Caspofungin


Article Author:
Laurena Dongmo Fotsing


Article Editor:
Tushar Bajaj


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/14/2019 2:27:00 PM

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 approval for the treatment of 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 osteomyelitis or infectious arthritis
  • Oropharyngeal candidiasis (thrush)
  • Candida 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 levels 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.

Reduction of the dose in hepatic insufficiency is recommended based on Child-Pugh (C-P) score. In critically ill patients, however, 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 maintenance dose of caspofungin is recommended with coadministration of potent inducers of cytochrome P450 3A4 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. A loading dose followed by a lower once-daily dose is therefore required to attain an initial therapeutic plasma level 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. It should neither 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 - An initial dose of 70 mg (loading dose) followed by 50 mg once IV daily. The daily dose may be increased to 70mg if there is no response or if cytochrome P450 3A4 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/m2 loading dose on day 1, followed by 50 mg/m2 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 1 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 erosions similar to those seen in toxic epidermal necrolysis (TEN). In fact, a case report by Lee et al. describes the development of a skin 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 known hypersensitivity 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, skin 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. These factors have led to its use for the treatment of several medical conditions.[1][8] However, it is important to note the side effects, albeit low in incidence, of caspofungin (Level II).[21] 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 inducers, which cause caspofungin levels to be subtherapeutic (Level I).[6] Before prescribing caspofungin for patients who are taking several medications, the physician should consult with:

  • The clinical pharmacist, to ensure that concomitant administration of the patient’s current medications and caspofungin is permissible. In the event, there is drug-drug interaction, the clinical pharmacist should notify the prescribing physician, who can then make a decision as to 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 with inpatient administration, and monitoring to treatment effectiveness as well as checking for adverse effects of the medication and reporting findings to the healthcare team.

Ultimately, adopting an interprofessional team approach with collaboration with infectious diseases 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 V]


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Caspofungin - Questions

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A 46-year-old female with a past medical history of HIV presents with a 3-week history of pain and difficulty swallowing. Oral fluconazole was prescribed ten days ago following a similar presentation, but the symptoms have not yet resolved. Her current medications are antiretrovirals and trimethoprim-sulfamethoxazole for Pneumocystis pneumonia prophylaxis. A month ago, her CD4 count was 60/µl, and her viral load was 315,000 copies/mL. Endoscopy reveals white plaques. The provider decides to start a new medication. Which markers should be monitored closely as a result of this regimen change?



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A 53-year-old hospitalized woman with a past medical history significant for diabetes, basal skin cancer, hypertension, and leukemia is evaluated for a new onset of chest pain, persistent fever, and hemoptysis. She was admitted four days ago due to fever and three episodes of cough productive of bright red blood. A diagnosis of invasive aspergillosis was made, and she was started on voriconazole. The team in charge of her care is planning to add a second drug to her current regimen. How is the new drug administered?



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A 35-year-old hospitalized woman with a history of paraplegia secondary to spinal cord injury and asthma is evaluated for persistent fever. She was admitted two weeks ago due to septic shock from an infected sacral pressure ulcer. After intravenous fluids, vasopressors, wound debridement, and a course of broad-spectrum antibiotics, the patient’s condition improved. But, in the past four days, she has been having recurring fevers. Vital signs include temperature 38.9 C (102 F), blood pressure 120/80 mmHg, and pulse 90/min. The physical exam reveals several white patches on the oral mucosa. The patient has a central venous catheter inserted in her right arm; there is mild tenderness upon palpation of the catheter site but no surrounding erythema. The sacral pressure ulcer has pink granulation tissue with a mild amount of serosanguinous fluid. A new set of blood cultures was ordered and grew budding yeasts. Which of the following drugs has the most favorable toxicity profile and would be appropriate for this patient?



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A 65-year-old hospitalized man with a history of seizures, hypertension managed with lisinopril and hydrochlorothiazide, and chronic myelocytic leukemia is evaluated in the morning due to recurrent fevers. A new anti-epileptic drug was recently added to his regimen. He was admitted 3 days ago for neutropenic fever and started on caspofungin. He denies any headaches, cough, abdominal pain, diarrhea, constipation, or dysuria. Vital signs include blood pressure 134/74 mmHg, temperature 38.5 C (101.4 F), pulse 73/min, and respirations 14 breaths/minute. The physical exam is unremarkable. The provider suspects that the persistent fevers could be associated with the new anti-epileptic agent. How did the drug most likely exert its effect?



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A 21-year-old hospitalized male is evaluated for persistent fever and chills for the last five days. He denies any night sweats, chest pain, shortness of breath, abdominal pain, or new-onset skin rash. He presented to the emergency department 5 days ago with a similar presentation for 24 hours. The patient was immediately admitted to the hospital and given piperacillin-tazobactam as initial therapy. The chest x-ray on admission did not show any abnormalities. He has a history of peripheral T-cell lymphoma for which he is undergoing chemotherapy. Vitals include temperature is 39 C (102.2 F), blood pressure 122/84 mmHg, pulse 104/min, and respirations 18/min. Physical examination is unremarkable. Laboratory results: leukocytes 420/µl with 19% neutrophils, hemoglobin 8 g/dL, hematocrit 24%, and platelets 68,000/µl. An antifungal medication that interferes with the cell wall synthesis by inhibiting the enzyme ß(1,3)-d-glucan synthase is added to his regimen. Which class of drugs does this drug belong to?



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A 32-year-old woman with a past medical history of acute myelocytic leukemia presents complaining of cough with a small amount of bright red blood. She had a one-week history of cough productive of thick brown sputum, fever, and pleuritic chest pain. A chest x-ray done 5 days ago revealed right upper lobe infiltrate; she was immediately started on oral antibiotics by her primary care provider. However, the symptoms persist. The patient underwent allogeneic stem cell transplantation for his acute myelocytic leukemia 5 weeks ago, which was complicated by acute graft-versus-host disease and neutropenia. Temperature is 39.5 C (103. 1 F), blood pressure is 100/62 mmHg, the pulse is 110/min, and respiratory rate is 20/min. The physical exam is significant for right-sided crackles. Laboratory results show leukocytes 1500/microL, hematocrit 28%, and platelets 138,000/microL. Chest x-ray shows a right upper lobe infiltrate, increased in size when compared to the previous x-ray. Chest CT-scan reveals several nodular lesions with surrounding ground-glass opacities in the right upper lobe. Sputum gram stain shows no organisms. What is the best initial therapy for this patient?



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Caspofungin - References

References

Patterson TF,Thompson GR 3rd,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. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016 Aug 15;     [PubMed]
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