title: Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis.
abstract: OBJECTIVE
  Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune-compromised patients such as organ-transplant recipients. Recently, voriconazole has been approved for first-line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung-transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter's tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without.
  
  
  METHODS
  Lung-transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student's t-test. Statistical significance was defined by P-value <0.05.
  
  
  RESULTS
  Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12.3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14.9 days vs. 8.3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole.
  
  
  CONCLUSIONS
  This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung-transplant recipients a median of 12.3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.
authors.affiliation: Département de Pharmacie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Thomas
authors.forename: V
authors.initials: V
authors.lastname: Korb
authors.forename: R
authors.initials: R
authors.lastname: Guillemain
authors.forename: T
authors.initials: T
authors.lastname: Caruba
authors.forename: V
authors.initials: V
authors.lastname: Boussaud
authors.forename: E
authors.initials: E
authors.lastname: Billaud
authors.forename: P
authors.initials: P
authors.lastname: Prognon
authors.forename: D
authors.initials: D
authors.lastname: Begué
authors.forename: B
authors.initials: B
authors.lastname: Sabatier
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001230:Aspergillus / Q000187:drug effects; D000077336:Caspofungin; D003550:Cystic Fibrosis / Q000628:therapy; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000097:blood; D055744:Invasive Pulmonary Aspergillosis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D055666:Lipopeptides; D016040:Lung Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012189:Retrospective Studies; D016559:Tacrolimus / Q000097:blood; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D007166:Immunosuppressive Agents; D055666:Lipopeptides; D011743:Pyrimidines; D014230:Triazoles; D000077336:Caspofungin; D065819:Voriconazole; D016559:Tacrolimus