Dataset Information

Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections.

ABSTRACT: In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20-5.32) mg/L p < 0.001, 180 min 2.2 (1.58-3.25) mg/L p < 0.001; free: 45 min 1.15 (0.88-1.42) mg/L p < 0.001, 180 min 0.5 (0.35-0.76) mg/L p < 0.001). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

SUBMITTER: Wilson RC

PROVIDER: S-EPMC11271292 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections.

Wilson Richard C RC Riezk Alaa A Arkell Paul P Ming Damien D Armiger Ryan R Latham Victoria V Gilchrist Mark J MJ Märtson Anne-Grete AG Hope William W WW Holmes Alison H AH Rawson Timothy M TM

Scientific reports 20240721 1

In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four time ...[more]

PMID: 39034340

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Project description:Gram-negative bacterial infections pose a significant challenge due to two major resistance elements, including the impermeability of the outer membrane and the overexpression of efflux pumps, which contribute to antibiotic resistance. Additionally, the coexistence of multispecies superbugs in mixed species biofilms further complicates treatment, as these infections are refractory to most antibiotics. To address this issue, combining obsolete antibiotics with non-antibiotic adjuvants that target bacterial membranes has shown promise in combating antibacterial resistance. However, the clinical translation of this cocktail therapy has been hindered by the toxicity associated with these membrane active adjuvants, mainly due to a limited understanding of their structure and mechanism of action. Towards this goal, herein, we have designed a small molecular adjuvant by tuning different structural parameters, such as the balance between hydrophilic and hydrophobic groups, spatial positioning of hydrophobicity and hydrogen bonding interactions, causing moderate membrane perturbation in bacterial cells without any toxicity to mammalian cells. Moderate membrane perturbation not only enhances the internalization of antibiotics, but also increases the intracellular concentration of drugs by hampering the efflux machinery. This revitalises the efficacy of various classes of antibiotics by 32-512 fold, without inducing toxicity. The leading combination not only exhibits potent bactericidal activity against A. baumannii biofilms but also effectively disrupts mature multispecies biofilms composed of A. baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which is typically resistant to most antibiotics. Importantly, the combination therapy demonstrates good biocompatibility and excellent in vivo antibacterial efficacy (>99% reduction) in a skin infection model of A. baumannii. Interestingly, A. baumannii shows reduced susceptibility to develop resistance against the leading combination, underscoring its potential for treating multi-drug resistant infections.

Dataset Information

Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections.

Publications

Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections.

Similar Datasets

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