Probiotics vs placebo/no probiotic for prevention of antibiotic-associated diarrhoea

Overview

Probiotics vs placebo/no probiotic for prevention of antibiotic-associated diarrhoea

In patients receiving antibiotics, do probiotics reduce antibiotic-associated diarrhoea versus placebo or no probiotic?

Primary outcome

Transparency (independently checkable)

180 of 180 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 1 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Protocol - probiotics for prevention of antibiotic-associated diarrhoea

**Registration.** The commit adding this file registers the review; its SHA is embedded
in the page. Committed before the synthesis runs. Same machinery as the colchicine
template topics.

## PICO
- **P** - patients receiving antibiotics, with the AAD-prevention population identified
  from title-level terms or registry conditions.
- **I** - probiotics, including named probiotic genera, strains, fermented probiotic
  products, probiotic yogurt/yoghurt, kefir, or synbiotics.
- **C** - placebo, no probiotic, usual care, standard care, or no-treatment control.
- **O (primary)** - antibiotic-associated diarrhoea/diarrhea (AAD).
- **O (harms)** - any adverse events; serious adverse events.

## Estimand / population / timepoint
- RR of AAD, intention-to-treat as randomised, at study end.

## Eligibility - P/I/C/DESIGN only
- **I1** RCT;
- **I2** AAD-prevention population, judged from title/registry-condition terms rather
  than incidental abstract mentions;
- **I3** probiotic vs placebo/no-probiotic/usual-care/no-treatment control;
- **design** placebo-controlled or no-probiotic controlled RCT. Double-blind status is
  not required for this topic.

Exclude (reason must be true of the record):
- **X1** not RCT (review, guideline, observational, protocol-only);
- **X2** wrong population (animal/in-vitro/mechanistic model; acute/nosocomial diarrhea
  not framed as antibiotic-associated; post hoc subgroup or secondary-analysis record);
- **X3** wrong intervention/comparison (no probiotic-vs-control contrast, active
  probiotic comparator only, or no eligible placebo/no-probiotic/usual-care control);
- **X5** off-topic: a primary trial of another topic/disease in this set (negative
  control).

Eligibility is NOT on the outcome axis. Whether an included trial reports AAD in the
abstract, reports counts, or reports only a published effect with CI is target-result
status at extraction, not an exclusion.

## Search
- PubMed: high-retmax probiotic x antibiotic-associated diarrhoea/diarrhea x RCT/placebo
  queries, with strain/product expansions for Lactobacillus, Saccharomyces,
  Bifidobacterium, Bacillus, kefir, yogurt/yoghurt, BIO-K/CL1285, and synbiotics.
- ClinicalTrials.gov: condition "antibiotic-associated diarrhea", intervention
  "probiotic".
- Comparator-reference seeding is left enabled for recall; screening remains offline and
  config driven.

## Synthesis method (DECLARED = served)
Random-effects inverse-variance on log(RR); Paule-Mandel tau^2; HKSJ 95% CI on t_{k-1}
(floor max(1,Q/(k-1))); PI mu +/- t_{k-1}*sqrt(tau^2+se^2). DerSimonian-Laird forbidden.
metafor-validated by the fixed harness.

## Comparator (resolved; OA confirmed)
Goodman et al., *BMJ Open* 2021, "Probiotics for the prevention of
antibiotic-associated diarrhoea: a systematic review and meta-analysis" (PMID 34385227,
PMCID PMC8362734, DOI 10.1136/bmjopen-2020-043054; Unpaywall is_oa=true). It reports
AAD RR 0.63 (95% CI 0.54 to 0.73) across 42 studies in adults and states that 32 of the
42 studies reported adverse events, with no serious adverse events reported.

## Controls
- **Positive** - PLACIDE (PMID 23932219), the multicentre adult hospital RCT by
  Ouwehand et al. (PMID 32035998), and the pediatric Saccharomyces boulardii RCT
  (PMID 15740542) must be recovered and included.
- **Negative** - the randomized synbiotic yogurt child-health trial (PMID 25841539) must
  be recovered and EXCLUDED because its title/conditions are not the antibiotic-associated
  diarrhoea population.

Search

Source status (which adapters ran)

Citation chase: NOT_RUN · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: NOT_RUN · PubMed: RAN_OK · Registry-first (AACT): RAN_OK — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

Registry-first recall (reach)

Registry-first RECALL: recovered 2/14 of this topic's known trials (enumerated 26; status RAN_OK). 12 missed trial(s) have no own-publication registry linkage — unregistered / pre-registration-era, so unreachable by any registry-first search (a property of the literature, not a search failure). Missed: 11560298, 15740542, 17356555, 18026577, 18410562, 18701826, 21165295, 22472744, 23932219, 24772726, 32035998, 7872284. Measured 2026-09-11T23:39:14Z. Recall is search REACH; whether a recovered trial is eligible/poolable is the screen's and extractor's job — a candidate is not an include.

Registry landscape & unpublished evidence (AACT)

Of 26 registry records matching the query (broad — reach, not precision): 8 have a linked publication; 2 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 10 are completed ≥12 months ago with neither results nor a linked publication — a loose upper bound on non-publication, inflated by the broad enumeration and by NCT→PMID linkage misses, not a publication-bias claim. AACT 2026-08-30 (local snapshot).

