Breakthrough Disseminated Aspergillus ustus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients Receiving Voriconazole or Caspofungin Prophylaxis

Abstract

Aspergillus ustus is an uncommon clinical species which is poorly susceptible to antifungals. We report two cases of A. ustus infections that occurred in allogeneic stem cell transplant recipients while they were receiving either voriconazole or caspofungin. Prolonged use of these new antifungal agents may increase the risk of the emergence of resistant organisms. CASE REPORTPatient 1 was a 29-year-old male, weighing 80 kg, who was diagnosed with acute lymphoblastic leukemia in October 2002. During initial chemotherapy-induced neutropenia, he developed fever, cough, and nodular pulmonary infiltrates visible by computed tomography (CT) scan, suggestive of possible lunginvasive aspergillosis (2). Cultures of sputum were negative for Aspergillus, and Aspergillus antigenemia (Platelia Aspergillus assay; Bio-Rad, Marnes-la-Coquette, France) remained negative (index Ͻ 0.5). Treatment with oral voriconazole (200 mg twice a day after the loading dose) was initiated on 22 December 2002. Granulocyte recovery occurred 4 days later and was associated with the complete resolution of pulmonary lesions. A myeloablative genoidentical hematopoietic stem cell transplant (HSCT) was performed during the first complete remission, on 13 March 2003. A pre-HSCT lung CT scan revealed no abnormality. Voriconazole was continued as a secondary prophylaxis. Between April 2003 and January 2004, the patient experienced three episodes of severe graft-versus-host disease (GVHD), which were treated with cyclosporine, an increased dosage of steroids, and mycophenolate mofetil. In September 2003, the patient, who was afebrile, developed several necrotic cutaneous lesions for which he was admitted to the hospital. The chest CT scan revealed a nonspecific infiltrate in the right inferior pulmonary lobe. Mycological examination of a cutaneous biopsy specimen revealed septate and branched hyphae consistent with Aspergillus spp. A culture yielded Aspergillus ustus, which was identified by morphological methods, with confirmation by sequencing of the ITS1-5.8S-ITS2 region (Fig. 1). Cultures of sputum were also positive for A. ustus. Several Aspergillus antigenemia tests were positive, with galactomannan index values of up to 3. Voriconazole was discontinued, and amphotericin B deoxycholate (1 mg/kg of body weight/day) was started. Six days later, the patient developed right-leg paresis. Brain magnetic resonance imaging (MRI) revealed a single frontal lesion compatible with aspergillosis. Treatment was switched to liposomal amphotericin B (3 mg/kg/day) and caspofungin (70 mg/day). The patient clinically improved, with complete regression of both cutaneous lesions and neurological abnormalities. Subsequent brain MRIs showed progressive regression of the lesion with scar formation. Subsequent lung CT scans showed a size decrease and excavitation of the pulmonary lesion. Aspergillus antigenemia decreased and remained negative after 18 December 2003. The patient later experienced several episodes of hemoptysis. Fungal hyphae compatible with a zygomycete wer...

Aspergillus calidoustus sp. nov., Causative Agent of Human Infections Previously Assigned to Aspergillus ustus

“…Antifungal susceptibility tests of A. calidoustus isolates show that most antifungal drugs have limited or no activity, which is in accordance with previous studies where "A. ustus" (A. calidoustus) isolates were found to be resistant to amphotericin B, echinocandins, and azole derivatives (5,6,21,36). The class of the triazoles has a prominent role in the management of patients with invasive aspergillosis, and breakthrough infections caused by "A. ustus" have been reported in patients treated with voriconazole and itraconazole (21).…”

“…The class of the triazoles has a prominent role in the management of patients with invasive aspergillosis, and breakthrough infections caused by "A. ustus" have been reported in patients treated with voriconazole and itraconazole (21). We found that even the most recently registered compound, posaconazole, which is commonly the drug with the greatest intrinsic activity against Aspergillus species, showed no in vitro activity.…”

“…At the same time, this species is considered a relatively rare human pathogen that can cause invasive infection in immunocompromised hosts. To date, only 22 cases of invasive aspergillosis have been reported to be caused by A. ustus (1,13,20,21,36,37,39; also O. V. Vasilenko, N. V. Bezmelnitsyn, S. A. Keselman, E. M. Shulutko, and A. V. Pivnik, unpublished data). Almost half of these cases were classified as primarily cutaneous aspergillosis, so the skin was suggested as the primary site of infection (17,30).…”

Aspergillus ustusInfections among Transplant Recipients

“…These outbreaks of A. ustus infections may be of infection control importance, as the clinical isolates exhibited low susceptibilities to multiple antifungal drugs, as was reported previously ( 12 , 17 ). Although we do not know breakpoints of A. fumigatus resistance, results of prior studies suggest that infection with organisms requiring high MICs of amphotericin or itraconazole is associated with poor clinical outcomes ( 37 , 38 ).…”

Diversity and Significance of Mold Species in Norwegian Drinking Water

“…Supporting this suggestion, the species was abundant in water from installations on arctic Svalbard, where water pipelines are heated because of permafrost (G. Hageskal and S. B. Rønning, unpublished results). A. ustus has not, to our knowledge, been isolated from water previously, and the finding of this fungus is particularly interesting because it has been reported from infections in humans and appears to be an emerging opportunistic pathogen in immunosuppressed patients (12,25,49). It is noteworthy that A. ustus was frequently isolated from hospital samples.…”