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

Abstract

Objectives To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral β-lactams. Methods 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. Results 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. Conclusions 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.

A low-volume LC/MS method for highly sensitive monitoring of phenoxymethylpenicillin, benzylpenicillin, and probenecid in human serum

“…[4][5][6] Despite the imperative to address rising resistance, delivering higher doses of oral penicillin causes challenges with saturable drug absorption and gastrointestinal side effects. [7][8][9] Consequently, achieving an optimal pharmacokinetic/ pharmacodynamic (PK/PD) prole through higher doses is not always feasible. [7][8][9] Exploring the potential of administering enhanced forms of targeted, oral narrow-spectrum medications presents an attractive avenue within regional antimicrobial stewardship initiatives.…”

“…[7][8][9] Consequently, achieving an optimal pharmacokinetic/ pharmacodynamic (PK/PD) prole through higher doses is not always feasible. [7][8][9] Exploring the potential of administering enhanced forms of targeted, oral narrow-spectrum medications presents an attractive avenue within regional antimicrobial stewardship initiatives. This approach may also prevent the necessity for prolonged intravenous treatment regimens in specic cases.…”

“…[7][8][9] Probenecid, p-(di-n-propylsulphamyl)-benzoic acid, exhibits potent inhibition of renal organic anion transporters, crucial players in the excretion of organic agents like penicillin. 8,[10][11][12] Consequently, co-administering probenecid signicantly reduces the renal clearance of penicillin, resulting in substantial increases in serum exposure. In simpler terms, combining probenecid with penicillin allows the attainment of comparable pharmacokinetic/pharmacodynamic (PK/PD) targets with lower penicillin doses, thereby enhancing therapeutic efficacy at a specied dosage level.…”

“…In simpler terms, combining probenecid with penicillin allows the attainment of comparable pharmacokinetic/pharmacodynamic (PK/PD) targets with lower penicillin doses, thereby enhancing therapeutic efficacy at a specied dosage level. 8,[10][11][12] Optimizing antibiotic dosing is pivotal in curbing the emergence of drug-resistant bacteria and potentially reducing unwanted side effects. One effective approach is therapeutic drug monitoring (TDM), a tailored strategy for individualized needs.…”

“…This approach may also prevent the necessity for prolonged intravenous treatment regimens in specific cases. 7–9…”