Caspofungin

DRUG CLASS

• Echinocandin (semisynthetic lipopeptide)
• Anti-fungal derived from Glarea lazoyensis

PHARMACEUTICS

• Off-white lyophilised powder reconstituted in water for immediate use
• 50 mg and 70 mg vials (with 35.7 mg and 50 mg sucrose respectively)
• Store at 2-8C
• Reconstituted infusion (e.g. 100 mL or 250 mL 09% NaCl or Hartmans) can be safely stored for up to 24 hours at 25C or 48h at 2-8C.
• Do not reconstitute in glucose containing infusions as caspofungin is not stable with glucose.

DOSING

• 70mg IV loading dose followed by 50mg IV daily (70mg in adults >80kg)
• Slow infusion over 1 hour
• Duration depends on severity of infection and response to treatment
  • continue for 14 days after last positive blood culture for invasive candidiasis 
  • minimum 14 days for most fungal infections, and at least 7 days after neutropenia and clinical symptoms resolve
  • continue for 72 hours after resolution of neutropenia in neutropenic sepsis

MECHANISM OF ACTION

Antifungal action

• Echinocandins inhibit synthesis of beta(1,3)-D-glucan
  • Essential component of cell walls of many yeast and moulds
  • Not present in mammalian cells
• Active against Aspergillus spp (fungistatic) and Candida spp (fungicidal), including:
  • Those with acquired resistance to amphotericin B, 5-flucytosine, and fluconazole
  • Isolates with multiple transport mutations
  • biofilms (more so than azoles and polyenes)
• Echinocandin resistance reported for Aspergillus species and non-albicans Candida spp.

INDICATIONS

• Invasive candidiasis
• Oesophageal candidiasis
• Invasive aspergillosis (intolerant or refractory to other therapies)
• Empiric treatment of neutropenic fever with high risk/ suspected fungal infection

CONTRA-INDICATIONS

• Hypersensitivity
• Metabolic disorders susceptible to sucrose load (e.g. fructose intolerance or sucrase-isomaltase insufficiency)

Precautions

• Moderate hepatic insufficiency: Child Pugh score 7 to 9
  • Reduce daily dose from 50mg to 35mg daily
• No adjustment for renal disease or renal replacement therapy

PHARMACOKINETICS

• A: poor oral availability; given IV
• D: 97% protein binding (albumin); 92% distributed to tissues; peak tissue concentration at 1-2 days
• M: spontaneous degradation to open ring structure, followed by hydrolysis and N-acetylation (including significant liver metabolism). Small amount of irreversible covalent adducts formed between intermediate products and plasma proteins.
• E: Plasma clearance 1-12 mL/min determined by distribution; Polyphasic elimination from plasma: short alpha-half time, beta half time of 9-11 h, and gamma half-time 45 h. Excreted via urine (41%) and feces (34%).

ADVERSE EFFECTS

• headache
• nausea, diarrhoea
• phlebitis
• pruritus

Uncommon/ rare

• Hypokalaemia, hypercalcaemia
• Hepatic dysfunction
• Anaemia, leucopenia, neutropenia
• Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
• Peripheral oedema
• Hypersensitivity

DRUG-DRUG INTERACTIONS (DDIs)

• Ciclosporin increases casponfungin levels; monitor LFTs
• Tacrolimus and caspofungin may affect each other’s levels; monitor tacrolimus levels and LFTs.
• Rifampicin and other CYP3A4 inducers may cause slight reduction in caspofungin levels.

OTHER

Other echinocandins can be used as alternatives to caspofungin, neither require dose reduction in hepatic or renal disease:

• Anidulofungin (e.g. 200mg IV loading dose, followed by 100mg IV daily) – spontaneously degrades in plasma
• Micafungin (e.g. 100mg IV daily) – mild CYP3A4 inhibitor, may be associated increased risk of liver tumours

Echinocandins have a more favourable safety profile than other anti-fungals (Mourad and Perfect, 2018)

REFERENCES

FOAM and web resources

• Australian Product Information – Caspofungin

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.
• Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J Antimicrob Chemother. 2018 Jan 1;73(suppl_1):i26-i32. doi: 10.1093/jac/dkx446. PMID: 29304209; PMCID: PMC6636388.