Optimized Antibiotic Management of Critically Ill Patients with Severe Pneumonia Following Multiplex Polymerase Chain Reaction Testing: A Prospective Clinical Exploratory Trial.

Molecular diagnostic testing is assumed to enable fast respiratory pathogen identification and contribute to improved pneumonia management. We set up a prospective clinical trial at a tertiary hospital intensive care unit including adult patients suspected of severe pneumonia from whom a lower respiratory tract sample could be obtained. During control periods (CPs), routine testing was performed, and during intervention periods (IPs), this testing was completed with the FilmArray Pneumonia Panel plus test (FA-PNEU) executed 24/7. The main objective was to measure the impact of FA-PNEU results in terms of reduced time to targeted antimicrobial treatment administration. Over a 10-month period, analysis was performed on 35 CP and 50 IP patients. The median time to targeted antimicrobial treatment administration was reduced to 4.3 h in IPs compared to 26.4 h in CPs, with 54% of IP patients having FA-PNEU results that led to a treatment modification, of which all but one were targeted. Modifications included 10 (37%) de-escalations, 7 (25.9%) escalations, 3 (11.1%) regimen switches, and 7 (25.9%) complete antimicrobial discontinuations. FA-PNEU results were available with a 42.3 h gain compared to routine identification. This prospective study confirmed retrospective data demonstrating the benefit of FA-PNEU testing in severe pneumonia management of critically ill patients through improved antimicrobial use.

The safety and efficacy of stem cells for the treatment of severe community-acquired bacterial pneumonia: A randomized clinical trial.

PURPOSE: Evaluate the safety profile of expanded allogeneic adipose-derived mesenchymal stem cell (eASC) for the treatment of severe community-acquired bacterial pneumonia (CABP). MATERIALS AND METHODS: Randomized, multicenter, double-blind, placebo-controlled, phase 1b/2a trial. Patients with severe CABP were enrolled to receive intravenous infusions of Cx611 or placebo. The primary objective was safety including hypersensitivity reactions, thromboembolic events, and immunological responses to Cx611. The secondary endpoints included the clinical cure rate, ventilation-free days, and overall survival (Day 90). RESULTS: Eighty-three patients were randomized and received infusions (Cx611: n = 42]; placebo: n = 41]. The mean age was similar (Cx611: 61.1 [11.2] years; placebo: 63.4 [10.4] years). The number of AEs and treatment-emergent AEs were similar (243; 184 and 2; 1) in Cx611 and placebo respectively. Hypersensitivity reactions or thromboembolic events were similar (Cx611: n = 9; placebo: n = 12). Each study arm had similar anti-HLA antibody/DSA levels at Day 90. The clinical cure rate (Cx611: 86.7%; placebo: 93.8%), mean number of ventilator-free days (Cx611: 12.2 [10.29] days; placebo: 15.4 [10.75] days), and overall survival (Cx611: 71.5%; placebo: 77.0%) did not differ between study arms. CONCLUSION: Cx611 was well tolerated in severe CABP. These data provide insights for future stem cell clinical study designs, endpoints and sample size calculation. TRIAL REGISTRATION: NCT03158727 (retrospectively registered: May 09, 2017). Full study protocol: https://clinicaltrials.gov/ProvidedDocs/27/NCT03158727/Prot_000.pdf.

Population pharmacokinetics and dosing simulations of total and unbound temocillin in the plasma and CSF of neurocritically ill patients with external ventricular drain-related cerebral ventriculitis.

BACKGROUND: Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF. OBJECTIVES: To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF. METHODS: Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF. RESULTS: All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L. CONCLUSIONS: The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed.