Probiotics for children receiving antibiotics

Transcription

1 Probiotics for children receiving antibiotics Main editor Reed A. Siemieniuk, Lyubov Lytvyn, Haresh Kirpalani, Bert Aertgeerts, Leigh-Anne Bakel, Peter Church, et al. Publishing Info v1.4 published on WikiRecs group 1 of 12

2 for children receiving antibiotics Contact Language en Start Date Last Edit Disclaimer 2 of 12

3 Sections 1 - Authors and disclosures Probiotics for children receiving antibiotics for an infection of 12

4 Summary of recommendations 2 - Probiotics for children receiving antibiotics for an infection Children 1 month to 2 years old receiving antibiotics for an infection. Strong Recommendation We recommend adjunctive probiotics rather than no probiotics. Children 2 to 18 years old receiving antibiotics for an infection. Weak Recommendation We suggest adjunctive probiotics rather than no probiotics. 4 of 12

5 1 - Authors and disclosures Reed A. Siemieniuk a,b, Lyubov Lytvyn c, Haresh Kirpalani d, Bert Aertgeerts e, Leigh-Anne Bakel f, Peter Church g, Ivan Florez h, Dhanasekhar Kesavelu i, Arnaud Merglen a,j, Charles Okwundu k, Jennifer Poh l, Maher Shahrour m, Ian Sinha n, Shannon Weir o, Baoping Xu p, Gordon H. Guyatt a, Bradley C. Johnston c,q,r a. Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Hamilton, Ontario, Canada, L8S 4K1 b. Department of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8 c. Systematic Overviews through advancing Research Technology, Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, University of Toronto, 686 Bay St, Toronto, Ontario, Canada, M5G 0A4 d. Division of Neonatology, The Children's Hospital of Philadelphia, 2nd Floor, Room th Street and Civic Center Boulevard, Philadelphia, Pennsylvania, USA, e. Academic Center for General Practice, Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Kapucijnenvoer 33, blok j, bus 7001, 3000 Leuven, Belgium f. Children's Hospital of Colorado, University of Colorado, East 17th Avenue, Aurora, Colorado, USA, g. Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, 555 University Ave, Toronto, Ontario, Canada, M5G 1X8 h. Department of Pediatrics, Universidad de Antioquia, Calle 67 # , Medellín, Colombia, i. Apollo Children s Hospital, No. 15, Shafee Mohammed Road, Thousand Lights, Chennai, Tamil Nadu , India j. Hôpital des Enfants - 6 rue Willy Donzé - CH-1211 Genève 14 - Switzerland k. Centre for Evidence-Based Health Care, Stellenbosch University, South Africa l. Department of Pharmacy and Divisions of Paediatric Medicine, Respirology & Surgical Services, The Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada, M5G 1X8 m. Al-Makassed Hospital, Al-Tour / Mount of Olives, Jerusalem, 22110, code n. Alder Hey Children s Hospital, Department of Women's and Children's Health, University of Liverpool, Liverpool, UK o. Child Health Evaluative Sciences, The Hospital for Sick Children, University of Toronto, 686 Bay St, Toronto, Ontario, Canada, M5G 0A4 p. Beijing Children's Hospital of Capital Medical University, Beijing, China q. Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, Canada, M5G 1X8 r. Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, 155 College St, Toronto, ON, Canada, M5T 3M6 Disclosures: Financial disclosures: Bradley Johnston has received financial support for a research study from Bio-K+, a company that produces and sells probiotics. Dr. Johnston was not a voting member of the guideline panel. No other panel members have any financial conflicts of interest to disclose. Intellectual disclosures: Lyubov Lytvyn, Gordon Guyatt, and Bradley Johnston are authors of systematic reviews on probiotics to prevent antibiotic-associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD). In the manuscripts the authors conclude that probiotics are effective for preventing AAD and CDAD. No other others have any intellectual conflicts of interest to disclose. Professional disclosures: No authors have any professional conflicts of interest to disclose. 5 of 12

