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Pharmacokinetic-pharmacodynamic target attainment and clinical outcomes in patients treated with oral flucloxacillin plus probenecid
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  • Philip Drennan,
  • Jared Green,
  • Sharon Gardiner ,
  • Sarah Metcalf,
  • Carl Kirkpatrick,
  • Richard Everts,
  • Mei Zhang,
  • Stephen Chambers
Philip Drennan
Royal Prince Albert Hospital
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Jared Green
Christchurch Hospital
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Sharon Gardiner
Christchurch Hospital
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Sarah Metcalf
Christchurch Hospital
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Carl Kirkpatrick
Monash University
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Richard Everts
Nelson Bays Primary Health
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Mei Zhang
University of Otago
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Stephen Chambers
University of Otago Christchurch
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Abstract

Aim Oral flucloxacillin may be co-administered with probenecid to increase flucloxacillin concentrations and increase attainment of pharmacokinetic-pharmacodynamic (PK-PD) targets. The aims of this study were to describe outcomes of patients treated with oral flucloxacillin plus probenecid as follow-on therapy from initial intravenous treatment, and to identify optimal dosing regimens when treating infections caused by susceptible Gram-positive organisms. Methods We performed a prospective observational study of adults treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly (with food) for proven or probable staphylococcal infections. We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, in order to estimate probability of PK-PD target attainment (fT>MIC), and used Monte Carlo simulation to explore optimal dosing regimens. Results The 45 patients (73% male) had a median (range) age of 49 years (20 – 74), weight of 90 kg (59 – 167), fat free mass (Janmahasatian) of 65 kg (38 – 89) and eGFR (CKD-EPI) of 89 mL/min/1.73m2 (41 – 124). The most common infections were osteomyelitis (n=18, 40%) and septic arthritis (n=12, 27%). Forty patients (89%) were cured 30 days after completion of therapy. 10 (22%) experienced nausea which did not require treatment alternation. Free flucloxacillin clearance depended on allometrically-scaled fat free mass, and increased by 1% for each unit increase in eGFR. Conclusion Oral flucloxacillin and probenecid was well-tolerated and efficacious. Patients with higher fat free mass and eGFR may require four times daily dosing and/or therapeutic drug monitoring to ensure PK-PD target attainment.

Peer review status:ACCEPTED

19 Dec 2020Submitted to British Journal of Clinical Pharmacology
21 Dec 2020Submission Checks Completed
21 Dec 2020Assigned to Editor
28 Dec 2020Reviewer(s) Assigned
14 Jan 2021Review(s) Completed, Editorial Evaluation Pending
22 Jan 2021Editorial Decision: Revise Major
22 Apr 20211st Revision Received
23 Apr 2021Submission Checks Completed
23 Apr 2021Assigned to Editor
23 Apr 2021Review(s) Completed, Editorial Evaluation Pending
02 May 2021Editorial Decision: Accept