Polyenes

Typically derived from the fermentation products of Streptomyces bacteria, polyene antifungals bind to ergosterol in the fungal cell membrane, allowing K+ and Na+ ions to leak out. Resistance (Ahmad et al, 2019).

Amphotericin B is often used for serious fungal infections and has earned the nickname ‘amphoterrible’ for its unpleasant side effects. Find out more about managing side effects during IV infusions.

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Amphotericin B

NAMES Amphotericin B Fungizone (Bristol-Myers Squibb Pharmaceuticals), AmBisome (Gilead), Abelcet (ABLC/Sigma Tau/Cephalon etc), Fungisome (Lifecare), and others.

APPROVAL It was discovered by E R Squibb and Sons which is now part of Bristol-Myers Squibb.  It was selected over other amphotericins and nystatin as being less toxic for intravenous administration.

STRUCTURE & MECHANISM Amphotericin B is a macrocyclic type compound similar in structure to nystatin. Its mechanism of action has not been fully elucidated but it involves binding to the cell membrane, leakage of potassium from the cell and possibly initiation of a lipid peroxidation cascade which irreversibly damages the cell membrane of fungi.  It has a substantially greater affinity for ergosterol (present in fungal cell membranes) than cholesterol explaining its greater effects against fungal cells than human cells and also its lack of activity against Pneumocystis jirovecii (which contains cholesterol in its cell membrane rather than ergosterol).  The first studies with amphotericin B were in the late 1950’s and it was made available for general use in the early 60’s.

FORMULATIONS & DOSAGES IV, oral or topical. It is not absorbed at all after oral or topical administration and so this mode of delivery is simply for prophylaxis or the treatment of mucosal infection. The original preparation of amphotericin B for intravenous use is a deoxycholate dispersion in dextrose (Fungizone, Bristol-Myers Squibb Pharmaceuticals). It is not compatible with sodium chloride or other ionic solutions.  Various lipid-incorporated preparations have developed and four are licensed and marketed.  The first to reach market was AmBisome (Gilead), which is a small unilamellar liposome (liposomal amphotericin B).  Subsequent to this, amphotericin B lipid complex (Abelcet, ABLC/Sigma Tau/Cephalon etc.) was developed and it comprises ribbons of lipid amphotericin B. The third marketed variety uses an alternative approach of combining cholesteryl sulphate complexes with amphotericin B to produce small discs of lipid amphotericin B together (Amphocil, Amphotec, ABCD; Alkpoharma, Indochina Healthcare, etc.). The fourth was developed in India and is known as Fungisome (Lifecare). Amphotericin B has been administered in Intralipid intravenously, but the efficacy of this mode of delivery is in doubt. The maximum dose of intravenous amphotericin B is governed by toxicity.  It is rarely possible to administer more than 1.5 mg/kg body weight daily of the original amphotericin B deoxycholate preparation and most patients do not tolerate more than 0.8-1 mg/kg body weight daily.  Larger doses of the lipid incorporated drugs have been used typically 3-5 mg/kg body weight of AmBisome, 5 mg/kg body weight of Abelcet and 4 mg/kg body weight of Amphocil. The optimal dose of Fungisome is not known, but the approved dose of 1 mg/kg may be too low for some indications such as invasive aspergillosis. Dosing of amphotericin B has been rather empirical and it has been difficult to show clear dose response relationships either with the daily dose administered or the total dose.  Test doses (to detect anaphylaxis) are not necessary any longer as the preparations of amphotericin B are purer. Detailed guidance on administration is given in Khoo et al, 1994. Oral amphotericin B has been given in doses varying from 10-500 mg 4 times a day with a 10 mg dose administered as a pastille for the treatment of oral thrush.  Doses as large as 200 mg have been used in the prophylaxis of fungal infections during neutropaenia and also for the treatment of azole resistant oropharyngeal candidiasis (Hood et al, 1998). Topical amphotericin B has also be administered with flucytosine in a pessary for azole-resistant Candida glabrata vaginitis (White et al, 1993). Examples of topical use of amphotericin B include bladder instillation, surgical wound irrigation, intraperitoneal catheter usage, intravitreal (eye) and use in the lumbar, ventricular, cisternal or subarachnoid spaces.  Doses vary widely for these indications and need to be checked.

ACTIVITY Amphotericin B is probably the most broad spectrum intravenous antifungal available.  – ACTIVE against Aspergillus spp., Blastomyces dermatitidis, Candida (all species except some isolates of Candida krusei and Candida lusitaniae), Coccidioides spp., Cryptococcus spp., Histoplasma spp., Paracoccidioides brasiliensis and most of the agents of zygomycosis (Mucorales), Fusarium spp. and other rarer fungi. – NOT SUFFICIENTLY ACTIVE against Scedosporium spp., Aspergillus terreus, Trichosporon spp., most of the species causing mycetoma and systemic infections due to Sporothrix schenckii. – RESISTANCE has been described in occasional isolates, usually acquired after long term therapy in the context of endocarditis, but is rare.

