Dysuria, UTI and Pyelonephritis (2 - 18 years) - Curbside
Dysuria, UTI and Pyelonephritis (2 - 18 years)
Editors: Dan Imler, MD, Nita Srinivas
Inclusion Criteria  (Any one criteria present)
  • Other clinical concern for UTI
  • Urinary or abdominal complaints (not asymptomatic bacteriuria)
Exclusion Criteria
  • Complicating functional or anatomical urologic history
  • Toxic appearance
  • Non-toilet trained
  • Male

Consider pediatric consult

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Evidence
Total Notes: 12
Evidence

1 UTI and Pyelonephritis

Infections of the urinary tract are a common and important diagnosis as they may lead to sepsis, renal scaring and chronic renal disease. Most urinary tract infections pathogenesis arise from ascending migration of gastrointestinal organisms from the urethral opening to the bladder or kidney.

Epidemiology

The prevalence of UTI in a large study looking at patients less than 19 years old (most older than 2 years) with urinary complaints and/or fever was 7.8 percent (6.6-8.9). For sexually active women the incidence is generally believed to be between 0.5 to 0.7 UTIs per person-year. For postmenopausal women, 0.07 UTIs per person per year. For young to middle age men who are healthy the incidence is 0.0005 to 0.0007 UTIs per person-year. The first episode of pyelonephritis in women has an incidence of 0.0012 to 0.0013 per person-year.



References:
  1. Prevalence of urinary tract infection in childhood: a meta-analysis.
    Shaikh N, Morone NE, Bost JE, Farrell MH
    Pediatr Infect Dis J. 2008 Apr;27(4):302-8.
  2. A prospective study of risk factors for symptomatic urinary tract infection in young women.
    Hooton TM, Scholes D, Hughes JP, Winter C, Roberts PL, Stapleton AE, Stergachis A, Stamm WE
    N Engl J Med. 1996;335(7):468.
  3. Risk factors associated with acute pyelonephritis in healthy women.
    Scholes D, Hooton TM, Roberts PL, Gupta K, Stapleton AE, Stamm WE
    Ann Intern Med. 2005;142(1):20.
  4. Predictors of urinary tract infection after menopause: a prospective study.
    Jackson SL, Boyko EJ, Scholes D, Abraham L, Gupta K, Fihn SD
    Am J Med. 2004;117(12):903.
  5. Population-based epidemiologic analysis of acute pyelonephritis.
    Czaja CA, Scholes D, Hooton TM, Stamm WE
    Clin Infect Dis. 2007;45(3):273.
  6. Urinary tract infections in healthy university men.
    Krieger JN, Ross SO, Simonsen JM
    J Urol. 1993;149(5):1046.
  7. An epidemiological survey of urinary tract infections among outpatients in Northern Norway.
    Vorland LH, Carlson K, Aalen O
    Scand J Infect Dis. 1985;17(3):277.

2 Symptomatic UTI

This pathway describes the diagnosis and care for patients with symptomatic UTIs. Although the urine is normally sterile, asymptomatic bactiuria does developed and needs to be addressed in certain populations (pregnancy, urologic interventions, etc.)



References:
  1. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.
    Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM, Infectious Diseases Society of America, American Society of Nephrology, American Geriatric Society
    Clin Infect Dis. 2005;40(5):643.

3 UTI/pyelonephritis

Complicated UTI/pyelonephritis

Patients with complicating factors have a much higher risk of treatment failure and complications compared to uncomplicated UTI/pyelonephritis. These patients should be carefully considered and consultation with urology, nephrology, OB/GYN and infectious disease specialists should be considered.

Although there is some debate if males may have uncomplicated UTIs, they are excluded from this pathway as their workup and management varies from females.

Symptomatic UTI

This pathway describes the diagnosis and care for patients with symptomatic UTIs. Although the urine is normally sterile, asymptomatic bactiuria does developed and needs to be addressed in certain populations (pregnancy, urologic interventions, etc.)



References:
  1. Does this woman have an acute uncomplicated urinary tract infection?
    Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S
    JAMA. 2002;287(20):2701.
  2. Site of infection in acute urinary-tract infection in general practice.
    Fairley KF, Carson NE, Gutch RC, Leighton P, Grounds AD, Laird EC, McCallum PH, Sleeman RL, O'Keefe CM
    Lancet. 1971;2(7725):615.
  3. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
    Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE, Infectious Diseases Society of America, European Society for Microbiology and Infectious Diseases
    Clin Infect Dis. 2011;52(5):e103.
  4. Management of urinary tract infections in adults.
    Stamm WE, Hooton TM
    N Engl J Med. 1993;329(18):1328.
  5. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.
    Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM, Hooton TM, Hooton TM, Hooton TM,
    Clin. Infect. Dis. 2005 Mar;40(5):643-54.

