Caspofungin

Continuing Education Activity

Caspofungin is a drug in the echinocandins class of medications used to manage and treat several medical conditions. These conditions include febrile neutropenia, candida infections, invasive candidiasis, esophageal candidiasis, and invasive aspergillosis. This activity reviews the mechanism of action, adverse reactions profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) critical for managing and treating the conditions mentioned above by an interprofessional team.

Objectives:

• Identify the mechanism of action of caspofungin.
• Review the potential adverse effects of caspofungin.
• Describe the appropriate monitoring for patients receiving caspofungin.
• Explain the importance of collaboration and communication among the interprofessional team to ensure appropriate administration of caspofungin and improve patient clinical outcomes.

Indications

Caspofungin acetate is the first antifungal medication of the echinocandins class to receive marketing approval from the Food and Drug Administration (FDA). Its introduction was in 2001, approved for use in adults and pediatric patients (3 months of age and older).[1]

The FDA-approved indications include:

• Febrile neutropenia: It is defined as a fever over 101 F (or 38 C) for 1 hour, with either an absolute neutrophil count (ANC) of less than or equal to 500 cells/microliter or alternately, an ANC of below or equal to 1000 cells/microliter with a projected nadir of under or equal to 500 cells/microliter. According to the Infectious Diseases Society of America (IDSA), empiric antifungal therapy is their recommendation for high-risk patients with persistent febrile neutropenia despite broad-spectrum antibiotic therapy. These antifungals include caspofungin, among others.[2]

• Invasive candidiasis: In a double-blind, randomized trial that compared the efficacy of caspofungin with amphotericin B in patients with invasive endocarditis, the more favorable outcome occurred in 73.4% of caspofungin recipients as opposed to 61.7% of amphotericin B recipients.[3] For the initial treatment of candidemia, the echinocandins are preferred agents over azoles under the following conditions: identification or suspicion of either C. glabrata or C. krusei or the patient’s candidemia was refractory to treatment with an azole agent.[4]

• Candida infections: candidemia, intra-abdominal abscesses, peritonitis, and pleural space infections

• Esophageal candidiasis: Several studies have found caspofungin to have a favorable treatment response comparable to fluconazole.[5][6] A year after the introduction of caspofungin, in 2002, Villanueva et al. conducted a double-blind, randomized trial with 177 HIV patients diagnosed with esophageal candidiasis. Researchers randomly assigned patients to two groups: caspofungin (50 mg IV) or fluconazole (200 mg IV), once daily for 7 to 21 days. There was a combined response of symptom resolution and significant endoscopic improvement 5 to 7 days after discontinuation of treatment. The treatment response was 81% and 85% for the patients in each group, caspofungin, and fluconazole, respectively.[5] The same year, a retrospective analysis performed by Kartsonis et al. demonstrated the effectiveness of caspofungin in fluconazole-resistant or refractory esophageal candidiasis. The treatment was successful in 11 of the 14 patients with in-vitro resistant isolates and 7 of the 11 patients with refractory disease. The use of caspofungin also appears to be associated with less toxic effects than IV amphotericin B in the management of esophageal candidiasis.[6][7]

• Invasive aspergillosis: Caspofungin has FDA approval to treat invasive aspergillosis in patients who are refractory to or intolerant of voriconazole, the primary antifungal agent.[1][8][9] Echinocandins are not recommended as first-line therapy.[2]

The non-FDA approved indications are:

• Candida spp. osteomyelitis or infectious arthritis
• Oropharyngeal candidiasis (thrush)
• Candida spp. cardiovascular system infections such as endocarditis and suppurative thrombophlebitis
• Candidiasis prophylaxis and aspergillosis prophylaxis in high-risk patients

Mechanism of Action

Caspofungin, along with other echinocandins, works by noncompetitive inhibition of the enzyme beta-(1,3)-D-glucan synthase, which is a critical component to the synthesis of the fungal cell wall; this enzyme is not present in mammalian cells.[10] 

Caspofungin exhibits a fungicidal activity against Candida species, including triazole-resistant isolates and fungistatic activity against Aspergillus species.[1][10] It displays triphasic nonlinear pharmacokinetics. After an initial intravenous administration of the drug, there is a rapid decrease in plasma concentrations due to tissue distribution, followed by a gradual re-release of the drug from the extravascular tissues as well as slow hepatic metabolism.[11][12] It undergoes hepatic metabolism via hydrolysis and slow N-acetylation into two inactive metabolites; dose reduction is, therefore, advisable in severe hepatic insufficiency.[11][12][13] Caspofungin also undergoes spontaneous disintegration to an open-ring compound.

