Echinocandins — Caspofungin, Micafungin, and Anidulafungin

Fungi possess a rigid cell wall composed primarily of beta-1,3-d-glucan, chitin, and mannoproteins. Beta-1,3-d-glucan is an essential structural polymer providing tensile strength and maintaining cell shape and osmotic integrity. Its synthesis is carried out by the enzyme complex beta-1,3-d-glucan synthase (GS), encoded by the FKS1 (glucan synthase subunit 1) and FKS2 (glucan synthase subunit 2) genes in Candida species. The echinocandins are cyclic lipopeptides that act as non-competitive inhibitors of this enzyme, binding to the Fks subunit at the inner leaflet of the plasma membrane and blocking glucan chain elongation. Because mammalian cells lack a cell wall and do not synthesize beta-1,3-d-glucan, the glucan synthase target is exquisitely fungal-specific, which accounts for the excellent tolerability profile of the class.

Echinocandins are fungicidal against most Candida species, which is their principal pharmacodynamic advantage over azoles in invasive candidiasis. Disruption of beta-1,3-d-glucan synthesis destabilizes the cell wall, leading to osmotic lysis and rapid cell death through a concentration-dependent mechanism. The pharmacodynamic index driving echinocandin efficacy is the ratio of the area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC), indicating that total drug exposure over time — not just the time above MIC — is the key determinant of effect.

Against Aspergillus species, echinocandins are fungistatic rather than fungicidal: they inhibit glucan synthesis at hyphal tips, producing swollen, abnormally branched hyphae, but do not kill existing hyphae. This distinction explains why echinocandin monotherapy is not first-line for invasive aspergillosis despite the class's otherwise strong record in invasive fungal disease.

All three echinocandins are large lipopeptide molecules not absorbed from the gastrointestinal (GI) tract, requiring intravenous (IV) administration for all therapeutic indications. Once administered, all are highly protein-bound (above 97 percent, primarily to albumin), achieve high concentrations in liver, spleen, lung, and kidney, and penetrate poorly into the central nervous system (CNS) and vitreous humor of the eye. This poor CNS and ocular penetration is a class limitation for Candida endophthalmitis and CNS candidiasis, conditions that require alternative or adjunctive therapy. None of the three echinocandins is significantly metabolized by cytochrome P450 (CYP) enzymes, which largely eliminates the CYP-mediated drug interaction burden that complicates azole use.

Echinocandins are active and fungicidal against the major Candida species: Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida krusei, and Candida dubliniensis. The critical advantage over fluconazole is retained activity against fluconazole-resistant Candida glabrata and intrinsically fluconazole-resistant Candida krusei. Against Candida parapsilosis and Candida guilliermondii, minimum inhibitory concentrations (MICs) are naturally higher than against other Candida species, reflecting intrinsically reduced glucan synthase inhibitor susceptibility. Clinical outcomes with echinocandin therapy for Candida parapsilosis are generally acceptable, but some guidelines recommend fluconazole as a preferred agent when the isolate is confirmed fluconazole-susceptible. Candida auris, the multidrug-resistant emerging pathogen, is typically echinocandin-susceptible and echinocandins are the drug of choice for Candida auris infections pending susceptibility data.

Echinocandins lack activity against Cryptococcus neoformans, which has minimal beta-1,3-d-glucan in its cell wall. They have no activity against the Mucorales, Fusarium species, or most hyalohyphomycetes other than Aspergillus. Against Aspergillus, activity is fungistatic and restricted to actively growing hyphal tips; established invasive aspergillosis requires a triazole or polyene as primary therapy.

The primary mechanism of acquired echinocandin resistance is mutation in the hot spot (HS) regions of the FKS1 or FKS2 genes encoding the Fks glucan synthase subunit. Two hot spot regions have been characterized: hot spot 1 spanning amino acids 641 to 649 and hot spot 2 spanning amino acids 1345 to 1365. Mutations at specific positions within these hot spots — most commonly serine-to-leucine or serine-to-phenylalanine substitutions — reduce echinocandin binding affinity for the Fks enzyme by several orders of magnitude.

Candida glabrata has the highest rates of acquired echinocandin resistance, with resistance rates of 5 to 13 percent reported in some centers following widespread echinocandin use. FKS mutations should be suspected in patients who have breakthrough candidemia while receiving echinocandin therapy, who have a history of prolonged echinocandin exposure, or whose isolates show rising MICs on repeat testing. Cross-resistance among all three echinocandins for FKS-mediated resistance is expected because all three target the same Fks hot spot regions. For suspected echinocandin resistance, liposomal amphotericin B is the standard alternative because azole resistance may co-exist in heavily pre-treated Candida glabrata isolates.

The 2016 Infectious Diseases Society of America (IDSA) guidelines recommend an echinocandin as preferred initial therapy for most patients with candidemia and invasive candidiasis, regardless of species. The shift from fluconazole reflects the increasing prevalence of fluconazole-resistant Candida glabrata, the superior fungicidal activity of echinocandins, and evidence of lower mortality with echinocandin initial therapy. Fluconazole remains acceptable for less severely ill patients with no prior azole exposure in settings where Candida glabrata or Candida krusei is unlikely, and it is the preferred step-down agent for oral de-escalation once susceptibility is confirmed and the patient is clinically stable. The recommended duration for uncomplicated candidemia is 14 days from the last positive blood culture in a patient with no deep-seated infection and documented removal of the intravascular catheter.

Transition to oral fluconazole after echinocandin induction is appropriate when all of the following criteria are met: clinical improvement with defervescence and hemodynamic stability, the patient is tolerating oral medications, blood cultures are documented negative, the species is confirmed fluconazole-susceptible, neutropenia has resolved if present, and there is no evidence of deep-seated infection requiring prolonged IV therapy. Patients with Candida glabrata and confirmed fluconazole susceptibility can step down to fluconazole; if azole resistance is documented, echinocandin therapy must continue for the full treatment course. Oral voriconazole is an alternative step-down for Candida krusei or azole-resistant isolates where susceptibility permits.

Among patients with significant hepatic impairment, anidulafungin or micafungin is preferred over caspofungin because neither requires dose adjustment for hepatic dysfunction. In solid organ transplant recipients receiving calcineurin inhibitors, micafungin or anidulafungin is preferred to avoid the caspofungin-cyclosporine alanine aminotransferase (ALT) elevation interaction and the caspofungin-tacrolimus pharmacokinetic interaction. In patients on rifampin-based tuberculosis regimens, caspofungin requires dose escalation to 70 mg once daily, or anidulafungin or micafungin can be used without adjustment. In the intensive care unit (ICU) with polypharmacy and multiorgan dysfunction, anidulafungin is an attractive choice because of its uniquely simple pharmacokinetic profile and absence of any drug interactions or organ-based dose adjustments.