Emerging Infectious Disease ISSN: 1080-6059

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Frequency and Evolution of Azole Resistance in Aspergillus fumigatus Associated with Treatment Failure¹

Susan J. Howard, Dasa Cerar, Michael J. Anderson, Ahmed Albarrag, Matthew C. Fisher, Alessandro C. Pasqualotto, Michel Laverdiere, Maiken C. Arendrup, David S. Perlin, and David W. Denning

Author affiliations: Regional Mycology Laboratory, Manchester, UK (S.J. Howard, D.W. Denning); University of Manchester, Manchester Academic Health Science Centre, Manchester (S.J. Howard, M.J. Anderson, A. Albarrag, D.W. Denning); University Medical Centre, Ljubljana, Slovenia (D. Cerar); Imperial College, London, UK (M.C. Fisher); Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (A.C. Pasqualotto); Hôpital Maisonneuve-Rosemont, Montreal, Québec, Canada (M. Laverdiere); Statens Serum Institut, Copenhagen, Denmark (M.C. Ardendrup); Public Health Research Institute, Newark, NJ, USA (D.S. Perlin)

Main Article

Table 2

Clinical information for 17 patients with azole resistant Aspergillus fumigatus infections*

Patient no.	Age, y/sex	City	No. isolates	Aspergillus disease	Other diseases, y	Daily dose, duration	Serum azole levels, mg/L†	Outcome	Survival
1	50/F	Cambridge, UK	1	CCPA with aspergilloma	Breast cancer, 1990; M. malmoense pulmonary tuberculosis, 1999 and 2005	Vori 200–400 mg, 18 mo	ND	Clinical and radiological failure	Alive
2	21/F	Copenhagen, Denmark	1	ABPA	CF, concomitant bacterial colonization with Staphylococcus aureus and Achromobacter	Itra 200 mg, 14 mo (plus previous courses)	ND	Unknown	Alive
3	40/F	Manchester, UK	2‡	CCPA with aspergilloma, then CFPA	Pulmonary TB with residual bilateral UL scarring and LUL cavity, 1986; smoke inhalation, 1989	Itra 400 mg, 90 mo	15.0–26.0§	Clinical failure	Died
4	72/M	Manchester, UK	3	CCPA with aspergilloma	COPD, squamous cell carcinoma with LUL segmentectomy, 1992	Itra 400 mg, >2 mo	2.9–11.3	No improvement	Died
5	43/M	Montreal, Quebec, Canada	2	Cerebral aspergillosis, Nov 1998	AML-M2, 1997; RUL lobectomy, 1997; AlloHSCT, 1998; GVHD	Itra 400 mg, 4 mo	ND	Regression of cerebral abscess, then IPA with respiratory failure	Died
6	60/M	Manchester, UK	2	CCPA with aspergilloma	COPD, M. szulgai pulmonary infection, 2003; celiac disease	Itra 200–400 mg, 1 mo	<0.8 (200 mg), 5.3–7.7 (400 mg)	Clinical failure	Died
7	77/M	Manchester, UK	1	Acute invasive pulmonary	COPD, possible bronchiectasis	Itra 600–400 mg, 1 mo; vori 400 mg, 12 d	17.0–21.0 (itra)	No improvement; switched to vori, developed toxicity	Died, without IPA
8	46/F	Northampton, UK	2	ABPA	Bronchiectasis, asthma,  AVR, hypermobility syndrome, M. xenopi pulmonary infection, 2007	Itra 200–400 mg, 9 mo	0.0–5.2	Initial improvement, then failure	Alive
9	46/M	Liverpool, UK	12	CCPA with bilateral aspergillomas, CFPA	Pulmonary sarcoidosis, 1988	Itra 200–400 mg, 30 mo	0.9–10.3	Clinical failure	Died
10	41/F	Manchester, UK	2	Aspergillus bronchitis	Bronchiectasis, onychomycosis, 2007; α-1-antitrypsin deficiency	Itra 400 mg pulse, 3 mo	ND	Itra resistance identified, so treated with posa	Alive
11	62/F	Manchester, UK	2	CCPA with aspergilloma	RUL pneumonia, 2002	Itra 400 mg, 1.5 mo	20.0–>25.6	No improvement	Alive
12	29/F	Manchester, UK (Malawi origin)	1	CCPA with 2 aspergillomas	Pulmonary TB, 1995; HIV positive, HAART	Itra 400 mg, 18 mo	2.5–8.4	Improvement then progression	Alive
13	64/M	Preston, UK	4	CCPA with aspergilloma	COPD, bronchiectasis, M. avium pulmonary infection, 2002 and 2006	Itra 600 mg, 10 mo	2.6–4.5	Progression	Alive
14	42/M	Birkenhead, UK	1	CCPA with LUL aspergilloma	Sarcoidosis, COPD, celiac disease; aspergilloma removed as part of left lung transplant, 2007¶	Itra 400 mg, 11 mo	13.8–17.8	Unchanged, switched to vori	Unknown
15	68/F	Wirral, UK	1	Sputum isolate	Cardiac transplant for congestive cardiomyopathy, 1999; chronic cough; 2007; polymyalgia rheumatica, hiatal hernia, oesophagitis	Not documented	NA	Not assessable	Alive
16	12/F	Liverpool, UK	1	Sputum isolate	Unknown	Unknown	Unknown	Unknown	Unknown
17	43/M	Manchester, UK	1	Sputum isolate	Unknown	Unknown	Unknown	Unknown	Unknown

*CCPA , chronic cavitary pulmonary aspergillosis; M., Mycobacterium; vori, voriconazole; ND, not determined; ABPA, allergic bronchopulmonary aspergillosis; CF, cystic fibrosis; itra, itraconazole; CFPA, chronic fibrosing pulmonary aspergillosis; TB, tuberculosis; UL, upper lobe; LUL, left upper lobe; COPD, chronic obstructive pulmonary disease; AML, acute myeloid leukemia; RUL, right upper lobe; AlloHSCT, allogeneic haematopoietic stem cell transplant; GVHD, graft versus host disease; IPA, invasive pulmonary aspergillosis; AVR, aortic valve replacement; posa, posaconazole; HAART, highly active antiretroviral therapy.
†Determined by bioassay (target range 5–15 mg/L).
‡Plus aspergilloma isolates studied, taken at autopsy.
§Received a generic formulation of itra, resulting in lower concentrations (i.e., 4.6 mg/L) and then probably was noncompliant at end of treatment period.
¶Successfully completed with vori treatment.

Main Article

¹These data were presented in part at the 2nd Advances Against Aspergillosis meeting, February 22–26, 2006, Athens, Greece; and 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27–30, 2006, San Francisco, CA, USA.

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