Critically evaluate the role of fluconazole in the management of the critically ill patient.
Fluconazole is an azole anti-fungal agent that has good bioavailability (can be administered enterally). It has a proven role in treatment of candidal (skin/mucosal/systemic) and cryptococcal infections as an alternative to amphotericin. It has much less activity against other fungal pathogens (e.g. aspergillus species). Usual duration of therapy is until evidence of active fungal infection has subsided. Specific anti-fungal sensitivities may be required. Usually fluconazole is very well tolerated, but observed adverse effects include an increase in trans-aminase enzymes, other gastrointestinal & haematological problems, adrenal suppression, and rare cases of QT prolongation and torsades de pointes. As fluconazole is predominantly renally excreted as the unchanged drug, dose adjustment is required with renal impairment. Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP2C, and as such may increase concentrations of various drugs (e.g. warfarin, theophylline, cyclosporin, oral hypoglycaemic agents, phenytoin, and midazolam). Recent interest has surrounded empiric therapy in patients with septic shock. One small prospective randomised study suggested improved 30 day and hospital mortality when 200 mg fluconazole was administered daily to patients with septic shock (due to either intra-abdominal source or nosocomial pneumonia) until resolution of shock. The majority of the benefits were attributable to the group with intra-abdominal sepsis. (Jacobs S et al. Crit Care Med 2003 31(7):1938-46)
Fluconazole also has a role in prophylactic therapy (e.g. HIV patients) and in prolonged maintenance therapy (e.g. HIV patients with cryptococcal meningitis or recurrent oropharyngeal candidiasis).
What do they mean, "critically evaluate fluconazole"?
Functionally, this question is analogous to "critically evaluate Thurday".
In contrast to other questions of this sort, which discuss the evidence behind some controversial practice or incompletely accepted study, this question asks about an azole antifungal drug.
Broadly, a summary of antifungal pharmacology is available to help answer similar quetsions in the future. It is difficult to approach this according to the classical template, but from the college answer it would seem that the examiners would have gladly accepted a list of uses for fluconazole, and some cautionary remarks about its elimination and interactions.
Rationale for use (...Indications for use?)
Rex, John H., M. G. Rinaldi, and M. A. Pfaller. "Resistance of Candida species to fluconazole." Antimicrobial Agents and Chemotherapy 39.1 (1995): 1.
Shorr, Andrew F., et al. "Fluconazole prophylaxis in critically ill surgical patients: A meta-analysis*." Critical care medicine 33.9 (2005): 1928-1935.
Sinnollareddy, Mahipal, et al. "Pharmacokinetic evaluation of fluconazole in critically ill patients." Expert opinion on drug metabolism & toxicology 7.11 (2011): 1431-1440.
Jacobs, Sydney, et al. "Fluconazole improves survival in septic shock: a randomized double-blind prospective study." Critical care medicine 31.7 (2003): 1938-1946.
Zervos, Emmanuel E., et al. "Fluconazole increases bactericidal activity of neutrophils through non-cytokine-mediated pathway." Journal of Trauma and Acute Care Surgery 41.3 (1996): 465-470.
Schuster, Mindy G., et al. "Empirical Fluconazole versus Placebo for Intensive Care Unit PatientsA Randomized Trial." Annals of internal medicine 149.2 (2008): 83-90.