High-Level Pan-Azole-Resistant Aspergillosis

Abstract

High-level pan-azole-resistant Aspergillus fumigatus was recovered from four patients with chronic lung disease. In one patient, the development of progressive resistance followed long-term azole therapy and switching between antifungal azoles. The highlevel pan-azole-resistant phenotypes were not associated with a specific cyp51A gene mutation. New strategies that avoid the development of progressive azole resistance are needed.A zole resistance in Aspergillus fumigatus is an emerging problem which is associated with treatment failure in patients with aspergillus diseases (1). Resistance is commonly due to mutations in the cyp51A gene (1) that typically lead to high-level resistance (MIC, Ն8 mg/liter) against one azole and low-level resistance (MICs close to the resistance breakpoint) against others (2, 3).We identified four A. fumigatus isolates with MIC of Ն8 mg/ liter for all mold-active azoles, measured using EUCAST methodology (4). We labeled this unique phenotype high-level pan-azole resistance. We analyzed the cyp51A gene sequence of the isolates, using previously published algorithms (5), and retrieved clinical data for these four patients (Table 1).The first patient was a 22-year-old male with cystic fibrosis. After being diagnosed with allergic bronchopulmonary aspergillosis (ABPA), he commenced itraconazole and steroid maintenance therapy. Fungal sputum cultures after 8 months of itraconazole therapy revealed an A. fumigatus isolate with the high-level pan-azole-resistant phenotype. The patient continued itraconazole maintenance therapy, and the high-level pan-azole-resistant isolate was not recovered from repeat cultures.The second patient was a 71-year-old male with a medical history of asthma, bronchiectasis, and intermittent culture positivity with itraconazole-and voriconazole-susceptible A. fumigatus. The patient did not meet diagnostic criteria for ABPA and was never treated with azoles. The high-level pan-azole-resistant A. fumigatus isolate was isolated once from a sputum sample; follow-up sputum cultures yielded azole-susceptible A. fumigatus.The third patient was a 47-year-old female with severe pulmonary sarcoidosis, complicated by a pneumothorax with subsequent pleural empyema. From this empyema, an azole-susceptible A. fumigatus isolate was cultured (itraconazole and voriconazole MICs, 0.5 mg/ liter; posaconazole MIC, 0.063 mg/liter). Treatment with itraconazole was started, later changed to voriconazole, and ultimately changed to posaconazole as a chronic suppressive therapy. After 18 months of azole therapy, the patient's disease progressed, and a sputum sample was ordered for fungal culture. This sample grew the high-level pan-azole-resistant isolate and induced a switch to liposomal amphotericin B therapy. Despite treatment, the patient's condition deteriorated, and she died of respiratory failure.The fourth patient was a 39-year-old male diagnosed with chronic granulomatous disease and ABPA. The patient had been treated for multiple episodes of invasive pulmonary aspergillosis, and...

Emergence of Azole-Resistant Aspergillus fumigatus from Immunocompromised Hosts in India

“…The same group pioneered resistance surveillance of environmental isolates and reported major TR/L98H mutations in 44/630 ARAF isolates (42); they also reported the first TR46/Y121F/T289A mutations in 6/1,210 resistant environmental isolates (50). TR/L98H is the most common cyp51A mutation and has been previously reported in this patient population from various parts of the world, namely, Nijmegen, Netherlands (Europe) (7,9,12,13); Germany (Europe) (11); Poland (Europe) (51), the United States (North America) (52); Taiwan (53); Australia (54); the Middle East (34,55); and New Delhi, India (15). However, this mutation has been linked with the environmental spread of resistance due to the increasing use of fungicidal azoles in agricultural practices in Copenhagen, Denmark (Europe) (56); Bogotá, Colombia (Latin America) (57); Kuwait (Middle East) (34); and New Delhi, India (36).…”

Emergence of Echinocandin Resistance Due to a Point Mutation in the fks1 Gene of Aspergillus fumigatus in a Patient with Chronic Pulmonary Aspergillosis

“…Even though acquired resistance during therapy is rare, epidemiological studies have shown that Aspergillus azole resistance has increased over the past decade in patients with prolonged exposure to azoles, notably those with CPA ( 3 ). Mutations in the cyp51A gene leading to amino acid substitutions in the target enzyme lanosterol 14α-demethylase are the major mechanism of azole resistance ( 1 , 4 , 5 ), yet non- cyp51A -mediated resistance has been recently reported ( 6 ).…”

Chronic Pulmonary Aspergillosis—Where Are We? and Where Are We Going?

“…The mechanisms driving the development of azole resistance in A. fumigatus are not well understood. It is unclear whether clinically significant azole resistance is acquired de novo within the host due to the selection pressure of prolonged azole therapy, or through host inhalation of an azole resistant environmental isolate, resistance developed in the context of prolonged exposure to agricultural azole based fungicides [ 95 , 208 , 209 , 210 , 211 , 212 , 213 , 214 ].…”