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• A C difficile diagnosis should be made by one of several widely available testing protocols, including a 2-step method using the common antigen assay to determine whether C difficile is present, followed by an enzyme immunoassay for toxins A and B to improve specificity. B
• Oral metronidazole should be used for initial treatment of mild to moderate C difficile infection, and oral vancomycin and possibly intravenous metronidazole for severe cases. A
• Metronidazole should not be used after an initial recurrence or for long-term therapy because of the risk of neurotoxicity. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Mary S, an 82-year-old patient you recently treated for bronchitis with a 3-day course of levofloxacin, calls your office complaining of diarrhea and abdominal cramps. She describes the diarrhea as nonbloody and particularly foul smelling and asks if she can take loperamide for her symptoms.
If Mary S were your patient, what would you tell her?
The incidence of Clostridium difficile infection (CDI) has been on the rise since 2000, when a common epidemic strain began circulating in North America.1 Although hospitalization or residency in a long-term care facility remains a classic risk factor for CDI, physicians in out-patient settings are increasingly likely to see patients with community-acquired CDI.
Recently updated guidelines from the Society for Health-care Epidemiology of America (SHEA) and the Infectious Diseases Society of America define CDI as the presence of diarrhea (≥3 unformed stools in 24 hours) and either a positive stool test for toxigenic C difficile or its toxins or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.2 That said, the clinical features of CDI are nonspecific and many patients do not fit the classic profile. So diagnosing CDI requires a high index of suspicion.
The text and tables that follow detail some surprising things about who is likely to develop CDI and which treatment options to employ (and, in some cases, avoid).
Is it CDI? Looking beyond the obvious
Antibiotic use and advanced age, like hospitalization, are classic risk factors for CDI.3 Diarrhea typically begins during or shortly after a course of antibiotics, but may develop as long as 8 weeks after treatment is completed. While any antibiotic, including metronidazole, can precipitate CDI, clindamycin, cephalosporins, extended-spectrum penicillins, and quinolones are most frequently implicated.4 Epidemiologic studies have suggested an association between gastric acid-reducing agents—primarily proton-pump inhibitors—and CDI.4-7 But this link remains controversial, as other investigations have not found a clear relationship.8
In addition to diarrhea, approximately 28% of patients with CDI develop a fever (as high as 104°F); 50% develop leukocytosis (up to 50,000 cells/mcL); and 22% develop abdominal pain, usually localized to the lower quadrants.9 These symptoms, however, are not specific to C difficile, and could be due to a different enteric pathogen, intra-abdominal sepsis, inflammatory bowel disease, or adverse effects of medication, among other causes.9
Markers for severe CDI include age >70 years, leukocyte count >20,000 cells/mcL, albumin level <2.5 g/dL, small-bowel obstruction or ileus, and a computed tomography (CT) scan showing colorectal inflammation.10 Severe CDI can lead to toxic megacolon, bowel perforation, sepsis, and even death.
In addition to considering CDI in patients with nonspecific symptoms, it is important to include it in the differential diagnosis of patients who do not fit the classic profile. In a recent study of patients with CDI at 4 Veterans Affairs facilities, almost half (49%) of those studied had no exposure to antimicrobial drugs. The researchers further found that the median age of patients with CDI was 61 years—younger than that found in previous studies—and that 20% of the cases were community-acquired.11
Consider CDI in children, too. Risk factors for CDI in pediatric patients include disruption of the normal microflora of the gastrointestinal tract, compromised immune status, poor diet, underlying health conditions, concurrent infections, and cancer.12
Diagnostic testing: Consider a 2-step assay
Patients with symptoms suggestive of CDI should undergo laboratory testing to confirm the diagnosis. TABLE 1 lists the tests that are widely available in the United States.3 Only liquid stools should be tested and just one sample should be sent to the lab, as multiple samples do not increase the diagnostic yield.13 In addition, tests should be used only for diagnosis, and not as a “test of cure.” This is because patients can shed C difficile toxin and spores for several weeks after completing treatment, and there are wide variations in the sensitivity of toxin assays.
Infants <1 year old have high rates of asymptomatic toxigenic strains of C difficile, and until 2008, recommendations from SHEA discouraged testing the stools of such young patients. Because of the difficulty in differentiating incidental colonization from true CDI in this patient population, the authors of a recent review suggested using more than one diagnostic approach when testing children <1 year of age.14
We advocate a 2-step assay—that is, testing for both glutamate dehydrogenase (GDH)—an antigen common to all strains of C difficile—and C difficile toxins A and B. The common antigen test is sensitive, but may detect carriers who do not have active disease. The enzyme immunoassay (EIA) for toxins A and B helps to improve specificity. Therefore, positive results of both tests would be considered a positive finding, negative results of both tests would be considered a negative finding, and one positive result with one negative result would require another test for toxin detection.3
The reverse-transcriptase polymerase chain reaction (RT-PCR) assay, which detects the toxin B gene of C difficile, is the newest test for CDI. The RT-PCR assay detects only toxigenic strains of C difficile, and all toxigenic strains produce toxin B, making it more specific than testing for the common antigen. The RT-PCR assay also has better sensitivity than the cytotoxin assay, which also tests for toxin B. The major limitation of the RT-PCR assay is the frequency of false-positive results in hospitalized patients with a high incidence of C difficile colonization.3
Routine laboratory studies, including a complete blood count with differential and a complete metabolic panel, are often useful to ascertain the presence and degree of leukocytosis, dehydration, and other metabolic abnormalities and to test for hypoalbuminemia. Fecal leukocytes can be seen in colitis and may be useful in select cases.
