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Current fluconazole dosing regimens in critically ill adults result in under-exposure during early therapy
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  • Indy Sandaradura,
  • Deborah Marriott,
  • Richard Day,
  • Ross Norris,
  • Edna Pang,
  • Sophie Stocker,
  • Stephanie Reuter Lange
Indy Sandaradura
Westmead Hospital
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Deborah Marriott
University of New South Wales
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Richard Day
St Vincent's Hopsital, Australia
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Ross Norris
St Vincent’s Hospital
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Edna Pang
St Vincent’s Hospital
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Sophie Stocker
University of Sydney
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Stephanie Reuter Lange
University of South Australia
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Aim: To evaluate current fluconazole dosing regimens against established pharmacodynamic targets in critically ill adults. Methods: Data from critically ill adults treated with fluconazole (n=30) were used to develop a population pharmacokinetic model. Probability of target attainment (PTA) (fAUC24/MIC >100) was determined from simulations for four previously proposed dosing regimens; (i) 400 mg once daily (ii) a 800 mg loading dose followed by 400 mg once daily, (iii) 400 mg twice daily and (iv) a 12 mg/kg loading dose followed by 6 mg/kg once daily. The effect of body weight (40, 70, 120 kg) and renal function (continuous renal replacement therapy (CRRT), 20, 60, 120, 180 mL/min glomerular filtration rates) on PTA was assessed. Results: Early (0-48 h) fluconazole target attainment for patients with Minimum Inhibitory Concentrations (MIC) of 2 mg/L was highly variable. PTA was highest with an 800 mg loading dose for underweight (40 kg) patients and with a 12 mg/kg loading dose for the remainder. End-of-treatment PTA was highest with 400 mg twice daily maintenance dosing for patients who were under- or normal- weight and 6 mg/kg maintenance dosing for overweight (120 kg) patients. None of the fluconazole regimens reliably attained early targets for MICs of ≥4 mg/L. Conclusion: Current fluconazole dosing regimens do not achieve adequate early target attainment in critically ill adults, particularly in those who are overweight, have higher renal function or are undergoing CRRT. Current fluconazole dosing strategies are generally inadequate to treat organisms with an MIC of ≥4 mg/L.