P-1092. Re-analysis of Pivmecillinam Randomized Clinical Trial Data According to 2019 US Food and Drug Administration Guidance for the Treatment of Uncomplicated Urinary Tract Infection
Bibliographic record
Abstract
Abstract Background Due to increasing prevalence of resistant uropathogens, there is urgent need in the USA for effective new oral antibiotics for treatment of uncomplicated urinary tract infection (uUTI). Pivmecillinam has been used to treat uUTI in Canada and Europe for > 40 years, is recommended as a first-line agent by the Infectious Diseases Society of America, and has high microbiologic activity against most antibiotic-resistant Enterobacterales. We present a re-analysis of clinical trial data, as per 2019 US Food and Drug Administration (FDA) guidance, that supported the recent US approval of pivmecillinam for treatment of uUTI.Table 1.Composite response rates at test-of-cure (micro-ITT population)185 mg of pivmecillinam is equivalent to 200 mg of pivmecillinam hydrochloride.CI, confidence interval; micro-ITT, microbiological intent-to-treat; QID, four times daily; TID, three times daily.1. Ferry SA et al. Scand J Prim Health Care. 2007;25:49–57. 2. Menday AP. Intl J Antimicrob Agents. 2000;13:183–187. 3. Vik I et al. PLoS Med. 2018;15:e1002569. Methods Detailed subject-level clinical data were retrieved from three historic randomized controlled trials (RCTs) including subjects treated with pivmecillinam 185 mg, three times daily for 3–7 days, and re-analyzed in accordance with the 2019 FDA guidance for uUTI. Efficacy endpoints were composite (clinical and microbiologic) response rates, clinical response rates, and microbiologic response rates, analyzed in the microbiological intent-to-treat population (urine culture ≥ 105 colony-forming units/mL; ≤ 2 microorganism species; no baseline pathogen non-susceptible to active comparator).Table 2.Clinical response rates at test-of-cure (micro-ITT population)185 mg of pivmecillinam is equivalent to 200 mg of pivmecillinam hydrochloride.CI, confidence interval; micro-ITT, microbiological intent-to-treat; QID, four times daily; TID, three times daily. 1. Ferry SA et al. Scand J Prim Health Care. 2007;25:49–57. 2. Menday AP. Intl J Antimicrob Agents. 2000;13:183–187. 3. Vik I et al. PLoS Med. 2018;15:e1002569. Results Efficacy in uUTI was demonstrated for the recommended dosage regimen of pivmecillinam in the three studies (total N=369 pivmecillinam, N=385 comparators). Composite response rates for pivmecillinam ranged from 62.0% to 71.7% (Table 1), clinical response rates from 63.5% to 82.7% (Table 2), and microbiologic response rates from 74.3% to 86.9% (Table 3). Efficacy of pivmecillinam was superior to placebo or ibuprofen and similar to cephalexin. Clinical and microbiologic response rates for pivmecillinam and comparators were generally numerically lower in the re-analysis versus original reports, reflecting the more stringent 2019 FDA criteria.Table 3.Microbiologic response rates at test-of-cure (micro-ITT population)185 mg of pivmecillinam is equivalent to 200 mg of pivmecillinam hydrochloride.CI, confidence interval; micro-ITT, microbiological intent-to-treat; QID, four times daily; TID, three times daily. 1. Ferry SA et al. Scand J Prim Health Care. 2007;25:49–57. 2. Menday AP. Intl J Antimicrob Agents. 2000;13:183–187. 3. Vik I et al. PLoS Med. 2018;15:e1002569. Conclusion This re-analysis of RCT data confirmed the efficacy of pivmecillinam in uUTI, and was used to support the recent US approval of oral pivmecillinam, 185 mg three times daily for 3–7 days, for the treatment of female patients aged ≥ 18 years with uUTI caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus. Disclosures Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Anita F. Das, PhD, Cidara: Advisor/Consultant|Contrafect: Advisor/Consultant|Iterum Therapeutics: Advisor/Consultant|Paratek: Advisor/Consultant|Utility therapeutics: Advisor/Consultant Niels Frimodt-Møller, MD DMSc, Eli Lilly Ltd: Stocks/Bonds (Private Company)|Pfizer Ltd: Stocks/Bonds (Private Company)|Rosco A/S: Advisor/Consultant Kalpana Gupta, MD, GlaxoSmithKline: Advisor/Consultant|IDSA GL on UTI: Uncompensated author|Iterum Therapeutics: Advisor/Consultant|PhenUtest Diagnostics: Advisor/Consultant|Qiagen Inc.,: Advisor/Consultant|UpToDate: Royalties for UTI topics|Utility Therapeutics Ltd: Advisor/Consultant Thomas Lodise, Jr., Pharm.D., PhD, MERCK: Advisor/Consultant Anne Santerre Henriksen, PhD, Utility therapeutics: Advisor/Consultant Morton Alexander, PhD, SNIPR biome: Shareholder|SNIPR biome: Stocks/Bonds (Private Company)|Union therapeutics: Shareholder|Union therapeutics: Stocks/Bonds (Private Company)|Utility therapeutics: Board Member|Utility therapeutics: Ownership Interest Florian Wagenlehner, MD, Astellas: Advisor/Consultant|AstraZeneca: Advisor/Consultant|Bionorica: Advisor/Consultant|DFG (German Research Foundation) funded research group BARICADE (FOR5427/1-466687329): Speaker|GSK: Advisor/Consultant|GSK: Principal investigator in a GSK-sponsored study|Janssen: Advisor/Consultant|Klosterfrau: Advisor/Consultant|MIP Pharma: Advisor/Consultant|OM Pharma: Advisor/Consultant|Spero: Advisor/Consultant|VenatoRX: Advisor/Consultant
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.098 | 0.225 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.006 | 0.014 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.003 |
| Open science | 0.003 | 0.001 |
| Research integrity | 0.004 | 0.006 |
| Insufficient payload (model declined to judge) | 0.052 | 0.008 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".