Imaging studies such as radiography, CT, and endoscopy have largely been superseded by lab testing for CDI. Plain radiographs are usually normal in patients with CDI, unless the patient has an ileus or toxic megacolon. CT is useful, however, in suspected cases of fulminant CDI or toxic megacolon, and may reveal colonic-wall thickening, pericolonic stranding, or ascites.9 Colonoscopy is preferred over sigmoidoscopy because up to one-third of patients with pseudomembranous colitis will have involvement of the right colon only.9 However, this test carries the risk of perforation in patients with fulminant colitis.
TABLE 1
Lab tests for C difficile infection
| Test | Substance detected | Time needed | Sensitivity | Specificity |
|---|---|---|---|---|
| Cytotoxin | Toxin B | 1-3 d | 95% | 90%-95% |
| Toxin culture | Toxigenic C difficile† | 3-5 d | >95% | 80%-90% |
| EIA toxin A or A/B | Toxin A or A/B | Hours | 75%-80% | 97%-98% |
| EIA GDH* | C difficile | Hours | 95%-100% | 70%-80% |
| EIA GDH* and toxin A/B | C difficile and C difficile toxin | Hours | 95%-100% | 97%-98% |
| RT-PCR | Toxigenic C difficile† | Hours | >98% | 80%-99% |
| *GDH is the common C difficile antigen. †All toxigenic strains produce toxin B. EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; RT-PCR, reverse-transcriptase polymerase chain reaction. Adapted from: Bartlett JG. Infect Control Hosp Epidemiol. 2010.3 | ||||
Treatment: What to consider, what to avoid
Of the 2 antibiotics most commonly used to treat CDI—metronidazole and vancomycin—only the latter has been approved by the US Food and Drug Administration for this indication. Nevertheless, metronidazole is generally recommended as first-line therapy and has the advantage of being much less expensive than vancomycin. However, an RCT found that oral vancomycin was superior to metronidazole in patients with severe disease.15 The time to resolution of diarrhea may be shorter with oral vancomycin than with metronidazole, as well.16
Recent guidelines suggest that clinicians consider 3 factors in deciding how to treat a first episode of CDI: the patient’s age, peak white blood cell count, and peak serum creatinine level.2 TABLE 2 presents an overview of treatment recommendations for both an initial episode of CDI and recurrences.
Treat severe CDI without delay. For patients with suspected severe CDI, treatment should be started empirically, without waiting for test results. Avoid antiperistaltic agents, which can obscure symptoms and precipitate toxic megacolon.2 Discontinue an antibiotic, if the patient is taking one, as soon as possible after the original infection has been adequately treated. If other infections need to be treated concurrently, we recommend that the course of treatment for CDI be extended until after the other antibiotic regimens have been stopped.
Avoid probiotics in this group. The use of probiotics, both for prevention and to help restore normal bowel flora in patients with CDI, has been advocated for many years. One RCT showed that a yogurt drink containing Lactobacillus and other bacteria reduced the risk of CDI in individuals ≥50 years of age who were taking antibiotics,17 but the guideline development panel recommended against using probiotics until larger trials have been completed.2
Probiotics are not without risk, and several cases of bacteremia have been reported.18,19 Immunocompromised patients appear to be at comparably higher risk, and probiotics should be avoided in this group. Numerous adjunctive agents, including intraluminal toxin binders, biotherapeutic agents, monoclonal antibodies, and a C difficile vaccine, are in various stages of development.2
How to handle recurrences
Relapse rates for CDI range from 6% to 25%,2 and affect patients who receive either vancomycin or metronidazole for the initial treatment. The mechanism relates to either relapse of the original infection or reinfection of susceptible patients with a new strain of C difficile.
Risk of relapse. Elderly patients treated with metronidazole seem to be particularly susceptible to CDI relapse.20 Other risk factors include the administration of non-C difficile antibiotics during or after treatment of CDI, a defective immune response against toxin A, glucocorticoid use, prior stroke, and concurrent use of a proton-pump inhibitor.21-25
TABLE 2 lists tapering and/or pulsed dosing of oral vancomycin as treatment for patients with a second recurrence. We often prescribe the following 6-week regimen, telling patients to take 125 mg vancomycin:
- 4 times a day for one week,
- then 2 times a day for one week,
- then once a day for one week,
- then every other day for one week, and
- finally, every 72 hours for 2 weeks.
Oral metronidazole should not be used beyond the first recurrence or for long-term therapy because of cumulative neurotoxicity, which can be irreversible.2
Management of patients whose CDI recurs after a long course of vancomycin is challenging. Oral rifaximin therapy (400 mg twice a day for 14 days), started immediately at the end of the oral vancomycin course, was shown to cure 7 of 8 patients with multiple relapses.26 Other potential treatment options are oral nitazoxanide, IV tigecycline, or IV immunoglobulin.
CASE You explain to Mary S that diagnostic tests are needed before you can determine whether she can safely take loperamide. When she comes in later that day, you collect a stool sample for C difficile antigen and toxin testing, and order a complete blood count and electrolyte panel.
The patient’s C difficile tests come back positive, her white blood cell count is <15,000 cells/mcL, and her creatinine level is ≤1.5 times her baseline, so you start her on oral metronidazole 500 mg every 8 hours for 14 days. (If the antigen assay had been positive and the toxin negative, you would have either repeated the test or treated Mary S empirically with metronidazole. If the initial antigen assay had been negative, you would have advised her to take the loperamide.)
