Version May 2024
INTRODUCTION — The development of echinocandins, the first class of antifungals to target the fungal cell wall, was a milestone achievement in antifungal chemotherapy. Echinocandins were discovered as fermentation metabolites with antifungal activity during screening programs for new antibiotics [1]. The candidate molecules were subsequently modified to improve solubility, antifungal spectrum of activity, and pharmacokinetic characteristics [2]. Four semi-synthetic echinocandin derivatives have been developed for clinical use: caspofungin, micafungin, anidulafungin, and rezafungin. A fifth compound, ibrexafungerp, is a triterpenoid antifungal that is structurally distinct from the echinocandins and is a semisynthetic derivative of the naturally occurring hemiacetal triterpene glycoside enfumafungin.
All four echinocandins are structurally similar cyclic hexapeptide antibiotics with modified N-linked acyl lipid side chains (figure 1), which play a role in anchoring the hexapeptide nucleus to the fungal cell membrane where the drug interacts with the target enzyme complex involved in cell wall synthesis [3]. Ibrexafungerp, which is also an inhibitor of glucan synthesis in fungi, interacts with the same target enzyme complex as the echinocandins but through another target site that appears to not interact with the lipid membrane in the same fashion. The four large lipopeptide echinocandins (anidulafungin, caspofungin, micafungin and rezafungin) have limited oral bioavailability and must be administered by intravenous infusion. Ibrexafungerp is unique in that it is absorbed in the gastrointestinal tract after oral administration and is currently available as an oral formulation. Experience with this antifungal class suggests that it is among the best tolerated and safest class of antifungals available.
The pharmacology of echinocandin antifungals and the triterpenoid glucan synthesis inhibitor, ibrexafungerp, will be reviewed here. Indications for the clinical use of these antifungals, susceptibility testing, and the pharmacology of other systemic antifungal agents, such as amphotericin B, the azoles, and flucytosine, are discussed separately. (See "Management of candidemia and invasive candidiasis in adults" and "Treatment and prevention of invasive aspergillosis" and "Antifungal susceptibility testing" and "Pharmacology of amphotericin B" and "Pharmacology of azoles" and "Pharmacology of flucytosine (5-FC)".)
OVERVIEW OF CLINICAL USES — Echinocandins are widely used for the treatment of invasive candidiasis, especially in critically ill and neutropenic patients [4]. They are also used for empiric antifungal therapy in patients with neutropenic fever. They are sometimes used in combination with a triazole (eg, voriconazole, isavuconazole, or posaconazole) for the initial treatment of invasive aspergillosis or as part of a combination antifungal regimen with voriconazole or a lipid formulation of amphotericin B for salvage therapy of invasive aspergillosis (see "Treatment and prevention of invasive aspergillosis"). Currently, ibrexafungerp is approved only for the treatment of vulvovaginal candidiasis (VVC) [5].
The major advantage of echinocandins relative to other antifungal agents is their fungicidal activity against Candida spp, including fluconazole-resistant C. glabrata and C. krusei, combined with their relatively low potential for renal or hepatic toxicity or serious drug-drug interactions. Echinocandins are also currently recommended as the drugs of choice for C. auris, although resistance has been reported [6]. Specific recommendations regarding the use of these agents are presented separately. (See "Management of candidemia and invasive candidiasis in adults" and "Treatment and prevention of invasive aspergillosis" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent'.)
Anidulafungin, caspofungin, and micafungin have been approved by the US Food and Drug Administration (FDA) for the treatment of esophageal candidiasis and invasive candidiasis in adults, and caspofungin has been approved for these indications in children over three months of age. Caspofungin has also been FDA approved in adults and children over three months of age as an empiric antifungal agent for febrile neutropenia and for salvage therapy of invasive aspergillosis in patients who have failed or are intolerant of other antifungal agents. Micafungin has also been FDA approved as a prophylactic agent for the prevention of Candida infections in adults undergoing hematopoietic cell transplantation. Rezafungin is approved for the treatment of candidemia and invasive candidiasis. Ibrexafungerp is approved for the treatment of vulvovaginal candidiasis (VVC) and recurrent VVC.
Because the four echinocandins share a similar spectrum of activity and mechanism of action, most experts consider these drugs to be interchangeable, particularly for the treatment of invasive candidiasis (see "Management of candidemia and invasive candidiasis in adults"). Ibrexafungerp should not be considered interchangeable with current echinocandins until further data are available.
The four echinocandins differ in terms of their dosing, pathways of metabolic elimination, and drug interaction profile. Therefore, these unique characteristics should be considered when selecting an echinocandin.
MECHANISM OF ACTION — Echinocandins and ibrexafungerp are noncompetitive inhibitors of beta-D-glucan synthesis. Beta-D-glucans are branched polysaccharides that serve as essential crosslinking components in the cell wall of many pathogenic fungi. By interfering key catalytic subunits (Fks1p and Fks2p) in the beta-(1,3)-D-glucan synthase enzyme complex, echinocandins deplete cell wall glucan crosslinking, resulting in a markedly weakened cell wall structure (figure 2) [7].
