Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill Intensive Care Unit patients

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Abstract

Severely ill Intensive Care Unit (ICU) patients have an increased risk of developing multiresistant Gram-positive infections, largely due to the inappropriate use of antimicrobials. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid, an antibiotic against Gram-positive infections, was characterised in eight critically ill patients admitted to the ICU. Remarkable variation amongst patients in the PK parameters of linezolid was observed, including a 5–7-fold difference in peak serum concentration (Cmax) (mean ± standard deviation 15.70 ± 6.58 mg/L) and 12-h area under the serum concentration–time curve (AUC0–12) (96.73 ± 56.45 mg h/L), although the minimum inhibitory concentration (MIC) was similar amongst patients. In particular, variation amongst patients was found in the ratio of AUC0–24/MIC (range 31.66–216.82, mean 96.73) and the percentage of time that the serum concentration exceeded the MIC (T > MIC) (range 53.4–100%), two parameters used to predict linezolid efficacy. These variations highlight the importance of individual monitoring of linezolid PK/PD properties in critically ill patients. Furthermore, it was observed that regardless of AUC0–24/MIC and T > MIC values, the clinical and microbiological responses of patients were primarily affected by the individual's pathophysiological condition. In summary, these findings point to highly variable PK/PD properties of linezolid in severely ill patients, providing the rationale for targeting linezolid dosage to each individual patient's specific properties. An optimal dosage regimen based on individual PK/PD properties and pathophysiological conditions will help reduce the occurrence of resistance in Gram-positive bacteria.

Introduction

Severely ill patients in the Intensive Care Unit (ICU) are often at risk of developing multiresistant Gram-positive bacterial infections. In fact, the growing incidence of the appearance and spread of multiresistant Gram-positive infections in the ICU constitutes a significant health problem in many countries [1], [2]. In developed countries, up to 52% of ICU patients with bacteraemia have attributable mortality, more than two-fold that of the general population (23%) [1]. Incorrect use of antimicrobials is a major risk factor contributing to the generation of multidrug-resistant microorganisms, thereby resulting in increased morbidity, mortality and costs [3].

Linezolid is a synthetic antimicrobial agent of the oxazolidinone class of antibiotics used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. As the first US Food and Drug Administration (FDA)-approved oxazolidinone, linezolid has a broad spectrum of activity against Gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant pneumococci and vancomycin-resistant Enterococcus faecalis and Enterococcus faecium [4], [5], [6], [7]. Recent studies have indicated that linezolid treatment for high-incidence ICU infections, including pneumonia and catheter-related bacteraemia, resulted in favourable clinical and microbiological responses [8], [9], [10]. However, organisms resistant to linezolid have emerged [11], [12], which could result in an increase in attributable mortality and morbidity in ICU patients.

Increased knowledge of the pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics is useful for optimising dosage. In particular, the ratio of the area under the serum concentration–time curve over 24 h divided by the minimum inhibitory concentration (AUC0–24/MIC) as well as the percentage of time that the drug concentration exceeds the MIC (T > MIC) are considered predictive parameters for the antimicrobial effect of linezolid. Previous studies in animal models suggest that linezolid has an increased antimicrobial effect against Streptococcus pneumoniae when linezolid free-fraction PD parameters (fT > MIC and fAUC0–24/MIC) reach >40% and range from 48 to 147, respectively [13]. However, in the case of severely ill patients, multiple pathophysiological factors could interfere with the PK/PD properties of drugs.

For instance, patients with major thermal injuries had increased non-renal clearance, which may result in PK alteration [14]. In addition, previous work has shown that clearance of linezolid was increased and that there was larger individual variability in dialysis patients [15]. Indeed, studies performed in severely ill patients indicate that the probability of eradication and clinical cure at specific infection sites was correlated with AUC0–24/MIC and T > MIC values [16], [17]. Specifically, higher success rates for linezolid treatment may occur at AUC0–24/MIC values of 80–120 and T > MIC values >85% [16]. Therefore, the aim of this study was to evaluate the PK/PD profile of linezolid in severely ill Chinese ICU patients.

Section snippets

Patients and experimental design

Patients in the ICU of The First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China) were included in this study and were selected according to the following criteria: (i) males or non-pregnant females aged ≥18 years with suspected or documented Gram-positive infections, including meticillin-sensitive S. aureus, MRSA, enterococci and coagulase-negative staphylococci; (ii) no allergies to linezolid; (iii) not currently exposed to other drugs that may interfere with the analysis of

Study population

Characteristics of the eight critically ill patients with Gram-positive bacterial infections included in the study are shown in Table 1.

Pharmacokinetics

First, the dynamic serum concentration of linezolid was monitored at baseline and at 0.5, 1, 2, 3, 6, 10 and 12 h after the first administration (Fig. 1). As shown in Fig. 1, the linezolid concentration reached a peak serum concentration (Cmax) at 1.4 h following administration. The average Cmax of all the patients tested was 15.70 ± 6.58 mg/L. Thereafter, the

Discussion

The pharmacokinetics/pharmacodynamics of linezolid have been investigated extensively in laboratory models, healthy volunteers and stable patients. However, very limited information exists regarding PK/PD parameters for linezolid in the most critically ill patients [21]. However, in China this drug has been used for clinical patients since 2007 and there have been no studies of Chinese critically ill patients since its implementation. In this study, the PK/PD properties of linezolid in severely

Acknowledgments

The authors would like to thank the doctors and nurses of the ICU of The First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China) for their essential contributions to this study.

Funding: This study was supported by Research Funding, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University (Xi’an, China) (No. 2008YK28).

Competing interests: None declared.

Ethical approval: The study protocol was approved by the Hospital Ethics Committee.

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    These two authors contributed equally to this work.

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