TYPICAL REGIMEN Lipid associated amphotericin B is considerably more expensive than amphotericin B deoxycholate. Amphotericin B is the systemic antifungal of choice in pregnancy. Oral therapy – Oral thrush 10 mg 4x daily – Azole resistant oral thrush 10-200 mg 4x daily – Prophylaxis of Candida infections in neutropaenia 200-500 mg 4x daily Intravenous therapy – The general approach to treating patients with serious infections is to use the maximum tolerated dose initially.  – The drug should never be administered in less than 60 minutes as it may cause arrhythmias and 2-4 hours is preferable for amphotericin B deoxycholate and Amphocil.  Deoxycholate doses  – Cryptococcal meningitis: >0.7 mg/kg daily (with flucytosine). – Candidaemia: 0.6-1 mg/kg per day. – Invasive aspergillosis: 1-1.25 mg/kg per day. – Histoplasmosis, blastomycosis and coccidioidomycosis (acute): 1 mg/kg daily. – Histoplasmosis and coccidioidomycosis (chronic): 0.5-1 mg/kg/day. – Penicillium marneffei infection: 0.8-1 mg/kg/day. – Mucorales infection: 1-1.5 mg/kg/day. – Doses of lipid amphotericin B preparation are usually 3-5x higher than deoxycholate amphotericin

PHARMACOKINETICS Amphotericin B is hardly absorbed from the gut.  After intravenous administration the drug appears to go through three phases of redistribution from the blood into a ‘fast’ tissue compartment (e.g. muscle) and a ‘slow’ tissue compartment (e.g. fat).  Over 90% of the drug is cleared from the bloodstream 12 hours after administration.  Considerable variations in serum concentrations and tissue concentrations are apparent between different individuals, whether using the lipid-based preparations or the deoxycholate preparation. Penetration into the urine, CSF, eye and vegetations on heart valves and bone is poor.  Tissue concentration of the lipid-based amphotericins is increased in the reticulo-endothelial system (liver and spleen), brain and slightly reduced in the lung and kidney.  The preparation with the highest brain concentrations is AmBisome.  Amphotericin B is barely metabolised and excreted extremely slowly for several weeks after administration.

DRUG INTERACTIONS There are few direct drug interactions with amphotericin B although synergistic nephrotoxicity with certain drugs such as IV contrast media, cyclosporin and aminoglycosides (gentamicin etc) can be problematic.  Low blood potassium (which is common) can produce problems with cardiac drugs such as digoxin

SIDE EFFECTS & TOXICITY Deoxycholate amphotericin B: Many side effects are associated with the intravenous administration of deoxycholate amphotericin B.  Approximately two thirds of patients suffer acute infusion-related toxicity which may include chills, fever, anaphylactoid-like reactions and rarely acute confused states. Management of these side effects is usually possible with acetaminophen (paracetamol), ibuprofen or aspirin and, if severe, small doses of opiates.  Hydrocortisone has been extensively used for this indication, but it tends to cause more immunosuppression and it is preferable to avoid it if possible.  If hydrocortisone is used a dose of 25 mg is adequate.  Renal dysfunction is common with amphotericin B usage and is primarily dose related, although occasional patients go into acute renal failure, after 1-3 doses.  The administration of saline intravenously (500-1000 ml) prior to amphotericin B infusion reduces renal toxicity but rarely abolishes it.  Low blood potassium and magnesium is common after days or weeks of amphotericin B therapy.  This can be partially prevented by the use of the diuretic amiloride (5 mg daily).  Chronic anaemia is common after several weeks of amphotericin B in addition to a general feeling of ill health and loss of appetite.  It usually takes 2-4 weeks for these symptoms to recover following a course of amphotericin B.  Amphotericin B tends to damage veins (phlebitis) and is usually therefore best administered through a central (large vein) intravenous line. – Lipid-associated amphotericin B: Lipid-based amphotericin B preparations cause less toxicity, particularly less renal toxicity.  Many units routinely use these preparations in patients who already have kidney dysfunction or are taking cyclosporin.  Lipid based preparations also cause less potassium loss. There are differences between the three preparations in their likelihood of acute infusion related toxicities.  Amphocil appears to have more infusion related toxicities than conventional amphotericin B, although these are usually manageable with the measures described above.  Abelcet has fewer infusion related toxicities than conventional amphotericin B and AmBisome fewer still.  Acute anaphylactoid reactions occurring with one preparation may not recur with another for reasons than are not entirely clear.  Anaemia and feelings of chronic ill-health are as common as with amphotericin B deoxycholate, after 2 – 3 weeks of therapy.

