Polyenes

Agents: amphotericin B, lipid formulations of amphotericin B, nystatin (topical)

For many years, amphotericin B deoxycholate was the standard of care for many systemic fungal infections, for both its broad antifungal spectrum and a lack of available alternatives. Polyenes work by binding to ergosterol in the cell membrane of fungi, disrupting its function. Amphotericin B is notable for its toxicities, principally nephrotoxicity and infusion-related reactions. To attenuate these toxicities, three lipid forms were developed: amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex,  and liposomal amphotericin B (LAmB).

Amphotericin B formulations have seen considerably less use since the introduction of the echinocandins and broad-spectrum azoles, but they still have utility. Activity against yeasts and many moulds, proven efficacy in understudied disease states, and a long history of use help maintain their place in the antifungal armamentarium.

Spectrum

Good: most species of  Candida and  Aspergillus, Cryptococcus neoformans, dimorphic fungi, many moulds

Moderate: Zygomycetes

Poor: Candida lusitaniae, Aspergillus terreus

Adverse Effects

Nephrotoxicity and infusion-related reactions are the most common adverse effects. Both direct effects on the distal tubule and indirect effects through vasoconstriction of the afferent arteriole cause the nephrotoxicity, and nephrotoxicity also leads to wasting of magnesium and potassium,  which thus need supplementation. Infusion-related reactions include fever, chills, and rigors and can be impressive. Less common adverse effects include increased transaminases and rash.

Dosing Issues

The multiple formulations of amphotericin B can lead to confusion over their dosing. Amphotericin B deoxycholate is generally dosed between 0.5 and 1.5 mg/kg/day, where the lipid formulations are dosed at 3–6 mg/kg/day. Whether the lipid formulations are equivalent is a matter of debate, but most clinicians dose them as if they are. Fatal overdoses of amphotericin B deoxycholate have been given when dosed as the lipid forms are—generally a 5*overdose. Mind your formulation.

Important Facts

• Amphotericin B nephrotoxicity can be attenuated by the process of sodium loading: administered boluses of normal saline before and after the amphotericin infusion. Sodium loading is an inexpensive and easy way of protecting the kidneys.

• Many practitioners administer such drugs as acetaminophen, diphenhydramine, and hydro-cortisone to decrease the incidence and severity of infusion-related reactions of amphotericin B.  Meperidine is often given to treat rigors when they develop, but be wary of using this drug in patients who develop renal dysfunction be-cause it has a neurotoxic metabolite that is eliminated renally.

• Whether differences in efficacy exist between the lipid formulations of amphotericin B is a matter of debate, but differences in safety do exist. In terms of infusion-related reactions,  ABCD seems to have the worst, while LAmB has the least. All of them have less nephrotoxicity than amphotericin B deoxycholate, but LAmB seems to have the least of all.

• Nystatin is used only topically because of poor tolerance when given systemically.

What They’re Good For

Amphotericin B formulations remain the drugs of choice for cryptococcal meningitis and serious forms of some other fungal infections, such as dimorphic fungi and some mould infections. Because of their broad spectrum, they are also a reasonable choice if fungal infection is suspected but the infecting organism is not known, as in febrile neutropenia. Their use in candidiasis and aspergillosis has declined with the availability of newer, safer agents.

Don’t Forget!

Double-check that dose of amphotericin B; which formulation are you using?

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.

مواضيع ذات صلة

Antifungal Chemotherapy

Pimaricin

Echinocandins

Posaconazole

Voriconazole

Itraconazole

Fluconazole

Introduction to Azoles

Antimetabolites

Introduction to Antifungal Drugs