ru-66647 and Bacterial-Infections

The advanced macrolides, azithromycin and clarithromycin, and the ketolide, telithromycin, are structural analogs of erythromycin. They have several distinct advantages when compared with erythromycin, including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once-daily administration, and improved tolerability. Clarithromycin and azithromycin are used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and Helicobacter pylori-associated peptic ulcer disease. Telithromycin is approved for the treatment of community-acquired pneumonia. Severe hepatotoxicity has been reported with the use of telithromycin.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Clarithromycin; Humans; Ketolides; Macrolides; Minocycline; Tetracyclines; Tigecycline

Topics: Bacteria; Bacterial Infections; Drug Interactions; Drug Resistance, Microbial; Humans; Ketolides; Macrolides

Increasing numbers of resistant bacteria and decreasing numbers of efficient antimicrobial agents demand for the development of new highly potent antimicrobial agents. The two main directions for the development of new antimicrobial agents are either the development of completely novel antimicrobial agents, or the modification of already existing antimicrobial molecules. The second direction proved to be a more successful and cost-efficient way of generating new antimicrobial agents. For this, chemical modifications have been included which render the antimicrobial agents insensitive to prevalent bacterial resistance mechanisms. However, detailed knowledge of the resistance mechanisms is indispensable. Molecular analysis of resistance mechanisms provides the required data to identify critical target structures. Furthermore, modification of antimicrobial agents makes it possible to escape known resistance mechanisms. In this report, two examples for such successful developments, one from human medicine (telithromycin) and the other from veterinary medicine (florfenicol), are presented.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Drug Design; Drug Resistance, Microbial; Humans; Ketolides; Technology, Pharmaceutical; Thiamphenicol; Veterinary Drugs

Telithromycin is the first of the ketolide antibacterials to receive US Food and Drug Administration (FDA) approval for clinical use. It is approved for the treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), and acute maxillary sinusitis (AMS) in adults.. This article reviews the mechanism of action, in vitro antimicrobial activity, pharmacokinetics and pharmacodynamics, clinical efficacy, safety, and drug-interaction profile of telithromycin.. Relevant studies were identified through a search of the English-language literature indexed on MEDLINE (1990-March 2005) using the terms telithromycin and HMR 3647, a review of the reference lists of identified articles, and a review of the briefing document prepared by the manufacturer of telithromycin for presentation to the FDA Anti-infective Drugs Advisory Committee. A search of abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy (2001-2004) also was performed.. The results of in vitro susceptibility studies suggest that telithromycin provides coverage against the key respiratory pathogens, both typical and atypical. In addition, telithromycin may be useful against multidrug-resistant strains of Streptococcus pneumoniae and against Haemophilus influenzae, irrespective of beta-lactamase production. In randomized, double-blind, comparative trials (against amoxicillin, amoxicillin/clavulanate, cefuroxime axetil, clarithromycin, moxifloxacin, or trovafloxacin), telithromycin had comparable efficacy to its comparators in the empiric treatment of CAP (4 studies), AECB (3 studies), and AMS (3 studies). Telithromycin is dosed at 800 mg (two 400-mg tablets) QD in community-acquired respiratory tract infections (RTIs). No dose adjustment is required in the elderly, patients with mild to moderate renal insufficiency, or patients with hepatic insufficiency. The majority of adverse events associated with telithromycin were mild to moderate, with gastrointestinal effects (diarrhea, nausea, vomiting) being the most commonly reported, followed by headache and dizziness. Telithromycin has been associated with elevations in hepatic transaminases and prolongation of the electrocardiographic QTc interval, although the significance of these findings is not known. Telithromycin is also a strong inhibitor of and substrate for the cytochrome P450 (CYP) 3A4 isozyme. Therefore, it is important to monitor for potential drug interactions with medications that prolong the QTc interval or are metabolized by the CYP system.. Telithromycin appears to be a useful option for the empiric treatment of community-acquired RTIs in adults. It may be particularly useful in the outpatient setting in areas with high rates of penicillin- and macrolide-resistant S pneumoniae; it may also be an alternative agent for patients who are allergic to beta-lactams and live in areas with a high prevalence of multidrug-resistant S pneumoniae or for those who have failed to respond to beta-lactam- or macrolide-based therapy.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Drug Interactions; Female; Half-Life; Humans; Ketolides; Kidney Diseases; Male; Metabolic Clearance Rate; Microbial Sensitivity Tests; Middle Aged; Randomized Controlled Trials as Topic; Tissue Distribution

