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Amphotericin B

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble, but possess less antifungal activity than the parent compound. Each mg of amphotericin B must contain not less than 750 micrograms of anhydrous drug. Amphotericin A may be found as a contaminant in concentrations not exceeding 5%. The commercially available powder for injection contains sodium desoxycholate as a solubolizing agent.

 

Storage/Stability/Compatibility - Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives—see directions for preparation in the Dosage Form section below).

 

After reconstitution, if protected from light, the solution is stable for 24 hours at room temperature and for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, the manufacturer recommends protecting the solution during administration. Additional studies however, have shown that potency remains largely unaffected if the solution is exposed to light for 8-24 hours.

 

Amphotericin B is reportedly compatible with the following solutions and drugs: D5W, D5W in sodium chloride 0.2%, heparin sodium, heparin sodium with hydrocortisone sodium phos­phate, hydrocortisone sodium phosphate/succinate and sodium bicarbonate.

 

Amphotericin B is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer’s, D5-normal saline, D5-lactated Ringer’s, amino acids 4.25% - dextrose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCl, cimetidine HCl, diphenhydramine HCl, dopamine HCl, edetate calcium disodium (Ca EDTA), gentamicin sulfate, kanamycin sulfate, lidocaine HCl, metaraminol bitartrate, methyldopate HCl, nitrofurantoin sodium, oxytetracycline HCl, penicillin G potassium/sodium, polymyxin B sulfate, potassium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracycline HCl, and verapamil HCl. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

 

Pharmacology - Amphotericin B is usually fungistatic, but can be fungicidal against some organisms depending on drug concentration. It acts by binding to sterols (primarily ergosterol) in the cell membrane and alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to “leak out”. Because bacteria and rickettisia do not contain sterols, amphotericin B has no activity against those organisms. Mammalian cell membranes do contain sterols (primarily cholesterol) and the drug’s toxicity may be a result of a similar mechanism of action, although amphotericin binds less strongly to cholesterol than ergosterol.

 

Amphotericin B has in vitro activity against a variety of fungal organisms, including Blastomyces, Aspergillus, Paracoccidiodes, Coccidiodes, Histoplasma, Cryptococcus, Mucor, and Sporothrix. Zygomycetes is reportedly variable in its response to amphotericin. Aspergillosis in dogs and cats does not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has in vivo activity against some protozoa species, including Leishmania spp. and Naegleria spp..

 

It has been reported that amphotericin B has immunoadjuvant properties, but further work is necessary to confirm the clinical significance of this effect.

 

Uses/Indications - Because the potential exists for severe toxicity associated with this drug, it should only be used for progressive, potentially fatal fungal infections. Veterinary use of amphotericin has been primarily in dogs, but other species have been treated successfully. For further information on fungal diseases treated, see the Pharmacology and Dosage sections.

 

Pharmacokinetics - Pharmacokinetic data on veterinary species is apparently unavailable. In humans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and must be given parenterally to achieve sufficient concentrations to treat systemic fungal infections. After intravenous injection, the drug reportedly penetrates well into most tissues, but does not penetrate well into the pancreas, muscle, bone, aqueous humor, pleural, pericardial, synovial, or peritoneal fluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels are approximately 3% of those found in the serum. Approximately 90-95% of amphotericin in the vascular compartment is bound to serum proteins.

 

The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. An initial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have been described. Seven weeks after therapy has stopped, amphotericin can still be detected in the urine. Approximately 2-5% of the drug is recovered in the urine in unchanged (biologically active) form.

 

Contraindications/Precautions/Reproductive Safety - Amphotericin is contraindicated in patients who are hypersensitive to it, unless the infection is life-threatening and no other alternative therapies are available.

 

Because of the serious nature of the diseases treated with systemic amphotericin, it is not contraindicated in patients with renal disease, but should be used cautiously with adequate monitoring.

 

The safety of amphotericin B during pregnancy has not been established, but there are apparently no reports of teratogenicity associated with the drug. The risks of therapy should be weighed against the potential benefits.

 

Adverse Effects/Warnings - Amphotericin B is notorious for its nephrotoxic effects and most canine patients will show some degree of renal toxicity after receiving the drug. The proposed mechanism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction in glomerular filtration rate. The drug may also directly act as a toxin to renal epithelial cells. Renal damage may be more common and severe in patients who receive higher individual doses.

 

The patient’s renal function should be aggressively monitored during therapy. A pre-treatment serum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium if possible), total plasma protein (TPP), packed cell volume (PCV), body weight, and urinalysis should be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight are rechecked before each dose is administered. Electrolytes and urinalysis should be monitored at least weekly during the course of treatment. Several different recommendations regarding stopping therapy when a certain BUN is reached have been made. Most clinicians recommend stop­ping, at least temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dl, serum crea­tinine >3 mg/dl or if other symptoms of systemic toxicity develop such as serious depression or vomiting.

 

At least two regimens have been used in the attempt to reduce nephrotoxicity in dogs treated with amphotericin. Mannitol (12.5 grams or 0.5 - 1 g/kg) given concurrently with amphotericin B (slow IV infusion) to dogs may reduce nephrotoxicity, but may also reduce the efficacy of the therapy, particularly in blastomycosis. Mannitol treatment also increases the total cost of therapy by approximately two times.

