ru-66647 and Respiratory-Tract-Infections

The emergence of bacterial resistance to commonly used antibiotics, such as macrolides, is complicating the management of respiratory tract infections (RTIs). Telithromycin, a ketolide antimicrobial structurally related to macrolides, is approved for the treatment of community-acquired RTIs, and shows lower pathogen resistance rates. The purpose of this study was to compare the efficacy and safety of telithromycin with clarithromycin, a macrolide routinely used as therapy for RTIs.. We performed a meta-analysis of relevant randomized-controlled trials (RCTs) identified in PubMed, the Cochrane Library, Embase, CNKI and VIP databases. The primary efficacy outcome was clinical treatment success assessed at the test-of-cure time in the per-protocol population, and the primary safety outcome was drug related adverse effects.. Seven RCTs, involving 2845 patients with RTIs, were included in the meta-analysis. Oral telithromycin and clarithromycin showed a similar clinical treatment success in modified intention to treat and per-protocol population (cure and improvement) (odds ratios (ORs): 0.84, 95% confidence intervals (CI): 0.64 - 1.11 and OR: 1.14, 95%CI: 0.71 - 1.85, respectively). Similar findings were obtained for secondary efficacy outcomes: clinical treatment success at a late post-therapy visit (OR: 0.92, 95%CI: 0.57 - 1.48) and microbiological treatment success at the test-of-cure time (OR: 1.14; 95%CI: 0.71 - 1.85). The safety outcome analysis indicated telithromycin had a similar risk of drug-related adverse effect and serious adverse effect with clarithromycin.. Our findings indicate that oral telithromycin and clarithromycin have similar treatment efficacy and adverse effect. The advantages of lower antimicrobial resistance rates, once-daily short-duration dosing and reported lower health-care costs make oral telithromycin a useful option for the empiric management of mild-to-moderate RTIs.

Topics: Anti-Bacterial Agents; Clarithromycin; Community-Acquired Infections; Humans; Ketolides; Randomized Controlled Trials as Topic; Respiratory Tract Infections

A case of mild hepatocellular injury associated with the administration of telithromycin in a patient with no risk factors for hepatotoxicity is presented.. A 44-year-old man with no significant past medical history arrived at the emergency room after six days of high fever, chills, headache, neck stiffness, and back pain. Five days earlier, he visited a family medicine clinic for his symptoms and oral telithromycin 800 mg daily was prescribed for a suspected upper-respiratory-tract infection. The patient stopped taking the drug after three days due to persistent symptoms. On admission, the patient's laboratory tests revealed an aspartate transaminase (AST) concentration of 68 units/L, an alanine transaminase (ALT) value of 155 units/L, and an erythrocyte sedimentation rate of 40 mm/hr. The patient was not taking any long-term medications, had taken only aspirin for his fever, and denied the use of alcohol and illegal drugs. The patient was admitted to the general medical unit with a diagnosis of possible viral hepatitis. His urine culture was negative, and serology tests later revealed no evidence of hepatitis A, B, or C. Ibuprofen, pantoprazole, and enoxaparin were prescribed. On hospital day 2, the patient's AST and ALT concentrations had decreased to 50 and 110 units/L, respectively. By day 3, the patient's symptoms had improved and he remained afebrile. His AST and ALT values had further decreased to 41 and 105 units/L, respectively. He was then diagnosed with acute viral upper-respiratory-tract infection with mild hepatotoxicity associated with telithromycin and was discharged home with orders for follow-up at the family medicine clinic.. A patient without risk factors for hepatotoxicity developed mild elevations in hepatic transaminases after receiving telithromycin for the treatment of a suspected upper-respiratory-tract infection.

