Synergistic interactions of sulfamethoxazole and azole antifungal drugs against emerging multidrug-resistant Candida auris

Hassan E Eldesouky; Xiaoyan Li; Nader S Abutaleb; Haroon Mohammad; Mohamed N Seleem

doi:10.1016/j.ijantimicag.2018.08.016

Synergistic interactions of sulfamethoxazole and azole antifungal drugs against emerging multidrug-resistant Candida auris

Int J Antimicrob Agents. 2018 Dec;52(6):754-761. doi: 10.1016/j.ijantimicag.2018.08.016. Epub 2018 Aug 24.

Authors

Hassan E Eldesouky¹, Xiaoyan Li², Nader S Abutaleb¹, Haroon Mohammad¹, Mohamed N Seleem³

Affiliations

¹ Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
² Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA; College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang, China.
³ Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA. Electronic address: mseleem@purdue.edu.

PMID: 30145250
DOI: 10.1016/j.ijantimicag.2018.08.016

Abstract

Candida auris is an emerging multidrug-resistant pathogen implicated in numerous outbreaks worldwide, with a notably high mortality rate (ca. 60%). A significant challenge with treatment of these infections is the resistance of C. auris to most antifungal drugs used clinically. Thus, finding co-drugs capable of overcoming resistance to frontline antifungals is of prime clinical importance. In this study, the ability of the combination of different sulfa drugs with azole antifungals to inhibit the growth of azole-resistant C. auris isolates was evaluated. Among the active sulfa drugs, sulfamethoxazole exhibited the most potent in vitro synergistic interactions with voriconazole and itraconazole. The sulfamethoxazole-voriconazole combination restored voriconazole's fungistatic activity against three of eight voriconazole-resistant clinical isolates. Similarly, the sulfamethoxazole-itraconazole combination restored itraconazole's fungistatic activity against three of four itraconazole-resistant clinical isolates. This activity was further confirmed in vivo in a Caenorhabditis elegans model of C. auris infection. The sulfamethoxazole-voriconazole combination enhanced survival of nematodes infected with C. auris by nearly 70%. Notably, these data indicate that the efficacy of this novel combination is dependent on the underlying mechanism of azole resistance. Mutant strains demonstrating azole resistance by either overproduction of or decreased affinity for the azole target (ERG11p) were found highly to be susceptible to the sulfamethoxazole-azole combination. However, this synergistic interaction was ineffective against mutant strains that demonstrated azole resistance via efflux pump hyperactivity. In conclusion, sulfamethoxazole represents a promising co-drug that can restore the efficacy of certain azole antifungal drugs against some azole-resistant isolates of C. auris.

Keywords: Antifungal; Azole resistance; Caenorhabditis elegans; Candida auris; ERG11p; Sulfamethoxazole.

MeSH terms

Animals
Antifungal Agents / pharmacology*
Antifungal Agents / therapeutic use
Caenorhabditis elegans
Candida / drug effects*
Candida / growth & development
Candidiasis / drug therapy
Disease Models, Animal
Drug Synergism*
Itraconazole / pharmacology*
Itraconazole / therapeutic use
Sulfamethoxazole / pharmacology*
Sulfamethoxazole / therapeutic use
Survival Analysis
Treatment Outcome
Voriconazole / pharmacology*
Voriconazole / therapeutic use

Substances

Antifungal Agents
Itraconazole
Sulfamethoxazole
Voriconazole