Diagnosis and interventions in lower respiratory tract infections.

In the elderly and in immunocompromised patients, respiratory tract infections are still a major cause of morbidity and mortality. The choice of a specific antibiotic treatment in pneumonia depends on the identification of the causative pathogen or on a judgment concerning the probable causative micro-organism. This judgment should be based on all the information obtained from clinical signs and symptoms, laboratory investigations of sputum and blood, and the pattern of infiltrations on chest X-ray. Different causative pathogens can be expected in bacterial and "atypical" community-acquired pneumonia than in hospital-acquired pneumonia. For the same reason, immunocompetent and immunocompromised patients have to be distinguished from each other. In chronic obstructive pulmonary disease, bronchial defenses will be impaired. Exacerbations can result from different causes, including infections of the bronchial mucosa. Most of these infections are of viral origin. Exacerbated pulmonary disease will result from bacterial bronchitis only in some patients. It is often difficult to assess the diagnosis "bacterial bronchitis." Evaluation of the effect of antibacterial treatment in exacerbated pulmonary disease is also difficult. Therapeutic interventions for these clinical conditions have to be directed primarily toward restoring or improving pulmonary host-defense factors. Fluoroquinolones, including lomefloxacin, have been shown to be effective in the treatment of lower respiratory tract infections caused by susceptible bacteria. Lomefloxacin presents a number of advantages: the drug has good bioavailability after oral and parenteral administration and penetrates well into bronchial secretions and lung tissue. In addition, lomefloxacin has no influence on the metabolic clearance of the methylxanthines theophylline and caffeine, which has been demonstrated for enoxacin, ciprofloxacin, and pefloxacin.

The effect of multiple-dose oral lomefloxacin on theophylline metabolism in man.

Single-dose plasma pharmacokinetics of theophylline (6 mg/kg intravenously) and renal excretion of theophylline and its metabolites, resulting from 8-oxidation and N-demethylation, were investigated in eight healthy volunteers before and at day 3 of concomitant oral administration of the quinolone derivative lomefloxacin (400 mg twice daily). Plasma samples were collected until 24.5 h, and urine samples were collected until 72 h after theophylline administration. The concentrations of theophylline and the major metabolites, resulting from N-demethylation and 8-oxidation, were measured utilizing a high-pressure liquid chromatography (HPLC) technique. No significant changes in theophylline half-life, volume of distribution, protein binding, total body clearance, or renal clearance were noted. In addition, renal excretion of unchanged theophylline, the products of the N-demethylation, 3-methylxanthine, and 1-methyluric acid, and the product of the 8-oxidation, 1,3-dimethyluric acid, were not altered by simultaneous administration of lomefloxacin. Orally administered lomefloxacin is absorbed quickly and to a high extent. During administration of 400 mg twice daily, plasma concentrations reached are well above minimum inhibitory concentration (MIC) values of pathogens that are frequently isolated in lower respiratory tract infections. This study shows that lomefloxacin in a twice daily dose of 400 mg does not effect theophylline metabolism. Lomefloxacin and theophylline can be coadministered without concern about effects of lomefloxacin on theophylline pharmacokinetics.

Drug-drug interactions affecting fluoroquinolones.

In a three-week study, the metabolism of the bronchodilator theophylline and its major metabolites formed by C-8 oxidation (1,3-dimethyluric acid) and N-demethylation (3-methylxanthine and 1-methyluric acid) was investigated in two healthy volunteers. Metabolic studies were performed following intravenous infusion of a single 6 mg/kg dose of aminophylline. During Week 1, theophylline was given alone (blank period), and during Weeks 2 and 3 it was given during oral coadministration of ofloxacin and enoxacin, respectively. Dosage of each quinolone was 200 mg twice daily for four days, starting three days prior to the theophylline infusion. During enoxacin coadministration, elimination half-lives of theophylline increased from 8.7 to 17.4 hours and from 6.1 to 12.3 hours, respectively. Total body clearance of theophylline decreased in both volunteers, whereas renal clearance did not alter. From this it was concluded that the decreased elimination results from a reduced metabolic clearance. During enoxacin coadministration, the formation of the metabolites 1-methyluric acid and 3-methylxanthine clearly was decreased, whereas the formation of 1,3-dimethyluric acid was less affected compared with the blank period. Interference with theophylline disposition by enoxacin is based predominantly on inhibition of microsomal N-demethylation. Ofloxacin comedication did not cause a change in the plasma parameters or renal excretion of theophylline and its metabolites compared with the blank period.