Topics: Acute Disease; Adult; Alanine Transaminase; Anti-Bacterial Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Humans; Ketolides; Liver; Male; Respiratory Tract Infections

Ketolides differ from macrolides by removal of the 3-O-cladinose (replaced by a keto group), a 11,12- or 6,11-cyclic moiety and a heteroaryl-alkyl side chain attached to the macrocyclic ring through a suitable linker. These modifications allow for anchoring at two distinct binding sites in the 23S rRNA (increasing activity against erythromycin-susceptible strains and maintaining activity towards Streptococcus pneumoniae resistant to erythromycin A by ribosomal methylation), and make ketolides less prone to induce methylase expression and less susceptible to efflux in S. pneumoniae. Combined with an advantageous pharmacokinetic profile (good oral bioavailability and penetration in the respiratory tract tissues and fluids; prolonged half-life allowing for once-a-day administration), these antimicrobial properties make ketolides an attractive alternative for the treatment of severe respiratory tract infections such as pneumonia in areas with significant resistance to conventional macrolides. For telithromycin (the only registered ketolide so far), pharmacodynamic considerations suggest optimal efficacy for isolates with minimum inhibitory concentration values < or = 0.25 mg/l (pharmacodynamic/pharmacokinetic breakpoint), calling for continuous and careful surveys of bacterial susceptibility. Postmarketing surveillance studies have evidenced rare, but severe, side effects (hepatotoxicity, respiratory failure in patients with myasthenia gravis, visual disturbance and QTc prolongation in combination with other drugs). On these bases, telithromycin indications have been recently restricted by the US FDA to community-acquired pneumonia, and caution in patients at risk has been advocated by the European authorities. Should these side effects be class related, they may hinder the development of other ketolides such as cethromycin (in Phase III, but on hold in the US) or EDP-420 (Phase II).

Topics: Animals; Anti-Bacterial Agents; Binding Sites; Humans; Ketolides; Macrolides; Respiratory Tract Infections

A pooled analysis of 14 Phase III studies was performed to establish the clinical and bacteriologic efficacy of telithromycin 800 mg once daily in the treatment of pneumococcal community-acquired respiratory tract infections (RTIs).. Data were examined from 5534 adult/adolescent patients with community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), or acute bacterial sinusitis, who had received telithromycin for 5-10 days or a comparator antibacterial.. Streptococcus pneumoniae was identified in 704/2060 (34.2%) bacteriologically evaluable patients. The respective per-protocol clinical cure rates for telithromycin and comparators were 94.3% and 90.0% (CAP); 81.5% and 78.9% (AECB); 90.1% and 87.5% (acute sinusitis); 92.7% and 87.6% (all indications). Clinical cure rates were 28/34 (82.4%) and 5/7, respectively, for penicillin-resistant infections, and 44/52 (84.6%) and 11/14, respectively, for erythromycin-resistant infections. Of 82 patients with pneumococcal bacteremia, 74 (90.2%) were clinically cured after telithromycin treatment, including 5/7 and 8/10 with penicillin- or erythromycin-resistant strains, respectively. Adverse events considered possibly related to study medication were reported by 1071/4045 (26.5%) telithromycin and 505/1715 (29.4%) comparator recipients. These events were generally of mild/moderate severity, and mainly gastrointestinal in nature.. As S. pneumoniae is the leading bacterial cause of community-acquired RTIs, and antibacterial resistance is increasing among this species, these findings support the use of telithromycin as first-line therapy in this setting.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Female; Follow-Up Studies; Humans; Ketolides; Male; Microbial Sensitivity Tests; Middle Aged; Pneumococcal Infections; Randomized Controlled Trials as Topic; Respiratory Tract Infections; Streptococcus pneumoniae; Treatment Outcome

This review discusses the clinicoradiological findings of community-acquired respiratory infections and the treatment strategy for respiratory infections. To make a differential diagnosis between bacterial pneumonia, pneumonia caused by atypical pathogens, and mycobacterial infections, it is very important to analyze the radiological findings of inflammatory lung diseases based on normal antomical structures. If clinicoradiological anlyses could make these differentiations, the appropriate treatment strategy for respiratory infections could be established. To accomplish this, exact orientations of pulmonary lobulus, acinus, and respiratory bronchioles is very important. Then, through analyzing chest CT findings and distribution patterns based on normal anatomical structures, estimation of causative pathogens could be possible. Especially, whether inflammatory exudates could pass Kohn's pores as well as Lambert's channel or not is very important factor to affect radiological findings of several pneumonia (as traditionally called "segmental" and "nonsegmental" distribution). To differentiate infections caused by Mycobacterium tuberculosis from nontuberculous mycobacteria, several important criteria have been demonstrated. Briefly, it has been suggested that Mycobacterium avium complex (MAC) respiratory infection is increasing especially in elderly women without underlying diseases. In MAC respiratory infection, right middle lobe and left lingula are frequently involved and centrilobular nodules and diffuse bronchiectases are characteristic radiological findings. Finally, the role of telithromycin in the treatment of respiratory infections is discussed.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Diagnosis, Differential; Humans; Ketolides; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Pneumonia, Bacterial; Radiography, Thoracic; Respiratory Tract Infections

The pharmacology, mechanisms of resistance, in vitro activity, clinical efficacy, pharmacokinetics, indications, adverse effects, dosage and administration, and place in therapy of telithromycin in the treatment of respiratory infections are reviewed.. Telithromycin is the first ketolide to be approved in the United States for use against common respiratory pathogens. The unique structure of telithromycin allows for enhanced binding to bacterial ribosomal RNA, thereby blocking protein synthesis. Its spectrum of activity includes pathogens implicated in common respiratory infections (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumonia, and Chlamydia pneumoniae) and multidrug-resistant isolates of pneumococcus. Clinical efficacy has been documented in several multicenter, comparative trials for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, and pharyngitis tonsillitis. Although studies have demonstrated that the clinical efficacy of telithromycin is comparable to macrolides, telithromycin is unique in that it provides activity against penicillin- and macrolide-resistant respiratory pathogens. The recommended dosage of telithromycin is 800 mg p.o. once daily. The most common adverse events resulting from telithromycin use include diarrhea, nausea, headache, dizziness, vomiting, loose stools, dysgeusia, and dyspepsia. The drug's adverse-event profile is comparable to that of similar agents. Telithromycin is a strong inhibitor of cytochrome P-450 isoenzyme 3A4; therefore, it can affect the efficacy and toxicity profile of medications that are metabolized by this isoenzyme.. Telithromycin is a reasonable addition to the current treatment options for upper-respiratory-tract infections. Its use should be restricted to infections caused by penicillin- and macrolide-resistant pathogens.

Topics: Anti-Bacterial Agents; Biological Availability; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Half-Life; Humans; Intestinal Absorption; Ketolides; Microbial Sensitivity Tests; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Respiratory Tract Infections; Tissue Distribution

Telithromycin, a recently approved ketolide antibiotic derived from 14-membered macrolides, is active against erythromycin-resistant pneumococci. Telithromycin has enhanced activity in vitro because it binds not only to domain V of ribosomal RNA (like macrolides do) but also to domain II. However, it is not active against streptococci and staphylococci with constitutive macrolide, lincosamide, and streptogramin B resistance. Telithromycin, available in an oral formulation, is approved by the US Food and Drug Administration for use in adults for treatment of (1) community-acquired pneumonia due to Streptococcus pneumoniae (including multidrug-resistant isolates), Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae; (2) acute exacerbation of chronic bronchitis due to S. pneumoniae, H. influenzae, or M. catarrhalis; or (3) acute bacterial sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, or methicillin- and erythromycin-susceptible Streptococcus aureus. It is not approved for treatment of tonsillitis, pharyngitis, or severe pneumococcal pneumonia. Unique visual adverse effects occurred in 0.27%-2.1% of patients receiving telithromycin therapy. Its enhanced activity against some common respiratory pathogens makes it a valuable addition to the available macrolides.

Topics: Anti-Bacterial Agents; Drug Interactions; Drug Resistance, Bacterial; Humans; Ketolides; Respiratory Tract Infections; Structure-Activity Relationship

The potential efficacy of an antibacterial depends not only on its spectrum of activity but also on its concentration at the site of infection. The tissue kinetics of telithromycin-the first ketolide antibacterial-are reviewed here. Telithromycin accumulates rapidly in white blood cells, inflammatory fluid, and cells and tissues of the upper and lower respiratory tract, with mean concentrations above the MICs of key respiratory pathogens. Tissue kinetics of telithromycin support facilitated delivery to the site of infection, good efficacy against intracellular respiratory pathogens and respiratory pathogens at extracellular sites in the airways, and effectiveness in the treatment of upper and lower respiratory tract infections (RTIs). The tissue kinetics profile of telithromycin, together with its microbiological profile, makes it a promising new antibacterial for the treatment of community-acquired RTIs.

Topics: Anti-Bacterial Agents; Bacteria; Clinical Trials as Topic; Humans; Ketolides; Leukocytes; Macrolides; Respiratory System; Respiratory Tract Infections; Tissue Distribution

Topics: Anti-Bacterial Agents; Bronchitis; Clinical Trials as Topic; Humans; Ketolides; Macrolides; Pharyngitis; Pneumonia, Bacterial; Respiratory Tract Infections; Sinusitis; Tonsillitis

Despite the revolutionary introduction of antibiotic therapy in the post-World War II era, primary care physicians continue to struggle with the issue of optimal treatment strategies for bacterial infection and the growing problem of antimicrobial resistance. The aggressive use of potent agents as first-line therapy maximises the potential for successful eradication of bacterial pathogens and slowing of the development of drug-resistant strains. Therapeutic drug monitoring and quantitative assessment of antibacterial potency are not always feasible in daily practice, but the pharmacodynamic profiles of antibacterials - which integrate pharmacokinetic profiles and microbiological properties - can be used to predict clinical success. Telithromycin possesses pharmacodynamic characteristics that make this novel ketolide an optimal choice for the empirical management of community-acquired respiratory tract infections.

Topics: Anti-Infective Agents; Community-Acquired Infections; Humans; Ketolides; Macrolides; Respiratory Tract Infections; Treatment Outcome

Ketolides are a new class of semi-synthetic agents derived from erythromycin A designed to overcome erythromycin A resistance in Streptococcus pneumoniae. Telithromycin (HMR 3647) is the first member of this new class to be approved for clinical use. Cethromycin (ABT-773) has been developed up to Phase III, but its further development seems questionable at the moment. Other ketolides are only in the first stages of preclinical development and may not be available within the foreseeable future. Ketolide compounds inhibit bacterial protein synthesis by interacting with the peptidyl transferase site of the 50S ribosomal subunit, and interact closely with domains II at A752 and V at A2058 and A2059 of the 23S rRNA. These compounds also inhibit the formation of the 50S subunit of the ribosome. Ketolides show good activity against the Gram-positive bacteria responsible for respiratory tract infections including penicillin G- and erythromycin A-resistant S. pneumoniae. The 15 clinical trials with telithromycin published to date include four randomized, double-blind comparative trials and three open-label studies in community-acquired pneumonia, three randomized double-blind trials in acute exacerbation of chronic bronchitis, two randomized double-blind trials in pharyngitis, and two double-blind comparative trials and one open-label trial in acute maxillary sinusitis. Clinical response rates were favourable in all clinical trials, with eradication rates in patients with pneumococcal bacteraemia and penicillin G- and erythromycin A-resistant pneumococcal infections at least as high as those of comparators. As resistance to macrolides continues to emerge, the availability of other ketolides besides telithromycin and a development programme for the application of ketolides in children would appear to be warranted to obtain a new class of antibiotics that may one day replace macrolides.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Clinical Trials as Topic; Humans; Ketolides; Macrolides; Respiratory Tract Infections

Telithromycin, a ketolide antibiotic used for the treatment of community-acquired respiratory infections, is widely prescribed in primary care practice. Treatment-related adverse events are mainly of gastrointestinal origin and generally mild in intensity. The authors report the first case of telithromycin-induced severe acute interstitial nephritis. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure.

Topics: Acute Disease; Adolescent; Humans; Ketolides; Kidney; Male; Methylprednisolone; Nephritis, Interstitial; Respiratory Tract Infections

Topics: Community-Acquired Infections; Contraindications; Drug Interactions; Drug Prescriptions; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Medical History Taking; Microbial Sensitivity Tests; Nurse Practitioners; Patient Selection; Primary Health Care; Respiratory Tract Infections; Severity of Illness Index; Treatment Outcome

Telithromycin (Ketek), Aventis Pharma), a ketolide, belongs to a new class of antibiotics that was developed for the treatment of upper and lower respiratory tract infections. The prevalence of penicillin and macrolide resistance among respiratory pathogens is increasing in the USA. Telithromycin is highly active against beta-lactam, macrolide and fluoroquinolone reduced-susceptibility pathogens. Its efficacy has been shown to be equal or superior to comparator agents in numerous studies. It has a broad in vitro spectrum versus usual respiratory pathogens and oral once-daily dosing that increases patient compliance. Telithromycin penetrates rapidly into neutrophils in bronchopulmonary tissue, with peak levels obtained in 1 to 2 h. Results of clinical trials show clinical-esponse rates similar to comparator agents. The most frequent adverse events involve the gastrointestinal system, with mild to moderate diarrhea and nausea. A low rate of discontinuation was observed in the studies. Telithromycin is an effective first-line treatment for mild to moderate respiratory infections in adults.

