Low attainment to PK/PD-targets for β-lactams in a multi-center study on the first 72 h of treatment in ICU patients

Abstract

Severe infections are life-threatening conditions commonly seen in the intensive care units (ICUs). Antibiotic treatment with adequate concentrations is of great importance during the first days when the bacterial load is the highest. Therapeutic drug monitoring (TDM) of β-lactam antibiotics has been suggested to monitor target attainment and to improve the outcome. This prospective multi-center study in seven ICUs in Sweden investigated pharmacokinetic/pharmacodynamic-target (PK/PD-target) attainment for cefotaxime, piperacillin-tazobactam and meropenem, commonly used β-lactams in Sweden. A mid-dose and trough antibiotic concentration blood sample were taken from patients with severe infection daily during the first 72 h of treatment. Antibiotic plasma concentrations were analysed by liquid chromatography-mass spectrometry (LC–MS). Antibiotic concentrations 100% time above MIC (minimal inhibitory concentration), (100% T > MIC) and four times above MIC 50% of the time (50% T > 4xMIC) were used as PK/PD-targets. We included 138 patients with the median age of 67 years and the median Simplified Acute Physiology Score 3 (SAPS3) of 59. Forty-five percent of the study-population failed to reach 100% T > MIC during the first day of treatment. The results were similar the following two days. There was a three-fold risk of not meeting the PK/PD target if the patient was treated with cefotaxime. For the cefotaxime treated patients 8 out of 55 (15%) had at least one end-dose concentrations below the level of detection during the study. Low age, low illness severity, low plasma creatinine, lower respiratory tract infection and cefotaxime treatment were risk factors for not reaching 100% T > MIC. In Swedish ICU-patients treated with β-lactam antibiotics, a high proportion of patients did not reach the PK/PD target. TDM could identify patients that need individual higher dosing regimens already on the first day of treatment. Further studies on optimal empirical start dosing of β-lactams, especially for cefotaxime, in the ICU are needed.Trial registration: The protocol was retrospectively registered 100216 (ACTRN12616000167460).

Beta‐lactam antibiotic concentrations in critically ill patients with standard and adjusted dosages: A prospective observational study

“…Our study shows that many critically ill patients are still under‐dosed, with a quarter of patients not achieving what could now be considered the most conservative target of 100%ƒT > MIC 11 . This is not the first study to show that standard dosing may be insufficient; 40% of patients in the DALI study did not achieve target levels 7 and in a recent Swedish study those numbers were 45% 22 . We decided to use standard non‐species specific breakpoints, as opposed to previous studies, that often have used higher breakpoints to include, what is often referred to as “worst case scenario.” 23,24 If higher breakpoints would have been used as targets, the proportion not reaching 100%ƒT > MIC would be even higher in the present study.…”

“…11 This is not the first study to show that standard dosing may be insufficient; 40% of patients in the DALI study did not achieve target levels 7 and in a recent Swedish study those numbers were 45%. 22 We decided to use standard non-species specific breakpoints, as opposed to previous studies, that often have used higher breakpoints to include, what is often referred to as "worst case scenario." 23,24 If higher breakpoints would have been used as targets, the proportion not reaching 100%…”

Beta-Lactam Dose Optimisation in the Intensive Care Unit: Targets, Therapeutic Drug Monitoring and Toxicity

“…Certain beta-lactam antibiotics may be better candidates for TDM compared to others. Low target attainment has been seen for imipenem, piperacillin, ceftazidime and cefepime, as compared to meropenem [53][54][55][56]. As seen in a post hoc analysis of the Merino trial, isolates had piperacillin-tazobactam MICs much closer to the breakpoint than meropenem, so the impact of TDM may be more pronounced for piperacillin [57].…”

Exploring the Impact of Model-Informed Precision Dosing on Procalcitonin Concentrations in Critically Ill Patients: A Secondary Analysis of the DOLPHIN Trial

“…Sepsis and septic shock are potentially life-threatening conditions in critically ill patients in whom timely initiation of antibiotic treatment is important to improve survival [ 1 ]. In the intensive care unit (ICU), 40–60% of the patients fail to achieve the currently recommended pharmacodynamic target (PDT) of antibiotics [ 2 , 3 , 4 , 5 ]. Due to extensive pathophysiological alterations, they are at risk of both over- and underdosing, increasing the chance of significant adverse events and therapeutic failure [ 6 , 7 ].…”