Question 3

College Answer

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).

Discussion

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.

Definition

• Fluconazole is a triazole antifungal agent.
• Its effect is exerted by its inhibition of ergosterol synthesis in the fungal cell wall.

Rationale for use (...Indications for use?)

• Fluconazole is an anti-yeast antifungal. It has good penetration into tissues, and is active against most forms of Candida albicans, as well as Cryptococcus.
• Indications for IV fluconazole include systemic candidiasis with candidaemia and cryptococcal meningitis.
• Indications also include severe localised infections, or infections of critical organs (eg. heart valves).

Advantages

• Most species of Candida albicansare susceptible
• For susceptible organisms, fluconazole is at least equal (if not superior) to amphotericin.
• It has good oral bioavailability
• It has relatively low toxicity
• It seems to enhance the bactericidal activity of neutrophils

Disadvantages

• Most species of non-albicans Candida and most other fungi are not suceptible.
  • If one were called upon to mindlessly repeat rote-learned names of fluconazole-resistant yeasts, one would say C.kruzei, C.glabrata, and C.parapsilosis
• Fluconazole needs adjustment in renal failure
• It interacts with numerous other drugs by inhibiting the CYP450 system of metabolism
• It may cause LFT derangement and QT prolongation.

Evidence

• Fluconazole prophylaxis for surgical patients does not reduce mortality.
• Fluconazole as a co-antibiotic in septic shock seems to reduce mortality according to one small trial.
• In 2008, a similar trial compared empirical fluconazole to placebo, and was terminated due to a lack of primary endpoint difference (i.e. placebo was equally effective)

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.