Vol. VI, No. III
  May/June 2003

  Jennifer Long,
  Pharm.D., BCPS

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 Pharmacotherapy
 Update Index

New Antifungal Agents
Additions to the Existing Armamentarium
(Part 1)

Introduction:
Invasive fungal infections are an important cause of morbidity and mortality, and the number of these cases has been increasing. For example, Candida is now the fourth leading cause of nosocomial infections. This rise may be partially due to medical advances that have enabled the survival of critically ill patients (e.g., intravascular catheters, total parenteral nutrition (TPN), broad spectrum antimicrobials, and dialysis). In addition, the profile of patients at risk for infection with opportunistic fungi, such as Aspergillus, is expanding (e.g., solid organ and bone marrow transplants, acquired immune deficiency syndrome (AIDS), and intensive chemotherapy regimens). It is therefore imperative that the armamentarium of antifungals expands to treat these infections. The ideal antifungal agent would 1) be fungicidal, 2) have a novel mechanism of action, 3) have a broad spectrum of activity, including resistant strains, and 4) be well tolerated. Recently, the Food and Drug Administration (FDA) approved two new antifungals, which may benefit patients with invasive fungal infections. Part I of this article will discuss the echinocandins, focusing on caspofungin, and Part II (in the next issue of Pharmacotherapy Update) will discuss the new azole antifungal, voriconazole.

Echinocandins:
The discovery of echinocandins began with papulacandin compounds which were first discovered as fatty acid derivatives of a disaccharide compound. Since their activity was limited to Candida spp. and in-vitro activity did not always correlate with in-vivo activity, these compounds were not pursued for development. In 1974, the first echinocandin agent, echinocandin B, was discovered; however, when the agent was noted to cause significant hemolysis, its development was discontinued. In 1980, another echinocandin, cilofungin, was discovered, but these clinical trials were also halted due to toxicity related to the solvent system required for systemic administration. Subsequently, pneumocandin compounds were found to inhibit glucan synthesis and have a broader spectrum of activity than echinocandins. To help broaden the spectrum of activity and decrease toxicity, today's echinocandin agents are a combination of the pneumo-candin and echinocandin structures. The echinocandin agents available, as well as in development, are listed in Table 1.

Most of this discussion will focus on caspofungin, the only agent currently FDA-approved.

Mechanism of Action: Echinocandins are non-competitive inhibitors of (1,3)-ß-D-glucan synthase, which is an enzyme that forms glucan polymers in the fungal cell wall. The enzyme has two subunits, one catalytic site in the plasma membrane and the other a GTP binding subunit that activates the catalytic site. By inhibiting this enzyme, echinocandins prevent > 90% of glucose incorporation into glucan. Because of their effect on the fungal cell wall, echinocandins have been referred to as the "penicillin of antifungals." Reported resistance to these agents is rare. However, in-vitro studies indicate mutations in FKS1 and FKS2 genes, which encode for membrane proteins that function as the catalytic site of the (1,3)-ß-D-glucan synthase, may lead to resistance.

Spectrum of Activity: Caspofungin is active against yeasts and moulds which possess (1,3)-ß-D-glucan synthase. Standard methods for in-vitro susceptibility testing for echinocandins have not been adopted. In-vitro studies tend to utilize the National Committee for Clinical Laboratory Standards (NCCLS) reference method; however, this has not been standardized for echinocandins and minimal inhibitory concentration (MIC) breakpoints have not been determined. A breakpoint of £ 1 mcg/mL has been proposed for Candida spp., but it is still under consideration. For the filamentous fungi, the NCCLS reference method is a poor in-dicator of susceptibility due to the novel mechanism of action of echinocandins. Since the echinocandins act on growth zones of the hyphae, it has been proposed to implement a minimal effective concentration (MEC). The MEC would be determined by visualization and defined as the lowest concentration able to produce the morphological change.

Yeasts. Caspofungin is active against many Candida spp., including those resistant (e.g., C. krusei) and less susceptible to azole antifungals (e.g., C. glabrata). The MIC for C. albicans, C. glabrata, and C. tropicalis tends to be < 1 mcg/mL. While the MICs tend to be higher for C. krusei, C. parapsilosis, and C. lusitaniae, caspofungin has demonstrated good in-vitro activity against these isolates. Caspofungin has the least activity against C. guilliermondii. Some in-vitro studies have demonstrated a fungistatic effect of caspofungin against Candida spp., yet other studies have reported fungicidal effects. One exciting development is the potential activity of caspofungin against C. albicans and C. parapsilosis growing as biofilms.

The echinocandins, including caspofungin, are not active against Cryptococcus neoformans. Possible reasons for the inactivity include a lower quantity of (1,3)-b-D-glucan in Cryptococcus, a lower inhibition of the enzyme, and/or the compounds difficulty in reaching the target enzyme due to the polysaccharide capsule of the organism.

Other yeasts, such as Trichosporon spp. and Rhodotorula appear to be resistant to caspofungin.

