Probiotics for the prevention of antibiotic-associated adverse events in children – a systematic review to inform development of a core outcome set

Introduction Routine use of probiotics during antibiotic therapy in children remains a subject of discussion. To facilitate synthesis of individual study results and guideline formulation, it is important to assess predefined, similar, and clinically important outcomes. Core outcome sets are a proposed solution for this issue. Aim of this review was to document choice, design, and heterogeneity of outcomes in studies that assessed the effects of probiotics used for the prevention of antibiotic-associated adverse events in children. Methods A systematic literature search covering three major databases was performed. Trials that evaluated oral probiotics’ use concomitant with antibiotic therapy in children were included. Data on outcome definitions, measurement instruments, and follow-up were extracted. The outcomes were assigned to predefined core areas and domains. Data were analyzed descriptively. Results Thirty-six trials were included in this review. Diarrhea, the most commonly reported outcome, had diagnostic criteria clearly defined only in 20 trials. In total, sixteen different definitions of diarrhea were identified. Diarrhea duration, severity and etiology were reported in 8, 4 and 6 studies, respectively. Nineteen studies assessed gastrointestinal symptoms other than diarrhea. Seven studies reported outcomes related to resource use or the economic impact of the intervention. Only 2 studies assessed outcomes related to life impact. None of the studies predefined adverse events of probiotic use. Conclusions Identified outcomes were characterized by substantial heterogeneity. Majority of outcomes were not designed to evaluate endpoints of real-life relevance. Results from this review suggest the need for a new core outcome set consisting of outcomes important for decision-making.


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The human gastrointestinal tract is colonized by hundreds of different microorganisms, 38 which together form the gut microbiota (1, 2). Use of antibiotics is one of the factors known to 39 alter the microbiota composition, which in turn may have an effect on an individual's health. 40 Typical adverse events associated with antibiotic use include various gastrointestinal symptoms 41 such as diarrhea, nausea, vomiting, and abdominal pain (3). Among them, antibiotic-associated 42 diarrhea (AAD), often defined as 'diarrhea that occurs in relation to antibiotic treatment with 43 the exclusion of other etiologies' (4), is the best documented. 44 Over 30 randomized controlled trials (RCTs), mostly with probiotics as an intervention, 45 have been performed to assess the prophylactic strategies for AAD in children (5). In the largest 46 observational study of 650 children published in 2003, the estimated AAD incidence in the 47 pediatric outpatient population was 11% (6). On the other hand, in a recent (2019) Cochrane 48 review (5), the incidence of AAD varied greatly from study to study, ranging from 2% (7) to 49 80% (8). In addition to estimates sometimes being derived from very small underpowered 50 studies (8-11), one of the factors responsible for this heterogeneity in reported incidences could 51 be the definition of AAD adopted by authors of different RCTs and the methods used for 52 measurement of this outcome. Among others, AAD diagnostic criteria vary between the studies 53 in the terms of stool frequency, time from the start of antibiotic therapy, and microbiological 54 methods, if any, used to exclude other etiologies of diarrhea. 55 Other potential effects of early-life microbiota alterations include later-life 56 consequences such as obesity (12), allergies (13), autoimmune disorders (14), and 57 neurodevelopmental abnormalities (15). The long-term health impact of probiotics and 58 antibiotics administered during infancy has been evaluated in some RCTs (16, 17), but this 59 outcome is not a part of a routine trial design. 60 According to the 2016 European Society for Pediatric Gastroenterology, Hepatology, 61 and Nutrition (ESPGHAN) guidelines, some probiotic strains may be effective in AAD 62 prevention (4). Consistent with this, a 2019 Cochrane systematic review of 33 studies concluded 63 that there is a moderate protective effect of probiotics for preventing AAD (5). Still, this use of 64 probiotics is the subject of a lasting discussion due to their cost, and the fact that AAD is usually 65 a mild and self-limiting disease (18). To draw practical conclusions from RCTs, it is important 66 to assess AAD severity and its impact on the patient's everyday life, including global 67 assessment and health-related quality of life, with agreed-upon definitions and outcomes. Clinical Trials (COMMENT) was published, proposing core outcomes for future use in RCTs 79 evaluating therapeutic and preventive strategies for acute gastroenteritis (21). However, authors 80 of this document did not include any statements regarding outcomes specific for AAD. Also, 81 no core outcome set to date has been proposed for use in trials in which probiotics are 82 administered concurrently with antibiotic therapy.

