Echinocandins (original) (raw)

OVERVIEW

Introduction

The echinocandins include anidulafungin, caspofungin, and micafungin and are a relatively new class of antifungal agents that are administered parenterally and are used in therapy or prevention of serious, invasive aspergillosis and candidal infections. All three agents can cause transient and asymptomatic serum aminotransferase elevations, and individual instances of acute liver injury have been observed during therapy with these agents, but none has been definitely shown to cause clinically apparent acute drug induced liver injury.

Background

The echinocandins are a relatively new class of antifungal agents, whose activity is due to inhibition of glucan synthetase, the enzyme that is responsible for synthesis of β-1, 3-D-glucan, an essential component of the cell wall of filamentous fungi, such as Aspergillus and Candida species. This enzyme inhibition results in alteration in the fungal membrane integrity, followed by cell ballooning and, for Candida cells, lysis. Three echinocandins are available for use: caspofungin (kas" poe fun' jin), micafungin (mye" ka fun' jin) and anidulafungin (ay nid" ue la fun' jin). Caspofungin was approved for use in the United States in 2001, micafungin in 2005 and anidulafungin in 2006. All three are given intravenously and currently approved for therapy of esophageal candidiasis and for severe, disseminated or invasive candidiasis. Caspofungin is also approved for use as a secondary therapy of invasive aspergillosis and as empirical therapy for presumed fungal infection in febrile, neutropenic patients. Micafungin is also approved for prophylaxis against candidiasis in hematopoietic stem cell transplant recipients. Caspofungin is available under the brand name Cancidas in a formulation for intravenous use, the recommended dose in adults being 70 mg on the first day of treatment followed by 50 or 100 mg daily. Micafungin is available under the brand name of Mycamine in an intravenous formation, the recommended dosage being 50 mg daily for prophylaxis and 100 to 150 mg daily for therapy of candidemia. Anidulafungin is available under the brand name of Eraxis in intravenous formulations and the recommended dosage for disseminated candidal infection is 200 mg on day 1 followed by 100 mg daily. The echinocandins are administered intravenously in a slow infusion over one hour (to decrease the risk of acute infusion reactions). Common side effects include phlebitis and the histamine-like reaction marked by rash, urticaria, flushing, bronchospam, hypotension and facial swelling.

Hepatotoxicity

Transient elevations in liver enzymes have occurred in 2% to 15% of patients treated with the echinocandins, typically returning to baseline after withdrawal of therapy. Clinically apparent hepatotoxicity has occurred in isolated cases; however, a causal relationship to the antifungal agent is often difficult to prove, as these agents are typically used in persons who are critically ill and have other conditions that are associated with liver injury. The largest experience has been with caspofungin, which may have a higher rate of serum enzyme elevations than with micafungin or anidulafungin and has more frequently been linked to cases of acute, symptomatic liver injury. Nevertheless, the product label for all three echinocandins mentions adverse events of serum enzyme elevations, hepatitis and acute liver failure.

Likelihood score: D (possible cause of clinically apparent liver injury).

Mechanism of Injury

The cause of serum aminotransferase elevations during echinocandin therapy is unknown. In preclinical studies in animals, highest drug concentrations are found in the liver and a direct toxic effect or production of a toxic intermediate may be the cause of the abnormalities.

Outcome and Management

The liver injury seen with caspofungin, micafungin and anidulafungin rarely progresses beyond mild serum enzyme elevations. Caution should be taken in patients with preexisting hepatic insufficiency in whom the likelihood of severe acute liver injury appears to be greatest. Product labels for the echinocandins recommend monitoring of liver tests during therapy, particularly in patients with underlying liver disease. The effects of rechallenge and cross reactivity to hepatic injury among the echinocandins has not been evaluated.

Drug Class: Antifungal Agents

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Anidulafungin – Eraxis®

Caspofungin – Cancidas®

Micafungin – Mycamine®

DRUG CLASS

Antifungal Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

ANNOTATED BIBLIOGRAPHY

References updated: 05 July 2017

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  (Textbook of pharmacology and therapeutics; the echinocandins have activity against fungal organisms acting to inhibit glucan synthesis; the 3 agents in clinical use have similar mechanism of action, but different pharmalogical properties).
• Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, Lupinacci R, et al.; Caspofungin Invasive Candidiasis Study Group. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347: 2020-9. [PubMed: 12490683]
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• Goto N, Hara T, Tsurumi H, Ogawa K, Kitagawa J, Kanemura N, Kasahara S, et al. Efficacy and safety of micafungin for treating febrile neutropenia in hematological malignancies. Am J Hematol 2010; 85: 872-6. [PubMed: 20882524]
  (Among 53 patients with febrile neutropenia treated with micafungin, 6 developed AST elevations, but all were transient, mild [<3 times ULN], and asymptomatic).
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  (Among 121 patients with invasive fungal infections randomized to receive either micafungin or caspofungin, ALT elevations occurred in 8.3% of caspofungin vs 6.7% of micafungin treated patients and were above 5 times ULN in 0% vs 3%, but no patient developed clinically apparent liver injury with jaundice).
• Kobayashi R, Suzuki N, Yoshida M, Iizuka S, Suzuki D, Sano H, Kudoh T. Efficacy and safety of micafungin for febrile neutropenia in pediatric patients with hematological malignancies: a multicenter prospective study. J Pediatr Hematol Oncol 2013; 35: e276-9. [PubMed: 23743960]
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  (Retrospective analysis of safety of two doses of micafungin for invasive fungal infections, found any elevation in ALT in 26% of 58 recipients of standard dose [150 mg/day: n=58] vs 27% of 26 recipients of high dose [300 mg/day], and elevations above 5 times ULN in only 1 patient in each group).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]
  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to an echinocandin).
• Jung DS, Tverdek FP, Jiang Y, Kontoyiannis DP. Switching to anidulafungin from caspofungin in cancer patients in the setting of liver dysfunction is associated with improvement of liver function tests. J Antimicrob Chemother 2015; 70: 3100-6. [PubMed: 26311837]
  (In a retrospective study of 61 patients who developed abnormal liver tests during treatment with caspofungin and were then switched to anidulafungin, values improved overall, mean ALT falling from 132 to 71 U/L and bilirubin from 2.5 to 2.2 mg/dL, suggesting that anidulafungin is less hepatotoxic than caspofungin).
• Kyriakidis I, Tragiannidis A, Munchen S, Groll AH. Clinical hepatotoxicity associated with antifungal agents. Expert Opin Drug Saf 2017; 16: 149-65. [PubMed: 27927037]
  (Review of the hepatotoxicity of antifungal agents discusses the frequency of serum enzyme elevations during anidulafungin, caspofungin and micafungin therapy but not clinically apparent liver injury).