Pharmacology of antifungal agents

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 like amphotericin and nystatin weaken fungal cell walls by binding to ergosterol. They are active against virtually all fungi and yeasts
  • Azoles like fluconazole and voriconazole prevent the synthesis of ergosterol from lanosterol by inhibiting lanosterol 14 α-demethylase. Early generation azoles are only effective against C.albicans.
  • Echinocandins like caspofungin inhibit fungal cell wall synthesis by blocking the synthesis of glucan by 1,3-β glucan synthase.
  • Exotic drugs include pyrimidine analogues (flucytosine for cryptococci) and microtube inhibitors (eg. griseofulvin for skin-based dermatophytes)


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.


  • A heptaene macrolide
  • Available in the (slightly) less toxic liposomal formulation (you are able to use higher doses, but you end up needing higher doses due to decreased efficacy)
  • Active against virtually all fungi and yeasts
  • Large volume of distribution, no reliance on renal clearance mechanisms
  • Toxicity:
    • Nephrotoxicity
    • Hypokalemia
    • Fever and chills upon administration
    • Renal tubular acidosis
    • Hypochromic normocytic anemia


  • Active against Candida species, and virtually nothing else
  • Not available in a systemic preparation: systemic toxicity was prohibitive (even more toxic than amphotericin)

Microtubular inhibitors

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.



  • Active only against dermatophytes: Microsporum, Epidermophyton, and Trichophyton
  • Binds to keratin, and lodges there permanently, offering long-term antifungal activity
  • Usually a topical agent
  • Metabolites are excreted in the urine, but the drug itself is almost completely insoluble in water
  • Only notable toxicity is neuritis

Pyrimidine analogues

Flucytosine is the only real member of this group. Fungi deaminate  flucytosine to 5-fluorouracil which results in impaired DNA synthesis.


  • Active against cryptococcus and candida species
  • Resistance develops readily when it is used on its own; it is usually combined with another agent
  • Small volume of distribution; relies on renal clearance and is readily cleared by dialysis
  • Toxicity:
    • Bone marrow suppression
    • Enterocolitis
    • Thrombocytopenia

Early-generation Azoles

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.


  • Active against Candida albicans, but most non-albicans species are resistant
  • Also active against Cryptococcus; no activity against Aspergillus
  • Penetrates well into the CSF
  • Interacts with many drugs: an inhibitor of CYP3A4 and CYP2C9
  • Small volume of distribution; relies on renal clearance and is readily cleared by dialysis
  • Toxicity:
    • LFT derangement
    • Alopecia
    • Drug interactions


  • 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


  • 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 for (against) routine post-operative use

Late-generation Azoles

The major generational change with azoles has been slower metabolism and less effect on human ergosterol synthesis.


  • Just like fluconazole, but with an extended spectrum.
  • Covers Candida albicans and non-albicans species, as well as Cryptococcus and Aspergillus
  • Highly protein bound and offering good tissue penetration
  • Volume of distribution is massive; not dependent on renal excretion, and not dialysable.
  • Also inhibits CYPs 2C19, 2C9, and CYP3A4 (thus, interacts with everything)
  • Toxicities:
    • Long QT interval
    • Hallucinations
    • Psychosis
    • Drug interactions


  • Just like itraconazole, but with an extended spectrum.
  • Antifungal spectrum is simialr to voriconazole; Candida albicans and non-albicans species, as well as Cryptococcus and Aspergillus.
  • Active against agents of mucormycosis
  • Like voriconazole, it is highly protein bound, not dependent on renal excretion, and not dialysable.
  • Inhibits CYP3A4
  • Toxicities:
    • Remarkably few! Generally well tolerated.

When might an azole not be enough?

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:

  • All Mucormycota moulds
  • Lomentospora sp.
  • Fusarium sp.
  • Pseudallescheria sp.
  • Talaromyces sp.
  • Candida auris

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:

  • The organism is intrinsically resistant to all azoles (eg. Mucor)
  • The susceptibility profile locally suggests a high prevalence of azole resistance (eg. haematology inpatient population)
  • Where azoles are contraindicated by patient allergy or dangerous drug interaction
  • The patient is already on prophylactic azole therapy (i.e treatment failure)
  • Where the azole is not expected to penetrate into the infected tissue - for example,  according to this excellent paper by Felton et al (2014),  most azoles have pretty poor penetration into the CSF, the prostate and the vitreous humour of the eye


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.


  • Active against Candida albicans and non-albicans species
  • Useless againt Cryptococcus, and sub-optimal against Aspergillus
  • Highly protein bound, not dependent on renal excretion, and not dialysable.
  • Minimal toxicity (perhaps LFT derangement)


  • Active against Candida albicans and non-albicans species.
  • Also useless againt Cryptococcus and sub-optimal against Aspergillus.
  • Exotic clearance mechanism:  degraded slowly first by opening the hexapeptide ring and then proteolysis of peptide bonds. Thus, requires no dose adjustment in any sort of organ system failure, be it renal or hepatic. Its the cisatracurium of antifungals.
  • Well tolerated, essentially without any systemic toxicity.


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.  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.