Beta-glucans account for approximately 30 to 60 percent of the cell wall mass in yeasts such as Candida species [8,9]. Beta-glucan depletion causes loss of resistance to osmotic forces and cell lysis among Candida spp, thereby having a fungicidal effect. In filamentous fungi, such as Aspergillus fumigatus, the bulk of beta-glucan synthesis is concentrated at the apical tips and branching points of hyphae [10-12]. Among filamentous fungi, echinocandin-induced beta-glucan depletion causes impeded growth at the tips and branching points of hyphae, resulting in dysmorphic hyphae; this growth inhibition has a fungistatic effect [13].
Beta-glucans and the intracellular beta-glucan synthase complex blocked by echinocandins are not present in human cells. For this reason, the echinocandins cause less collateral toxicity than amphotericin B formulations or the triazoles and are implicated in fewer drug-drug interactions. In addition, the mechanism of action of the echinocandins appears to complement the antifungal effects of the other antifungal drug classes, offering the potential for combination therapy. (See "Treatment and prevention of invasive aspergillosis", section on 'Combination therapy'.)
Echinocandins may also amplify host immune responses by unmasking antigenic beta-glucan epitopes, thereby accelerating host cellular recognition and inflammatory responses [14-18]. However, the evidence supporting such immunomodulatory effects is limited to in vitro studies and murine models.
MICROBIOLOGIC ACTIVITY — Given the widespread distribution of beta-glucans in the fungal cell wall and the high degree of homology of FKS genes among diverse fungal genera, echinocandins would be predicted to exhibit activity against a wide spectrum of fungal pathogens. However, the echinocandins and ibrexafungerp are primarily effective against Candida and Aspergillus species, with relatively weak activity against other molds and yeasts, including Cryptococcus neoformans [3]. Differences in fungal cell wall construction may influence echinocandin penetration or render some fungal species less susceptible to the effects of beta-glucan synthesis inhibition [1].
Candida species — All four of the echinocandins exhibit excellent potency against Candida spp [19]. C. albicans, C. glabrata, and C. tropicalis are highly susceptible to all three agents, whereas elevated minimum inhibitory concentrations (MICs) have been seen for C. parapsilosis and C. guilliermondii (table 1) [19,20]. Acquired resistance to the echinocandins remains sporadic [21,22] and varies by region [23] but has been documented for individual cases of infection with C. albicans, C. glabrata, C. lusitaniae, C. tropicalis, and C. parapsilosis [22,24-29].
Of note, there is increasing concern that some triazole-resistant C. glabrata bloodstream isolates are also resistant to the echinocandins. In a surveillance study of the in vitro susceptibility of 1669 C. glabrata bloodstream isolates collected in the United States between 2006 and 2010, 162 isolates (9.7 percent) were resistant to fluconazole, of which 98.8 percent were also not susceptible to voriconazole (MIC >0.5 mcg/mL), and 9.3, 9.3, and 8.0 percent were resistant to anidulafungin, caspofungin, and micafungin, respectively [20]. Of the 162 isolates that were resistant to fluconazole, 18 (11.1 percent) were resistant to one or more of the echinocandins; all of these isolates contained an FKS1 or FKS2 mutation. In comparison, there were no echinocandin-resistant strains detected among 110 fluconazole-resistant C. glabrata isolates tested between 2001 and 2004, years in which only one echinocandin, caspofungin, was available, and echinocandins were used sparingly. In a population-based analysis of echinocandin resistance in 1380 bloodstream isolates of C. glabrata from four United States cities collected between 2008 and 2013, 3 to 4 percent of strains were resistant to all three echinocandins, and approximately one-third of echinocandin-resistant strains were cross-resistant to fluconazole [30]. Nearly all of the isolates with an FKS1 or FKS2 mutation were resistant to at least one echinocandin. Worldwide surveillance data from the SENTRY program (2016 to 2018) have reported echinocandin resistance rates ranging from 2.1 to 3.2 percent [31].
A 10-year study of C. glabrata bloodstream infections at a single medical center in the United States showed an increase in echinocandin resistance from 4.9 percent in 2001 to 12.3 percent in 2010 [32]. This resistance was confirmed by the presence of FKS mutations; strains categorized as susceptible did not possess acquired mutations. Echinocandin resistance was associated with echinocandin treatment. Among 118 episodes of C. glabrata infection in which the infecting strain was categorized as susceptible using the clinical breakpoints, 109 (92.4 percent) had successful outcomes at day 10 of treatment with micafungin. Conversely, among 13 episodes of C. glabrata infection in which the strain was categorized as resistant using the clinical breakpoints and treated with micafungin monotherapy, 5 (38.5 percent) did not respond or responded initially but relapsed or recurred. Among 78 fluconazole-resistant isolates, 11 (14.1 percent) were resistant to one or more echinocandins and 8 (10.3 percent) were resistant to all echinocandins. Another retrospective single-center study reported that FKS mutations were identified in 18 percent of 72 patients with C. glabrata candidemia and were associated with an eightfold risk of treatment failure [33].