Filamentous fungi. Caspofungin is active against Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger. In-vitro studies have demonstrated indifference, additive, and synergistic effect when echinocandins are combined with either amphotericin or voriconazole. Clinical trials in humans are needed to determine the benefits of these combinations in treating Aspergillus infections.

Caspofungin is active against other filamentous fungi such as Pseudoallescheria boydii, Paecilmyes variotii, and Scedosporium apiospermum. Caspofungin is not active against Paecilomyces lilacinus, Scedosporium prolificans, Fusarium or Rhizopus. Caspofungin is active against other rare moulds including Alternaria, Curvularia, Exophiala, and Fonsecaea.

Dimorphic fungi. Caspofungin is active against Blastomyces dermatitidis. In a study, using immuno-competent mice, some activity was demonstrated against Histoplasma capsulatum, however models using immunocompromised mice showed only modest effect. Sporothrix schenckii appears less susceptible to caspofungin.

Pneumocystis carinii. Echinocandins are active against the cyst forms of P. carinii since they contain (1,3)-b-D-glucan in their walls. The activity against the trophozoite form is not well known. Since there is no standard method for susceptibility testing against P. carinii, studies have been done directly on animals.

Pharmacokinetics: Because of poor oral absorption due to large molecular weight, the echinocandins are only available in intravenous (IV) formulations. For example, less than 1% of caspofungin is absorbed when administered orally. Caspofungin is highly protein bound (~97%). Following a single 70 mg dose, caspofungin demonstrates linear pharmacokinetics, achieving mean peak and trough concentrations of 12 and 1.3 mcg/mL, respectively. An initial loading dose of 70 mg, followed by 50 mg daily, results in trough concentrations > 1 mcg/mL. The echinocandins have poor penetration into the brain or cerebral spinal fluid (CSF) in absence of inflammation due to the large molecular weight, high protein binding, and high water-soluble properties. However, in clinical trials, a few patients with central nervous system (CNS) aspergillosis have appeared to respond to therapy with caspofungin. Other data regarding tissue penetration for caspofungin are not available. Plasma concentrations decline in a poly-phasic manner and are divided into three main phases. The a-phase lasts 1 to 2 hours and is associated with distribution into the tissues. The ß-phase, 9 to 11 hours, represents the time during which bound drug penetrates tissue. This phase is also characterized by log-linear behavior from 6 to 48 hours post-dose, with plasma levels decreasing roughly 10-fold during this time period. Therefore, distribution rather than excretion, is the predominate factor influencing plasma clearance. Finally, the γ phase has a half-life of 40 to 50 hours and likely represents the slow redistribution effect of the drug from tissues. Hence, a loading dose is necessary and once daily administration is possible. Caspofungin will also remain in tissue stores even after discontinuation of drug for a period of time. It is metabolized by hydrolysis and N-acetylation and does not appear to be a substrate for the cytochrome P450 system. Caspofungin and its metabolites are excreted in the feces and urine with only ~1.4% excreted unchanged in the urine. Pharmacokinetic studies in special populations suggest no dose adjustment is necessary based on age, gender, race, or in renal insufficiency. For patients with moderate hepatic insufficiency (e.g., Child-Pugh 7 to 9), it is recommended to decrease the daily maintenance dose to 35 mg. There are insufficient data available in patients with severe hepatic insufficiency to make dosing recommendations. Finally, caspofungin is not dialyzable.

Drug Interactions: Caspofungin is not an inhibitor, inducer, or substrate of the cytochrome P450 system, nor of P-glycoprotein, however, pharmacokinetic studies have demonstrated important drug interactions. Co-administration of carbamazepine (Tegretol®), dexamethasone (Decadron®), efavirenz (Sustiva®), nevirapine (Viramune®), phenytoin (Dilantin®), or rifampin (Rifadin®) results in a decrease in the caspofungin area-under-the-curve (AUC). The exact mechanism of these interactions is unknown, but may be due to the induction of a minor oxidative pathway or transport mechanism. Increasing the daily maintenance dose to 70 mg should be considered in patients receiving these agents concomitantly and especially in those patients not clinically responding to caspofungin therapy. In healthy volunteer studies, cyclosporine (Neoral®; Sandimmune®) increased the AUC of caspofungin by ~35%. Furthermore, these individuals were also noted to have increased liver function tests. Caspofungin had no effect on the pharmacokinetics of cyclosporine. Further studies evaluating this interaction are ongoing, however, at the present time the concurrent use of cyclosporine and caspofungin is not recommended. Although tacrolimus (Prograf®) does not appear to affect caspofungin levels, caspofungin can decrease tacrolimus levels by ~20 to 25% (i.e., tacrolimus doses may need to be increased in patients receiving caspofungin).

