Amphotericin-B in dermatology-a review

Amphotericin B (AmB) is one of the most potent antifungal drugs against invasive fungal infections which has stood the test of time. AmB deoxycholate (d‑AmB) was first preparation of AmB, marketed in 1959. The COVID19 pandemic had again highlighted its role with the rise in cases of mucormycosis. Recently a review reappraising the drug profile of AmB and its use in the field of dermatology was published in the Indian Dermatology Online Journal.

AmB is a macrolide polyene antifungal, obtained from soil actinomycete Streptomyces nodosus via the process of fermentation. As AmB is amphoteric and water‑insoluble, only parenteral formulations are available. Due to the infusion‑related reactions and nephrotoxicity of the drug, lipid‑based formulations were prepared such as liposomal AmB (l‑AmB), AmB lipid complex (ABLC), and AmB colloidal dispersion (ABCD). Recently, various topical formulations of AmB have been successfully used in cutaneous leishmaniasis and mucormycosis. The salient points related to the four formulations of AmB have been summarized in the table-1 below.

Mechanism of Action

AmB acts via selective binding to ergosterol, a key component of the fungal cell membrane, leading to the formation of pores on the cell membrane. Pore formation results in K+ efflux, fungal glycolysis inhibition, and Mg++ efflux with simultaneous proton influx. The increased acidification of fungal cytoplasm results in the precipitation of proteins and subsequent cell death. Additional mechanisms proposed include oxidative damage via free radical formation and stimulation of the phagocytic system to aid fungal clearance.

FDA Approved Indications of Liposomal AmB -

1. Empirical therapy for presumed fungal infection in febrile, neutropenic patients.

2. Cryptococcal meningitis in HIV infected patients

3. Patients with Aspergillus species, Cryptococcus species, or Candida species infection refractory to amphotericin B deoxycholate, or patients with renal impairment or prior hypersensitivity to amphotericin B deoxycholate.

4. Treatment of visceral leishmaniasis.

Dermatological Uses of AmB

Leishmaniasis

The action of AmB in leishmaniasis is attributed to its selective affinity to bind to ergosterol present in the parasite's cell membrane. Other mechanisms postulated include cell membrane disruption by lipid peroxidation, endosome‑lysosome fusion inhibition, apoptosis, and stimulation of INF‑Y production resulting in macrophage activation.

Mucocutaneous leishmaniasis:

i. Systemic therapy

AmB and miltefosine are the preferred drug of choice. L‑AmB is the standard formulation preferred. Recommended WHO dosing is 2–3 mg/kg per day, by infusion, up to 40–60 mg/kg total dose. Immunocompromised patients often need higher and prolonged therapy. The treatment regime comprises 3 mg/kg L‑AMB for 5 consecutive days followed by the 6th dose on day 10.

ii. Topical therapy:

The first successful use described was in 1999 using AmB in 5% ethanol. The aim of topical formulation was to prevent systemic toxicity. As of now, studies regarding topical AmB are not encouraging for cutaneous leishmaniasis. However, various other formulations of topical AmB such as liposomal, nanoparticles, ultra‑deformable liposomes, and micro needling–based delivery are under trials.

iii. Intralesional therapy:

The first use of intralesional AmB was by Vahid et al where 2 mg/mL was injected into lesions

weekly for up to 12 weeks with 61.4% of the patients showing complete recovery.(2) A comparative trial has shown AmB 2.5 mg/mL to be equally efficacious as 5 mg/mL.(3)

Post kala azar dermal leishmaniasis:

L‑AmB is the second‑line treatment of post kala azar dermal leishmaniasis in patients where miltefosine is contraindicated. Combination therapy of L‑AmB and miltefosine has been shown to be superior in efficacy and safety in patients with PKDL.

Recommended dosing:

i. Africa: L‑AmB: 2.5 mg/kg per day by infusion for 20 days

ii. Asian countries: D‑AmB: 1 mg/kg per day by infusion, up to 60–80 doses over 4 months.

L‑AmB: 30 mg/kg in 6 weekly divided doses of 5 mg/kg

Cutaneous mucormycosis

Systemic therapy

It is caused by opportunistic fungi of class Glomerulomycota via penetrative trauma, commonly affecting patients with immunosuppression and uncontrolled diabetes. Treatment of choice is AMB along with surgical debridement and control of underlying immunosuppression. Treatment is to be started within 5 days of diagnosis. Recommended duration is up to clinical or radiological resolution or at least 6–8 weeks of therapy. Successful use of L‑AmB in cutaneous mucormycosis in preterm neonates and infants has also been described.

Recommended dosing:

i. D‑AMB: 0.5–1 mg/kg/day in immunocompetent and 1–1.5 mg/kg/day in immunosuppressed individuals.

ii. L‑AmB: 5–10 mg/kg/day.

Congenital candidiasis and neonatal candidiasis:

Systemic therapy:

Systemic therapy with AMB is recommended in neonates with widespread dermatitis due to Candida, disseminated invasive disease, respiratory distress in the immediate neonatal period and/or sepsis. AmB at the dosage of 0.5–1 mg/kg/day is preferred, whereas L‑AmB (35 mg/kg/day) is reserved for invasive cases or patients with renal insufficiency. Systemic therapy

is continued for a duration of 21–28 days. The infectious disease society of America recommends the use of amphotericin B deoxycholate oral suspension as an alternative for fluconazole‑refractory oral candidiasis.

