Polyenes
The polyenes are amphipathic macrolide antibiotics produced by Streptomyces species. Amphotericin B, introduced in 1958, remains the broadest spectrum fungicidal agent, used for the most severe and life threatening mycoses, despite its toxicity. Nystatin and natamycin are used topically, because they are too toxic for systemic use. Lipid formulations of amphotericin B reduce toxicity and increase the delivered dose.
| Mechanism | Details |
|---|---|
| Ergosterol binding | Amphotericin B binds ergosterol in the fungal cell membrane, forming extramembranous aggregates (a sterol sponge) that extract ergosterol, and transmembrane pores that cause leakage of potassium, protons, and other ions, with rapid cell death |
| Oxidative damage | Production of reactive oxygen species, with lipid peroxidation |
| Immune modulation | Stimulation of macrophages and cytokines (through Toll like receptor 2) |
| Selectivity | The affinity for ergosterol is higher than for cholesterol, but binding to cholesterol causes toxicity to human cells |
| Pharmacodynamics | Concentration dependent killing with a prolonged post antifungal effect; the ratio of peak concentration to MIC predicts efficacy |
| Group | Activity |
|---|---|
| Yeasts | Candida species (resistance or reduced susceptibility in Candida lusitaniae, Candida guilliermondii, Candida auris in part, and Candida haemulonii), Cryptococcus, Malassezia, Rhodotorula (active), Trichosporon (poor activity) |
| Hyaline moulds | Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger (active; Aspergillus terreus and Aspergillus nidulans variable to resistant), Fusarium (variable, with lower activity against Fusarium solani complex), Scedosporium (poor), Lomentosporium prolificans (resistant), Paecilomyces (Purpureocillium lilacinum resistant) |
| Mucorales | Active (the drug of choice), with reduced activity in Cunninghamella and Mucor circinelloides |
| Dimorphic fungi | Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, Talaromyces, and Emergomyces are active |
| Dematiaceous fungi | Variable |
| Parasites | Leishmania (visceral and mucocutaneous), Naegleria fowleri |
| Resistance | Rare; due to reduced ergosterol in the membrane (ERG2, ERG3, ERG6, and ERG11 mutations), with modified membrane sterols and an increase in catalase |
| Formulation | Composition and properties | Typical dose |
|---|---|---|
| Amphotericin B deoxycholate (conventional) | Micelles with sodium deoxycholate; the cheapest; the most toxic | 0.5 to 1 mg per kg once daily (1 to 1.5 mg per kg for Mucorales); 0.7 mg per kg for candidiasis and 0.7 to 1 mg per kg for cryptococcal meningitis (with flucytosine); maximum 1.5 mg per kg |
| Liposomal amphotericin B | Unilamellar liposomes of 80 nanometres (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, cholesterol); highest plasma peak, least nephrotoxic, and brain tissue penetration | 3 to 5 mg per kg once daily (up to 10 mg per kg in Mucorales and in central nervous system disease); 3 mg per kg for empirical therapy and visceral leishmaniasis; prophylaxis 1 to 2 mg per kg or 3 to 5 mg per kg twice weekly |
| Amphotericin B lipid complex | Ribbon like lipid complexes (dimyristoyl phosphatidylcholine and phosphatidylglycerol); high lung, liver, and spleen levels; more infusion reactions than the liposomal form | 5 mg per kg once daily |
| Amphotericin B colloidal dispersion | Cholesteryl sulphate disks; more infusion reactions; not widely available | 3 to 4 mg per kg once daily |
| Inhaled (nebulised) amphotericin B | Liposomal or lipid complex given by nebuliser, for prophylaxis (lung transplant) and adjunctive treatment | Liposomal 12.5 mg twice weekly or 25 mg three times weekly (prophylaxis, with limited evidence) |
| Other routes | Intrathecal and intraventricular (deoxycholate 0.01 to 0.5 mg daily, in dextrose, increasing as tolerated, up to 1 mg, for refractory meningitis); intravitreal (5 to 10 micrograms per 0.1 mL); intrapleural and intraperitoneal; bladder irrigation (50 mg in 1 L of sterile water, daily for 5 days, limited evidence); topical and lozenge forms | Limited evidence |
Dosing for specific infections is as follows:
- candidaemia: liposomal 3 to 5 mg per kg once daily
- cryptococcal meningitis: liposomal 3 to 4 mg per kg once daily, or a single dose of 10 mg per kg in some regimens for HIV, with flucytosine and fluconazole
- invasive aspergillosis: liposomal 3 to 5 mg per kg once daily
- mucormycosis: liposomal 5 to 10 mg per kg once daily
- histoplasmosis and blastomycosis: liposomal 3 to 5 mg per kg once daily
- visceral leishmaniasis: liposomal 3 mg per kg on days 1 to 5, 14, and 21, a total of 21 mg per kg, or a single dose of 10 mg per kg in some regions
| Parameter | Details |
|---|---|
| Absorption | Not absorbed from the gut (oral use is for gut decontamination only) |
| Distribution | The deoxycholate form is highly protein bound (above 95 percent) and has a large volume of distribution; tissue levels are high in the liver, spleen, lung, and kidney; levels in cerebrospinal fluid, vitreous, and urine are low (about 2 to 4 percent of serum levels), although brain tissue levels are adequate with liposomal preparations |
| Liposomal form | High peak plasma levels (about 80 micrograms per mL at 5 mg per kg), a lower volume of distribution, and a long terminal half life (about 100 hours); the liposomes are taken up by the reticuloendothelial system |
| Lipid complex | Rapid tissue uptake, with low plasma levels |
| Elimination | Slow, by non renal routes; terminal half life of about 15 days in the conventional form; no dose adjustment in renal or hepatic failure; not removed by dialysis |
| Concentration in tissue | Persists for weeks after therapy |
| Adverse effect | Features | Prevention and management |
|---|---|---|
| Infusion related reactions | Fever, chills, rigors, headache, nausea, hypotension, and bronchospasm within 1 to 3 hours; rare cardiorespiratory events with rapid infusion; with liposomal forms, a complement activation related pseudoallergy (chest tightness, flank and back pain, and flushing in the first minutes) | Slow the infusion (2 to 6 hours for deoxycholate, over 1 to 2 hours for liposomal forms), premedicate with paracetamol, an antihistamine, and hydrocortisone 25 to 50 mg (or pethidine 25 mg for rigors), and stop and restart more slowly when pseudoallergy occurs |
| Nephrotoxicity | Dose related; afferent arteriolar constriction with reduced glomerular filtration, tubular damage, distal renal tubular acidosis, a concentrating defect (nephrogenic diabetes insipidus), and wasting of potassium and magnesium; occurs in 30 to 80 percent with the conventional form and less with lipid forms (liposomal: 15 to 30 percent) | Saline loading (500 to 1000 mL of 0.9 percent sodium chloride before and after the dose), correct hypovolaemia, avoid nephrotoxic drugs, use a lipid formulation in patients at risk, and reduce the dose or stop when creatinine doubles |
| Electrolyte disturbance | Hypokalaemia, hypomagnesaemia, hypocalcaemia, and hypophosphataemia | Supplement potassium (40 to 120 mmol per day) and magnesium, and monitor daily at the start |
| Haematological | Normocytic anaemia (reduced erythropoietin), and rarely thrombocytopenia and leucopenia | Monitor the blood count weekly |
| Hepatic | Raised aminotransferases and alkaline phosphatase | Monitor liver tests |
| Phlebitis | With the conventional form | Central line, dilution, and rotation of the site |
| Cardiac | Arrhythmia and cardiac arrest with rapid infusion or hyperkalaemia; QT prolongation with hypokalaemia | Avoid bolus administration, and correct electrolytes |
| Neurological | Arachnoiditis, seizures, and neuropathy with intrathecal use | Dose and care |
| Others | Anorexia, nausea, vomiting, myalgia, and weight loss | Supportive care |
- Reconstitute in sterile water, and dilute in 5 percent dextrose (do not use saline for dilution because it causes precipitation); some lipid preparations are filtered through a 1 micron filter.
- A test dose of 1 mg (conventional form) over 20 to 30 minutes is used by some units, though it does not predict reactions reliably.
- Infusion times are 2 to 6 hours for the conventional form, 30 to 120 minutes for liposomal amphotericin B, and about 2 hours for the lipid complex.