Among patients with underlying hematologic disease, infection with an echinocandin-resistant strain of C. glabrata, C. parapsilosis, or C. tropicalis was associated with threefold higher rates of 14- and 30-day mortality [34].
●Rezafungin achieves higher drug exposures relative to older echinocandins, a factor that may allow the drug to retain activity against some resistant strains [35].
Similarly, ibrexafungerp, which appears to bind at a different site of the FKS1/FKS2 enzyme complex, may retain activity against some echinocandin-resistant strains with FKS1/2 mutations that impact anidulafungin, caspofungin, and micafungin [36,37].
●Most Candida auris isolates are susceptible to the echinocandins, but echinocandin resistance is increasing [6]. (See "Management of candidemia and invasive candidiasis in adults".)
These findings emphasize the importance of continuing surveillance for resistance using standardized antifungal susceptibility testing. (See "Antifungal susceptibility testing", section on 'Echinocandins' and "Management of candidemia and invasive candidiasis in adults".)
Candida biofilms — Echinocandins and ibrexafungerp appear to retain activity against biofilm-embedded Candida species. Under sessile biofilm-like conditions, the MICs for amphotericin B and fluconazole may increase by 10- to 1000-fold [38,39]. Biofilm growth in C. albicans is associated with increased secretion of carbohydrates, including beta-(1,3)-D-glucan [40], which has been shown to directly inhibit the activity of both fluconazole and amphotericin B [41-43]. In contrast, echinocandin and ibrexafungerp MICs are minimally affected when tested in biofilm versus non-biofilm conditions, and a biofilm-embedded inoculum of C. albicans can be reduced by >99 percent at the echinocandin concentrations achieved in vivo [38,39]. These in vitro data suggest that echinocandins may be particularly useful antifungal agents for prosthetic device or catheter-associated infections in which biofilm-embedded organisms can be associated with recurrent candidemia.
Other yeasts — Echinocandins and ibrexafungerp lack clinically useful activity against Cryptococcus neoformans, and Cryptococcus gattii, even though beta-(1,3)-D-glucan synthase from Cryptococcus spp is exquisitely sensitive to inhibition by caspofungin, and beta-(1,3)-D-glucan is present in the fungal cell wall [3]. Breakthrough infections with other rare yeasts intrinsically resistant to echinocandins (non-Candida, non-Cryptococcus) have been reported in immunocompromised patients during echinocandin treatment and should be considered in the differential diagnosis of fungemia in any patient with recent echinocandin or ibrexafungerp exposure [44,45]. Compensatory cell wall mechanisms, melanin, and drug degradation pathways may contribute to the inherent resistance of this species to echinocandins.
Dimorphic fungi — Echinocandins and ibrexafungerp have only modest activity against the mycelial phase of the dimorphic fungi, Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides spp. Echinocandins are not considered to be effective agents for therapy of dimorphic fungal infections.
Aspergillus — Growth of Aspergillus species is inhibited at very low echinocandin and ibrexafungerp concentrations in vitro, with the effects predominantly observed at apical and sub-apical branching points where cell wall remodeling and beta-glucan synthase are most active [11,46]. As such, MIC endpoints for Aspergillus are determined differently for echinocandins and ibrexafungerp than for other antifungals. The lowest echinocandin concentration resulting in grossly abnormal hyphal forms (small, compact, highly branched hyphae as compared with the normally elongated hyphal forms) are defined at the minimum effective concentration (MEC) [13]. MEC ranges for most Aspergillus species fall into what would be considered the susceptible range (table 1).
Other molds — Echinocandins and ibrexafungerp have only modest or weak activity against non-Aspergillus molds. This is sometimes more apparent in vivo than in vitro, suggesting that their effects are partially mediated through unmasking of immunogenic epitopes on the fungal cell wall [47]. Modest echinocandin activity has been reported in vitro for some phaeohyphomycetes, including Alternaria spp, Bipolaris spp, Cladophialophora bantiana, Phialophora spp, Exophiala spp, Fonsecaea pedrosi, Paecilomyces variotti, Acremonium strictum, and Scedosporium apiospermum [48-51], but echinocandins are not used to treat infections due to these organisms.
Pneumocystis jirovecii — In experimental models of Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP), echinocandins are effective agents for prophylaxis but are less effective for established pneumonia [52,53]. The limited treatment efficacy of echinocandins can be explained by the fact that the glucan synthase target for echinocandin activity is expressed only during the cystic but not the trophic life cycle of P. jirovecii [53,54]. Therefore, fungal clearance of established infection is relatively weak with echinocandins compared with established therapies such as trimethoprim-sulfamethoxazole [48,55]. However, the role for echinocandins in treating or preventing PCP in humans is evolving. Case reports of progression of disease in patients receiving echinocandins have been published. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
RESISTANCE — Although echinocandins are used extensively as a first-line treatment for invasive candidiasis and less commonly as part of salvage regimens for invasive aspergillosis, acquired echinocandin resistance has been relatively rare to date but is possibly increasing, especially among C. glabrata and C. auris. (See 'Candida species' above.)
