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Polyene Macrolide Antibiotics


Amphotericin B is the model polyene macrolide antibiotic and is the sole member of this class used systemically. Polyene antifungal antibiotics are large molecules, consisting of a long polyene, lipid-soluble component and a markedly hydrophilic component. Amphotericin B acts as both a weak base and a weak acid, and as such is amphoteric. The polyene macrolides have been isolated from various strains of bacteria; amphotericin B is an antibiotic product of Streptomyces nodosus. Amphotericin B, nystatin, and pimaricin (natamycin) are the only polyene macrolide antibiotics used in veterinary medicine. The polyenes are poorly soluble in water and the common organic solvents. They are reasonably soluble in highly polar solvents such as dimethylformamide and dimethyl sulfoxide. In combination with bile salts, such as sodium deoxycholate, amphotericin B is readily soluble (micellar suspension) in 5% glucose. This colloidal preparation has been used for IV infusion. The polyenes are unstable in aqueous, acidic, or alkaline media but in the dry state, in the absence of heat and light, they remain stable for indefinite periods. They should be administered parenterally (diluted in 5% dextrose) as freshly prepared aqueous suspensions. Lack of stability indicates that labeled expiration dates be adhered to once the product is diluted. Amphotericin B is also prepared as liposomal and lipid-based preparations, enhancing its safety without loss of efficacy.

Antifungal Activity

The polyenes bind to sterol components in the phospholipid-sterol membranes of fungal cells to form complexes that induce physical changes in the membrane. The number of conjugated bonds and the molecular size of a particular polyene macrolide influence its affinity for different sterols in fungal cell membranes. Amphotericin B has a greater affinity for fungal ergosterol, the major sterol in fungal membranes, than for eukaryotic (host) cell membrane cholesterol. The long polyene structure causes the formation of channels in the fungal cell membrane. The resultant loss of membrane permeability results in the loss of critically important molecules. Potassium ion efflux from the fungal cell and hydrogen ion influx cause internal acidification and a halt in enzymatic functions. Sugars and amino acids also eventually leak from an arrested cell. Fungistatic effects are most often evident at usual polyene concentrations. High drug concentrations and pH values between 6.0 and 7.3 in the surrounding medium may lead to fungicidal rather than fungistatic action.

In addition to these direct effects on susceptible yeasts and fungi, evidence suggests that amphotericin B may also act as an immunopotentiator (both humoral and cell mediated), thus enhancing the host's ability to overcome mycotic infections.

Polyene macrolides are inherently resistant to dermatophytes. Acquired resistance to the polyene antifungal macrolides is rare both clinically and in vitro. Pythium, a pseudofungus, is less susceptible, because it contains limited ergosterol in its cell membranes. Resistance has been documented for Candida spp, which are among the more rapidly growing fungal organisms. In general,resistance develops slowly and does not reach high levels, even after prolonged treatment.

The polyene antibiotics have broad antifungal activity against organisms ranging from yeasts to filamentous fungi and from saprophytic to pathogenic fungi, but there are great differences between the susceptibilities of the various species and strains of fungi. They are ineffective against dermatophytes. In vitro susceptibilities (both resistant and highly susceptible) do not always correlate well with the clinical response, which suggests that host factors may also play a role. Many algae and some protozoa (Leishmania, Trypanosoma, Trichomonas, and Entamoeba spp) are sensitive to the polyenes, but these compounds have no significant activity against bacteria, actinomycetes, viruses, or animal cells. Amphotericin B is effective against yeasts (eg, Candida spp, Rhodotorula spp, Cryptococcus neoformans), dimorphic fungi (eg, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis), dermatophytes (eg, Trichophyton, Microsporum, and Epidermophyton spp), and molds. It also has been used successfully to treat disseminated sporotrichosis, pythiosis, and zygomycosis, although it may not always be effective. Nystatin is mainly used to treat mucocutaneous candidiasis, but it is effective against other yeasts and fungi. The antimicrobial activity of pimaricin is similar to that of nystatin, although it is mainly used for local treatment of candidiasis, trichomoniasis, and mycotic keratitis.

Amphotericin B is available as an IV solution complexed to bile acids but also as several different preparations complexed to lipid mixtures. Because reticuloendothelial cells phagocytize the lipid component, directed delivery to the site of fungal infection is facilitated, reducing renal exposure. Prolonged antifungal activity (compared with nonliposomal preparations) has been documented.

Pharmacokinetic Features

The polyene macrolide antibiotics are poorly absorbed from the GI tract. Amphotericin B is usually administered IV or topically and occasionally locally, intrathecally, or intraocularly. Nystatin and piramycin are mostly applied topically. Nystatin is given PO to treat intestinal candidiasis. Absorption is minimal from sites of local application.

Amphotericin B is widely distributed in the body after IV infusion. It associates with cholesterol in host cell membranes throughout the body and is subsequently released slowly into the circulation. Penetration into the CSF, saliva, aqueous humor, vitreous humor, and hemodialysis solutions is generally poor. Amphotericin B becomes highly bound to plasma lipoproteins (~95%). Complexing amphotericin B with various lipid-based products alters the distribution.

The disposition of amphotericin B is not well described in companion animals. Approximately 5% of a total daily dose of amphotericin B is excreted unchanged in the urine. Over a 2-wk period, ~20% of the drug may be recovered in the urine. The hepatobiliary system accounts for 20%–30% of excretion. The fate of the remainder of amphotericin B is unknown.

