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Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections

https://doi.org/10.1016/j.ijantimicag.2010.03.007Get rights and content

Abstract

The present study aimed at assessing unbound extracellular concentrations of linezolid in inflamed soft tissue and bone of diabetic patients suffering from severe bacterial foot infections. Linezolid was administered intravenously twice daily at a dosage of 600 mg. At steady-state conditions, the microdialysis technique was utilised to sample serially interstitial space fluid from inflamed subcutaneous adipose tissue and metatarsal bone from 0–8 h post dose in three representative patients. Mean peak concentrations of free linezolid in plasma, healthy subcutis, inflamed subcutis and cancellous bone were 16.6 ± 3.0, 15.5 ± 2.5, 15.8 ± 2.8 and 15.1 ± 4.1 mg/L, respectively. The degree of tissue penetration as expressed by the ratio of the area under the concentration–time curve of free linezolid from 0–12 h (fAUC0–12) in tissue to the fAUC0–12 in plasma was 1.32 ± 0.09, 1.12 ± 0.22 and 1.09 ± 0.11 for healthy subcutis, inflamed subcutis and bone, respectively. Based on currently available pharmacokinetic/pharmacodynamic targets, we conclude that linezolid administered at 600 mg twice daily may be considered an effective treatment in diabetic patients suffering from bacterial foot infection complicated by osteomyelitis.

Introduction

In patients with diabetes, serious complications such as peripheral neuropathy combined with bacterial foot infections account for a large number of hospital stays and are a major cause of non-traumatic amputations of the lower limb. Appropriate management of these complications often requires intravenous (i.v.) administration of potent antimicrobial agents supported by surgical intervention. However, measures like these require co-ordinated interdisciplinary work between surgeons, clinicians, clinical pharmacologists and microbiologists because of uncertainty regarding resistance rates, rapidly evolving outbreaks of multiresistant bacterial strains following long-term therapy with broad-spectrum antibiotics, and incomplete knowledge of drug tissue penetration. Thus, choosing the right antimicrobial agent is essential in these situations.

Linezolid has demonstrated potent in vitro activity against problematic bacteria such as meticillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-resistant Gram-positive bacteria [1]. The ability of linezolid to penetrate into the extracellular space fluid of soft tissues is well documented in healthy volunteers and critically ill patients [2], [3]. However, the rate and extent of penetration of linezolid into bone tissue is controversial in the medical literature [4], [5], [6], [7].

Thus, in the present study we aimed to determine the ability of linezolid to penetrate into bone and the interstitium of inflamed subcutaneous adipose tissue in a small representative cohort of diabetic patients suffering from severe diabetic foot infection (DFI). Recently, the microdialysis technique, which was used in this study, was also employed to assess unbound concentrations of linezolid in cancellous bone tissue of healthy pigs as well as fosfomycin concentrations in healthy and inflamed tissue of diabetic patients presenting with bacterial foot infections complicated by osteomyelitis [7], [8].

Section snippets

Subjects and methods

This study was performed at the Division of Plastic Surgery, Department of Surgery, Landeskrankenhaus Universitätsklinikum Graz (State Hospital University Clinic of Graz, Graz, Austria). Analytical work was performed at the laboratory of J&P Medical Research Ltd. (Vienna, Austria).

Results

No adverse events related to the study drug or to the microdialysis procedure were observed. Key pharmacokinetic parameters of linezolid in healthy and inflamed subcutaneous adipose tissue and in metatarsal bone are summarised in Table 1. Pharmacokinetic profiles are depicted in Fig. 1.

The degree of tissue penetration as expressed by the free (f) tissue to plasma ratios of the AUC from 0–12 h (fAUC0–12tissue/fAUC0–12plasma) was 1.32 ± 0.09, 1.12 ± 0.22 and 1.09 ± 0.11 for healthy subcutis, inflamed

Discussion

MRSA infections associated with unfavourable outcomes are becoming increasingly problematic in diabetic foot clinics [10]. As moderate-to-severe DFI is frequently linked to osteomyelitis of adjacent bones, the ability of certain antibiotic agents to penetrate bone tissue needs to be taken into consideration when aiming for successful treatment of DFI. However, the vast majority of presently available pharmacokinetic data regarding bone tissues focuses on tissue homogenates, which provide no

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Data from this study will be presented as an abstract and poster at the 4th Austrian Conference on Infectious Diseases, 5–8 May 2010, Saalfelden, Austria.

1

These authors contributed equally to this work.

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