- Monitoring: creatinine, urea, potassium, magnesium, sodium, bicarbonate, and full blood count at baseline and then daily to three times weekly, with liver tests weekly.
- Avoid or monitor with nephrotoxic drugs (ciclosporin, tacrolimus, aminoglycosides, vancomycin, contrast agents, and non steroidal anti-inflammatory drugs), with digoxin (hypokalaemia), and with corticosteroids and diuretics (potassium loss).
- Use in pregnancy: liposomal forms are the preferred agent in invasive disease; breastfeeding: little excretion in milk.
- Children: tolerated better, with doses of 1 to 1.5 mg per kg of conventional form, and liposomal 3 to 5 mg per kg.
- Cost: the conventional form is the cheapest, and the liposomal form is the preferred drug where available and affordable.
| Indication | Role |
|---|---|
| Cryptococcal meningitis | Induction with flucytosine (1 to 2 weeks), a single high dose of liposomal amphotericin B (10 mg per kg) with flucytosine and fluconazole in HIV in some regimens |
| Invasive candidiasis | Alternative (and for Candida auris with echinocandin resistance and in endocarditis, meningitis, and endophthalmitis) |
| Invasive aspergillosis | Alternative to voriconazole or isavuconazole, and for azole resistant disease |
| Mucormycosis | First line |
| Endemic mycoses | Induction for severe disease (histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, talaromycosis, emergomycosis) |
| Fusariosis | First line or in combination |
| Empirical therapy | Persistent fever in neutropenia |
| Prophylaxis | In haematology and transplant patients (low dose lipid forms), and inhaled in lung transplant |
| Visceral leishmaniasis | Liposomal amphotericin B |
| Amoebic meningoencephalitis | In combination (limited evidence) |
| Local use | Intravitreal, intrathecal, bladder irrigation, and nebulised |
| Feature | Details |
|---|---|
| Spectrum and mechanism | A polyene active against Candida species (not against moulds as a rule), acting as amphotericin B; resistance is rare |
| Absorption | Not absorbed from the gut, skin, or mucosa, and too toxic for intravenous use |
| Oral suspension | 100 000 units per mL, 4 to 6 mL (400 000 to 600 000 units) four times daily, held in the mouth before swallowing, for 7 to 14 days (oropharyngeal candidiasis; continued for 48 hours after resolution); infants 1 mL four times daily |
| Intestinal candidiasis | Tablets of 500 000 to 1 000 000 units three times daily |
| Vaginal | Pessaries of 100 000 units nightly for 14 days |
| Topical | Cream, ointment, or powder 100 000 units per gram two to three times daily for cutaneous candidiasis |
| Prophylaxis | Oral suspension in the neutropenic and in premature infants (1 mL of 100 000 units per mL three times daily, with limited evidence) |
| Adverse effects | Nausea, vomiting, diarrhoea, and rash; allergy; the taste is poor |
| Feature | Details |
|---|---|
| Spectrum | Active against Fusarium, Aspergillus, Candida, Curvularia, and many filamentous fungi |
| Use | Ophthalmic suspension 5 percent for fungal keratitis (the drug of choice for filamentous keratitis, and superior to voriconazole 1 percent in a randomised trial for Fusarium); one drop every hour while awake for the first 1 to 2 days, then every 2 hours, tapered over 2 to 3 weeks according to response |
| Other uses | Topical and food preservation (the E235 additive); lozenges and creams in some countries |
| Penetration | Poor into the deep cornea, so debridement of the epithelium and combination with other drugs are used in deep disease |
| Adverse effects | Local irritation, conjunctival hyperaemia, and delayed epithelial healing |
| Feature | Deoxycholate | Liposomal | Lipid complex |
|---|---|---|---|
| Usual dose | 0.5 to 1 mg per kg daily | 3 to 5 mg per kg daily (up to 10) | 5 mg per kg daily |
| Nephrotoxicity | Highest | Lowest | Intermediate |
| Infusion reactions | Frequent | Fewer (pseudoallergy in some) | Frequent |
| Peak plasma level | Low | High | Low |
| Brain tissue levels | Low | Higher | Low |
| Cost | Lowest | Highest | High |
| Preferred | Where lipid forms are unavailable | Most indications | An alternative when liposomal is unavailable |