Amphotericin B has a biphasic elimination pattern. The initial phase lasts 24 hr, during which levels fall rapidly (70% for plasma and 50% for urine). The second elimination phase has a 15-day half-life, during which plasma concentrations decline very slowly. Amphotericin B is usually infused IV, every 48–72 hr, until the total cumulative dosage has been reached. The disposition of the various lipid-complexed amphotericin B products is variable, Because of its small size, AmBisome® is characterized by the slowest uptake by reticuloendothelial cells and thus the highest plasma drug concentrations of amphotericin B. However, the amount of free versus complexed amphotericin B is not clear. AmBisome also was able to achieve CNS concentrations and was associated with the least nephrotoxicity in human studies. AmBisome has been studied in Beagles. Achievable amphotericin concentrations were much higher at equivalent doses of AmBisome compared with other products; further, dogs were able to well tolerate 4 mg/kg for 30 days. Amphotericin concentrations accumulate with multiple dosing when administered as AmBisome.

Therapeutic Indications and Dose Rates

Amphotericin B is used principally to treat systemic mycotic infections. Despite its ability to cause nephrotoxicity (see Adverse Effects and Toxicity), amphotericin B remains a commonly used antifungal agent because of its effectiveness. Multiple approaches to delivery have been described in an attempt to minimize nephrotoxicity. In addition, dosing continues until a maximal cumulative dose is reached, with the amount varying with the fungal organism. Nystatin is primarily indicated for treatment of mucocutaneous (skin, oropharynx, vagina) or intestinal candidiasis; pimaricin is mainly used in therapeutic management of mycotic keratitis.

General dosages for some polyene macrolide antibiotics are listed in Table: Dosages of Polyene Macrolide AntibioticsTables. The dose rate and frequency should be adjusted as needed for the individual animal.

Table 1

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Special Clinical Concerns

Oral administration of nystatin can lead to anorexia and GI disturbances. The IV infusion of amphotericin B can cause an anaphylactoid reaction due to direct mast cell degranulation. A pre-test dose is recommended to detect this reaction, and pretreatment with H1 antihistamines and short-acting glucocorticoids may be appropriate. Thrombophlebitis may occur with perivascular leakage. The primary toxicity associated with amphotericin B is nephrotoxicity. Within 15 min of IV administration of amphotericin B, renal arterial vasoconstriction occurs and lasts for 4–6 hr. This leads to diminished renal blood flow and glomerular filtration. Because amphotericin B binds to the cholesterol component in the membranes of the distal renal tubules, a change in permeability occurs in these cells, leading to polyuria, polydipsia, concentration defects, and acidification abnormalities. The net result is a distal renal tubular acidosis syndrome. The metabolic acidosis leads to bone buffering, the excessive release of calcium into the circulation, and ultimately nephrocalcinosis due to calcium precipitation in the acidic environment of the distal tubules. Almost every animal treated with amphotericin B develops some degree of renal impairment, which may become permanent depending on the total cumulative dose.

The administration of amphotericin B can lead to a number of other adverse effects, including anorexia, nausea, vomiting, hypersensitivity reactions, drug fever, normocytic normochromic anemia, cardiac arrhythmias (and even arrest), hepatic dysfunction, CNS signs, and thrombophlebitis at the injection site.

A number of adjuvant therapies are used to minimize adverse events of amphotericin B. Pretreatment with antiemetic and antihistaminic agents prevents the nausea, vomiting, and hypersensitivity reactions. Giving corticosteroids IV also limits severe hypersensitivity reactions. Mannitol (1 g/kg, IV) with each dose of amphotericin B, and sodium bicarbonate (2 mEq/kg, IV or PO, daily) may help prevent acidification defects, metabolic acidosis, and azotemia; however, clinical evidence of efficacy has not been proved. Saralasin (6–12 mcg/kg/min, IV) and dopamine (7 mcg/kg/min, IV) infusions have prevented oliguria and azotemia induced by amphotericin B in dogs. Administering IV fluids or furosemide before amphotericin B prevents pronounced decreases in renal blood flow and glomerular filtration rate. Newer preparations in which amphotericin B is mixed with lipid or liposomal vehicles (particularly liposomes) are safer and have maintained efficacy.

Amphotericin B may be combined with other antimicrobial agents with synergistic results. This often allows both the total dose of amphotericin B and the length of therapy to be decreased. Examples include combinations of 5-flucytosine and amphotericin B for treatment of cryptococcal meningitis, minocycline and amphotericin B for coccidioidomycosis, and imidazole and amphotericin B for several systemic mycotic infections. Rifampin may also potentiate the antifungal activity of amphotericin B.

Drugs that should be avoided during amphotericin B therapy include aminoglycosides (nephrotoxicity), digitalis drugs (increased toxicity), curarizing agents (neuromuscular blockade), mineralocorticoids (hypokalemia), thiazide diuretics (hypokalemia, hyponatremia), antineoplastic drugs (cytotoxicity), and cyclosporine (nephrotoxicity).

Treatment with polyene macrolide antibiotics increases plasma bilirubin, CK, AST, ALT, BUN, eosinophil count, and urine protein, and decreases plasma potassium and platelet count.

Last full review/revision November 2015 by Dawn Merton Boothe, DVM, PhD

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