ru-66647 and Chronic-Disease

To demonstrate equivalence in the clinical efficacy of telithromycin vs clarithromycin treatment of outpatients with acute exacerbations of chronic bronchitis (AECB), and to compare the tolerability and respiratory-related health-care resource utilization associated with these treatment regimens.. A randomized, double-blind, multicenter, clinical study was conducted at 105 centers in 14 countries. Adult outpatients (age > or = 30 years) received oral telithromycin, 800 mg qd for 5 days (n = 270), or oral clarithromycin, 500 mg bid for 10 days (n = 282), for the treatment of AECB. Clinical and bacteriologic outcomes were assessed at the posttherapy/test-of-cure (TOC) visit (days 17 to 24; per-protocol population). Health-care resource utilization data were collected for each patient by investigators blinded to study medication up to the late posttherapy visit (days 31 to 36).. Clinical cure rates at the posttherapy/TOC visit were comparable between the groups (telithromycin, 193 of 225 patients [85.8%]; clarithromycin, 206 of 231 patients [89.2%]); bacteriologic outcome was satisfactory for 59 of 72 telithromycin-treated patients (81.9%) vs 63 of 76 clarithromycin-treated patients (82.9%). Health-care resource utilization assessed up to the late posttherapy visit was lower in the telithromycin treatment group than the clarithromycin treatment group, with significantly fewer hospitalizations for respiratory-related causes (one hospitalization vs eight hospitalizations for a total of 4 inpatient days vs 39 inpatient days, respectively), significantly fewer AECB-related emergency department visits (0 vs 8), and fewer unscheduled outpatient visits (11 vs 18). Fewer telithromycin-treated patients reported days lost from work (21 of 91 patients [23.1%]; 133 days) compared with those receiving clarithromycin (30 of 98 patients [30.6%]; 141 days). Telithromycin was well tolerated; adverse events considered possibly related to study medication were reported by 61 of 269 patients (22.7%) and 100 of 280 patients (35.7%) receiving telithromycin and clarithromycin, respectively.. In this study, 5-day telithromycin treatment was as effective and well tolerated as 10-day clarithromycin treatment for patients with AECB, and was associated with a reduced utilization of health-care resources.

Topics: Acute Disease; Adult; Aged; Bronchitis; Chronic Disease; Clarithromycin; Disease Progression; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Health Care Rationing; Humans; Ketolides; Male; Middle Aged; Single-Blind Method; Smoking; Vital Capacity

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co-administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI.

Topics: Area Under Curve; Carbamates; Chronic Disease; Computer Simulation; Drug Interactions; Humans; Ketolides; Kidney Diseases; Models, Biological; Piperazines; Piperidines; Purines; Sildenafil Citrate; Sulfones

The 14-membered macrolides, such as clarithromycin (CAM) and erythromycin (EM), are effective against diffuse panbronchiolitis. However, there have been no studies on the effects of telithromycin (TEL) on chronic respiratory infection in vivo. In this study, we determined the effect of TEL on an experimental murine model of chronic respiratory infection caused by Pseudomonas aeruginosa with biofilm formation. TEL significantly reduced the number of viable bacteria but had no effect on the proliferation of lymphocytes. In contrast, CAM decreased the number of lymphocytes but had no effect on the number of viable bacteria in the lung. These results suggest that TEL and CAM have different effects on chronic respiratory infection caused by P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Chronic Disease; Clarithromycin; Disease Models, Animal; Ketolides; Lung; Lymphocytes; Male; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

Mycoplasma pneumoniae infection has been associated with chronic lung disease. Treatment of chronic pulmonary mycoplasmosis has not been well investigated. BALB/c mice were intranasally inoculated once with M. pneumoniae or with sterile media (uninfected controls). Infected mice were treated with telithromycin or placebo daily for 10 days in the chronic phase of disease (18 months after inoculation). Mice (n=43) were evaluated before therapy and 1 day after completion of telithromycin. Treatment of infected mice with telithromycin at 18 months after infection significantly reduced chronic pulmonary histological inflammation compared with infected mice given placebo; however, this treatment did not improve airway obstruction or airway hyperresponsiveness. Therapy longer than 10 days may be necessary to improve pulmonary function.