Echinocandin resistance is discussed in detail separately. (See "Antifungal susceptibility testing", section on 'Echinocandins' and "Management of candidemia and invasive candidiasis in adults" and "Treatment and prevention of invasive aspergillosis", section on 'Combination therapy'.)
PHARMACOKINETICS — Although the echinocandins share similar spectra of activity, each agent differs in its pathway of metabolism, resulting in distinguishable half-lives, drug interaction profiles, and dosing strategies (table 2) [3,56]. Due to their large molecular weights, echinocandins are minimally absorbed after oral administration and are available only in intravenous formulations. However, the triterpenoid glucan synthesis inhibitor, ibrexafungerp, is available in an oral formulation. All four echinocandins and ibrexafungerp exhibit a high degree of binding to plasma proteins and distribute minimally to cerebrospinal fluid, urine, and the eye. Ibrexafungerp achieves high concentrations in the vaginal mucosa and remains soluble at a lower pH [57]. Echinocandins are not primarily metabolized by cytochrome P450 nor are they substrates or inhibitors of P-glycoprotein pumps, making them less likely targets of drug-drug interactions compared with other systemic antifungals (see 'Dosing' below and 'Renal insufficiency' below and 'Hepatic insufficiency' below and 'Drug interactions' below). However, ibrexafungerp is a substrate of CYP3A4 and P-glycoprotein. In vitro, ibrexafungerp is also an inhibitor of CYP2C8, CYP3A4, the P-glycoprotein transporter, and the OATP1B3 transporter [58].
Caspofungin — Caspofungin exhibits triphasic nonlinear pharmacokinetics [59]. Following an initial intravenous infusion, tissue distribution accounts for an initial rapid fall in plasma levels, followed by gradual re-release of drug from extravascular tissues coupled with slow hepatic metabolism, yielding a net terminal half-life of 27 to 50 hours [56,60-62]. A loading dose followed by a lower once-daily dose is therefore required to attain an initial therapeutic plasma level and avoid drug accumulation. Caspofungin degrades spontaneously and is also metabolized via hydrolysis and N-acetylation to two inactive metabolites [59,61]. It is non-dialyzable, and less than 2 percent of active drug is excreted via the urinary tract.
Dose adjustment is unnecessary for patients with renal insufficiency. However, dose reduction for severe hepatic insufficiency is recommended. (See 'Dosing' below and 'Caspofungin' below.)
Several drugs have been shown to induce the metabolism of caspofungin: rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, and phenytoin. An increased maintenance dose of caspofungin is therefore recommended when any of these agents are given concurrently with caspofungin.
Micafungin — Micafungin demonstrates linear elimination pharmacokinetics, producing a terminal half-life of approximately 15 hours in adults [56,63]. It is metabolized hepatically by arylsulfatase, catechol O-methyltransferase, and hydroxylation. Less than 1 percent of unchanged drug is excreted in the urine. Like caspofungin, it is non-dialyzable, and dose adjustment for renal insufficiency is unnecessary. Elimination pharmacokinetics in advanced hepatic insufficiency are not well defined. Micafungin is subject to relatively few drug-drug interactions.
Modest increases in exposure to sirolimus, itraconazole, and nifedipine have been described in patients receiving micafungin [64]. (See 'Dosing' below and 'Micafungin' below.)
Anidulafungin — Anidulafungin exhibits linear elimination pharmacokinetics that are predictable and relatively stable across a broad range of patient age, weight, sex, and disease states. Anidulafungin is not metabolized but instead eliminated by slow spontaneous degradation, resulting in a terminal half-life of 40 to 50 hours [63]. A loading dose is necessary to achieve rapid therapeutic concentrations. Less than one percent of unchanged drug is excreted in the urine. It is non-dialyzable and dose adjustment for renal or hepatic insufficiency is unnecessary. Few drug-drug interactions are expected. (See 'Dosing' below and 'Anidulafungin' below.)
Rezafungin — Rezafungin exhibits linear and dose-proportional increases in the Cmax and AUC at daily doses up to 400 mg, with prolonged (terminal t½ 150 hours) elimination. The pharmacokinetics are modestly affected by sex, active infection, body surface area, and serum albumin, but dosing adjustments based on these conditions is not recommended [58]. Rezafungin undergoes minimal metabolism and is excreted mostly unchanged in the feces [65].
Ibrexafungerp — Ibrexafungerp reaches maximal plasma concentrations four to six hours after oral administration. The Cmax and AUC increased by 32 and 38 percent respectively in healthy volunteers when administered with a high fat meal compared to fasted conditions. The mean steady state volume of distribution is approximately 600 L with high accumulation in vaginal tissue. Ibrexafungerp is eliminated mainly via CYP3A4 metabolism and biliary excretion with an elimination half-life of 20 hours. A mean of 90 percent of the drug (51 percent unchanged) is recovered in the feces and 1 percent is recovered in the urine.