You schedule a follow-up visit a day or 2 after starting therapy. If the patient is dehydrated or her symptoms have not improved by then, hospitalization may be required.
TABLE 2
Treatment recommendations for C difficile infection
| Clinical description | Clinical evidence | Recommended treatment |
|---|---|---|
| Initial episode (mild or moderate) | Leukocytosis with a white cell count <15,000 cells/mcL and creatinine <1.5 times premorbid level | Metronidazole (oral) 500 mg TID for 10-14 d |
| Initial episode (severe) | Leukocytosis with a white cell count ≥15,000 cells/mcL or creatinine ≥1.5 times premorbid level | Vancomycin (oral) 125 mg QID for 10-14 d |
| Initial episode (severe, complicated) | Hypotension or shock, ileus, megacolon | Vancomycin 500 mg QID (oral or by NG tube) plus metronidazole 500 mg (IV). If complete ileus, consider adding rectal instillation of vancomycin |
| First recurrence | Same as initial episode | |
| Second recurrence | Vancomycin in a tapered and/or pulsed regimen | |
| NG, nasogastric. Adapted from: Cohen SH, et al. Infect Control Hosp Epidemiol. 2010.2 | ||
CORRESPONDENCE
Richard R. Watkins, MD, MS, Division of Infectious Diseases, Akron General Medical Center, 224 West Exchange Street, Suite 290, Akron, OH 44302; [email protected]
1. Gerding DN. Global epidemiology of Clostridium difficile infection in 2010. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S32-S34.
2. Cohen SH, Gerding DH, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.
3. Bartlett JG. Detection of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S35-S37.
4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.
5. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294:2989-2995.
6. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243-245.
7. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784-790.
8. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM. 2000;93:175-181.
9. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis. 2008;46(suppl 1):S12-S18.
10. Henrich TJ, Krakower D, Bitton A, et al. Clinical risk factors for severe Clostridium difficile-associated disease. Emerg Infect Dis. 2009;15:415-422.
11. Kutty PK, Woods CW, Sena AC, et al. Risk factors for and estimated incidence of community-associated Clostridium difficile infection, North Carolina, USA. Emerg Infect Dis. 2010;16:197-204.
12. Pituch H. Clostridium difficile is no longer just a nosocomial infection or an infection of adults. Int J Antimicrob Agents. 2009;33(suppl 1):S42-S45.
13. Mohan SS, McDermott BP, Parchuri S, et al. Lack of value of repeat stool testing for Clostridium difficile toxin. Am J Med. 2006;119:356.e7-e8.
14. Bryant K, McDonald LC. Clostridium difficile infections in children. Pediatr Infect Dis J. 2009;28:145-146.
15. Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-307.
16. Belmares J, Gerding DN, Parada JP, et al. Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect. 2007;55:495-501.
17. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335:80.-
18. Ledoux D, Labombardi VJ, Karter D. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin’s disease. Int J STD AIDS. 2006;17:280-282.
19. Hammerman C, Bin-Nun A, Kaplan M. Safety of probiotics: comparison of two popular strains. BMJ. 2006;333:1006-1008.
20. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590.
21. Nair S, Yadav D, Corpuz M, et al. Clostridium difficile colitis: factors influencing treatment failure and relapse—a prospective evaluation. Am J Gastroenterol. 1998;93:1873-1876.
22. Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008;70:298-304.
23. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease. Am J Gastroenterol. 2010;105:2040-2049.
24. Cadena J, Thompson GR, 3rd, Patterson JE, et al. Clinical predictors and risk factors for relapsing Clostridium difficile infection. Am J Med Sci. 2010;339:350-355.
25. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170:772-778.
26. Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:846-848.
• A C difficile diagnosis should be made by one of several widely available testing protocols, including a 2-step method using the common antigen assay to determine whether C difficile is present, followed by an enzyme immunoassay for toxins A and B to improve specificity. B
• Oral metronidazole should be used for initial treatment of mild to moderate C difficile infection, and oral vancomycin and possibly intravenous metronidazole for severe cases. A
• Metronidazole should not be used after an initial recurrence or for long-term therapy because of the risk of neurotoxicity. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Mary S, an 82-year-old patient you recently treated for bronchitis with a 3-day course of levofloxacin, calls your office complaining of diarrhea and abdominal cramps. She describes the diarrhea as nonbloody and particularly foul smelling and asks if she can take loperamide for her symptoms.
If Mary S were your patient, what would you tell her?
The incidence of Clostridium difficile infection (CDI) has been on the rise since 2000, when a common epidemic strain began circulating in North America.1 Although hospitalization or residency in a long-term care facility remains a classic risk factor for CDI, physicians in out-patient settings are increasingly likely to see patients with community-acquired CDI.
Recently updated guidelines from the Society for Health-care Epidemiology of America (SHEA) and the Infectious Diseases Society of America define CDI as the presence of diarrhea (≥3 unformed stools in 24 hours) and either a positive stool test for toxigenic C difficile or its toxins or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.2 That said, the clinical features of CDI are nonspecific and many patients do not fit the classic profile. So diagnosing CDI requires a high index of suspicion.
The text and tables that follow detail some surprising things about who is likely to develop CDI and which treatment options to employ (and, in some cases, avoid).
