Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion☆
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.
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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)
The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus
Clin Microbiol Infect
(2006)- et al.
Relationship between pharmacokinetics and pharmacodynamics of beta-lactams and outcome
Clin Microbiol Infect
(2004) - et al.
Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials
Lancet Infect Dis
(2005) - et al.
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine
Chest
(1992) - et al.
Continuous infusion of β-lactam antibiotics in severe infections: a review of its role
Int J Antimicrob Agents
(2007) - et al.
High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency
Int J Antimicrob Agents
(2006) - et al.
Emergence of methicillin-resistant Staphylococcus aureus with intermediate glycopeptide resistance: clinical significance and treatment options
Drugs
(2001) - et al.
Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study
J Antimicrob Chemother
(2004) - et al.
Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme
Clin Pharmacokinet
(2003) - et al.
Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial
Clin Pharmacokinet
(2003)
Efficacy of linezolid in treatment of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus
Antimicrob Agents Chemother
Antibiotic pharmacokinetic and pharmacodynamic considerations in critical illness
Intensive Care Med
Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability
Clin Pharmacokinet
Down-modulation of granulocyte macrophage-colony stimulating factor receptor on monocytes during human septic shock
Crit Care Med
Sepsis-induced apoptosis causes progressive profound depletion of B and CD4 + T lymphocytes in humans
J Immunol
Monocyte deactivation in septic patients: restoration by IFN-gamma treatment
Nat Med
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Presented in part at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 16–19 December 2005, Washington, DC.