- Amphotericin B has long been regarded as a cornerstone antifungal agent due to its broad-spectrum activity against a wide range of fungal pathogens. However, its use is often limited by dose-dependent toxicity, particularly nephrotoxicity. To enhance efficacy, broaden antifungal coverage, reduce resistance development, and minimize side effects, Amphotericin B is frequently employed in combination therapies with other antifungal agents or adjunctive drugs. These combinations are especially valuable in treating invasive or refractory fungal infections, as well as in immunocompromised patients.
- One of the most studied and clinically relevant combinations involves Amphotericin B with flucytosine. This synergistic pairing is particularly effective in the treatment of cryptococcal meningitis, especially in HIV-infected individuals. Amphotericin B disrupts fungal cell membranes, enhancing the intracellular uptake of flucytosine, which inhibits nucleic acid synthesis. This dual mechanism not only improves fungal clearance but also allows for lower dosing of each agent, reducing toxicity and delaying resistance emergence.
- Another notable combination is Amphotericin B with azoles, such as fluconazole, itraconazole, or voriconazole. While azoles inhibit ergosterol biosynthesis, Amphotericin B binds to ergosterol and forms pores in the fungal cell membrane. This interaction can be complex—sometimes synergistic and other times antagonistic—depending on the timing and concentration of each drug. Sequential or staggered administration is often preferred to avoid potential interference in ergosterol availability, which could reduce Amphotericin B’s efficacy. This combination approach is useful in treating resistant strains or mixed fungal infections.
- Amphotericin B is also used in combination with echinocandins like caspofungin or micafungin, particularly in severe or refractory cases of invasive candidiasis and aspergillosis. Echinocandins inhibit β-glucan synthesis in the fungal cell wall, which complements the membrane-disrupting action of Amphotericin B. Studies have shown improved outcomes in some patient populations, especially those with compromised immune systems or infections caused by biofilm-forming fungi, where monotherapy is often insufficient.
- Beyond antifungals, Amphotericin B is being explored in combination with antiparasitic agents for the treatment of leishmaniasis. Liposomal Amphotericin B (e.g., AmBisome) combined with miltefosine or paromomycin is used in visceral and cutaneous leishmaniasis to enhance cure rates and overcome regional drug resistance. These regimens are particularly relevant in endemic areas where monotherapy has become less effective.
- Emerging research is also investigating the combination of Amphotericin B with immunomodulatory agents, iron chelators, or nanoparticle carriers to improve drug targeting and reduce toxicity. Nanotechnology-based systems, such as liposomes and polymeric nanoparticles, not only enhance drug delivery but also provide opportunities for co-encapsulation of Amphotericin B with synergistic agents, opening new avenues for tailored antifungal therapies.
