Other antifungals: polyenes, echinocandins and allylamines

Quick revision

Amphotericin B punches pores straight through the fungal membrane by binding ergosterol, the echinocandins instead attack the fungal cell wall by blocking 1,3-beta-D-glucan synthase, and terbinafine blocks an earlier step of ergosterol synthesis than the azoles do — three separate mechanisms whose toxicity profiles (severe nephrotoxicity, a comparatively clean safety record, and hepatotoxicity respectively) are just as distinct as their targets.

• Amphotericin B binds ergosterol in the fungal cell membrane and forms transmembrane pores, causing leakage of monovalent ions (Na+, K+, H+, Cl-) and cell death — a direct membrane-disrupting mechanism, not enzyme inhibition. (1)
• Liposomal amphotericin B formulations meaningfully reduce infusion-related reactions and nephrotoxicity compared with conventional amphotericin B deoxycholate, though a real risk of nephrotoxicity remains even with the liposomal form. (1) (7)
• The echinocandins (caspofungin, micafungin, anidulafungin) noncompetitively inhibit 1,3-beta-D-glucan synthase, an enzyme with no mammalian counterpart, blocking synthesis of an essential fungal cell-wall component rather than acting on the membrane at all. (2) (5)
• Echinocandins are fungicidal against most Candida species (including many azole-resistant strains) but only fungistatic against Aspergillus, and none of them is labelled for or effective against Cryptococcus neoformans. (5)
• Echinocandins have a comparatively low incidence of adverse effects and minimal drug-drug interactions relative to the azoles, though caspofungin still requires dose reduction in moderate hepatic impairment and interacts with cyclosporine and tacrolimus. (2) (5)
• Terbinafine is a non-competitive inhibitor of fungal squalene epoxidase, an earlier step in ergosterol synthesis than the azoles' target, and it is the labelled treatment of choice for dermatophyte onychomycosis. (4) (6)
• Oral terbinafine carries a hepatotoxicity warning that includes reported liver failure, transplant and death, requiring baseline and periodic liver function testing, and it can cause taste and smell disturbance that is occasionally severe, prolonged or permanent. (4) (6)
• Micafungin's label discloses hepatic tumours (carcinomas and adenomas) seen in a rodent toxicology study, though whole-life carcinogenicity studies in animals have not been conducted for the drug. (3)

Overview

This class exists as a grouping of convenience as much as mechanism: polyenes, echinocandins and allylamines share no single molecular target with one another, and the only thing that truly unites them for teaching purposes is that none of them is an azole. That said, each has a genuinely distinct and testable mechanism, and together they cover ground the azoles do not: the oldest reliable systemic antifungal still in clinical use, the newest major antifungal mechanism to reach clinical practice, and the standard treatment for dermatophyte nail disease. (7)

Amphotericin B, a polyene first developed decades before the azoles, works by direct physical disruption rather than enzyme inhibition. It binds ergosterol in the fungal cell membrane and assembles into transmembrane channels, and the resulting leakage of monovalent ions across the compromised membrane is what kills the cell. That same ergosterol-binding affinity is also amphotericin B's central liability, because ergosterol's mammalian counterpart, cholesterol, is structurally similar enough that some binding and membrane disruption occurs in human cells too — which is the mechanistic root of the drug's well-known nephrotoxicity. Liposomal formulations do not change the mechanism; they change delivery, reducing (without eliminating) both infusion-related reactions and nephrotoxicity relative to the older conventional deoxycholate formulation. (1)

The echinocandins represent a genuinely newer idea: rather than targeting the fungal membrane at all, they target the fungal cell wall, specifically by noncompetitively inhibiting 1,3-beta-D-glucan synthase, the enzyme that builds an essential glucan polymer found in fungal but not mammalian cells. That mammalian-cell absence is a large part of why this subclass has a comparatively favourable safety profile and relatively few drug interactions next to the azoles or amphotericin B. Their spectrum, however, is uneven by design: they are reliably fungicidal against Candida species, including many that are azole-resistant, but only fungistatic against Aspergillus, and they have no meaningful activity against Cryptococcus neoformans at all — a gap worth remembering precisely because it is easy to assume a modern, well-tolerated antifungal must be broad-spectrum. (2) (5)

