Audit of antimicrobial stewardship in medical inpatients in Waikato, New Zealand 2021.

AIMS: Given the threat of rising antimicrobial resistance (AMR), 10 audit standards were selected to audit antimicrobial stewardship (AMS) in secondary care to assess guideline adherence and establish quality improvement initiatives in antimicrobial prescribing. METHODS: Patients were included if they received intravenous (IV) antibiotics across seven medical wards in Waikato or Thames hospitals, New Zealand, in November 2021. Audit standards were defined from the regional antimicrobial prescribing policy and adult antimicrobial guidelines. RESULTS: In total, 205 patients were audited. Microbiological sampling standards were met in 87 of 126 occasions (69.0%). Antimicrobial choices adhered to guidelines in 89 of 163 patients (54.6%), where guidelines were available. Documentation of antimicrobial indications in the medical notes and antimicrobial review at 48 to 72 hours met the standards at over 90%. Only 2 of 13 patients (15.4%) receiving piperacillin/tazobactam or a carbapenem were discussed with Infectious Diseases (ID). Documentation of indications and durations on paper-based medication charts was infrequent, around 12%. Evaluating for health equity, similar results were observed for Maori and non-Maori. CONCLUSIONS: Our audit identified specific areas for AMS quality improvement initiatives. Regular audit should become an essential element of the New Zealand AMS strategy. We believe increased AMS resources are required.

Population pharmacokinetics of free flucloxacillin in patients treated with oral flucloxacillin plus probenecid.

Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination. METHODS: We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly for proven or probable staphylococcal infections. Steady-state mid-dose-interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration). RESULTS: Flucloxacillin disposition was best described by a 1-compartment model with a lag time and first-order absorption. Free flucloxacillin clearance depended on probenecid, allometrically-scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid. CONCLUSION: The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6-hourly dosing to achieve PK/PD targets. The regimen was well-tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.

In healthy volunteers, taking flucloxacillin with food does not compromise effective plasma concentrations in most circumstances.

It is usually recommended that flucloxacillin is given on an empty stomach. The aim of this study was to compare total and free flucloxacillin concentrations after oral flucloxacillin, given with and without food, based on contemporary pharmacokinetic and pharmacodynamic targets. Flucloxacillin 1000 mg orally was given to 12 volunteers, after a standardised breakfast and while fasting, on two separate occasions. Flucloxacillin concentrations over 12 hours were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, and pharmacodynamic endpoints related to target concentration achievement, were compared in the fed and fasting states. For free flucloxacillin, the fed/fasting area under the concentration-time curve from zero to infinity (AUC0-∞) ratio was 0.80 (p<0.01, 90% CI 0.70-0.92), the peak concentraton (Cmax) ratio 0.51 (p<0.001, 0.42-0.62) and the time to peak concentration (Tmax) ratio 2.2 (p<0.001, 1.87-2.55). The ratios for total flucloxacillin concentrations were similar. The mean (90% CI) fed/fasting ratios of free concentrations exceeded for 30%, 50% and 70% of the first 6 hours post-dose were 0.74 (0.63-0.87, fed inferior p<0.01), 0.95 (0.81-1.11, bioequivalent) and 1.15 (0.97-1.36, fed non-inferior), respectively. Results for 8 hours post-dose and those predicted for steady state were similar. Comparison of probability of target attainments for fed versus fasting across a range of minimum inhibitory concentrations (MICs) were in line with these results. Overall, this study shows that food reduced the AUC0-∞ and Cmax, and prolonged the Tmax of both free and total flucloxacillin concentrations compared with the fasting state, but achievement of free concentration targets associated with efficacy was in most circumstances equivalent. These results suggest that taking flucloxacillin with food is unlikely to compromise efficacy in most circumstances.