CLINICAL INQUIRIES F ROM THE F AMILY P RACTICE I NQUIRIES N ETWORK What is the best way to evaluate patients with acute diarrhea. Using retrospective 6 acute diarrhea? reviews, Bauer and colleagues developed a pre- diction rule for cases of infectious diarrhea. The “modified 3-day rule” recommends stool cultures EVIDENCE-BASED ANSWER Limited evidence for patients with diarrhea beginning more than 3 delineates the relative probabilities of causes of acute days after hospitalization only when they fall into 1 diarrhea, typically defined as a diarrheal disease last- of the following groups: patients older than 65 ing 14 days or fewer, in the developed world. Viruses years with permanently altered organ function, (rotavirus, Norwalk, and other enteric viruses) are those with HIV or neutropenia, those hospitalized responsible for most cases. Stool culture helps to iden- during suspected nosocomial outbreaks, and those tify bacterial causes (Salmonella, Shigella, enterotoxic suspected of nondiarrheal manifestations of enteric Escherichia coli), especially in patients with fever and infection.6 When the modified rule was applied bloody stool. A modified 3-day rule (eg, performing prospectively, only 2 cases were missed. Both only Clostridium difficile toxin tests on low-risk patients were at risk for immunosuppression, patients who have been hospitalized for 3 or more although they did not strictly meet the modified cri- days) leads to a more rational use of stool cultures teria. Neither required treatment.6 without missing cases of clinically significant disease. (Grade of recommendation: D, based on limited stud- RECOMMENDATIONS FROM OTHERS The ies, reliance on expert opinion, and consensus.) Infectious Diseases Society of America’s practice guidelines for the evaluation and treatment of acute EVIDENCE SUMMARY More than 2 million cases diarrhea recommends that stool culture for bacteria of infectious diarrhea are documented in the United (including enterotoxic E coli) should be considered States annually. Infectious diarrhea is the second in patients with community- or travel-acquired diar- leading cause of morbidity and mortality worldwide. rhea, especially when fever or bloody stool is pre- Published data have focused on the etiology of diar- sent. In hospitalized patients, only toxin tests for C rhea in the developing world, and more commonly difficile are recommended. Testing for acute para- on the clinical evaluation and treatment of patients sitic diseases should be reserved only for patients with diarrhea and dehydration. whose symptoms persist after 7 days.1 While most research on acute diarrhea focuses on infectious causes, noninfectious causes should also Lynda Montgomery, MD be considered (eg, drug-induced diarrhea, inflam- Boston University Family Medicine matory bowel disease).1 Viral causes are most com- mon; in children, viruses are responsible for 70% to Caryn Scoville, MLS 80% of cases of diarrhea.2 A prospective study of 147 Health Sciences Library US children with acute, mild diarrhea demonstrated University of Missouri–Columbia that rectal swabs yielded a positive test for an infec- tious agent in 60.5% of cases (Table).3 Clinical Commentary by Les Hall, MD, at http:// A case-control study of stool cultures for rotavirus www.fpin.org. in adult patients found that 14% of 683 with diar- rhea and 5% of 1115 without diarrhea shed 4 REFERENCES rotavirus. A recent systematic review found no 1. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines TABLE 1 published stud- for the management of infectious diarrhea. Clin Infect Dis 2001; ies about the 32:331–51. Etiologic agents in US children 2. Merrick N, Davidson B, Fox S. Treatment of acute gastroenteri- with acute diarrhea likelihood of tis: too much and too little care. Clin Pediatr (Phila) 1996; specific diag- 35:429–35. 3. Caeiro JP, Mathewson JJ, Smith MA, Jiang ZD, Kaplan MA, Infectious agent Percent noses in chil- Dupont HL. Etiology of outpatient pediatric nondysenteric diar- Rotavirus 29.3% dren presenting rhea: a multicenter study in the United States. Pediatr Infect Dis J 1999; 18:94–7. Giardia lamblia 15% to the hospital 4. Nakajima H, Nakagomi T, Kamisawa T, et al. Winter seasonality Pathogenic Escherichia coli 15% with diarrhea.5 and rotavirus diarrhoea in adults. Lancet 2001; 357(9272):1950. Some evi- 5. Armon K, Stephenson T, MacFaul R, Eccleston P, Werneke U. An Multiple agents 10% evidence and consensus based guideline for acute diarrhoea Data from Caeiro JP, Mathewson JJ, Smith MA, Jiang ZD, Kaplan dence supports a management. Arch Dis Child 2001; 85:132–42. MA, Dupont HL. Etiology of outpatient pediatric nondysenteric diar- structured diag- 6. Bauer TM, Lalvani A, Fehrenbach J, et al. Derivation and vali- rhea: a multicenter study in the United States. Pediatr Infect Dis J dation of guidelines for stool cultures for enteropathogenic bac- 1999; 18:94–7. nostic strategy teria other than Clostridium difficile in hospitalized adults. JAMA for hospitalized 2001; 285:313–9. Members of the Family Practice Inquiries Network