Caspofungin - A Promising Breakthrough for Managing Systemic Fungal Infections

Overview

Caspofungin is a recently developed antimycotic medication that is effectively used in the treatment of invasive (spread through the bloodstream) fungal infections. It belongs to a new group of antifungal agents known as echinocandins. The United States Food and Drug Administration (FDA) approved Caspofungin for clinical use on 26th January 2001. Caspofungin is notably the first echinocandin antifungal to receive a global license for therapeutic use. By exhibiting a novel antifungal activity of blocking the cell wall synthesis of the fungus, Caspofungin is categorized as a glucan synthase inhibitor. It exerts antifungal activity against Candida species, including non-albicans subtypes and Aspergillus species.

Various clinical studies have documented the enhanced clinical efficacy and superior tolerability of Caspofungin. It has a better safety profile and is well tolerated compared to other antifungal agents that are currently used in treating systemic fungal infections. It is injected intravenously and is given to both adults as well as children (from three months of age and above). Also, Caspofungin exhibits negligible potential for drug interactions which favors its concomitant use with other therapies. These unique characteristics make Caspofungin an extremely valuable and essential novel antifungal agent that widens the existing therapeutic armamentarium used in the management of systemic fungal infections.

Indications

Caspofungin is an effective echinocandin antifungal indicated in adults and also pediatric patients (three months of age and above) for treating the following conditions:

FDA-Approved Indications

• As empirical therapy for possible fungal infections (presumptively opportunistic) in neutropenic (reduced number of neutrophils, a type of white blood cells) patients with febrile illness.

• To treat candidemia and other candida infections such as peritonitis, pleural space infections, and intra-abdominal abscesses.

• In the treatment and management of invasive aspergillosis, especially when the patients become refractory and unresponsive, or intolerant to other antifungal therapies.

• In order to treat esophageal candidiasis.

• In the treatment and management of invasive candidiasis in adult as well as pediatric patients aged three months and above.

Non-FDA-Approved Indications

• Osteomyelitis and infectious arthritis due to Candida species.

• Oropharyngeal candidiasis (OPC).

• Cardiovascular infections like endocarditis or suppurative thrombophlebitis that are caused by Candida species.

• As prophylaxis to prevent candidiasis or aspergillosis in susceptible individuals and high-risk patients.

Contraindications

The use of Caspofungin is contraindicated in individuals who are known to develop allergies, hypersensitivity reactions, or anaphylaxis to the drug or any of its components.

Available Strengths and Dosage Forms

• Available Dosage Forms - Caspofungin is available as lyophilized powder or cake (white to off-white in color) in a glass vial containing 50 mg (milligram) or 70 mg of the drug compound to be reconstituted for intravenous (IV) infusion.

• 50-mg Caspofungin Vial -It is a single-dose vial with a plastic cap and a red aluminum band containing 50 mg Caspofungin, which equals 55.5 mg of the active ingredient, caspofungin acetate.

• 70-mg Caspofungin Vial - It is a similar vial marked with a yellow or orange aluminum band containing 70 mg Caspofungin, equivalent to 77.7 mg of the active ingredient, Caspofungin acetate.

• Storage and Handling - These lyophilized vials of Caspofungin are refrigerated and stored at two to eight degrees Celsius (36 to 46 Degrees Fahrenheit). It should be kept away from direct sunlight and out of reach of children.

Recommended Dosage and Administration

• Route of Administration - Caspofungin is administered intravenously as a slow infusion over a duration of one hour only by a trained healthcare provider. It should not be injected into the veins as a single bolus dose (single shot injection).

• Recommended Dosage for Adults -In adult patients (18 years of age and above), 70 mg of Caspofungin is slowly infused (intravenously) as the initial loading dose on day one, followed by 50 mg of the drug (maintenance dose) once per day for all clinical indications excluding esophageal candidiasis.

• In esophageal candidiasis, 50 mg of Caspofungin is administered once per day without the preceding loading dose.

• Recommended Dosage for Children - In pediatric patients (from three months to 17 years of age), the dosing of Caspofungin is calculated according to the body surface area (BSA) of the individuals.