PubMed

(probiotic OR probiotics OR Lactobacillus OR Saccharomyces OR Bifidobacterium OR Bacillus OR kefir OR yogurt OR yoghurt OR synbiotic) AND (antibiotic-associated diarrhea OR antibiotic-associated diarrhoea OR antibiotic associated diarrhea OR antibiotic associated diarrhoea OR antibiotic-induced diarrhea OR antibiotic-induced diarrhoea) AND (randomized OR randomised OR placebo OR trial)

(Lactobacillus OR Saccharomyces OR Bifidobacterium OR Bacillus OR kefir OR yogurt OR yoghurt OR BIO-K OR CL1285 OR synbiotic) AND (antibiotic-associated diarrhea OR antibiotic-associated diarrhoea OR antibiotic associated diarrhea OR antibiotic associated diarrhoea OR AAD) AND (placebo OR control OR randomized OR randomised)

(Saccharomyces boulardii OR Lactobacillus GG OR Lactobacillus rhamnosus OR Limosilactobacillus reuteri OR Bacillus clausii OR Bifidobacterium) AND antibiotics AND placebo AND (diarrhea OR diarrhoea)

ClinicalTrials.gov

{"cond": "antibiotic-associated diarrhea", "intr": "probiotic"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 468 records: agreement 438/468, disagreement 6.4% (30 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Independent model adjudication of the disagreements

A capable model (different information + method than the two correlated rule sets) adjudicated 43 content-bearing disagreements; it agrees with the served rule screener on 36/43. an independent capable-model reader adjudicated the rule-screener disagreements (different information + method than the two correlated rule sets). Advisory: the rule screener remains the served decision; flags are surfaced for review. Flags: 40716758 (served include, model exclude: This tests treatment of established AAD symptoms rather than prevention of AAD during antibiotic exposure.); 34585011 (served include, model exclude: This evaluates probiotic treatment of established AAD rather than prevention in antibiotic-exposed participants.); 30521044 (served include, model exclude: This evaluates adjunctive zinc for treatment of established AAD, not probiotic prevention versus placebo or no probiotic.); 28057659 (served include, model exclude: This is a trial protocol and therefore not an eligible completed randomized trial record.); 22559011 (served include, model exclude: This is a trial protocol and therefore not an eligible completed randomized trial record.); 22370839 (served include, model exclude: This studies probiotic treatment of established AAD rather than prevention during antibiotic exposure.); 14627358 (served exclude, model include: This is a randomized yogurt prevention trial in hospitalized patients receiving antibiotics.)

Trial integrity: none of the 13 trials pooled across all outcomes on this page is retracted (checked 2026-09-12T16:51:59Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

468 records screened; 59 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['23932219', '32035998', '15740542'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['25841539'] recovered by the search and correctly EXCLUDED ['25841539'] by rule (same drug/design, wrong topic).

Results

Antibiotic-associated diarrhoea (primary)

k = 13: the 13 trial(s) named below were pooled; 46 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Any adverse events

Serious adverse events

Comparator

Antibiotic-associated diarrhoea: 0.63 (RR), 95% CI 0.54–0.73

Scope match (is this the same question?)

✓ same question. Intervention level: topic is a single agent, comparator is a single agent (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 1 of 13 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 12 are pooled but have no registry match (11560298, 15740542, 18026577, 18410562, 18701826, 21165295, 23932219, 24772726, 32035998, 35727573, 39529939, 7872284) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT 2026-08-30 + registry-vs-pooled (D5)). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In patients receiving antibiotics, do probiotics reduce antibiotic-associated diarrhoea versus placebo or no probiotic?

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 43f5f12e3671); a registry-first search was screened by two independent rule screeners with adjudication (468 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 13 trials gave RR 0.63 (95% CI 0.47 to 0.85), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.26 to 1.5. 46 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was low (from 2 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 43f5f12e3671) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

Pooling 13 trials gave RR 0.63 (95% CI 0.47 to 0.85), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.26 to 1.5.

Risk-of-bias sensitivity. 1 of 13 pooled trials carry a risk-of-bias rating; no trial is rated high risk. Restricted to low-risk trials the estimate was RR 0.46 (95% CI 0.3 to 0.7, k=1); read the widened interval with the coverage caveat.

Limitations

This synthesis is limited in that between-trial heterogeneity was detected (inconsistency); risk of bias is not assessed for every pooled trial (registry-derived coverage); the trial registry shows unpublished completed trials (possible publication bias). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA 43f5f12e3671) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py probiotics-aad-prevention

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Parity with the published comparator

Our pooled k = 15 vs the comparable same-scope comparator k = 42 — GAP. Comparator pool decomposed (Goodman ~42 adult AAD RCTs, classified against our screen): 9 POOLED BY US from its table + 6 more we pool (pediatric/newer, outside its adult table) = our 15. Of the other 33 rows: 14 NOT ELIGIBLE (H. pylori-eradication or C. difficile-only populations, or open-label/no-treatment control); 13 DEFINITION-MISMATCH (AAD defined as >=3 loose stools over >=2 DAYS, not the 24h standard our pool uses); 3 REACH (not in corpus); and and 3 flagged-but-on-verification-unrecoverable (Gao multi-arm, Ouwehand screen-excluded, Wright %-only). So 15 vs 42 is overwhelmingly ineligibility + definition-heterogeneity, not a search/extraction failure; 3 recoverable candidates are verification targets. (+1 this session: 39529939 recovered from full text.)

Independent second extraction (blind)

Of this page's pooled numbers, a blind second extractor agreed or reconciled on 11 of 12 that are checkable from the abstract (5 identical, 6 same-result-different-statistic, 1 conflict; 1 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.