Cefepime-Taniborbactam in Complicated Urinary Tract Infection.
Wagenlehner FM, Gasink LB, McGovern PC, Moeck G, McLeroth P, Dorr M, Dane A, Henkel T, CERTAIN-1 Study Team
- DOI
- 10.1056/NEJMoa2304748
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-22
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/c35f9410-98dd-44e2-bff0-8ce363cd5818 is authoritative.
How this rating was calculated
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- CitationsUnresolved reference ×2−0.5★
- ReportingData & code availability partially met−0.25★
- No data or code availability links were detected to verify.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy outcome is a composite of microbiologic and clinical success. Microbiologic success is a surrogate endpoint (reduction of bacteria in urine culture), and while clinical success is a patient-reported outcome, the composite is not a hard clinical outcome. The paper does not provide evidence linking the surrogate (microbiologic eradication) to long-term clinical outcomes, nor does it demonstrate target engagement at the tested dose beyond in vitro activity.
“The primary efficacy outcome was a composite of both microbiologic and clinical success in the microITT population at test of cure on trial days 19 to 23.”
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and well-reported phase 3 randomized controlled trial with rigorous design, clear ethical approvals, and appropriate statistical methods. The main weaknesses are minor reporting gaps: the data sharing statement is not detailed in the text, statistical software is not named, and adherence to a reporting guideline is not explicitly stated.
Both reviewers independently scored all eight dimensions and agreed on every status, so no divergence needed reconciliation. The statistics verification component recomputed only 1 reported test (consistent), so the broader statistical analysis is not fully machine-verified. The citation component flagged 2 references as not found in registry, which are addressed in the action items.
Numerical inconsistencies
None foundValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
Checked — nothing surfaced.
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- CONSISTENTreported p = .009 · recomputed p = .010Reviewers 1, 2Primary outcome superiority p-value from difference in proportions and 95% CI.
“treatment difference of 12.6 percentage points (95% confidence interval [CI], 3.1 to 22.2; P = 0.009)”
Taken as given: The treatment difference is 0.126 (12.6 percentage points).; The 95% CI is two-sided.; The CI is for a difference in proportions (not a ratio).Method: Recomputed two-sided p-value from the reported difference and 95% CI using the normal approximation (pCI function).How we recomputed it: pCI(0.126, 0.031, 0.222, 0)
Overstated conclusions
1 finding · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
5 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Cefepime–taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis.The primary outcome showed a statistically significant difference with a p-value of 0.009 and a CI excluding zero.Evidence: Primary outcome: 207/293 (70.6%) vs 83/143 (58.0%), difference 12.6 percentage points (95% CI 3.1 to 22.2; P=0.009).
Cefepime–taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem.
Conclusionreviewer’s wording - supportedReviewer 1The safety profile of cefepime–taniborbactam was similar to that of meropenem.Adverse event rates were comparable, and serious adverse events were similar in frequency.Evidence: Adverse events occurred in 35.5% vs 29.0%; serious adverse events in 2.0% vs 1.8%.
Adverse events occurred during treatment in 35.5% of the patients in the cefepime–taniborbactam group and in 29.0% of those in the meropenem group.
Resultsreviewer’s wording - supportedReviewers 1, 2Differences in treatment response were sustained at late follow-up.Composite and clinical success were higher in the cefepime–taniborbactam group at late follow-up, with CIs excluding zero for composite success.Evidence: Composite success at late follow-up: 187/293 (63.8%) vs 74/143 (51.7%), difference 12.1 (95% CI 2.2 to 21.9).
Differences in treatment response were sustained at late follow-up, at which time cefepime–taniborbactam had both higher composite success and higher clinical success than meropenem.
Resultsreviewer’s wording - supportedReviewer 1Cefepime–taniborbactam had composite success in 8 of 10 patients with meropenem-resistant pathogens.The claim is directly supported by the reported data in the extended microITT population.Evidence: In the extended microITT population, cefepime–taniborbactam had composite success at test of cure in 8 of 10 patients with meropenem-resistant pathogens.
In the extended microITT population, cefepime–taniborbactam had composite success at test of cure in 8 of 10 patients with meropenem-resistant pathogens.
Resultsreviewer’s wording - supportedReviewer 2Cefepime–taniborbactam had a safety profile similar to that of meropenem.Adverse event rates were similar, and serious adverse events were comparable.Evidence: Adverse events: 35.5% vs 29.0%; serious adverse events: 2.0% vs 1.8%.
“Cefepime–taniborbactam and meropenem had similar safety profiles.”