• The initial loading dose of Caspofungin for all clinical indications is 70 mg per square meter which is administered on day one, subsequently followed by 50 mg per square meter once per day. Both the loading dose as well as the maintenance dose must not go beyond 70 mg, regardless of the calculated dosing for a particular child.

• The body surface area (BSA) of the patient is calculated using the Mosteller formula (square root of the height in centimeters multiplied by the weight in kilograms divided by 3600) and expressed in square meters.

Preparation for Intravenous Infusion

Caspofungin is supplied in lyophilized form in single-dose vials, which needs to be reconstituted and prepared for intravenous infusion administration in the following aseptic technique.

Reconstitution of Caspofungin

• The refrigerated Caspofungin vial is equilibrated to room temperature.

• Solutions such as 0.9 percent sodium chloride injection (10.8 mL), bacteriostatic water for injection (containing Methylparaben and Propylparaben), and sterile water for injection are added aseptically to the vial.

• Each Caspofungin vial is provided with intentional overfill according to the diluent volume to be added.

• On adding the diluents, the lyophilized Caspofungin is mixed gently until it is completely dissolved to obtain a clear solution.

• The reconstituted Caspofungin solution is visually examined for the presence of particulate matter, sediments, or notable discoloration in the final preparation.

• This reconstituted solution should be used immediately or could be stored for a maximum duration of one hour at or below 25 degrees Celsius (less than or equal to 77 degrees Fahrenheit). This preparation is only for single-dose only, and unused portions should be discarded.

Dilution of the Reconstituted Caspofungin Solution in the Intravenous Bag

• The recommended volume (mL) of reconstituted the volume of drug equal to the calculated loading dose or calculated maintenance dose is transferred aseptically to the intravenous (IV) bag that contains 250 mL (milliliter) of sodium chloride injection ( 0.9 percent, 0.45 percent, or 0.225 percent) or Lactated Ringer's injection.

• The dilution is adjusted in such a way that the final concentration does not exceed 0.5 mg/mL (milligram/milliliter). Also, within 24 hours (stored at less than or equal to 25 degrees Celsius), this diluted infusion in the IV bag should be used.

• For Pediatric Patients - Only the required volume of Caspofungin which is equivalent to the calculated dose (loading or maintenance), is removed from the reconstituted solution for dilution. The maximum dose (loading or maintenance) in the final dilution must not exceed 70 mg despite the calculated dose for pediatric patients.

• Drug Incompatibility - Caspofungin must not be mixed or co-infused with other IV medications and drugs. Diluents with dextrose (alpha-D-glucose) should not be used for dilution since Caspofungin is not stable in such diluting solutions.

Warnings and Precautions

• Hypersensitivity Reactions - Possible risk of developing anaphylaxis or histamine-mediated adverse side effects such as angioedema, bronchospasm, facial swelling, and pruritus. Administration of Caspofungin is discontinued when initial signs of hypersensitivity develop, and appropriate management is followed.

• Hepatotoxicity - The risk of developing liver injury causing hepatitis, hepatic dysfunction, and hepatic failure has been documented. Abnormal levels of liver enzymes are indicative of hepatic injury. Regular monitoring of liver function tests (LFT) helps in preventing hepatic failure.

For Patients

What Are Invasive Fungal Infections?

The prevalence and global distribution of fungal infections in recent decades subsequently increases the risk of systemic (spreading throughout the body through blood flow) fungal infections in susceptible individuals whose immune (ability to fight infections) system is defective or compromised. Diseases like AIDS (Acquired Immune Deficiency Syndrome), increased incidence of chemotherapy, surgical procedures like organ and bone marrow transplantation, and immunosuppressant therapies have led to the rise of vulnerable and immunocompromised individuals. Invasive fungal infections are progressively associated with increased morbidity and eventual mortality. Treatment and management of such systemic fungal infections are challenging due to their nonspecific clinical symptoms and face difficulty in eradicating, particularly in immunocompromised patients.