The advanced macrolides, azithromycin and clarithromycin, and the ketolide telithromycin are structural analogues of erythromycin. They have several distinct advantages when compared with erythromycin including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once daily administration, and improved tolerability. This article reviews the pharmacokinetics, antimicrobial activity, clinical use, and adverse effects of these antimicrobial agents.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Clarithromycin; Humans; Ketolides; Macrolides

In patients with infection, improving the probability of positive treatment outcomes depends on optimizing the interactions between the host, pathogen, and drug. In this setting, optimal regimens must be utilized which not only maximize effectiveness in a specific patient, but also minimize the development of microbial resistance. The probability of achieving a specifically targeted antimicrobial exposure can be assessed using Monte Carlo simulation, a technique which integrates an agent's in vitro potency distribution (i.e., minimum inhibitory concentrations [MICs]) with the pharmacokinetic profile. The targeted pharmacodynamic parameters assessed by this technique include the ratio of peak concentration (C(max)) to MIC (C(max) : MIC); the ratio of the area under the plasma concentration-time curve (AUC) to MIC (AUC : MIC), and the time the drug concentration exceeds the MIC (T > MIC). Some antimicrobials, e.g., the aminoglycosides, are most effective/bactericidal when they have a high C(max) : MIC ratio; others, e.g., the fluoroquinolones, are more effective when the AUC : MIC ratio is high. In both of these scenarios, organism eradication is concentration-dependent, and the therapeutic goal is to maximize drug exposure. Like the fluoroquinolones, the efficacy of telithromycin, a newly developed ketolide, is most related to the AUC : MIC ratio. Outcome for other agents, such as the beta-lactams, is best predicted by the T > MIC; in this case, organism eradication is time-dependent, and the therapeutic goal is to optimize the duration of antimicrobial exposure. This article discusses how the use of currently available antimicrobials can be optimized through an appreciation of pharmacodynamic profiling.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Monte Carlo Method; Predictive Value of Tests; Treatment Outcome

Infections of the lower respiratory tract, such as community-acquired pneumonia (CAP) and acute bacterial exacerbations of chronic bronchitis (AECB), comprise the more serious respiratory tract infections (RTIs), and are associated with considerable morbidity and mortality, particularly in groups such as the very young, the elderly and those with co-morbid illness. Up to 80% of community-acquired RTIs are caused by Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis and are usually treated empirically. However, antibacterial resistance among common respiratory tract pathogens currently threatens the usefulness of existing therapies. The new ketolide antibacterial, telithromycin, has been developed specifically to provide optimal empirical treatment of community-acquired RTIs in the face of widespread antibacterial resistance. Telithromycin 800 mg once-daily offers efficacy equivalent to currently available antibacterials in the treatment of lower RTIs. Moreover, telithromycin demonstrates excellent activity in the treatment of CAP and AECB patients at risk for increased morbidity and mortality, including elderly patients, those with severe infections, and those with CAP complicated by pneumococcal bacteraemia. Telithromycin is also extremely effective in the treatment of patients with lower RTIs caused by atypical and intracellular pathogens (such as Mycoplasma pneumoniae, Legionella pneumophila and Chlamydophila [Chlamydia] pneumoniae--increasingly recognized as important aetiological agents of RTIs, particularly CAP), or by pathogens resistant to beta-lactams and macrolides. Telithromycin therefore represents a promising new agent for the empirical treatment of community-acquired RTIs.

Topics: Anti-Bacterial Agents; Bacterial Infections; Bronchitis, Chronic; Community-Acquired Infections; Delivery of Health Care; Drug Evaluation; Humans; Ketolides; Macrolides; Pneumonia; Risk Factors; Treatment Outcome

Antimicrobial resistance amongst common respiratory pathogens has increased worldwide at an alarming rate and now threatens the clinical usefulness of a number of antibacterial agents. A major concern is the selection of resistance in the community, which tends to parallel the (often inappropriate) overuse of such agents. Such problems highlight the need for new antibacterial agents that retain activity against bacterial strains resistant to existing agents, and have a low potential to select for resistance or induce cross-resistance. Telithromycin is the first of a new family of antibacterials--the ketolides--and has been designed specifically for the treatment of community-acquired respiratory tract infections (RTIs). Numerous in vitro studies confirm the potent activity of telithromycin against pathogens commonly implicated in community-acquired RTIs, irrespective of their beta-lactam, macrolide or fluoroquinolone susceptibility. Against pneumococci, for example, MICs were < or = 1 mg/L irrespective of penicillin susceptibility, with > or = 98% of macrolide-resistant strains inhibited at < or = 0.5 mg/L, regardless of the underlying mechanism of resistance (including erm, mef and ribosomal L4 mutations). Against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase-positive strains, telithromycin is at least as potent as azithromycin. In addition, telithromycin has a very low potential for selection of resistant isolates or induction of cross-resistance. Importantly, and unlike existing macrolides, telithromycin does not induce MLS(B) resistance, a finding explained by the presence of the innovative 3-keto group in its chemical structure. Telithromycin therefore represents an important addition to the therapeutic armamentarium in an era of increasing antimicrobial resistance, with an expected low likelihood of the development of resistance in clinical use.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Microbial; Humans; Ketolides; Macrolides