Terbinafine, an allylamine, sits apart from both of the above because its primary clinical role is dermatological rather than systemic-invasive-disease treatment: it is the labelled treatment for onychomycosis of the toenail or fingernail caused by dermatophytes. Mechanistically it acts earlier in the same ergosterol biosynthesis pathway the azoles interrupt later, by non-competitively inhibiting squalene epoxidase, the enzyme that converts squalene to squalene epoxide. The consequence is twofold: ergosterol synthesis falls, but squalene itself also accumulates inside the fungal cell to a degree that is directly toxic, which is part of why terbinafine can be fungicidal against the dermatophytes it targets rather than merely fungistatic. Its own defining risk is hepatotoxicity, serious enough that the label requires liver function testing before starting oral therapy and periodically during it. (4) (6)

Classification and drug examples

Three subclasses, three mechanisms, three very different typical clinical roles: membrane-disrupting polyenes for severe invasive and disseminated disease, cell-wall-targeting echinocandins mainly for invasive candidiasis, and the allylamine terbinafine mainly for dermatophyte nail and skin infection.

Mechanism of action

The three subclasses here interrupt fungal survival at three different structural levels. Polyenes act directly on the finished fungal membrane by binding the ergosterol already embedded in it and physically punching pores through the lipid bilayer. Echinocandins act on the fungal cell wall, a structure fungi have and mammalian cells do not, by blocking the enzyme that synthesises one of its essential polymers. Terbinafine acts upstream in ergosterol biosynthesis itself, at an earlier enzymatic step than the azoles, so that both ergosterol depletion and toxic squalene accumulation contribute to fungal cell death.

Molecular target

Ergosterol in the fungal cell membrane (polyenes); fungal 1,3-beta-D-glucan synthase (echinocandins); fungal squalene epoxidase (terbinafine)

Pharmacodynamic effect

Amphotericin B is generally fungicidal; echinocandins are fungicidal against Candida but only fungistatic against Aspergillus; terbinafine is fungicidal against the dermatophytes it targets

Effect kinetics

Amphotericin B and the echinocandins act relatively directly once bound to their target (membrane or cell wall integrity fails quickly); terbinafine's effect builds as intracellular squalene accumulates over the course of therapy

1. Amphotericin B binds ergosterol already present in the fungal membrane

   Unlike the azoles or terbinafine, amphotericin B does not block a synthesis enzyme; it binds the finished sterol molecule directly wherever it sits in the membrane. (1)

2. Bound amphotericin B molecules assemble into transmembrane pores

   Multiple amphotericin B molecules aggregate around bound ergosterol to form channels spanning the membrane. (1)

3. Monovalent ions leak through the pore and the cell dies

   The label states this directly: the channels lead 'to alterations in cell permeability through which monovalent ions (Na+, K+, H+, and Cl-) leak out of the cell resulting in cell death.' (1)

4. Echinocandins instead block synthesis of a cell-wall component before it is ever built

   Caspofungin noncompetitively inhibits beta-(1,3)-D-glucan synthase, the enzyme responsible for synthesising an essential glucan polymer of the fungal cell wall; because this enzyme has no counterpart in mammalian cells, the mechanism is highly fungus-selective. (2) (5)

5. Terbinafine blocks an earlier ergosterol-pathway enzyme, squalene epoxidase, causing both ergosterol depletion and toxic squalene buildup

   Terbinafine is a non-competitive inhibitor of squalene epoxidase, the enzyme that converts squalene to squalene epoxide; blocking it both starves the pathway of ergosterol downstream and lets squalene accumulate intracellularly to levels that are themselves toxic to the fungal cell. (4) (6)

Spectrum of activity

Spectrum here is where the practical differences between these three subclasses become sharpest, particularly the echinocandins' well-defined gap against Cryptococcus and terbinafine's dermatophyte focus.