6 2 - Probiotics for children receiving antibiotics for an infection Four out of every 5 people are prescribed antibiotics every year; use is higher in children than in the general population[1]. Antibioticassociated diarrhea (AAD) is a common side effect of antibiotics with approximately 2-20% of children receiving antibiotics experiencing diarrhea[2]. Generally, AAD is mild and causes discomfort, which can lead to medication non-adherence. In rare circumstances, AAD is severe and is associated with malnutrition and dehydration, which occasionally require hospitalization (or prolonged hospitalization for children already in the hospital). AAD can be associated with numerous pathogens, Clostridium difficile being the most common (C. difficleassociated diarrhea, CDAD)[3][4]. CDAD can lead to serious complications like toxic megacolon and sepsis, however, severe cases are uncommon in children[5]. Adjuctive probiotic therapy has been proposed as a prophylactic option against AAD and CDAD in children receiving antibiotics. We used the best available evidence on relative effects[6] and baseline risk of AAD[2] to inform our clinical practice recommendations for probiotics in children receiving antibiotics. Children 1 month to 2 years old receiving antibiotics for an infection. Strong Recommendation We recommend adjunctive probiotics rather than no probiotics. Practical Info Lactobacillus rhamnosus GG (4 trials, n=711) and Saccharomyces boulardii (4 trials, n=1611) containing 5 to 40 billion colony forming units/ day have been studied the most for AAD prevention in children. To assess differences that may exist between species, the Cochrane review conducted a priori subgroup analyses. The subgroup test of interaction did not identify statistical evidence of a difference between species although this does not preclude the possibility that species or strain related differences exist A reasonable regimen is 10 to 40 billion colony forming units per day. The dosage should be taken in divided doses (e.g. 5 to 20 billion in morning; 5 to 20 billion in evening). Probiotics should generally not be taken within 30 minutes of antibiotics. Key Info Benefits and harms Benefits of probiotics include a reduced incidence of antibiotic associated diarrhea (AAD), severe AAD, and Clostridium difficileassociated diarrhea (CDAD). Among otherwise healthy children, probiotics do not increase the risk of gastrointestinal side effects or of probiotic-related sepsis. Quality of evidence For probiotics, we have moderate certainty that the estimated effects for reduced incidence of AAD, gastrointestinal side effects, and probiotic-related sepsis are close to the true effects, low certainty for severe AAD, and very low certainty for CDAD. Preference and values Patients and their caregivers are likely to place a relatively higher value on preventing AAD, particularly severe AAD than on the relatively minimal costs and burden of probiotics. Resources and other considerations Probiotics are generally inexpensive and accessible throughout the world. Many caregivers with lower disposable income, particularly those without socialized pharmacare or private insurance, may not have the means to afford probiotics. 6 of 12

7 Rationale We issue a strong recommendation for probiotics in children less than 2 years because we believe that the desirable consequences clearly outweigh the undesirable consequences when compared to no probiotics. Although we are only moderately certain in the effect on AAD, the effect was large and there is little evidence of harm. Probiotics are generally inexpensive and widely available. Clinical Question/ PICO Population: Intervention: Comparator: Children 1 month to 2 years old Adjunctive probiotic therapy No probiotic therapy Summary Adjunctive probiotics probably reduce the risk of antibiotic-associated diarrhea (AAD) by approximately 10%, might slightly reduce the risk of severe AAD, and could slightly reduce the risk of CDAD by a small amount. Adjunctive probiotics probably do not result in an increased risk of gastrointestinal side effects or probiotic-related sepsis. Outcome Timeframe Study results and measurements Absolute effect estimates No probiotic therapy Adjunctive probiotic therapy Certainty in effect estimates (Quality of evidence) Summary AAD <2 years Relative risk 0.46 (CI 95% ) Based on data from 3,898 patients in 22 studies. Follow up 1-12 weeks Difference: 97 fewer ( CI 95% 117 fewer - 70 fewer ) Moderate inconsistency. Probiotics appear to decrease the incidence of AAD. Severe AAD <2 years 0.46 ( ) Based on data from 3,898 patients in 22 studies. Follow up 1-12 weeks 18 8 Difference: 10 fewer ( CI 95% 12 fewer - 7 fewer ) Low inconsistency and indirectness. Probiotics may decrease the incidence of severe AAD by a small amount. GI side effects Relative risk 1 (CI 95% ) Based on data from 2,455 patients in 16 studies. Follow up 1-4 weeks Difference: 0 fewer ( CI 95% 10 fewer - 10 more ) Moderate indirectness. Probiotics do not appear to increase the risk of gastrointestinal side effects. Probioticrelated sepsis Relative risk 1 Based on data from 2,455 patients in 16 studies. Follow up 1-4 weeks 0 0 Difference: 0 more ( CI 95% 0 fewer - 3 more ) Moderate No probioticrelated sepsis events reported in the 16 of 22 studies reporting adverse events. Probiotics do not appear to increase the risk of sepsis. 7 of 12