Is it CDI? Looking beyond the obvious
Antibiotic use and advanced age, like hospitalization, are classic risk factors for CDI.3 Diarrhea typically begins during or shortly after a course of antibiotics, but may develop as long as 8 weeks after treatment is completed. While any antibiotic, including metronidazole, can precipitate CDI, clindamycin, cephalosporins, extended-spectrum penicillins, and quinolones are most frequently implicated.4 Epidemiologic studies have suggested an association between gastric acid-reducing agents—primarily proton-pump inhibitors—and CDI.4-7 But this link remains controversial, as other investigations have not found a clear relationship.8
In addition to diarrhea, approximately 28% of patients with CDI develop a fever (as high as 104°F); 50% develop leukocytosis (up to 50,000 cells/mcL); and 22% develop abdominal pain, usually localized to the lower quadrants.9 These symptoms, however, are not specific to C difficile, and could be due to a different enteric pathogen, intra-abdominal sepsis, inflammatory bowel disease, or adverse effects of medication, among other causes.9
Markers for severe CDI include age >70 years, leukocyte count >20,000 cells/mcL, albumin level <2.5 g/dL, small-bowel obstruction or ileus, and a computed tomography (CT) scan showing colorectal inflammation.10 Severe CDI can lead to toxic megacolon, bowel perforation, sepsis, and even death.
In addition to considering CDI in patients with nonspecific symptoms, it is important to include it in the differential diagnosis of patients who do not fit the classic profile. In a recent study of patients with CDI at 4 Veterans Affairs facilities, almost half (49%) of those studied had no exposure to antimicrobial drugs. The researchers further found that the median age of patients with CDI was 61 years—younger than that found in previous studies—and that 20% of the cases were community-acquired.11
Consider CDI in children, too. Risk factors for CDI in pediatric patients include disruption of the normal microflora of the gastrointestinal tract, compromised immune status, poor diet, underlying health conditions, concurrent infections, and cancer.12
Diagnostic testing: Consider a 2-step assay
Patients with symptoms suggestive of CDI should undergo laboratory testing to confirm the diagnosis. TABLE 1 lists the tests that are widely available in the United States.3 Only liquid stools should be tested and just one sample should be sent to the lab, as multiple samples do not increase the diagnostic yield.13 In addition, tests should be used only for diagnosis, and not as a “test of cure.” This is because patients can shed C difficile toxin and spores for several weeks after completing treatment, and there are wide variations in the sensitivity of toxin assays.
Infants <1 year old have high rates of asymptomatic toxigenic strains of C difficile, and until 2008, recommendations from SHEA discouraged testing the stools of such young patients. Because of the difficulty in differentiating incidental colonization from true CDI in this patient population, the authors of a recent review suggested using more than one diagnostic approach when testing children <1 year of age.14
We advocate a 2-step assay—that is, testing for both glutamate dehydrogenase (GDH)—an antigen common to all strains of C difficile—and C difficile toxins A and B. The common antigen test is sensitive, but may detect carriers who do not have active disease. The enzyme immunoassay (EIA) for toxins A and B helps to improve specificity. Therefore, positive results of both tests would be considered a positive finding, negative results of both tests would be considered a negative finding, and one positive result with one negative result would require another test for toxin detection.3
The reverse-transcriptase polymerase chain reaction (RT-PCR) assay, which detects the toxin B gene of C difficile, is the newest test for CDI. The RT-PCR assay detects only toxigenic strains of C difficile, and all toxigenic strains produce toxin B, making it more specific than testing for the common antigen. The RT-PCR assay also has better sensitivity than the cytotoxin assay, which also tests for toxin B. The major limitation of the RT-PCR assay is the frequency of false-positive results in hospitalized patients with a high incidence of C difficile colonization.3
Routine laboratory studies, including a complete blood count with differential and a complete metabolic panel, are often useful to ascertain the presence and degree of leukocytosis, dehydration, and other metabolic abnormalities and to test for hypoalbuminemia. Fecal leukocytes can be seen in colitis and may be useful in select cases.
Imaging studies such as radiography, CT, and endoscopy have largely been superseded by lab testing for CDI. Plain radiographs are usually normal in patients with CDI, unless the patient has an ileus or toxic megacolon. CT is useful, however, in suspected cases of fulminant CDI or toxic megacolon, and may reveal colonic-wall thickening, pericolonic stranding, or ascites.9 Colonoscopy is preferred over sigmoidoscopy because up to one-third of patients with pseudomembranous colitis will have involvement of the right colon only.9 However, this test carries the risk of perforation in patients with fulminant colitis.
TABLE 1
Lab tests for C difficile infection
| Test | Substance detected | Time needed | Sensitivity | Specificity |
|---|---|---|---|---|
| Cytotoxin | Toxin B | 1-3 d | 95% | 90%-95% |
| Toxin culture | Toxigenic C difficile† | 3-5 d | >95% | 80%-90% |
| EIA toxin A or A/B | Toxin A or A/B | Hours | 75%-80% | 97%-98% |
| EIA GDH* | C difficile | Hours | 95%-100% | 70%-80% |
| EIA GDH* and toxin A/B | C difficile and C difficile toxin | Hours | 95%-100% | 97%-98% |
| RT-PCR | Toxigenic C difficile† | Hours | >98% | 80%-99% |
| *GDH is the common C difficile antigen. †All toxigenic strains produce toxin B. EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; RT-PCR, reverse-transcriptase polymerase chain reaction. Adapted from: Bartlett JG. Infect Control Hosp Epidemiol. 2010.3 | ||||
Treatment: What to consider, what to avoid
Of the 2 antibiotics most commonly used to treat CDI—metronidazole and vancomycin—only the latter has been approved by the US Food and Drug Administration for this indication. Nevertheless, metronidazole is generally recommended as first-line therapy and has the advantage of being much less expensive than vancomycin. However, an RCT found that oral vancomycin was superior to metronidazole in patients with severe disease.15 The time to resolution of diarrhea may be shorter with oral vancomycin than with metronidazole, as well.16
Recent guidelines suggest that clinicians consider 3 factors in deciding how to treat a first episode of CDI: the patient’s age, peak white blood cell count, and peak serum creatinine level.2 TABLE 2 presents an overview of treatment recommendations for both an initial episode of CDI and recurrences.