Major clinical uses

Pharmacokinetics

• This page gives no dose regimens by design. Loading and maintenance dosing for the echinocandins, infusion protocols for liposomal amphotericin B, and treatment duration for terbinafine belong in a current prescribing reference used by the treating clinician.
• None of caspofungin's metabolism runs primarily through CYP450, which is a real and testable point of contrast with the azoles' heavy CYP450 dependence and is part of why this subclass has 'minimal drug interactions' relative to the azole class. (5)
• Terbinafine's CYP2D6 inhibition is clinically real: its own label describes roughly a two-fold increase in peak concentration and a five-fold increase in AUC of desipramine, a CYP2D6 substrate, when co-administered. (4)

Adverse effects

Common

• Infusion-related reactions (chills, rigors, fever): Reported with both conventional and liposomal amphotericin B, though liposomal amphotericin B caused chills/rigors in 18% of patients on day 1 versus 54% with conventional amphotericin B in labelled comparative data. (1)
• Gastrointestinal effects and phlebitis: Common with caspofungin, including diarrhoea, nausea, vomiting and injection-site phlebitis, alongside chills and fever. (2) (5)
• Headache and gastrointestinal upset: Common with oral terbinafine, generally mild and self-limited. (6)

Serious adverse effects

• Nephrotoxicity: A defining risk of amphotericin B; the liposomal label defines nephrotoxicity as a doubling of creatinine over pretreatment levels and reports a materially lower incidence with the liposomal formulation than with conventional amphotericin B, without eliminating the risk. Renal function and electrolytes (potassium, magnesium) are monitored throughout treatment. (1)
• Electrolyte disturbance (hypokalemia, hypomagnesemia): Reported with amphotericin B; labelled comparative data show hypokalemia (potassium ≤2.5 mmol/L at any time) in 6.7% of liposomal amphotericin B patients versus 11.6% with conventional amphotericin B. Electrolytes are monitored and repleted as needed during treatment. (1)
• Hepatotoxicity: Both echinocandins and terbinafine carry hepatotoxicity risk: caspofungin requires liver enzyme monitoring, particularly with concomitant cyclosporine; oral terbinafine has caused liver failure, sometimes leading to transplant or death, which is why pre-treatment and periodic liver function testing is required. Baseline liver function testing before starting oral terbinafine, with periodic monitoring during treatment, and prompt discontinuation if signs of liver injury develop. (2) (4)
• Hypersensitivity reactions, including anaphylaxis: Serious hypersensitivity reactions including shock have been reported with micafungin, and terbinafine is contraindicated in patients with a prior allergic reaction to it because of anaphylaxis risk. Discontinue the drug and treat appropriately if a hypersensitivity reaction occurs. (3) (4)
• Taste and smell disturbance (terbinafine): Terbinafine's label describes taste disturbance, including taste loss, that can be severe, prolonged, or in rare cases permanent, and has been associated with reduced food intake and weight loss. This is discussed with patients before starting oral terbinafine and is a reason for reassessment if it develops. (4) (6)

Drug-specific effects

• Amphotericin B (liposomal): Nephrotoxicity and infusion reactions are reduced, not eliminated, by the liposomal formulation — a genuine but partial safety improvement over conventional amphotericin B deoxycholate. (1)
• Micafungin: The only drug in this page whose label specifically discloses hepatic tumours (carcinomas and adenomas) observed in a rodent toxicology study, alongside the statement that whole-life carcinogenicity studies in animals have not been conducted. (3)
• Terbinafine: The taste/smell disturbance and hepatotoxicity risk profile are specific enough to this drug within the class that they drive its own dedicated pre-treatment counselling and monitoring requirements. (4)

Contraindications, precautions and interactions

Contraindications

• Terbinafine: chronic or active liver disease, and a history of allergic reaction to oral terbinafine because of the risk of anaphylaxis. (4)
• Micafungin: known hypersensitivity to micafungin sodium, any component of the product, or other echinocandins. (3)

Precautions

• Renal function and electrolytes are monitored throughout amphotericin B therapy given its nephrotoxicity and electrolyte-wasting effects. (1)
• Liver function is monitored during caspofungin therapy, particularly with concomitant cyclosporine. (2)
• Baseline and periodic liver function testing is required before and during oral terbinafine therapy given its hepatotoxicity risk. (4)

Drug interactions

• Cyclosporine: Increases caspofungin AUC by approximately 35%; liver enzyme monitoring is recommended during concurrent use. (2)
• Tacrolimus: Caspofungin reduces tacrolimus blood concentrations, so tacrolimus levels are monitored during concurrent use. (2)
• CYP2D6 substrates (e.g. desipramine): Terbinafine inhibits CYP2D6 and meaningfully raises exposure to CYP2D6 substrates, shown in its own label as roughly a two-fold rise in peak concentration and a five-fold rise in AUC of desipramine. (4)
• Other nephrotoxic agents: Concomitant use with other nephrotoxic drugs raises the risk of renal impairment during amphotericin B therapy and is a general caution addressed in the prescribing reference. (7)

Resistance mechanisms

Comparison tables

High-yield exam pearls

• Amphotericin B is the only drug on this page that acts by direct physical membrane disruption rather than inhibiting an enzyme. (1) It is what makes amphotericin B mechanistically distinct not just from the echinocandins and terbinafine here, but from the azoles too, and it directly explains why its toxicity (nephrotoxicity from cross-reaction with cholesterol-containing human membranes) looks so different from an enzyme-inhibitor's toxicity.
• Echinocandins target a fungal cell-wall enzyme with no mammalian counterpart — that is the direct, mechanistic reason for their comparatively clean safety profile. (5) It is a clean cause-and-effect exam link: no human enzyme homolog, so no analogous human toxicity mechanism, unlike amphotericin B's cholesterol cross-reactivity or the azoles' CYP450 cross-reactivity.
• No echinocandin covers Cryptococcus neoformans — a specific, high-yield spectrum gap, not a general weakness. (5) It is the exact opposite pattern from amphotericin B and fluconazole, both of which do cover cryptococcal disease, so an exam question testing 'which drug would you NOT use for cryptococcal meningitis' should point straight at this subclass.
• Terbinafine's target, squalene epoxidase, sits upstream of the azoles' target (lanosterol 14-alpha-demethylase) in the same ergosterol pathway. (6) Confusing the two enzymes is a common error; the pathway position also explains terbinafine's dual mechanism of harm — both ergosterol depletion and toxic squalene accumulation.
• Liposomal amphotericin B reduces nephrotoxicity, it does not remove it. (1) Labelled comparative data still show a real, just smaller, incidence of renal and electrolyte abnormalities with the liposomal form, which is why renal monitoring continues even when the 'safer' formulation is chosen.

Common exam traps

• Trap: Assuming echinocandins are broad-spectrum simply because they are well tolerated and modern. Actually: Tolerability and spectrum are separate questions here: echinocandins have no activity against Cryptococcus neoformans and are only fungistatic, not fungicidal, against Aspergillus, despite their favourable safety profile against Candida. (5)
• Trap: Treating amphotericin B's nephrotoxicity as fully solved by using the liposomal formulation. Actually: Liposomal amphotericin B's own labelled comparative data show a lower, not zero, incidence of nephrotoxicity and electrolyte disturbance relative to conventional amphotericin B; renal monitoring remains standard practice. (1)
• Trap: Assuming terbinafine and the azoles inhibit the same enzyme because both act in the 'ergosterol pathway.' Actually: Terbinafine inhibits squalene epoxidase, an earlier step than the azoles' target, lanosterol 14-alpha-demethylase; the two mechanisms are adjacent in the same pathway but are not the same enzyme and are not cross-resistant by the same mutation. (6) (8)
• Trap: Assuming oral terbinafine is essentially risk-free because it is commonly used for a cosmetic-seeming indication like toenail fungus. Actually: Its label describes hepatotoxicity serious enough to require pre-treatment and periodic liver function testing, including reported cases of liver failure, transplant and death, and it is contraindicated outright in patients with chronic or active liver disease. (4)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

