Echinocandins

Updated March, 2010

 

Alexander Imhof, M.D., Kieren A. Marr, M.D.

 

CLASS

               The echinocandins are a class of semisynthetic antifungal lipopeptides that are structurally characterized by a cyclic hexapeptide core linked to variably configured lipid side chains. These drugs inhibit glucan synthase, the enzyme responsible for synthesis of β1-3 linked glucan, a major polysaccharide component of the cell wall of several pathogenic fungi (122). The β 1-3 glucan synthase complex is composed of 2 subunits: a plasma membrane-bound catalytic subunit (FKS) and an activating subunit. The activating subunit, with guanosine triphosphatase activity, activates the catalytic subunit, which polymerizes UDP-glucose into fibrils of glucan and extrudes the polymer through the plasma membrane into the cell wall. Inhibition is thought to be non-competitive, but the precise mechanism by which these drugs interact with the enzyme complex to inhibit synthesis of glucan is not well defined.

               Echinocandins have been in development for a number of years, with initial indications targeting infection caused by Pneumocystis and Candida species. Cilofungin was the first echinocandin that reached Phase II clinical development for its activity against Candida sp.(110, 134), but its development was suspended due to toxicities related to the intravenous vehicle (162). Caspofungin acetate (Cancidas, Merck & Co., Inc., Whitehouse Station, NJ) was the first echinocandin to receive marketing approval by several countries. It is a water-soluble, semisynthetic derivative of pneumocandin B, a fermentation product isolated from the fungus Glarea Zozoyensis (1). Specifically, it is a l-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-l-ornithine)-5[(3R)-3-hydroxy-L-ornithine] diacetate salt of pneumocandin B, with the molecular formula C52H88N100152C2H4O2 (Figure 1a) and a molecular weight of 1213.42 d. The other current echinocandins are micafungin (Mycamine, Astellas Pharma Inc, Deerfield, IL, Figure 1b) and anidulafungin (Eraxis, Ecalta (in Europe), Pfizer Inc, NY, Figure 1c). Micafungin is synthesized from a naturally occurring compound isolated from the culture broth of the fungus Coleophoma empetri (29, 73). Anidulafungin is a semisynthetic, lipopeptide antifungal agent derived from echinocandin B0, a fermentation product of the fungus Aspergillus nidulans (178). The FDA-approved indications for clinical use of caspofungin, micafungin and anidulafungin are listed in Table 1 (182). These three drugs have similar pharmacological properties (89, 122, 165); similarities and differences in drugs within the class will be detailed in following sections.

 

ANTIFUNGAL ACTIVITY

Spectrum of Activity

               All current echinocandins have activity against Candida sp., as well as several molds. Fungicidal activity against Candida species allow for measurement of clear growth end-points and interpretable Minimal Inhibitory Concentrations (MIC) using reference broth microdilution methods published by the Clinical and Laboratory Standards Institute (CLSI) (117). Efficacy of caspofungin, micafungin and anidulafungin has been demonstrated against Candida sp, including azole-resistant strains (11, 92, 135, 164). In vitro studies of micafungin revealed a 5-10 fold increase of the inhibitory activity, compared with the activity of caspofungin, against C. albicans, C. glabrata, C. tropicalis, and C. dubliniensis (125). Minimal inhibitory concentrations of drugs that cause 90% growth inhibition relative to growth controls (MIC90) are summarized in Table 2. Typically, MIC90’s are very low for Candida species, although relatively higher MIC90’s have been noted among several C. parapsilosis and C. guillermondii isolates (101, 135, 176). Although breakpoints for resistance have not been defined, MIC90’s of Candida species are thought to be well within the susceptible range. Caspofungin and Micafungin have been demonstrated to have activity against biofilms formed by Candida albicans or C. glabrata but not those formed by C. tropicalis or C. parapsilosis (12, 33, 14). However, other authors showed that caspofungin is active against biofilms formed by C. parapsilosis (86).

               Similar to caspofungin and micafungin, anidulafungin shows favorable in vitro fungicidal activity against a broad range of Candida species, including C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, Candida famata, Candida rugosa, and Candida stellatoidea (Table 2). Anidulafungin is also effective against species of Candida that are intrinsically resistant to fluconazole (Candida krusei), or amphotericin B (Candida lusitaniae).

               The relative activity against molds has been particularly difficult to quantify using CLSI broth dilution methods for conidium-forming filamentous fungi (document M38-A) (118), largely because the drugs cause damage to growing cells comprising filamentous tips and branch points, but do not yield clear endpoints in turbidity using classical broth dilution assays (Figure 2) (10, 21, 101, 151). Minimum inhibitory concentration (MIC) values reported by clinical laboratories also vary greatly with the culture medium used, the incubation time, the assay methodology (i.e. serum content of the media), and the defined end point of growth inhibition (7, 9, 11, 16, 31, 35, 91, 120). Various experimental methods are being studied for determining the MIC for Aspergillus sp, including examination of morphologic changes of hyphae (Minimal effective concentration, MEC) (50), disk diffusion (9), E-Test (50), and agardilution (71). Caspofungin, micafungin and anidulafungin activity reported against various Aspergillus species, as measured using both MIC90 and MECs, are summarized in Table 3.

