Département de Pharmacie, Hôpital Européen Georges Pompidou, Paris, France.
J Clin Pharm Ther. 2010 Feb;35(1):49-53. doi: 10.1111/j.1365-2710.2009.01061.x.
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.
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.
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.
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.
侵袭性肺曲霉病（IPA）是免疫功能低下患者（如器官移植受者）的严重致死原因。最近，伏立康唑已被批准用于 IPA 的一线治疗。理论上，应在 24 小时内达到最佳伏立康唑血药浓度（根据最近的研究，优于 1mg/L）。但实际上，在肺移植受者中似乎需要更长的时间。因此，目前在这个空白期使用卡泊芬净联合伏立康唑来预防曲霉菌属感染。本研究的首要目的是研究使用该联合疗法治疗的曲霉菌属感染及其可接受性。比较了肺移植受者中达到明显活性血药浓度的中位时间，分别比较了囊性纤维化患者和非囊性纤维化患者。
回顾性确定了 2002 年至 2008 年期间作为一线治疗接受伏立康唑和卡泊芬净联合治疗的肺移植受者。采用学生 t 检验比较囊性纤维化患者和其他患者达到有效伏立康唑血药浓度的天数中位数。P 值<0.05 定义为统计学意义。
4 例患者在移植前因曲霉菌属定植而接受治疗，90 天时其培养结果为阴性。11 例患者被诊断为确诊或疑似侵袭性曲霉病，其中 14 例完全缓解。报告了幻觉（2 例）和显著肝毒性（2 例）。在 15 例研究的移植受者中，观察到达到有效伏立康唑血药浓度的中位时间为 12.3 天。囊性纤维化患者的时间似乎比其他患者长（14.9 天 vs. 8.3 天）。伏立康唑可能使他克莫司血药浓度（5-15ng/ml）升高。
本回顾性研究描述了囊性纤维化肺移植转诊中心治疗这种罕见且严重疾病的实际经验。伏立康唑和卡泊芬净联合治疗具有良好的安全性，几乎所有患者均获得了良好的临床结局。我们表明，在 15 例肺移植受者中，伏立康唑达到足够高的血药浓度需要中位 12.3 天。伏立康唑联合卡泊芬净可在伏立康唑可能处于亚治疗水平时提供曲霉菌属感染覆盖，具有良好的耐受性。