Adverse Effects: Caspofungin is generally well tolerated. The most common adverse events from clinical trials include fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the injection site (2.9%). Caspofungin is a basic polypeptide that may cause histamine release from mast cells. Symptoms of histamine release were noted in ~3% of patients during clinical trials and the majority of these reactions were facial flushing during the infusion. Allergic reactions have been infrequent and anaphylaxis has only been reported in one case. Reported drug-related laboratory abnormalities include increases in alkaline phosphatase (2.9%), eosinophils (3.2%), urine protein (4.9%), urine red blood cells (2.2%), and decreases in serum potassium (2.9%). Animal studies showed caspofungin to be embryotoxic, therefore it is listed as a pregnancy-risk category C and should only be used in pregnant women if the benefit outweighs the risk.

Clinical Trials:
Aspergillosis.
The trial which gained FDA-approval for caspofungin as salvage therapy for invasive aspergillosis has only been presented in abstract form. The authors conducted a multicenter, non-comparative study of 83 patients with invasive aspergillosis who were refractory or intolerant of standard therapy and ~25% of these patients were neutropenic. An independent panel of experts determined the response to therapy and found a complete or partial response in 45% of patients. Additionally, caspofungin appeared to be well tolerated. It is important to note that the majority of patients received at least 21 days of prior therapy, presumably with an amphotericin product. It has been questioned whether or not this trial truly supports caspofungin monotherapy, since the half-life of amphotericin is quite long. Therefore, the results of this trial can not be extrapolated for use of caspofungin as primary therapy for invasive aspergillosis.

Candidiasis (Esophageal).
Two trials have evaluated the safety and efficacy of caspofungin in the treatment of esophageal candidiasis. First, there was a randomized, double-blind, phase II trial that compared caspofungin 50 mg or 70 mg/day to amphotericin 0.5 mg/kg/day. Patients (n=128; caspofungin 50 mg n=46, caspofungin 70 mg n=28, amphotericin n=54) from seven centers in Latin America were enrolled. The patients were stratified based on disease severity and the primary outcome was a favorable response after 14 days of treatment. There was no difference among the groups in terms of treatment response or time to symptom resolution. A favorable response was found in 74% of the patients treated with caspofungin 50 mg/day, 89% treated with caspofungin 70 mg/day, and 63% treated with amphotericin. Adverse events were lower in the caspofungin-treated patients compared to the amphotericin-treated patients.

A second multicenter, randomized, double-blind, non-inferiority trial was performed to determine the efficacy and safety of caspofungin versus fluconazole in esophageal candidiasis. Patients were randomized to caspofungin 50 mg/day (n= 81) or fluconazole 200 mg/day (n= 94) for 7 to 21 days. The response rates were 82% (95% CI; 71-89) for the caspofungin group and 85% (95% CI; 76-92) for the fluconazole group. The symptoms resolved in 95% of patients in both groups with a median of 5 days of treatment. No difference was found in relapse rates among the groups. In summary, caspofungin appears to be as effective as fluconazole and amphotericin in the treatment of esophageal candidiasis.

Candidiasis (Invasive).
A randomized, double-blind, double-dummy trial compared caspofungin to amphotericin for invasive candidiasis. Patients received 1) caspofungin 70 mg, then 50 mg/day or 2) amphotericin 0.6 to 1 mg/kg/day for a minimum of 10 days. Both groups could then be switched to oral fluconazole 400 mg/day. Two-hundred twenty-four patients met the criteria for the modified intention-to-treat (MITT) analysis (i.e., those patients with clinical evidence of infection and positive culture from blood or from a sterile site and at least one dose of treatment). Approximately 80% of patients in both groups were candidemic and 75% had a recent central catheter. The number of non-catheter related invasive candidiasis infections were low in both groups. Caspofungin and amphotericin had similar response rates in the MITT (73% for caspofungin and 63% for amphotericin). Moreover, the amphotericin group had significantly more adverse effects than the caspofungin group.

Based upon the results of this study, caspofungin received FDA-approval for the treatment of invasive candidiasis.

Indications and Dosing: Caspofungin is FDA-approved for the following indications: 1) treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole), 2) candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections, and 3) esophageal candidiasis. However, caspofungin has not been studied as initial therapy for invasive aspergillosis, nor has it been studied in endocarditis, osteomyelitis, and meningitis due to Candida.

The recommended dose of caspofungin is a single loading dose of 70 mg IV, followed by 50 mg IV every 24 hours, and should be infused over 1 hour. For patients with moderate hepatic insufficiency (e.g., Child-Pugh 7 to 9), a change is not recommended for the initial loading dose, but the maintenance dose should be decreased to 35 mg IV every 24 hours. There is insufficient clinical experience for dosing recommendations in patients with severe hepatic insufficiency (e.g., Child-Pugh >9). In addition, renal dose adjustment is not necessary.

Formulary Restrictions:
At the Cleveland Clinic, caspofungin is restricted to the Department of Infectious Diseases for the following indications: 1) treatment of presumed or documented invasive fungal infections, 2) combination therapy for invasive mould infections, and 3) second-line therapy for Candida infections in patients intolerant to or who have failed amphotericin/azole therapy.