Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients

Abstract

Background Increasing resistance of Aspergillus fumigatus to triazoles in high-risk populations is a concern. Its impact on mortality is not well understood, but rates from 50% to 100% have been reported. Objectives To determine the prevalence of voriconazole-resistant A. fumigatus invasive aspergillosis (IA) and its associated mortality in a large multicentre cohort of haematology patients with culture-positive IA. Methods We performed a multicentre retrospective study, in which outcomes of culture-positive haematology patients with proven/probable IA were analysed. Patients were stratified based on the voriconazole susceptibility of their isolates (EUCAST broth microdilution test). Mycological and clinical data were compared, along with survival at 6 and 12 weeks. Results We identified 129 A. fumigatus culture-positive proven or probable IA cases; 103 were voriconazole susceptible (79.8%) and 26 were voriconazole resistant (20.2%). All but one resistant case harboured environment-associated resistance mutations in the cyp51A gene: TR34/L98H (13 cases) and TR46/Y121F/T289A (12 cases). Triazole monotherapy was started in 75.0% (97/129) of patients. Mortality at 6 and 12 weeks was higher in voriconazole-resistant cases in all patients (42.3% versus 28.2%, P = 0.20; and 57.7% versus 36.9%, P = 0.064) and in non-ICU patients (36.4% versus 21.6%, P = 0.16; and 54.4% versus 30.7%; P = 0.035), compared with susceptible ones. ICU patient mortality at 6 and 12 weeks was very high regardless of triazole susceptibility (75.0% versus 66.7%, P = 0.99; and 75.0% versus 73.3%, P = 0.99). Conclusions A very high prevalence of voriconazole resistance among culture-positive IA haematology patients was observed. The overall mortality at 12 weeks was significantly higher in non-ICU patients with voriconazole-resistant IA compared with voriconazole-susceptible IA.

Burden of serious fungal infections in the Netherlands

“…We calculated that 145 patients (11.3%) with invasive aspergillosis may be infected with an azole resistant isolate. This is a significant finding as patients with voriconazole resistant invasive aspergillosis had a 20%‐25% increased day‐42 mortality compared to patients with voriconazole susceptible infection 41,42 . However, the resistance frequency in patients is based on positive cultures, irrespective of presence of invasive aspergillosis.…”

First azole‐resistant Aspergillus fumigatus isolates with the environmental TR46/Y121F/T289A mutation in Iran

“…Invasive aspergillosis due to azole‐resistant A fumigatus has become a major medical concern associated with high mortality in immunocompromised individuals . Azole resistance in A fumigatus emerges due to long‐term treatment with azole antifungals, but also extensive exposure of the fungus to azole compounds in the environment is a major driver of resistance selection . Resistance to azole drugs in A fumigatus is mainly linked to multiple amino acid substitutions in the cyp 51A gene.…”

Invasive pulmonary aspergillosis treatment duration in haematology patients in Europe: An EFISG, IDWP‐EBMT, EORTC‐IDG and SEIFEM survey

“…Moreover, prolonged use of large spectrum AF such as triazoles and echinocandins are associated with the emergence of resistant fungi. In Europe, azole‐resistant Aspergillus strains are recently emerging in several countries with up to 20% of refractory IPA related to resistant strains in selected areas . Pan‐resistant fungi emerge such as Mucorales , Scedosporium, azole‐resistant Candida or new emerging fungi as Rasamsonia argillacea species or Saprochaeta clavata .…”