Addition of probenecid to oral β-lactam antibiotics: a systematic review and meta-analysis

Wilson, Richard C ORCID: 0000-0002-3275-6932, Arkell, Paul, Riezk, Alaa, Gilchrist, Mark, Wheeler, Graham, Hope, William ORCID: 0000-0001-6187-878X, Holmes, Alison H ORCID: 0000-0001-5554-5743 and Rawson, Timothy M ORCID: 0000-0002-2630-9722 (2022) Addition of probenecid to oral β-lactam antibiotics: a systematic review and meta-analysis. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 77 (9). pp. 2364-2372.

Text Probenecid_Review_JACrevision_CLEAN2.docx - Author Accepted Manuscript Download (998kB)

Abstract

<h4>Objectives</h4>To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral β-lactams.<h4>Methods</h4>Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral β-lactam [flucloxacillin, penicillin V, amoxicillin (± clavulanate), cefalexin, cefuroxime axetil] alone (comparator). ROBINS-I and ROB-2 tools were used. Data on antibiotic therapy, infection diagnosis, primary and secondary outcomes relating to pharmacokinetics and clinical outcomes, plus adverse events were extracted and reported descriptively. For a subset of studies comparing treatment failure between probenecid and control groups, meta-analysis was performed.<h4>Results</h4>Overall, 18/295 (6%) screened abstracts were included. Populations, methodology and outcome data were heterogeneous. Common populations included healthy volunteers (9/18; 50%) and those with gonococcal infection (6/18; 33%). Most studies were crossover trials (11/18; 61%) or parallel-arm randomized trials (4/18; 22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral β-lactams increased total AUC (7/7; 100%), Cmax (5/8; 63%) and serum t½ (6/8; 75%). Probenecid improved PTA (2/2; 100%). Meta-analysis of 3105 (2258 intervention, 847 control) patients treated for gonococcal disease demonstrated a relative risk of treatment failure in the random-effects model of 0.33 (95% CI 0.20-0.55; I2 = 7%), favouring probenecid.<h4>Conclusions</h4>Probenecid-boosted β-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral β-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.

Item Type:	Article
Uncontrolled Keywords:	Humans, Gonorrhea, beta-Lactams, Monobactams, Amoxicillin, Probenecid, Anti-Bacterial Agents
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	11 Nov 2022 15:03
Last Modified:	14 Oct 2023 13:33
DOI:	10.1093/jac/dkac200
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3166174