Feasibility of Continuous Infusion of Cefiderocol in Conjunction with the Establishment of Therapeutic Drug Monitoring in Patients with Extensively Drug-Resistant Gram-Negative Bacteria.

BACKGROUND AND OBJECTIVE: Resistance to antibacterial substances is a huge and still emerging issue, especially with regard to Gram-negative bacteria and in critically ill patients. We report a study in six patients infected with extensively drug-resistant Gram-negative bacteria in a limited outbreak who were successfully managed with a quasi-continuous infusion of cefiderocol. METHODS: Patients were initially treated with prolonged infusions of cefiderocol over 3 h every 8 h, and the application mode was then switched to a quasi-continuous infusion of 2 g over 8 h, i.e. 6 g in 24 h. Therapeutic drug monitoring (TDM) was established using an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. RESULTS: Determined trough plasma concentrations were a median of 50.00 mg/L [95% confidence interval (CI) 27.20, 74.60] and steady-state plasma concentrations were a median of 90.96 mg/L [95% CI 37.80, 124]. No significant differences were detected with respect to acute kidney injury/continuous renal replacement therapy. Plasma concentrations determined from different modes of storage were almost equal when frozen or cooled, but markedly reduced when stored at room temperature. CONCLUSIONS: (Quasi) continuous application of cefiderocol 6 g/24 h in conjunction with TDM is a feasible mode of application; the sample for TDM should either be immediately analyzed, cooled, or frozen prior to analysis.

Antimicrobial stewardship in the ICU in COVID-19 times: the known unknowns.

Since the start of the COVID-19 pandemic, there has been concern about the concomitant rise of antimicrobial resistance. While bacterial co-infections seem rare in COVID-19 patients admitted to hospital wards and intensive care units (ICUs), an increase in empirical antibiotic use has been described. In the ICU setting, where antibiotics are already abundantly-and often inappropriately-prescribed, the need for an ICU-specific antimicrobial stewardship programme is widely advocated. Apart from essentially warning against the use of antibacterial drugs for the treatment of a viral infection, other aspects of ICU antimicrobial stewardship need to be considered in view of the clinical course and characteristics of COVID-19. First, the distinction between infectious and non-infectious (inflammatory) causes of respiratory deterioration during an ICU stay is difficult, and the much-debated relevance of fungal and viral co-infections adds to the complexity of empirical antimicrobial prescribing. Biomarkers such as procalcitonin for the decision to start antibacterial therapy for ICU nosocomial infections seem to be more promising in COVID-19 than non-COVID-19 patients. In COVID-19 patients, cytomegalovirus reactivation is an important factor to consider when assessing patients infected with SARS-CoV-2 as it may have a role in modulating the patient immune response. The diagnosis of COVID-19-associated invasive aspergillosis is challenging because of the lack of sensitivity and specificity of the available tests. Furthermore, altered pharmacokinetic/pharmacodynamic properties need to be taken into account when prescribing antimicrobial therapy. Future research should now further explore the 'known unknowns', ideally with robust prospective study designs.