Dose and Administration

1. Initial dose: 0.1-0.3 mg/kg IV infusion over 2-6 hours.
2. Maintenance dose: 0.5-1 mg/kg IV every 24 hours or every 72 hours.
   (0.3 mg/kg if used concurrently with flucytosine).
   Infuse over 2-6 hours.
3. May need to treat for 4-6 weeks. Dose does need to be reduced with pre-existing impaired renal function. However, if GFR falls below 10% of normal during therapy, withhold dose for 2-5 days.

Indications

1. Systemic candidiasis.
2. Congenital candidiasis.
3. Other systemic fungal infections.

Contraindications and Precautions

1. Hypersensitivity to amphotericin B.
2. Minor, superficial fungal infections.
3. Caution in preterm infants, especially extreme immaturity.
4. Caution in infants with renal, hepatic or gastrointestinal dysfunction.

Clinical Pharmacology

Amphotericin B is a polyene antifungal antibiotic that is active against a wide range of yeasts and yeast-like fungi including Candida albicans. The mechanism of action depends on its binding to a sterol moiety, ergosterol, present in the membrane of sensitive fungi. May be fungicidal or fungistatic, depending on the drug concentration obtained and the sensitivity of the fungus.

Absorption from the gastrointestinal tract is negligible, even with very large doses. After IV administration only a small percentage of the drug remains in the plasma compartment. High binding (> 90%) to human plasma protein. CSF concentrations of amphotericin B are only 2-4% of the serum concentrations. Details of tissue distribution and metabolism of amphotericin B are not known. No comprehensive studies of pharmacokinetics have been reported for infants. Drug may accumulate in tissues to a significant concentration and be excreted renally for months.

Dosage schedules for amphotericin B have been devised following observations of toxicity with large doses and other clinical experiences. The initial dose is doubled on each subsequent day until the desired dosage is achieved. The usual maintenance dose is 0.5-1.0 mg/kg IV given daily or every other day over 2-6 hours. Recommended therapeutic serum concentrations of amphotericin B range between 0.2 and 0.5 mg/L. No objective data exists regarding the appropriate length of therapy required, although most infants have been treated for an average of 40 days (range 14-70 days). Amphotericin is frequently employed in combination with flucytosine.

Possible Adverse Effects

1. Venous irritation, soft tissue injury at IV injection site.
2. Fever.
3. Gastrointestinal disturbances (nausea, vomiting, haemorrhagic gastroenteritis).
4. Hypocalcaemia.
5. Anaemia (common), thrombocytopenia, neutropenia (rare).
6. Nephrotoxicity.
7. Cardiovascular toxicity.
8. Seizures.
9. Acute liver failure.

Interactions

1. Corticosteroids enhance potassium depletion.
2. Digoxin increases risk of digitalis toxicity in potassium depleted patients.
3. Flucytosine synergistic effect.
4. May increase renal toxicity with other nephrotoxic drugs.

Special Considerations

1. Amphotericin B should be used primarily for treatment of infants with progressive and potentially fatal fungal infections.
2. Amphotericin must be used under close clinical supervision. Toxic manifestations are not fully characterised.
3. Starting doses have ranged from 0.1 to 0.3 mg/kg given IV over a period of 2-6 hours. The dose is increased by 0.1-0.2 mg/kg/day, as tolerated, until a maximum of 1 mg/kg/day is achieved. The usual maintenance dose is 0.5-1.0 mg/kg/day given daily or every other day over 2-6 hours.
4. Recommended therapeutic serum concentrations of amphotericin range between 0.2 and 0.5 mg/L. However, serum levels are not routinely measured because of uncertainties with their interpretation.