               Studies have also examined the effects of echinocandins on other opportunistic fungi, such as Pneumocystis jiroveci, Histoplasma capsulatum, Coccidioides immitis, and Cryptococcus neoformans. Caspofungin, micafungin, and anidulafungin have variable in vitro activity against H. capsulatum, and appear to have a limited treatment role (49, 61, 80). Micafungin exhibited potent activity against few Penicillium species, Paecilomyces liacinus, and Paecilomyces variotii. Micafungin was also active against the mycelial forms of H. capsulatum, B. dermatitidis, and C. immitis (MIC range, 0.0078 to 0.0625 µg/ml), but it was very weakly active against their yeast-like forms (MIC range, 32 to >64 micro g/ml). Micafungin also has more activity against the mycelial forms than the yeast-like forms of Paracoccidioides brasiliensis, Penicillium marneffei, and S. schenckii (116). Although caspofungin treatment was effective in reducing tissue burdens of C. immitis in mice (57), further in vivo investigation is needed before these drugs can be recommended for treatment of these infections in humans. Echinocandins also have some in vitro activity against Pneumocystis jiroveci. Activity appears to be limited, however, to the cyst form, which has β-(1,3)-glucan in the cell wall; these drugs are not active against the trophozoite which does not rely on β-(1,3)-glucan for structural integrity. Treatment with caspofungin was found to decrease the number of P. jiroveci cysts by 90% in immunosuppressed rats (140). These results suggest a prophylactic role, since the trophozoite is more prevalent in acute disease and the cyst predominates in latent disease (72), however, without demonstration of definitive activity, these drugs cannot be recommended above other therapeutic alternatives.

               As a class, echinocandins have limited activity against Cryptococcus neoformans (47, 188), which appear to have a target with reduced affinity for the drug, a lesser contribution of β-1-3 linkages to glucan structure, and a reduction of caspofungin activity by melanin (175). However, in vitro studies that examined combinations of drugs against C. neoformans demonstrated some evidence of synergism between caspofungin and amphotericin B (19). In combination with fluconazole, addition of caspofungin or anidulafungin resulted in synergism and additivity, in a strain-dependent manner; no antagonism has been reported (147).

               In vitro activity of echinocandins in combination with triazoles and amphotericin products has also been evaluated for Candida species and molds. No evidence of antagonism was noted using the combination of caspofungin/micafungin and amphotericin B or fluconazole against C. albicans (19, 147). Caspofungin was synergistic with both fluconazole and voriconazole against C. parapsilosis, but indifference was noted in combination with amphotericin B (177). The combination of caspofungin or anidulafungin and amphotericin B are synergistic or additive against Aspergillus species in vitro; antagonism has not been reported (8, 19, 139). Experiments with clinical isolates of A. fumigatus found that synergy with caspofungin were observed with either conventional or lipid-complexed amphotericin B (28). Similar results have been reported using the combination of caspofungin and voriconazole (131), and caspofungin with either itraconazole or posaconazole (100, 152). Combination of micafungin and amphotericin B against Aspergillus species were largely indifferent but never antagonistic (29). The combination of micafungin and nikkomycin Z was synergistc against A. fumigatus. However, this combination was indifferent to other Aspergillus and Fusarium species. A combination of micafungin with voriconazole was additive (64). The potential role of echinocandins administered in combination with other antifungal agents for aspergillosis is currently an active area of clinical investigation.

               The bulk of in vivo studies of the efficacy of echinocandins for candidiasis have been performed in mice. In immunocompetent and immunosuppressed mouse models, caspofungin, micafungin and anidulafungin were effective against disseminated candidiasis favorably with that of antifungal agents such as amphotericin B, amphotericin B lipid complex, and fluconazole (1, 2, 19, 99, 132). In addition, caspofungin and micafungin were noted to decrease tissue-colony counts of C. glabrata, and C. krusei (17, 60, 121). In one study, a single dose of caspofungin was more effective than amphotericin B at clearing C albicans from kidney tissue (1). In another mouse model of invasive candidiasis with C. tropicalis, micafungin more effectively reduced tissue colony forming units compared to fluconazole and amphotericin B (184).

               Numerous animal studies have evaluated the efficacy of caspofungin (1, 2, 21), micafungin (70, 95, 106) and anidulafungin (180) for preventing and treating aspergillosis. In general, the echinocandins yielded similar results with amphotericin B with regards to clinical parameters such as survival, but decreasing fungal burden has been difficult to quantify. This may be explained by the drug’s mechanism of action, which could result in fragmented hyphae and a paradoxical increase in colony forming units upon culture.

Pharmacodynamic Effects

Fungicidal Effects: In general, echinocandins have more "cidal“ effects against Candida species compared to filamentous organisms. In vitro studies demonstrated concentration-dependent fungicidal activity of caspofungin, micafungin and anidulafungin against several isolates of Candida tropicalis, C. parapsilosis, C. lusitaniae, C. guilliermondii, C. krusei, C. pseudotropicalis, and C. glabrata (16, 19, 46, 48, 112, 182). In contrast, echinocandins are inhibitory, but not fungicidal against Aspergillus species. Evidence collected using viability dyes indicated that only fungal cells that are actively producing cell wall at hyphal apices and branch points are killed by caspofungin, micafungin and anidulafungin (21, 145, 185).