The reduction of the dose in hepatic insufficiency is recommended based on Child-Pugh (C-P) score. However, in critically ill patients, the dose should not be reduced unless there is evidence of liver cirrhosis.[14] No dose reduction is necessary for renal impairment; echinocandin passage through the membranes seems low because of high protein binding, 97% to albumin.[15] Additionally, an increase in the maintenance dose of caspofungin is recommended with the coadministration of potent inducers of cytochrome P450 3A4 (CYP3A4) metabolism. Some of these agents may include rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, and phenytoin.[6] Concomitant use of caspofungin with cyclosporine has also been linked to increased caspofungin-induced hepatotoxicity, although a number of case reports describe patients treated with both drugs without clinically important signs or symptoms of liver toxicity.[16][17][18][19]

The pharmacokinetics of caspofungin also show an increased accumulation as the dose increases, and there is a dose-related dependency in the time to reach steady-state upon multiple-dose administration. Therefore, a loading dose followed by a lower once-daily dose is required to attain an initial therapeutic plasma concentration and avoid drug accumulation. This approach results in a trough concentration of at least 1 mcg/mL (proposed target concentration in invasive infections; derived from in vitro susceptibility testing of Candida spp.).[13][20] 

Caspofungin has a short alpha-phase half-life (t 1/2 ) of 1 to 2 hours (volume of distribution of 9.7L) and a beta-phase t 1/2 of 9 to 11 hours that exhibits log linearity. Unlike the other phases, the gamma-phase t 1/2 of 40 to 50 hours appears to be nonlinear and is responsible for the accumulation of caspofungin over time. Caspofungin gets slowly eliminated from plasma, with a clearance of 10 to 12 ml/minute. Approximately 75% of a radioactive dose gets recovered after 27 days, with 41% in urine and 35% in feces. Only about 2% of caspofungin is excreted unchanged in the urine.[6][13]

Administration

Caspofungin acetate is administered solely by the intravenous (IV) route. Because the echinocandins have a large molecular weight, they are poorly bioavailable for oral use. The IV infusion should take place slowly over an hour, and it should not be given by IV bolus administration nor mixed or co-infused with other medications. Do not use diluents containing dextrose (alpha-D-glucose). 

The dosage forms include 50 mg and 70 mg.[12] The dosage varies by patient population.

Adult Patients (18 years of age and older)

For all indications except esophageal candidiasis - administer an initial dose of 70 mg (loading dose) followed by 50 mg once IV daily. The daily dose may be increased to 70 mg if there is no response or if cytochrome P450 3A4 (CYP3A4) inducers such as rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, and phenytoin are coadministered. The maximum daily dose should not exceed 70 mg.

For esophageal candidiasis, the dose is 50 mg once daily with no loading dose.

Pediatric Patients (3 months to 17 years of age)

The basis for dosing is on the patient’s body surface area.

For all indications - a single 70 mg/m^2 loading dose on day 1, followed by 50 mg/m^2 once daily 

Hepatic Impairment

The dosage for adult patients with moderate hepatic impairment is reduced: 35 mg once daily, with a 70 mg loading dose on day one where appropriate. 

Drug Interactions

Use of caspofungin with cytochrome P450 3A4 inducers (see above), the daily dose may be increased to 70 mg. The maximum daily dose should not exceed 70 mg. 

For patients not showing any improvement, the daily dose may increase to 70 mg. The maximum daily dose should not exceed 70 mg. 

Adverse Effects

Caspofungin has a relatively low incidence of adverse effects; the most commonly reported adverse events include chills, fever, phlebitis/thrombophlebitis, tachycardia, nausea, vomiting, rash, abdominal pain, headache, and diarrhea.[6] Reports also exist of a modest elevation of aminotransferases has also been reported. 

Caspofungin has been found to cause skin erosions similar to those seen in toxic epidermal necrolysis (TEN). A case report by Lee et al. describes the development of a rash - erythematous macules and plaques - that quickly progressed to blisters and skin erosions after the administration of caspofungin in an 86-year-old-man with disseminated Candida krusei infection.[21]

Contraindications

The main contraindication is a known hypersensitivity reaction to caspofungin acetate or any other ingredients in the formulation.