ResultsFind in source
Premise concern: surrogate not validated for clinical benefit.
- INADEQUATESurrogate endpointThe primary efficacy outcome is a composite of microbiologic and clinical success. Microbiologic success is a surrogate endpoint (reduction of bacteria in urine culture), and while clinical success is a patient-reported outcome, the composite is not a hard clinical outcome. The paper does not provide evidence linking the surrogate (microbiologic eradication) to long-term clinical outcomes, nor does it demonstrate target engagement at the tested dose beyond in vitro activity.
“The primary efficacy outcome was a composite of both microbiologic and clinical success in the microITT population at test of cure on trial days 19 to 23.”
- ADEQUATEEffect sizeThe treatment difference for the primary composite outcome was 12.6 percentage points (95% CI, 3.1 to 22.2; P=0.009), which is statistically significant and clinically meaningful in the context of an infectious disease trial. The effect is anchored to a regulatory endpoint and supported by consistent secondary outcomes.
“Cefepime–taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009).”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites multiple prior studies on the threat of resistant organisms and the in vitro/in vivo activity of cefepime–taniborbactam, establishing the scientific need. The rationale linking the drug's mechanism to the trial objective is explicit. Limitations of prior work are implicitly addressed by the phase 3 design, though not explicitly framed as addressing prior limitations.
Randomization method (central computer-generated sequence, block size 6, stratified) and unit (patient) are reported. Blinding is described (double-blind, double-dummy, with unblinded pharmacy staff). Power analysis is provided (≥396 microITT patients, >90% power). Inclusion/exclusion criteria are detailed. Outlier handling is addressed via missing-data imputation (counted as failures). Controls are inherent in the active-comparator design. Independent replication is not applicable for a single pivotal trial.
“An interactive-response system was used for randomization with a central computer-generated sequence and a block size of 6.”
“The trial sponsor, investigators, site staff members who were participating in patient care or clinical evaluations, and patients were not aware of treatment assignments.”
“The trial sponsor, investigators, site staff members who were participating in patient care or clinical evaluations, and patients were not aware of treatment assignments.”
Sex, age, race/ethnicity, BMI, renal function, infection type, and comorbidities are reported in Table 1. Both sexes are enrolled, so sex justification is not applicable. Age and health status are reported. Species/strain and housing are not applicable for a human trial.
“Female sex — no. (%) 161 (54.9) 69 (48.3)”
“Age Mean 56.5±17.6 55.8±17.9”
“Female sex — no. (%) 161 (54.9) 69 (48.3)”
“Age Mean 56.5±17.6 55.8±17.9”
The trial was conducted in accordance with ICH-GCP and the Declaration of Helsinki, with approval by an independent ethics committee at each site. Written informed consent was obtained from all patients. Regulatory compliance is explicitly stated.
“All the patients provided written informed consent.”
“All the patients provided written informed consent.”
Cefepime–taniborbactam and meropenem are named with doses and regimens. The manufacturer (Venatorx) is implied. No bench reagents or software are used, so other criteria are not applicable.
The primary analysis uses a two-sided 95% CI for the difference in proportions (Miettinen and Nurminen method) and a two-sided P value. Effect sizes are reported with CIs. Missing data are handled as treatment failures. Software is not explicitly named, but the analysis is standard. Data presentation includes forest plots and tables with per-group n. Mathematical plausibility checks are not applicable for large-N continuous outcomes.
“12.6 (3.1 to 22.2)”
“The difference in success between treatments (cefepime–taniborbactam minus meropenem) was calculated with the 95% confidence interval of between-group differences according to the Miettinen and Nurminen method.”
“with a treatment difference of 12.6 percentage points (95% confidence interval [CI], 3.1 to 22.2; P = 0.009)”
“12.6 (3.1 to 22.2)”
The paper states 'A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.' This is vague and does not specify the access mechanism. For a clinical trial, managed access is acceptable, but the statement is not concrete. No code is shared.
“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”
“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”
The trial is registered (NCT03840148). Methods are detailed. Reporting guideline adherence is implied by NEJM standards but not explicitly stated. All outcomes are reported, including negative results. Limitations are discussed in the Discussion. Conclusions are proportional. Funding and COI are disclosed.
“CERTAIN-1 ClinicalTrials.gov number, NCT03840148.”
“CERTAIN-1 ClinicalTrials.gov number, NCT03840148.”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
1 finding · worst lowReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
- References not resolvable to a published paperRecomputed
Checked 38 references by DOI: 28 verified — 2 DOI unresolved, 8 no DOI (shown, not verified).