The existing diverse variety of fungal pathogens requires advanced diagnostics and precise clinical skills to enhance their detection and therapeutic management. Aspergillus species and Candida species are the most frequently reported fungal pathogens that cause life-threatening invasive fungal infections. Along with these commonly encountered fungal infections, such as candidiasis and aspergillosis, new invasive fungal infections are also reported, which are caused by emerging fungi (Emergomyces and Blastomyces helices). While the majority of invasive fungal infections in immunodeficient individuals occur due to opportunistic fungi, primary fungi (Coccidioides and Histoplasma) also cause invasive infections in healthy individuals. The progressive rise in global travel and medical care advances (newer antibiotics and immunotherapies) contribute to the increased incidence of systemic fungal infections.

How Effective Is Caspofungin Against Invasive Fungal Infections?

Antifungal medications are therapeutic agents that destroy fungi by blocking or suppressing fungal replicative activity such as growth and reproduction. Recent scientific research and clinical studies have contributed to the progressive growth and innovative development of an effective antifungal arsenal. However, most of the frequently prescribed antifungal agents are associated with drug-related toxic side effects and incompatible drug interactions and are also extremely expensive.

Caspofungin is the most preferred antifungal agent for treating invasive (spread of infections into the blood circulation) fungal infections because of its enhanced tolerability and effective mechanism of action. Caspofungin is a newly developed antifungal echinocandin that belongs to the class of antimycotic agents for systemic use (injected intravenously). The characteristics of Caspofungin which contribute to its effective clinical use are as follows:

• Caspofungin is widely well tolerated and exhibits a novel antifungal activity.

• It is the first echinocandin medication to be approved by the FDA for global marketing.

• Its use is clinically approved in both adult individuals and children (from the age of three months and above).

• Caspofungin exhibits its antifungal activity by blocking beta-(1,3)-D-glucan synthase, a crucial enzyme needed for synthesizing the cell wall of the fungus.

• This interference with the cell wall synthesis of fungus subsequently decreases beta-(1,3)-D-glucan production, which is a vital structural component of the fungal cell wall. Eventually, the cell wall of the fungus gets weakened and ruptures resulting in the termination of fungal growth.

• Caspofungin inhibits beta-(1,3)-D-glucan synthase enzyme, which is present only in fungal cells and not in mammalian cells. Hence, Caspofungin is not toxic to human cells.

• It is active against Candida and Aspergillus species and is commonly used in the treatment of candida infections and invasive aspergillosis.

• Caspofungin is injected intravenously only by a trained healthcare provider as a slow infusion to prevent toxic side effects.

• Low incidence of drug interactions and adverse reactions, riskless safety profile, and minimal overall therapeutic costs are significant assets for the use of Caspofungin in the management of invasive fungal infections.

What Are the Side Effects Caused by Caspofungin?

Caspofungin does not cause adverse side effects in most people. Its overall safety efficacy has been studied and documented in 34 clinical research studies. Some of the commonly reported side effects are listed below:

• Fever (pyrexia).

• Infused vein complications (infections at the injection site).

• Nausea.

• Vomiting.

• Flushing.

• Phlebitis (irritation of the vein).

• Thrombophlebitis (blood clot formation in the veins).

• Headache.

• Unspecified pain.

• Rash.

• Anemia.

• Abdominal pain.

• Diarrhea.

• Facial edema.

• Flu-like illness.

• Myalgia.

• Paresthesia (burning or prickling sensation, especially in hands and feet).

• Induration (hardening of skin tissues).

• Chills.

• Pruritus (skin irritation and itching sensation).

• Hypotension.

• Tachycardia (abnormally increased heart rate).

• Increased levels of liver enzymes (alkaline aspartate aminotransferase and alanine aminotransferase) indicate drug-induced liver injury.

• Increase in alkaline phosphatase and potassium levels in the blood.

What Are the Guidelines and Precautions for Using Caspofungin?

Caspofungin is a reliable antifungal prescription medication for treating systemic fungal infections. The following guidelines and precautions should be followed to ensure safe and effective therapeutic outcomes during Caspofungin therapy.

• Caspofungin administration should only be initiated by an experienced physician or a healthcare provider who is trained in managing invasive fungal infections.

• The prepared solution is visually inspected before infusion. If the solution appears cloudy or contains any precipitates, it should be discarded immediately.

• Caspofungin must not be mixed or co-infused with other drugs. Diluents with dextrose should not be used for reconstitution.

• Any known allergic episodes and ongoing treatments must be informed to the doctor prior to the initiation of Caspofungin therapy.

• It is intravenously given once a day, slowly over a duration of one hour, and should not be injected as a bolus dose.

• If any development of side effects occurs, it should be immediately reported to the doctor.

• Missed Dose - In case of a missed dose, the doctor should be immediately contacted for a new schedule of dosing. Doubling doses is prohibited.

• Overdose - If overdosing occurs, it must be informed at the poison control center, and supportive care to be initiated immediately.

• Disposal - Unused and expired vials should be discarded properly and should not be flushed or thrown into the drains.

For Doctors

Clinical Pharmacology of Caspofungin

Pharmacodynamics

Caspofungin is a member of the echinocandin family and belongs to the class of antimycotics for systemic use. It possesses a novel mechanism of action and is categorized as a glucan synthase inhibitor. Unlike recently available antifungal agents that widely exert their antimycotic action on the cell membrane of the fungus, Caspofungin is the first parenteral echinocandin to inhibit the synthesis of the fungal cell wall. Caspofungin is effective in treating patients having invasive aspergillosis and systemic candidiasis, such as candida esophagitis. Structurally, Caspofungin is an echinocandin lipopeptide with antimycotic properties which is derived as a semisynthetic preparation (fermentation product) from the fungus Glarea lozoyensis. Its active ingredient is Caspofungin acetate and the drug is administered solely as a slow intravenous (IV) infusion. Caspofungin has a large molecular weight, and its oral bioavailability is very poor; hence not preferred for oral use.

Mechanism of Action

• Caspofungin exhibits antimycotic activity against Candida (including non-albicans subtypes) and Aspergillus species.

• Beta-(1,3)-D-glucan is an integral structural component of the fungal cell wall. It is present only in fungal cells and not seen in mammalian cells.

• Caspofungin inhibits the synthesis of this cell wall structural component by noncompetitively inhibiting the beta-(1,3)-D-glucan synthase enzyme, which is vital for its production.

• Reduced production of beta-(1,3)-D-glucan disrupts the integrity of the fungal cell wall resulting in perforation and rupturing fungal cell wall.

• Caspofungin shows fungicidal activity against regions of active fungal cell growth, such as budding (Candida species) and hyphae formation (Aspergillus species).

Antimycotic Activity

Clinical studies show that Caspofungin is active against the majority of fungal strains. Its antimicrobial efficacy correlates to the beta-(1,3)-D-glucan synthesis activity in the fungal species.

• Yeast Strains - Most of the Candida species (including resistant strains such as Candida krusei), strains such as Candida glabrata, which are less susceptible to antifungals like azoles, and also Amphotericin B resistant strains are susceptible to Caspofungin. However, caspofungin does not show antifungal activity against the fungus that lacks beta-(1,3)-D-glucan, such as Cryptococcus neoformans.

• Filamentous Fungus Strains - Caspofungin shows antimycotic activity against the majority of Aspergillus fungal strains (Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus).

• Strains of Pneumocystis Jiroveci - Caspofungin is effective against Pneumocystis jiroveci cysts that are often resistant to triazoles and Amphotericin B.

• No reliable antimycotic activity is documented against Histoplasma capsulatum strains.

Susceptibility Testing and Resistance

Susceptibility testing for Caspofungin is well documented in its clinical trial database. The data shows that most Candida isolates are susceptible to Caspofungin. A wider susceptibility efficacy favors the use of Caspofungin in invasive candidiasis and esophageal candidiasis. However, the Caspofungin susceptibility pattern of various fungal strains from recent clinical isolates is under continuous surveillance to detect any development of resistant strains. Cases of reduced susceptibility or resistant development should be immediately reported to global regulatory organizations such as CDC (Centers for Disease Control and Prevention).