Among adults, acute sinusitis, tonsillitis/pharyngitis, community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB) are the most commonly encountered respiratory tract infections (RTIs) in the community. Empiric antibacterial therapy is the most widely used approach for the treatment of such infections. The appropriate antibacterial requires consideration of a number of patient-, pathogen- and drug-related factors. One additional factor is the global spread of resistance among common respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, which limits the utility of existing antibacterials. Telithromycin (HMR 3647), the first of a new family of antibacterials, the ketolides, was designed specifically to provide optimal therapy for community-acquired RTIs. This agent, which has a broad spectrum of antibacterial activity against common respiratory pathogens (including resistant strains and atypical/intracellular organisms), has been clinically and bacteriologically evaluated against gold-standard comparators in a series of phase III clinical trials. The results of these studies demonstrate that telithromycin, at a dosage of 800 mg once daily, is an effective, well-tolerated agent for the treatment of the most commonly encountered community-acquired RTIs. Moreover, telithromycin meets the challenge of increasing antibacterial resistance. High rates of clinical cure and bacteriologic eradication were achieved, even in patients infected with problematic resistant pathogens such as penicillinG- and macrolide-resistant S. pneumoniae. In summary, telithromycin represents a promising new antibacterial for the treatment of community-acquired RTIs. With high efficacy and bacterial eradication rates, good tolerability and convenient once-daily administration, telithromycin therapy should result in increased patient compliance and improved outcomes, thereby minimizing the risk of developing antibacterial resistance.

Topics: Anti-Bacterial Agents; Bacterial Infections; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Humans; Ketolides; Macrolides; Respiratory Tract Infections; Treatment Outcome

The ketolide telithromycin (HMR-3647; Ketek), a derivative of clarithromycin, has been launched by Aventis Pharma (formerly Hoechst Marion Roussel) for the treatment of respiratory tract infections with gram-positive or gram-negative cocci, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, intracellular pathogens, atypical microorganisms, toxoplasma or anaerobic bacteria. By May 2001, filings in the US and EU had been completed and a filing in Japan was expected to take place in the fourth quarter of 2001. In July 2001, telithromycin was granted marketing authorization by the EC for the treatment of community-acquired respiratory tract infections, including those caused by bacteria resistant to commonly used antibiotics. In October 2001, the product was launched in Germany. In March 2000, telithromycin was submitted to the US FDA and the EMEA, under the EU centralized approval procedure, for approval for the treatment of community-acquired pneumonia (CAP), acute sinusitis, acute exacerbations of chronic bronchitis and tonsillitis/pharyngitis. The company had expected to launch the product in early 2001. The CPMP issued a positive opinion for all four indications on April 23 2001. In September 2001, the company indicated that it expected the product to be launched in Japan in 2002. The FDA's Anti-infectives Advisory Committee was due to review telithromycin for all the submitted indications on January 29 2001; however, this was postponed. This postponement was thought to be at Aventis' request in order to discuss the potential for a resistant pneumococcal infection labeling which would boost product sales. The revised date for the meeting was April 26 2001, at which the Anti-Infective Drugs Advisory Committee of the FDA recommended approval of telithromycin for the treatment of CAP in patients 18 years of age or older. The committee failed to recommend approval for the use of the drug for the remaining three indications for which it was filed, citing concerns over potential cardiovascular risk and liver toxicity; at this time, the company was in active discussions with the FDA regarding approval of the remaining three indications. An approvable letter for CAP, acute bacterial exacerbations of chronic bronchitis and acute bacterial sinusitis was received by the company in June 2001; Aventis also received a non-approvable letter for the treatment of tonsillitis/pharyngitis at this time. In April 1999, ABN Amro predicted annual sales of

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Ketolides; Macrolides; Structure-Activity Relationship