answer clinical questions with the best available evidence in a concise, reader- friendly format. Each peer-reviewed answer is based on a standard search of resources, including MEDLINE, the Cochrane Library, and InfoRetriever, and is graded for level of evidence (http://cebm.jr2.ox.ac.uk/docs/levels.html). The collected Clinical Inquiries can be found at http://www.jfponline.com and http://www.fpin.org; the latter site also includes the search strategy used for each answer. The Journal of Family Practice • JUNE 2002 • VOL. 51, NO. 6 ■ 575 CLINICAL INQUIRIES Are any oral iron formulations better TABLE tolerated than ferrous sulfate? Representative average wholesale prices* for various iron supplement formulations EVIDENCE-BASED ANSWER Ferrous salt prepara- Iron tions (ferrous sulfate, ferrous gluconate, and ferrous supplement Generic or Cost of 1-month fumarate) are equally tolerable. (Grade of recom- group brand name Dosage course mendation: A, based on randomized controlled Ferrous salts Ferrous sulfate Tablet: 325 mg $0.63 to $5.11 trial.) Controlled-release iron preparations cause less (generic) po tid (90 tabs) nausea and epigastric pain than conventional ferrous Ferrous fumarate Tablet: 300 mg $1.80 (60 tabs) sulfate (grade of recommendation: A, based on ran- (generic) (99 mg iron) po bid domized controlled trials), although the discontinua- tion rates between the 2 iron formulations were sim- Ferrous gluconate Tablet: 325 mg $2.70 to $5.00 (generic) (36 mg iron) po tid (90 tabs) ilar. Ferrous sulfate remains the standard first-line treatment of iron-deficiency anemia given its gener- Controlled- Slow FE Tablet: 160 mg $18.92 (90 tabs) al tolerability, effectiveness, and low cost. release (Novartis) (50 mg iron) po tid Ferro-Grad-500 Tablet: 105 mg iron $31.84 (60 tabs) EVIDENCE SUMMARY A randomized, double- (Abbott) po bid blinded, placebo-controlled study in 1496 subjects Polysaccharide– Niferex-150 Capsule: 150 mg $10.50 (30 caps) examined side-effect rates of 3 iron salt formulations iron complex (Schwarz Pharma) iron po qd using equal dosages of elemental iron (Table).1 Carbonyl iron Feosol Tablet: 50 mg $18.38 (90 tabs) Gastrointestinal (GI) side-effect rates were not sig- (SmithKline iron po tid nificantly different. The side-effect rate in the ferrous Beecham) sulfate group (23%) was significantly different from *2001 Drug Topics, Red Book. Daily dosages given here deliver 150 to 210 mg of elemental iron and are for comparison of average costs. Actual dosage should be adjusted according to the that of the placebo group (14%); thus, for every 11 calculated need for iron replacement and the results of laboratory monitoring. patients treated with ferrous sulfate, 1 patient would have GI side effects attributable to the iron salt dard oral iron preparation, and assert that claims of (number needed to harm [NNH] = 11). improved tolerability of one oral iron preparation Two formulations—controlled-release iron prepa- over another have not been substantiated. rations and polysaccharide–iron complexes— decrease the amount of iron presented to the prox- Todd McDiarmid, MD imal GI tract. Three large randomized trials assessed Moses Cone Family Practice Residency tolerability of controlled-release iron preparations Greensboro, NC compared with ferrous sulfate.2–4 The only double- E. Diane Johnson, MLS blinded study found a lower rate of nausea and epi- J. Otto Lottes Health Sciences Library gastric pain in the controlled-release iron formula- University of Missouri–Columbia tion among 1376 blood donors receiving 200 mg/day elemental iron (3.3% vs 6.4%, P < .05, NNH Clinical Commentary by Andrea Gordon, MD, at = ~32).2 A nonblinded randomized trial of 543 non- http://www.fpin.org. anemic adult patients taking 50 mg/day elemental REFERENCES iron also found a lower rate of stomach-related side 1. Hallberg L, Ryttinger L, Solvell L. Side-effects of oral iron therapy. effects in the controlled-release group (12.2% vs A double-blind study of different iron compounds in tablet form. 3 Acta Med Scand Suppl 1966; 459:3–10. 27.2%, P < .001, NNH = ~7). However, none of the 2. Rybo G, Solvell L. Side-effect studies on a new sustained release 3 studies showed a difference in the discontinuation iron preparation. Scand J Haematol 1971; 8:257–64. rates between the 2 iron formulations. Comparative 3. Brock C, Curry H, Hanna C, Knipfer M, Taylor L. Adverse effects of iron supplementation: a comparative trial of a wax-matrix iron constipation rates among the trials were conflicting. preparation and conventional ferrous sulfate tablets. Clin Ther Two small, nonblinded, randomized trials of poly- 1985; 7:568–73. saccharide–iron complexes reported conflicting 4. Elwood PC, Williams G. A comparative trial of slow-release and conventional iron preparations. Practitioner 1970; 204:812–5. results. A study of 159 subjects found fewer subjects 5. Jacobs P, Coghlan P. Comparative bioavailability of ferric polymal- discontinuing the polysaccharide–iron complex taken tose and ferrous sulphate in iron-deficient blood donors.