Postantifungal Effects:  Echinocandins demonstrate significant postantifungal effects against Candida, but not Aspergillus species. In one study, exposure of C. albicans strains to 1 hour of concentrations above the MIC resulted in a postantifungal effect of >12 hours, measured using time-kill methods. The duration of postantifungal effect was shown to decrease sharply to 0 to 2 hours after 1 hour of exposure to concentrations below the MIC, suggesting that this effect is concentration dependent (47). In contrast, radiometric assays have shown caspofungin to have a relatively short postantifungal effect against A. fumigatus (143). The postantifungal effects of micafungin of Candida sp. was also influenced by the drug concentration, with the highest concentration resulting in the longest observed postantifungal effects. The highest concentration tested, four times the MIC, resulted in a postantifungal effects of more than 9.8 h for 50% of the tested isolates (range, 0.9 to ≥20.1 h) 48.

Effects on Host Immunity: Reports on the effects of human sera on the antifungal activity of caspofungin, micafungin and anidulafungin against Candida and Aspergillus spp are conflicting. In an in vitro preclinical evaluation of caspofungin, the susceptibility of C. albicans to caspofungin was not significantly influenced by the addition of human serum (19), however addition of 50% mouse serum resulted in an insignificant increase in MIC (decreased susceptibility) (19).

               In another study, serum increased caspofungin MICs an average of 2-fold, with a range of 1- to 16-fold, while it had a more pronounced effect on anidulafungin and micafungin, increasing the MIC an average of 16-fold with a range of 8- to 256-fold for anidulafungin and an average of 64-fold with a range of 32- to 128-fold for micafungin (126). However, human serum potentiated the antifungal activity of caspofungin against Aspergillus (31). Although the exact mechanism of this enhancement is unknown, it does not appear to be related to the presence of complement or formation of an Aspergillus antibody in human sera. The same investigators also examined the effect of human monocytes and macrophages on the antifungal activity of caspofungin against A. fumigatus. Caspofungin co-cultured with human monocytes for 24 hours had significantly greater inhibitory activity against Aspergillus hyphal growth compared with controls. Similar results were observed for caspofungin co-cultured with human macrophages, but not with polymorphonuclear neutrophils (32). However, micafungin enhanced the polymorphonuclear leukocytes oxidative burst dose dependently (56). Results of other studies suggest that anidulafungin and micafungin work human cooperatively with effector cells, and anidulafungin can sensitize germinating Aspergillus conidia for damage by host cells (22, 34). Whether results of these studies are clinically meaningful is unknown; it has been hypothesized that indirect effects on host defense is one possible explanation for the better antifungal activity against A. fumigatus measured in in vivo studies compared to in vitro studies.

 

MECHANISM OF ACTION

               Echinocandins are noncompetitive inhibitors of the enzyme β-(1,3)-glucan synthase, which catalyzes the polymerization of uridine diphosphate-glucose (UDP-glucose) into β-(1,3)-glucan, a structural component of the fungal wall. Decreased β-(1,3)-glucan results in a loss of cell integrity and rigidity (101), and ballooning of cellular contents from the weakened cell wall, which can result in cell lysis.

               Glucan synthase is an UDP-glucosyl-transferase located in the fungal cell membrane. Glucan synthesis occurs on the cytoplasmic side of the membrane, and glucan chains get extruded toward the periplasmic space for incorporation into the cell wall (153, 154). In a large number of fungi, the β-(1,3)-glucan synthase complex is composed of 2 subunits: a plasma membrane-bound catalytic subunit (FKS) and an activating subunit (RHO) (20, 88, 89, 141). The activating subunit, with guanosine triphosphatase activity, activates the catalytic subunit, which then polymerizes UDP-glucose into fibrils of glucan and extrudes the polymer through the plasma membrane (88, 89). Precisely how echinocandins inhibit the function of the β-(1,3)-glucan synthase enzyme is not currently known, although activity is thought to be through non-competitive mechanisms (101). Cryptococcus neoformans contains only a single copy of a homologue of FKS1 whose expression is essential for cell viability (166). The FKS homologue of C. neoformans appears to be under the transcriptional control of calcineurin (39). It was observed that exposure to caspofungin was associated with a reduction in β-(1,6) glucan of the cryptococcal cell wall, raising the possibility that the drugs have additional mechanisms of action in specific organisms (52).

Mechanisms of Resistance

Organisms Commonly Resistant:  Organisms that do not rely on β-(1,3) linked glucan for cell wall integrity, such as Cryptococcus neoformans, are typically less susceptible to echinocandins compared to organisms that contain a large amount of glucan in β-(1,3) linkage. Echinocandins also have little to no in vitro activity against Blastomyces dermatitidis, Fusarium sp., Sporothrix schenckii, Rhizopus sp and other Zygomycetes, and Histoplasma capsulatum. Certain Candida species, such as C. parapsilosis and C. guillieriermondii typically demonstrate higher MICs compared to other Candida species, however, the clinical significance of this observation is uncertain (18, 73, 94, 114, 162, 178). Breakthrough infections with C. parapsilosis and Trichosporon species have been reported in patients receiving echinocandins (3, 30, 58, 105).

