Antifungal resistance and treatment strategies: combination therapy

F. Barchiesi

Author address: 

Universití  Politecnica delle Marche, Ancona, Italy

Abstract: 

Invasive fungal infections have high rates of morbidity and mortality, particularly in immunocompromised patients. Currently available antifungal agents include azoles (i.e.: fluconazole, itraconazole, voriconazole [VORI], and posaconazole), polyenes (i.e.: amphotericin B [AMB] and its lipid derivatives), all of which act by altering the cellular membrane, the echinocandins (i.e.: caspofungin [CAS], micafungin [MICA], and anidulafungin), which act by inhibition of 1,3-β -glucan synthase required for the formation of the cell wall, and flucytosine [5FC] which acts intracellularly by inhibiting the protein synthesis of the fungal cell. Thus, similarly to other branches of antiinfective therapy (i.e.: antibacterial of antiretroviral drugs), the possibility to use combination approaches does exist in antifungal therapy as wellhttp://www.journals.uchicago.edu/doi/full/10.1086/588475?cookieSe t=1 - rf8. There are several possible reasons for using two antifungals simultaneously, including delay or prevention of the emergence of drug-resistant mutants. However, in-vitro and in-vivo evidence is often conflicting and clinical trials in this area are limited. For Aspergillus species, both in vitro and experimental animal models of infections, the combinations of AMB-CAS, AMB-VOR, VOR-CAS, and VOR-MICA showed positive effects to justify their evaluation in clinical trials. Similarly, pre-clinical studies showed that combination of polyenes-echinocandins or azoles-echinocandins might be beneficial against difficult-to-treat Candida species (i.e.: C. glabrata). On the other hand, most clinical studies showed similar outcomes for combination antifungal therapy when compared to monotherapy, although secondary endpoints and sub-analyses often showed advantages for the combinations in endpoints such as culture sterilisation (i.e.: 5FC-AMB vs AMB in infections due to Cryptococcus neoformans). Therefore, well-controlled, randomized, multicenter clinical trials are still required to adequately determine the most efficacious antifungal combinatorial regimen for a given fungal infection.
2009

abstract No: 

W11.4

Full conference title: 

4th Trends in Medical Mycology
    • TIMM 4th (2012)