DISCUSSION
Our study retrospectively describes the use of nebulized voriconazole to treat IPA in a third referral hospital. Compounded voriconazole solution for nebulization characteristics are adequate for nebulization, it is well tolerated and voriconazole is not absorbed into systemic circulation even in long treatments.
This study has been performed in the real-world setting, allowing the inclusion of complex patients who represent the potential target population of this treatment. Even if the sample of patients is limited, determination of serum concentration of voriconazole has allowed us to evaluate the rate of voriconazole absorption and the great length of some of the treatments have provided reliable information about safety.
Literature available about the use of nebulized voriconazole in humans is scarce. Jolle et al . have reported the use of nebulized voriconazole in combination with oral treatment in a young patient with CF to treat a severe pulmonary infection caused by Scedosporium apiospermum , they concluded that it was safe and effective (18).  Hilberg et al . published a series of 3 cases of IPA caused byAspergillus spp. successfully treated with inhaled voriconazole monotherapy (40 mg every 12-24 hours) (19). Authors reported an adequate tolerability to voriconazole nebulization, as our results confirm. The efficacy reported by these case reports is better than we observed in our study; however, authors’ conclusions should be taken cautiously since there might be a bias towards publishing only cases with positive outcomes.
This study has some limitations. First, since it is a retrospective study, voriconazole plasma concentration was not consistently measured in all patients so there is missing information. Second, different excipients contained in each voriconazole brand could have an impact on treatment toxicity and absorption, even if we did not detect any differences. Third, patients included were highly complex and some of them were sedated; thus, our capacity to detect AE might have been restricted. Finally, due to the limited sample and the absence of a control group, it is not possible to draw conclusions about treatment effectiveness.
Our study has shown that voriconazole solution is suitable for nebulization, it is well tolerated and it is not absorbed into the systemic circulation even in long treatments. Therefore, the pulmonary route of administration could be an interesting option to treat complex pulmonary infections and/or colonizations when preferred treatments are not efficient, there is toxicity due to systemic treatment or there is risk of DDI. Further research is needed in order to assess voriconazole nebulization efficacy to treat specific clinical situations.