Topics: Anti-Bacterial Agents; Clinical Trials as Topic; Community-Acquired Infections; Drug Interactions; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Respiratory Tract Infections

The global emergence of antibacterial resistance among common and atypical respiratory pathogens in the last decade necessitates the strategic application of antibacterial agents. The use of bactericidal rather than bacteriostatic agents as first-line therapy is recommended because the eradication of microorganisms serves to curtail, although not avoid, the development of bacterial resistance. Bactericidal activity is achieved with specific classes of antimicrobial agents as well as by combination therapy. Newer classes of antibacterial agents, such as the fluoroquinolones and certain members of the macrolide/lincosamine/streptogramin class have increased bactericidal activity compared with traditional agents. More recently, the ketolides (novel, semisynthetic, erythromycin-A derivatives) have demonstrated potent bactericidal activity against key respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Moraxella catarrhalis. Moreover, the ketolides are associated with a low potential for inducing resistance, making them promising first-line agents for respiratory tract infections.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Ketolides; Macrolides; Pneumonia, Pneumococcal; Respiratory Tract Infections; Streptococcus pneumoniae

Telithromycin (HMR 3647) is the first ketolide introduced into clinical practice. Ketolides are semisynthetic derivates of erythromycin A that carry novel biological properties on the erythronolide A ring. This new class of antimicrobials was designed to overcome current resistance mechanisms against erythromycin A within Gram-positive cocci. Ketolides do not induce macrolide-lincosamide-streptogramin B (MLS(B)) resistance and are active against erythromycin resistance methylase gene (erm)-carrying Gram-positive cocci. This review summarizes published data on telithromycin and intends to define the challenge that a new antimicrobial brings to medical practice.

Topics: Animals; Anti-Bacterial Agents; Base Sequence; Clinical Trials as Topic; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Molecular Sequence Data; Respiratory Tract Infections; RNA, Bacterial

Pathogens implicated in community-acquired respiratory tract infections are becoming increasingly resistant to anti-bacterial therapies. Thus, there is an urgent need for new agents with activity against current resistant respiratory tract pathogens and a low potential to select for resistance or induce cross-resistance to existing antibacterial agents. Telithromycin, the first ketolide antibacterial agent to undergo clinical development, has enhanced binding to bacterial ribosomal RNA. Through its unique structure, telithromycin retains activity against resistant respiratory pathogens and has shown high efficacy in the treatment of respiratory tract infections. On the basis of phase 3 clinical trial experience, telithromycin appears safe and well tolerated across various patient populations, including high-risk groups.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Interactions; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Ketolides; Macrolides; Primary Health Care; Respiratory Tract Infections

Resistance to antibiotics in community acquired respiratory infections is increasing worldwide. Resistance to the macrolides can be class-specific, as in efflux or ribosomal mutations, or, in the case of erythromycin ribosomal methylase (erm)-mediated resistance, may generate cross-resistance to other related classes. The ketolides are a new subclass of macrolides specifically designed to combat macrolide-resistant respiratory pathogens. X-ray crystallography indicates that ketolides bind to a secondary region in domain II of the 23S rRNA subunit, resulting in an improved structure-activity relationship. Telithromycin and cethromycin (formerly ABT-773) are the two most clinically advanced ketolides, exhibiting greater activity towards both typical and atypical respiratory pathogens. As a subclass of macrolides, ketolides demonstrate potent activity against most macrolide-resistant streptococci, including ermB- and macrolide efflux (mef)A-positive Streptococcus pneumoniae. Their pharmacokinetics display a long half-life as well as extensive tissue distribution and uptake into respiratory tissues and fluids, allowing for once-daily dosing. Clinical trials focusing on respiratory infections indicate bacteriological and clinical cure rates similar to comparators, even in patients infected with macrolide-resistant strains.

