Strangely, the raw untreated pharmacology does occasionally come up in this otherwise very pragmatic clinical-based exam. Antifungal pharmacology has come up as a broad theme in Question 13 from the first paper of 2010, albeit briefly. More disturbingly, in Question 3 from the first paper of 2004 the college demanded some significant discussion of fluconazole. This will never happen again, as we now have the primary exam to take care of all those sorts of SAQs. Modern questions will most likely take the shape of Question 21 from the second paper of 2022, where candidates were asked about situations where an azole drug would not be appropriate
Antifungals are discussed in full by Russell E. Lewis in his 2011 article for the Mayo Clinic Proceedings ("Current Concepts in Antifungal Pharmacology"). However, my main source for this information was Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Ed.
All molecule images are from Wikimedia Commons.
The drugs below are presented by class (in order of chronological appearance).
In brief summary:
Polyenes weaken fungal cell walls by binding to ergosterol. The cell wall becomes permeable, and the fungal cells swell with fluid and die. There are probably about 200 different polyenes with some sort of antifungal activity.
Griseofulvin is the only member of this group. It is essentially colchicine for fungi: it binds to tubulin, impairing synthesis of microtubules and thus preventing the formation of the mitotic spindle.
Flucytosine is the only real member of this group. Fungi deaminate flucytosine to 5-fluorouracil which results in impaired DNA synthesis.
Azoles in general inhibit 14-α-sterol demethylase, an enzyme involved in the synthesis of ergosterol for the fungal cell membrane. This results in the accumulation of 14-α-methylsterols, the presence of which disrupts the organisation and integrity of fungal cell walls and impairs membrane-bound enzymes.
Advantages
Disadvantages
Evidence for (against) routine post-operative use
The major generational change with azoles has been slower metabolism and less effect on human ergosterol synthesis.
Question 21 from the second paper of 2022 asked the candidates to "list four situations where an azole would NOT be appropriate first line empiric treatment". It would have probably been a waste of those two marks to simply list four organisms that are typically expected to be resistant to azole drugs. Still, in case the reader is wondering, there's a list of these:
Furthermore, non-albicans Candida species are usually resistant to first generation azoles, such as fluconazole. For a more detailed list of azole resistances, a huge list is available in Van Rhijn et al (2021). But this is probably not what the examiners wanted, as that list of fungi is a gallery of fairly rare pathogens and to be able to list them off the top of your head is unlikely to be a necessary characteristic for a passable intensivist. Another, perhaps better, approach to this answer, would be to list a series of situations where the azole drug would be inappropriate:
These drugs inhibit fungal cell wall synthesis by blocking the synthesis of glucan by 1,3-β glucan synthase. This leads to increased permeability, osmotic bloat, and cell death.
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Ed.
Lewis, Russell E. "Current concepts in antifungal pharmacology." Mayo Clinic Proceedings. Vol. 86. No. 8. Elsevier, 2011.
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.
Fisher, Matthew C., et al. "Tackling the emerging threat of antifungal resistance to human health." Nature Reviews Microbiology 20.9 (2022): 557-571.
Van Rhijn, Norman, et al. "CYP51 paralogue structure is associated with intrinsic azole resistance in fungi." MBio 12.5 (2021): e01945-21.
Felton, Timothy, Peter F. Troke, and William W. Hope. "Tissue penetration of antifungal agents." Clinical microbiology reviews 27.1 (2014): 68-88.