The correlation between phenotypic and genotypic evidence for triazole antifungal drug resistance in Aspergillus fumigatus: a systematic review and evaluation of primary laboratory data from the Mycology Reference Centre Manchester

Abstract

Abstract

Introduction

The detection of triazole resistant isolates of Aspergillus fumigatus appear to be rising, as are the proportion of those that express multi-azole resistance, which is having a significant adverse impact upon patient outcomes and is likely responsible for increased morbidity and mortality. Infection with A. fumigatus predominantly infects persons with immunocompromised diseases or conditions or those who are taking immunosuppressive drugs, and thus, as the prevalence of these states is increasing, the efficacy of anti-fungal agents and prevention of resistance is essential to achieving desirable results.

Aim

This systematic review aimed to explore the correlation between in vitro susceptibility testing of resistant A. fumigatus isolates and the mutations found in the triazole target cyp51A gene using molecular methods of characterisation, in order to determine whether resistance patterns could be predicted.

Methods

Databases of MEDLINE, EMBASE, the Cochrane registry and Web of Science were searched in July 2019 using an appropriate set of search terms. Articles were restricted to English language and no exclusions were placed upon publication date or setting, in order to acquire highly generalisable data. Data was extracted using a pre-defined database and this was supplemented by local data from the Mycology Reference Centre Manchester that was collected retrospectively using anonymised electronic laboratory records. Data was analysed using a simple tabular and narrative approach.

Results/Discussion

A total of 22 articles were deemed eligible for review and secondary data evaluation. The results showed that resistance of A. fumigatus to itraconazole and posaconazole as determined by susceptibility testing was evident across all cyp51A genotypes, whilst voriconazole resistance was partly spared among G54 and L98 substitutions. The principle mutational hot spots comprised G54, L98, G138, M220, Y431 and G448 substitutions, whilst a number of others were scantly reported and present among both resistant and sensitive isolates. Given the heterogeneous resistance patterns displayed by A. fumigatus, it does not appear possible to accurately predict the resistance phenotype of the fungus.

Conclusion

Overall, as the resistance of Aspergillus fumigatus continues to increase and the number of available treatment options continues to decline, there is an imminent need to address antifungal resistance both on agricultural, clinical and academic grounds. It is recommended that patients with Aspergillus fumigatus isolates are subject to resistance screening, in order to more appropriately inform antifungal therapy, which is currently in contradiction to current European guidelines.