Detection of Cross-Resistance Between Methotrexate and Azoles in Candida albicans and Meyerozyma guilliermondii: An In Vitro Study

Abstract

In recent years, there has been a rapid increase in the incidence of Candida infections. The different species of the genus Candida vary in their virulence abilities and susceptibility to antifungal agents, depending on several external factors. The result of such modifications may be cross-resistance, which is understood as an acquired resistance to a certain antimicrobial agent after exposure to another drug. The aim of this study was to determine the possibility of cross-resistance between fluconazole, voriconazole, itraconazole, and methotrexate in Candida albicans and Meyerozyma guilliermondii (syn. Candida guilliermondii ). Fifteen strains of M. guilliermondii and eight strains of C. albicans , including the standard strains, were tested. For all strains, the minimum inhibitory concentrations (MICs) for fluconazole, voriconazole, and itraconazole were determined before and after stimulation with methotrexate. The median MICs in M. guilliermondii before and after stimulation were 9.333 and 64 mg/L ( p = 0.005) for fluconazole; 0.917 and 1.667 mg/L ( p = 0.001) for itraconazole, respectively. No significant change in MIC was observed for voriconazole. For C. albicans strains, the median MICs before and after stimulation were 0.917 and 64 mg/L ( p = 0.012) for fluconazole; 0.344 and 1.135 mg/L ( p = 0.018) for voriconazole, respectively. There was no significant change in MIC values for itraconazole. Thus, this study demonstrates the presence of cross-resistance between voriconazole, itraconazole, fluconazole, and methotrexate for the selected strains. Methotrexate exposure induces different responses when certain drugs are used for various species. Therefore, if a patient was previously exposed to methotrexate, there may be a higher risk of treatment failure with fluconazole than with other azoles such as voriconazole for fungemia caused by M. guilliermondii or itraconazole for C. albicans infection.

Does Systemic Methotrexate Therapy Induce Azole Resistance among Endogenous Candida Strains?

“…Cross-resistance, which has been the subject of numerous studies in recent decades, remains an important clinical problem in the treatment of diseases caused by pathogenic microorganisms. This term refers to a situation where one drug induces resistance to another drug or a group of drugs that have not exerted a selective pressure on the organism acquiring resistance [ 8 , 9 , 10 , 25 ]. A well-known example of cross-resistance occurring in bacteria is co-resistance to macrolides, lincosamides, and streptogramin B (MLSB), which may be caused by methylation of the large ribosome subunit encoded by the ermA, ermB, ermC or ermF genes [ 25 ].…”

“…This gene is responsible for the synthesis of the membrane pump (CaMdr1p) removing xenobiotics, including methotrexate and fluconazole, from yeast cells [ 26 ]. There are numerous studies describing this phenomenon [ 7 , 8 , 9 , 10 , 26 ]. The authors of a recent study, examining the ability of methotrexate to induce resistance to fluconazole, itraconazole, and voriconazole in C. albicans and Meyerzyme guilliermondii , observed a significant increase in the median MIC for fluconazole and voriconazole—in the case of the former species, as well as for fluconazole and itraconazole—in the case of the latter.…”

“…It has been observed that Candida spp. strains incubated with methotrexate (MTX) develop multi-drug cross-resistance to azoles [ 7 , 8 , 9 , 10 ]. Although the phenomenon was described in vitro, there is a lack of data on its occurrence in vivo among patients treated with cytostatics [ 10 ].…”

“…strains incubated with methotrexate (MTX) develop multi-drug cross-resistance to azoles [ 7 , 8 , 9 , 10 ]. Although the phenomenon was described in vitro, there is a lack of data on its occurrence in vivo among patients treated with cytostatics [ 10 ]. The mechanism of Candida cross-resistance to azoles is complex and results, among others, from the increase in the expression of the CaMDR1 gene ( Candida albicans Multi Drug Resistance) under the influence of induction with methotrexate, but also with other not structurally or functionally related substances such as benomyl, diethyl malonate, or o-phenanthroline [ 7 , 8 , 9 ].…”

“…It is possible that other commonly used cytostatics may also reduce the sensitivity of clinical isolates of Candida spp. to some antifungal agents [ 10 ].…”