Topical therapy:

Topical formulation of AmB has been used for the treatment of oral candidiasis, but the availability of such formulations is a major limiting factor.

Other indications:

• Anecdotal case reports of successful use of AmB have been described in cutaneous fusariosis, protothecosis, primary cutaneous aspergilloisis, cutaneous histoplasmosis, chromoblastomycosis and blastomycosis.

Contraindications

AmB is contraindicated in those patients with known hypersensitivity to it or one of the preservatives.

Storage and Administration

To be stored in dry form at 2–8°C away from light. The salient points to remember during infusion and monitoring of AmB have been summarized as follows-

Intravenous infusion of AmB

Test dose: A test dose of 0.1 mg/kg, and total not exceeding 1 mg is given by infusion over 20-60 min. Infusion after test dose is given over 2-6 h usually via a distal vein. Pre‑treatment with acetaminophen, diphenhydramine, or corticosteroids administered approximately 30 min before infusion can be done in patients developing infusion‑related toxicities. Proper hydration and potassium supplementation are important.

Monitoring during AmB therapy

 Infusion‑related toxicities : like nausea, vomiting, and chills occurring either immediately or within 15 min-3 h of infusion.

 Nephrotoxicity- daily monitoring of serum creatinine is recommended.

 Consider switching to liposomal AmB in case serum creatinine rises over 2.5 mg/dL or reduction of the dose of d‑AmB by 50%.

 Hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia are noted with AmB therapy.

 Potassium and magnesium supplementation along with hydration with normal saline is essential during amphotericin B infusions.

D‑AmB: A total of 50 mg vial is reconstituted with 10 mL sterile water (5 mg/mL) and shaken till the solution becomes clear. This is further diluted to 0.1 mg/mL with 500 mL 5% dextrose and then administered immediately. L‑AmB: A total of 50 mg is reconstituted with 12 mL sterile water (4 mg/mL) and shaken to obtain clear fluid. Further dilution with an appropriate amount of reconstituted solution and 5% dextrose can be done to provide 1–2 mg/mL concentration for adults and 0.2–0.5 mg/mL concentration for infants and small children.

Drug Interactions

Dose‑dependant nephrotoxicity and infusion‑related electrolyte imbalance can be augmented by ongoing concomitant medication. Tacrolimus or cyclosporine used in kidney transplant patients increases AMB‑related toxicity. Increased risk of hypokalemia occurs with the concomitant use of digoxin and corticosteroids.

AmB in Paediatric Population

The safety and effectiveness of AmB in pediatric leishmaniasis have been well documented in the literature. D‑AmB is more hepatotoxic than L‑AmB with no difference in infusion‑related toxicities or nephrotoxicity. Recommended dosing is similar to adults. (3–5 mg/kg/day for 5 days and then another dose on day 10).

AmB in Pregnancy and Lactation

Pregnancy: AmB is a category B drug and thus can be used if clinically indicated. It is the safest antifungal drug during pregnancy with established safety and efficacy of both liposomal and d‑AmB.

Lactation: Whether AmB gets secreted in breast milk is not known, but because it is highly protein‑bound, has a large molecular weight, and is not absorbed orally, it can be used in nursing mothers but with caution.

AmB in Special Population

No dose adjustment is necessary for patients with renal impairment based on CrCl estimate. Liposomal AmB has been successfully administered in patients with pre‑existing renal impairment. Effect of liposomal AmB in patients with hepatic impairment is not known

AmB Resistance

Fortunately, resistance to AmB is still rare compared to other anti‑fungal drugs. Two possible theories have been put forward- One is that AmB targets a major cell membrane component, ergosterol unlike other antifungals which target an enzyme. Another theory proposed is an association of AmB with severe fitness trade‑offs. Resistance that is MIC>2 mg/L is mostly species‑specific and has emerged slowly with some clinical isolates with AmB. Studies on drug combination in vitro and in vivo have suggested that imidazoles can induce AmB resistance.

The following methods of AmB resistance have been suggested:

1. Alterations in sterol composition in the fungal cell membrane. It involves mutations in genes

related biosynthesis pathway. Similar mutations in Candida species being a mechanism of resistance have been reported.

2. Reduction in polyene‑induced oxidative stress may allow better tolerability to AmB. Intrinsically, AmB resistant organisms such as Aspergillus tereus have shown this mechanism of resistance.

3. Alteration in the fungal cell wall has also shown AmB resistance. An increase in the 1, 3 α‑glucan fraction and 1,3‑β‑glucan in Aspergillus flavus and Candida tropicalis, respectively have been postulated to cause resistance.

Source

1. Agarwal A, Kar BR. Amphotericin-B in dermatology. Indian Dermatol Online J 2022;13:152-8.

2. Vahid MG, Elham V, Bita K, Yalda N. Efficacy of intralesional amphotericin B in cutaneous leishmaniasis. Indian J Dermatol 2014;59:631.

3. Goswami P, Ghiya BC, Kumar V, Rekha S, Mehta RD. Comparison of efficacy of two different concentrations of intralesional amphotericin B in the treatment of cutaneous leishmaniasis; A randomized controlled trial. Indian Dermatol Online J 2019;10:627-31.

4. Ramesh V, Dixit KK, Sharma N, Singh R, Salotra P. Assessing the Efficacy and Safety of liposomal amphotericin B and miltefosine in combination for treatment of post Kala-Azar dermal leishmaniasis. J Infect Dis 2020;221:608-17.