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
CCC 700 6

Critical Care

Compendium

REFERENCES

FOAM and web resources

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

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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