This study compared the clinical efficacy, time to symptom resolution, and tolerability of a 5-day regimen of telithromycin with a 10-day regimen of high-dose amoxicillin-clavulanate in acute bacterial sinusitis (ABS).. In this multinational (41 centers in Canada, Germany, Greece, Portugal, and Turkey), open-label, noninferiority study, patients >/=18 years old (n=298) with a clinical (>7 days' symptoms) and radiological (air/fluid level, total opacification, mucosal thickening >/=10 mm) diagnosis of ABS were randomized to receive telithromycin 800 mg once daily for 5 days or amoxicillin-clavulanate 875/125 mg twice daily for 10 days. Clinical efficacy and tolerability were assessed at the test-of-cure visit (days 17-21). Time to symptom resolution was based on patients' daily diary assessment of individual symptoms.. The per-protocol clinical success rate (primary endpoint) with telithromycin (88.6% (109/123)) was noninferior to that with amoxicillin-clavulanate (88.8% (111/125)) (95% confidence interval: -8.9 to 8.5). In the modified intention-to-treat (mITT) population, the median time for 50% reduction of total symptom scores was significantly shorter for telithromycin (4 days) vs. amoxicillin-clavulanate (5 days; p=0.044); median times for 75% reduction of total symptom scores were: telithromycin, 7 days; amoxicillin-clavulanate, 8 days (p=0.115). The median time for reduction of total symptom scores to the absent/very mild category (mITT population) was 6 days for telithromycin vs. 8 days for amoxicillin-clavulanate (p=0.04). All treatment-emergent adverse events (TEAEs) were mostly gastrointestinal and occurred in 20.7% (30/145) of telithromycin-treated patients vs. 31.8% (47/148) of amoxicillin-clavulanate-treated patients (p=0.034). One serious AE was reported in the telithromycin group, but it was considered not to be related to treatment.. This open-label, randomized study demonstrated that treatment of ABS with telithromycin resulted in comparable clinical efficacy, shorter times to symptom resolution, and fewer total TEAEs than treatment with amoxicillin-clavulanate.

Topics: Acute Disease; Adult; Amoxicillin; Anti-Bacterial Agents; Bacterial Infections; beta-Lactam Resistance; Drug Administration Schedule; Female; Haemophilus influenzae; Humans; Ketolides; Male; Middle Aged; Outcome Assessment, Health Care; Quality of Life; Sinusitis; Streptococcus pneumoniae; Surveys and Questionnaires

The aim of this study was to evaluate the efficacy and tolerance of 5 days of telithromycin (800 mg once a day) in the treatment of bacteriologically proven acute maxillary sinusitis (AMS).. Two hundred and sixty-three patients with a clinically diagnosed AMS and purulent rhinorrhea were included in this prospective, multicenter, non-comparative open-labeled French study. Pus was sampled from the middle meatus before inclusion. The bacterial origin of the infection was confirmed by a scientific committee (presence of leucocytes/bacteria on direct microscopic examination of pus, and positive culture).. Seven to 14 days after the end of the treatment the clinical success rate (cure and improvement) was 91% (63/69 patients) in the per protocol bacteriologically documented (PPb) population and 90% (231/257 patients) in the modified intent-to-treat population. The main strains identified in the 69 patients of PPb population were Streptococcus pneumoniae (47.8%, of which 15 strains with reduced susceptibility to penicillin and 15 erythromycin resistant strains), Haemophilus influenzae (14.5%), Branhamella catarrhalis (8.7%) and Streptococcus aureus (29.0%). Drug tolerance was assessed on 263 patients as satisfactory with mainly gastro-intestinal disorders considered to be related to the treatment in 7.6% of patients. No serious adverse event related to the study drug was reported.. The efficacy of telithromycin 800 mg once daily for 5 days is confirmed in the treatment of AMS, even for those due to S. Pneumoniae.

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Bacterial Infections; Female; France; Humans; Ketolides; Male; Maxillary Sinusitis; Recurrence; Reproducibility of Results; Safety

To compare the clinical and bacteriologic efficacy and safety of short-duration treatment with telithromycin given for 5 days with moxifloxacin given for 10 days in adults with acute bacterial rhinosinusitis (ABRS).. In this prospective, double-blind, parallel-group, randomized, multicenter study, adult patients (N = 349) with ABRS were randomized to oral telithromycin (800 mg once daily for 5 days) or to oral moxifloxacin (400 mg once daily for 10 days) and followed for 31 to 36 days. Clinical outcome was determined by the investigator at the posttherapy/test of cure (TOC) visit. Bacteriologic outcome was determined by comparing cultures taken at the pretreatment visit with cultures obtained at the posttherapy/TOC visit. The primary objective was to demonstrate equivalence of clinical cure rates in the per-protocol population between treatment groups at the posttherapy/TOC visit.. Clinical success at TOC (primary endpoint) was achieved in 87.4% of patients in the telithromycin group compared with 86.9% for moxifloxacin (per-protocol patients; 0.5% difference between treatment groups; 95% confidence interval [CI], -8.1, 9.2; P = 0.8930). The bacteriologic success rates were 94.1% and 93.9%, respectively (0.2% difference between treatment groups; 95% CI, -14.2, 14.5; P = 0.9734). Overall treatment-emergent adverse events for both drugs (mostly gastrointestinal) were mild to moderate in intensity.. The clinical and bacteriologic efficacy of telithromycin 800 mg once daily for 5 days was equivalent to that of moxifloxacin 400 mg once daily for 10 days, establishing telithromycin as an important treatment option for ABRS.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Aza Compounds; Bacterial Infections; Double-Blind Method; Drug Administration Schedule; Female; Fluoroquinolones; Humans; Ketolides; Macrolides; Male; Middle Aged; Moxifloxacin; Prospective Studies; Quinolines; Rhinitis; Sinusitis; Time Factors

Solithromycin, a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide, was tested against a 2014 collection of 6,115 isolates, including Streptococcus pneumoniae (1,713 isolates), Haemophilus influenzae (1,308), Moraxella catarrhalis (577), Staphylococcus aureus (1,024), and beta-hemolytic streptococci (1,493), by reference broth microdilution methods. The geographic samples included 2,748 isolates from the United States, 2,536 from Europe, 386 from Latin America, and 445 from the Asia-Pacific region. Solithromycin was observed to be very active against S. pneumoniae (MIC50/90, 0.008/0.12 μg/ml), demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 μg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 μg/ml), with all strains being inhibited at a solithromycin MIC of ≤1 μg/ml. Against H. influenzae, solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 μg/ml), and both of these compounds were 2-fold less active than azithromycin (MIC50/90, 0.5/1 μg/ml). All but one of the M. catarrhalis isolates were inhibited by solithromycin at ≤0.25 μg/ml. Solithromycin inhibited 85.3% of S. aureus isolates at ≤1 μg/ml, and its activity was lower against methicillin-resistant (MIC50/90, 0.06/>32 μg/ml) than against methicillin-susceptible (MIC50/90, 0.06/0.06 μg/ml) isolates. Little variation in solithromycin activity was observed by geographic region for the species tested. Solithromycin was very active against beta-hemolytic streptococci (MIC50/90, 0.015/0.03 μg/ml), and all isolates were inhibited at MIC values of ≤0.5 μg/ml. In conclusion, solithromycin demonstrated potent activity against global and contemporary (2014) pathogens that represent the major causes of community-acquired bacterial pneumonia. These data support the continued clinical development of solithromycin for the treatment of this important indication.

Topics: Anti-Bacterial Agents; Asia; Azithromycin; Bacterial Infections; Community-Acquired Infections; Epidemiological Monitoring; Europe; Haemophilus influenzae; Humans; International Cooperation; Ketolides; Latin America; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Staphylococcus aureus; Streptococcus; Streptococcus pneumoniae; Triazoles; United States

The activity of telithromycin and comparator antibacterials was examined in isolates of Streptococcus pneumoniae and Haemophilus influenzae isolated from patients with community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), or sinusitis during year 5 (2003-2004) of the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin global resistance surveillance study. Among S. pneumoniae, penicillin nonsusceptibility and erythromycin resistance were 35.7% and 36.0%, respectively. beta-Lactamase was produced by 12.3% of H. influenzae isolates. beta-Lactamase-negative ampicillin-resistant strains, mainly from Japan, comprised 5.2% of global H. influenzae isolates. Telithromycin and levofloxacin were the most active agents tested against S. pneumoniae and H. influenzae (>99% of isolates susceptible) isolated from patients with CAP, AECB, or bacterial sinusitis. Amoxicillin-clavulanate, levofloxacin, and telithromycin were the most active agents against multidrug-resistant S. pneumoniae.

Topics: Adolescent; Adult; Ampicillin Resistance; Anti-Bacterial Agents; Bacterial Infections; beta-Lactamases; Child; Child, Preschool; Community-Acquired Infections; Haemophilus influenzae; Humans; Japan; Ketolides; Respiratory Tract Infections; Streptococcus pneumoniae; Young Adult

Topics: Acute Disease; Anti-Bacterial Agents; Bacterial Infections; Conflict of Interest; Drug Industry; Humans; Ketolides; Periodicals as Topic; Practice Guidelines as Topic; Rhinitis; Sinusitis; United States

Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial; Drug Resistance, Microbial; Haemophilus Infections; Haemophilus influenzae; Humans; International Cooperation; Ketolides

Topics: Anti-Bacterial Agents; Asthma; Bacterial Infections; Drug Approval; Humans; Ketolides; Liver Failure, Acute; Product Surveillance, Postmarketing; United States; United States Food and Drug Administration

