Personalized ß-lactam dosing in patients with coronavirus disease 2019 (COVID-19) and pneumonia: A retrospective analysis on pharmacokinetics and pharmacokinetic target attainment.

ABSTRACT: Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non-species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.

Decreased Linezolid Serum Concentrations in Three Critically Ill Patients: Clinical Case Studies of a Potential Drug Interaction between Linezolid and Rifampicin.

Linezolid is a valuable treatment option for treating infections caused by multi-resistant gram-positive pathogens. Lack of effective linezolid levels due to the co-administration of rifampicin has been described in healthy subjects. However, the clinical significance of this potential drug interaction (DI) for critically ill patients is still unclear. This was a retrospective analysis of 3 critically ill patients with the combination therapy of linezolid and rifampicin or rifampicin pre-treatment. Despite increasing the dose of linezolid, the majority of observed linezolid trough concentrations in all 3 patients were below 2 mg/l. Furthermore, linezolid trough concentrations remained below 2 mg/l after discontinuation of rifampicin. This potential DI between linezolid and rifampicin could lead to treatment failure. Therefore, we strongly recommend that linezolid serum concentrations be monitored in patients with rifampicin co-administration or rifampicin pretreatment.

Anti-infective drugs during continuous hemodialysis - using the bench to learn what to do at the bedside.

PURPOSE: The main objective of this study was to investigate the clearance of 11 selected anti-infectives in an in vitro model of continuous veno-venous hemodialysis (CVVHD), in order to suggest rational dosing strategies for clinical practice. METHODS: Ceftazidime, ciprofloxacin, flucloxacillin, gentamicin, linezolid, meropenem, metronidazole, piperacillin, rifampicin, vancomycin and voriconazole were studied in two different solvents (sodium chloride 0.9% and HSA 5%) using a multifiltrate dialysis device by Fresenius Medical Care (Bad Homburg, Germany). For each solution, prefilter, postfilter, and dialysate samples were drawn simultaneously during one hour of dialysis and were assayed. RESULTS: The clearance of all drugs except rifampicin in sodium chloride 0.9% was comparable (mean 1.76 ± 0.11 l/h). The clearance of these agents in human serum albumin solution 5% was reduced by between 5.3% and 72.2%. The unbound drug fraction correlated with a lower clearance in HSA 5% (Pearson correlation coefficient r = 0.933; p = 0.00008). No correlation between clearance in HSA 5% and the drugs' molecular weight was found (Pearson correlation coefficient r = 0.388; p = 0.268). Rifampicin was detected to bind to the surface of the polysulfone filter used. Dialysis clearance of ceftazidime, gentamicin, linezolid, meropenem, metronidazole, piperacillin and vancomycin during CVVHD accounted for over 25% of the total body clearance of population pharmacokinetic data for renally impaired patients. CONCLUSIONS: The results from this study highlight that dose adaptations are needed for most of the drugs under investigation for patients undergoing CVVHD. In combination with polysulfone filters, rifampicin should be used with care in this setting.