Amphotericin B

 

Antibiotic Class

Antifungal agent

Antimicrobial Spectrum

Fungi:  Candida albicans, C. tropicalis, C. parapsilosis, C. krusei, C. guilliermondii, Cryptococcus neoformans, Aspergillus fumigatus, A. flavus, A.niger, Absidia corymbifera, Rhizopus oryzae, R. rhizopodiformis, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schencki, Malasezzia furfur

Mechanism of Action

Induces membrane permeability by forming complexes with ergosterol located in fungal membranes, leading to intracellular leakage and cell death. 

Pharmacodynamics

Peak serum level in relation to MIC is the pharmacodynamic parameter of best predictive outcome, while the AUC:MIC ratio and T > MIC are only slightly less predictive.

Pharmacokinetics

Absorption:  generally classified as a non-absorbable drug, however, oral administration may result in low but detectable blood concentrations

Distribution:  minimal amounts enter the aqueous humor, bile, CSF (inflamed or noninflamed meninges), amniotic fluid, pericardial fluid, pleural fluid, and synovial fluid

Metabolism:  elimination half life is approximately 24 hours; only 3% of the toal administered dose of amphotericin B is excreted as unchanged drug

Elimination:  urine; ~ 40% eliminated over 7 day period

Plasma protein binding:  ~90 to 95%

Volume of distribution: 4 L/kg

Adverse Effects

CNS – headache, chills, fever

Renal – nephrotoxicity

Gastrointestinal – dyspepsia, epigastric pain, anorexia, cramping, weight loss

Cardiovascular – hypotension

Respiratory – tachypnea

Hematologic – normochromic normocytic anemia

Other – muscle and joint pain, anaphylaxis (rare), hypomagnesemia, hypokalemia

Dosage

Table 3

Disease state based dosing

Renal Failure:  In case of deterioration of renal function (defined as a doubling of serum creatinine from baseline), a brief cessation of drug administration for one or several days has been advocated.

Hepatic failures:  No dosage adjustment required.

Dosing during Continuous Renal Replacement Therapy

Abbreviations:

CVVH (Continuous venovenous hemofiltration)

CVVHD (Continuous venovenous hemodialysis)

CVVHDF (Continuous venovenous hemodiafiltration)

Amphotericin B deoxycholate:

CVVH: 0.4-1mg/kg q24h

CVVHD or CVVHDF: 0.4-1mg/kg q24h

Amphotericin B lipid complex

CVVH: 3-5mg/kg q24h

CVVHD or CVVHDF: 3-5mg/kg q24h

Amphtericin B liposomal

CVVH: 3-5mg/kg q24h

CVVHD or CVVHDF: 3-5mg/kg q24h

Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD or CVVHDF which combine dialysis with fluid removal.

Contraindications/Warnings/Precautions

Contraindications:  Hypersensitivity to amphotericin B

Precautions:  Anaphylaxis has been reported.  During initial dosing, the drug should be administered under close observation.

Drug Interactions

Aminoglycosides, cyclosporine, antineoplastic agents (cisplatin, nitrogen mustard compounds) – nephrotoxic effects

Skeletal muscle relaxants and digitalis glycosides – hypokalemia may be exaggerated

Flucytosine – amphotericin B may increase the toxicity of flucytosine

Pregnancy

Category B: No evidence of risk in humans but studies inadequate.

Monitoring Requirements

Renal function (monitor Scr), Electrolyes (especially potassium and magnesium)

Generic names/Brand names/Manufacturer