Treat severe CDI without delay. For patients with suspected severe CDI, treatment should be started empirically, without waiting for test results. Avoid antiperistaltic agents, which can obscure symptoms and precipitate toxic megacolon.2 Discontinue an antibiotic, if the patient is taking one, as soon as possible after the original infection has been adequately treated. If other infections need to be treated concurrently, we recommend that the course of treatment for CDI be extended until after the other antibiotic regimens have been stopped.
Avoid probiotics in this group. The use of probiotics, both for prevention and to help restore normal bowel flora in patients with CDI, has been advocated for many years. One RCT showed that a yogurt drink containing Lactobacillus and other bacteria reduced the risk of CDI in individuals ≥50 years of age who were taking antibiotics,17 but the guideline development panel recommended against using probiotics until larger trials have been completed.2
Probiotics are not without risk, and several cases of bacteremia have been reported.18,19 Immunocompromised patients appear to be at comparably higher risk, and probiotics should be avoided in this group. Numerous adjunctive agents, including intraluminal toxin binders, biotherapeutic agents, monoclonal antibodies, and a C difficile vaccine, are in various stages of development.2
How to handle recurrences
Relapse rates for CDI range from 6% to 25%,2 and affect patients who receive either vancomycin or metronidazole for the initial treatment. The mechanism relates to either relapse of the original infection or reinfection of susceptible patients with a new strain of C difficile.
Risk of relapse. Elderly patients treated with metronidazole seem to be particularly susceptible to CDI relapse.20 Other risk factors include the administration of non-C difficile antibiotics during or after treatment of CDI, a defective immune response against toxin A, glucocorticoid use, prior stroke, and concurrent use of a proton-pump inhibitor.21-25
TABLE 2 lists tapering and/or pulsed dosing of oral vancomycin as treatment for patients with a second recurrence. We often prescribe the following 6-week regimen, telling patients to take 125 mg vancomycin:
- 4 times a day for one week,
- then 2 times a day for one week,
- then once a day for one week,
- then every other day for one week, and
- finally, every 72 hours for 2 weeks.
Oral metronidazole should not be used beyond the first recurrence or for long-term therapy because of cumulative neurotoxicity, which can be irreversible.2
Management of patients whose CDI recurs after a long course of vancomycin is challenging. Oral rifaximin therapy (400 mg twice a day for 14 days), started immediately at the end of the oral vancomycin course, was shown to cure 7 of 8 patients with multiple relapses.26 Other potential treatment options are oral nitazoxanide, IV tigecycline, or IV immunoglobulin.
CASE You explain to Mary S that diagnostic tests are needed before you can determine whether she can safely take loperamide. When she comes in later that day, you collect a stool sample for C difficile antigen and toxin testing, and order a complete blood count and electrolyte panel.
The patient’s C difficile tests come back positive, her white blood cell count is <15,000 cells/mcL, and her creatinine level is ≤1.5 times her baseline, so you start her on oral metronidazole 500 mg every 8 hours for 14 days. (If the antigen assay had been positive and the toxin negative, you would have either repeated the test or treated Mary S empirically with metronidazole. If the initial antigen assay had been negative, you would have advised her to take the loperamide.)
You schedule a follow-up visit a day or 2 after starting therapy. If the patient is dehydrated or her symptoms have not improved by then, hospitalization may be required.
TABLE 2
Treatment recommendations for C difficile infection
| Clinical description | Clinical evidence | Recommended treatment |
|---|---|---|
| Initial episode (mild or moderate) | Leukocytosis with a white cell count <15,000 cells/mcL and creatinine <1.5 times premorbid level | Metronidazole (oral) 500 mg TID for 10-14 d |
| Initial episode (severe) | Leukocytosis with a white cell count ≥15,000 cells/mcL or creatinine ≥1.5 times premorbid level | Vancomycin (oral) 125 mg QID for 10-14 d |
| Initial episode (severe, complicated) | Hypotension or shock, ileus, megacolon | Vancomycin 500 mg QID (oral or by NG tube) plus metronidazole 500 mg (IV). If complete ileus, consider adding rectal instillation of vancomycin |
| First recurrence | Same as initial episode | |
| Second recurrence | Vancomycin in a tapered and/or pulsed regimen | |
| NG, nasogastric. Adapted from: Cohen SH, et al. Infect Control Hosp Epidemiol. 2010.2 | ||
CORRESPONDENCE
Richard R. Watkins, MD, MS, Division of Infectious Diseases, Akron General Medical Center, 224 West Exchange Street, Suite 290, Akron, OH 44302; [email protected]
• A C difficile diagnosis should be made by one of several widely available testing protocols, including a 2-step method using the common antigen assay to determine whether C difficile is present, followed by an enzyme immunoassay for toxins A and B to improve specificity. B
• Oral metronidazole should be used for initial treatment of mild to moderate C difficile infection, and oral vancomycin and possibly intravenous metronidazole for severe cases. A
• Metronidazole should not be used after an initial recurrence or for long-term therapy because of the risk of neurotoxicity. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Mary S, an 82-year-old patient you recently treated for bronchitis with a 3-day course of levofloxacin, calls your office complaining of diarrhea and abdominal cramps. She describes the diarrhea as nonbloody and particularly foul smelling and asks if she can take loperamide for her symptoms.