Topics: Animals; Anti-Bacterial Agents; Chronic Disease; Disease Models, Animal; Female; Ketolides; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycoplasma pneumoniae; Plethysmography; Pneumonia, Mycoplasma

To investigate the correlation between in vitro susceptibility of isolates and clinical outcomes with telithromycin in respiratory tract infections.. The activity of telithromycin was determined by in vitro susceptibility testing of key respiratory tract pathogens isolated from patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute maxillary sinusitis enrolled in 14 Phase III/IV clinical trials evaluating the clinical efficacy of telithromycin.. In this pooled analysis, telithromycin mode minimum inhibitory concentration (MIC) and MIC90, respectively, were: 0.016 and 0.03 mg/l against Streptococcus pneumoniae (n=626); 0.03 and 0.5 mg/l for penicillin-resistant S. pneumoniae (n=56); 0.03 and 1 mg/l for erythromycin-resistant S. pneumoniae (n=81); 2 and 4 mg/l against Haemophilus influenzae (including beta-lactamase producers; n=627); both 0.12 mg/l for Moraxella catarrhalis (n=159) and both 0.25 mg/l for Staphylococcus aureus (n=124). Telithromycin (5 or 7-10 days) resulted in overall clinical and bacteriologic success rates of 88.1% (1593/1808) and 89% (1593/1789), respectively.. High levels of in vitro susceptibility to telithromycin are paralleled by high rates of clinical cure and bacteriologic eradication.

Topics: Acute Disease; Adolescent; Adult; Bacteria; Bronchitis; Chronic Disease; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Community-Acquired Infections; Female; Humans; In Vitro Techniques; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Pneumonia; Randomized Controlled Trials as Topic; Sinusitis

Chronic Chlamydia pneumoniae infections have been associated with atherosclerosis, but clear knowledge about how these infections should be treated is lacking. We studied the effect of a new ketolide antibiotic, telithromycin, on chronic C. pneumoniae lung infection. Female C57BL/6J mice on a 0.2% cholesterol diet were inoculated intranasally with C. pneumoniae either two or three times every fourth week. Telithromycin was given to the mice subcutaneously at 75 mg/kg of body weight once daily for 5 or 10 days, starting at 3 days after the last inoculation. Samples were taken at 4 and 12 weeks after the last inoculation. The presence of C. pneumoniae DNA in lung tissue was demonstrated by PCR and the detection of lipid accumulation in the aortic sinus by Oil-Red-O staining. C. pneumoniae DNA positivity and inflammatory reactions in the lung tissue of the mice inoculated twice were significantly affected by treatment after both inoculations or only after the second inoculation at 12 weeks. Intimal lipid accumulation in the aortic sinus was also slightly but significantly less abundant in the mice treated after both inoculations compared to the levels in those treated only after the second inoculation for 10 days (geometric means, 823 and 4,324 microm(2), respectively; P = 0.033). No differences between the infected, untreated controls and the group inoculated three times and treated for 5 days were seen. We conclude that telithromycin is effective in preventing the development of chronic C. pneumoniae infection and intimal lipid accumulation in C56BL/6J mice when the treatment is given after each inoculation.

Topics: Animals; Aorta, Thoracic; Chlamydia Infections; Chlamydophila pneumoniae; Chronic Disease; DNA; Ketolides; Lipid Metabolism; Lung; Mice; Mice, Inbred C57BL; Myocardium; Reverse Transcriptase Polymerase Chain Reaction; Sinus of Valsalva

Topics: Acute Disease; Anti-Bacterial Agents; Bronchitis; Chronic Disease; Community-Acquired Infections; Emergency Treatment; Hospitalization; Humans; Ketolides; Macrolides; Patient Selection; Pneumonia, Bacterial

Topics: Acute Disease; Anti-Bacterial Agents; Chronic Disease; Clinical Trials as Topic; Coronary Disease; Diabetes Complications; Drug Interactions; Humans; Ketolides; Macrolides; Respiratory Tract Infections; Risk Factors; Time Factors

Topics: Anti-Bacterial Agents; Bacterial Infections; Bronchitis; Chronic Disease; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Treatment Outcome