There is currently inadequate data regarding the use of caspofungin in pregnancy; thus, clinicians should use it cautiously. When treatment of systemic fungal infections is necessary during pregnancy, Amphotericin B is the first-line therapy; other agents are alternatives.[22] 

Monitoring

Given the hepatic adverse effects associated with caspofungin, monitoring the liver function is essential.

Caspofungin is known to release histamine in peripheral blood cells, which predisposes patients to potentially developing histamine-mediated symptoms ranging from severe to fatal anaphylaxis. As a result, monitoring patients for anaphylaxis, rash, or histamine-related reactions (e.g., facial swelling, bronchospasm, a sensation of warmth) is of paramount importance to decrease the risk of morbidity and mortality.[23][24][25]

Toxicity

Although these rarely occur, clinically significant hepatitis, hepatomegaly, hyperbilirubinemia, and there are reports of hepatic failure with the echinocandins. Checking hepatic aminotransferases regularly during caspofungin therapy is thus recommended.

Enhancing Healthcare Team Outcomes

Caspofungin has significant assets, which include its safety profile and minimal drug interactions, but its use still requires the efforts of an engaged interprofessional team. These factors have led to its use in the treatment of several medical conditions.[1][8] However, it is essential to note the side effects, albeit low in incidence, of caspofungin.[21] [Level 2] Monitoring patients’ liver function to minimize toxicity is also critical, especially given the fact this organ metabolizes the drug. Furthermore, caspofungin is associated with some drug-drug interactions, especially CYP450 3A4 (CYP3A4) inducers, which cause caspofungin concentrations to become subtherapeutic.[6] [Level 1] Before prescribing caspofungin for patients who are taking several medications, the physician should consult with:

• The clinical pharmacist ensures that concomitant administration of the patient’s current medications and caspofungin is permissible. In the event of drug-drug interactions, the clinical pharmacist should notify the prescribing physician, who can then decide the appropriate course of action based on the patient’s clinical findings and comorbidities.

• The obstetrician-gynecologist, as the use of caspofungin in pregnancy, is currently not recommended in the US.[22] [Level II] It should only be administered to pregnant women if the potential benefit outweighs the potential risk to the fetus.[6]

Nursing will also play a significant role in inpatient administration, monitoring treatment effectiveness, checking for adverse effects of the medication, and reporting findings to the healthcare team.

Ultimately, adopting an interprofessional team approach with collaboration with infectious disease physicians and other sub-specialties, primary care physicians, nurses, pharmacists, and other healthcare personnel is essential to facilitate the administration of the drugs based on current guidelines and maximize patient outcomes while minimizing any adverse reactions. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Morris MI, Villmann M. Echinocandins in the management of invasive fungal infections, part 1. Am J Health Syst Pharm. 2006 Sep 15;63(18):1693-703. [PubMed: 16960253]

2.

Patterson TF, Thompson GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63(4):e1-e60. [PMC free article: PMC4967602] [PubMed: 27365388]

3.

Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, Lupinacci R, Sable C, Kartsonis N, Perfect J., Caspofungin Invasive Candidiasis Study Group. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002 Dec 19;347(25):2020-9. [PubMed: 12490683]

4.

Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, Sobel JD, Pappas PG, Kullberg BJ., Mycoses Study Group. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012 Apr;54(8):1110-22. [PubMed: 22412055]

5.

Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, Smietana JM, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002 Sep;113(4):294-9. [PubMed: 12361815]

6.

Keating G, Figgitt D. Caspofungin: a review of its use in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis. Drugs. 2003;63(20):2235-63. [PubMed: 14498760]

7.

Kartsonis N, DiNubile MJ, Bartizal K, Hicks PS, Ryan D, Sable CA. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J Acquir Immune Defic Syndr. 2002 Oct 01;31(2):183-7. [PubMed: 12394797]

8.

Morris MI, Villmann M. Echinocandins in the management of invasive fungal infections, Part 2. Am J Health Syst Pharm. 2006 Oct 01;63(19):1813-20. [PubMed: 16990627]

9.

Maertens J, Raad I, Petrikkos G, Boogaerts M, Selleslag D, Petersen FB, Sable CA, Kartsonis NA, Ngai A, Taylor A, Patterson TF, Denning DW, Walsh TJ., Caspofungin Salvage Aspergillosis Study Group. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. 2004 Dec 01;39(11):1563-71. [PubMed: 15578352]

10.

Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of antifungals. Ann Pharmacother. 2009 Oct;43(10):1647-57. [PubMed: 19724014]

11.