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Our primary aim was to systematically document the definitions of AAD, as well as all 84 of the methods used to measure and describe this outcome, in studies that assessed the effect(s) 85 of probiotics used for AAD prevention. Additionally, we aimed to document any other 86 outcomes reported in studies on probiotic use during antibiotic therapy, provided that they were 87 used to examine probiotics' effect(s) in the prevention of antibiotic-associated adverse events.  Studies that reported only laboratory outcomes (e.g., only stool microbiota composition) 99 were not included in this review. Since the main focus of this review was the prevention of     The data from the included studies were extracted using an abstraction form developed 121 specifically for this review. Extracted data included standard characteristics of studies (author, 122 publication year, country, study type and setting, age and number of participants, indication for 123 antibiotic treatment, type of antibiotics, investigated probiotic, and type of control group) and 124 data specific to the outcomes. Each identified outcome was assigned to one of 4 core areas: 125 "life impact", "resource use", "pathophysiological manifestations" or "death", in accordance 126 with the OMERACT Filter 2.0 (22). Specific outcomes were also assigned to one of the 127 predefined outcome domains included within the core areas. In case of identification of an 128 outcome not falling into any of the predefined domains, a new domain was created. An 129 explanation of the outcome-related taxonomy used in the article is presented in Table 1. The 130 data extraction and assignment of the outcomes to the core areas and domains were done 131 independently by JŁ and QG, and any differences in opinion were resolved by discussion. The 132 data extracted for each identified outcome included: outcome name in accordance with the 133 terminology used in the original publication, outcome characteristics (e.g., incidence, duration, 134 severity, primary/secondary outcome), outcome definition, outcome measurement instruments, 135 and follow-up. The outcome was considered as primary if either: 1) the authors of the original 136 study declared it as such, or 2) a sample size calculation was performed for this specific 137 outcome. The data for purely biochemical or microbiological outcomes (e.g., microbiota 138 composition) were not extracted, because their documentation and evaluation would require an 139 entirely different methodological approach.

Term Definition Examples
Core area An aspect of health or a health condition that needs to be measured to appropriately assess the effects of a health intervention.   Table. 164 165 Among the included studies, 32 (89%) were RCTs, and the remaining 4 were NRTs.

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The total number of participants was 5506, ranging from 18 to 653 children in individual trials.    In 2 studies, (7, 10), the GSRS was used to assess the gastrointestinal symptoms (56).  Only 2 studies assessed outcomes from "life impact" core area. A single study reported 257 data on absence from school/day care, missed parental days at work, and overall health (38), 258 and another study reported the data on duration of hospital stay (31). The majority of those studies did not utilize a validated instrument to assess the construct of 266 diarrhea, the combination of stool frequency and consistency, did not report data on diarrhea 267 duration and/or severity, and did not perform any microbiological tests to rule out its infectious Cochrane review on pediatric AAD, substantial heterogeneity (I²=57%) was found in the 303 analysis of diarrhea incidence (5 performed the microbiological testing is much more likely to be an actual AAD.

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The most commonly assessed outcome from the 'diarrhea' domain was incidence data.
322 Surprisingly, other outcomes that are arguably more patient important, such as diarrhea duration 323 or severity, were rarely reported. Furthermore, even the most anticipatory criterion for diarrhea 324 diagnosis was 'at least 3 loose or watery stools per day for at least 48 hours'. This constitutes a 325 relatively mild course of illness, especially assuming that the symptoms are likely to resolve on 326 the third day after occurrence(65). Based only on the data for diarrhea incidence, it is difficult 327 to assess whether the reported effect of any intervention was of actual importance to the 328 patients. Other GI outcomes that could contribute to drawing clinically significant conclusions 329 such as abdominal pain or vomiting, were only assessed in a small portion of the studies, even 330 though they are likely to occur during antibiotic treatment(3). When they were reported, authors 331 typically assessed incidence rather than duration or severity, again focusing on outcomes they