8 Rated down due to risk of bias from selective outcome reporting. Clostridium difficile diarrhea Relative risk 0.4 (CI 95% ) Based on data from 605 patients in 3 studies. Follow up 2 weeks Difference: 35 fewer ( CI 95% 49 fewer - 2 fewer ) Very Low imprecision, risk of bias (possible selective outcome reporting), and indirectness in baseline estimate. Probiotics could reduce the risk of CDAD. Details about studies used and certainty down- and upgrading AAD <2 years reference: Primary study Risk of bias: No serious Inconsistency: Serious The magnitude of statistical heterogeneity was high, with I^2=55%. ; Indirectness: No serious Imprecision: No serious Severe AAD <2 years No studies available reference: No studies available Risk of bias: No serious Inconsistency: Serious The magnitude of statistical heterogeneity was high, with I^2=55%. ; Indirectness: Serious We assumed the same relative risk reduction as all-severity AAD. ; Imprecision: No serious GI side effects reference: Control arm of reference used for intervention Risk of bias: No serious Inconsistency: No serious Indirectness: Serious Definition of adverse effects varied widely by study. ; Imprecision: No serious Very few events (81 total), but absolute events are very small. ; Probiotic-related sepsis reference: Control arm of reference used for intervention Risk of bias: Serious Only 16 of 22 RCTs reported adverse events. ; Inconsistency: No serious Indirectness: No serious Imprecision: No serious Clostridium difficile diarrhea reference: Control arm of reference used for intervention Risk of bias: Serious Selective outcome reporting. ; Inconsistency: No serious Indirectness: Serious Baseline estimate taken from RCTs. ; Imprecision: Serious Very few events (25 total). ; 8 of 12

9 Children 2 to 18 years old receiving antibiotics for an infection. Weak Recommendation We suggest adjunctive probiotics rather than no probiotics. Practical Info Lactobacillus rhamnosus (4 trials, n=711) and Saccharomyces boulardii (4 trials, n=1611) containing 5 to 40 billion colony forming units/day have been studied the most for AAD prevention in children. To assess differences that may exist between species, the Cochrane review conducted a priori subgroup analyses. The subgroup test of interaction did not identify statistical evidence of a difference between species although this does not preclude the possibility that species or strain related differences exist A reasonable regimen is 10 to 40 billion colony forming units per day. The dosage should be taken in divided doses (e.g. 5 to 20 million in morning; 5 to 20 billion in evening). Probiotics should generally not be taken within 30 minutes of antibiotics. Key Info Benefits and harms Benefits of probiotics include a reduced incidence of antibiotic associated diarrhea (AAD), severe AAD, and Clostridium difficileassociated diarrhea (CDAD). Among otherwise healthy children, probiotics do not increase the risk of gastrointestinal side effects or of probiotic-related sepsis. Quality of evidence For probiotics, we have moderate certainty that the estimated effects for reduced incidence of AAD, gastrointestinal side effects, and probiotic-related sepsis are close to the true effects, low certainty for severe AAD, and very low certainty for CDAD. Preference and values Patients are likely to place different value on benefits and burden associated with probiotics. Patients and their caregivers who place a high value on preventing AAD and a relatively lower value on cost and burden are likely to chose to use probiotics. Patients and their caregivers who place a higher value on cost and burden of administration might reasonably chose not to use probiotics. Resources and other considerations Probiotics are generally inexpensive and accessible throughout the world. Many caregivers with lower disposable income, particularly those without socialized pharmacare or private insurance, may not have the means to afford probiotics. Rationale We issue a weak recommendation for probiotics in children older than 2 years because we believe that the desirable consequences outweigh the undesirable consequences when compared to no probiotics. We did not issue a strong recommendation because the effect size was small for prevention of AAD and very small for preventing severe AAD. Probiotics are generally inexpensive and widely available, but costs may be prohibitive in some circumstances. Clinical Question/ PICO Population: Intervention: Comparator: Children 2 to 18 years old Adjunctive probiotic therapy No probiotic therapy 9 of 12

