Dose and Administration

Intravenous^1,2,3

1. Administer the first dose over 4 hours or more, then if tolerated administer subsequent doses over 2 hours or more (the exact time may vary using a drug libabry on pump so ensure the full dose is given).

2. Use the first 30 minutes of the first dose as a “test dose” to observe for adverse reactions

3. Incremental treatment is inappropriate¹.

4. If renal impairment during therapy then extend dose interval.

5. May need to treat for 4-6 weeks.

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. Recommended therapeutic serum concentrations of amphotericin B range between 0.2 and 0.5 mg/L; however there is no evidence to support an association between serum drug concentrations and toxicity³. 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. Anaphylaxis, fever, vomiting, hypotension, arrhythmias, seizures
2. Hypokalaemia, hypomagnesaemia² 
3. Anaemia , thrombocytopenia,
4. Nephrotoxicity.
5. Cardiovascular toxicity.
6. Abnormal liver function (discontinue therapy)²
7. Venous irritation, soft tissue injury at IV injection site.

Interactions

1. Increased risk of hypoklaemia. with corticosteroids, loop diuretics (eg. frusemide), and thiazide diuretics (eg. hydrochlorothiazide, chlorothiazide).
2. Increased risk of digitalis toxicity in potassium depleted patients on digoxin.
3. Flucytosine synergistic effect and increased risk of flucytosine toxicity.
4. Increased risk of renal toxicity with other nephrotoxic drugs eg. gentamicin, amikacin, vancomycin.

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. The first 30 minutes of the first dose is used as a test dose to observe for adverse reactions eg. arrhythmias.
4. Concommitant administration of sodium chloride at 4 mmol/kg/day reduces the risk of nephrotoxicity.³
5. Monitor fluid balance, potassium, magnesium, renal and liver function.