title: Breakthrough pulmonary Aspergillus fumigatus infection with multiple triazole resistance in a Spanish patient with chronic myeloid leukemia.
abstract: BACKGROUND
  An allogeneic hematopoietic cell transplantation (allo-HCT) patient presented with chronic pulmonary aspergillosis associated to pulmonary graft versus host disease (GVHD) and was treated for a long time with several antifungal agents that were administered as prophylaxis, combination therapies, and maintenance treatment. The patient suffered from a breakthrough invasive pulmonary aspergillosis due to Aspergillus fumigatus after long-term antifungal therapy.
  
  
  METHODS
  Several isolates were analyzed. First isolates were susceptible in vitro to all azole agents. However, after prolonged treatment with itraconazole and voriconazole a multiple azole resistant A. fumigatus isolate was cultured from bronchoalveolar lavage (BAL) when the patient was suffering from an invasive infection, and cavitary lesions were observed.
  
  
  RESULTS
  Analysis of the resistant mechanisms operating in the last strain led us to report the first isolation in Spain of an azole resistant A. fumigatus strain harboring the L98H mutation in combination with the tandem repeat (TR) alteration in CYP51A gene (TR-L98H). Long-term azole therapy may increase the risk of resistance selecting strains exhibiting reduced susceptibility to these compounds. However, since the isolates were genetically different the suggestion that could be made is that the resistance was not induced during the prolonged azole therapy but the patient might simply have acquired this resistant isolate from the environment, selected by the therapy.
  
  
  CONCLUSIONS
  These findings suggest that in all long-term treatments with antifungal agents, especially with azoles, repeated sampling and regular susceptibility testing of strains isolated is necessary as resistant isolates could be selected.
authors.affiliation: Servicio de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Spain.
authors.forename: Emilia
authors.initials: E
authors.lastname: Mellado
authors.forename: Rafael
authors.initials: R
authors.lastname: De La Camara
authors.forename: Buenaventura
authors.initials: B
authors.lastname: Buendía
authors.forename: Juan L
authors.initials: JL
authors.lastname: Rodriguez-Tudela
authors.forename: Manuel
authors.initials: M
authors.lastname: Cuenca-Estrella
mesh_terms: D000328:Adult; D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D000077336:Caspofungin; D003131:Combined Modality Therapy; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology / Q000627:therapeutic use; D017809:Fatal Outcome; D005260:Female; D005656:Fungal Proteins / Q000235:genetics* / Q000502:physiology; D006086:Graft vs Host Disease / Q000150:complications / Q000188:drug therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications* / Q000188:drug therapy / Q000601:surgery; D055666:Lipopeptides; D017354:Point Mutation; D011183:Postoperative Complications / Q000188:drug therapy / Q000209:etiology / Q000382:microbiology*; D055732:Pulmonary Aspergillosis / Q000188:drug therapy / Q000209:etiology / Q000382:microbiology*; D012008:Recurrence; D013030:Spain; D013045:Species Specificity; D019172:Transplantation Conditioning / Q000009:adverse effects; D014184:Transplantation, Homologous; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D007166:Immunosuppressive Agents; D055666:Lipopeptides; D014230:Triazoles; C068538:liposomal amphotericin B; D000666:Amphotericin B; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D000077336:Caspofungin