The pharmacokinetics of tazobactam (500 mg) administered intravenously alone were compared with the pharmacokinetics of tazobactam coadministered with piperacillin (4 g), and the penetration into an inflammatory exudate in six healthy males was studied. Piperacillin influenced the pharmacokinetics of tazobactam. The mean levels of tazobactam in plasma at 4 h were 0.6 ,ug/ml when it was given alone and 1.2 ,ug/ml when it was given with piperacillin (P = 0.0003). The mean total clearances of tazobactam were 203.5 and 134.2 ml/min (P = 0.035) when it was given alone and with piperacillin, respectively. There were no significant differences in the elimination half lives, areas under the concentration-time curve from 0 h to infinity, or volumes of distribution. Inflammatory exudate penetration was rapid, and the mean maximum levels of tazobactam attained were 6.4 and 11.3 ,Lg/ml when it was given alone or with piperacillin, respectively (P < 0.06). The mean percent penetration of tazobactam and the area under the concentration-time curve from 0 h to infinity in inflammatory exudate were greater when tazobactam was given with piperacillin. The mean 24-h urinary recoveries of tazobactam were 63.7% ± 7.9% when it was given alone and 56.8% ± 2.7% when it was given with piperacillin. The explanation for the differences in the pharmacokinetics of tazobactam when it was administered alone compared with those when it was given with piperacillin was unclear.Piperacillin, a broad-spectrum penicillin (13), is susceptible to hydrolysis by a range of P-lactamases, including the plasmid-mediated enzymes found in the members of the family Enterobacteriaceae and other genera such as Richmond and Sykes group III (12) and the enzymes commonly found in Staphylococcus aureus and Bacteroides fragilis. A number of P-lactamase inhibitors have been combined with other broad-spectrum penicillins, such as clavulanic acid with amoxicillin (8) and ticarcillin (1, 8) and sulbactam with ampicillin (6), which are protective of the active P-lactam.Tazobactam has been combined with piperacillin in a combination of 1:8 (9, 10), and preliminary studies suggest that the pharmacokinetics of these two agents are well matched. Results of preliminary studies in humans (3) and rats (16) suggest that the elimination of tazobactam is slower in the presence of piperacillin than when tazobactam is administered alone. In the present study, the pharmacokinetics and penetration into an inflammatory fluid of tazobactam alone and tazobactam combined with piperacillin were investigated in healthy volunteers by using a cantharidine-induced blister model (15). MATERIALS AND METHODSSix healthy adult male volunteers participated in the study after Ethical Committee approval and written informed consent were obtained. The volunteers were aged 22 to 38 years (mean age, 29.7 years), weighed between 66.2 and 82.5 kg (mean weight, 72.9 kg), and had a mean height of 1.77 m (range, 1.72 to 1.81 m). The body weights were within 10% for their age and height. Their medical histori...

The in-vitro activity of sparfloxacin (AT-4140), a new difluorinated quinolone, was compared with those of ciprofloxacin, temafloxacin and selected members of other groups of antimicrobial agents, against 651 recent distinct clinical isolates and strains with known mechanisms of resistance. Three strains of Chlamydia trachomatis were also studied. The MICs for 90% of the Enterobacteriaceae were between 0.06 and 1 mg/l; for Pseudomonas aeruginosa the MIC90 was 2 mg/l. Sparfloxacin was 16-fold more active against Acinetobacter spp. than ciprofloxacin. For Staphylococcus spp., Streptococcus, spp. and Enterococcus faecalis the MIC90 was between 0.25 and 1 mg/l; sparfloxacin was four-fold more active against Str. pneumoniae than ciprofloxacin. Ninety percent of strains of Haemophilus influenzae, Branhamella catarrhalis and Neisseria spp. were inhibited by less than 0.03 mg/l; for Bacteroides fragilis the MIC90 was 1 mg/l. The three strains of Chl. trachomatis were susceptible to 0.06-0.12 mg/l sparfloxacin, which was 16-fold more active than ciprofloxacin. There was cross resistance among the quinolones, but not between the quinolones and other groups of antimicrobials. The protein binding of sparfloxacin was 40% and serum had little effect on its activity.

A single 400-mg oral dose of sparfloxacin was given to each of six healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharides-induced inflammatory fluid, and urine over the subsequent 52 h. The mean peak concentration in plasma of 1.6 tag/ml was attained at a mean time of 2.7 h postdose. The mean peak concentration in inflammatory fluid of 1.3 ,g/ml was attained at a mean time of 5 Antibiotic assays were performed within 1 h of sample collection by using a plate diffusion method; the test organism was Escherichia coli 4004 (Bayer AG, Wuppertal, Germany); the medium used was Iso-Sensitest agar (pH 7.2; Oxoid Ltd., Basingstoke, United Kingdom). Standards were prepared by using human serum (Bradshaw Biologicals, Leicester, United Kingdom) for serum samples, 70% human serum (to simulate the protein content of the inflammatory fluid) in pH 7 phosphate buffer for inflammatory fluid samples, and phosphate buffer at pH 7 for urine samples. Samples were applied by filling 5-mm-diameter wells cut into the plates, which were then incubated in air overnight at 30°C. The coefficient of variation within the assay was 9.4% at 0.75 ,ug/ml and 6.5% at 0.1 ,g/ml. The coefficients of variation between assays were 5.9 and 7.9%, respectively.The lower limit of sensitivity was 0.1 pg/ml. The standard range for the assay was 0.06 to 1 ,g/ml, and the assay was linear between these values.Physical examinations and measurements of initial signs were repeated 3 and 7 days after the dose was administered.Pharmacokinetic analysis of the plasma samples was performed by using the GPHARM program (4), assuming a two-compartment model using a weighted least-squares algorithm. Pharmacokinetic analysis of blister fluid samples was based on standard graphical methods (3, 5). The area under the curve for time zero to infinity (AUCO,) was derived from the knowledge of the AUC for time zero to 52 h, the elimination constant, and the concentration at t = 52 h. RESULTSThe mean concentrations in plasma and inflammatory fluid obtained are shown in Fig.

The pharmacokinetics and penetration into a cantharidine-induced inflammatory exudate of meropenem was studied in six volunteers following a single 1-g intravenous dose. Concentrations in plasma, urine, and the inflammatory exudate were determined by a microbiological assay. The mean elimination half-life of meropenem in plasma was 1.1 h, with the concentration in plasma declining from a mean of 23.6 ,ug/ml at 1 h to 0.7 ,ug/mi at 6 h. The inflammatory fluid penetration was rapid (time to maximum concentration of drug in serum, 0.75 h), and the penetration was 111%. The recovery of meropenem in urine at 24 h was 65.4% of the administered dose.Meropenem is a new carbapenem antimicrobial agent which shares with imipenem an a-hydroxyethyl at C-4 but differs in that it has a methyl group at C-1 and a dimethylcarbamoylpyrrolidinethio side chain at C-3 (8). It is probable that the C-3 substituent accounts for the enhanced activity of this agent against gram-negative bacteria (3, 5). Of considerable importance is the fact that studies in animals suggest that meropenem is relatively more stable to hydrolysis by the renal dehydropeptidase I (DHP-I) (3) than imipenem, and preliminary studies in humans confirm this stability, suggesting that a DHP-I enzyme inhibitor such as cilastatin is not necessary (1). This property is probably associated with the methyl substituent at C4, as other agents with this structure have been associated with enhanced resistance to DHP-I (13).In this study we investigated the pharmacokinetics of meropenem in healthy volunteers, including the penetration of this agent into a chemically induced mild inflammatory exudate (14). (2) to give a line of best fit for the standard curve. The lower limit of sensitivity of the assay was 0.1 ,ug/ml. Three internal controls were used; and the mean coefficients of variation of the assay between days were 6.3% at 0.4 ,ug/ml, 6.8% at 3.0 ,ug/ml, and 5.9% at 20 ,ug/ml.Pharmacokinetic analysis of meropenem in serum was performed with the GPHARM program (4) by assuming a two-compartment model using the computational algorithm of peeling, with seven to eight points being fitted to the elimination phase. The structural model assumed a bolus injection. No corrections were applied for the 5-min infusion. Pharmacokinetic parameters for the inflammatory fluid were determined by standard graphical methods of individual volunteer data (12). This included the area under the concentration-time curve (AUC), which was calculated by a log-linear trapezoidal rule procedure. The percent penetration of meropenem into inflammatory exudate was calculated by comparing the AUC from 0 h to infinity (AUC0,C) in inflammatory exudate with that in serum. Figure 1 depicts the levels of meropenem in plasma and inflammatory fluid following the 1,000-mg bolus injection, and Table 1 shows the derived pharmacokinetic data. The RESULTS

BackgroundExtracts of chicory root have anti-inflammatory properties in vitro and in animal models of arthritis. The primary objective of this investigator-initiated, Phase 1, placebo-controlled, double blind, dose-escalating trial was to determine the safety and tolerability of a proprietary bioactive extract of chicory root in patients with osteoarthritis (OA). Secondary objectives were to assess effects on the signs and symptoms of this disorder.MethodsIndividuals greater than 50 years of age with OA of the hip or knee were eligible for trial entry. A total of 40 patients were enrolled in 3 cohorts and were treated with escalating chicory doses of 600 mg/day, 1200 mg/day and 1800 mg/day for 1 month. The ratio of active treatment to placebo was 5:3 in cohorts 1 and 2 (8 patients) each and 16:8 in cohort 3 (24 patients). Safety evaluations included measurement of vital signs and routine lab tests at baseline and the end of the treatment period. Efficacy evaluations at baseline and final visits included self-assessment questionnaires and measurement of the 25-foot walking time.ResultsIn the highest dose cohort, 18 patients who completed treatment per protocol were analyzed for efficacy. In this group, 13 patients showed at least 20% improvement in the defined response domains of pain, stiffness and global assessment: 9 of 10 (90%) patients randomized to active treatment with chicory and 4 of 8 (50%) patients randomized to placebo (P = 0.06). In general, the treatment was well-tolerated. Only one patient who was treated with the highest dose of chicory had to discontinue treatment due to an adverse event.ConclusionsThe results of this pilot study suggest that a proprietary bioactive extract of chicory root has a potential role in the management of OA and merits further investigation. Clinicaltrials.gov identifier: NCT 01010919.