If Mary S were your patient, what would you tell her?
The incidence of Clostridium difficile infection (CDI) has been on the rise since 2000, when a common epidemic strain began circulating in North America.1 Although hospitalization or residency in a long-term care facility remains a classic risk factor for CDI, physicians in out-patient settings are increasingly likely to see patients with community-acquired CDI.
Recently updated guidelines from the Society for Health-care Epidemiology of America (SHEA) and the Infectious Diseases Society of America define CDI as the presence of diarrhea (≥3 unformed stools in 24 hours) and either a positive stool test for toxigenic C difficile or its toxins or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.2 That said, the clinical features of CDI are nonspecific and many patients do not fit the classic profile. So diagnosing CDI requires a high index of suspicion.
The text and tables that follow detail some surprising things about who is likely to develop CDI and which treatment options to employ (and, in some cases, avoid).
Is it CDI? Looking beyond the obvious
Antibiotic use and advanced age, like hospitalization, are classic risk factors for CDI.3 Diarrhea typically begins during or shortly after a course of antibiotics, but may develop as long as 8 weeks after treatment is completed. While any antibiotic, including metronidazole, can precipitate CDI, clindamycin, cephalosporins, extended-spectrum penicillins, and quinolones are most frequently implicated.4 Epidemiologic studies have suggested an association between gastric acid-reducing agents—primarily proton-pump inhibitors—and CDI.4-7 But this link remains controversial, as other investigations have not found a clear relationship.8
In addition to diarrhea, approximately 28% of patients with CDI develop a fever (as high as 104°F); 50% develop leukocytosis (up to 50,000 cells/mcL); and 22% develop abdominal pain, usually localized to the lower quadrants.9 These symptoms, however, are not specific to C difficile, and could be due to a different enteric pathogen, intra-abdominal sepsis, inflammatory bowel disease, or adverse effects of medication, among other causes.9
Markers for severe CDI include age >70 years, leukocyte count >20,000 cells/mcL, albumin level <2.5 g/dL, small-bowel obstruction or ileus, and a computed tomography (CT) scan showing colorectal inflammation.10 Severe CDI can lead to toxic megacolon, bowel perforation, sepsis, and even death.
In addition to considering CDI in patients with nonspecific symptoms, it is important to include it in the differential diagnosis of patients who do not fit the classic profile. In a recent study of patients with CDI at 4 Veterans Affairs facilities, almost half (49%) of those studied had no exposure to antimicrobial drugs. The researchers further found that the median age of patients with CDI was 61 years—younger than that found in previous studies—and that 20% of the cases were community-acquired.11
Consider CDI in children, too. Risk factors for CDI in pediatric patients include disruption of the normal microflora of the gastrointestinal tract, compromised immune status, poor diet, underlying health conditions, concurrent infections, and cancer.12
Diagnostic testing: Consider a 2-step assay
Patients with symptoms suggestive of CDI should undergo laboratory testing to confirm the diagnosis. TABLE 1 lists the tests that are widely available in the United States.3 Only liquid stools should be tested and just one sample should be sent to the lab, as multiple samples do not increase the diagnostic yield.13 In addition, tests should be used only for diagnosis, and not as a “test of cure.” This is because patients can shed C difficile toxin and spores for several weeks after completing treatment, and there are wide variations in the sensitivity of toxin assays.
Infants <1 year old have high rates of asymptomatic toxigenic strains of C difficile, and until 2008, recommendations from SHEA discouraged testing the stools of such young patients. Because of the difficulty in differentiating incidental colonization from true CDI in this patient population, the authors of a recent review suggested using more than one diagnostic approach when testing children <1 year of age.14
We advocate a 2-step assay—that is, testing for both glutamate dehydrogenase (GDH)—an antigen common to all strains of C difficile—and C difficile toxins A and B. The common antigen test is sensitive, but may detect carriers who do not have active disease. The enzyme immunoassay (EIA) for toxins A and B helps to improve specificity. Therefore, positive results of both tests would be considered a positive finding, negative results of both tests would be considered a negative finding, and one positive result with one negative result would require another test for toxin detection.3
The reverse-transcriptase polymerase chain reaction (RT-PCR) assay, which detects the toxin B gene of C difficile, is the newest test for CDI. The RT-PCR assay detects only toxigenic strains of C difficile, and all toxigenic strains produce toxin B, making it more specific than testing for the common antigen. The RT-PCR assay also has better sensitivity than the cytotoxin assay, which also tests for toxin B. The major limitation of the RT-PCR assay is the frequency of false-positive results in hospitalized patients with a high incidence of C difficile colonization.3
Routine laboratory studies, including a complete blood count with differential and a complete metabolic panel, are often useful to ascertain the presence and degree of leukocytosis, dehydration, and other metabolic abnormalities and to test for hypoalbuminemia. Fecal leukocytes can be seen in colitis and may be useful in select cases.
Imaging studies such as radiography, CT, and endoscopy have largely been superseded by lab testing for CDI. Plain radiographs are usually normal in patients with CDI, unless the patient has an ileus or toxic megacolon. CT is useful, however, in suspected cases of fulminant CDI or toxic megacolon, and may reveal colonic-wall thickening, pericolonic stranding, or ascites.9 Colonoscopy is preferred over sigmoidoscopy because up to one-third of patients with pseudomembranous colitis will have involvement of the right colon only.9 However, this test carries the risk of perforation in patients with fulminant colitis.
