Oral metronidazole and oral vancomycin are
 equally effective treatments for Clostridium difficile- associated diarrhea (CDAD) (strength of recommendation [SOR]: A, based on randomized trials). Oral vancomycin is considerably more expensive and may select for colonization with vancomycin-resistant enterococci, leading the American College of Gastroenterology to recommend oral metronidazole as preferred therapy (SOR: C, expert opinion). They recommend therapy with vancomycin for those who are pregnant, breast feeding, less than 10years old, nonresponders to metronidazole, critically ill, or allergic or intolerant to metronidazole (SOR: C, expert opinion)

Meadows, Susan E.

Ohl, Michael E.

Stevermer, James J.

University of Missouri: MOspace

C L I N I C A L  I N Q U I R I E S176 FEBRUARY 2005 / VOL 54, NO 2 · The Journal of Family Practicemagnesium deficiency based on physiologicprinciples as listed in the Table, but none provide data on the relative frequency of thevarious causes in the general population or specific subgroups.6–9David R. Mouw, MD, PhD, Robyn A. Latessa, MD,University of North Carolina, MAHEC Family PracticeResidency, Asheville, NC; Elaine J. Sullo, MLS, East Carolina University, Laupus Library, Greenville, NC■ CLINICAL COMMENTARYWe need to know when magnesiumreplacement improves patient outcomesTreating the underlying cause of hypomagne-semia makes sense. However, even though cli-nicians often treat “the numbers,” it is not clearthat magnesium replacement therapy is benefi-cial in the absence of symptoms caused by thehypomagnesemia. For example, hypomagne-semia is common for patients with acutemyocardial infarction, but magnesium replace-ment therapy has not been shown to improveoutcomes in 2 large randomized trials, theFourth International Study of Infarct Survival(ISIS 4)14 and Magnesium in Coronaries(MAGIC).15 We need better-designed random-ized trials to know for what clinical conditionsmagnesium replacement leads to improvedpatient-oriented outcomes. John Hickner, MD, MSc, Department of FamilyMedicine, The University of Chicago Pritzker School of Medicine, Chicago, IllREFERENCES1. Schimatschek HF, Rempis R. Prevalence of hypomagne-semia in an unselected German population of 16,000 indi-viduals. Magnes Res 2001; 14:283–290.2. Ma J, Folsom AR, Melnick SL, et al. Associations of serumand dietary magnesium with cardiovascular disease,hypertension, diabetes, insulin, and carotid arterial wallthickness: the ARIC study. Atherosclerosis Risk inCommunities Study. J Clin Epidemiol 1995; 48:927–940.3. Ryzen E, Wagers PW, Singer FR, Rude RK. Magnesiumdeficiency in a medical ICU population. Crit Care Med1985; 13:19–21. 4. Elisaf M, Merkouropoulos M, Tsianos EV, SiamopoulosKC. Pathogenic mechanisms of hypomagnesemia in alco-holic patients. J Trace Elem Med Biol 1995; 9:210–214. 5. Wong ET, Rude RK, Singer FR, Shaw ST Jr. A high preva-lence of hypomagnesemia and hypermagnesemia in hospi-talized patients. Am J Clin Pathol 1983; 79:348–353. 6. Topf JM, Murray PT. Hypomagnesemia and hypermagne-semia. Rev Endocr Metab Disord 2003; 4:195–206.7. Whang R, Hampton EM, Whang DD. Magnesium home-ostasis and clinical disorders of magnesium deficiency.Ann Pharmacother 1994; 28:220–226.8. Kelepouris E, Agus ZS. Hypomagnesemia: renal magne-sium handling. Semin Nephrol 1998; 18:58–73. 9. Dacey MJ. Hypomagnesemic disorders. Crit Care Clin2001; 17:155–173.10. Richardson WS, Wilson MC, Guyatt GH, Cook DJ,Nishikawa J. Users’ Guides to the Medical Literature: XV.How to use an article about disease probability for differ-ential diagnosis. Evidence-Based Medicine WorkingGroup. JAMA 1999; 281:1214–1219. 11. Jackson CE, Meier DW. Routine serum magnesium analy-sis. Correlation with clinical state in 5,100 patients. AnnIntern Med 1968; 69:743–748.12. Whang R, Ryder KW. Frequency of hypomagnesemia andhypermagnesemia. Requested vs routine. JAMA 1990;263:3063–3064.13. Rubeiz GJ, Thill-Baharozian M, Hardie D, Carlson RW.Association of hypomagnesemia and mortality in acutelyill medical patients. Crit Care Med 1993; 21:203–209.14. ISIS-4 (Fourth International Study of Infarct Survival)Collaborative Group. ISIS-4: a randomised factorial trialassessing early oral captopril, oral mononitrate, and intra-venous magnesium sulphate in 58,050 patients with sus-pected acute myocardial infarction. Lancet 1995;345:669–685. 