Simultaneous quantification of linezolid, tinidazole, norfloxacin, moxifloxacin, levofloxacin, and gatifloxacin in human plasma for therapeutic drug monitoring and pharmacokinetic studies in human volunteers.

BACKGROUND: Linezolid may be administered in combination with norfloxacin, gatifloxacin, levofloxacin, moxifloxacin, and tinidazole for the treatment of various infections, such as urinary and respiratory tract infections, to improve the efficacy of the treatment or to reduce the duration of therapy. Knowledge of the antibiotic plasma concentrations combined with bacterial susceptibility evaluated in terms of minimum inhibitory concentration would optimize treatment efficacy while limiting the risk of dose-related adverse effects and avoiding suboptimal concentrations. METHODS: A new high-performance liquid chromatography assay method was developed and validated for determination of the above-mentioned drugs in small samples of human plasma. After protein precipitation with acetonitrile:methanol (1:1, vol/vol), satisfactory separation was achieved on a Hypersil BDS C18 column (250 × 4.6 mm, 5 µm) using a mobile phase comprising 20 mM sodium dihydrogen phosphate-2 hydrate (pH = 3.2) and acetonitrile at a ratio of 75:25, vol/vol; the elution was isocratic at ambient temperature with a flow rate of 1.5 mL/min. The ultraviolet detector was set at 260 nm. The validated method was applied to assay real plasma samples used for pharmacokinetic studies and therapeutic drug monitoring of the selected drugs. RESULTS: The assay method described was found to be rapid, sensitive, reproducible, precise, and accurate. Linearity was demonstrated over the concentration ranges as follows: 0.1-30 µg/mL for linezolid and tinidazole; 0.05-5 µg/mL for norfloxacin; and 0.1-10 µg/mL for moxifloxacin, levofloxacin, and gatifloxacin (mean r = 0.9999, n = 12). The observed within- and between-day assay precisions were within 12.5%, whereas accuracy ranged between 92.0% and 112% for all the analytes. The lower limit of quantification was 0.1 µg/mL for all the analytes except norfloxacin which was 0.05 µg/mL. CONCLUSIONS: This assay method was valid within a wide range of plasma concentrations and may be proposed as a suitable method for pharmacokinetic studies, therapeutic drug monitoring implementation, and routine clinical applications, especially for some populations of patients who receive a combination of these drugs.

Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits.

Investigation was carried out in adult New Zealand white rabbits to study the influence of curcumin pre-treatment on pharmacokinetic disposition of norfloxacin following single oral administration. Sixteen rabbits were divided into two groups of eight each consisting of either sex. Animals in group-I were administered norfloxacin (100 mg/kg body weight p.o), while animals in group-II received similar dose of norfloxacin after pre-treatment with curcumin (60 mg/kg body weight per day, 3 days, p.o). Blood samples were drawn from the marginal ear vein into heparin-coated vials at 0 (zero time), 5, 10, 15, 30 min and 1, 2, 4, 6, 12 and 24 h post-treatment. Plasma norfloxacin concentrations were determined by high performance liquid chromatography. The plasma concentration-time profile of norfloxacin was adequately described by a one-compartment open model. The pharmacokinetic data revealed that curcumin-treated animals had significantly (p < or = 0.05) higher area under the plasma concentration time curve and area under the first moment of plasma drug concentration-time curve. Prior treatment of curcumin significantly (p < or = 0.05) increased elimination half-life and volume of distribution of norfloxacin. Further treatment with curcumin reduced loading and maintenance doses by 26% and 24% respectively.

Treatment of encrusted cystitis caused by Corynebacterium group D2 with norfloxacin, ciprofloxacin, and teicoplanin in an experimental model in rats.

