AMPHOTERICIN B
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 inwater and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basicmedia. These salts are more water soluble, but possess less antifungal activity than the parentcompound. Each mg of amphotericin B must contain not less than 750 micrograms of anhydrousdrug. Amphotericin A may be found as a contaminant in concentrations not exceeding 5%. Thecommercially available powder for injection contains sodium desoxycholate as a solubolizing agent.
Form section below).
After reconstitution, if protected from light, the solution is stable for 24 hours at room temperatureand for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, themanufacturer recommends protecting the solution during administration. Additional studieshowever, have shown that potency remains largely unaffected if the solution is exposed to light for8-24 hours.
Amphotericin B is reportedly compatible with the following solutions and drugs: D5W, D5W insodium 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: normalsaline, lactated Ringer's, D5-normal saline, D5-lactated Ringer's, amino acids 4.25% - dextrose25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCl, cimetidine
HCl, diphenhydramine HCl, dopamine HCl, edetate calcium disodium (Ca EDTA), gentamicinsulfate, kanamycin sulfate, lidocaine HCl, metaraminol bitartrate, methyldopate HCl, nitrofurantoinsodium, oxytetracycline HCl, penicillin G potassium/sodium, polymyxin B sulfate, potassiumchloride, 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).
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 catsdoes not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has invivo activity against some protozoa species, including Leishmania spp. and Naegleria spp..
It has been reported that amphotericin B has immunoadjuvant properties, but further work isnecessary to confirm the clinical significance of this effect.
The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. Aninitial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have beendescribed. 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.
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 apparentlyno reports of teratogenicity associated with the drug. The risks of therapy should be weighedagainst the potential benefits.
The patient's renal function should be aggressively monitored during therapy. A pre-treatmentserum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium ifpossible), total plasma protein (TPP), packed cel volume (PCV), body weight, and urinalysisshould be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight arerechecked before each dose is administered. Electrolytes and urinalysis should be monitored at leastweekly during the course of treatment. Several different recommendations regarding stoppingtherapy when a certain BUN is reached have been made. Most clinicians recommend stopping, atleast temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dl, serum creatinine >3mg/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 withamphotericin. 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 byapproximately 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 beenpostulated for amphotericin B toxicity; increased sodium load at the glomerulus may help preventthat feedback. One clinician (Foil 1986), uses 5 ml/kg of normal saline given in two portions, beforeand after amphotericin B dosing and states that is has been "... helpful in averting renalinsufficiency... ".
Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and manyclinicians 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.
Amphotericin B therapy may cause potassium-loss or hypokalemia. This may be of particularconcern in patients receiving cardiac glycosides (e.g., digoxin), skeletal muscle relaxants, orother potassium-depleting drugs (e.g., thiazide or loop diuretics). Corticosteroids mayexacerbate 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.) havealso been reported against fungi susceptible to amphotericin B. Antagonism of activity has beensuggested between amphotericin B and miconazole. Further studies need to confirm this, however.
Reconstitution with saline solutions or with solutions containing a preservative may causeprecipitation.
Storage, Stability, Compatibility
Vials of amphotericin B powder for injection should be storedin the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must bedone with sterile water for injection (no preservatives¯see directions for preparation in the DosageForm section below).
After reconstitution, if protected from light, the solution is stable for 24 hours at room temperatureand for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, themanufacturer recommends protecting the solution during administration. Additional studieshowever, have shown that potency remains largely unaffected if the solution is exposed to light for8-24 hours.
Amphotericin B is reportedly compatible with the following solutions and drugs: D5W, D5W insodium 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: normalsaline, lactated Ringer's, D5-normal saline, D5-lactated Ringer's, amino acids 4.25% - dextrose25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCl, cimetidine
HCl, diphenhydramine HCl, dopamine HCl, edetate calcium disodium (Ca EDTA), gentamicinsulfate, kanamycin sulfate, lidocaine HCl, metaraminol bitartrate, methyldopate HCl, nitrofurantoinsodium, oxytetracycline HCl, penicillin G potassium/sodium, polymyxin B sulfate, potassiumchloride, 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
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 thecell membrane and alters the permeability of the membrane allowing intracellular potassium andother 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 containsterols (primarily cholesterol) and the drug's toxicity may be a result of a similar mechanism ofaction, 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 catsdoes not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has invivo activity against some protozoa species, including Leishmania spp. and Naegleria spp..
It has been reported that amphotericin B has immunoadjuvant properties, but further work isnecessary to confirm the clinical significance of this effect.
Uses, Indications
Because the potential exists for severe toxicity associated with this drug, itshould 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 furtherinformation on fungal diseases treated, see the Pharmacology and Dosage sections.Pharmacokinetics - AMPHOTERICIN B
Pharmacokinetic data on veterinary species is apparently unavailable. Inhumans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and mustbe given parenterally to achieve sufficient concentrations to treat systemic fungal infections. Afterintravenous injection, the drug reportedly penetrates well into most tissues, but does not penetratewell into the pancreas, muscle, bone, aqueous humor, pleural, pericardial, synovial, or peritonealfluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels areapproximately 3% of those found in the serum. Approximately 90-95% of amphotericin in thevascular compartment is bound to serum proteins.The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. Aninitial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have beendescribed. 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 alternativetherapies 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 apparentlyno reports of teratogenicity associated with the drug. The risks of therapy should be weighedagainst the potential benefits.
Adverse Effects, Warnings
Amphotericin B is notorious for its nephrotoxic effects and mostcanine patients will show some degree of renal toxicity after receiving the drug. The proposedmechanism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction inglomerular filtration rate. The drug may also directly act as a toxin to renal epithelial cells. Renaldamage 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-treatmentserum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium ifpossible), total plasma protein (TPP), packed cel volume (PCV), body weight, and urinalysisshould be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight arerechecked before each dose is administered. Electrolytes and urinalysis should be monitored at leastweekly during the course of treatment. Several different recommendations regarding stoppingtherapy when a certain BUN is reached have been made. Most clinicians recommend stopping, atleast temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dl, serum creatinine >3mg/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 withamphotericin. 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 byapproximately 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 beenpostulated for amphotericin B toxicity; increased sodium load at the glomerulus may help preventthat feedback. One clinician (Foil 1986), uses 5 ml/kg of normal saline given in two portions, beforeand after amphotericin B dosing and states that is has been "... helpful in averting renalinsufficiency... ".
Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and manyclinicians 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 overdoseof amphotericin B. Because of the toxicity of the drug, dosage calculations and solution preparationprocedures should be double-checked. If an accidental overdose is administered, renal toxicity maybe 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 orvancomycin.Amphotericin B therapy may cause potassium-loss or hypokalemia. This may be of particularconcern in patients receiving cardiac glycosides (e.g., digoxin), skeletal muscle relaxants, orother potassium-depleting drugs (e.g., thiazide or loop diuretics). Corticosteroids mayexacerbate 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.) havealso been reported against fungi susceptible to amphotericin B. Antagonism of activity has beensuggested between amphotericin B and miconazole. Further studies need to confirm this, however.
Reconstitution with saline solutions or with solutions containing a preservative may causeprecipitation.