice for patients with first episodes of mild-to-moderate C difficile infection [22] - also used for 1st recurrence of mild-moderate C difficile colitis initially treated with metronidazole - vancomycin or fidaxomicin rather than metronidazole for initial infection [82] c) IV metronidazole 500 mg every 6 hours if oral therapy NOT possible [7] - possible ileus or toxic megacolon sufficient to warrant IV therapy [5] d) recurrence after metronidazole therapy is common [10] (47-58% in 2003-2004 {higher in elderly}) e) avoid during pregnancy f) do NOT use metronidazole for second recurrence because of risk of neurotoxicity [22] 7) vancomycin (oral) a) more effective than metronidazole [3,21] - equally effective for mild-moderate C difficile colitis [3] b) 125 mg PO QID for 10-14 days [8,22] - > 14 days may be needed for patients with inflammatory bowel disease [89] c) indications [3] 1] first episodes 2] severe first episodes [22,71] - severe or persistent diarrhea & offending antibiotic cannot be stopped - see Laboratory: & Clinical manifestations: for severity 3] recurrent disease - other than 1st recurrence of mild-moderate C difficile colitis initially treated with metronidazole - prolonged course (6 weeks) of vancomycin with tapering or pulse doses at the end of treatment (see below) [3] - fidaxomicin may be indicated in patients previously treated with vancomycin [5] 4] when a delay in laboratory confirmation of > 1 day is expected [5] - unless otherwise specified, assume a delay in laboratory confirmation [5] d) oral vancomycin + IV metronidazole for fulminant infection [82.93] e) vanocomycin enema + IV metronidazole if ileus is present [3,93] f) IV vancomycin NOT effective [7] 8) fidaxomicin 200 mg BID (Dificid) FDA-approved 5/11 [40] - initial treatment of severe C difficile colitis [3] - either vancomycin or fidaxomicin can be used 1st line [93] - fidaxomicin is preferred agent for severe or non-severe C difficile colitis [3] - recurrent C difficile colitis after prior treatment with vancomycin [5] 9) for patients continuing to receive antibiotics, vancomycin & fidaxomicin with equal efficacy [96] 10) other antibiotics: nitazoxanide, oral bacitracin 11) 15-20% of patients have recurrence a) retest to confirm C difficile prior to treating relapse - tissue culture for cytotoxic effects of enterotoxin B may be preferable to EIA [20] b) treat initial relapse of mild to moderate C difficile colitis with 2nd course of initial antibiotic [3] c) 90% respond to treatment of relapse with the initial antibiotic [5] d) addition of bezlotoxumab (Zinplava) to standard-of-care antibiotics is superior to antibiotics alone for preventing recurrent Clostridium difficile colitis (17% vs 28%) [[69] e) fidaxomicin 200 mg BID (Dificid) for recurrent C difficile colitis after prior treatment with vancomycin [5] f) 2nd recurrence: vancomycin taper (6-8 weeks of therapy) - 125 mg PO QID for 10-14 days - 125 mg PO BID for 7 days - 125 mg PO QD for 7 days - 125 mg PO QID for 7 days reduces risk of 2nd recurrence 54% vs 70% [68] - 125 mg PO every 2-3 days for 2-4 weeks [3] - no similar benefit for metronidazole [68] 12) refractory C difficile colitis - fecal transplantation via colonoscopy [33] - repeated testing positive for C difficile enterotoxin A or enterotoxin B [6] - may be treatment of choice for refractory C difficile colitis [48] - fecal transplantation associated with reduced incidence of sepsis, shorter hospital stay & reduced mortality vs antiotics [88] - oral capsules of frozen fecal material improved symptoms of C difficile colitis in a small study [53] - repeat fecal transplantation for recurrence within 8 weeks of initial of initial fecal transplantation [91] - coadministration of oral tolevamer (experimental) - alternatives to fecal transplantation - fecal transplantation superior to fidaxomicin [84] - intravenous tigecycline may be alternative [19] - tapering-dose schedule for 6 weeks + 5 oz of kefir with every meal (TID) for duration of antibiotic taper & for 7 weeks afterwards may be an option in patients not candidates for stool transplantation [52] - vancomycin + rifampin 600 mg BID - vancomycin + Saccharomyces cerevisiae (brewer's yeast) beginning 4 days prior to 10 days of vancomycin - vancomycin + cholestyramine 4 gm BIB 13) do not retest, unless treating symptoms refractory to treatment - if retesting, order tissue culture for cytotoxic effects of enterotoxin B 14) surgery: total colectomy a) fulminant colitis with perforation b) toxic megacolon 15) prophylaxis: a) antimicrobial stewardship - 1/4 of Clostridium difficile infections can be prevented by reducing hospital prescriptions for high-risk antibiotics by 1/3 - fluoroquinolones - beta-lactam/beta-lactamase inhibitors - extended-spectrum cephalosporins b) probiotics - Saccharomyces boulardii may be of benefit [5,12] - Lactobaciilus may be useful [16] - probiotics Bifidobacterium, Lactobacilli, Saccharomyces, & Streptococcus reduces risk of C-difficile diarrhea in patients on antibiotics by 66% [36] - benefit uncertain in immunosuppressed patients - Lactobacillus in combination with either Streptococcus or both Bifidobacterium & Streptococcus may be of benefit [72] - children & hospitalized patients benefit most (NNT=12-20) [79] - other probiotics NOT of benefit [12] - probiotics should not be used for primary or secondary prevention [91] c) fecal transplantation effective in reducing risk among patients prescribed antibiotics [3] d) ultraviolet wavelength C germicidal irradiation appears effective in eliminating infectivity of C difficile spores from hospital rooms formerly occupied by patients with C-difficile colitis [70] e) prophylaxis with vancomycin not effective [86] 16) prevention - sodium hypochlorite for decontamination of all potentially contaminated surfaces [5] - alcohol-based hand rubs do not eradicate C difficile spores - wash hands with soap & water - contact precautions Comparative biology: - taurocholate analog CamSA inhibits C difficile spore germination & prevents disease in mice [38] Notes: - a U.S. federal educational project helped hospital staff reduce quinolone use & C difficile infections by 20% [90] - review article [57]

Related

Clostridium difficile; Clostridioides difficile

General

infectious diarrhea; infectious colitis bacterial enteritis

References

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