Stone JA, Xu X, Winchell GA, Deutsch PJ, Pearson PG, Migoya EM, Mistry GC, Xi L, Miller A, Sandhu P, Singh R, deLuna F, Dilzer SC, Lasseter KC. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother. 2004 Mar;48(3):815-23. [PMC free article: PMC353127] [PubMed: 14982770]

12.

Stone JA, Holland SD, Wickersham PJ, Sterrett A, Schwartz M, Bonfiglio C, Hesney M, Winchell GA, Deutsch PJ, Greenberg H, Hunt TL, Waldman SA. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother. 2002 Mar;46(3):739-45. [PMC free article: PMC127465] [PubMed: 11850256]

13.

Kofla G, Ruhnke M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur J Med Res. 2011 Apr 28;16(4):159-66. [PMC free article: PMC3352072] [PubMed: 21486730]

14.

Kurland S, Furebring M, Löwdin E, Eliasson E, Nielsen EI, Sjölin J. Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels. Antimicrob Agents Chemother. 2019 Jun;63(6) [PMC free article: PMC6535551] [PubMed: 30962329]

15.

Weiler S, Seger C, Pfisterer H, Stienecke E, Stippler F, Welte R, Joannidis M, Griesmacher A, Bellmann R. Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy. Antimicrob Agents Chemother. 2013 Aug;57(8):4053-7. [PMC free article: PMC3719695] [PubMed: 23733471]

16.

Anttila VJ, Piilonen A, Valtonen M. Co-administration of caspofungin and cyclosporine to a kidney transplant patient with pulmonary Aspergillus infection. Scand J Infect Dis. 2003;35(11-12):893-4. [PubMed: 14723374]

17.

Veroux M, Macarone M, Fiamingo P, Cappello D, Gagliano M, Di Mare M, Vizcarra D, Spataro M, Giuffrida G, Sorbello M, Severino V, Veroux P. Caspofungin in the treatment of azole-refractory esophageal candidiasis in kidney transplant recipients. Transplant Proc. 2006 May;38(4):1037-9. [PubMed: 16757256]

18.

Candoni A, Mestroni R, Damiani D, Tiribelli M, Michelutti A, Silvestri F, Castelli M, Viale P, Fanin R. Caspofungin as first line therapy of pulmonary invasive fungal infections in 32 immunocompromised patients with hematologic malignancies. Eur J Haematol. 2005 Sep;75(3):227-33. [PubMed: 16104879]

19.

Groetzner J, Kaczmarek I, Wittwer T, Strauch J, Meiser B, Wahlers T, Daebritz S, Reichart B. Caspofungin as first-line therapy for the treatment of invasive aspergillosis after thoracic organ transplantation. J Heart Lung Transplant. 2008 Jan;27(1):1-6. [PubMed: 18187079]

20.

Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, Herbrecht R, Ruiz-Palacios G, Young JA, Baddley JW, Strohmaier KM, Tucker KA, Taylor AF, Kartsonis NA., Caspofungin High-Dose Study Group. A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis. 2009 Jun 15;48(12):1676-84. [PubMed: 19419331]

21.

Lee MC, Ni YW, Wang CH, Lee CH, Wu TW. Caspofungin-induced severe toxic epidermal necrolysis. Ann Pharmacother. 2010 Jun;44(6):1116-8. [PubMed: 20407030]

22.

Moudgal VV, Sobel JD. Antifungal drugs in pregnancy: a review. Expert Opin Drug Saf. 2003 Sep;2(5):475-83. [PubMed: 12946248]

23.

Biswal S. Complete heart block in a neutropenic patient with aspergillosis: An unusual adverse effect of caspofungins. J Pharmacol Pharmacother. 2012 Oct;3(4):342-4. [PMC free article: PMC3543560] [PubMed: 23326111]

24.

Kounis NG. Caspofungin-induced fatal complete heart block: Another manifestation of Kounis syndrome. J Pharmacol Pharmacother. 2013 Apr;4(2):161-2. [PMC free article: PMC3669582] [PubMed: 23761719]

25.

Cleary JD, Schwartz M, Rogers PD, de Mestral J, Chapman SW. Effects of amphotericin B and caspofungin on histamine expression. Pharmacotherapy. 2003 Aug;23(8):966-73. [PubMed: 12921242]

Disclosure: Laurena Dongmo Fotsing declares no relevant financial relationships with ineligible companies.

Disclosure: Tushar Bajaj declares no relevant financial relationships with ineligible companies.