Mechanisms of Resistance:  The mechanism(s) of echinocandin resistance are being studied. Candida albicans repeatedly exposed to subinhibitory concentrations of caspofungin in vitro can develop increased MICs (19). Mutations in FKS1 and FKS2 genes have been associated with high-levels of resistance (>l0-fold increase in MIC) in Candida species to echinocandins (15, 78, 87, 129), and deletion of the GNSI gene were associated with low-levels of resistance (<l0-fold increase in MIC) (87). In Saccharomyces cerevisiae, overexpression of Sbe2p, a Golgi protein involved in cell wall formation, also resulted in a low-level of echinocandin resistance (123). Clinical isolates of C. albicans, C. glabrata and C. krusei with high MICs have been described (13, 68, 74, 78, 93, 129).

               Development of in vitro resistance in Aspergillus sp. has been generated by serial passage, but the mechanism was not defined (55). In another study, a point mutation inserted into A. fumigatus FKS1 at the equivalent “hot spot” region that has been described in C. albicans was shown to confer resistance to echinocandins (146). To date, however, this has not been observed in clinical A. fumigatus isolates.

               The mechanism(s) of intrinsic resistance of some fungi are being evaluated as well. In Fusarium solani, which exhibits decreased susceptibility to the organism, resistance is only partially caused by differences in the FKS1 gene  (66). The mechanisms by which C. parapsilosis demonstrates high MICs to echinocandins are also being evaluated; one recent study noted that inhibition of mitochondrial respiratory pathways enhanced C. parapsilosis susceptibility to caspofungin, but did not alter susceptibility to fluconazole (27).

               While efflux pumps are typically an important mechanism associated with resistance of azole antifungals in Candida species and Aspergillus species (104, 148), their role in conferring resistance to echinocandins is not currently understood. Early studies reported that echinocandins did not appear to be substrates for efflux pumps (11, 87), but another study reported that constitutive over expression of the Candida albicans ATP binding cassette transporter, Cdr2p, conferred resistance to caspofungin (150). Whether this is the result of efflux of the drug, or other changes in the cell wall or membrane is currently unknown. Results of another study suggested that over-expression of CDR1, CDR2 or MDR1 did not result in decreased susceptibility to echinocandins (119). It has been recently described that Candida sp. which are susceptible to echinocandins can grow in vitro at concentrations above the MIC’s for caspofungin (108, 159). This “paradoxical effect” appears to be strain- and species-dependent and may be associated with differential regulation of chitin and beta-1,6 glucan synthesis in the fungal cell wall (26, 160). For reasons not yet defined, there appears to be differences between echinocandins, with caspofungin having the strongest paradoxical effect in in vitro studies (26, 53). However, this in vitro phenomenon was not recapitulated in animal models, nor has it been described in clinical studies (36). Hence, results of multiple studies suggest that there are clinically important fungi that are intrinsically resistant to echinocandins, and some fungi can become resistant to echinocandins both in vitro and in vivo. Mechanisms are complex, and potentially associated both with mutations and/or differences in FKS subunits of glucan synthase genes, and/or its regulation. The in vitro phenomenon of the “paradoxical effect” has not been fully recapitulated in clinical experience.

Methods to Overcome or Prevent Resistance: Since microbial resistance to echinocandins has not yet become a large clinical problem, few efforts have been placed into describing preventative mechanisms. However, one older study demonstrated that mutations in the calcineurin-signaling pathway were associated with a hypersensitivity to echinocandins (128). Whether administration of calcineurin inhibitors can decrease resistance, as has been described with azole-resistant Candida isolates, is currently unknown.

 

PHARMACOKINETICS

Absorption

               All echinocandins have a low oral bioavailability, and are currently available only by intravenous infusion (67, 182). Preclinical animal studies showed that caspofungin is minimally absorbed after oral administration, with an absolute bioavailability of only 0.3% to 1% in mice and 9% in dogs (122). Similar studies for anidulafungin demonstrated a fasting absorption of 5 to 10% in dogs (5, 122). It is not likely that oral formulations will become available for any of the current echinocandins.

Distribution

               All echinocandins demonstrate a high amount (caspofungin 96.5%, micafungin 99.5%, anidulafungin more than 80% (69, 163, 182) of protein binding and relatively low volume of distributions. The volume of distribution for caspofungin estimates 9.67 L at steady state (5, 122, 162). Animal studies have demonstrated extensive tissue distribution for all echinocandins, although these drugs do not cross intact blood-brain barriers and concentrations in brain tissues are relatively low. When given intraperitoneally to mice, caspofungin was distributed into tissues with a volume of distribution estimating 0.1 l-0.27 L/kg, and the highest drug concentrations were measured in the liver. Tissue:plasma ratios measured were 16 in liver, 2.9 in kidneys, 2.0 in large intestine, 1.3 in small intestine, 1.1 in lungs, 1.0 in spleen, 0.3 in heart, 0.2 in thigh, and 0.1 in brain (67).

Routes of Elimination

Metabolism: Caspofungin is slowly metabolized in the liver by hydrolysis and N-acetylation, with some of the drug excreted relatively unchanged in bile (162).  Micafungin is metabolized in the liver and excreted in an inactive form into bile and urine, with <1% of the drug found in urine in an unchanged form. Micafungin is not metabolized by the CYP 450 system (29, 54). Anidulafungin is not metabolized, but undergoes slow chemical degradation to inactive moieties, that lack the cyclic structure necessary for activation. In healthy volunteers, almost all of a single radiolabelled dose of anidulafungin was recovered in the feces (<10% as intact anidulafungin, and >90% as small, tertiary degradation products (115).