Some Caspofungin-reduced susceptibility and resistant strains of Candida and Aspergillus have been reported resulting in clinical treatment failures. These variations are due to mutations in genes encoding for the glucan synthase enzyme. Molecular studies are in progress to assess Caspofungin resistance in certain fungal isolates.

Pharmacokinetics

• Absorption and Distribution - Caspofungin exhibits the triphasic nonlinear type of pharmacokinetics. Following initial parenteral administration, the drug levels in plasma rapidly decrease because of enhanced tissue distribution.

• Subsequently, the distributed drug gets gradually re-released from the extravascular tissues and undergoes slow metabolism in the liver.

• Hepatic Metabolism - Caspofungin undergoes hydrolysis and N-acetylation, producing inactive metabolites. Dose reduction needs to be followed in case of severe hepatic dysfunction.

• Bioavailability - It shows high protein (albumin) binding of 97 percent and an initial half-life of one to two hours followed by a biological half-life of nine to 11 hours. The plasma accumulation of Caspofungin increases with dosage. Hence, the dose calculation of the following doses should be carefully done to avoid excessive drug accumulation.

• Elimination - The total renal clearance rate of Caspofungin is 12 mL/minute. Caspofungin is primarily eliminated through the kidneys (41 percent in urine) and also in feces (35 percent). Traces (two percent) of unchanged Caspofungin are also detected in urine.

Toxicities

Caspofungin shows minimal adverse drug reactions. Toxicities that are reported during clinical use of Caspofungin are commonly associated with overdosage, hypersensitivity, or hepatic impairment. Some of the reported toxic side effects are as follows:

• Hepatobiliary complications lead to hyperbilirubinemia and hepatic dysfunction.

• Cardiovascular insufficiency results in swelling or peripheral edema.

• Metabolic disturbances such as hypercalcemia and increased potassium levels in plasma.

• Potential histamine-induced symptoms such as rash, pruritus, facial swelling, and bronchospasm.

• Events of Stevens-Johnson syndrome (SJS) along with toxic epidermal necrolysis (TEN), have also been reported with the use of Caspofungin.

• Anaphylaxis.

• Toxic skin erosions.

Drug Interactions

• Combination therapy of Caspofungin with other antifungals like Amphotericin B and triazoles shows synergistic effects and favorable outcomes in treating invasive fungal infections, especially aspergillosis.

• Plasma levels of Caspofungin markedly decrease when concomitantly used with potent cytochrome (CYP3A4) inducers such as Rifampin, Carbamazepine, Phenytoin, and Dexamethasone. In these circumstances, the dosage of Caspofungin should be increased when required.

• Caspofungin, when given along with Cyclosporine, causes an increase in liver enzymes. Regular monitoring of liver function tests is essential in such cases.

• Caspofungin significantly reduces plasma levels of Tacrolimus when concomitantly administered. Hence, appropriate dosage adjustments for Tacrolimus are advised.

Special Considerations

• Pregnancy - Based on studies on animal models, Caspofungin could cause harmful effects on the fetus. Therefore its use is not recommended during pregnancy.

• Nursing and Lactating Mothers- The effect of Caspofungin during lactation and breastfeeding is not yet documented. Adequate precautions are to be followed when administering to nursing mothers.

• Pediatric Use - The safety and clinical efficacy of Caspofungin have not yet been documented in neonates as well as infants below three months of age.

• Geriatric Use - Though no significant dose adjustments are recommended for elderly patients (above 65 years of age), regular monitoring is mandatory since some elderly individuals show increased sensitivity to Caspofungin.

• Hepatic Impairment- Reduction in dose is recommended for adult individuals having moderate hepatic insufficiency.

• Renal Impairment - Caspofungin shows excellent renal tolerability, so no specific dosage adjustments are required for renal impairment patients. Also, no additional dosing changes are required after hemodialysis since Caspofungin is non-dialyzable.