Oral doses of norfloxacin (80 mg/kg of body weight per day) and ciprofloxacin (25 and 80 mg/kg/day) and intramuscular doses of teicoplanin (5 mg/kg/day), all administered once a day for 10 days, were evaluated as a means of preventing encrusted cystitis caused by Corynebacterium group D2. Zinc disks dipped into a 24-h broth culture of these microorganisms were inserted into the bladders of female Wistar rats, and treatment was started 14 days after bacterial challenge. The appearance of encrusted cystitis was directly related to a documented urinary tract infection by these coryneforms (71.7 and 0% for rats with positive and negative urine cultures, respectively). All rats that died between days 18 to 43 after bacterial challenge presented very severe encrusted cystitis, which was prevented by teicoplanin and high doses of ciprofloxacin. Rats surviving up to day 44 after bacterial challenge were sacrificed; they presented a lower incidence of encrusted cystitis which was also less severe, with teicoplanin and a high dose of ciprofloxacin being more active in reducing the rate of positive cultures (78.8 and 65.7% reduction, respectively). All antibiotics and doses used were active in vivo at preventing encrusted cystitis by Corynebacterium group D2, but the best therapeutic effect was obtained with teicoplanin.

Correlates of therapeutic efficacy in experimental methicillin-resistant Staphylococcus aureus endocarditis.

Seventy animals with experimental aortic valve endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) were randomized to receive: no therapy; pefloxacin 40 or 80 mg/kg/day i.v.; or vancomycin 30 mg/kg/day i.v. Vancomycin caused a more rapid decrease in intravegetation MRSA counts than pefloxacin at 40 or 80 mg/kg/day (p less than 0.001, p less than 0.05, respectively, therapy day 3). The major correlate of therapeutic efficacy in this study was the significantly higher mean intravegetation levels achieved by vancomycin (16.8 +/- 6.1 micrograms/g) versus those attained by pefloxacin therapy at either 40 (1.6 +/- 0.13 micrograms/g) or 80 mg/kg/day (2.8 +/- 0.53 micrograms/g, p less than 0.005, p less than 0.025, respectively).

The diffusion of pefloxacin into bone and the treatment of osteomyelitis.

Pefloxacin was evaluated in the treatment of bone infections. A clinical trial was performed in 15 patients with chronic osteitis (5 Staphylococcus aureus, 5 Pseudomonas aeruginosa, 3 Serratia sp., 1 Proteus mirabilis, and a mixed infection with a Streptococcus faecalis and Escherichia coli). Patients were given pefloxacin 400 mg 12-hourly iv for 48 h followed by oral treatment. Bone biopsies from the iliac crest were carried out after at least seven days treatment, 2 h after the last dose. Serum levels were estimated at the same time. In 13 patients the pefloxacin levels were between 2 and 10 mg per g of bone and always greater than, or equal to, the MIC for the infecting organism. In 11 patients treated for six months and followed up for up to 14 months after the completion of treatment, the therapy was successful. In another two patients, the results were excellent with closure of fistulae, but there was only limited follow-up. There were two failures: in one (post-radiation osteitis) the infection persisted and in the other there was intolerance of the antimicrobial. In both cases there was no increase in the MIC of pefloxacin against the organisms. Three patients underwent operations for orthopaedic indications, after at least two months of treatment. Bone cultures from the initial focus remained sterile. Side-effects were mild.

Pefloxacin in acute exacerbations of chronic bronchitis.

Forty-three patients admitted to hospital with acute purulent exacerbations of chronic bronchitis were treated with 400 mg pefloxacin twice daily for ten days. The first 20 patients were given the first dose of the drug as a 60 min intravenous infusion. Serum and sputum concentrations of pefloxacin were measured microbiologically at intervals on the first treatment day and the sputum was cultured before, during, and after the course of pefloxacin. Two patients died from unrelated causes during the follow-up and one refused to continue treatment. All strains of Haemophilus influenzae and Branhamella catarrhalis were eradicated at end-of-treatment but eight strains of Streptococcus pneumoniae and three of Pseudomonas aeruginosa were cultured and the sputum remained purulent despite the pefloxacin. Peak serum concentrations averaged approximately 4.5 mg/l after the infusion and 5 mg/l on oral administration, the corresponding sputum concentrations being 3.8 and 4.6 mg/l, respectively. MICs for H. influenzae were 0.06 mg/l, or less. Mode MICs for the pre- and post-treatment strains of Str. pneumoniae were 4 and 16 mg/l, and the corresponding values for Ps. aeruginosa were 2 and 16 mg/l. The poor results in pseudomonas and pneumococcal infections could largely be explained by the degree of resistance among these organisms.