Might Confounding Factors Have an Effect on Suboptimal Dosing of Fluconazole in Critically Ill Patients?

LETTER

In a recent issue of Antimicrobial Agents and Chemotherapy, Muilwijk et al. evaluated the fluconazole pharmacokinetics (PK) and dosing in critically ill patients and concluded that there is wide variability in pharmacokinetic characteristics among intensive care unit (ICU) patients (1). We read this article with great interest and particularly agree with the authors’ comments on the impact of fluconazole pharmacokinetics compared with echinocandins in head-to-head comparison studies (2, 3). However, we think that some confounding factors should be taken into consideration during the pharmacokinetic analysis of the results.

Fluconazole is frequently involved in drug interactions due to its association with cytochrome P450 (CYP) enzymes. Yu et al. stated that 92.3% of the hospitalized patients treated with fluconazole had a potential interaction (4). In the Muilwijk et al. (1) study, it was stated that no interaction was observed with fluconazole. However, considering the use of many drugs in intensive care patients, it is a concern that significant interactions may have been ignored and fluconazole blood levels may also be affected by the interactions (5, 6).

In addition, patients had a median weight of 82 kg (up to 120 kg) and a median body mass index (BMI) of 26.8 kg/m² (up to 38.6 kg/m²) in this study. These values, ranging from excessive body weight to extreme obesity, may cause changes in the volume of distribution and hence the concentration of drugs, including fluconazole (7). It is important to evaluate the effect of body weight, which is one of the factors that may affect fluconazole pharmacokinetics on serum concentration and efficacy of fluconazole.

Critical illness has a potential for changing PK profiles of drugs, particularly in those that are mainly eliminated via kidney such as fluconazole (8). In the study by Muilwijk et al. (1), it was stated that kidney functions were evaluated by using one of the Cockcroft-Gault (stated in the method) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (Table 1 in reference 1) formulas. Although those are frequently used estimators for renal function (even the CKD-EPI equation which is most recently developed), they were developed in non-ICU patients and not validated in the ICU patient population (9).

Another issue was that it was unclear in the scatterplot (Fig. 1 in reference 1) whether the doses were given on the day of sampling or whether the doses were the total doses since the treatment was initiated. As can be seen in Table 1 of reference 1 in regard to fluconazole daily doses, frequent dose changes were undertaken during treatment.

In view of the comments above, we believe that the results of this study do not provide a strong level of evidence for fluconazole dose implementation in clinical practice, and studies in which the mentioned confounding factors are included and tested are required. The impact of this study would be greatly strengthened by the inclusion of a detailed explanation of drug interactions and effect of body weight.