Antifungal Therapy: New and Evolving Therapies

Yasmine Nivoix; Marie-Pierre Ledoux; Raoul Herbrecht

Disclosures

Semin Respir Crit Care Med. 2020;41(1):158-174. 

In This Article

Echinocandins

Echinocandins, first available in the early 2000s, are the most recent class of systemic antifungals and have an innovative mechanism of action, good safety profile, and high fungicidal activity against yeasts. Three molecules are currently available: caspofungin, anidulafungin, and micafungin.

Mechanism of Action and Antifungal Spectrum

Echinocandins are cyclic lipopeptides that inhibit fungal wall synthesis (Figure 1).[74,75] They are obtained from the fermentation of several fungi such as A. nidulans, A. aculeatus, and Zalerion arboricola. They inhibit in a noncompetitive manner the synthesis of (1, 3)-β-D-glucan, a polysaccharide that is a major component of fungal cell walls and is absent in mammalian cells. The target of echinocandins is a heteromeric enzyme: this complex comprises at least a regulatory subunit, Rho1, that requires activation by guanosine triphosphate, and a catalytic subunit, encoded by gene FKS. The inhibition of glucan synthesis leads to osmotic instability and fungal wall lysis. This results in a decrease in yeast budding and inhibition of growth at the ends of hyphae in molds.

Caspofungin has a wide spectrum of in vitro activity including Candida spp., Aspergillus spp., and some other molds and dimorphic fungi.[76–78] It has fungicidal activity against Candida spp., notably C. albicans (even if fluconazole-resistant), C. glabrata, C. tropicalis, and, with decreasing sensitivity, C. krusei, C. lusitaniae, and C. guilliermondii.[76] There is no cross-resistance with azoles. It is, on the other hand, inactive against C. neoformans, Trichosporon spp., Fusarium spp., Scedosporium spp., and the agents of mucormycosis. Synergistic activity has been shown between AmB and capsofungin in vitro against A. fumigatus, A. flavus, A. niger, and A. terreus.[79]

Anidulafungin has fungicidal activity against most Candida spp., including strains with an intrinsic resistance (C. krusei) or a decreased sensitivity (C. glabrata).[80] However, C. guilliermondii and C. parapsilosis seem to be less susceptible to anidulafungin than other species. Like caspofungin, anidulafungin has no in vitro activity against C. neoformans and Trichosporon spp. It also shows no activity against Fusarium spp., mucormycoses agents, and Blastomyces dermatitidis.

Similar to other echinocandins, micafungin has in vitro fungicidal activity against Candida spp., notably C. albicans, C. glabrata, C. tropicalis, and, with decreasing sensitivity, C. lusitaniae and C. krusei. Minimum inhibitory concentration (MIC) values are higher for C. parapsilosis and C. guillermondii.[81] Micafungin has lower MIC values for Aspergillus spp. than AmB or itraconazole, but it does not seem to exert fungicidal activity. It is inactive against Fusarium spp. and Mucorales.

Clinical Pharmacokinetics

Caspofungin plasma concentration increases proportionally with the injected dose in healthy individuals who receive a single dose of 5 to 100 mg.[78,82,83] The volume of distribution is low (9.67 L) and protein binding is high (96%). Caspofungin undergoes spontaneous degradation into an open cyclic compound. It is then slowly metabolized by peptidic hydrolysis and N-acetylation and, to a lesser extent, by CYP.[84] Inactive metabolite elimination is mostly urinary (41%) and digestive (35%). Only a small amount of active unaltered compound is found in urine (less than 5%). Tissue distribution 36 to 48 hours after administration reaches 92%, with a high titer in the liver, spleen, and digestive tract. Lung concentrations are similar to plasma. Urine and cerebrospinal fluid concentrations are negligible. Systemic clearance is around 12 mL/minute, with a triphasic mode.

