Linezolid dose adjustment according to therapeutic drug monitoring helps reach the goal concentration in severe patients, and the oldest seniors benefit more

(2023) 23:840 Xu et al. BMC Infectious Diseases https://doi.org/10.1186/s12879-023-08831-7 BMC Infectious Diseases Open Access RESEARCH Linezolid dose adjustment according to therapeutic drug monitoring helps reach the goal concentration in severe patients, and the oldest seniors benefit more Ying Xu1†, Xilan Yang2†, Pei Liang3 and Chen Qu4* Abstract Background The elderly with severe infection increased dramatically in intensive care unit (ICU). Proper antimicrobial therapy help improve the prognosis. Linezolid, as an antimicrobial drug, is commonly utilized to treat patients infected with methicillin-resistant S. aureus and vancomycin-resistant enterococci. Clinical evidence suggests elderly patients prone to linezolid overexposure. Here, we describe the results of three years’ linezolid adjustment experiences according to therapeutic drug monitoring (TDM), especially in the oldest old. Methods Linezolid therapeutic drug monitoring data were collected between January 2020 and November 2022 from patients who were admitted to ICU and treated with linezolid. All the patients started with a dosage of 600 mg, twice daily. The first TMD was carried out ten minutes before the seventh administration. The dosage adjustment was determined by the doctor according to the first TMD and patients’ condition, and the repeated TDM was conducted as required. The dosage adjustment in different age group was recorded. Laboratory data were compared between the old and the oldest old. The high mortality risk of the oldest old was also explored. Results Data of 556 linezolid TDM from 330 patients were collected. Among which, 31.6%, 54.8%, and 75% of patients had supra-therapeutic linezolid trough concentrations at the first TDM assessment in different age group, leading to the dosage adjustment rate of 31.0%, 40.3%, 68.8% respectively. The linezolid dosage adjustments according to TDM help to reach therapeutic concentration. The oldest old was in high risk of linezolid overexposure with lowercreatinine clearance. The norepinephrine maximum dosage but not linezolid C min was associated with 28-day mortality in the oldest old. Conclusions Elderly patients with linezolid conventional 600 mg twice-daily dose might be at a high risk of overexposure, especially in the oldest old. The linezolid dosage adjustments according to TDM help reach the therapeutic concentration. The high mortality of the oldest old was not related with initial linezolid overexposure. Keywords Linezolid, Therapeutic drug monitoring, Trough concentration, The elderly † Ying Xu and Xilan Yang contributed equally to this work and should be regarded as co-first authors. *Correspondence: Chen Qu Full list of author information is available at the end of the article © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xu et al. BMC Infectious Diseases (2023) 23:840 Introduction Severe infection is common and frequently fatal in the elderly in intensive care unit (ICU) [1]. Mortality was increased with age, from 10% in children to 38.4% in those > 85 years old [2]. Proper antimicrobial therapy help improve the prognosis [3]. The methicillin-resistant S. aureus and vancomycin-resistant enterococci are considered the most common gram-positive bacteria found in ICU, and linezolid, as an antimicrobial drug, is commonly utilized to treat patients [4]. Various antibiotics vary from different pharmacodynamic indexes. Vancomycin, for example, the optimal therapeutic pharmacokynetic/pharmacodynamic (PK/ PD) indices is area under the 24 h concentration–time curve / the minimum inhibitory concentration (AUC/ MIC) > 400, approximately trough concentration (Cmin) 15–20 mg/L [5, 6]. Linezolid is a kind of time-dependent antibiotic, the AUC/MIC > 80 and the percentage of time that the plasma concentrations surpass the MIC (T > MIC = 85–100%) are the optimal PK/PD indices. Linezolid Cmin is commonly used in practice instead. After the initial linezolid treatment, the Cmin is assumed to be maintained between 2 to 7 μg/mL [7]. In general, linezolid is administered at a dose of 600 mg twice daily via oral and/or intravenous infusion. Dosing adjustment is considered unnecessary in elderly patients given on the drug’s label sheet. However, some evidences show significant association between patients’ age and linezolid exposure [8–10]. Compared with younger patients, the old and the very old patients have linezolid Cmin three-fold higher when treated with the conventional 600-mg twice daily dose [10]. A prospective pilot study revealed the fact that patients aged > 70 years had drug Cmin exceeding 8 mg/L treated with the conventional dose [10]. Increasing evidence demonstrated that exceeding the upper therapeutic safety threshold might lead to linezolid-related adverse events, such as thrombocytopenia, lactic acidosis, and hyponatremia [11–15]. Thus, therapeutic drug monitoring (TDM) of linezolid was strongly recommended, especially in the elderly [16]. Up to date, the proportion of persons aged 85 and over, the so-called “oldest old” is increasing dramatically worldwide [17]. However, there have been limited experiences of linezolid in the oldest old. Whether there was a relationship between the high mortality and linezolid overexposure was also not clear in patients aged 85 and over. Thus, we described the results of three years’ linezolid trough concentration and dose adjustment in elderly patients under the guidance of TDM and its effect on prognosis. Page 2 of 8 Materials and methods This retrospective study was conducted in ICU of Nanjing Drum Tower Hospital from January 2020 to November 2022. It involved 556 samples from 330 patients who received parenteral linezolid treatment with actual initial dosage of 600 mg twice daily longer than three days. Exclusion criterion was duration of linezolid therapy less than three days. This study was approved by the Medical Ethics Committee of the Nanjing Drum Tower Hospital, the (...truncated)