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

Abstract

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)(2012)(2013)(2014)(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.

Azole resistance in Aspergillus species in Southern Taiwan: An epidemiological surveillance study

“…However, the prevalence of azole‐resistant A fumigatus has significantly increased over the past two decades, threatening the effectiveness of first‐line antifungal therapy . The reported mortality rate of IA caused by azole‐resistant A fumigatus was significantly increased compared with IA caused by azole‐susceptible strains . It is believed that resistant isolates emerge due to the widespread use of agricultural azole antifungals .…”

“…5 The reported mortality rate of IA caused by azole-resistant A fumigatus was significantly increased compared with IA caused by azole-susceptible strains. 6 It is believed that resistant isolates emerge due to the widespread use of agricultural azole antifungals. 7 An expert panel recommended moving away from azole monotherapy for patients suspected of having IA, when regional environmental resistance frequencies exceed 10%.…”

Elevated prevalence of azole resistant Aspergillus fumigatus in urban versus rural environments in the United Kingdom

“…Moreover, clinical cases of aspergillosis with AR Af isolates harbouring either TR 34 /L98H or TR 46 /Y121F/T289A continue to emerge (19, 20), with one study specifically linking a fatal case of aspergillosis to a genotypically indistinguishable isolate sourced from the patients own home (21). Retrospective studies of patients with invasive aspergillosis (IA) and infected with azole-resistant genotypes of A. fumigatus show an excess mortality of 25% at day 90 when compared against patients with wild-type-infections (22).…”

Prospective CYP2C19‐Guided Voriconazole Prophylaxis in Patients With Neutropenic Acute Myeloid Leukemia Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations

“…26 Furthermore, several studies have suggested that unfavorable clinical outcomes, including mortality, associated with initial low voriconazole concentrations are not completely overcome by subsequently prescribing higher doses based on therapeutic drug monitoring. 6,8,27,28 Our results demonstrate that CYP2C19 genotyping to preemptively guide voriconazole therapy greatly decreases the incidence of initial low steady-state concentrations. Combining preemptive CYP2C19 genotyping with therapeutic drug monitoring to further refine dosage is a potential strategy for avoidance of initial and prolonged subtherapeutic concentrations.…”

“…The median incubation time for invasive aspergillosis in patients with neutropenic AML is estimated to be 14 days, thus a breakthrough fungal infection could occur before adjustment of voriconazole dosage based on plasma concentrations . Furthermore, several studies have suggested that unfavorable clinical outcomes, including mortality, associated with initial low voriconazole concentrations are not completely overcome by subsequently prescribing higher doses based on therapeutic drug monitoring . Our results demonstrate that CYP2C19 genotyping to preemptively guide voriconazole therapy greatly decreases the incidence of initial low steady‐state concentrations.…”