15. Magnesium in Coronaries (MAGIC) Trial Investigators.Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in theMagnesium in Coronaries (MAGIC) Trial: a randomisedcontrolled trial. Lancet 2002; 360:1189–1196. What are effective therapiesfor Clostridium difficile–associated diarrhea?■ EVIDENCE-BASED ANSWEROral metronidazole and oral vancomycin areequally effective treatments for Clostridium dif-ficile–associated diarrhea (CDAD) (strength ofrecommendation [SOR]: A, based on random-ized trials). Oral vancomycin is considerablymore expensive and may select for colonizationwith vancomycin-resistant enterococci, leadingthe American College of Gastroenterology torecommend oral metronidazole as preferredtherapy (SOR: C, expert opinion). They recom-mend therapy with vancomycin for those whoare pregnant, breast feeding, less than 10C L I N I C A L  I N Q U I R I E SFEBRUARY 2005 / VOL 54, NO 2 · The Journal of Family Practice 177C O N T I N U E Dyears old, nonresponders to metronidazole,critically ill, or allergic or intolerant to metron-idazole (SOR: C, expert opinion). Treat first recurrences the same as primaryinfection. In persons with recurrent infection,addition of the probiotic agent Saccharomycesboulardii reduces the risk of further recur-rences (SOR: B, single RCT). Little other evi-dence exists to guide therapy for subsequentrecurrences.■ EVIDENCE SUMMARYTwo randomized controlled trials have com-pared the efficacy of oral metronidazole and oralvancomycin for treatment of CDAD.1,2 Both stud-ies demonstrated statistically equivalent curerates exceeding 90%, with relapse rates of 10%to 20% for each drug. These small trials lackedthe power to detect small but potentially signif-icant differences in treatment response. No published data exist indicating that van-comycin is more effective than metronidazole in any clinical setting. A dose-range studyshowed that 125 mg of oral vancomycin 4 timesa day is as effective as higher doses.3 Patientswho cannot take medication by mouth shouldreceive intravenous metronidazole, 500 mg 4times per day. Unlike vancomycin, metronida-zole achieves potentially effective concentra-tions in the intestinal lumen following intra-venous administration.4Treatment of first recurrences of infectionwith metronidazole or vancomycin producesresponse rates similar to treatment of initialMedical treatment of C difficile–associated diarrheaIndication TreatmentFirst episode of C difficile–associated diarrhea Metronidazole, 500 mg orally 3 times daily (SOR: A; SOR: C for preference over vancomycin) for 10 daysFirst episode, allergy, or intolerance to metronidazole, Vancomycin, 125 mg orally 4 times daily pregnant, breast feeding, or age <10 years for 10 days(SOR: A; SOR: C for preference over metronidazole)Unable to take oral medication (SOR: C) Metronidazole 500 mg IV 4 times dailyFirst recurrence (SOR: C) As for first episode or Option #1 belowSecond or greater recurrence:Option #1 (SOR: B, single RCT) Metronidazole or vancomycin, plus S boulardii(500 mg twice daily [3 x 1010 CFUs])Option #2 (SOR: C) Vancomycin or metronidazole plus rifampin 300 mg oral twice daily for 10 daysOption #3 (SOR: C) Vancomycin tapered dose:125 mg orally 4 times daily for 7 days125 mg orally twice daily for 7 days125 mg orally once daily for 7 days125 mg orally every other day for 7 days125 mg orally every 3 days for 14 daysOption #4 (SOR: C) Vancomycin plus cholestyramine 4 g twice daily for 10 daysTA B L EC L I N I C A L  I N Q U I R I E S178 FEBRUARY 2005 / VOL 54, NO 2 · The Journal of Family Practiceinfections.5 A minority of patients suffers multi-ple relapses of infection, and there are few datato guide therapy in this setting. A randomized, double-blinded, placebo-controlled study evaluated the impact of addingthe probiotic agent Saccharomyces boulardiito either metronidazole or vancomycin.6 For persons with recurrent infection, addition of S boulardii led to a 30% decrease in the absoluterisk of relapse (64% relapse vs 34%; numberneeded to treat=3; P<.05). There was also anonsignificant trend toward reduced recurrencesin the treatment of primary infections. The 2minor side effects noted with this treatmentwere dry mouth (number needed to harm[NNH]=11) and constipation (NNH=9). Sboulardii capsules are available from health foodstores and via the Internet. Several publishedcase series describe various additional approach-es to therapy of recurrent CDAD (Table).