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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. [ABSTRACT FROM AUTHOR]

Invasive fungal infections (IFI) are a common infection-related cause of death in immunocompromised patients. Approximately 10 million people are at risk of developing invasive aspergillosis annually. Detailed study of the pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal drugs has resulted in a better understanding of optimal regimens for populations, drug exposure targets for therapeutic drug monitoring, and establishing in vitro susceptibility breakpoints. Importantly, however, each is an example of a "one size fits all strategy", where complex systems are reduced to a singularity that ensures antifungal therapy is administered safely and effectively at the level of a population. Clearly, such a notion serves most patients adequately but is completely counter to the covenant at the centre of the clinician–patient relationship, where each patient should know whether they are well-positioned to maximally benefit from an antifungal drug. This review discusses the current therapy of fungal infections and areas of future research to maximise the effectiveness of antifungal therapy at an individual level. [ABSTRACT FROM AUTHOR]

Background: There is a need to examine the impact of increasingly prevalent antibiotic shortages on patient outcomes and on the emergence and spread of antimicrobial resistance (AMR)., Objectives: To: 1) assess patterns and causes of shortages, 2) investigate the effect of shortages on health systems and patient outcomes, and 3) identify strategies for forecasting and managing shortages., Data Sources: PubMed/MEDLINE, EMBASE, Scopus, and Web of Science., Study Eligibility Criteria: Studies published in English during January 2000-July 2023., Participants: Healthcare, policy and strategic teams managing and responding to shortages. Patient populations (adult and children) affected by shortages., Interventions: Strategies, policies, and mitigation options for managing and responding to antibiotic drug shortages., Risk of Bias: Methodological quality of included studies was reviewed using the most appropriate tool from Joanna Briggs Institute critical appraisal tool for each study design., Methods: Data synthesis was qualitative and quantitative using descriptive statistics., Results: The final analysis included 74 studies (61/74, 82.4% high-income countries). Shortages were most reported for piperacillin-tazobactam (21/74, 28.4%) with most of the reported antibiotics being in the WHO Watch category (27/54, 51%). Frequent cause of shortages was disruption in manufacturing including supply of active pharmaceutical ingredient and raw materials. Clinical implications of shortages included increased length of hospital stay, treatment failure after using inferior alternative agents and negative impact on antimicrobial stewardship programmes (AMS). Robust economic impact analysis of shortages is unavailable. Successfully reported mitigation strategies were driven by AMS and infectious diseases teams in hospitals., Conclusions: Antibiotic shortages are directly or indirectly driven by economic viability and reliance on single source ingredients. The limited data on clinical outcomes indicates mixed effect with some infections becoming more difficult to treat, though there is no robust data on the impact of shortages on AMR. The mitigation strategies to manage shortages rely heavily on AMS teams., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)