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

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 &gt; MIC) and four times above MIC 50% of the time (50% T &gt; 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 &gt; 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 &gt; 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.Title in Web of Science: Low attainment to PK/PD-targets for beta-lactams in a multi-center study on the first 72 h of treatment in ICU patients</p

Population pharmacokinetics of cefotaxime in intensive care patients

PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. METHODS: This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. RESULTS: A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p &lt; 0.001), reducing IIV from 68 to 49%. CONCLUSION: A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support

EUCAST rapid antimicrobial susceptibility testing (RAST) in blood cultures: Validation in 55 european laboratories

© The Author(s) 2020.Objectives: When bloodstream infections are caused by resistant bacteria, rapid antimicrobial susceptibility testing (RAST) is important for adjustment of therapy. The EUCAST RAST method, directly from positive blood cultures, was validated in a multi-laboratory study in Europe. Methods: RAST was performed in 40 laboratories in northern Europe (NE) and 15 in southern Europe (SE) from clinical blood cultures positive for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus or Streptococcus pneumoniae. Categorical results at 4, 6 and 8 h of incubation were compared with results for EUCAST standard 16–20 h disc diffusion. The method, preliminary breakpoints and the performance of the laboratories were evaluated. Results: The total number of isolates was 833/318 in NE/SE. The number of zone diameters that could be read (88%, 96% and 99%) and interpreted (70%, 81% and 85%) increased with incubation time (4, 6 and 8 h). The categorical agreement was acceptable, with total error rates in NE/SE of 2.4%/4.9% at 4 h, 1.1%/3.5% at 6 h and 1.1%/3.3% at 8 h. False susceptibility at 4, 6 and 8 h of incubation was below 0.3% and 1.1% in NE and SE, respectively, and the corresponding percentages for false resistance were below 1.9% and 2.8%. After fine-tuning breakpoints, more zones could be interpreted (73%, 89% and 93%), with only marginally affected error rates. Conclusions: The EUCAST RAST method can be implemented in routine laboratories without major investments. It provides reliable antimicrobial susceptibility testing results for relevant bloodstream infection pathogens after 4–6 h of incubation