Renal Excretion:  None of the echinocandins are excreted by the kidneys to a great degree. Only 1.44% of the total dose of caspofungin, and 15% of micafungin are excreted unchanged by the kidneys, with total renal clearances of 1 µl/min, and 11 mL/hr/kg, respectively (5, 29). Renal excretion of anidulafungin or its degradents was negligible (115).

Pharmacokinetic Parameters

               The pharmacokinetic parameters of echinocandins (in adults) are summarized in Table 4. Plasma caspofungin elimination is typically triphasic, with mean α, β, and γ half-lives of 1 to 2, 9 to 11, and 40 to 50 hours, respectively (162).

               Caspofungin is administered as a single loading dose of 70 mg, followed by 50 mg daily. In normal volunteer studies, a single 70 mg dose of intravenous caspofungin resulted in mean peak plasma concentrations of 10.45 µg/ml and trough concentrations of 1.19 µg/ml. Mean trough concentrations were >1 µg/mL in subjects who received the loading dose, whereas they were <I µg/mL in subjects who did not receive the loading dose. In healthy subjects, multiple dosing at 70 mg IV was associated with moderate accumulation (25%-50% after 3 weeks). Excretion of caspofungin and its metabolites is slow, with 75.1% of radioactive products recovered (40.7% in urine, 34.4% in feces).

               Pharmacokinetics of micafungin has been investigated in healthy adult human volunteers, as well as in ill, hospitalized subjects. With a dose-proportional increase in maximum concentration (Cmax) and the area under the curve for 0–24 h (AUC0–24) observed, investigators determined linear plasma pharmacokinetics for intravenous micafungin. The half-life ranged from 14 to 15 h. The mean peak plasma concentration (±SD) (day 7) was 2.46 ± 0.27 g/mL. The elimination half life varied in febrile neutropenic pediatric patients, from 12 to 13 hours on day 1 to 21 hours after 4 days of infusion (29, 54). The pharmacokinetics of micafungin was not significantly altered in patients with severe renal dysfunction (GFR less than 30 ml/min) (59).

               After oral doses of anidulafungin (up to 1000 mg), an elimination half-life of about 30 hours has been reported in healthy subjects. Half-life data following intravenous use in healthy adults revealed 29 hours, a population model of anidulafungin pharmacokinetics demonstrated a <20% difference in clearance rate, regardless of weight, sex, and disease severity, with enough overlap among categories that the differences were deemed to have little clinical significance (42, 115, 178).

CNS/CSF Distribution

               In animal models, echinocandins appear to reach brain tissue after IV infusion, but do not cross into the cerebrospinal fluid to a significant degree. The following brain: plasma ratios have been reported for the different echinocandins: 0.1 for caspofungin, 0.01 for micafungin, and 0.14 for anidulafungin (62, 63, 64, 67). When micafungin was given at 0.5, 1, and 2 mg/kg of body weight intravenously once daily for a total of 8 days in rabbits, the drug was not detectable in cerebrospinal fluid. However, the concentration in brain tissue ranged from 0.08 to 0.18 µg/g (64). In a pharmacokinetic study of anidulafungin in rabbits, measurable concentrations of anidulafungin in brain tissue were noted at dosages of 0.5 mg/kg in another animal model (63).

Effect of Disease States

Renal Insufficiency:  After administration of a single 70-mg IV dose of caspofungin, volunteers with moderate renal insufficiency (creatinine clearance 31-49 mL/min), severe renal insufficiency (5-30 ml/min), and endstage renal disease (<10 mL/min and dialysis dependent) had moderate increases in caspofungin plasma concentrations compared with control subjects, with an increase in AUC ranging from 30% to 49%. Nevertheless, based on the finding that mild to severe renal impairment had no remarkable effect on trough concentrations in patients receiving multiple doses of caspofungin (50 mg/d) in clinical trials, the manufacturer does not recommend dose adjustment in patients with renal insufficiency (161).

               Micafungin pharmacokinetic parameters were compared between 2 groups of subjects with either normal renal function (creatinine clearance >80 mL/min) or severe renal dysfunction (creatinine clearance <30 mL/min) following single-dose of 100 mg micafungin. Regression analyses failed to demonstrate a significant correlation between creatinine clearance and any of the pharmacokinetic parameters studied. Dose adjustments do not appear to be required in patients with renal impairment (171). Similarly, there was no apparent change in pharmacokinetics of anidulafungin in people who had variable degrees of renal insufficiency (169, 170, 178, 44).

