Treating infections that caused by Antimicrobial-Resistant Aspergillus

 Treating infections caused by antimicrobial-resistant Aspergillus presents a significant challenge in healthcare settings, particularly among immunocompromised patients such as those with HIV/AIDS, hematological malignancies, solid organ transplants, or receiving immunosuppressive therapy. Aspergillus species are ubiquitous fungi that can cause a range of infections, including invasive aspergillosis, allergic bronchopulmonary aspergillosis, and chronic pulmonary aspergillosis. The emergence of resistance to antifungal agents, particularly azoles, echinocandins, and polyenes, complicates the management of Aspergillus infections and highlights the need for alternative treatment strategies.

Azoles, including voriconazole, itraconazole, and posaconazole, are the cornerstone of therapy for invasive aspergillosis. However, resistance to azoles has been increasingly reported among clinical isolates of Aspergillus, particularly Aspergillus fumigatus, the most common species associated with invasive disease. Azole resistance in Aspergillus is primarily mediated by mutations in the cyp51A gene, encoding the target enzyme lanosterol 14-alpha-demethylase, which interferes with the binding of azole antifungals. Additionally, overexpression of efflux pumps and alterations in drug permeability contribute to azole resistance.

In cases of azole-resistant Aspergillus infections, alternative antifungal agents such as echinocandins or liposomal amphotericin B may be considered. Echinocandins, including caspofungin, micafungin, and anidulafungin, inhibit the synthesis of β-1,3-glucan, a key component of the fungal cell wall. While echinocandins are generally less active against Aspergillus than azoles, they may still have efficacy, particularly when combined with other antifungal agents or in salvage therapy for refractory cases.

Polyenes, such as amphotericin B formulations (including liposomal amphotericin B), bind to ergosterol in the fungal cell membrane, leading to membrane disruption and fungal cell death. Polyenes have broad-spectrum activity against Aspergillus, including azole-resistant strains, and are often used as salvage therapy or in combination with other antifungal agents.

Combination therapy with multiple antifungal agents, such as azoles plus echinocandins or azoles plus polyenes, may be considered for severe or refractory cases of Aspergillus infection, although data supporting the efficacy of combination therapy are limited.

In addition to antifungal therapy, management of antimicrobial-resistant Aspergillus infections requires optimization of host factors, including immunosuppression reduction, correction of underlying immunodeficiencies, and supportive care measures to enhance host defense mechanisms.

Prevention of antimicrobial-resistant Aspergillus infections relies on infection control measures, including environmental surveillance, proper ventilation systems, and adherence to hand hygiene practices in healthcare settings. Antifungal stewardship programs aimed at optimizing antifungal use and minimizing the emergence of resistance are also essential.

In conclusion, treating infections caused by antimicrobial-resistant Aspergillus requires a multidisciplinary approach that considers the underlying host factors, antimicrobial susceptibility patterns, and available treatment options. Continued surveillance of antifungal resistance and research into new antifungal agents are crucial for addressing the evolving threat of antimicrobial resistance in Aspergillus infections.

References:

1. Patterson TF, Thompson GR, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4)
   .
2. Verweij PE, Chowdhary A, Melchers WJG, Meis JF. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles?. Clin Infect Dis. 2016;62(3):362-368.
3. van der Linden JW, Arendrup MC, Warris A, et al. Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerg Infect Dis. 2015;21(6):1041-1044.
4. Meis JF, Chowdhary A, Rhodes JL, Fisher MC, Verweij PE. Clinical implications of globally emerging azole resistance in Aspergillus fumigatus. Philos Trans R Soc Lond B Biol Sci. 2016;371(1709):20150460