PHARMACODYNAMICS — The plasma drug concentration profile that optimizes the antifungal efficacy of echinocandins and ibrexafungerp has been described in animal models of invasive candidiasis and aspergillosis [66]. Echinocandins appear to exhibit concentration-dependent killing against Candida spp based upon in vivo studies showing a fungicidal effect proportional to the maximum (peak) plasma drug concentration and a persistent antifungal effect after plasma drug concentration falls below minimum inhibitory concentration (MIC) [66]. Fungicidal efficacy against Candida spp also appears to correlate with the area under time-concentration curve to minimum inhibitory concentration ratio (AUC:MIC) [61]. The optimal pharmacodynamic parameters for killing or inhibiting Aspergillus spp, however, are not clearly defined [66,67]. Furthermore, therapeutic drug monitoring with standardized plasma drug concentration ranges or targets for echinocandins has not been established, and revised dosing strategies evaluated in animal models have not identified promising dosing tools for further assessment in humans [61,66].
DOSING
Adult dosing — The dosing of echinocandins and ibrexafungerp depends upon the indication. Clinicians should consult the drug information topics or the individual topic reviews for each infection for more detailed information about the use of each drug. Details about specific interactions may be obtained by using the drug interactions program included within UpToDate. (See "Management of candidemia and invasive candidiasis in adults" and "Treatment and prevention of invasive aspergillosis".)
Pediatric dosing — Pharmacokinetic studies demonstrate an increased rate of clearance for micafungin and caspofungin among neonates, infants, and younger children compared with adolescents and adults [68-75]. Accordingly, larger doses of micafungin and caspofungin on the basis of milligrams per kilogram are required for small children and infants compared with adults. No large trials have evaluated dosing in low birthweight neonates, a population at high risk for developing invasive candidiasis. Both caspofungin and micafungin have FDA approval for use in children; dosing instructions for caspofungin are based upon body surface area for children aged three months or older [76]. Micafungin is dosed in children four months or older according to body weight and the indications for use [64]. No data are available for pediatric dosing of ibrexafungerp.
Clinicians should consult the pediatric drug information topics or the individual topic reviews for each infection for more detailed information about the use of each drug. Details about specific interactions may be obtained by using the drug interactions program included within UpToDate. (See "Treatment of Candida infection in neonates" and "Candidemia and invasive candidiasis in children: Management", section on 'Antifungal agents'.)
Dose adjustments
Enzyme inhibition — Strong CYP3A4 and P-glycoprotein inhibitors (eg, ketoconazole) increased the ibrexafungerp AUC by 5.8-fold and Cmax by 2.5-fold. Moderate CYP3A4 inhibitors (eg, diltiazem) increased the ibrexafungerp AUC by 2.5-fold and the Cmax by 2.2-fold, but no dosing adjustment is recommended. Similarly, proton pump inhibitors (eg, pantoprazole) decreased the ibrexafungerp AUC by 25 percent and Cmax by 22 percent; this is likely due to pH effects on gastrointestinal absorption, and no dosage adjustment is recommended. Based on these findings, the ibrexafungerp dose should be reduced to 150 mg 12 hours apart for one day with concomitant use of a strong CYP3A inhibitor, and no dosage adjustment is recommended in patients taking weak or moderate CYP3A inhibitors.
Enzyme induction — An increased maintenance dose of caspofungin of 70 mg daily is suggested for adult patients if treated concomitantly with rifampin [76]. For pediatric patients receiving rifampin, a dose of 70 mg/m2 (up to 70 mg) of caspofungin is suggested. A similar adjustment of caspofungin is recommended if the patient is concurrently receiving other drugs that are potent inducers of cytochrome P450 3A4 metabolism (eg, carbamazepine, dexamethasone, efavirenz, nevirapine, or phenytoin). (See 'Drug interactions' below.)
Renal insufficiency — Echinocandins and ibrexafungerp are not extensively cleared by the kidney and are not dialyzable; therefore, dose adjustment is not required in patients with renal insufficiency, including patients who are receiving hemodialysis or continuous renal replacement therapy (continuous venovenous hemofiltration or continuous venovenous hemodialysis) [64,76-78].
Hepatic insufficiency — Anidulafungin is inactivated by gradual spontaneous degradation and not metabolized hepatically; therefore, dose adjustment for hepatic insufficiency is not needed [77].
Micafungin does not require dose reduction for mild or moderate hepatic insufficiency, and no recommendation is available for use in severe hepatic insufficiency [64].
For patients with mild hepatic insufficiency (Child-Pugh class A; score ≤6), the caspofungin prescribing information recommends no dose reduction [59]. For moderate hepatic insufficiency (Child-Pugh class B; score 7 to 9), the prescribing information recommends no reduction in the loading dose but a reduction in the maintenance dose to 35 mg once daily. No recommendation is available for use in severe hepatic insufficiency (Child-Pugh score >9). A pharmacokinetic study in patients with cirrhosis admitted to a liver unit with acute decompensation and intensive care unit (ICU) patients with acute hepatic insufficiency has suggested that dose reduction of caspofungin in those with moderate (Child-Pugh class B; score 7 to 9) or severe hepatic insufficiency (Child-Pugh class C; score 10 to 15) results in suboptimal drug exposures [79]. Based on these data, we favor full doses of caspofungin for patients with hepatic insufficiency (including acute-onset liver dysfunction and cirrhosis) regardless of the severity of hepatic insufficiency to avoid subtherapeutic exposure. An alternative is to use an echinocandin that does not require dose reduction for patients with moderate to severe liver disease.