TABLE 1
Lab tests for C difficile infection
| Test | Substance detected | Time needed | Sensitivity | Specificity |
|---|---|---|---|---|
| Cytotoxin | Toxin B | 1-3 d | 95% | 90%-95% |
| Toxin culture | Toxigenic C difficile† | 3-5 d | >95% | 80%-90% |
| EIA toxin A or A/B | Toxin A or A/B | Hours | 75%-80% | 97%-98% |
| EIA GDH* | C difficile | Hours | 95%-100% | 70%-80% |
| EIA GDH* and toxin A/B | C difficile and C difficile toxin | Hours | 95%-100% | 97%-98% |
| RT-PCR | Toxigenic C difficile† | Hours | >98% | 80%-99% |
| *GDH is the common C difficile antigen. †All toxigenic strains produce toxin B. EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; RT-PCR, reverse-transcriptase polymerase chain reaction. Adapted from: Bartlett JG. Infect Control Hosp Epidemiol. 2010.3 | ||||
Treatment: What to consider, what to avoid
Of the 2 antibiotics most commonly used to treat CDI—metronidazole and vancomycin—only the latter has been approved by the US Food and Drug Administration for this indication. Nevertheless, metronidazole is generally recommended as first-line therapy and has the advantage of being much less expensive than vancomycin. However, an RCT found that oral vancomycin was superior to metronidazole in patients with severe disease.15 The time to resolution of diarrhea may be shorter with oral vancomycin than with metronidazole, as well.16
Recent guidelines suggest that clinicians consider 3 factors in deciding how to treat a first episode of CDI: the patient’s age, peak white blood cell count, and peak serum creatinine level.2 TABLE 2 presents an overview of treatment recommendations for both an initial episode of CDI and recurrences.
Treat severe CDI without delay. For patients with suspected severe CDI, treatment should be started empirically, without waiting for test results. Avoid antiperistaltic agents, which can obscure symptoms and precipitate toxic megacolon.2 Discontinue an antibiotic, if the patient is taking one, as soon as possible after the original infection has been adequately treated. If other infections need to be treated concurrently, we recommend that the course of treatment for CDI be extended until after the other antibiotic regimens have been stopped.
Avoid probiotics in this group. The use of probiotics, both for prevention and to help restore normal bowel flora in patients with CDI, has been advocated for many years. One RCT showed that a yogurt drink containing Lactobacillus and other bacteria reduced the risk of CDI in individuals ≥50 years of age who were taking antibiotics,17 but the guideline development panel recommended against using probiotics until larger trials have been completed.2
Probiotics are not without risk, and several cases of bacteremia have been reported.18,19 Immunocompromised patients appear to be at comparably higher risk, and probiotics should be avoided in this group. Numerous adjunctive agents, including intraluminal toxin binders, biotherapeutic agents, monoclonal antibodies, and a C difficile vaccine, are in various stages of development.2
How to handle recurrences
Relapse rates for CDI range from 6% to 25%,2 and affect patients who receive either vancomycin or metronidazole for the initial treatment. The mechanism relates to either relapse of the original infection or reinfection of susceptible patients with a new strain of C difficile.
Risk of relapse. Elderly patients treated with metronidazole seem to be particularly susceptible to CDI relapse.20 Other risk factors include the administration of non-C difficile antibiotics during or after treatment of CDI, a defective immune response against toxin A, glucocorticoid use, prior stroke, and concurrent use of a proton-pump inhibitor.21-25
TABLE 2 lists tapering and/or pulsed dosing of oral vancomycin as treatment for patients with a second recurrence. We often prescribe the following 6-week regimen, telling patients to take 125 mg vancomycin:
- 4 times a day for one week,
- then 2 times a day for one week,
- then once a day for one week,
- then every other day for one week, and
- finally, every 72 hours for 2 weeks.
Oral metronidazole should not be used beyond the first recurrence or for long-term therapy because of cumulative neurotoxicity, which can be irreversible.2
Management of patients whose CDI recurs after a long course of vancomycin is challenging. Oral rifaximin therapy (400 mg twice a day for 14 days), started immediately at the end of the oral vancomycin course, was shown to cure 7 of 8 patients with multiple relapses.26 Other potential treatment options are oral nitazoxanide, IV tigecycline, or IV immunoglobulin.
CASE You explain to Mary S that diagnostic tests are needed before you can determine whether she can safely take loperamide. When she comes in later that day, you collect a stool sample for C difficile antigen and toxin testing, and order a complete blood count and electrolyte panel.
The patient’s C difficile tests come back positive, her white blood cell count is <15,000 cells/mcL, and her creatinine level is ≤1.5 times her baseline, so you start her on oral metronidazole 500 mg every 8 hours for 14 days. (If the antigen assay had been positive and the toxin negative, you would have either repeated the test or treated Mary S empirically with metronidazole. If the initial antigen assay had been negative, you would have advised her to take the loperamide.)
You schedule a follow-up visit a day or 2 after starting therapy. If the patient is dehydrated or her symptoms have not improved by then, hospitalization may be required.
