Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion

https://doi.org/10.1016/j.ijantimicag.2007.09.009Get rights and content

Abstract

Pharmacokinetics and pharmacodynamics are significantly altered in critically ill septic patients and the risk of prolonged periods with concentrations below the minimum inhibitory concentration (MIC) and of low area under the serum concentration–time curve/MIC (AUC/MIC) ratios is of concern. We compared the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid administered by intermittent or continuous infusion in critically ill septic patients. Patients were divided into two groups: intermittent infusion (Group I) (600 mg/12 h); or continuous infusion (Group C) (300 mg intravenous loading dose +900 mg continuous infusion on Day 1, followed by 1200 mg/daily from Day 2). Linezolid serum levels were monitored for 72 h and microbiological data were collected. The clinical outcome was monitored. Sixteen patients completed the study. MICs of susceptible pathogens were 2 mg/L for 80% of the isolates. In Group I, linezolid trough serum levels (Cmin) varied widely and were below the susceptibility breakpoint (4 mg/L) during the study period; in 50% of patients Cmin was <1 mg/L. In Group C, mean linezolid serum levels were more stable and, starting from 6 h, were significantly higher than Cmin levels observed in Group I and were always above the susceptibility breakpoint. Time that the free drug concentration was above the MIC (Tfree > MIC) of > 85% was more frequent in Group C than in Group I (P < 0.05). Finally, with continuous infusion it was possible to achieve AUC/MIC values of 80–120 more frequently than with intermittent infusion (P < 0.05). According to PK/PD parameters, continuous infusion has theoretical advantages over intermittent infusion in this population of patients.

Introduction

Linezolid, an oxazolidinone derivative, has been shown to be a valid therapeutic alternative to glycopeptides against multiresistant Gram-positive strains, which are particularly frequent in Intensive Care Units (ICUs) [1], [2], [3]. Consistent with in vitro findings, linezolid is a time-dependent antimicrobial agent with persistent post-antibiotic effect [4]. The pharmacokinetic/pharmacodynamic (PK/PD) parameters best suitable to define its activity are time with serum concentrations higher than the minimum inhibitory concentration (T > MIC) and area under the serum concentration–time curve/minimum inhibitory concentration (AUC/MIC) ratio [5]. In vitro time–kill experiments have demonstrated linezolid to be a bacteriostatic antimicrobial agent with T > MIC of at least 40% being predictive of efficacy. However, in an in vivo model of endocarditis, when serum levels higher than the MIC were maintained for >75% of the dosing interval, linezolid also demonstrated bactericidal activity [6]. Linezolid serum levels with T > MIC of >50% for pathogens with MICs of 2–4 mg/L can be obtained by administration of 600 mg every 12 h (q12h) in healthy volunteers [7], suggesting that continuous infusion (the best antimicrobial administration modality for most time-dependent antibiotics as it prolongs effective serum levels [8]) may not be essential. However, in critically ill septic patients alterations in PK parameters, mostly due to an increase in the volume of drug distribution (V) and/or drug clearance (CL), are frequently observed, and suboptimal serum and tissue concentrations are achieved when drugs are administered at the same dosage studied in healthy volunteers or in less seriously ill patients (for review see [9], [10]). Moreover, since critically ill septic patients are often immunosuppressed [11], [12], [13], antimicrobials with bactericidal activity may be more effective than those exhibiting only bacteriostatic activity. On the basis of these considerations, it is important to optimise PK/PD parameters. Accordingly, in one study conducted in seriously ill adult patients, higher success rates were achieved when T > MIC exceeded 85% and AUC/MIC values were between 80 and 120 [5].

To date, few data are available regarding the PK/PD of linezolid in critically ill septic patients and the drug is thus administered according to data obtained in healthy subjects or other types of patients. However, there is high interindividual variability in linezolid interstitial concentrations in patients with sepsis or septic shock, suggesting that a scheme of more frequent daily dosing would be more appropriate in these patients [14]. Therefore, in this study we compared two different modalities of linezolid administration (intermittent versus continuous infusion) in critically ill septic patients to establish which is better according to the PK/PD profile.

Section snippets

Patients and methods

This was a prospective, open-label, randomised study performed in a university hospital ICU. Written informed consent was obtained from all study participants.

Results

Between February 2005 and March 2006, 18 septic ICU patients were considered eligible for the study. One patient died before completing serum sample collection and one was excluded because he developed renal failure with ClCR < 40 mL/min during the sampling period. Therefore, data relating to 16 patients (8 per group) were available for analysis.

Clinical and demographic parameters are reported in Table 1. The two groups of patients were similar in terms of demographic characteristics, organ

Discussion

This study shows that administration of 600 mg of linezolid q12h to our critically ill patients is characterised by wide fluctuations in serum levels, with trough serum concentrations always below the susceptibility breakpoint (4 mg/L) and in one-half of the patients even below 1 mg/L. In contrast, serum concentrations during continuous infusion were always above the susceptibility breakpoint. According to time–kill experiments, linezolid is a time-dependent antimicrobial and the T > MIC and AUC/MIC

References (33)

  • C.F. Dailey et al.

    Efficacy of linezolid in treatment of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus

    Antimicrob Agents Chemother

    (2001)
  • R. Mehrotra et al.

    Antibiotic pharmacokinetic and pharmacodynamic considerations in critical illness

    Intensive Care Med

    (2004)
  • F. Pea et al.

    Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability

    Clin Pharmacokinet

    (2005)
  • C. Pangault et al.

    Down-modulation of granulocyte macrophage-colony stimulating factor receptor on monocytes during human septic shock

    Crit Care Med

    (2006)
  • R.S. Hotchkiss et al.

    Sepsis-induced apoptosis causes progressive profound depletion of B and CD4 + T lymphocytes in humans

    J Immunol

    (2001)
  • W.D. Döcke et al.

    Monocyte deactivation in septic patients: restoration by IFN-gamma treatment

    Nat Med

    (1997)
  • Cited by (145)

    • Simultaneous determination of a novel oxazolidinone anti-tuberculosis OTB-658 and its metabolites in monkey blood by LC-MS/MS

      2021, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
    • Dosage regimen and toxicity risk assessment of linezolid in sepsis patients

      2020, International Journal of Infectious Diseases
    View all citing articles on Scopus

    Presented in part at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 16–19 December 2005, Washington, DC.

    View full text