The pharmacokinetics of ibrexafungerp are not altered in patients with Child-Pugh Class A or B hepatic impairment. The impact of severe hepatic impairment (Child-Pugh Class C) is unknown.
Obesity — Body weight is an important variable influencing the volume of distribution and clearance of echinocandins; higher total body clearance of caspofungin has been observed among patients >75 kg receiving intensive care [80-82]. In a pharmacokinetic study among patients with body mass index <25, 25 to 40, and >40 kg/m2, micafungin clearance increased in proportion to weight among patients 65 to 150 kg [82]. Similarly, in a pharmacokinetic/pharmacodynamic analysis of the EMPIRICUS trial (micafungin 100 mg daily versus placebo in ICU patients with sepsis and mechanical ventilation), the likelihood of attaining area under time-concentration curve/minimum inhibitory concentration targets decreased as patient weight increased, especially in patients with sequential organ failure assessment scores >10 [83].
For patients >75 kg with sepsis and/or mechanical ventilation, we suggest a daily dose increase of 25 to 50 percent for all echinocandins [82]. No data are currently available for ibrexafungerp dosing in obesity.
Extracorporeal membrane oxygenation — Lipophilic highly protein-bound drugs may be sequestered in the extracorporeal membrane oxygenation (ECMO) circuit resulting in subtherapeutic plasma concentrations. While all four echinocandins and ibrexafungerp are highly protein bound in blood, caspofungin and micafungin are more hydrophilic (log P values <1) versus anidulafungin (log P 2.9). Conflicting evidence from ex vivo binding studies versus case suggest a modest impact of the ECMO circuit in echinocandin pharmacokinetics [84]; however, interpretation of these data may be affected by timing of sampling (early versus late in the course of ECMO when circuit binding may be saturated), the ECMO circuit configuration and materials, and pharmacokinetic changes associated with critical illness itself. Therefore, no standard dosing adjustments for echinocandins are available for patients receiving ECMO.
ADVERSE EFFECTS — Echinocandins are well tolerated, and all four members of the class have similar types of adverse effects. Serious adverse effects requiring drug discontinuation occur less frequently with the echinocandins than with other classes of systemic antifungals.
Hepatotoxicity — Modest asymptomatic elevations of aminotransferases (in 7 to 14 percent) and alkaline phosphatase (in 4 to 12 percent) are the most frequently reported laboratory abnormalities in healthy volunteers and patients treated with echinocandins [76]. Liver enzyme abnormalities are generally less common in patients treated with echinocandins compared with those receiving amphotericin B formulations or azoles. Although rare, clinically significant hepatitis, hepatomegaly, hyperbilirubinemia, and hepatic failure have been reported with the echinocandins, although causality has not been conclusively established. Regular monitoring of hepatic aminotransferases during echinocandin therapy is suggested.
Infusion and hypersensitivity reactions — Infusion and nonimmune-related histamine-release symptoms, including rash, pruritus, hypotension, bronchospasm, and angioedema, have been reported rarely with each of the echinocandins [3]. Similar to vancomycin, these reactions are likely mediated by direct stimulation of the mas-related G-protein protein receptor 2 (MRGPRX2) causing histamine release. Such reactions have been reported with anidulafungin and rezafungin when the drug is infused at a rate that exceeds 1.1 mg/minute [77]. In most patients, these effects are transient and are easily managed by slowing the infusion rate and supportive care.
Delayed (type IV) hypersensitivity reactions manifesting as a maculopapular rash are rare, although eosinophilia has been observed in 3 percent of patients receiving caspofungin [85]. Anaphylaxis has been reported rarely with each of the echinocandins. Post-marketing reports for caspofungin include rare cases consistent with a hypersensitivity syndrome, erythema multiforme, Stevens-Johnson syndrome, and skin exfoliation, although it is not clear that these reactions were caused by caspofungin [76].
Fever appears to be more common with caspofungin than other echinocandins, with rates ranging from 4 to 26 percent in clinical trials compared with <1 percent for anidulafungin and micafungin [86].
Injection site pain — Injection site pain and phlebitis have been reported more frequently with caspofungin (4 to 25 percent) than micafungin (1 to 14 percent) or anidulafungin (<1 percent), particularly when caspofungin is administered through a peripheral catheter. If these adverse effects occur, the infusion can be slowed down or the echinocandin can be administered in a more dilute solution.
