{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:34:28Z","timestamp":1790534068263,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Centre for Antimicrobial Optimisation"},{"name":"CAMO"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral \u03b2-lactams.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral \u03b2-lactam [flucloxacillin, penicillin V, amoxicillin (\u00b1\u200aclavulanate), 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 \u03b2-lactams increased total AUC (7\/7; 100%), Cmax (5\/8; 63%) and serum t\u00bd (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\u20130.55; I2\u200a=\u200a7%), favouring probenecid.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Probenecid-boosted \u03b2-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral \u03b2-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkac200","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T07:44:42Z","timestamp":1655797482000},"page":"2364-2372","source":"Crossref","is-referenced-by-count":24,"title":["Addition of probenecid to oral \u03b2-lactam antibiotics: a systematic review and meta-analysis"],"prefix":"10.1093","volume":"77","author":[{"given":"Richard C","family":"Wilson","sequence":"first","affiliation":[{"name":"National Institute for Health and Care Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London , Hammersmith Campus, Du Cane Road, London W12 0NN , UK"},{"name":"Centre for Antimicrobial Optimisation, Imperial College London, Hammersmith Hospital , Du Cane Road, Acton, London W12 0NN , UK"},{"name":"Imperial College Healthcare NHS Trust, Hammersmith Hospital , Du Cane Road, London W12 0HS , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Arkell","sequence":"additional","affiliation":[{"name":"Centre for Antimicrobial Optimisation, Imperial College London, Hammersmith Hospital , Du Cane Road, Acton, London W12 0NN , UK"},{"name":"Imperial College Healthcare NHS Trust, Hammersmith Hospital , Du Cane Road, London W12 0HS , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Riezk","sequence":"additional","affiliation":[{"name":"Centre for Antimicrobial Optimisation, Imperial College London, Hammersmith Hospital , Du Cane Road, Acton, London W12 0NN , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Gilchrist","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London , Hammersmith Campus, Du Cane Road, London W12 0NN , UK"},{"name":"Centre for Antimicrobial Optimisation, Imperial College London, Hammersmith Hospital , Du Cane Road, Acton, London W12 0NN , UK"},{"name":"Imperial College Healthcare NHS Trust, Hammersmith Hospital , Du Cane Road, London W12 0HS , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Imperial Clinical Trials Unit, Imperial College London , Stadium House, Wood Lane, London W12 7RH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hope","sequence":"additional","affiliation":[{"name":"Centre for Excellence in Infectious Diseases Research (CEIDR), University of Liverpool , Liverpool L7 8TX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison H","family":"Holmes","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London , Hammersmith Campus, Du Cane Road, London W12 0NN , UK"},{"name":"Centre for Antimicrobial Optimisation, Imperial College London, Hammersmith Hospital , Du Cane Road, Acton, London W12 0NN , UK"},{"name":"Imperial College Healthcare NHS Trust, Hammersmith Hospital , Du Cane Road, London W12 0HS , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2630-9722","authenticated-orcid":false,"given":"Timothy M","family":"Rawson","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London , Hammersmith Campus, Du Cane Road, London W12 0NN , UK"},{"name":"Centre for Antimicrobial Optimisation, Imperial College London, Hammersmith Hospital , Du Cane Road, Acton, London W12 0NN , UK"},{"name":"Imperial College Healthcare NHS Trust, Hammersmith Hospital , Du Cane Road, London W12 0HS , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"key":"2022120516522420100_dkac200-B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12012-011-9145-8","article-title":"The history and future of probenecid","volume":"12","author":"Robbins","year":"2012","journal-title":"Cardiovasc Toxicol"},{"key":"2022120516522420100_dkac200-B2","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.ejps.2014.04.004","article-title":"Inhibitory effects of p-aminohippurate and probenecid on the renal clearance of adefovir and benzylpenicillin as probe drugs for organic anion transporter (OAT) 1 and OAT3 in humans","volume":"59","author":"Maeda","year":"2014","journal-title":"Eur J Pharm Sci"},{"key":"2022120516522420100_dkac200-B3","article-title":"Sexually transmitted diseases treatment guidelines","volume":"64","author":"Frieden","year":"2015","journal-title":"MMWR"},{"key":"2022120516522420100_dkac200-B4","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S1473-3099(17)30724-7","article-title":"Classifying antibiotics in the WHO Essential Medicines List for optimal use\u2014be AWaRe","volume":"18","author":"Sharland","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"2022120516522420100_dkac200-B5","author":"WHO"},{"key":"2022120516522420100_dkac200-B6","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1093\/jac\/dkz122","article-title":"From \u2018OPAT\u2019 to \u2018COpAT\u2019: implications of the OVIVA study for ambulatory management of bone and joint infection","volume":"74","author":"Seaton","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"2022120516522420100_dkac200-B7","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1093\/jac\/dku517","article-title":"Outpatient