4 Risk factors for urinary infections

Several symptoms and their combinations significantly increase the risk of urinary infections and may be used to determine the pre-test probability for disease thus informing the need to test and individual.

In children several large studies have looked at the risk of UTI based on symptoms. Likelihood ratios have been establish to predict the diagnosis:

  • Abdominal pain (LR 6.3)
  • Back pain (LR 3.6)
  • Dysuria, frequency, or both (LR 2.2)
  • New-onset urinary incontinence (LR 4.6)

In young to middle aged women the likelihood of UTI with any urinary symptom (dysuria, frequency, urgency, suprapubic pain, or hematuria) exceeds 50 percent. That rises to 90 percent if they have dysuria and frequency without vaginal discharge.



References:
  1. Does this child have a urinary tract infection?
    Shaikh N, Morone NE, Lopez J, Chianese J, Sangvai S, D'Amico F, Hoberman A, Wald ER
    JAMA. 2007;298(24):2895.
  2. Epidemiology of symptomatic urinary tract infection in childhood.
    Winberg J, Andersen HJ, Bergström T, Jacobsson B, Larson H, Lincoln K
    Acta Paediatr Scand Suppl. 1974;(252):1-20.
  3. Diagnosis and management of pediatric urinary tract infections.
    Zorc JJ, Kiddoo DA, Shaw KN
    Clin Microbiol Rev. 2005;18(2):417.
  4. Does this woman have an acute uncomplicated urinary tract infection?
    Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S
    JAMA. 2002;287(20):2701.

5 Age associated risk factors

There may be significant overlap in symptomology between sexually transmitted infections (STI) and urinary tract infections (UTI). In addition, urinary tract infections in pregnancy may place the mother and fetus at increased risk and are not discussed in this pathway.

Although specific populations are at risk for STI/pregnancy at age 11 or younger, many formal bodies recommend approaching a sexual history in females at age 12 or 13. Providers should be vigilant to assess for factors that may predispose younger children to the risk of pregnancy or STI. In addition, some females older than 11 may appear developmentally immature for discussions of sexual activity and provider judgment is key to determining the individual risk level of these patients.

In adolescent and young adults, providers have been shown to have poor ability to differentiate between STI and UTI based on urinary symptoms and urinalysis. In well appearing patients with no symptoms of pyelonephritis it may be reasonable to wait for culture or GC/CT results prior to treatment, or if follow up is of a concern, provide empiric treatment.



References:
  1. Screening for Nonviral Sexually Transmitted Infections in Adolescents and Young Adults
    American Academy of Pediatrics Committee on Adolescence and Society for Adolescent Health and Medicine
    Pediatrics Vol. 134 No. 1 July 1, 2014e302 -e311
  2. Sexually transmitted diseases treatment guidelines, 2010.
    Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC).
    MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1-110.
  3. Adolescent female with urinary symptoms: a diagnostic challenge for the pediatrician.
    Prentiss KA, Newby PK, Vinci RJ.
    Pediatr Emerg Care. 2011 Sep;27(9):789-94.

6 Treatment without testing

With the high probability (greater than 90 percent) of urinary tract infection in adult women with dysuria and frequency in the absence of vaginal discharge or irritation providers may consider empiric treatment for UTI without diagnostic testing. 



References:
  1. Does this woman have an acute uncomplicated urinary tract infection?
    Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S
    JAMA. 2002;287(20):2701.

7 Urinalysis & culture results

A UTI is the systemic response to a bacterial infection in the urine with pyruira representing the immune response measurable on urinalysis. Pyuria is interpreted as nitrite OR leukocyte esterase AND microscopy showing bacteria or > 10 WBC / hpf in the setting of a clinical syndrome consistent with UTI. With a UA positive for nitrate or leukacyte esterase the sensitivity is 75 percent and specificity of 82 percent. However, a negative UA should not be used to definitely rule out the diagnosis of UTI in the setting of high clinical suspicion even if both tests are negative. Of note, the use of bladder analgesics (phenazopyridine) ingestion of beets (14 percent of patients may develop beeturia) may cause false negatives in urine dipsticks.

