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

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.

Antimicrobial stewardship: are we failing in cross-specialty clinical engagement?

BACKGROUND: Antimicrobial resistance (AMR) is a public health priority and leading patient safety issue. Globally, antimicrobial stewardship (AMS) has been integral in promoting therapeutic optimization whilst minimizing harmful antimicrobial use. A cross-sectional, observational study was undertaken to investigate the coverage of AMS and antibacterial resistance across clinical scientific conferences in 2014, as a surrogate marker for current awareness and attributed importance. METHODS: Clinical specialties were identified, and the largest corresponding clinical scientific/research conferences in 2014 determined (i) within the UK and (ii) internationally. Conference characteristics and abstracts were interrogated and analysed to determine those related to AMS and AMR. Inter-specialty variation was assessed using χ(2) or Fisher's exact statistical analysis. RESULTS: In total, 45 conferences from 23 specialties were analysed representing 59,682 accepted abstracts. The UK had a significantly greater proportion of AMS-AMR-related abstracts compared with international conferences [2.8% (n = 221/7843) compared with 1.8% (n = 942/51,839); P < 0.001]. Infection conferences contained the greatest proportion of AMS-AMR abstracts, representing 20% (732/3669) of all abstracts [UK 66% (80/121) and international 18% (652/3548); P < 0.0001]. AMS-AMR coverage across all general specialties was poor [intensive care 9% (116/1287), surgical 1% (8/757) and medical specialties 0.64% (332/51,497)] despite high usage of antimicrobials across all. CONCLUSIONS: Despite current AMS-AMR strategies being advocated by infection specialists and discussed by national and international policy makers, AMS-AMR coverage remained limited across clinical specialty scientific conferences in 2014. We call for further intervention to ensure specialty engagement with AMS programmes and promote the AMR agenda across clinical practice.

Homogeneity of antimicrobial policy, yet heterogeneity of antimicrobial resistance: antimicrobial non-susceptibility among 108,717 clinical isolates from primary, secondary and tertiary care patients in London.

OBJECTIVES: We examined the 4 year trend in antimicrobial susceptibilities and prescribing across levels of care at two London teaching hospitals and their multisite renal unit, and for the surrounding community. METHODS: Laboratory and pharmacy information management systems were interrogated, with antimicrobial use and susceptibilities analysed between hospitals, within hospitals and over time. RESULTS: A total of 108,717 isolates from 71,687 patients were identified, with significant differences (at P < 0.05) in antimicrobial susceptibility between and within hospitals. Across the 4 years, rates of ESBL-/AmpC-producing Enterobacteriaceae ranged from 6.4% to 10.7% among community isolates, 17.8% to 26.9% at ward level and 25.2% to 52.5% in critical care. Significant variations were also demonstrated in glycopeptide-resistant enterococci (ward level 6.2%-17.4%; critical care 21.9%-56.3%), MRSA (ward level 18.5%-38.2%; critical care 12.5%-47.9%) and carbapenem-resistant Pseudomonas spp. (ward level 8.3%-16.9%; critical care 19.9%-53.7%). Few instances of persistently higher resistance were seen between the hospitals in equivalent cohorts, despite persistently higher antimicrobial use in Hospital 1 than Hospital 2. We found significant fluctuations in non-susceptibility year on year across the cohorts, but with few persistent trends. CONCLUSIONS: The marked heterogeneity of antimicrobial susceptibilities between hospitals, within hospitals and over time demands detailed, standardized surveillance and appropriate benchmarking to identify possible drivers and effective interventions. Homogeneous antimicrobial policies are unlikely to continue to be suitable as individual hospitals join hospital networks, and policies should be tailored to local resistance rates, at least at the hospital level, and possibly with finer resolution, particularly for critical care.