■ RECOMMENDATIONS FROM OTHERSThe American College of Gastroenterology andthe American College of Physicians treatmentguidelines for CDAD both call for treatmentwith oral metronidazole 250 mg 4 times daily or500 mg 3 times daily.7,8 The American College ofGastroenterology recommends vancomycin (125mg orally 4 times daily) when there is an intol-erance or confirmed resistance to metronida-zole, failure of response, when the patient ispregnant, breast feeding, or under 10 years ofage, critically ill from colitis, or when the diar-rhea could be related to Staphylococcus aureus.In milder cases, treatment may involve only dis-continuation of antibiotics and supportive thera-py with observation. Opiates and antispasmod-ics should be avoided. These guidelines do notrecommend any treatment over another for ther-apy of multiple recurrences. Michael E. Ohl, MD, James J. Stevermer, MD,MSPH, Susan Meadows, MLS, Department of Familyand Community Medicine, University of Missouri–ColumbiaREFERENCES1. Teasley DG, Gerding DN, Olson MM, et al. Prospectiverandomised trial of metronidazole versus vancomycin forClostridium-difficile-associated diarrhoea and colitis.Lancet 1983; 2:1043–1046.2. Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM,Graninger W. Comparison of vancomycin, teicoplanin,metronidazole, and fusidic acid for the treatment ofClostridium difficile-associated diarrhea. Clin Infect Dis1996; 22:813–818.3. Fekety R, Silva J, Kauffman C, Buggy B, Deery HG.Treatment of antibiotic-associated Clostridium difficilecolitis with oral vancomycin: comparison of two dosageregimens. Am J Med 1989; 86:15–19.4. Bolton RP, Culshaw MA. Faecal metronidazole concentra-tions during oral and intravenous therapy for antibioticassociated colitis due to Clostridium difficile. Gut 1986;27:1169–1172.5. Bartlett JG, Tedesco FJ, Shull S, Lowe B, Chang T.Symptomatic relapse after oral vancomycin therapy ofantibiotic-associated pseudomembranous colitis.Gastroenterology 1980; 78:431–434.6. McFarland LV, Surawicz CM, Greenberg RN, Fekety R,Elmer GW, Moyer KA et al. A randomized placebo-con-trolled trial of Saccharomyces boulardii in combinationwith standard antibiotics for Clostridium difficile disease.JAMA 1994; 271:1913–1918.7. Fekety R. Guidelines for the diagnosis and management ofClostridium difficile-associated diarrhea and colitis.American College of Gastroenterology, Practice ParametersCommittee. Am J Gastroenterol 1997; 92:739–750.8. Hurley, B. W. and Nguyen, C. C. Drug therapy: use ofantimicrobial agents as first-line drug therapy for CDAD.PIER: Clinical Guidance from ACP, 2004. Available at:pier.acponline.org/physicians/diseases/d320/d320.html.Accessed on July 14, 2004.■ CLINICAL COMMENTARYDiscontinue the offending antibiotic andtreat the infection; prevent outbreaks viapatient-to-patient transmissionMost cases of Clostridium difficile–associateddiarrhea are caused by antibiotic use; it istherefore one of the most common nosocomialinfections. In addition to discontinuing use ofthe offending antibiotic and treating the infec-tion, it is also important to prevent further out-breaks via patient-to-patient transmission. Inour hospital, once a patient is diagnosed withC difficile, contact precautions are instituted. Ifthe patient is incontinent, isolation in a singleroom is required. If the patient is continentFor those with recurrent infection,addition of S boulardii decreasedthe absolute risk of relapse by 30%

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