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.

Background

Therapeutic drug monitoring (TDM) has been suggested to optimize antimicrobial target attainment, typically using 100%T_>MIC, in β-lactam treatment in the ICU. The MIC parameter used in this equation is mostly the worst case scenario MIC (MIC_WCS)—the highest MIC the empirical treatment should cover. However, the impact of the MIC parameter used in pharmacokinetic/pharmacodynamic calculations has been poorly investigated.

Objectives

To assess the influence of target attainment rates for two different MIC parameters using actual MICs of the causative pathogens as the primary reference.

Methods

In a Swedish multicentre study of target attainment for 138 ICU patients treated with β-lactams, the causative pathogen was isolated and subjected to reference MIC testing. Whenever the strain belonged to the WT distribution, we assigned it to the category MIC_ECOFF (epidemiological cut-off value). In the calculations we compared the MIC_ECOFF and the MIC_WCS.

Results

The proportion of patients with target attainment failure for all antibiotics using 100%T_>MIC was 45% (95% CI, 37%–53%) for MIC_WCS and 23% (95% CI, 16%–31%) for MIC_ECOFF. When the target 50%T_>4×MIC was used, corresponding attainment failures were 57% (95% CI, 49%–66%) and 25% (95% CI, 17%–32%) for MIC_WCS and MIC_ECOFF, respectively.

Conclusions

MIC_WCS can overestimate target attainment failure. The use of MIC_WCS could be one reason for the difficulties in establishing a relationship between target failure and mortality in other studies. Based on findings herein, the MIC_ECOFF, which is based on the MIC of the causative pathogen, should be considered a more suitable alternative. When no pathogen is detected, the MIC_ECOFF of likely pathogens according to infection type should be used.

OBJECTIVES: This study aimed to predict the impact of different infusion strategies on pharmacokinetic/pharmacodynamic (PK/PD) target attainment and the potential risk for toxicity in an ICU cohort treated with β-lactams.

METHOD: Using collected patient data from 137 adult ICU patients, and applying population PK models, individual PK parameters were estimated and used to predict concentrations and target attainment following cefotaxime 2 g q8h, piperacillin/tazobactam 4.5 g q6h and meropenem 1 g q8h, applying 15 min short infusions (SI), 3 h extended infusions (EI) and 24 h continuous infusion (CI). The MIC level of the most common primary pathogens, and the worst-case scenario (WCS) pathogen, were used in analyses.

RESULTS: For primary pathogens, target was reached in 94% (129/137) using SI. For WCS pathogens treated with piperacillin/tazobactam and meropenem, 78% (65/83) and 92% (76/83) reached target using SI and EI, respectively. However, target attainment was lower for cefotaxime [SI: 31% (17/54), EI: 44% (24/54)]. Overall, the number of individuals with potentially toxic concentrations was low, both in EI (n = 7) and SI (n = 5). For CI and WCS, target was reached in 50% (27/54), 96% (54/56) and 93% (25/27) for cefotaxime, piperacillin/tazobactam and meropenem, respectively.

CONCLUSIONS: In a Swedish ICU cohort target attainment rates for primary pathogens were high regardless of infusion strategy. In WCS pathogens, SI was insufficient, suggesting the benefit of routine use of EI or CI. However, for cefotaxime, target attainment remained low also with EI and CI. The use of CI might lead to unnecessarily high concentrations, but well-established toxicity levels are lacking and future studies are warranted.