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Measuring flucytosine concentrations - TDM

Measuring flucytosine concentrations - TDM. David W. Denning The University of Manchester. Intended Learning Outcomes. To understand the pharmacokinetics of flucytosine, relevant to under- and over-dosing. To appreciate the different methods used for measuring flucytosine concentrations.

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Measuring flucytosine concentrations - TDM

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  1. Measuring flucytosine concentrations - TDM David W. Denning The University of Manchester

  2. Intended Learning Outcomes To understand the pharmacokinetics of flucytosine, relevant to under- and over-dosing To appreciate the different methods used for measuring flucytosine concentrations To know how to interpret flucytosine concentrations in the clinical setting

  3. Flucytosine – key facts • Flucytosine is: • A small water soluble molecule • Is almost completely excreted in the urine • Penetrates all tissues, including CSF, vitreous and urine • Does not accumulate(except in renal failure) so is usually dosed 4x daily • Is converted slowly into 5-fluorouracil in the body, if present at high concentrations for several days

  4. Flucytosine dosing Standard dosing is 25 mg/kg every 6 hours So a 50 kg woman would receive 1.25 g 4x a day (a total of 5 g per day) A 10 kg child would receive 250 mg 4x a day A 100 kg adult would receive 2.5 g 4x a day (a total of 10 g per day) Olderliterature and current data sheets recommend 37.5 - 50 mg/kg every 6 hours - this is unnecessarily high

  5. Flucytosine dosing and renal failure • Dosing frequency adjustment in renal dysfunction • Creatinine clearance <40 to >20 ml /min: 25 mg/kg every 12 hours • Creatinine clearance <20 to >10 ml /min: 25 mg/kg every 24 hours • Creatinine clearance <10 ml /min: an initial single dose of 25 mg/kg; subsequent doses should be calculated according to the results of regular monitoring of the serum concentration of the drug, which should not be allowed to exceed 80 micrograms/ml • Blood levels of 25 to 50 micrograms/ml (mg/L) are normally effective

  6. 20.5% had THERAPEUTIC levels 40.5% had LOW levels Neonates had high levels more frequently than non-neonates 5.1% had UNDETECTABLE levels 60.8% vs 37.3%; P <0.001 38.9% had HIGH levels Pasqualotto et al, J AntimicrobChemother 2007; 59:791

  7. Indications for flucytosine TDM • Not usually required except in: • Renal failure and impairment • Neonates • Patients on haemofiltration and/or dialysis • Patients on ECMO or other filters • Patients with very short guts (usually on long term total parenteral nutrition) • In long term therapy to check appropriate oral dosing Ashbeeet al, J AntimicrobChemother 2014; 69:1162

  8. Target flucytosine concentrations Too low Too high Ideal >100 mg/L peak <20 mg/L trough Peak = 50-100 mg/L Trough = 20-40 mg/L Ashbeeet al, J AntimicrobChemother 2014; 69:1162

  9. Flucytosine assay methods • Bioassay • High-pressure liquid chromatography (HPLC) • Gas-liquid chromatography • Fluorometry • Enzymatic methods

  10. Flucytosine bioassay • Most patients on dual antifungal therapy • Different bioassay organisms are used which are resistant to other antifungals – so knowledge of the other drugs important. Amphotericin B diffusion poor in agar, so not a reading problem • Overnight incubation • Dynamic range 12.5-200 mg/L

  11. Flucytosine TDM summary Recommendations from the British Society for Medical Mycology Recent evidence from large scale trials in Africa in cryptococcal meningitis in AIDS indicate that these patients do not need TDM – check dosing frequency in renal impairment and failure Ashbeeet al, J AntimicrobChemother 2014; 69:1162

  12. Thank You

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