Hepatic Insufficiency: The effect of hepatic insufficiency on caspofungin pharmacokinetics was evaluated in a Phase I pilot study. Eight subjects with mild hepatic insufficiency (Child-Pugh score 5-6) and 8 subjects with moderate hepatic insufficiency (Child-Pugh score 7-9) were administered a single dose of caspofungin (70 mg IV). The extent of absorption of caspofungin (denoted by AUC) increased by 55% (90% CI, 32 to 86) and 76% (90% CI, 51 to 106) in patients with mild and moderate hepatic insufficiency, respectively, compared with historical healthy control subjects (161). Another study evaluated the impact of dose-adjustment of caspofungin on pharmacokinetics in 8 subjects with mild hepatic insufficiency, 8 subjects with moderate hepatic insufficiency, and 16 healthy subjects matched by age, sex, and body weight. Control subjects and those with mild hepatic insufficiency received a 70-mg IV loading dose of caspofungin on day 1 followed by 50 mg IV daily for the remainder (13 days) of the study. Subjects with moderate hepatic insufficiency received a 70-mg loading dose of caspofungin IV on day 1, followed by 35 mg IV daily on days 2 through (14). The AUC on day 14 increased by 21% (90% CI, 4 to 39) and 7% (90% CI,-10 to 28) in subjects with mild and moderate hepatic insufficiency, respectively, compared with control subjects. On the basis of this preliminary study, the investigators did not recommend dose adjustment for patients with mild hepatic insufficiency. In patients with moderate hepatic insufficiency, however, they recommended that after the initial 70-mg loading dose, the maintenance dose be reduced to 35 mg/d. No pharmacokinetic data on caspofungin are available in patients with severe hepatic insufficiency (Child-Pugh score >9) (161).

               In patients with severe hepatic insufficiency (Child-Pugh score>9) treated with anidulafungin 50 mg daily, plasma concentration of anidulafungin decreased, plasma clearance is increased, and total distribution volume is doubled compared to healthy volunteers (167, 44).

               In subjects with moderate hepatic disease (Child–Pugh score 7–9) who received a single 100 mg dose of micafungin, individuals with moderate hepatic dysfunction exhibited reduction in peak concentration and AUC of approximately 22% compared to healthy subjects. The observed increased clearance was believed to be the result of decreased albumin binding by micafungin and subsequent greater hepatic extraction. Despite the reduced systemic exposure, blood concentrations of micafungin remained above those thought to be necessary for antifungal activity. The authors concluded that among patients with moderate hepatic dysfunction, no dose adjustments would be required  (172).

 

DOSAGE

Adults and Children

               The recommended adult dosage for caspofungin is 70 mg IV on day 1 followed by 50 mg/d thereafter. Caspofungin should be infused slowly over 1 hour and is not compatible with any dilution that contains dextrose.

               Anidulafungin is administered parenterally once daily. In treating esophageal candidiasis, the initial (loading) dose of anidulafungin is 100 mg, followed by 50 mg/day. In patient with candidemia and other deep-tissue Candida infections, a loading dose of 200 mg on day 1 is followed by 100 mg/day thereafter.

               Micafungin is administered intravenously as a one-hour infusion once daily. The recommended dosage for adults is 50 mg/day for antifungal prophylaxis during pre-engraftment period in SCT recipients and 150 mg/day for the treatment of esophageal candidiasis (29).

               Specific recommendations for dosing of echinocandins in children have not yet been made available. Initial pediatric studies suggest that the increased dosing required for caspofungin in children may not extend to the other two echinocandins (158).

Zaoutis T. et al. A Prospective, Multicenter Study of Caspofungin for the Treatment of Documented Candida or Aspergillus Infections in Pediatric Patients. PEDIATRICS. 2009 Mar;123(3):877-84.

Renal Failures

               No dose adjustment in mild, moderate or severe renal insufficiency is required for all echinocandins. As none of the echinocandins in clinical use dialyzable, no dose adjustment is necessary for patient with hemodialysis (29, 44, 54, 115, 162, 178).

Hepatic Failures

               Dose adjustment for caspofungin was not deemed necessary in the setting of mild hepatic dysfunction, however, in patients with moderate hepatic insufficiency (Child-Pugh 7 to 9), daily maintenance doses should be reduced from 50 mg to 35 mg (after administration of a 70 mg loading dose on the first day 24. Fewer data exist for micafungin and anidulafungin, but studies showed that dose adjustment for micafungin may not be indicated in the setting of moderate liver disease (172).

               Anidulafungin levels in patients with mild or moderate hepatic impairment were not significantly different from those measured in healthy subjects. In patients with severe hepatic impairment, the decreases in exposure, compared with control subjects, were considered to be secondary to ascites and edema and to be within the variability observed in healthy subjects. Consequently, no dosage adjustment of anidulafungin has been recommended for any degree of hepatic impairment (43, 167, 178).

Pregnancy

               Caspofungin and anidulafungin have been shown to be embryotoxic in animal studies, producing incomplete ossification of the skull and torso and an increased incidence of cervical ribs. Micafungin sodium administration to pregnant rabbits (resulted in visceral abnormalities and abortion). Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter. Consequently, all echinocandins are designated a Pregnancy Category C drug (animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans) The distribution of caspofungin, micafungin anidulafungin and its metabolites in human milk is not known, the drug is excreted in the milk of animals at concentrations similar to those in maternal plasma. The use of all echinocandins in pregnant women and nursing mothers should be avoided (4, 24, 54, 111, 115, 161).