The first objective was to investigate the in vitro activity of telithromycin against respiratory tract pathogens in comparison with other antimicrobial agents. The second objective was to identify the influence of the erm(B) and mef(A) genes on the susceptibility of Streptococcus pneumoniae to telithromycin.. The in vitro activity of telithromycin against S. pneumoniae, Moraxella catarrhalis and Haemophilus influenzae, isolated from the UK and 40 macrolide-resistant S. pneumoniae from four different countries was compared with a variety of antimicrobial agents. The 140 isolates were examined for the presence of the erm(B) and mef(A) genes. The impact of 5% CO(2) on susceptibility testing was also investigated.. Telithromycin showed greatest activity against S. pneumoniae, but also had good activity against M. catarrhalis and H. influenzae, which was independent of their resistance profiles to other antibiotics. The MIC(90) of telithromycin for S. pneumoniae was 0.12 mg/L, which was 64-fold lower than the lowest macrolide MIC; 21% of the S. pneumoniae were macrolide resistant. Thirty-eight per cent of the macrolide-resistant strains were erm(B)-positive and 62% were mef(A)-positive, but no strain contained both genes. The activity of telithromycin was similar to that of azithromycin against both M. catarrhalis and H. influenzae, Erythromycin was slightly less active: 1% and 8% of M. catarrhalis and H. influenzae, respectively, were resistant to erythromycin, but none were resistant to telithromycin. Five per cent of the S. pneumoniae strains and 4% of the H. influenzae strains changed from telithromycin susceptible to non-susceptible entirely because of the incubation conditions. The MIC(50)s and MIC(90)s of S. pneumoniae, M. catarrhalis and H. influenzae increased by one dilution when incubated in CO(2).. Telithromycin has shown high in vitro activity against S. pneumoniae, including those strains that are macrolide susceptible and resistant as well as M. catarrhalis and H. influenzae. This study has also demonstrated that there is no cross-resistance between erythromycin and telithromycin. The impact of 5% CO(2) on susceptibility testing should be investigated further before providing definite guidelines on telithromycin susceptibility testing.

Topics: Anti-Bacterial Agents; Bacterial Infections; Carbon Dioxide; Drug Resistance, Bacterial; Genes, Bacterial; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Streptococcus pneumoniae

The in vitro activity of a new fluoroquinolone, ABT-492, was determined.. MICs were compared with those of two beta-lactams, telithromycin, ciprofloxacin and four later generation fluoroquinolones. The effects of human serum and of inoculum concentration were also investigated.. MIC data indicate that ABT-492 has potent activity against Gram-positive organisms with enhanced anti-staphylococcal activity compared with earlier fluoroquinolones, in addition to activity against beta-haemolytic streptococci, pneumococci including penicillin- and fluoroquinolone-resistant strains and vancomycin-susceptible and -resistant Enterococcus faecalis but not Enterococcus faecium. ABT-492 was the most active agent tested against Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, fluoroquinolone-susceptible Neisseria gonorrhoeae and anaerobes. Good activity was observed for ABT-492 amongst the Enterobacteriaceae and anaerobes tested, but ciprofloxacin showed superior activity for species of Proteus, Morganella and Providencia, as well as for Pseudomonas spp. In common with the other fluoroquinolones tested, organisms with reduced susceptibility to ciprofloxacin had raised MIC(90)s to ABT-492. The one isolate of H. influenzae tested with reduced fluoroquinolone susceptibility had an ABT-492 MIC close to that of the population lacking a mechanism of quinolone resistance. ABT-492 was more active than ciprofloxacin against Chlamydia spp. An inoculum effect was observed with a number of isolates of Staphylococcus aureus, Streptococcus pneumoniae, E. faecium, Klebsiella spp. and Escherichia coli, in addition to moderately raised MICs in the presence of 70% serum protein. The clinical significance of these findings is yet to be determined.. ABT-492 is a new fluoroquinolone with excellent activity against both Gram-positive and Gram-negative organisms, with many potential clinical uses.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Bacterial Infections; Chlamydia trachomatis; Chlamydophila pneumoniae; Ciprofloxacin; Erythromycin; Fluoroquinolones; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Quinolones

Topics: Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Drug Approval; Drug Design; Drug Resistance, Bacterial; Flavin-Adenine Dinucleotide; Humans; Ketolides; Macrolides; United States

Telithromycine is the first ketolide on the market. Its characteristics are the two sites fixation on the bacterial ribosomia and and as a consequence a good activity on the majority of penicillin and macrolides resistant bacteria, included S. pneumonia and S. pyogenes. Telithromycine represents an alternative to beta-lactames and moxifloxacine to treat communautary pneumonia, bacterial pharyngoamygdalitis, suppurative sinusitis and bronchitis. There are nevertheless problems with drugs interactions and risk of resistance development.