Topics: Anti-Bacterial Agents; Clinical Trials as Topic; Drug Resistance, Multiple, Bacterial; Erythromycin; Humans; Ketolides; Macrolides; Respiratory Tract Infections; Streptococcus pneumoniae

Recent data from surveillance studies suggest that levels of resistance to macrolide, lincosamide and streptograminB (MLSB) antibacterials in respiratory tract pathogens, particularly Streptococcus pneumoniae, are rising and limiting the usefulness of these drugs. New agents that do not select for resistance are essential to safeguard the future of antibacterial efficacy. The ketolides, of which telithromycin is the first to be registered for clinical use, represent a new class of antibacterials developed specifically for optimal empirical treatment of respiratory tract infections (RTIs). Although derived chemically from macrolides, the ketolides, which possess innovative structural modifications, form a unique class in the macrolide family. A keto function at position 3 of the erythronolide A ring replaces the L-cladinose moiety, generating a class of compounds that, unlike 14- and 15-membered ring macrolides, will not induce MLSB resistance in vitro. A large aromatic N-substituted C11,12-carbamate side chain allows a more effective interaction with domain II of the 23S rRNA, enhancing binding to bacterial ribosomes and allowing binding to MLSB-resistant ribosomes. This novel structure allows ketolides to exert intrinsic activity against respiratory tract pathogens, avoid induction of MLSB resistance, and retain activity against MLS(B)-resistant strains. Furthermore, ketolides have a low potential to select for resistance and cross-resistance both in vitro and in vivo, making them an attractive option for the empirical treatment of RTIs.

Topics: Anti-Bacterial Agents; Drug Design; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Mutation; Respiratory Tract Infections; Streptococcal Infections; Streptococcus pneumoniae

With the global spread of antibacterial resistance, selecting appropriate therapy for respiratory tract infections (RTIs) presents a major challenge. Current opinion favours short-duration chemotherapy, which can improve patient compliance, thereby reducing potential resistance, minimize toxicodynamic profiles and decrease treatment costs. Neither microbiological nor pharmacokinetic (PK) data alone can determine whether a drug is suitable for short-duration therapy. Pharmacodynamics (PD) seeks to integrate PK and microbiological data into models that can then be used to predict clinical outcomes and to guide rational dosing strategies. Telithromycin is the first ketolide antibacterial to undergo clinical development. Its novel structure provides enhanced microbiological activity, even against beta-lactam and macrolide-resistant pathogens, and the potential to minimize the selection of resistance. PK profiling of telithromycin reveals that once-daily oral administration of 800 mg achieves plasma concentrations that exceed the MICs of key respiratory pathogens throughout most of the dosing period. PK-PD modelling indicates that the AUC:MIC ratio is predictive of outcome for this antibacterial. Telithromycin achieves high AUC:MIC ratios, has a prolonged postantibiotic effect, shows excellent penetration into respiratory and inflammatory tissues and has a long elimination half-life from these tissues. These variables strongly suggest that telithromycin is suitable for short-duration therapy and a once-daily dosing regimen.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Administration Schedule; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Patient Compliance; Respiratory Tract Infections; Time Factors

To review the chemistry, spectrum of activity, pharmacology, clinical efficacy, and safety of telithromycin.. A MEDLINE search from 1966 to December 2000 was performed via OVID and PubMed using the following search terms: HMR 3647, HMR3647, Ketek, RU 66647, and telithromycin. An extensive review of retrieved literature, abstracts from international scientific conferences, and minutes from regulatory authority meetings was also performed.. Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the antimicrobial activity, clinical efficacy, pharmacology, and safety of telithromycin.. Several chemical modifications to the macrolide structure have led to the development of telithromycin, the first ketolide antimicrobial that demonstrates improved activity against penicillin- and macrolide/azalide-resistant Streptococcus pneumoniae due to its unique binding to the ribosomal target site. Although telithromycin may be useful in the treatment of community-acquired respiratory tract infections due to its activity against common typical and atypical pathogens, questions concerning its reliable activity against Haemophilus influenzae need to be addressed. Telithromycin's pharmacokinetics permit once-daily dosing for abbreviated periods and good distribution into lung tissue and phagocytic cells. Clinical and bacteriologic cure rates have been similar to those of comparator agents in human efficacy trials; however, the incidence of adverse gastrointestinal events were generally higher with telithromycin patients. Like other macrolides and many newer fluoroquinolones, telithromycin's ability to prolong the QTc interval is a potential safety issue, especially in elderly patients with predisposing conditions or those who are concurrently receiving drugs that are substrates for CYP2D6 and 3A4. Liver function test elevations demonstrated during clinical trials, although not overtly severe, may warrant monitoring in some patients taking multiple hepatically metabolized/cleared agents.. Telithromycin offers potential advantages over traditional macrolides/azalides for community-acquired respiratory tract infections caused by macrolide-resistant pathogens. Further studies are needed to elucidate its clinical efficacy against H. influenzae, potential drug interactions, and safety in various subpopulations.

