Determination of Tissue Penetration and Pharmacokinetics of Linezolid in Patients with Diabetic Foot Infections Using
            <i>In Vivo</i>
            Microdialysis

Wiskirchen, Dora E.; Shepard, Ashley; Kuti, Joseph L.; Nicolau, David P.

doi:10.1128/aac.00445-11

Cited by 47 publications

(40 citation statements)

References 26 publications

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“…In contrast, there appears to be little difference between linezolid tissue and plasma concentrations in patients with diabetes [10,11]. Linezolid steady-state tissue concentrations determined using in vivo microdialysis in three patients with diabetes and severe bacterial lower limb infections were similar to plasma and bone concentrations within 1 h of initiating a linezolid infusion, indicating rapid and complete linezolid penetration into the interstitial space [10].…”

Section: Discussionmentioning

confidence: 77%

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus

Eckmann

Nathwani

Lawson

et al. 2015

Clinical Microbiology and Infection

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Suboptimal antibiotic penetration into soft tissues can occur in patients with poor circulation due to peripheral vascular disease (PVD) or diabetes. We conducted a real-world analysis of antibiotic treatment, hospital resource use and clinical outcomes in patients with PVD and/or diabetes receiving linezolid or vancomycin for the treatment of methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections (MRSA cSSTIs) across Europe. This subgroup analysis evaluated data obtained from a retrospective, observational medical chart review study that captured patient data from 12 European countries. Data were obtained from the medical records of patients ≥ 18 years of age, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Hospital length of stay and length of treatment were compared between the treatment groups using inverse probability of treatment weights to adjust for clinical and demographic differences. A total of 485 patients had PVD or diabetes and received treatment with either vancomycin (n = 258) or linezolid (n = 227). After adjustment, patients treated with linezolid compared with vancomycin respectively had significantly shorter hospital stays (17.9 ± 13.6 vs. 22.6 ± 13.6 days; p < 0.001) and treatment durations (12.9 ± 7.9 vs. 16.4 ± 8.3 days; p < 0.001). The proportions of patients prescribed oral, MRSA-active antibiotics at discharge were 43.2% and 12.4% of patients in the linezolid and vancomycin groups, respectively (p < 0.001). The reduction in resource use may result in lower hospital costs for patients with PVD and/or diabetes and MRSA cSSTIs if treated with linezolid compared with vancomycin.

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Section: Discussionmentioning

confidence: 77%

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus

Eckmann

Nathwani

Lawson

et al. 2015

Clinical Microbiology and Infection

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“…Regardless of Linezolid's low protein binding of about 30 %, it is still preferable to determine free concentrations, not only in plasma but also in other compartments, especially if these values are used as PK input for PK/PD analysis. Linezolid's protein binding is not concentration dependent but is quite variable between and within patients (Wiskirchen et al 2011 ). Therefore, in vivo microdialysis methods that measure only free concentrations in body fl uids over time provide valuable data.…”

Section: Linezolid Concentration At the Site Of Infectionmentioning

confidence: 99%

PK/PD of Oxazolidinones

Theuretzbacher

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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Linezolid, the fi rst available compound in the group of oxazolidinones, provides an effective alternative for the treatment of multidrug-resistant (MDR) Gram-positive bacteria. Linezolid's iv and oral availability expands its usage to the outpatient setting. In vitro, animal, and clinical studies have defi ned an appropriate PK/PD index for linezolid, its correlation with the dosage regimen, and clinical outcome. Due to linezolid's wide interpatient variability, some patients may have increased risk of inadequate drug exposure. As these patients are not readily identifi ed, therapeutic drug monitoring may be necessary for critically ill patient populations as well as in long-term treatment. As alternative antibiotics are scarce, resistance development requires special attention. The selection of linezolid resistant mutants, especially with enterococci, and the emergence of mobile resistance determinants that affect a wide range of other ribosome-targeting antibiotics, will most likely spur the emergence and spread of linezolid resistance. Increasing drug exposure in an attempt to reduce selection pressure may not be feasible due to concentration dependent toxicity. On the other hand, combination therapy may positively impact exposure/resistance relationship, but our knowledge in this area remains incomplete. Employing PK/PD models to defi ne dosing strategies and using antibiotic combinations to reduce selection pressure on linezolid-resistant mutants are major tasks yet to be undertaken.

