Probiotics for the prevention of pediatric antibiotic-associated diarrhea

Abstract

Antibiotics alter the microbial balance commonly resulting in antibiotic‐associated diarrhea (AAD). Probiotics may prevent AAD via providing gut barrier, restoration of the gut microflora, and other potential mechanisms of action. The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children. MEDLINE, Embase, CENTRAL, CINAHL, and the Web of Science (inception to 28 May 2018) were searched along with registers including the ISRCTN and Clinicaltrials.gov. We also searched the NICE Evidence Services database as well as reference lists from relevant articles. Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion. Study selection, data extraction, and risk of bias assessment were conducted independently by two authors. Dichotomous data (incidence of AAD, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea) as mean difference (MD), along with corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For studies reporting on microbiome characteristics using heterogeneous outcomes, we describe the results narratively. The certainty of the evidence was evaluated using GRADE. Thirty‐three studies (6352 participants) were included. Probiotics assessed included Bacillus spp., Bifidobacterium spp., Clostridium butyricum , Lactobacilli spp. , Lactococcus spp., Leuconostoc cremoris , Saccharomyces spp., or Streptococcus spp., alone or in combination. The risk of bias was determined to be high in 20 studies and low in 13 studies. Complete case (patients who did not complete the studies were not included in the analysis) results from 33 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control. After 5 days to 12 weeks of follow‐up, the incidence of AAD in the probiotic group was 8% (259/3232) compared to 19% (598/3120) in the control group (RR 0.45, 95% CI 0.36 to 0.56; I² = 57%, 6352 participants; NNTB 9, 95% CI 7 to 13; moderate certainty evidence). Nineteen studies had loss to follow‐up ranging from 1% to 46%. After making assumptions for those lost, the observed benefit was still statistically significant using an extreme plausible intention‐to‐treat (ITT) analysis, wherein the incidence of AAD in the probiotic group was 12% (436/3551) compared to 19% (664/3468) in the control group (7019 participants; RR 0.61; 95% CI 0.49 to 0.77; P <0.00001; I² = 70%). An a priori available case subgroup analysis exploring heterogeneity indicated that high dose (≥ 5 billion CFUs per day) is more effective than low probiotic dose (< 5 billion CFUs per day), interaction P value = 0.01. For the high dose studies the incidence of AAD in the probiotic group was 8% (162/2029) compared to 23% (462/2009) in the control group (4038 participants; RR 0.37; 95% CI 0.30 to 0.46; P = 0.06; moderate certainty evidence). For the low dose studies the incidence of AAD in the probiotic group was 8% (97/1155) compared to 13% (133/1059) in the control group (2214 participants; RR 0.68; 95% CI 0.46 to 1.01; P = 0.02). Again, assumptions for loss to follow‐up using an extreme plausible ITT analysis was statistically significant. For high dose studies the incidence of AAD in the probiotic group was 13% (278/2218) compared to 23% (503/2207) in control group (4425 participants; RR 0.54; 95% CI 0.42 to 0.70; P <0.00001; I² = 68%; moderate certainty evidence). None of the 24 trials (4415 participants) that reported on adverse events reported any serious adverse events attributable to probiotics. Adverse event rates were low. After 5 days to 4 weeks follow‐up, 4% (86/2229) of probiotics participants had an adverse event compared to 6% (121/2186) of control participants (RD 0.00; 95% CI ‐0.01 to 0.01; P < 0.00001; I² = 75%; low certainty evidence). Common adverse events included rash, nausea, gas, flatulence, abdominal bloating, and constipation. After 10 days to 12 weeks of follow‐up, eight studies recorded data on our secondary outcome, the mean duration of diarrhea; with probiotics reducing diarrhea duration by almost one day (MD ‐0.91; 95% CI ‐1.38 to ‐0.44; P <0.00001; low certainty evidence). One study reported on microbiome characteristics, reporting no difference in changes with concurrent antibiotic and probiotic use. The overall evidence suggests a moderate protective effect of probiotics for preventing AAD (NNTB 9, 95% CI 7 to 13). Using five criteria to evaluate the credibility of the subgroup analysis on probiotic dose, the results indicate the subgroup effect based on high dose probiotics (≥ 5 billion CFUs per day) was credible. Based on high‐dose probiotics, the NNTB to prevent one case of diarrhea is 6 (95% CI 5 to 9). The overall certainty of the evidence for the primary endpoint, incidence of AAD, based on high dose probiotics was moderate due to the minor issues with risk of bias and inconsistency related to a diversity of probiotic agents used. Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction by almost one day. The benefit of high dose probiotics (e.g. Lactobacillus rhamnosus or Saccharomyces boulardii ) needs to be confirmed by a large well‐designed multi‐centered randomized trial. It is premature to draw firm conclusions about the efficacy and safety of 'other' probiotic agents as an adjunct to antibiotics in children. Adverse event rates were low and no serious adverse events were attributable to probiotics. Although no serious adverse events were observed among inpatient and outpatient children, including small studies conducted in the intensive care unit and in the neonatal unit, observational studies not included in this review have reported serious adverse events in severely debilitated or immuno‐compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation. Probiotics for the prevention of antibiotic‐associated diarrhea in children What is antibiotic‐associated diarrhea? Antibiotic‐associated diarrhea (AAD) occurs when antibiotics disturb the natural balance of "good" and "bad" bacteria in the intestinal tract causing harmful bacteria to multiply beyond their normal numbers. The symptoms of AAD include frequent watery bowel movements and crampy abdominal pain. What are probiotics? Probiotics are found in dietary supplements or yogurts and contain potentially beneficial bacteria or yeast. Probiotics may restore the natural balance of bacteria in the intestinal tract. What did the researchers investigate? The researchers investigated whether probiotics prevent AAD in children receiving antibiotic therapy and whether probiotics causes any harms (side effects). The researchers searched the medical literature extensively up to May 28, 2018. What did the researchers find? Thirty‐three studies were reviewed and provide the best available evidence. The studies tested 6352 children (3 days to 17 years of age) who were receiving probiotics co‐administered with antibiotics to prevent AAD. The participants received probiotics ( Lactobacilli spp., Bifidobacterium spp., Streptococcus spp. , or Saccharomyces boulardii alone or in combination), placebo (pills not including probiotics), other treatments thought to prevent AAD (i.e. diosmectite or infant formula) or no treatment. The studies were short‐term, ranging in length from 5 days to 12 weeks. Analyses showed that probiotics are effective for preventing AAD. The incidence of AAD in the probiotic group was 8% (259/3232) compared to 19% (598/3120) in the control group, demonstrating a moderate reduction (11% fewer will suffer diarrhea). For every 9 children treated, probiotics will prevent one case of diarrhea. Further, evidence suggests that higher dose probiotics (≥ 5 billion CFUs per day) reduce the incidence of AAD. Eight per cent (162/2029) of the high dose probiotics group had AAD compared to 23% (462/2009) in the control group, demonstrating a moderate to large reduction (15% fewer suffer diarrhea). Probiotics were generally well tolerated, and minor side effects (e.g. rash, nausea, gas, flatulence, abdominal bloating, constipation) occurred infrequently. . Evidence suggested that probiotics are effective for a moderate reduction in duration of diarrhea (almost one day). Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day appear most appropriate for preventing AAD in children receiving antibiotics. It is premature to draw conclusions about the effectiveness and safety of 'other' probiotic agents for preventing AAD. Although no serious probiotic‐related side effects were observed among the mostly otherwise healthy children who participated in the studies, serious side effects have been reported in observational studies not included in this review, including severely debilitated or immuno‐compromised children with underlying risk factors including central venous catheter (a flexible tube used to give medicines) use and disorders associated with bacterial or fungal translocation (the passage of bacteria from the gut to other areas of the body).