Topics: Anti-Bacterial Agents; Bacterial Infections; Humans; Ketolides; Macrolides

Telithromycin is one of the ketolides, characterised by a 3-keto group instead of L-cladinose and a C(11)-C(12) carbamate link by an alkyl chain to a pyridinum and imidazolium ring side chain. We evaluated in vitro and in vivo antibacterial activities of telithromycin against gynaecological pathogens.. In the vitro study, the antibacterial activity of telithromycin against 180 isolates (isolated in the year 2000) of Streptococcus agalactiae (n = 33), Enterococcus faecalis (n = 22), Neisseria gonorrhoeae (n = 30), Peptostreptococcus anaerobius (n = 20), Finegoldia magna (n = 20), Bacteroides fragilis (n = 25) and Prevotella bivia (n = 30) was compared with that of erythromycin A, clarithromycin, azithromycin, ampicillin and levofloxacin. In the in vivo study, the efficacy of telithromycin was evaluated using experimental intra-abdominal abscesses in mice caused by B. fragilis (minimum inhibitory concentration of telithromycin 0.5 mg/l).. In the in vitro study, telithromycin inhibited more than 50% of clinical isolates of S. agalactiae, E. faecalis, N. gonorrhoeae, P. anaerobius, F. magna, B. fragilis and P. bivia at concentrations of 0.016, 0.063, 0.063, 0.032, 0.032, 0.5 and 0.25 mg/l, respectively. Telithromycin inhibited more than 90% of these clinical isolates at concentrations of 0.016, 4, 0.125, 0.063, 0.063, 4 and 1 mg/l, respectively. In the in vivo study, telithromycin inhibited abscess formation and significantly decreased viable cell counts in abscesses in comparison with the untreated group.. These in vitro and in vivo antibacterial activities suggest that telithromycin could be a potential candidate for the treatment of bacterial infections complicated by chlamydial infection.

Topics: Abdominal Abscess; Animals; Anti-Bacterial Agents; Bacterial Infections; Bacteroidaceae; Bacteroides fragilis; Enterococcus faecalis; Female; Genital Diseases, Female; Gram-Negative Aerobic Rods and Cocci; Gram-Positive Cocci; Ketolides; Macrolides; Mice; Microbial Sensitivity Tests; Neisseria gonorrhoeae; Peptostreptococcus; Prevotella; Streptococcus agalactiae

Thirteen multinational, Phase III studies were conducted to establish the efficacy of telithromycin 800 mg once daily in the treatment of community-acquired respiratory tract infections (RTIs).. Data were analyzed from 4,743 adult patients participating across four indications: community-acquired pneumonia (CAP) of mild to moderate severity, acute exacerbations of chronic bronchitis (AECB), acute maxillary sinusitis (AMS) and tonsillitis/pharyngitis.. Treatment with telithromycin for either 5 days (AECB, AMS and tonsillitis/pharyngitis) or 7-10 days (CAP and AMS) provided high rates of clinical and bacteriologic cure (5-day, 87.0% and 86.0%, respectively; 7 to 10-days, 90.3% and 90.5%, respectively) that were equivalent to those of a 10-day course of comparator antibacterials (86.5% and 86.5%, respectively). The clinical efficacy of telithromycin extended to high-risk CAP and AECB patients and to all key respiratory pathogens, including Streptococcus pneumoniae strains resistant to penicillin or erythromycin and atypical/intracellular pathogens. Telithromycin was generally well-tolerated across patient groups.. These findings support the use of telithromycin as an effective therapy for the treatment of community-acquired RTIs.

Topics: Acute Disease; Adolescent; Adult; Aged; Bacterial Infections; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Respiratory Tract Infections; Retrospective Studies; Risk Assessment; Treatment Outcome

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

The prevalence of antibiotic resistance in bacterial pathogens associated with community-acquired respiratory tract infections is increasing. Ketolides, semi-synthetic derivatives of erythromycin, overcome the macrolide resistance mechanisms found in Streptococcus pneumoniae and Streptococcus pyogenes, two key pathogens. They also have improved potency and longer post-antibiotic effects, while maintaining the antibacterial spectrum of the macrolide class. The new ketolides cethromycin (ABT-773) and telithromycin have overall antibacterial properties that suggest they will be clinically useful new antibiotics and are undergoing clinical development and regulatory review.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Proteins; Drug Resistance, Microbial; Erythromycin; Humans; Ketolides; Macrolides; Methyltransferases; Ribosomes

Topics: Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Humans; Ketolides; Macrolides; Multicenter Studies as Topic; Respiratory Tract Infections; Treatment Outcome