 

Sodium loading prior to treating has garnered considerable support in recent years. A tubuloglomerular feedback mechanism that induces vasoconstriction and decreased GFR has been postulated for amphotericin B toxicity; increased sodium load at the glomerulus may help pre­vent that feedback. One clinician (Foil 1986), uses 5 ml/kg of normal saline given in two portions, before and after amphotericin B dosing and states that is has been “... helpful in averting renal insufficiency... ”.

 

Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and many clinicians recommend using reduced dosages in this species (see Dosage section).

 

Other adverse effects that have been reported with amphotericin B include anorexia, vomiting, hypokalemia, phlebitis and fever.

 

Overdosage/Acute Toxicity - No case reports were located regarding acute intravenous over­dose of amphotericin B. Because of the toxicity of the drug, dosage calculations and solution preparation procedures should be double-checked. If an accidental overdose is administered, re­nal toxicity may be minimized by administering fluids and mannitol as outlined above in the Adverse effects section.

 

Drug Interactions - Since the renal effects of other nephrotoxic drugs may be additive with amphotericin B, avoid, if possible the concurrent or sequential use of aminoglycosides (gentamicin, amikacin, kanamycin, etc), polymyxin B, colistin, cisplatin, methoxyflurane or vancomycin. Amphotericin B therapy may cause potassium-loss or hypokalemia. This may be of particular concern in patients receiving cardiac glycosides (e.g., digoxin), skeletal muscle relaxants, or other potassium-depleting drugs (e.g., thiazide or loop diuretics). Corticosteroids may exac­erbate the potassium-losing effects of amphotericin.  Synergy between amphotericin and flucytosine can occur against strains of Cryptococcus and Candida spp., but increased flucytosine toxicity may also occur. Synergism with rifampin (against Candida, Histoplasma, and Aspergillus) and tetracycline (Cryptococcus and Candida spp.) have also been reported against fungi susceptible to amphotericin B. Antagonism of activity has been suggested between amphotericin B and miconazole. Further studies need to confirm this, however. Reconstitution with saline solutions or with solutions containing a preservative may cause precipitation.

 

Doses -

Note: Some clinicians have recommended administering a 1 mg test dose (less in small dogs or cats) IV over anywhere from 20 minutes to 4 hours and monitoring pulse, respiration rates, temperature, and if possible, blood pressure. If a febrile reaction occurs some clinicians recommend adding a glucocorticoid to the IV infusion solution or using an antipyretic prior to treating, but these practices are controversial.

 

A recently published study (Rubin et al. 1989) demonstrated less renal impairment and systemic adverse effects in dogs who received amphotericin B IV slowly over 5 hours in 1 L of D5W than in dogs who received the drug IV in 25 ml of D5W over 3 minutes.

 

Horses:

For treatment of susceptible systemic fungal infections:

a)   0.3 mg/kg in D5W IV (Robinson 1987)

b)   For phycomycoses and pulmonary mycoses: After reconstitution (see below) transfer appropriate amount of drug to 1L of D5W and administer using a 16 g needle IV at a rate of 1 L/hr. Dosage schedule follows:

Day 1:  0.3 mg/kg IV

Day 2:  0.45 mg/kg IV

Day 3:  0.6 mg/kg IV; then every other day for 3 days per week (MWF or TTHSa) until clinical signs of improvement or toxicity takes place. It toxicity occurs, a dose may be skipped, dose reduced or dosage interval lengthened. Administration may ex­tend from 10-80 days. (Brumbaugh 1987)

 

 

Monitoring Parameters - Also see Adverse effects section

1)   BUN and serum creatinine every other day while dosage is being increased, and at least weekly thereafter during therapy

2)   Serum electrolytes (sodium, potassium and magnesium) weekly

3)   Liver function tests weekly

4)   CBC weekly

5)   Urinalysis weekly

6)   TPP at least weekly

7)   Animal’s weight

 

 

Client Information - Clients should be informed of the potential seriousness of toxic effects that can occur with amphotericin B therapy, as well as the costs associated with therapy.

 

Dosage Forms/Preparations/FDA Approval Status/Solution Preparation -

 

Veterinary-Approved Products: None

 

Amphotericin B  for Powder for Injection 50 mg/vial (as deoxycholate); Fungizone® Intravenous  (Bristol-Myers Squibb); (Rx);Amphotericin B® (Pharma-Tek); (Rx)

Directions for reconstitution/administration: Using strict aseptic technique and a 20 gauge or larger needle, rapidly inject 10 ml of sterile water for injection (without a bacterio­static agent) directly into the lyophylized cake; immediately shake well until solution is clear. A 5 mg/ml colloidal solution results. Further dilute (1:50) for administration to a concentration of 0.1 mg/ml with 5% dextrose in water (pH >4.2). An in-line filter may be used during administration, but must have a pore diameter >1 micron.

 

Amphotericin B Suspension for Injection: 100 mg/20 ml (as lipid complex) in single use vials with 5 micron filter needles:Abelcet®  (Liposome Co.) (Rx)

 

Amphotericin B; for Powder for Injection 50 mg/vial (as cholesteryl) in 20 ml vials with 52.8 mg sodium cholesteryl sulfate & 100 mg (as cholesteryl) in 50 ml vials with 52.8 mg sodium cholesteryl sulfate; Amphotec® (Sequus Pharmaceuticals) (Rx)

 

Amphotericin B; for Powder for Injection 50 mg/vial (as liposomal) in single use vials with 5 micron filter needles:AmBisome®  (Fujisawa) (Rx)

 

Amphotericin B is also available in a topical formulation.


 

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