What are the newer antifungal (antifungal) agents used for treating various fungal infections?

Newer Antifungal Agents for Treating Fungal Infections

The newest antifungal agents available include the echinocandins (caspofungin, micafungin, anidulafungin, and rezafungin), expanded-spectrum triazoles (voriconazole, posaconazole, and isavuconazole), and lipid formulations of amphotericin B, with echinocandins and voriconazole representing the most significant advances in treating invasive fungal infections. 1

Echinocandins: The Newest Class

Echinocandins represent the first entirely new class of antifungal agents with a novel mechanism of action—inhibiting β-(1,3)-D-glucan synthase in the fungal cell wall. 1

Available Echinocandins

• Caspofungin was the first licensed echinocandin, approved for candidemia, invasive candidiasis, esophageal candidiasis, empirical therapy in febrile neutropenia, and salvage therapy for invasive aspergillosis 1

• Micafungin is approved for esophageal candidiasis, candidemia/invasive candidiasis, and prophylaxis of Candida infections in hematopoietic stem cell transplant recipients 1

• Anidulafungin is indicated for candidemia, other Candida infections, and esophageal candidiasis 1

• Rezafungin is the newest echinocandin, approved specifically for candidemia and invasive candidiasis in adults with limited or no alternative treatment options 1

Clinical Advantages of Echinocandins

• Echinocandins demonstrate fungicidal activity against Candida species and fungistatic activity against Aspergillus species 1

• Combined patient-level data analysis from multiple randomized controlled trials shows echinocandins as first-line therapy are associated with lower mortality compared to all other initial interventions for candidemia 1

• Caspofungin demonstrated equivalent efficacy to amphotericin B deoxycholate for invasive candidiasis (83% candidemia cases) but with significantly better tolerability 1

• Key advantages include relatively low toxicity profiles and limited drug-drug interactions compared to azoles 1

Expanded-Spectrum Triazoles

Voriconazole

• Voriconazole is available in both oral and parenteral formulations and has become the primary treatment for invasive aspergillosis 1, 2

• Voriconazole demonstrates activity against fluconazole-resistant Candida isolates: among 12 HIV-infected patients with fluconazole-refractory esophageal candidiasis, 7 were cured and 3 improved 1

• For Candida krusei infections, voriconazole achieved response in 7 of 10 patients (70%) with invasive disease 1

• Voriconazole showed comparable efficacy to amphotericin B followed by fluconazole for candidemia in non-neutropenic patients (41% vs 41% success rates at 12 weeks) 3

• Important caveat: voriconazole was associated with more adverse events than fluconazole in esophageal candidiasis trials 1

Posaconazole

• Posaconazole demonstrates broad-spectrum antifungal activity and is recommended as Category 1 evidence for prophylaxis in neutropenic patients with acute myeloid leukemia and myelodysplastic syndromes receiving induction or reinduction chemotherapy 1, 2

• Posaconazole is an option for salvage or maintenance therapy in mucormycosis in addition to amphotericin B 1

• Posaconazole was among the agents in active development as of 2004 and has since become established in clinical practice 1

Isavuconazole

• Isavuconazole (administered as isavuconazonium sulfate prodrug) is approved in the United States and Europe for invasive aspergillosis and invasive mucormycosis 4

• Isavuconazole offers once-daily dosing in both oral and intravenous formulations with a more favorable safety profile and fewer drug interactions compared to voriconazole 4, 5

• Isavuconazole is recommended as a Category 2B alternative for antifungal prophylaxis in high-risk neutropenic patients 1

Other Triazoles in Development

• Ravuconazole and albaconazole were under early clinical evaluation but their future remains uncertain 1, 2

Lipid Formulations of Amphotericin B

• Liposomal amphotericin B (L-AmB) represents a significant advance over conventional amphotericin B deoxycholate, with reduced nephrotoxicity and infusion-related toxicity while allowing higher doses 1, 6

• L-AmB achieves better CNS penetration at higher doses and is active against Candida biofilms, unlike amphotericin B deoxycholate 1

• L-AmB is the drug of choice for mucormycosis, where it is often preferred over amphotericin B deoxycholate due to reduced nephrotoxicity 1

• Lipid formulations have significantly reduced nephrotoxicity incidence compared to amphotericin B deoxycholate (which causes nephrotoxicity in up to 24% of patients), though at increased drug acquisition cost 1, 6

Clinical Application by Infection Type

For Invasive Candidiasis

• Echinocandins are preferred first-line agents based on mortality data, with caspofungin dosed as 70 mg loading dose followed by 50 mg daily in adults 1

• Fluconazole remains appropriate for less critically ill patients and step-down therapy after clinical stabilization 7

For Invasive Aspergillosis

• Voriconazole is the primary treatment choice when radiological presentations are consistent with invasive aspergillosis and galactomannan antigen is positive 1, 7

• Alternative options include L-AmB, echinocandins, or itraconazole 1

For Mucormycosis

• L-AmB is the drug of choice, with posaconazole or isavuconazole as options for salvage or maintenance therapy 1, 7, 4

• Aggressive surgical debridement is mandatory for optimal outcomes in mucormycosis 1, 7

Critical Drug Interaction Considerations

• CYP3A4 inhibition by mold-active azoles (voriconazole, posaconazole, isavuconazole) can lead to toxicity when combined with proteasome inhibitors, tyrosine kinase inhibitors, and vinca alkaloids used in cancer therapy 1

• Azoles should be stopped several days before administering potentially interacting drugs, with some institutions waiting at least 10 days 1

• Echinocandin prophylaxis may be considered as an alternative when azole drug interactions are problematic 1

Common Pitfalls to Avoid

• Do not assume all newer agents have data for all indications: anidulafungin lacks data for empirical therapy in neutropenia and pre-emptive therapy for aspergillosis 1

• Despite availability of newer agents with excellent in vitro activity, mortality in candidemia trials has remained consistently between 23% and 40% 1

• Echinocandins have limited or no activity against Cryptococcus neoformans and filamentous fungi other than Aspergillus, making them inappropriate for empirical therapy when these pathogens are suspected 1

• Voriconazole requires awareness of drug interactions, particularly with anticonvulsants in CNS aspergillosis cases 1