Multiple-azole-resistantAspergillus fumigatusosteomyelitis in a patient with chronic granulomatous disease successfully treated with long-term oral posaconazole and surgery

Abstract

We describe a patient with chronic granulomatous disease and proven Aspergillus fumigatus osteomyelitis of the midfoot, while receiving itraconazole-prophylaxis. The isolate proved resistant to itraconazole as well as voriconazole, and showed reduced susceptibility to posaconazole. Although molecular analysis demonstrated the presence of a 53 base pair tandem repeat in the promoter region for cyp51A, i.e., the gene coding for the target enzyme of the azole antifungals, there were no mutations in the cyp51A gene. Since transformation of the promoter region into wild-type strains did not result in an azole resistant phenotype, a yet unknown mutation was suspected. The patient was treated with extensive surgery and two weeks of caspofungin therapy, followed by one year of posaconazole therapy. He made a complete recovery and did not experience any side effects. Long-term posaconazole proved to be a safe and effective treatment for multi-azole resistant A. fumigatus osteomyelitis in this immunocompromised patient.

Emergence of Disseminated Infections Due to Geosmithia argillacea in Patients with Chronic Granulomatous Disease Receiving Long-Term Azole Antifungal Prophylaxis

“…However, long-term azole prophylaxis during CGD has been associated with the emergence of multiple-resistant Aspergillus fumigatus or of new intrinsically less susceptible Aspergillus spp. (9,14).…”

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

“…However, the management of IA has become more complicated due to the emergence of azole resistance in A. fumigatus (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Surveillance studies indicate that azole resistance is increasing in Europe, the Middle East, Asia, Africa, and Australia and, most recently, in North and South America as well (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

Molecular Epidemiology of Aspergillus fumigatus Isolates Harboring the TR 34 /L98H Azole Resistance Mechanism

“…Medical triazoles, such as itraconazole, voriconazole, and posaconazole, play an important role in the management of Aspergillus diseases. However, azole resistance is an emerging problem in A. fumigatus and has been shown to be associated with increased probability of treatment failure (10,11,19,20,30,35,37,39,41).Azole resistance is commonly due to mutations in the cyp51A gene, which encodes 14-␣-demethylase in the ergosterol biosynthesis pathway. In azole-resistant clinical A. fumigatus isolates, a wide variety of cyp51A mutations, such as substitutions at codons G54, G138, P216, F219, M220, and G448, have been found (5,11,29).…”

“…Medical triazoles, such as itraconazole, voriconazole, and posaconazole, play an important role in the management of Aspergillus diseases. However, azole resistance is an emerging problem in A. fumigatus and has been shown to be associated with increased probability of treatment failure (10,11,19,20,30,35,37,39,41).…”