Amphotericin B (conventional and liposomal)

CLASS OF DRUG

• amphipathic and amphoteric polyene macrolide (derived from Streptomyces nodosus)
• Anti-fungal agent

PHARMACEUTICS

IV formulations

• Conventional amphotericin B (C-AMB) 
  • 50,000 units/vial
  • Formulated with deoxycholate, which forms micelles (0.035 nm) to overcome water insolubility of amphotericin B at pH 7
  • Yellow powder that forms a colloid of 0.4um particles in water (can be trapped by 0.22um filters used in IV lines)
• Liposomal amphotericin B (L-AMB)
  • 50mg vials
  • Lyophilised powder
  • Small (100 nm), unilamellar liposomal vesicle formulation when resonconstituted with sterile water for IV use
• Other lipid formulations with distinct pharmacological characteristics also exist:
  • amphotericin B colloidal dispersion (ABCD) containing cholesteryl sulfate
  • amphotericin B lipid complex (ABLC) formulations containing 2 phospholipids

Other

• Amphotericin lozenge 20mg (oral topical use)

DOSING

C-AMB

• 0.3-0.6 mg/kg IV via slow infusion (e.g. 6 hours) in 5% glucose via a dedicated line

L-AMB

• 3-6 mg/kg IV over 1-2 hours via a dedicated or 5% glucose-flushed line

Alternate routes have been used:

• Intra-thecal C-AMB for Coccidiodes meningitis
• Intra-ocular C-AMB (and vitrectomy) for fungal endophthalmitis
• Inhalational L-AMB

INDICATIONS

Deep and/or systemic mycoses including:

• Candida esophagitis and systemic candidiasis
• Invasive mucormycosis 
• Cryptococcal meningitis (with-5 flucyosine)
• Severe or rapidly progressive endemic mycoses (histoplasmosis, blastomycosis, coccidiomycosis, penicilliosis)
• invasive aspergillosis (salvage therapy)
• Neutropenic sepsis unresponsive to anti-bacterials

Protozoal infections:

• Amoebic meningitis
• Leishmaniasis

CONTRA-INDICATIONS/ PRECAUTIONS

Known hypersensitivity

Precautions

• Dose adjust if:
  • renal impairment
  • renal replacement therapy
  • Cardiac dysfunction (may not tolerate infusino reactions)

Where possible, azoles or echinocandins are generally preferred due to their favourable adverse effect profiles

MECHANISM OF ACTION

• Amphotericin B binds ergosterol in the membrane of sensitive fungi
  • forms aggregates that sequester ergosterol and disrupt cell membrane function resulting in fungal cell death and/or form pores that increase cell membrane permeability and leakage resulting in cell death (K+ and Mg2+ efflux,inhibition of glycolysis, and influx of protons)
  • Infusion reactions are due to induction of proinflammatory response in innate immunity cells signalling through TLR2 and CD14. L-AMB diverts this to a TL4 response resulting in less upregulation of the pro-inflammatory response and an attenuated infusion reaction.
• Broadest spectrum anti-fungal currently known
  • Fungicidal
  • limited activity against the protozoa Leishmania spp. and Naegleria fowleri
  • No anti-bacterial activity

PHARMACOKINETICS

Not that different amphotericin formulations have different pharmacokinetic characteristics due to their different lipid contents. Information on C-AMB and L-AMB is presented below.

• A: negligible oral bioavailability; IV L-AMB achieves higher concentrations (Cmax) than C-AMB (L-AMB has less uptake by phagocytic system)
• D: 95% protein binding (lipoproteins); VD 2-4 L/kg for C-AMB and 0.1 L/kg for L-AMB; initial plasma t1/2 = 24-48h for C-AMB with slow redistribution from tissues (non-linear behaviour at high concentrations). Accumulates preferentially in liver and spleen, a lesser extent in lungs and kidneys, and little penetration into brain, CSF, vitreous humour, or amniotic fluid.
• M: probable hepatic metabolism
• E: <5% of C-AMB excreted unchanged in the urine and feces at 24 week (L-AMB even less, presumably remains sequestered in tissues); Clearance 0.5-1 mL/min/kg for C-AMB and 0.2 mL/min/kg for L-AMB; terminal elimination t1/2 = 15 days for C-AMB and 152h for L-AMB.

ADVERSE EFFECTS

C-AMB has a higher risk of acute kidney injury and infusion reactions, and an overall worse adverse effect profile, than other formulations such as L-AMB

• Nephrotoxicity (dose-dependent; usually reversibl; increased with concurrent nephrotoxic agents)
  • Common with C-AMB; L-AMB is the least nephrotoxic formulation
  • Renal tubular acidosis with K and Mg wasting
  • Acute kidney injury
• Infusion-related reactions (least common with L-AMB; <1 hour duration; tend to decrease with repeated infusions)
  •  Fever, chills are common
  • Tachypnea, stridor, and hypotension
  • Phlebitis 

Other adverse reactions:

• Hypokalemia
• Hypomagnesaemia
• Hepatotoxicity
• GI: anorexia, nausea, vomiting, weight loss
• CNS: headache, visual disturbance, hearing loss, convulsions, peripheral neuropathy
• Dysrhythmias
• arthralgia, myalgia
• pulmonary oedema
• nephrogenic diabetes insipidus
• ​​Blood dyscrasias (anaemia, leukopenia, thrombocytopenia)
• severe cutaneous adverse reactions (SCAR)
• Hypersensitivity (bronchospasm, anaphylaxis are rare)

DRUG-DRUG INTERACTIONS (DDIs)

Additive effects with other nephrotoxic agents and drugs will similar adverse effect profiles

PREGNANCY/ LACTATION

Pregnancy Category B

Not known if excreted into breast milk

OTHER

Use of C-AMB

• C-AMB is the cheapest formulation, access to other formulations may be limited in resource-poor settings
• C-AMB is tolerated better in neonates than in other groups so is still used in this setting

Infusion-related reactions

• Pre-treatment with paracetamol and/or hydrocortisone 0.7 mg/kg at start of infusing
• pethidine/ meperide may be used for treatment

Nephrotoxicity

• IV fluid loading prior to infusion appears to be protective (e.g. 1L 0.9% NaCl)

Monitoring

• FBC
• UEC
• LFTs

REFERENCES

FOAM and web resources

• FDA product information – Ambisome
• LITFL CCC – Fungi and anti-fungal agents

Journal articles and textbooks

• Brunton, L., Hilal-Dandan, R., Knollman, B. (2017). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition. United States: McGraw-Hill Education. Ch 61.
• Dockrell, H., Goering, R., Chiodini, P. L., Zuckerman, M. (2018). Mims’ Medical Microbiology and Immunology. United Kingdom: Elsevier. Ch 34.
• Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013 Jun;73(9):919-34. doi: 10.1007/s40265-013-0069-4. PMID: 23729001.
• Smith, S., Scarth, E. (2016). Drugs in Anaesthesia and Intensive Care. United Kingdom: Oxford University Press. p30-31