A pharmacokinetic analysis of posaconazole oral suspension in the serum and alveolar compartment of lung transplant recipients.

Invasive fungal infections cause significant morbidity and mortality after lung transplantation. Fungal prophylaxis following lung transplantation is not standardised, with transplant centres utilising a variety of regimens. Posaconazole is a broad-spectrum antifungal triazole that requires further investigation within the setting of lung transplantation. This prospective, single-centre, observational study explored the pharmacokinetics of posaconazole oral suspension (POS) in the early perioperative period following lung transplantation in 26 patients. Organ recipients were scheduled to receive 400mg POS twice daily for 6 weeks as primary antifungal prophylaxis. Therapeutic drug monitoring (TDM) of serum posaconazole levels was performed in accordance with local clinical protocols. Bronchoalveolar lavage fluid (BALF) was sampled during routine bronchoscopies. Posaconazole levels were measured both in serum and BALF using mass spectrometry. Posaconazole levels were highly variable within lung transplant recipients during the perioperative period and did not achieve 'steady-state'. Serum posaconazole concentrations positively correlated with levels within the BALF (r=0.5527; P=0.0105). Of the 26 patients, 10 failed to complete the study for multiple reasons and so the trial was terminated early. Unlike study findings in stable recipients, serum posaconazole levels rarely achieved steady-state in the perioperative period; however, they do reflect the concentrations within the airways of newly transplanted lungs. The role of POS as primary prophylaxis in the perioperative period is uncertain, but if used TDM may be helpful for determining attainment of therapeutic levels.

De novo HLA sensitization and antibody mediated rejection following pregnancy in a heart transplant recipient.

Here we report a case wherein both donor-specific and third-party, paternal, HLA class II specific antibodies developed following a spontaneous miscarriage resulting in antibody-mediated rejection in a patient who had undergone an orthotopic cardiac transplant six years earlier.

Intravenous inotropic agents in heart failure.

Inotropes are some of the most commonly used drugs in intensive care. However, their value in treating patients with heart failure is limited and prolonged use is associated with an increased mortality. Nevertheless inotropic agents increase cardiac contractility and can improve the cardiac output of patients with heart failure.

Initial experience with sirolimus and mycophenolate mofetil for renal rescue from cyclosporine nephrotoxicity after heart transplantation.

Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. We evaluated a CNI elimination protocol in 14 patients with renal impairment at 48.3 +/- 36.0 months after heart transplantation. The mean serum creatinine was 321 +/- 107 micromol/L; cyclosporine (n=13) or tacrolimus (n=1) was discontinued with sirolimus commenced immediately, initially aiming for a target trough level of 16 (12 to 20) ng/mL. If patients were not receiving mycophenolate (MMF) this was initiated at 1 g bid. The transfer period was covered with a tapering course of corticosteroids. In addition to monitoring clinical status, hematology, biochemistry, and sirolimus levels, graft function was assessed by echocardiography, ECG, and, where indicated, endomyocardial biopsy. Renal function improved in 12 patients (with 6 having a greater than 40% decrease in serum creatinine), remained unchanged in 1, and deteriorated in 1. Two patients who were converted at 15 and 139 months after transplantation experienced grade 3A rejection. One patient experienced a fall in ejection fraction without histologic evidence of rejection. Sirolimus was discontinued in three patients because of side effects: bone marrow suppression, presumed lymphocytic pneumonitis, and generalized acneform rash complicated by an axillary abcess; 50% of patients continue on sirolimus. In conclusion, withdrawal of CNIs after heart transplantation resulted in an improvement in renal function in most patients: 43% experienced a substantial improvement. CNI elimination protocols need to be refined to reduce the risk of breakthrough rejection and to minimize side effects while protecting renal function after heart transplantation.