Background and Purpose: Cefiderocol (FDC) application on critically ill patients is still limited: recommended dosing regimens are usually derived from studies on healthy subjects, but critical illness is always associated with physio/pathological alterations in patients, resulting in drug concentration perturbation. Furthermore, there is a scant real-life data addressing particular sub-populations, like morbidly/obese and augmented renal clearance patients, making pharmacokinetics/pharmacodynamics (PK/PD) target recommendation debated. The aim of this study was to present FDC PK/PD values in patients from morbidly to pathologically obese and with augmented renal clearance. Experimental Approach: Ten patients with K. pneumoniae NDM infections were enrolled. Plasma therapeutic drug monitoring was performed after steady-state at different timings. The conventional PK/PD target of fT>MIC has been considered, along with a more aggressive target of fT>6 x MIC; evaluated clinical outcomes were microbiological eradication and 30 days mortality. Key Results: A correlation between weight and 30 days mortality was highlighted. The percentage of failure in achieving the microbiological eradication progressively increased with higher BMI. Furthermore, 100% patients reached the conventional PK/PD target of fCmin>4 mg/L; while, when evaluating a more aggressive target of 100% fT>6 x MIC (2 mg/L), different factors showed an influence as FDC minimum free concentration, area under the concentration time curve and drug clearance. Conclusion and Implications: Our study may be useful in real-world evidence, highlighting the important influence of BMI and high value of clearance in achieving the microbiological target, suggesting that further study and the use of therapeutic drug monitoring in this context are needed.

Background: Antiretroviral therapy reduces systemic inflammation and immune activation, but not to levels like HIV-negative. Limited drug penetration within tissues has been argued as potential mechanism of persistent inflammation. Data on the role of inflammation on plasma/intracellular (IC) pharmacokinetics (PK) of ARV drugs through to downregulation/expression of cytochrome P450 3A/membrane transport proteins are limited. Aim of this study was to investigate the correlation between inflammation markers and plasma/IC PK of different ARVs regimen in HIV-positive patients. Methods: We included in the study ART-treated HIV+ pts switching to 3 different ARV regimens: 1) DTG-based dual-therapy plus boosted-PIs, 2) DTG-based triple-therapy without PIs, 3) DRV/c-based triple-therapy. Plasma and IC ARV drugs concentration means at the end of dosing interval (T0), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed. Results: 60 samples from pts included in the switching study were used for measuring plasma and IC concentrations of HIV drugs. No significative differences between CRP, sCD14, IL-6 and LPS values in 3 arms of therapy were observed. Significant correlation was observed between tenofovir plasma concentrations and sCD14 (p<0.001), DRV plasma concentration and sCD14 (p=0,07) and DRV IC/plasma ratio and Log10 IL-6 concentrations (p=0.04). Furthermore, in 24 pts on DTG-TT, we observed a negative trend between DTG IC concentrations and sCD14 (p=0.09). Conclusions: Our preliminary data support the hypothesis of lower IC concentrations of DRV and DTG in pts with higher plasma IM, suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.