Anidulafungin displays linear pharmacokinetics in a wide range of single daily doses (15–130 mg).[83] Low interindividual variability of systemic exposure (25%) has been described. In humans, anidulafungin strongly binds to plasma proteins (more than 99%). The volume of distribution is between 30 and 50 L, with good tissue diffusion in the lungs, liver, spleen, and kidneys, but poor diffusion in the brain and very poor in the eyes. No hepatic metabolism of anidulafungin has been observed. It is not a substrate for and does not induce or inhibit CYP in any clinically relevant manner. Systemic clearance is around 1 L/hour, with a biphasic mode. Around 30% of an administered dose, of which 10% is active compound, is eliminated in feces within 9 days. Less than 1% is eliminated in the urine; hence, there is negligible renal clearance.

Micafungin pharmacokinetics are linear for usual daily dosage between 12.5 and 200 mg and between 3 and 8 mg/kg.[83,85] After IV administration, micafungin plasma concentration decreases in a biexponential manner. Micafungin is rapidly distributed into tissues, with a volume of distribution of 18 to 19 L. In plasma, micafungin strongly binds to proteins (more than 99%), mostly to albumin, and independent of serum trough (10–100 μg/mL). It is metabolized into several inactive compounds: catechol form M1, methoxy form M2, and hydroxylated form M5, but these are minority components in the bloodstream compared with unaltered micafungin. Even though micafungin is a substrate of CYP3A4 in vitro, in vivo metabolism does not rely much on this pathway. The half-life of micafungin, around 10 to 17 hours, remains constant up to 8 mg/kg doses. Total clearance is 0.15 to 0.3 mL/minute/kg in adult patients, independent of the number of doses. Elimination is mostly extrarenal (71% are found in feces and 12% in the urine).

Dosage and Adjustments

The recommended dose of caspofungin consists of one loading dose of 70 mg followed by a daily administration of 50 mg (Table 6). In case of moderate hepatic impairment, no loading dose should be administered and the daily dose is reduced to 35 mg. In case of severe liver impairment, dosage adjustment is not well defined but is advisable. No dose adjustment is needed in the case of mild hepatic or renal impairment. The recommended dose of anidulafungin is 100 mg/day after one loading dose of 200 mg. No adjustment is warranted in the case of renal or hepatic impairment. The recommended dose of micafungin ranges from 100 to 200 mg/kg according to the patient's weight. The pharmacokinetics of micafungin have not been well studied in patients with severe hepatic impairment.

Drug–Drug Interactions

Caspofungin does not inhibit CYP enzymes and is not a substrate of P-gp.[86,87] However, some drug–drug interactions have been documented:

  • Cyclosporine A: caution should be used with cyclosporine coadministration as it can result in transient liver enzyme increases, warranting close monitoring of liver function.

  • Tacrolimus: a decrease in the antirejection drug trough concentration up to 26% has been described. Laboratory monitoring is therefore recommended to adjust tacrolimus levels.

  • Enzyme inducers (such as efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, carbamazepine): the caspofungin maintenance dose should be kept 70 mg/day.

No particular precaution is needed for administering caspofungin with AmB, azoles, or mycophenolate mofetil.

Anidulafungin and micafungin have a low potential for drug–drug interaction so they do not warrant dose adjustment with coadministered medications.

Tolerability

Caspofungin is known to be well tolerated.[78] The most frequent side effect is chemical phlebitis with infusion. Other side effects are digestive disturbances (nausea, vomiting, diarrhea), increase of liver enzymes, skin reactions (rash, edema, pruritus), anemia, and generalized symptoms (fever, pain, headaches).

Anidulafungin can be responsible for transitory flushing, pruritus, rash, or urticaria.[80] Less frequently described are hypokalemia, diarrhea, seizures, headaches, and liver enzyme increases, which makes liver function test monitoring prudent.

The safety profile of micafungin is close to that of caspofungin, with a special concern for liver enzyme increases, which can be severe or even lead to lethal hepatitis.[81] Monitoring of hepatic tests is recommended, as is avoidance of micafungin in patients with severe hepatic impairment.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....