10 Summary Adjunctive probiotics probably reduce the risk of antibiotic-associated diarrhea (AAD) by approximately 1-2%, might slightly reduce the risk of severe AAD, and could slightly reduce the risk of CDAD by a small amount. Adjunctive probiotics probably do not result in an increased risk of gastrointestinal side effects or probiotic-related sepsis. Outcome Timeframe Study results and measurements Absolute effect estimates No probiotic therapy Adjunctive probiotic therapy Certainty in effect estimates (Quality of evidence) Summary AAD 2-18 years Relative risk 0.46 (CI 95% ) Based on data from 3,898 patients in 22 studies. Follow up 1-12 weeks Difference: 16 fewer ( CI 95% 19 fewer - 12 fewer ) Moderate inconsistency. Probiotics appear to decrease the incidence of AAD by a small amount. Severe AAD 2-18 years Relative risk 0.46 (CI 95% ) Based on data from 3,898 patients in 22 studies. Follow up 1-12 weeks 3 1 Difference: 2 fewer ( CI 95% 2 fewer - 1 fewer ) Low inconsistency and indirectness. Probiotics may decrease the incidence of AAD by a small amount. GI side effects Relative risk 1 (CI 95% ) Based on data from 2,455 patients in 16 studies. Follow up 1-4 weeks Difference: 0 fewer ( CI 95% 10 fewer - 10 more ) Moderate indirectness. Probiotics do not appear to increase the risk of gastrointestinal side effects. Probioticrelated sepsis Relative risk 1 Based on data from 2,455 patients in 16 studies. Follow up 1-4 weeks 0 0 Difference: 0 more ( CI 95% 0 fewer - 3 more ) Moderate No probioticrelated sepsis events reported in the 16 of 22 studies reporting adverse events. Rated down due to risk of bias from selective outcome reporting. Probiotics do not appear to increase the risk of sepsis. Clostridium difficile diarrhea Relative risk 0.4 (CI 95% ) Based on data from 605 patients in 3 studies. Follow up 2 weeks Difference: 35 fewer ( CI 95% 49 fewer - 2 fewer ) Very Low imprecision, risk of bias (possible selective outcome reporting), and Probiotics could reduce the risk of CDAD 10 of 12

11 indirectness in baseline estimate. Details about studies used and certainty down- and upgrading AAD 2-18 years reference: Primary study Risk of bias: No serious Inconsistency: Serious The magnitude of statistical heterogeneity was high, with I^2=55%. ; Indirectness: No serious Imprecision: No serious Severe AAD 2-18 years reference: No studies available Risk of bias: No serious Inconsistency: Serious The magnitude of statistical heterogeneity was high, with I^2=55%. ; Indirectness: Serious Imprecision: No serious GI side effects reference: Control arm of reference used for intervention Risk of bias: No serious Inconsistency: No serious Indirectness: Serious Definition of adverse effects varied widely by study. ; Imprecision: No serious Very few events (81 total), but absolute events are very small. ; Probiotic-related sepsis reference: Control arm of reference used for intervention Risk of bias: Serious Only 16 of 22 RCTs reported adverse events. ; Inconsistency: No serious Indirectness: No serious Imprecision: No serious Clostridium difficile diarrhea reference: Control arm of reference used for intervention Risk of bias: Serious Selective outcome reporting. ; Inconsistency: No serious Indirectness: Serious Baseline estimate taken from RCTs. ; Imprecision: Serious Very few events (25 total). ; 11 of 12

12 References [1] Hicks LA, Taylor TH, Hunkler RJ U.S. outpatient antibiotic prescribing, The New England journal of medicine 2013;368(15): null Pubmed Journal [2] Turck D, Bernet J-P, Marx J, Kempf H, Giard P, Walbaum O, Lacombe A, Rembert F, Toursel F, Bernasconi P, Gottrand F, McFarland LV, Bloch K Incidence and risk factors of oral antibiotic-associated diarrhea in an outpatient pediatric population.. Journal of pediatric gastroenterology and nutrition 2003;37(1):22-6-null Pubmed [3] Dickinson B, Surawicz CM Infectious diarrhea: an overview.. Current gastroenterology reports 2014;16(8):399-null Pubmed Journal [4] Khanna S, Baddour LM, Huskins WC, Kammer PP, Faubion WA, Zinsmeister AR, Harmsen WS, Pardi DS The epidemiology of Clostridium difficile infection in children: a population-based study.. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2013;56(10): null Pubmed Journal [5] Schwartz KL, Darwish I, Richardson SE, Mulvey MR, Thampi N Severe clinical outcome is uncommon in Clostridium difficile infection in children: a retrospective cohort study.. BMC pediatrics 2014;14 28-null Pubmed Journal [6] Goldenberg JZ, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC Probiotics for the prevention of pediatric antibiotic-associated diarrhea.. The Cochrane database of systematic reviews 2015;(12):CD null Pubmed Journal 12 of 12