Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018.

We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR34/L98H (69%) and TR46/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR34/L98H isolates, which hampers the use of current PCR-based resistance tests.

Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study.

BACKGROUND: Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%-100% in patients infected with a triazole-resistant Aspergillus fumigatus, but a direct comparison with triazole-susceptible IA is lacking. METHODS: A 5-year retrospective cohort study (2011-2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated. RESULTS: Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P = .017) and 25% on day 90 (62% vs 37%; P = .0038). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P = .045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P = .016), despite switching to appropriate antifungal therapy after a median of 10 days. CONCLUSIONS: Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality.

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

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.

Azole resistance surveillance in Aspergillus fumigatus: beneficial or biased?

Azole resistance is a growing concern with Aspergillus fumigatus, and may cause increased mortality in patients with azole-resistant invasive aspergillosis (IA). Microbial surveillance has been recognized as a fundamental component of resistance management. Surveillance information may be used to inform decisions regarding health services and research funding allocation, to guide local infection control in hospitals and communities, and to direct local and national drug policies and guidelines. Azole resistance frequencies have been based on screening of unselected A. fumigatus isolates, on the number of azole-resistant cases within a cohort of patients with a specific Aspergillus disease, or on analysis of patients within a specific risk group. The various surveillance approaches differ in their aims, as well as in their associated advantages and drawbacks. Nevertheless, a wide range of azole resistance frequencies has been reported, partly due to the denominator used. As most azole resistance is believed to develop in the environment and, as a consequence, azole-naive patients may present with azole-resistant aspergillosis, experts recommended a 10% resistance frequency threshold above which the standard treatment choice, i.e. voriconazole, should be reconsidered. We believe that local resistance rates based on Aspergillus disease and/or risk group should be leading for decisions regarding empirical antifungal therapy in specific units. In addition, patient factors should be considered, such as admission to the ICU. Collecting valid surveillance data may be challenging in azole resistance due to numerous factors that present potential biases. Surveillance research may benefit from further standardization, which may be facilitated through the recently instituted International Society for Human and Animal Mycology (ISHAM) Aspergillus Resistance Surveillance Working Group.

Diagnosis and management of aspergillosis in the Netherlands: a national survey.

A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B.