Fluconazole and Obesity Dose Adjustment

Description	Reference
Candidiasis: 12mg/kg x1 load, then 6mg/kg q24h (TBW)   Doses up to 1200 mg daily have been reported in the literature for Cryptococcus meningitis - In critically ill, esp with CrCl > 50, higher doses may be warranted to achieve PK/PD target of fAUC/MIC > 100, esp if MIC > 2 Candida spp - Consider TDM for severe infections   *TBW = Total body weight = Actual body weight	SHC Healthcare 2020 http://med.stanford.edu/bugsanddrugs/guidebook/_jcr_content/main/panel_builder_584648957/panel_0/download_1186887683/file.res/SHC%20Obesity%20Dosing%20Guide.pdf
Population PK models devised in patient populations with BMI classifications of obese (30–40 kg/m2 ) and morbidly obese (.40 kg/m2 ) suggest that fluconazole should be dosed based on total body weight (12 mg/kg loading dose, followed by 6 mg/kg/day maintenance) adjusted for renal function.	Pea & Lewis. Overview of antifungal dosing in invasive candidiasis. J Antimicrob Chemother 2018; 73 Suppl 1: i33–i43
A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter   The results of this study suggest that a higher fixed fluconazole dose (i.e., 400 mg daily) is required in these patients when they are infected by less susceptible Candida spp. (MIC of 2 mg/liter). Our results show that a loading dose of 12 mg/kg followed by a maintenance dose of 6 or 12 mg/kg/day is required to achieve either the low or high PK/PD target. Finally, loading doses should be weight based, whereas maintenance doses should be prescribed according to renal function.	Alobaid et al. Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients. Antimicrob Agents Chemother 60:6550 –6557. doi:10.1128/AAC.01088-16 https://aac.asm.org/content/aac/60/11/6550.full.pdf
Larger dose possibly required but data insufficient for a firm recommendation   Case reports suggest larger dose required in critically ill obese patients. Recent paper suggests that weight based dosing (12 mg/kg load, then 6 mg/kg/day using total BW) reaches desired PK/PD targets more reliably than fixed dosing; clinical validation required.	Sanford apps
·      Obese patients are less likely to achieve the dose/MIC and AUC/MIC ratios of fluconazole that have been previously associated with decreased mortality. ·      Fluconazole should be dosed based on total body weight to achieve the AUC/MIC ratios that have previously been associated with favorable responses. ·      Fluconazole has a favorable adverse effect profile.   Doses of up to 1200 mg/day for two weeks have been described in the literature – for cryptococcal meningitis U/L HIV positive patients in Malawi as standard dose of 800 mg daily is less efficacious there – NOT obese population. [https://pubmed.ncbi.nlm.nih.gov/25375145/]	Payne & Hall. Dosing of antifungal agents in obese people.  Expert Rev Anti Infect Ther. 2016;14(2):257-67

Accessed by JCK Ho on 29.11.2020