tacrolimus and Pulmonary-Aspergillosis

Drug-drug interactions between azoles and calcineurin inhibitors can cause issues for organ transplant specialists. Clinical practice guidelines for the treatment of solid-organ transplant recipients with invasive aspergillosis infection are lacking. Here, we present a patient who developed pulmonary aspergillosis after liver transplant. The patient had prolonged treatment with echinocandin that was not effective. A drug-drug interaction between azoles and tacrolimus caused issues for the clinical physician. We adjusted the doses, and the patient was successfully treated. A reduction in the tacrolimus dose, intensive monitoring of associated parameters, and elimination of risk exposures are important for a favorable outcome.

Topics: Antifungal Agents; Calcineurin Inhibitors; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Opportunistic Infections; Pulmonary Aspergillosis; Tacrolimus; Treatment Outcome; Voriconazole

Topics: Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Pulmonary Aspergillosis; Pyrimidines; Tacrolimus; Triazoles; Voriconazole

Invasive fungal infections (IFIs) are a major cause of death in organ transplant patients. The murine hydrocortisone-mediated immunosuppression model of pulmonary aspergillosis is commonly used to characterise IFIs in these patients. However, this model does not take into account the effects of calcineurin inhibitors on transplant immunity to IFIs or the fungal calcineurin pathway, which is required for both virulence and antifungal drug resistance. To address these two issues, a new and clinically relevant transplant immunosuppression model of tacrolimus (FK506) and hydrocortisone-associated pulmonary aspergillosis was developed. We first characterised IFIs in 406 patients with a lung transplant. This showed that all of the patients with pulmonary aspergillosis were immunosuppressed with calcineurin inhibitors and steroids. Murine pharmacokinetic studies demonstrated that an ideal dose of 1 mg/kg/day of FK506 intraperitoneally produced blood trough levels in the human therapeutic range (5-12 ng/ml). There was increased mortality from pulmonary aspergillosis in a transplant-relevant immunosuppression model using both FK506 and hydrocortisone as compared with immunosuppression using hydrocortisone only. Lung histopathology showed neutrophil invasion and tracheobronchitis that was associated with reduced lung tumour necrosis factor-α (TNFα), JE (homologue of human MCP-1) and KC (homologue of human IL-8) at 24 hours, but increased lung TNFα, JE and KC at 48 hours when fungal burden was high. Furthermore, FK506 directly impaired fungal killing in alveolar macrophages in vitro, with FK506-mediated inhibition of the radial growth of Aspergillus fumigatus in vitro occurring at the low concentration of 5 ng/ml. Taken together, these findings show that the immunosuppressive activity of FK506 outweighs its antifungal activity in vivo. These observations demonstrate that FK506 impairs innate immune responses and leads to an incremental increase in susceptibility to IFIs when it is combined with steroids. This new and clinically relevant mouse model of invasive aspergillosis is a valuable addition to the further study of both fungal immunity and antifungal therapy in organ transplantation.

Topics: Animals; Aspergillus fumigatus; Chemokine CCL2; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hydrocortisone; Immunosuppression Therapy; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-8; Lung Transplantation; Male; Mice; Pneumonia; Pulmonary Aspergillosis; Risk Factors; Steroids; Survival Analysis; Tacrolimus; Tumor Necrosis Factor-alpha