In order to definitively diagnose a UTI there must be a urinalysis that suggests infection (pyuria and/or bacteriuria) AND one of the following

  • Suprapubic aspiration: > 1,000 cfus
  • Catheter sample: > 50,000 cfus (often reported as 10-50,000 cfus depending on lab) 
  • Clean catch sample: > 100,000 cfus

These cultures should consist of a single predominant organism to be considered positive.



References:
  1. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
    Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB
    Pediatrics. 2011;128(3):595.
  2. Treatment of urinary tract infections.
    Hoberman A, Wald ER
    Pediatr Ann. 1999;28(11):688.
  3. Asymptomatic infections of the urinary tract.
    Kass EH.
    Trans Assoc Am Physicians. 1956;69:56.
  4. Pyuria and bacteriuria in urine specimens obtained by catheter from young children with fever.
    Hoberman A, Wald ER, Reynolds EA, Penchansky L, Charron M
    J Pediatr. 1994;124(4):513.
  5. Does this woman have an acute uncomplicated urinary tract infection?
    Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S
    JAMA. 2002;287(20):2701.
  6. Laboratory in the diagnosis and management of urinary tract infections.
    Pappas PG
    Med Clin North Am. 1991;75(2):313.
  7. Things that go red in the urine; and others that don't.
    Thompson WG
    Lancet. 1996;347(8993):5.

8 Bacterial culture

Because the majority of patients with an uncomplicated urinary tract infection are infected with well described pathogens, urine culture is not universally required. However, patients with pyelonephritis, recurrent UTI and younger children are at higher risk of infection with atypical or resistant organisms. All patients with these diagnoses should have a urine culture obtained.



References:
  1. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA).
    Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE
    Clin Infect Dis. 1999;29(4):745.
  2. Clinical practice. Acute uncomplicated urinary tract infection in women.
    Fihn SD
    N Engl J Med. 2003;349(3):259.
  3. The impact of empirical management of acute cystitis on unnecessary antibiotic use.
    McIsaac WJ, Low DE, Biringer A, Pimlott N, Evans M, Glazier R
    Arch Intern Med. 2002;162(5):600.
  4. Increasing antimicrobial resistance and the management of uncomplicated community-acquired urinary tract infections.
    Gupta K, Hooton TM, Stamm WE
    Ann Intern Med. 2001;135(1):41.

9 Uncomplicated pyelonephritis

Outpatient therapy for uncomplicated pyelonephritis may be efficacious. Nitrofurantoin, fosfomycin and pivmecillinam should be avoided in pylenonephritis as it does not achieve adequate concentrations in renal tissues. Fluroquinolones have been the mainstay of outpatient empirical treatment of acute uncomplicated pyelonephritis. However, increasing resistance has put into question their efficacy. Oral third-generation cephalosporins have good activity against the majority of pathogens causing pyelonephritis and may be considered first line therapy for pyelonephritis. In all cases, referral to local antibiograms will provide the best match of antimicrobial to bacterial resistance patterns.



References:
  1. Pediatric-specific antimicrobial susceptibility data and empiric antibiotic selection.
    Boggan JC, Navar-Boggan AM, Jhaveri R
    Pediatrics. 2012 Sep;130(3):e615-22.
  2. Treatment of pyelonephritis in an observation unit.
    Ward G, Jorden RC, Severance HW
    Ann Emerg Med. 1991;20(3):258.
  3. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
    Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE, Infectious Diseases Society of America, European Society for Microbiology and Infectious Diseases
    Clin Infect Dis. 2011;52(5):e103.
  4. In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010.
    Sanchez GV, Master RN, Karlowsky JA, Bordon JM
    Antimicrob Agents Chemother. 2012 Apr;56(4):2181-3.
  5. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial.
    Talan DA, Stamm WE, Hooton TM, Moran GJ, Burke T, Iravani A, Reuning-Scherer J, Church DA
    JAMA. 2000;283(12):1583.
  6. A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis.
    Peterson J, Kaul S, Khashab M, Fisher AC, Kahn JB
    Urology. 2008;71(1):17.
  7. Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis.
    Talan DA, Klimberg IW, Nicolle LE, Song J, Kowalsky SF, Church DA
    J Urol. 2004;171(2 Pt 1):734.

