The pharmacokinetics of multiple-dose linezolid were determined following administration of five 600-mg oral doses given every 12 h to each of six healthy male volunteers. Concentrations of the drug were determined in plasma and inflammatory blister fluid using high-pressure liquid chromatography. A mean peak concentration in plasma of 18.3 g/ml (standard deviation [SD], 6.0) was attained at a mean time of 0.7 h (SD, 0.3) after the final dose. The penetration into the inflammatory fluid was 104% (SD, 20.7). A mean peak concentration of 16.4 g/ml (SD, 10.6) was attained in the inflammatory fluid at 3 h (SD, 0.6) after the final dose. The elimination half-life from serum and inflammatory fluid was 4.9 (SD, 1.8) and 5.7 (SD, 1.7) h, respectively. The area under the concentration-time curve in plasma and blister fluid was 140.3 (SD, 73.1) and 155.3 (SD, 80.1) g ⅐ h/ml, respectively. These data suggest that linezolid has good tissue penetration, and we can predict that it will be successful in the treatment of a variety of gram-positive infections.Linezolid belongs to a new class of antibiotics, the oxazolidinones. It acts by selectively inhibiting the initiation of bacterial protein synthesis and has been shown to possess in vitro and in vivo activity against gram-positive organisms, including Streptococcus pneumoniae strains that are resistant to penicillin, methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium with phenotypes Van A, B, and C (2,6,9,11,13). The aim of this study was to assess the pharmacokinetics and tissue penetration of linezolid following multiple oral doses of 600 mg. A blister technique was used to assess tissue penetration since blister fluid mimics inflammatory exudate and hence is a model of likely pharmacokinetics at the site of infection (10). MATERIALS AND METHODSSubjects. Eight healthy volunteers, with a mean age of 29.6 years (standard deviation [SD], 8.7), a mean weight of 78.6 kg (SD, 7.1), and a mean height of 180.4 cm (SD, 14.1), gave written informed consent to participate in this study. One volunteer was unable to attend the actual study day due to febrile illness; therefore, only seven participants were studied. Exclusion criteria for the trial included any history of significant illness or atopy, recent participation in another drug trial, and use of prescription or nonprescription drugs (particularly monoamine oxidase inhibitors) within 14 or 7 days of the study, respectively. All volunteers underwent a full medical history, an examination and a full blood count, clotting, renal, and liver function tests, and urinalysis and a urine drugsof-abuse screen, all of which were normal. The hospital's ethics committee granted approval for this study.Drug administration. The volunteers were given one 600-mg linezolid tablet every 12 h for 2.5 days (a total of five doses). The first dose was given in the hospital with the physician present for the first hour. Doses two and three were self-administered by the volunteer at home. This was confirmed b...

The lipopeptide antimicrobial daptomycin was administered intravenously at a dose of 4 mg/kg of body weight to seven healthy male volunteers. The concentrations of daptomycin in plasma, cantharidin-induced inflammatory fluid, and urine were measured by a microbiological assay. The mean ؎ standard deviation peak concentrations in plasma and inflammatory fluid were 77.5 ؎ 8.3 and 27.6 ؎ 9.5 g/ml, respectively; the mean terminal elimination half-lives were 7.74 and 13.2 h, respectively. The overall penetration of total drug into the inflammatory fluid (measured by ratio of the area under the concentration-time curve from 0 to 24 h for inflammatory fluid compared with that for plasma) was 68.4%. The mean urinary recovery over 24 h was 59.7%.Daptomycin is a cyclic lipopeptide antimicrobial with in vitro activity against gram-positive organisms including vancomycinresistant enterococci, methicillin-resistant staphylococci, and "heterodrug-resistant" glycopeptide- , abstr. 2293, p. 183, 2000). In vitro studies to date have shown that daptomycin is rapidly bactericidal, with treatment with daptomycin resulting in greater than 3 log reductions in 8 h for methicillin-resistant S. aureus, vancomycin-resistant enterococci, and glycopeptideresistant S. aureus (1). Daptomycin is being investigated against complicated skin and skin structure infections in two large phase III trials by use of a dose of 4 mg/kg of body weight every 24 h. There is little recent published information on the pharmacokinetics of this compound; hence, the aim of the present study was to investigate the pharmacokinetics of daptomycin following the administration of a single intravenous dose of 4 mg/kg. In addition, a cantharidin-induced inflammatory blister technique was used to assess the penetration of this compound into an inflammatory exudate (2). MATERIALS AND METHODSSeven healthy male volunteers (age range, 21 to 28 years; mean weight, 78.5 kg; weight range, 70.1 to 95.2 kg; mean height, 179.8 cm; height range, 173 to 195 cm) gave written informed consent following hospital ethical committee approval of the protocol. Exclusion criteria included atopy, liver and renal disease, and significant central nervous system pathology.All volunteers underwent a full medical history examination and routine hematological and biochemical investigations. On the evening prior to the study two 0.2% cantharidin-impregnated plasters (1 by 1 cm) were placed on each subject's forearm to induce inflammatory blister formation. The volunteers received only clear fluids in the 8 h prior to administration of the plasters.The volunteers received daptomycin at a dose of 4 mg/kg of body weight administered in 50 ml of normal saline over 30 min. For the next 2 h only clear fluids were taken by mouth, after which a light diet was allowed. Blood samples were obtained at time zero (at the beginning of infusion), 0.25 h (halfway through the infusion), 0.5 h (at the end of the infusion), and 0.58, 0.75, 1, 1.5, 2, 4, 6, 8, 12, and 24 h after the infusion. Blister fluid was samp...

The pharmacokinetics and tissue penetration of gemifloxacin were determined during a 24 h period following oral administration of a single 320 mg dose to each of 10 healthy male volunteers. Concentrations of the drug in plasma, inflammatory blister fluid and urine were determined using a microbial assay. A peak plasma concentration (mean +/- S.D.) of 2.33 +/- 0.5 mg/L was reached at 1.20 +/- 0.4 h. Mean penetration into inflammatory fluid was 61.19 +/- 10.4%. A peak concentration of 0.74 +/- 0.3 mg/L was reached in the inflammatory fluid at a mean time of 3.40 +/- 1.7 h. The mean elimination half-life from serum and inflammatory fluid was 5.94 +/- 0.4 and 6.27 +/- 2.4 h, respectively. Urinary excretion of the drug at 24 h post-dose was 36.11% of the total given. These results demonstrate that gemifloxacin penetrates into the site of inflammation and reaches sufficient concentrations to inhibit many pathogens.

The pharmacokinetics of a single dose of BMS 284756 were determined following oral administration of a 600-mg dose to eight healthy male volunteers. Concentrations of the drug were measured in plasma and a cantharidine-induced inflammatory exudate by a microbiological assay. The mean peak concentration in plasma of 10.4 g/ml (standard deviation [SD], 1.3 g/ml) was attained at a mean time of 1.2 h (SD, 0.5 h) after the dose. The penetration into the inflammatory exudate was 82% (SD, 15.7%). A mean peak concentration of 7.2 g/ml (SD, 2.4 g/ml) was attained in the inflammatory exudate at 5.3 h (SD, 1.5 h). The elimination half-lives from plasma and inflammatory fluid were 9.8 h (SD, 1.1 h) and 8.5 h (SD, 1.9 h), respectively. The areas under the concentration-time curves for plasma and inflammatory fluid were 96.7 g ⅐ h/ml (SD, 10.3 g ⅐ h/ml) and 77.9 g ⅐ h/ml (SD, 19.2 g ⅐ h/ml), respectively.BMS 284756 (T-3811ME) is a novel, orally and parenterally available, 6-des-fluorinated quinolone antimicrobial which displays a high degree of in vitro activity against a broad range of bacterial pathogens (1, 3). Preliminary data (D. A. Gajjar, D. M. Grasela, A. Bello, Z. Ge, and L. Christopher, 40th ICAAC, abstr. 2259, p. 36, 2000 suggest that the pharmacokinetics of this agent are dose related and that the elimination half-life supports a once-daily dosing regimen. There is little information on the ability of this agent to penetrate tissues. Here, we studied the pharmacokinetics of a single 600-mg oral dose in healthy adult volunteers and measured penetration into a cantharadine-induced inflammatory exudate (5).Eight healthy male volunteers, with a mean age of 28.1 years (range, 22 to 41 years), a mean weight of 78.4 kg (range, 73.6 to 84.9 kg), and a mean height of 178 cm (range, 173 to 185 cm) gave written informed consent to participate in this study following hospital ethics committee approval. Exclusion criteria for the study included any history of significant illness or atopy, recent participation in another drug trial, and the use of prescription or nonprescription drugs within 7 days of the study. All volunteers underwent a full medical history, examination, hematological and biochemical profiles, urinalysis, and drugsof-abuse screening prior to enrollment, all of which were normal. A 12-lead electrocardiogram (ECG) was performed on enrollment, within 24 h prior to dosing and 24 h postdose. The hematological and biochemical profiles were similarly repeated.The volunteers received 600 mg of BMS 284756 (as 200-plus 400-mg tablets) on the morning of the study following a 12-h overnight fast. The tablets were taken with 240 ml of water. The volunteers received only clear fluids for 2 h thereafter, and then a full diet was resumed.Two 0.2% cantharidine-impregnated plasters were placed on the volunteers' forearms about 12 h prior to drug administration, in order to induce blister formation. Blood (10 ml) and inflammatory fluid (50 l) samples were taken at 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 h postdose.A microbiolog...