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“…Bacterial density over time was determined by taking a sample from each model at predetermined time points (0, 1, 2, 4,6,8,10,12,14,18,24,26,30,36,38,42,48,50,56,60,62,66, and 72 h) and serially diluting it in normal saline. Aliquots of diluted samples were plated for quantitative culture utilizing Trypticase soy agar plates (100-mm diameter) with 5% sheep blood.…”

Section: Methodsmentioning

confidence: 99%

“…Comorbidities often present in patients with cSSSI, including diabetes mellitus and peripheral vascular disease, can result in altered and varied tissue perfusion to the site of infection, making it increasingly difficult to predict antibiotic concentrations at the site of infection (8)(9)(10)(11)(12). Previous studies have demonstrated vancomycin's ability to penetrate the extravascular interstitial fluid (9,13,14).…”

mentioning

confidence: 99%

In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure

Hamada

Kuti

Nicolau

2016

Antimicrob Agents Chemother

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Vancomycin is considered a first-line antibiotic for complicated skin and skin structure infections (cSSSI) because of the risk of methicillin-resistant Staphylococcus aureus (MRSA). The vancomycin exposure of tissue can vary widely in patients with cSSSI, yet most models test only the average exposure. The in vitro pharmacodynamic model was used to simulate three tissue exposure levels attained by administering vancomycin at 1 g every 12 h (q12h), based on the median (50th), 25th, and 10th percentile tissue area under the concentration-time curve (AUC) values observed during an in vivo microdialysis study of diabetic patients. Four clinical isolates (two of MRSA [vancomycin MIC, 1 and 2 g/ml] and two of methicillin-susceptible S. aureus [MSSA] [MIC, 1 and 2 g/ml]) were evaluated. Experiments were performed over 72 h in duplicate. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) during the final 24-h dosing interval (48 to 72 h) (AUBC 48 -72 ) was calculated. Reductions in the 72-h number of CFU/ml and AUBC 48 -72 at the different exposure levels were compared. Target tissue vancomycin exposure levels for the 50th (AUC 0 -12 , 102.0 ؎ 9.1 g · h/ml), 25th (AUC 0 -12 , 44.3 ؎ 1.8 g · h/ml), and 10th (AUC 0 -12 , 25.3 ؎ 3.1 g · h/ml) percentiles were obtained in all studies. No differences in the 72-h number of CFU or AUBC were observed between exposure levels when all of the isolates were analyzed together. However, for the two MRSA isolates, the 10th percentile exposure level achieved a lower 72-h number of CFU/ml (؊1.4 ؎ 0.4 log 10 CFU/ml, P ‫؍‬ 0.007) and a greater AUBC 48 -72 (97.1 ؎ 20.0 log 10 CFU · h/ml, P ‫؍‬ 0.011) than the higher exposure levels. The majority of the tissue exposure levels achieved with a vancomycin dosing regimen of 1 g q12h resulted in substantial killing of MSSA and MRSA; however, the lowest exposure levels observed in a minority of the population may explain the poor vancomycin response. C omplicated skin and skin structure infections (cSSSI) are among the most common infections in hospitalized patients (1, 2). These infections are frequently caused by Gram-positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes (2). Methicillin-resistant S. aureus (MRSA) can be present in as many as 60% of cases (3, 4) and has been linked with outcomes worse than those of methicillin-susceptible S. aureus (MSSA) infections (5, 6). As a result of this epidemiology and the long history of vancomycin use, it is considered a first-line antibiotic for the empirical treatment of cSSSI (2, 7).In addition to possessing in vitro microbiological activity against the causative pathogen, the treatment antibiotic must be able to penetrate to the site of infection with sufficient exposure to kill the organism. Comorbidities often present in patients with cSSSI, including diabetes mellitus and peripheral vascular disease, can result in altered and varied tissue perfusion to the site of infection, making it increasingly difficult to predict a...

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Determination of Tissue Penetration and Pharmacokinetics of Linezolid in Patients with Diabetic Foot Infections Using In Vivo Microdialysis

Cited by 47 publications

References 26 publications

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus

PK/PD of Oxazolidinones

In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure

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