Nystatin

NAMES Nystatin Nystin, Mycostatin, and others.

APPROVAL A polyene antifungal originally isolated from Streptomyces noursei in 1950 by Elizabeth Lee Hazen and Rachel Fuller Brown. It was named after the laboratories in which they worked in 1954 – New York State Department of Health. Streptomyces noursei is a soil organism isolated from a farm (owned by William Nourse). It was first used in patients and licensed for use in the 1950’s. It was patented in 1957 and all royalties donated to research.

STRUCTURE & MECHANISM Like all polyenes, it binds to ergosterol in the fungal cell membrane, leading to potassium loss and fungal cell death.

FORMULATIONS & DOSAGES Topical only. Dosing is described in units. For vaginal candidiasis, pessaries of 100 mg are give daily for 6 days, 200 mg for 3 days, and 500 mg as a single dose. Alternatively 1%, 2% or 10% vaginal cream delivering roughly the same doses as pessaries, may be used, for the same duration. Nystatin cream is also used to treat penile candidiasis (balanitis). Nystatin 10 mg lozenges or troches are used to treat oral candidiasis. They are taken 5 times daily for 14 days for treatment, or 3 times daily for prevention of oral candidiasis. Most topical skin preparations are 1% cream, lotion or spray, which should be applied 2 or 3 times daily for 2-4 weeks. Nystatin is effective for seborrhoeic dermatitis, nappy rash due to Candida, some cases of ringworm, tinea cruris and athlete’s foot. A 1% solution can be used for otitis externa. For inflammatory conditions such as seborrhoeic dermatitis, combined preparations with topical corticosteroid are helpful.

ACTIVITY – ACTIVE against most Candida spp. as well as Cryptococcus neoformans, Aspergillus spp., Histoplasma capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis and Sporothrix schenckii. Nystatin has also been used to treat other fungal problems as Dutch Elm disease and to restore water-damaged mouldy artwork. – RESISTANCE: some documented in Candida albicans, especially among oral isolates in patients with AIDS treated with Nystatin. Typical rates of resistance, in Candida albicans in a general hospital are 3-6%.

PHARMACOKINETICS Nystatin is practically insoluble in water. Applied on the skin it penetrates on the surface layer (epidermis), with no systemic absorption. Between 3-10% is absorbed systemically after vaginal administration. Nystatin is metabolised by the liver.

DRUG INTERACTIONS There are very few drug/drug interactions with Nystatin. Pessaries of clotrimazole may damage latex condoms or diaphragms, and additional contraceptive measures are wise.

SIDE EFFECTS & TOXICITY Nystatin is generally well tolerated but nausea, vomiting, unpleasant mouth and pruritus (itching) have been reported with oral lozenges. Local skin irritation and a burning sensation are reported after use on the skin. Nystatin may be given in pregnancy.

Natamycin

NAMES Natamycin Pimaricin, Pimafucin, Natadrops, Natacyn

APPROVAL Originally isolated from Streptomyces natalensis found in a soil sample from Natal, South Africa.  Natamycin was discovered in DSM laboratories in 1955. Similar to other polyenes, natamycin binds to ergosterol in the fungal cell membrane.   Natamycin is also used in the food industry as an effective preservative (known as E235).

STRUCTURE & MECHANISM Natamycin blocks fungal growth by binding specifically to ergosterol without permeabilising the membrane where it inhibits vacuole fusion at the priming phase and interferes with membrane protein functions.

FORMULATIONS & DOSAGES Topical only It should be protected from light. As a 5% ophthalmic suspension, natamycin is used in the treatment of fungal keratitis, especially for Fusarium infection. Hourly use is important early in therapy. Early intense treatment with natamycin results in a 75% visual recovery in patients with moderate or mild fungal keratitis and a 60% recovery in those with severe fungal keratitis. A 1% ointment is also available and may be used for skin fungal infection. Natamycin 10 mg lozenges are used to treat oral candidiasis: 4-6 times daily for 14 days (treatment), or 3 times daily (prophylaxis). They have also bee used to treat Candida vaginitis or thrush, and might have a particular place in treating fluconazole resistant Candida glabrata vaginitis.

ACTIVITY – ACTIVE against most Candida spp. Aspergillus spp., Fusarium spp. and other rarer fungi that cause keratitis.   – RESISTANCE: Secondary or acquired resistance is probably rare, but not extensively studied.

PHARMACOKINETICS Natamycin is poorly soluble in water and not absorbed through the skin or mucous membranes, including the vagina. Very little is absorbed through the gastrointestinal tract. After ocular application, therapeutic concentrations are present within the infected cornea, but not in intraocular fluid.

DRUG INTERACTIONS Very few

SIDE EFFECTS & TOXICITY May cause some irritation on skin or mucous membranes.