parenteral antimicrobial therapy and antimicrobial stewardship: challenges and checklists","volume":"70","author":"Gilchrist","year":"2015","journal-title":"J Antimicrob Chemother"},{"key":"2022120516522420100_dkac200-B8","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions","volume":"12","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"2022120516522420100_dkac200-B9","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"28","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"2022120516522420100_dkac200-B10","first-page":"478","article-title":"Oral penicillin with and without benemid in the treatment of gonorrhea","volume":"38","author":"Jacoby","year":"1954","journal-title":"Am J Syph Gonorrhea Vener Dis"},{"key":"2022120516522420100_dkac200-B11","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0954-6111(08)80018-2","article-title":"The use of probenecid to increase the serum amoxycillin levels in patients with bronchiectasis","volume":"84","author":"Allen","year":"1990","journal-title":"Respir Med"},{"key":"2022120516522420100_dkac200-B12","first-page":"211","article-title":"Clinical pharmacological studies of amoxycillin: effect of probenecid","volume":"55","author":"Barbhaiya","year":"1979","journal-title":"Br J Vener Dis"},{"key":"2022120516522420100_dkac200-B13","doi-asserted-by":"crossref","first-page":"S250","DOI":"10.1093\/infdis\/129.Supplement_2.S250","article-title":"Single-dose oral therapy for uncomplicated gonorrhea: comparison of amoxicillin and ampicillin given with and without probenecid","volume":"129","author":"Karney","year":"1974","journal-title":"J Infect Dis"},{"key":"2022120516522420100_dkac200-B14","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/cpt1969106810","article-title":"Cephalexin: microbiological effects and pharmacologic parameters in man","volume":"10","author":"Meyers","year":"1969","journal-title":"Clin Pharmacol Ther"},{"key":"2022120516522420100_dkac200-B15","first-page":"1198","article-title":"Comparison of amoxicillin and ampicillin in single dose oral treatment of males with gonococcal urethritis","volume":"111","author":"Mitchell","year":"1974","journal-title":"Can Med Assoc J"},{"key":"2022120516522420100_dkac200-B16","doi-asserted-by":"crossref","first-page":"669","DOI":"10.3109\/00365548909021696","article-title":"Pharmacokinetic comparison of two models of endocarditis prophylaxis with amoxycillin","volume":"21","author":"Paulsen","year":"1989","journal-title":"Scand J Infect Dis"},{"key":"2022120516522420100_dkac200-B17","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1097\/00007435-198510000-00003","article-title":"Single-dose cefuroxime axetil in the treatment of uncomplicated gonorrhea: a controlled trial","volume":"12","author":"Reichman","year":"1985","journal-title":"Sex Transm Dis"},{"key":"2022120516522420100_dkac200-B18","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1136\/bmj.3.5824.441","article-title":"Cephalexin levels in human bile in presence of biliary tract disease","volume":"3","author":"Sales","year":"1972","journal-title":"Br Med J"},{"key":"2022120516522420100_dkac200-B19","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1093\/jac\/13.6.629","article-title":"The effect of probenecid on serum amoxycillin concentrations up to 18\u2005hours after a single 3\u2005g oral dose of amoxycillin: possible implications for preventing endocarditis","volume":"13","author":"Shanson","year":"1984","journal-title":"J Antimicrob Chemother"},{"key":"2022120516522420100_dkac200-B20","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/jac\/12.3.273","article-title":"Amoxycillin\/clavulanic acid: the effect of probenecid","volume":"12","author":"Staniforth","year":"1983","journal-title":"J Antimicrob Chemother"},{"key":"2022120516522420100_dkac200-B21","first-page":"443","article-title":"Single-dose oral treatment of gonorrhea in men and women, using ampicillin alone and combined with probenecid","volume":"47","author":"Bro-Jorgensen","year":"1971","journal-title":"Br J Vener Dis"},{"key":"2022120516522420100_dkac200-B22","first-page":"353","article-title":"Ampicillin serum levels and treatment results in gonorrhoea","volume":"49","author":"Eriksson","year":"1973","journal-title":"Br J Vener Dis"},{"key":"2022120516522420100_dkac200-B23","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jinf.2019.09.004","article-title":"Probenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers","volume":"80","author":"Everts","year":"2020","journal-title":"J Infect"},{"key":"2022120516522420100_dkac200-B24","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jinf.2021.05.037","article-title":"Probenecid effects on cephalexin pharmacokinetics and pharmacodynamics in healthy volunteers","volume":"83","author":"Everts","year":"2021","journal-title":"J Infect"},{"key":"2022120516522420100_dkac200-B25","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3109\/00365515209060641","article-title":"Influence of probenecid on serum penicillin concentration after oral administration of penicillin","volume":"4","author":"Frisk","year":"1952","journal-title":"Scand J Clin Lab Invest"},{"key":"2022120516522420100_dkac200-B26","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1128\/AAC.30.2.333","article-title":"Cefuroxime axetil for treatment of uncomplicated gonorrhea","volume":"30","author":"Gottlieb","year":"1986","journal-title":"Antimicrob