ru-66647 and trovafloxacin

The efficacy of telithromycin has been assessed in six Phase III studies involving adults with mild to moderate community-acquired pneumonia (CAP) with a degree of severity compatible with oral therapy. Patients received telithromycin 800 mg once daily for 7-10 days in three open-label studies (n=870) and three randomized, double-blind, comparator-controlled studies (n=503). Comparator antibacterials were amoxicillin 1000 mg three-times daily, clarithromycin 500 mg twice daily and trovafloxacin 200 mg once daily. Clinical and bacteriological outcomes were assessed 7-14 days post-therapy. Among telithromycin-treated patients, per-protocol clinical cure rates were 93.1 and 91.0% for the open-label and comparative studies, respectively. Telithromycin treatment was as effective as the comparator agents. High eradication and clinical cure rates were observed for infections caused by key pathogens: Streptococcus pneumoniae including isolates resistant to penicillin G and/or erythromycin A (95.4%), Haemophilus influenzae (89.5%) and Moraxella catarrhalis (90%). Telithromycin was also highly effective in patients with infections caused by atypical and/or intracellular pathogens and those at increased risk of morbidity. Telithromycin was generally well tolerated. Telithromycin 800 mg once daily for 7-10 days offers a convenient and well-tolerated first-line oral therapy for the empirical treatment of mild to moderate CAP.

Topics: Aged; Amoxicillin; Anti-Bacterial Agents; Anti-Infective Agents; Clarithromycin; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Double-Blind Method; Fluoroquinolones; Humans; Ketolides; Macrolides; Naphthyridines; Penicillins; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Treatment Outcome

A randomised, double-blind study of adults with community-acquired pneumonia (CAP) resulted in clinical cure rates of 90.0% for telithromycin and 94.2% for trovafloxacin. Bacteriological eradication rates were also comparable for both treatments. All high-risk patients (i.e. > or = 65 years old [n=25], Pneumonia Severity Index score > or = 111 [n=16], pneumococcal bacteraemia [n=4]) were clinically cured. In infections caused by Mycoplasma pneumoniae and Chlamydophila (Chlamydia) pneumoniae, clinical cure rates were 93.3% (14/15) for telithromycin and 100% (16/16) for trovafloxacin. Possibly drug-related, treatment-emergent adverse events (TEAEs) were considered mild and occurred in 47.2% of telithromycin and 33.0% of trovafloxacin patients. The most frequently reported, possibly drug-related, TEAEs were diarrhoea and nausea for telithromycin and diarrhoea and headache for trovafloxacin. Serious TEAEs occurred in 1.9% of telithromycin and 1.8% of trovafloxacin subjects and were considered not drug related. No deaths occurred during the study. Telithromycin and trovafloxacin were safe and comparable in efficacy in these patients with CAP.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Infective Agents; Community-Acquired Infections; Double-Blind Method; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Ketolides; Macrolides; Male; Middle Aged; Naphthyridines; Pneumonia, Pneumococcal; Risk Factors; Treatment Outcome

Idiosyncratic drug-induced hepatotoxicity accounts for about 13% of all cases of acute liver failure, therefore cited as the most frequent reason for post-marketing drug withdrawal. Despite this, the underlying mechanisms remain poorly understood due to lack in adequate screening assays and predictive in vitro models. Hepatic transporters play a crucial role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition, including toxicity and loss of efficacy. Inflammation is one condition for demonstrated variable drug response, attributed in part, to changes in function of drug transporters. The present study investigates the implication of two important hepatic transporters (MDR1 and MRP2) in idiosyncratic drug-induced hepatotoxicity in the presence and absence of an inflammatory context. The synergistic effect of idiosyncratic drugs (Trovafloxacin, nimesulide, telithromycin, and nefazodone) and inflammatory stimuli (TNF-α + LPS) on the efflux activity of hepatic transporters was studied using microvolume cytometry. Our results demonstrated on the one hand that both MDR1 and MRP2 are variably implicated in idiosyncratic drug-induced liver injury and on the other hand that the occurrence of an inflammatory reaction during idiosyncratic drug therapy can noticeably modulate this implication. In the absence of an inflammatory stress, none of the four tested drugs modulated the efflux activity of MRP2; nevertheless telithromycin and nefazodone inhibited the efflux activity of MDR1. Upon occurrence of an inflammatory stress, the inhibitory potential of trovafloxacin, nimesulide, and nefazodone on the efflux activity of MRP2 was noticeably revealed, while the telithromycin and nefazodone-induced inhibition of MDR1 was clearly attenuated. Knowledge of underlying mechanisms may significantly contribute to elimination of potential hepatotoxic drugs long before marketing and to prevention of drug-induced hepatotoxicity.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Sub-Family B Member 4; Biological Transport; Chemical and Drug Induced Liver Injury; Flow Cytometry; Fluoroquinolones; Gene Expression Regulation; Hep G2 Cells; Hepatocytes; Humans; Inflammation; Ketolides; Lipopolysaccharides; Liver; Naphthyridines; Piperazines; Sulfonamides; Triazoles; Tumor Necrosis Factor-alpha; Xenobiotics

Pneumococci can enter and survive inside human lung alveolar carcinoma cells. We examined the activity of azithromycin, gentamicin, levofloxacin, moxifloxacin, penicillin G, rifampin, telithromycin, and trovafloxacin against pneumococci inside and outside cells. We found that moxifloxacin, trovafloxacin, and telithromycin were the most active, but only telithromycin killed all intracellular organisms.

Topics: Anti-Bacterial Agents; Aza Compounds; Azithromycin; Fluoroquinolones; Gentamicins; Humans; Ketolides; Levofloxacin; Macrolides; Microbial Sensitivity Tests; Moxifloxacin; Naphthyridines; Ofloxacin; Penicillin G; Quinolines; Rifampin; Streptococcus pneumoniae; Tumor Cells, Cultured