10 Uncomplicated cystitis

In uncomplicated cystitis the most common causative pathogen is E. coli accounting for more than 90 percent of infections. There have been reported increases in E coli resistance to trimethoprim-sulfamethoxazole (TMP-SMX), amoxicillin-clavulanate, and first-generation cephalosporins however these are dependent on local resistance patterns. Second and third-generation cephalosporins have been shown to be highly active against E. coli and other gram-negative organisms, but may have limited activity against Enterococcus. Despite its history of resistance, Nitrofurantoin has been shown to have improved resistance patterns in many parts of the world and may be considered a first line therapy for uncomplicated cystitis.

Overall, no antibiotic is currently the ideal therapy for uncomplicated cystitis and local antibiograms should steer the provider to the optimal therapy.



References:
  1. Antibiotic resistance trends in paediatric uropathogens.
    Gaspari RJ, Dickson E, Karlowsky J, Doern G
    Int J Antimicrob Agents. 2005;26(4):267.
  2. Bacterial susceptibility to oral antibiotics in community acquired urinary tract infection.
    Prais D, Straussberg R, Avitzur Y, Nussinovitch M, Harel L, Amir J
    Arch Dis Child. 2003;88(3):215.
  3. Increasing antibiotic resistance among urinary tract isolates.
    Ladhani S, Gransden W
    Arch Dis Child. 2003;88(5):444.
  4. Cephalosporin resistant urinary tract infections in young children.
    Mehr SS, Powell CV, Curtis N
    J Paediatr Child Health. 2004;40(1-2):48.
  5. Pediatric-specific antimicrobial susceptibility data and empiric antibiotic selection.
    Boggan JC, Navar-Boggan AM, Jhaveri R
    Pediatrics. 2012 Sep;130(3):e615-22.
  6. Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women.
    Gupta K, Hooton TM, Roberts PL, Stamm WE
    Arch Intern Med. 2007;167(20):2207.
  7. Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis.
    McKinnell JA, Stollenwerk NS, Jung CW, Miller LG
    Mayo Clin Proc. 2011;86(6):480.
  8. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
    Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE, Infectious Diseases Society of America, European Society for Microbiology and Infectious Diseases
    Clin Infect Dis. 2011;52(5):e103.

11 Urinary analgesic

Although most uncomplicated urinary tract infections respond to therapy within 48 hours, patients may have decreased discomfort with the use of urinary analgesics such as phenazopyridine. These medications are oral and over the counter making it easy for the patient to source (although patients have been shown to commonly misuse this medication and only few RCTs have looked at these medications). Patients should be told not to chronically use this medication as it may mask recurrent UTI symptoms and has been associated with rare, but severe side effects if used inappropriately.