Gastrointestinal — Nausea, vomiting, diarrhea, and abdominal pain have been reported in approximately 1 to 3 percent of patients receiving echinocandin therapy but rarely result in drug discontinuation [64,76,77]. For ibrexafungerp, the most common adverse effects include nausea, vomiting, abdominal pain, and diarrhea.
Renal toxicity — No significant drug-related nephrotoxicity was observed with any of the echinocandins or with ibrexafungerp in clinical trials or documented in postmarketing surveillance [64,76,77]. Modest rates of hypokalemia have been observed with all four echinocandins (2 to 11 percent), which may represent renal wasting.
Hematologic effects — Anemia, leukopenia, neutropenia, and thrombocytopenia have been reported and are limited to rare case reports (<1 percent) [64,76,77].
Cardiac toxicity — Echinocandins have been associated with low rates of cardiac adverse effects, especially relative to amphotericin B and triazoles. Some acute cardiovascular events in patients may be associated with histamine release during intravenous infusion. A review of preclinical and animal studies suggested that caspofungin and anidulafungin may have a greater potential for direct mitochondrial injury in cardiac myocytes compared with micafungin [87]. However, the clinical significance of these observations is unknown, and documented cases of heart failure with caspofungin, anidulafungin, or micafungin are extremely rare (one to four cases per year for each echinocandin).
PREGNANCY
Fetal development — There are no adequate studies of the echinocandins in pregnant women [64,76,77]. Embryo-fetal development studies in rats and mice performed with doses twofold higher than human exposures resulted in skeletal changes in rat fetuses and increased abortion and visceral abnormalities in rabbits. Echinocandins appear to cross the placental barrier in rats and could be detected in the plasma of the fetus.
All four echinocandins are classified as pregnancy category class C agents; they should therefore only be used if the potential benefit justifies the risk to the fetus.
Ibrexafungerp causes fetal harm and is contraindicated in pregnancy. Before beginning treatment, it is important to verify pregnancy status in persons of reproductive potential, and reassessment of pregnancy status prior to each dose is recommended if ibrexafungerp is used monthly for recurrent vulvovaginal candidiasis (VVC). For treatment of VVC, effective contraception should be used during treatment and for at least four days after the last dose or continued for an entire treatment period for recurrent VVC.
Breast milk — It is unknown whether caspofungin, micafungin, anidulafungin, or rezafungin are excreted in human breast milk. Because all four echinocandins are 90 percent bound to plasma proteins and have poor oral bioavailability, they are unlikely to reach the milk and be absorbed by the infant. Therefore, if echinocandin therapy is required by the mother, there is no specific indication to discontinue breastfeeding [88]. No information is available on the use of ibrexafungerp during breastfeeding. The drug is over 99 percent protein bound, so excretion in breast milk is likely to be very low. If ibrexafungerp is required by the mother of an older infant, there is no specific recommendation to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant [88].
Mutagenesis — Echinocandins do not show evidence of mutagenic or genotoxic potential when evaluated by the standard battery of in vitro and in vivo tests [64,76,77]. Fertility in rats is not affected by intravenous administration of any of the echinocandins. Long-term studies in animals to evaluate the carcinogenic potential of these echinocandins have not been performed.
DRUG INTERACTIONS — Echinocandins are not significant inhibitors or inducers of cytochrome P450 metabolism or p-glycoprotein drug efflux transporters. As a result, echinocandins generally have a lower risk for pharmacokinetic drug-drug interactions compared with other systemic antifungals. Of the comparatively few significant drug interactions involving echinocandins that have been identified to date, most involve the effect of caspofungin or micafungin upon immunosuppressive agents or the effect of other drugs upon caspofungin via enzyme induction.
Ibrexafungerp is unique in that it is both a substrate and inhibitor of CYP3A4 and P-glycoprotein. Therefore, ibrexafungerp has a greater potential for drug-drug interactions compared to other echinocandins.
Echinocandin drug interactions will be briefly reviewed here. In addition, details about specific interactions may be obtained by using the drug interactions program included within UpToDate.
Caspofungin — The mechanism(s) by which caspofungin interacts with other drugs have not been firmly established. It has been suggested that organic anion transporting polypeptides, such as OATP-1B1, which mediate uptake of some drugs to hepatocytes, may play a role in drug interactions of caspofungin [62,89].
Cyclosporine is an inhibitor of OATP-1B1 transporters and, when administered concurrently with caspofungin, has been shown to increase the total plasma concentration exposure of caspofungin (also known as area under curve [AUC]) by approximately 35 percent [76]. On the other hand, caspofungin caused no significant alteration of cyclosporine time versus plasma concentration profile [76]. The US Food and Drug Administration (FDA)-approved product information recommends caution when caspofungin and cyclosporine are given concurrently due to potentially increased risk of hepatotoxicity as evidenced by transient elevations in hepatic aminotransferases. Should the benefits of concurrent therapy outweigh the risks, monitoring of liver function tests is warranted [67,76].
Caspofungin decreases tacrolimus serum concentrations by approximately 20 percent; however, no additional interventions are recommended beyond routine monitoring of tacrolimus blood levels, and dosage adjustment is necessary to avoid effects of subtherapeutic levels, including acute graft rejection [67,76,90].