TABLE 2
Treatment recommendations for C difficile infection
| Clinical description | Clinical evidence | Recommended treatment |
|---|---|---|
| Initial episode (mild or moderate) | Leukocytosis with a white cell count <15,000 cells/mcL and creatinine <1.5 times premorbid level | Metronidazole (oral) 500 mg TID for 10-14 d |
| Initial episode (severe) | Leukocytosis with a white cell count ≥15,000 cells/mcL or creatinine ≥1.5 times premorbid level | Vancomycin (oral) 125 mg QID for 10-14 d |
| Initial episode (severe, complicated) | Hypotension or shock, ileus, megacolon | Vancomycin 500 mg QID (oral or by NG tube) plus metronidazole 500 mg (IV). If complete ileus, consider adding rectal instillation of vancomycin |
| First recurrence | Same as initial episode | |
| Second recurrence | Vancomycin in a tapered and/or pulsed regimen | |
| NG, nasogastric. Adapted from: Cohen SH, et al. Infect Control Hosp Epidemiol. 2010.2 | ||
CORRESPONDENCE
Richard R. Watkins, MD, MS, Division of Infectious Diseases, Akron General Medical Center, 224 West Exchange Street, Suite 290, Akron, OH 44302; [email protected]
1. Gerding DN. Global epidemiology of Clostridium difficile infection in 2010. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S32-S34.
2. Cohen SH, Gerding DH, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.
3. Bartlett JG. Detection of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S35-S37.
4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.
5. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294:2989-2995.
6. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243-245.
7. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784-790.
8. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM. 2000;93:175-181.
9. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis. 2008;46(suppl 1):S12-S18.
10. Henrich TJ, Krakower D, Bitton A, et al. Clinical risk factors for severe Clostridium difficile-associated disease. Emerg Infect Dis. 2009;15:415-422.
11. Kutty PK, Woods CW, Sena AC, et al. Risk factors for and estimated incidence of community-associated Clostridium difficile infection, North Carolina, USA. Emerg Infect Dis. 2010;16:197-204.
12. Pituch H. Clostridium difficile is no longer just a nosocomial infection or an infection of adults. Int J Antimicrob Agents. 2009;33(suppl 1):S42-S45.
13. Mohan SS, McDermott BP, Parchuri S, et al. Lack of value of repeat stool testing for Clostridium difficile toxin. Am J Med. 2006;119:356.e7-e8.
14. Bryant K, McDonald LC. Clostridium difficile infections in children. Pediatr Infect Dis J. 2009;28:145-146.
15. Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-307.
16. Belmares J, Gerding DN, Parada JP, et al. Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect. 2007;55:495-501.
17. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335:80.-
18. Ledoux D, Labombardi VJ, Karter D. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin’s disease. Int J STD AIDS. 2006;17:280-282.
19. Hammerman C, Bin-Nun A, Kaplan M. Safety of probiotics: comparison of two popular strains. BMJ. 2006;333:1006-1008.
20. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590.
21. Nair S, Yadav D, Corpuz M, et al. Clostridium difficile colitis: factors influencing treatment failure and relapse—a prospective evaluation. Am J Gastroenterol. 1998;93:1873-1876.
22. Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008;70:298-304.
23. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease. Am J Gastroenterol. 2010;105:2040-2049.
24. Cadena J, Thompson GR, 3rd, Patterson JE, et al. Clinical predictors and risk factors for relapsing Clostridium difficile infection. Am J Med Sci. 2010;339:350-355.
25. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170:772-778.
26. Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:846-848.
1. Gerding DN. Global epidemiology of Clostridium difficile infection in 2010. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S32-S34.
2. Cohen SH, Gerding DH, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.
3. Bartlett JG. Detection of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S35-S37.
4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.
5. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294:2989-2995.
6. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243-245.
7. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784-790.
8. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM. 2000;93:175-181.
9. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis. 2008;46(suppl 1):S12-S18.
10. Henrich TJ, Krakower D, Bitton A, et al. Clinical risk factors for severe Clostridium difficile-associated disease. Emerg Infect Dis. 2009;15:415-422.
11. Kutty PK, Woods CW, Sena AC, et al. Risk factors for and estimated incidence of community-associated Clostridium difficile infection, North Carolina, USA. Emerg Infect Dis. 2010;16:197-204.
12. Pituch H. Clostridium difficile is no longer just a nosocomial infection or an infection of adults. Int J Antimicrob Agents. 2009;33(suppl 1):S42-S45.
13. Mohan SS, McDermott BP, Parchuri S, et al. Lack of value of repeat stool testing for Clostridium difficile toxin. Am J Med. 2006;119:356.e7-e8.
14. Bryant K, McDonald LC. Clostridium difficile infections in children. Pediatr Infect Dis J. 2009;28:145-146.
15. Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-307.
16. Belmares J, Gerding DN, Parada JP, et al. Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect. 2007;55:495-501.
17. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335:80.-
18. Ledoux D, Labombardi VJ, Karter D. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin’s disease. Int J STD AIDS. 2006;17:280-282.
19. Hammerman C, Bin-Nun A, Kaplan M. Safety of probiotics: comparison of two popular strains. BMJ. 2006;333:1006-1008.
20. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590.
21. Nair S, Yadav D, Corpuz M, et al. Clostridium difficile colitis: factors influencing treatment failure and relapse—a prospective evaluation. Am J Gastroenterol. 1998;93:1873-1876.
22. Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008;70:298-304.
23. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease. Am J Gastroenterol. 2010;105:2040-2049.
24. Cadena J, Thompson GR, 3rd, Patterson JE, et al. Clinical predictors and risk factors for relapsing Clostridium difficile infection. Am J Med Sci. 2010;339:350-355.
25. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170:772-778.
26. Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:846-848.