 

ADVERSE EFFECTS

               Overall, adverse events (AE) related to echinocandins are generally infrequent and mild. In normal volunteer and clinical studies of caspofungin, the most frequently reported drug-related AEs were mild to moderate infusion-related reactions and headache. Dermatologic effects (eg, flushing, erythema, wheals, or rash), facial edema, or respiratory symptoms (wheezing or bronchoconstriction) associated with histamine release were also noted. The most common laboratory adverse event has been elevation of liver transaminase levels, which have been noted to be dose related, but mild and reversible upon cessation of the drug (24, 161). Eosinophilia was also reported (161).

               Adverse events associated with micafungin administration are infrequent and most often mild (29, 40). The most frequently reported drug-related side effects included nausea, vomiting, diarrhea, bilirubinemia, and increased liver function test levels, none of which were considered serious or dose-limiting. Local phlebitis and thrombophlebitis at the infection site was reported in patients who were treated with micafungin via a peripherial vein. Possible histamine-mediated symptoms (rash, pruritus, and vasodilatation) and isolated cases of anaphylaxis and hemolysis have been also reported (29).

               The most common clinical adverse events associated with administration of anidulafungin include headache, elevated alanine transaminase (ALT), dizziness and nausea. Occasional infusion reactions have also been observed upon administration of intravenous anidulafungin, which typically include symptoms of nausea, dyspnea, and facial flushing; these symptoms were shown to be unrelated to blood histamine levels (4, 178).

 

MONITORING REQUIREMENTS

               Routine monitoring of blood or tissue levels of echinocandins is not currently recommended. Because of potential complications associated with therapy in these typically complex patients, obtaining routine serum chemistries, hepatic enzymes, and complete blood counts is prudent.

 

DRUG INTERACTIONS

               In general, echinocandins are poor substrates for CYP450 enzymes, and do not interact with P-glycoprotein, which mediates efflux of a variety of drugs from cells (4, 14, 24, 29, 40, 111, 178). Thus, fewer drug interactions have been noted with this class of compounds compared to other antifungals, such as triazoles, which may be both substrates and inhibitors of several CYP450 isoenzymes. One clinically meaningful drug interaction that has been noted is with cyclosporine and caspofungin, although the precise mechanism of this interaction is not completely understood. In healthy subject studies, concurrent cyclosporin administration increased the AUC of caspofungin by approximately 35%, which was associated with mild, reversible elevations in hepatic transaminases. Although administration of caspofungin with cyclosporin has not been recommended because of this potential interaction, clinical experience has accumulated in this setting, and results of two small studies suggested that the interaction may not be clinically meaningful (103, 149). Cyclosporin also increases the AUC of micafungin and anidulafungin, but to a lesser degree (13% 173 and 21% 45, respectively); these drugs have been co-administered without dose adjustments in both healthy volunteer studies and clinical studies without apparent complications. None of the echinocandins appear to interact with tacrolimus. However, in the presence of steady state micafungin, serum concentration of sirolimus and nifedipine increased by 21% and 18%, respectively. Patients receiving sirolimus or nifedipin in combination with micafungin should be closely monitored for sirolimus or nifedipine toxicity (29).

               A drug-drug interaction study with rifampin in healthy volunteers showed a 30% decrease in caspofungin trough concentrations. Patients on rifampin should receive 70 mg of caspofungin daily. In addition, results from regression analyses of patient pharmacokinetic data suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition is inducible. When caspofungin is co-administered with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of caspofungin should be considered (24).

 

CLINICAL INDICATIONS

               The FDA-approved indications for clinical use of caspofungin, micafungin and anidulafungin are listed in Table 1 (182).

Empirical Treatment and Prophylaxis in Neutropenic Patients:  In a randomized, multicenter double-blind study involving more than 1000 neutropenic patients with refractory fever, the administration of caspofungin (70 mg loading dose, followed by 50 mg) resulted in a similar outcome as liposomal amphotericin B (3mg/kg/day). Overall success rates were 33.9 and 33.7% in patients treated with caspofungin and liposomal ampotericin B, respectively (183).

               The efficacy of caspofungin or itraconazole for antifungal prophylaxis in patients treated for AML or myelodisplastic syndrome was evaluated in open-labeled randomized trial. 52% of 106 patients treated with caspofungin completed the study without fungal infection. However, in a total of seven patients in the caspofungin group developed documented invasive fungal infections (two with candidemia, two with disseminated Trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp) (107).

               Micafungin (50 mg) was studied relative to fluconazole (400 mg) in a large, randomized, double-blind, multi-institutional comparative study antifungal prophylaxis in neutropenic patients. With efficacy defined as the incidence of proven, probable and possible invasive fungal infection, with the latter encompassing receipt of other empirical therapy, micafungin appeared superior to that of fluconazole (80% vs. 73.5%; p = 0.03) (174).

               The efficacy of anidulafungin in antifungal prophylaxis or treatment of refractory neutropenic fever has not been evaluated. Recent reports have emphasized that breakthrough infections with multiple fungi occur during receipt of echinocandins; studies report the development of invasive infection with Trichosporon species and Aspergillus species, as well as development of resistance in Candida species (discussed in earlier sections) (3, 58, 96, 105, 130, 186).