Agents Chemother"},{"key":"2022120516522420100_dkac200-B27","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1111\/j.1476-5381.1969.tb08513.x","article-title":"Cephalexin: human studies of absorption and excretion of a new cephalosporin antibiotic","volume":"37","author":"Gower","year":"1969","journal-title":"Br J Pharmacol"},{"key":"2022120516522420100_dkac200-B28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3109\/inf.1980.12.issue-3.10","article-title":"Dicloxacillin and flucloxacillin twice daily with probenecid in staphylococcal infections: a clinical and pharmakokinetic evaluation","volume":"12","author":"Hedstr\u00f6m","year":"1980","journal-title":"Scand J Infect Dis"},{"key":"2022120516522420100_dkac200-B29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1365-2125.2011.04080.x","article-title":"Therapeutic drug monitoring of antimicrobials","volume":"73","author":"Roberts","year":"2012","journal-title":"Br J Clin Pharmacol"},{"key":"2022120516522420100_dkac200-B30","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1128\/AAC.01582-09","article-title":"Meropenem dosing in critically ill patients with sepsis receiving high-volume continuous venovenous hemofiltration","volume":"54","author":"Bilgrami","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"2022120516522420100_dkac200-B31","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1128\/AAC.38.5.931","article-title":"Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model","volume":"38","author":"Mouton","year":"1994","journal-title":"Antimicrob Agents Chemother"},{"key":"2022120516522420100_dkac200-B32","doi-asserted-by":"crossref","first-page":"4920","DOI":"10.1128\/AAC.49.12.4920-4927.2005","article-title":"Optimization of meropenem minimum concentration\/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa","volume":"49","author":"Tam","year":"2005","journal-title":"Antimicrob Agents Chemother"},{"key":"2022120516522420100_dkac200-B33","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1097\/MCC.0b013e3283021b3a","article-title":"Better outcomes through continuous infusion of time-dependent antibiotics to critically ill patients?","volume":"14","author":"Roberts","year":"2008","journal-title":"Curr Opin Crit Care"},{"key":"2022120516522420100_dkac200-B34","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1164\/rccm.201601-0024OC","article-title":"Continuous versus intermittent \u03b2-lactam infusion in severe sepsis. a meta-analysis of individual patient data from randomized trials","volume":"194","author":"Roberts","year":"2016","journal-title":"Am J Respir Crit Care Med"},{"key":"2022120516522420100_dkac200-B35","first-page":"w14368","article-title":"Prolonged administration of \u03b2-lactam antibiotics - a comprehensive review and critical appraisal","volume":"146","author":"Osthoff","year":"2016","journal-title":"Swiss Med Wkly"},{"key":"2022120516522420100_dkac200-B36","doi-asserted-by":"crossref","first-page":"l5337","DOI":"10.1136\/bmj.l5337","article-title":"Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study","volume":"4","author":"Skoog St\u00e5hlgren","year":"2019","journal-title":"BMJ"},{"key":"2022120516522420100_dkac200-B37","doi-asserted-by":"crossref","first-page":"14887","DOI":"10.1111\/bcp.14887","article-title":"Population pharmacokinetics of free flucloxacillin in patients treated with oral flucloxacillin plus probenecid","volume":"87","author":"Drennan","year":"2021","journal-title":"Br J Clin Pharmacol"},{"key":"2022120516522420100_dkac200-B38","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1086\/340056","article-title":"Once-daily intravenous cefazolin plus oral probenecid is equivalent to once-daily intravenous ceftriaxone plus oral placebo for the treatment of moderate-to-severe cellulitis in adults","volume":"34","author":"Grayson","year":"2002","journal-title":"Clin Infect Dis"},{"key":"2022120516522420100_dkac200-B39","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2165\/00003088-198106020-00004","article-title":"Clinical pharmacokinetics of probenecid","volume":"6","author":"Cunningham","year":"1981","journal-title":"Clin Pharmacokinet"},{"key":"2022120516522420100_dkac200-B40","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/2110-5820-2-35","article-title":"Does \u03b2-lactam pharmacokinetic variability in critically ill patients justify therapeutic drug monitoring? A systematic review","volume":"2","author":"Sime","year":"2012","journal-title":"Ann Intensive Care"},{"key":"2022120516522420100_dkac200-B41","doi-asserted-by":"crossref","first-page":"E335","DOI":"10.1016\/S2589-7500(19)30131-1","article-title":"Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin\u202f: a first-in-human evaluation in healthy volunteers","volume":"7","author":"Rawson","year":"2019","journal-title":"Lancet Digit Heal"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/77\/9\/2364\/47589437\/dkac200.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/77\/9\/2364\/47589437\/dkac200.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T15:08:32Z","timestamp":1670252912000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/77\/9\/2364\/6612118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,21]]},"references-count":41,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,6,21]]},"published-print":{"date-parts":[[2022,8,25]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkac200","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,9,1]]},"published":{"date-parts":[[2022,6,21]]}}}