Penetration of isavuconazole into the epithelial lining fluid of patients with pulmonary fungal infections. Comment on: ‘Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions’

We read with great interest the study by Bergmann and colleagues recently published in the Journal of Antimicrobial Chemotherapy. The authors provide new data on the pharmacokinetics of isavuconazole after intravenous infusion in different target sites: cerebrospinal fluid, PBMCs and epithelial lining fluid (ELF) of 12 healthy volunteers.1 Isavuconazole is the most recently marketed triazole antifungal. It exhibits interesting pharmacological properties (almost 100% oral bioavailability, prolonged half-life, large distribution volume) with a good safety profile and broad antifungal spectrum, a combination that makes it an attractive option for the treatment of invasive fungal infections (IFI).2 However, data on organ diffusion are still lacking. As for pulmonary aspergillosis that remains the most common filamentous IFI, diffusion into both lung tissue and ELF is critical to ensure efficacy. Although preclinical studies have shown good lung tissue penetration in a mouse model,3 human data remain scarce. Bergmann et al. studied healthy volunteers and reported a mean ELF concentration of 0.94 mg/L (SD 0.46) with flat kinetics in the concentration-time profiles.1 Another recent study in lung transplant recipients reported a mean ELF concentration of 1.92 mg/L under steady-state conditions.4 However, no study has so far investigated isavuconazole penetration into the ELF in non-lung transplanted patients with fungal infections, which represents most patients receiving isavuconazole.5 Given the persisting concerns on the reliability of studies based on healthy participants to accurately reflect the kinetic and magnitude ELF concentrations in critically ill patients with pneumonia,6 we implemented a prospective case series to describe the penetration of isavuconazole into the ELF of patients with pulmonary fungal infections in a real-life setting. The study was part of the Observational Population Pharmacokinetics of Anti-infectives in Hospitalized Patients (OptiPOP) study (clinicaltrials.gov NCT02998411) conducted at three university hospitals in France from June 2022 to July 2023. Eligible patients were adult patients treated with isavuconazole for at least 2 weeks (to reach steady state) who underwent bronchoscopy with broncho-alveolar lavage (BAL) as a part of their standard medical care, and serum sampling for isavuconazole trough concentration within 72 hours before or after bronchoscopy were prospectively enrolled. Isavuconazole was administered orally or intravenously with a loading dose (200 mg/8 h for the first 48 h) followed by a maintenance dose (from day 3, 200 mg/24 h) that could be modified by physicians as per manufacturer guidelines. In our centres, therapeutic drug monitoring for isavuconazole is part of the standard of care. BAL and serum sample were collected to measure isavuconazole concentrations using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Isavuconazole concentrations in the ELF were calculated from BAL concentrations as reported elsewhere7: estimated isavuconazole ELF concentration = (BAL isavuconazole × serum urea (mmol/L))/BAL urea (mmol/L). Isavuconazole ELF diffusion was estimated as ELF concentration/serum trough concentration of isavuconazole, assuming steady state in both compartments and flat kinetics in the ELF (as suggested by the work of Bergmann and colleagues).1 The protocol was approved by the Institutional Review Board CPP Ile de France II (number 2016-10-09). All patients gave their informed consent. Three patients were prospectively enrolled, all receiving isavuconazole for possible/probable IFIs (Table 1).8,9 Two had fungal documentation available, both evidencing triazole-susceptible Aspergillus fumigatus. Steady-state serum isavuconazole trough concentrations were 1.76, 2.20 and 3.15 mg/L. In ELF isavuconazole concentrations were 0.43, 1.39 and 2.25 mg/L and the estimated diffusions in ELF were 0.24, 0.63 and 0.71. Patients’ characteristics and isavuconazole concentrations ANCA, anti-neutrophil cytoplasmic antibody; MPO, myeloperoxydase antibody; CT, computed tomography; MIC, minimum inhibitory concentration. aIsavuconazole dosage was left to the discretion of the treating physicians. Patients’ characteristics and isavuconazole concentrations ANCA, anti-neutrophil cytoplasmic antibody; MPO, myeloperoxydase antibody; CT, computed tomography; MIC, minimum inhibitory concentration. aIsavuconazole dosage was left to the discretion of the treating physicians. Isavuconazole has been shown to be a viable therapeutic option in invasive aspergillosis5 and invasive mucormycosis. Our results extend those of Bergmann et al. and show moderate penetration of isavuconazole into the ELF of real-life and eventually severely ill patients with possible/probable pulmonary fungal infections in the range of those collected in healthy people in Bergmann et al.1 However, they also call for caution given their important 2-fold variability. The potential impact of this variability, which may result in low antifungal concentrations in certain patients’ ELF, on the occurrence of breakthrough pulmonary IFI, as observed in some patients receiving prophylactic isavuconazole, remains unproven thus far.10 Our study has several limitations intrinsic to its observational design. Its small sample size limits the generalizability of our results. Additionally, we were unable to collect samples from the same patient at several time points in ELF and plasma; this could have biased the estimation of the ELF diffusion. The limited sample size also precluded the calculation of a pharmacokinetic model for isavuconazole diffusion. In conclusion, our results suggest that the penetration of isavuconazole into the ELF in real-life patients with fungal lung infection appears moderate and variable. Further studies are needed to replicate these results. This study was caried out as part of standard of care management. The authors declare that they have no conflicts of interest. A.M., E.C. and C.C. conceptualized the study. L.F.B. and S.B. performed the pharmacological tests. All authors participated in the data collection. A.M., C.C. and E.C. wrote the first draft of this manuscript. All authors critically revised and approved the final manuscript. E.C. and C.C. are the guarantors of the study, had full access to all the data and took responsibility for the integrity of the data and the accuracy of the data analysis.