Amphotericin B
**Amphotericin B** is a potent, systemic polyene macrolide antifungal agent reserved for progressive, potentially fatal mycotic infections (e.g., blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis). Due to its poor oral bioavailability, it must be administered parenterally (typically IV). The conventional form, **amphotericin B deoxycholate**, is notorious for causing significant **nephrotoxicity**, which limits its use and requires intensive monitoring. Newer **lipid-based formulations** (e.g., liposomal amphotericin B, amphotericin B lipid complex) encapsulate the drug in lipid vehicles. These formulations are significantly less nephrotoxic, allow for higher cumulative doses, and penetrate tissues (like lungs, liver, and spleen) better, though they are considerably more expensive. *Clinical Pearl:* While highly effective against many dimorphic fungi, aspergillosis in dogs and cats often does not respond satisfactorily to amphotericin B therapy.
Mecanismo: Amphotericin B is fungistatic or fungicidal depending on the concentration. It works by binding to sterols—primarily **ergosterol**—in the fungal cell membrane. This binding creates transmembrane pores → alters membrane permeability → allows intracellular **potassium (K+)**, magnesium, and other vital cellular constituents to leak out → leading to fungal cell death. *Toxicity Mechanism:* Mammalian cell membranes contain cholesterol. While amphotericin B has a higher affinity for ergosterol, it still binds to mammalian cholesterol to some degree. This cross-reactivity, particularly in renal epithelial cells, is the primary mechanism behind its dose-limiting nephrotoxicity. It also induces renal vasoconstriction, leading to a decreased glomerular filtration rate (GFR).
Dosificación por especie
- Susceptible systemic fungal infections (Llama) · 1 mg test dose, then initially at 0.3 mg/kg IV over 4 hours... Subsequent doses were increased by 10 mg and given every 48 hours until reaching 1 mg/kg q48h IV for 6 weeks · IV · q48h · 6 weeks · Single case report in a Llama (Coccidioidomycosis).
- Susceptible systemic fungal infections (Rapid-Infusion Technique) · 0.25 mg/kg IV over 5 minutes, then 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given · IV · 3 times a week · Until 9-12 mg/kg accumulated · Dilute in 30 mL of 5% dextrose. Flush with 10 mL D5W before and after.
- Susceptible systemic fungal infections (Slow IV Infusion Technique) · 0.25 mg/kg IV over 4-6 hours, then 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given · IV · 3 times a week · Until 9-12 mg/kg accumulated · Dilute in 250-500 mL of D5W.
- Systemic fungal infections (Dehydrated/compromised) · 0.5 mg/kg diluted in D5W given by slow IV over 15 minutes (normal renal) or 3-6 hours (compromised renal) · IV · Every other day · Until cumulative dose of 8-10 mg/kg (or higher depending on disease) · Must rehydrate before administration. Discontinue if BUN exceeds 50 mg/dL.
- Systemic mycoses (Lipid-based: AmBisome, Amphocil, Abelcet) · Test dose of 0.5 mg/kg; then 1-2.5 mg/kg IV q48h (or Monday, Wednesday, Friday) for 4 weeks or until the total cumulative dose is reached · IV · q48h · 4 weeks or until cumulative dose reached · 1 mg/kg for susceptible yeast/dimorphic fungi (cumulative 12 mg/kg); 2-2.5 mg/kg for resistant filamentous fungi (cumulative 24-30 mg/kg).
- Systemic mycoses (ABLC; Abelcet) · 2-3 mg/kg IV three days per week for a total of 9-12 treatments (cumulative dose of 24-27 mg) · IV · 3 days per week · 9-12 treatments · Dilute to 1 mg/mL in D5W and infuse over 1-2 hours.
Vías de administración
Contraindicaciones
- Patients with known hypersensitivity to amphotericin B (unless the infection is life-threatening and no alternatives exist)
Efectos adversos
- Nephrotoxicity (very common, dose-dependent)
- Anorexia and vomiting
- Hypokalemia and hypomagnesemia
- Distal renal tubular acidosis
- Phlebitis at injection site
- Cardiac arrhythmias
- Non-regenerative anemia
- Fever (can be mitigated with NSAIDs or low-dose steroids)
- Tachycardia, tachypnea, lethargy, restlessness (horses)
- Calcinosis cutis (dogs)
Interacciones farmacológicas
- Corticosteroids · May exacerbate the potassium-losing effects of amphotericin B.
- Digoxin · Amphotericin B-induced hypokalemia may exacerbate digoxin toxicity.
- Flucytosine · In vitro synergy against Cryptococcus and Candida, but may also increase flucytosine toxicity. · minor
- Nephrotoxic Drugs (Aminoglycosides, Polymyxin B, Cisplatin, Cyclosporine, etc.) · Additive renal toxicity; avoid concurrent or sequential use if possible.
- Potassium-Depleting Drugs (Thiazide or Loop Diuretics) · Increased risk of severe hypokalemia.
- Saline Solutions or Preservative-containing Solutions · Reconstituting amphotericin B deoxycholate with these solutions may cause precipitation.
- Skeletal Muscle Relaxants (Tubocurarine) · Amphotericin B-induced hypokalemia may enhance curariform effects.
- Fluorouracil · Amphotericin may increase the toxic effects of fluorouracil. · major
- Doxorubicin · Amphotericin may increase the toxic effects of doxorubicin. · major
- Methotrexate · Amphotericin may increase the toxic effects of methotrexate. · major
- Nephrotoxic drugs · Concurrent use significantly increases the risk of severe nephrotoxicity. · major
Monitorización
- BUN and serum creatinine (before each dose or every other day during dose escalation, then at least weekly)
- Serum electrolytes including sodium, potassium, and magnesium (weekly)
- Liver function tests (weekly)
- CBC and Packed Cell Volume (PCV) (weekly)
- Urinalysis (weekly)
- Total plasma protein (TPP) (at least weekly)
- Body weight
Sobredosis
Acute intravenous overdose reports are rare. Because of the severe toxicity of the drug, dosage calculations and solution preparation procedures must be double-checked. If an accidental overdose occurs, **renal toxicity** is the primary concern. Toxicity may be minimized by aggressively administering **intravenous fluids** and **mannitol** to maintain GFR and promote diuresis.
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