1. What is the immediate cause of fungal cell death after amphotericin B binds ergosterol in the membrane?

   • Inhibition of glucan synthase
   • Formation of transmembrane pores causing leakage of monovalent ions
   • Inhibition of squalene epoxidase
   • Blockade of the fungal ribosome
   Show answer

   Answer: Formation of transmembrane pores causing leakage of monovalent ions

   Amphotericin B forms transmembrane channels after binding ergosterol, and leakage of ions such as Na+, K+, H+ and Cl- through these channels causes cell death, a direct physical mechanism rather than enzyme inhibition. (1)

2. Which enzyme do the echinocandins inhibit?

   • Lanosterol 14-alpha-demethylase
   • Squalene epoxidase
   • 1,3-beta-D-glucan synthase
   • Dihydropteroate synthase
   Show answer

   Answer: 1,3-beta-D-glucan synthase

   Echinocandins such as caspofungin noncompetitively inhibit beta-(1,3)-D-glucan synthase, blocking synthesis of an essential fungal cell-wall polymer that has no mammalian counterpart. (2) (5)

3. Which organism is NOT covered by echinocandin therapy?

   • Candida albicans
   • Candida glabrata
   • Cryptococcus neoformans
   • Candida krusei
   Show answer

   Answer: Cryptococcus neoformans

   Echinocandins have no meaningful activity against Cryptococcus neoformans, despite being fungicidal against most Candida species including some azole-resistant strains. (5)

4. What enzyme does terbinafine inhibit, and how does its position in the ergosterol pathway compare with the azoles?

   • Lanosterol 14-alpha-demethylase, the same target as the azoles
   • Squalene epoxidase, an earlier step in ergosterol synthesis than the azoles' target
   • 1,3-beta-D-glucan synthase, a cell-wall target unrelated to ergosterol
   • Dihydrofolate reductase, unrelated to fungal membranes
   Show answer

   Answer: Squalene epoxidase, an earlier step in ergosterol synthesis than the azoles' target

   Terbinafine non-competitively inhibits squalene epoxidase, which acts earlier in the ergosterol biosynthesis pathway than the azoles' target, lanosterol 14-alpha-demethylase. (6)

5. What is required before starting oral terbinafine, given its labelled risk profile?

   • An ECG for QT monitoring
   • Baseline liver function testing
   • A renal biopsy
   • HIV testing
   Show answer

   Answer: Baseline liver function testing

   Oral terbinafine's label requires pre-treatment evaluation of liver function given reported hepatotoxicity, including liver failure, transplant and death, with periodic monitoring during treatment. (4)

6. Does the liposomal formulation of amphotericin B eliminate its nephrotoxicity risk?

   • Yes, liposomal amphotericin B carries no renal risk
   • No, it reduces but does not eliminate nephrotoxicity relative to conventional amphotericin B
   • No, liposomal amphotericin B is actually more nephrotoxic
   • Nephrotoxicity is not associated with any amphotericin B formulation
   Show answer

   Answer: No, it reduces but does not eliminate nephrotoxicity relative to conventional amphotericin B

   Labelled comparative data show a lower, but still present, incidence of nephrotoxicity and electrolyte disturbance with liposomal amphotericin B compared with the conventional deoxycholate formulation, which is why renal monitoring continues regardless of formulation. (1)

Frequently asked questions

References

1. AMBISOME (amphotericin B liposomal) — prescribing information DailyMed, U.S. National Library of Medicine
2. CANCIDAS (caspofungin acetate) — prescribing information DailyMed, U.S. National Library of Medicine
3. MYCAMINE (micafungin sodium) — prescribing information DailyMed, U.S. National Library of Medicine
4. Terbinafine tablet — prescribing information DailyMed, U.S. National Library of Medicine
5. Caspofungin StatPearls Publishing / NCBI Bookshelf
6. Terbinafine StatPearls Publishing / NCBI Bookshelf
7. Antifungal Agents StatPearls Publishing / NCBI Bookshelf
8. Antifungal Ergosterol Synthesis Inhibitors StatPearls Publishing / NCBI Bookshelf

Related drug classes

• Azole antifungals
• Influenza antivirals

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