We compared the oral antibacterial activities of telithromycin (HMR 3647), a new ketolide drug, in different infections induced in mice by Staphylococcus aureus, Streptococcus pneumoniae, streptococci, enterococci, and Haemophilus influenzae with those of various macrolides and pristinamycin. Unlike all other comparators, telithromycin displayed a high therapeutic activity, particularly in septicemia induced by erythromycin A-resistant pathogens, where the ketolide was the only active compound, displaying effective doses between 3 and 26 mg/kg of body weight. Against H. influenzae, telithromycin was the most effective compound. Telithromycin displayed bacteriostatic behavior against S. pneumoniae and H. influenzae. The ketolide was also active against thigh muscle infection induced by S. aureus. The pharmacokinetic properties of telithromycin accounted for its outstanding well-balanced oral in vivo efficacy against both gram-positive cocci, whatever their phenotype of resistance, and H. influenzae.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Biological Availability; Erythromycin; Half-Life; Injections, Intravenous; Ketolides; Macrolides; Male; Mice; Microbial Sensitivity Tests; Virginiamycin

Topics: Adult; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Delivery, Obstetric; Female; Genital Diseases, Female; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Pregnancy; Pregnancy Complications, Infectious

The comparative activity of telithromycin (HMR 3647) against 419 human anaerobic isolates was determined by the agar dilution method. At concentrations of

Topics: Anti-Bacterial Agents; Azithromycin; Bacteria, Anaerobic; Bacterial Infections; Clarithromycin; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Roxithromycin

The aim of the present investigation was to determine the in vitro activity of HMR 3647 compared with other antimicrobial agents against anaerobic bacteria. The activity of HMR 3647 was determined against 342 clinical isolates of anaerobic bacteria by the agar dilution method and was compared with azithromycin, clarithromycin, roxithromycin, erythromycin, cefoxitin, imipenem, clindamycin and metronidazole. Among the macrolides HMR 3647 and among the beta-lactams imipenem were the most active agents tested. Anaerobic cocci (50 strains) had the following minimum inhibitory concentrations (MICs): HMR 3647, range 0.016-0.125 mg/l; imipenem, range 0.016-0.064 mg/l. Propionibacterium acnes (30 strains): HMR 3647, 0.016-1.0 mg/l; imipenem, 0.032-0.064 mg/l. Clostridium perfringens (30 strains): HMR 3647, 0.125 mg/l; imipenem, 0.016-0.5 mg/l. Clostridium difficile (50 strains): HMR 3647, 0.125-256 mg/l; imipenem, 4.0-8.0 mg/l. Bacteroides fragilis (102 strains): HMR 3647, 0.032-16 mg/l; imipenem, 0.064-0.25 mg/l. Bacteroides and Prevotella species (50 strains): HMR 3647, 0.016-4.0 mg/l; imipenem, 0.016-0.25 mg/l. Fusobacterium nucleatum (30 strains): HMR 3647, 0.016-8.0 mg/l; imipenem, 0.008-0.064 mg/l. HMR 3647 may be useful as treatment and prophylaxis for infections due to anaerobic bacteria.

Topics: Anti-Bacterial Agents; Bacteria, Anaerobic; Bacterial Infections; Humans; Ketolides; Lactams; Macrolides

The in-vitro activity of HMR 3647, a novel ketolide, was investigated in comparison with those of erythromycin A, roxithromycin, clarithromycin (14-membered ring macrolides), amoxycillin-clavulanate and ciprofloxacin against 719 recent clinical Gram-positive, Gram-negative and anaerobic isolates and type cultures. HMR 3647 generally demonstrated greater activity than the other compounds with MIC90s of < or =0.5 mg/L, except for Staphylococcus epidermidis (MIC90 > 128 mg/L), Haemophilus influenzae (MIC90 = 2 mg/L), Enterococcus faecalis (MIC90 = 2 mg/L), Enterococcus faecium (MIC90 = 1 mg/L) and the anaerobes, Bacteroides fragilis (MIC90 = 2 mg/L) and Clostridium difficile (MIC90 = 1 mg/L). In general, an increase in the size of the inoculum from 10(4) to 10(6) cfu on selected strains had little effect on the MICs of HMR 3647. Additionally, the in-vitro activity of HMR 3647 was not affected by the presence of either 20 or 70% (v/v) human serum. The antichlamydial activity of HMR 3647 was generally greater than that of commonly used antichlamydial antimicrobials.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Bacterial Infections; Chlamydia; Chlamydia Infections; Ciprofloxacin; Humans; Ketolides; Lactams; Macrolides; Microbial Sensitivity Tests; Serum Bactericidal Test