β-Lactam Pharmacokinetic/Pharmacodynamic Target Attainment in Intensive Care Unit Patients: A Prospective, Observational, Cohort Study

• Published in: Antibiotics (Basel) Vol. 12; no. 8; p. 1289
• Main Authors: Guilhaumou, Romain, Chevrier, Constance, Setti, Jean Loup, Jouve, Elisabeth, Marsot, Amélie, Julian, Nathan, Blin, Olivier, Simeone, Pierre, Lagier, David, Mokart, Djamel, Bruder, Nicolas, Garnier, Marc, Velly, Lionel
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 05.08.2023; MDPI
• Subjects: Amides; Antibiotics; antimicrobial; Antimicrobial agents; Bacteria; Cefepime; Cefotaxime; Ceftazidime; Cohort analysis; Creatinine; Dosage; dosing; Drug dosages; Infections; Intensive care; Length of stay; Life Sciences; Meropenem; Mortality; Multivariate analysis; Observational studies; Optimization; Overdose; Patients; Pharmacodynamics; Pharmacokinetics; Plasma; therapeutic drug monitoring; β-Lactam antibiotics; pharmacokinetics; antimicrobial; intensive care; dosing; pharmacodynamics; therapeutic drug monitoring
• ISSN: 2079-6382; 2079-6382
• DOI: 10.3390/antibiotics12081289

Background: The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. Methods: This prospective, observational, cohort study was performed in three ICUs. Four ß-lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7. The primary pharmacokinetic/pharmacodynamic target was an unbound ß-lactam plasma concentration four times above the bacteria’s minimal inhibitory concentration during the whole dosing interval. The demographic and clinical covariates associated with target attainment were evaluated. Results: A total of 170 patients were included (426 blood samples). The percentages of empirical ß-lactam underdosing at D1 were 66% for cefepime, 43% for cefotaxime, 47% for ceftazidime, and 14% for meropenem. Indexed creatinine clearance was independently associated with treatment underdose if increased (adjusted odds ratio per unit, 1.01; 95% CI, 1.00 to 1.01; p = 0.014) or overdose if decreased (adjusted odds ratio per unit, 0.95; 95% CI, 0.94 to 0.97; p < 0.001). Pharmacokinetic/pharmacodynamic target attainment was significantly increased after ß-lactam dosage adjustment between day 1 and day 4 vs. no adjustment (53.1% vs. 26.2%; p = 0.018). Conclusions: This study increases our knowledge on the optimization of ß-lactam therapy in ICU patients. A large inter- and intra-patient variability in plasmatic concentrations was observed, leading to inadequate exposure. A combined indexed creatinine clearance and TDM approach enables adequate dosing for better pharmacokinetic/pharmacodynamic target attainment.