Infections Caused by Candida Species: Randomized trials have also established clinical utility of caspofungin for treatment of oropharyngeal and esophageal, and invasive candidiasis (6, 75, 76, 114, 156, 179, 114, 157). In a randomized comparative study, caspofungin (70 mg loading dose then 50 mg/d) was equivalent to, but better tolerated than amphotericin B deoxycholate (0.6-1.0 mg/kg/d) for invasive candidiasis (114).

               The efficacy of micafungin in the treatment of esophageal candidiasis in patients with AIDS was shown in one dose-ranging trial and 2 randomized double-blinded trials (37, 38, 84). Notably, in studies that compared caspofungin and anidulafungin with fluconazole for esophageal candidiasis, relapse rates were higher in the echinocandin-treated groups (28% for caspofungin, 17% for fluconazole, 35.6% for anidulafungin, and 10.5% for fluconazole) (29, 133,  181). Reasons for such a discrepancy in the relapse rates remain unclear (29).

               Open-label studies supported the efficacy of micafungin in the management of candidemia (81, 82). In one open-label, noncomparative study of micafungin for the treatment of candidemia in 126 patients, overall success was noted in 83.3% of patients (124). Micafungin was recently studied relative to liposomal amphotericin B and caspofungin, in large, randomized, double-blind trials (90, 127). Micafungin (100 mg/day) was found to be as effective, but less toxic than liposomal amphotericin B (90). Another study compared outcomes of invasive candidiasis after therapy with micafungin (100 mg daily), micafungin (150 mg daily) and caspofungin (70 mg followed by 50 mg daily (127). No significant differences in mortality, relapsing and emergent infections, or adverse events was observed between study arms (127).

               In a randomized, double-blind, noninferiority trial of treatment for invasive candidiasis, anidulafungin was shown to be noninferior to fluconazole. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole; in this study, there was a trend to better survival in patients who received andiulafungin (p=0.13) (144).

Colombo AL, et al.  Caspofungin Use in Patients with Invasive Candidiasis caused by Common Non-albicans Candida Species: Review of the Caspofungin Database.  Antimicrob Agents Chemother 2010;Mar 15 [Epub ahead of print]

Invasive Aspergillosis:  The treatment of invasive aspergillosis with caspofungin, and micafungin has not been examined in a randomized, controlled manner. Most data available are from open-label studies for the treatment of refractory aspergillosis.

               The data supporting use of caspofungin for "salvage“ therapy of aspergillosis were generated by a small, historic-controlled trial or during compassionate use program that demonstrated a response rate approximating 40% in patients who received caspofungin after failure (intolerance or refractoriness) of other antifungals (77, 98).

               In a multinational, non-comparative study conducted to examine proven or probable (pulmonary only) Aspergillus species infection, a favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients treated with micafungin alone or in combination with another systemic antifungal agent. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to invasive aspergillosis (41).

               An open-label micafungin study from Japan reported success rates of 60% (6 of 10 patients) for invasive pulmonary aspergillosis—67% (6 of 9) for chronic necrotizing pulmonary aspergillosis, and 55% (12 of 22) for pulmonary aspergilloma (81). Studies on the clinical efficacy of anidulafungin in refractory invasive aspergillosis have not been published.

               More recent attention has been placed into the potential application of echinocandins administered in combination with other antifungals for invasive aspergillosis. Animal models, case reports and small series of patients suggest that caspofungin or micafungin, administered with triazoles or amphotericin formulations, may result in optimal clinical outcomes (23, 25, 83, 85, 97, 102, 155, 187), however, randomized trials will be necessary to define the utility of echinocandin-based combination therapies.

Gubler C, Wildi SM, et al.  Disseminated Invasive Aspergillosis with Cerebral Involvement Successfully Treated with Caspofungin and Voriconazole.  Infection. 2007;35(5):364-6.

Yokote T, Akioka T, et al.  Successful treatment with micafungin of invasive pulmonary aspergillosis in acute myeloid leukemia, with renal failure due to amphotericin B therapy.  Ann Hematol 2004;83(1):64-6.

Izumikawa K, et al.  Clinical efficacy of micafungin for chronic pulmonary aspergillosis.  Med Mycol. 2007;45(3): 273-278.

Chou LS, Lewis RE, et al.  Caspofungin as primary antifungal prophylaxis in stem cell transplant recipients. Pharmacotherapy 2007;27(12):1644-1650.

               In summary, echinocandins represent a new class of antifungals that have a novel mechanism of action, targeting cell wall synthesis rather than cell membrane integrity. Three compounds, caspofungin, micafungin, and anidulafungin, have similar activity profiles, with minor differences relating to pharmacokinetic parameters. All of these drugs should add greatly to the armamentarium of antifungals available for therapy of diseases caused by the most common yeasts and molds.

 

TABLES AND FIGURES

Table 1: Comparison of FDA Approved Indications for Echinocandins in Clinical Use

Table 2. In Vitro Activity of Caspofungin, Micafungin and Anidulafungin Against Candida sp.

Table 3. In vitro activity of caspofungin, micafungin and anidulafungin against Aspergillus sp.

Table 4. Pharmacokinetic parameters of caspofungin, micafungin and anidulafungin

Figure 1. Structure of (a) Caspofungin, (b) Micafungin, and (c) Anidulafungin.

Figure 2. Effects of In Vitro Echinocandin Exposure to (a) Candida species, (b) Aspergillus species.

 

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