References:
  1. Time to symptom relief for uncomplicated urinary tract infection treated with extended-release ciprofloxacin: a prospective, open-label, uncontrolled primary care study.
    Klimberg I, Shockey G, Ellison H, Fuller-Jonap F, Colgan R, Song J, Keating K, Cyrus P
    Curr Med Res Opin. 2005 Aug;21(8):1241-50.
  2. Urinary tract analgesics for the treatment of patients with acute cystitis: where is the clinical evidence?
    Pergialiotis V, Arnos P, Mavros MN, Pitsouni E, Athanasiou S, Falagas ME.
    Expert Rev Anti Infect Ther. 2012 Aug;10(8):875-9.
  3. Oral dye therapy in urogenital infections.
    Walther H, Willoughby RM.
    Am. J. Surg.25(3),460–466 (1934).
  4. Urinary tract disorders. Clinical comparison of flavoxate and phenazopyridine.
    Gould S.
    Urology. 1975 May;5(5):612-5.
  5. Ancillary use of phenazopyridine (Pyridium) in urinary tract infections.
    Trickett PC.
    Curr Ther Res Clin Exp. 1970 Jul;12(7):441-5.
  6. Evaluation of the efficacy of phenazopyridine Hydrochloride (Formula PD-F-0016) as a urinary analgesic in women with urinary tract infections.
    Gilderman L, Hendry D, Patrick K.
    FDA’s Dockets Management. Protocol Number: 99-001-P (2001).
  7. Phenazopyridine does not improve catheter discomfort following gynecologic surgery.
    Anderson C, Chimhanda M, Sloan J, Galloway S, Sinacore J, Brubaker L.
    Am J Obstet Gynecol. 2011 Mar;204(3):267.e1-3.
  8. Ciprofloxacin bioavailability is enhanced by oral co-administration with phenazopyridine: a pharmacokinetic study in a Mexican population.
    Marcelín-Jiménez G, Angeles AP, Martínez-Rossier L, Fernández S A.
    Clin Drug Investig. 2006;26(6):323-8.
  9. Chocolate-colored blood with normal artery oxygen: methemoglobinemia related to phenazopyridine.
    Yu CH, Wang CH, Chang CC.
    Am J Med Sci. 2011 Apr;341(4):337.
  10. Multiple adverse effects of pyridium: a case report.
    Haigh C, Dewar JC.
    South Med J. 2006 Jan;99(1):90-2.
  11. Acute renal failure caused by phenazopyridine
    Vega J.
    Rev Med Chil. 2003 May;131(5):541-4.
  12. Acute kidney failure caused by phenazopyridine overdose.
    Rivas R, Martínez Torres A, Bohorques R, Martínez Albelo I.
    Nefrologia. 2001 Jan-Feb;21(1):97-8.
  13. Chronic severe hemolytic anemia from phenazopyridine.
    Siddiqui MA.
    Ann Intern Med. 1995 Jan 15;122(2):156; author reply 157.
  14. Chronic severe hemolytic anemia related to surreptitious phenazopyridine abuse.
    Thomas RJ, Doddabele S, Karnad AB.
    Ann Intern Med. 1994 Aug 15;121(4):308.
  15. Consumer Knowledge of Over-the-Counter Phenazopyridine
    Shi CW, Asch SM, Fielder E, Gelberg L, Nichol MB.
    Ann Fam Med. May 2004; 2(3): 240–244.
  16. Usage Patterns of Over-the-counter Phenazopyridine (Pyridium)
    Shi CW, Asch SM, Fielder E et al.
    J Gen Intern Med. Apr 2003; 18(4): 281–287.

12 Probiotics

Large systemic reviews have shown that probiotics are efficacious and safe for the treatment and prevention of antibiotic associated diarrhea in children and adults. The largest trial showed a 42 percent lower risk of diarrhea with a number needed to treat of 13. However, given the heterogeneity of the data, optimal dosing and probiotic organism is not possible (Bacillus, Bifidobacterium, Enterococcus, Lactobacillus, Saccharomyces, Streptococcus) although no significant difference in effectiveness was found between organisms used.

Since up to 10 percent of patients treated with antibiotics will develop diarrhea routine use of probiotics is recommended as long as there are no contraindications.



References:
  1. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials.
    Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE
    Lancet Infect Dis. 2006;6(6):374.
  2. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis.
    D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ
    BMJ. 2002;324(7350):1361.
  3. Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis.
    Van Niel CW, Feudtner C, Garrison MM, Christakis DA
    Pediatrics. 2002;109(4):678.
  4. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease.
    McFarland LV
    Am J Gastroenterol. 2006;101(4):812.
  5. Probiotics for the prevention of pediatric antibiotic-associated diarrhea.
    Johnston BC, Supina AL, Ospina M, Vohra S
    Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004827.
  6. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials.
    Szajewska H, Ruszczyński M, Radzikowski A
    J Pediatr. 2006;149(3):367.
  7. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis.
    Hempel S, Newberry SJ, Maher AR, Wang Z, Miles JN, Shanman R, Johnsen B, Shekelle PG
    JAMA. 2012 May;307(18):1959-69.
  8. Meta-analysis: probiotics in antibiotic-associated diarrhoea.
    Videlock EJ, Cremonini F
    Aliment Pharmacol Ther. 2012;35(12):1355.
  9. Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial.
    Pozzoni P, Riva A, Bellatorre AG, Amigoni M, Redaelli E, Ronchetti A, Stefani M, Tironi R, Molteni EE, Conte D, Casazza G, Colli A
    Am J Gastroenterol. 2012;107(6):922.
  10. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial.
    Allen SJ, Wareham K, Wang D, Bradley C, Hutchings H, Harris W, Dhar A, Brown H, Foden A, Gravenor MB, Mack D
    Lancet. 2013;382(9900):1249.
  11. Probiotics have clinical, microbiologic, and immunologic efficacy in acute infectious diarrhea.
    Chen CC, Kong MS, Lai MW, Chao HC, Chang KW, Chen SY, Huang YC, Chiu CH, Li WC, Lin PY, Chen CJ, Li TY
    Pediatr Infect Dis J. 2010;29(2):135.