Coadministration of caspofungin with rifampin has been shown to induce caspofungin metabolism via an unknown mechanism [91]; rifampin-mediated induction of OATP-1B1 may contribute. Therefore, an increased maintenance dose of 70 mg per day of caspofungin is recommended in patients who are receiving concomitant rifampin [92]. A similar dose increase is recommended in patients receiving other enzyme inducers, such as efavirenz, nevirapine, phenytoin, dexamethasone, and carbamazepine [76]. (See 'Enzyme induction' above.)
Micafungin — Micafungin modestly reduces the clearance of cyclosporine, sirolimus (rapamycin), and nifedipine [64]. Routine dose adjustments of these agents are not necessary, but cyclosporine and sirolimus serum concentrations should be monitored. For patients receiving micafungin and nifedipine, blood pressure should be monitored and the dose of nifedipine can be reduced if necessary [64].
Anidulafungin — Among the echinocandins, anidulafungin is the least likely to be an object, or cause, of a pharmacokinetic drug interaction because it is not a substrate, inhibitor, or inducer of cytochrome P450 or P-glycoprotein. Anidulafungin does not alter the metabolism or clearance of cyclosporine. A modest increase (22 percent) in the total drug plasma concentration exposure (AUC) of anidulafungin was observed when coadministered with cyclosporine [93]. The modest degree of this effect does not require dose adjustment or other specific management.
Concurrent administration of rifampin, tacrolimus, liposomal amphotericin B, or a variety of other substrates, inducers, or inhibitors of cytochrome P450 does not have a significant impact on the plasma drug concentration profile of anidulafungin [80].
Rezafungin — In both in vitro and in vivo studies, rezafungin demonstrates a low drug interaction potential via CYP substrate/transporter pathways and commonly prescribed comedications, suggesting that coadministration is unlikely to result in clinically significant drug interactions [94].
Ibrexafungerp — Ibrexafungerp coadministration (750 or 1500 mg/day) resulted in a 1.42-, 1.40-, and 2.82- fold increase in the AUC of tacrolimus (sensitive CYP3A substrate and P-glycoprotein substrate), dabigatran (P-glycoprotein substrate), and pravastatin (OATP1B substrate), respectively. However, because of the high doses used in the studies and the expected short duration of ibrexafungerp therapy, these results did not result in recommended dosing changes [58].
SUMMARY AND RECOMMENDATIONS
●Available echinocandins – Four semisynthetic echinocandin derivatives have been developed for clinical use: caspofungin, micafungin, anidulafungin, and rezafungin. (See 'Introduction' above.)
Ibrexafungerp is a triterpenoid antifungal with a similar mechanism of action as echinocandins that is available orally. However, it is only approved for the treatment of vulvovaginal and recurrent vulvovaginal candidiasis (VVC).
●Mechanism and spectrum of activity – Echinocandins are believed to elicit their antifungal activity by binding to the Fks protein subunit of the enzyme, thereby blocking the beta-(1,3)-D-glucan synthesis (figure 2). These agents are fungicidal for susceptible Candida and fungistatic for Aspergillus spp. (See 'Mechanism of action' above and 'Microbiologic activity' above.)
●Clinical uses – Echinocandins are widely used for the treatment of invasive candidiasis, especially in critically-ill and neutropenic patients, and less commonly in salvage regimens for invasive aspergillosis. They are also used for empiric antifungal therapy in patients with febrile neutropenia. Experience with this antifungal class suggests that it is the best tolerated and safest class available.(See 'Overview of clinical uses' above.)
●Selecting an echinocandin – Because all four echinocandins share a similar spectrum of activity and mechanism of action, most experts consider these drugs to be interchangeable, particularly for the treatment of invasive candidiasis (table 1). However, the four echinocandins differ in terms of their dosing, pathways of metabolic elimination, and drug interaction profile. Therefore, it is important to appreciate these unique characteristics when selecting an echinocandin (table 2) (see 'Overview of clinical uses' above and 'Pharmacokinetics' above). Ibrexafungerp has a similar spectrum to the echinocandins but uniquely different pharmacokinetics and is only approved for the treatment of VVC and recurrent VVC.
●Advantages – The major advantages of echinocandins relative to other antifungal agents are their fungicidal activity against Candida spp, including fluconazole-resistant C. glabrata and C. krusei, combined with their relatively low potential for renal or hepatic toxicity or serious drug-drug interactions (see 'Overview of clinical uses' above). Echinocandins are the drugs of choice for C. auris but resistance is increasing, emphasizing the importance of susceptibility testing.
●Adverse effects – Echinocandins are well tolerated, and all four members of the class have similar types of adverse effects. Serious adverse effects requiring drug discontinuation occur less frequently with the echinocandins than with other classes of systemic antifungals (see 'Adverse effects' above). Ibrexafungerp is also well tolerated but may be associated with gastrointestinal side effects and is contraindicated in pregnancy because of risk of fetal harm.
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