- UNRESOLVED10.1001/jama.2018.0439Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trialCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1001/jama.2022.17035Cefepime/enmetazobactam for complicated urinary tract infectionsCited DOI does not resolve to any Crossref record.
- NO DOIAntimicrobial resistance in the EU/EEA (EARS-Net): annual epidemiological report for 2021No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINo time to wait: securing the future from drug-resistant infections: report to the Secretary-General of the United NationsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAntimicrobial resistance surveillance in Europe 2022 — 2020 dataNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIComplicated urinary tract infections: developing drugs for treatment. Guidance documentNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGuideline on the evaluation of medicinal products indicated for treatment of bacterial infectionsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPerformance standards for antimicrobial susceptibility testing. CLSI supplement M100No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMerrem IV (meropenem for injection), for intravenous use: initial U.S. approval: 1996No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMaxipime (cefepime hydrochloride) for injection, for intravenous or intramuscular use: initial U.S. approval: 1996No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
None foundWording, consistency and formatting errors that need correcting before submission.
Checked — nothing surfaced.
No copyedit issues found.
The published paper is methodologically robust and transparent, with only minor reporting gaps that do not undermine its conclusions. An informed reader should weigh the minor omissions (data sharing details, software identification, explicit CONSORT adherence) and the two references that could not be located in registries, but these do not warrant retraction or major correction.
- 1.HIGHdata codeIn the Data Availability section, specify the exact access mechanism and conditions for the data sharing statement, e.g., 'available upon request to the corresponding author after approval of a proposal and with a data access agreement'.The current statement is vague and does not provide readers with a concrete path to access the data, which is a common expectation for clinical trials.
- 2.HIGHreportingIn the Methods, explicitly state adherence to a reporting guideline such as CONSORT, and mention that the CONSORT checklist is provided as supplementary material.Explicitly naming the reporting guideline improves transparency and helps readers verify that all CONSORT items are addressed.
- 3.HIGHstatisticsIn the Statistical Analysis section, name the statistical software and version used (e.g., SAS version 9.4) to improve reproducibility.Naming the software is a standard reproducibility requirement and was flagged by both reviewers as a minor omission.
- 4.HIGHotherVerify the reference 'Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial' (DOI 10.1001/jama.2018.0439) — it was not found in Crossref/OpenAlex; correct the DOI or citation details if erroneous.A reference that cannot be located in any registry may be fabricated or contain an incorrect DOI, which is an integrity concern.
- 5.HIGHotherVerify the reference 'Cefepime/enmetazobactam for complicated urinary tract infections' (DOI 10.1001/jama.2022.17035) — it was not found in Crossref/OpenAlex; correct the DOI or citation details if erroneous.A reference that cannot be located in any registry may be fabricated or contain an incorrect DOI, which is an integrity concern.
- 6.MEDIUMreportingIn the Discussion, explicitly acknowledge the limitation that the trial was not powered for subgroup analyses and that multiplicity was not controlled for secondary outcomes.This is a common reviewer expectation and improves the transparency of the interpretation of secondary and subgroup results.
- 7.MEDIUMreportingIn the Results, consider reporting the number of patients with missing data for the primary outcome and how they were handled beyond the general statement.Providing specific missing-data counts helps readers assess the robustness of the primary analysis.
- 8.MEDIUMreportingIn the Methods, provide more detail on the randomization sequence generation and allocation concealment to fully meet CONSORT requirements.While the current description is adequate, more detail would fully satisfy CONSORT and enhance reproducibility.
- 9.MEDIUMreportingIn the Discussion, address the potential impact of the high proportion of patients from Eastern Europe on generalizability more explicitly.Geographic imbalance can affect generalizability, and explicitly discussing it strengthens the limitations section.
- 10.MEDIUMreportingIn the Results, report the exact number of patients with each adverse event leading to discontinuation, as currently only percentages are given.Providing exact counts improves transparency and allows readers to assess the clinical significance of adverse events.
- 11.MEDIUMstatisticsIn the Methods, clarify whether the analysis of the primary outcome was adjusted for stratification factors, as this is a common expectation.Clarifying adjustment for stratification factors helps readers understand the analysis and its potential biases.
- 12.LOWdata codeProvide the data sharing statement content in the main text or supplement, rather than only referencing it as available at NEJM.org.Including the full statement improves accessibility and transparency for readers who may not access the NEJM platform.
- 13.LOWdata codeConsider including a statement on the availability of the statistical analysis plan or protocol in a public repository.Public availability of the protocol and SAP enhances transparency and allows independent verification of the analysis.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.