Topics: Adult; Anti-Bacterial Agents; Area Under Curve; Biological Availability; Drug Interactions; Humans; Intestinal Absorption; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Respiratory Tract Infections

Current antimicrobial therapy for community-acquired respiratory tract infections (RTIs) is empirical and is influenced by local differences in etiology and bacterial susceptibility. As the rates of resistance and cross-resistance to currently available classes of antimicrobial agents increase, their effectiveness becomes compromised. These issues demand improved strategies for antimicrobial usage, and the development of new agents that do not select resistance are essential to safeguard future antimicrobial efficacy. Strategies to minimize antimicrobial resistance among common RTIs include reducing antimicrobial consumption and controlling the development and spread of resistance through appropriate prescribing and the use of short-duration, once-daily treatments to improve patient compliance. Importantly, the ketolides, which are a new family of antimicrobials, have been recently developed specifically for the treatment of community-acquired RTIs. The first member of this new family, telithromycin, has been shown to have potent activity against common and atypical respiratory pathogens, including beta-lactam- and macrolide-resistant strains, and has a low potential to select for or induce cross-resistance. These properties, combined with its good tolerability across patient groups, make telithromycin an attractive option for the first-line empiric treatment of RTIs with the potential to limit the future development of resistance.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Community-Acquired Infections; Drug Resistance, Microbial; Humans; Ketolides; Macrolides; Patient Compliance; Respiratory Tract Infections; Streptococcus pneumoniae

Telithromycin, the first of the ketolide antimicrobials, has been specifically designed to provide potent activity against common and atypical/intracellular or cell-associated respiratory pathogens, including those that are resistant to beta-lactams and/or macrolide-lincosamide-streptograminB (MLS(B)) antimicrobials. Against gram-positive cocci, telithromycin possesses more potent activity in vitro and in vivo than the macrolides clarithromycin and azithromycin. It retains its activity against erm-(MLS(B)) or mef-mediated macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes and against Staphylococcus aureus resistant to macrolides through inducible MLS(B) mechanisms. Telithromycin also possesses high activity against the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis, regardless of beta-lactamase production. In vitro, it shows similar activity to azithromycin against H. influenzae, while in vivo its activity against H. influenzae is higher than that of azithromycin. Telithromycin's spectrum of activity also extends to the atypical, intracellular and cell-associated pathogens Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae. In vitro, telithromycin does not induce MLS(B) resistance and it shows low potential to select for resistance or cross-resistance to other antimicrobials. These characteristics indicate that telithromycin will have an important clinical role in the empirical treatment of community-acquired respiratory tract infections.

Topics: Anti-Bacterial Agents; Chlamydophila pneumoniae; Gram-Negative Bacteria; Gram-Positive Cocci; Haemophilus influenzae; Humans; Ketolides; Legionella pneumophila; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Mycoplasma pneumoniae; Respiratory Tract Infections; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes

The effectiveness of empirical treatment for respiratory tract infections (RTIs) with commonly available antimicrobials is threatened by the development of microbial resistance and cross-resistance between treatments. Pharmacokinetic and pharmacodynamic profiling of antimicrobial agents is increasingly being used to select the most appropriate treatment and dosage schedules for RTIs. In addition to enhancing management strategies with existing treatments, these profiles have played a key part in identifying dosage schedules for a new family of semisynthetic antimicrobials, the ketolides. The first member of this family, telithromycin, has potent activity against both common and atypical pathogens involved in RTIs and does not induce resistance to the macrolide-lincosamide-streptogramin B (MLS(B)) antimicrobials in vitro. Its pharmacokinetic profile reveals that telithromycin can be administered once daily without regard for meals, requires no dose reduction in elderly patients or those with hepatic impairment, and penetrates rapidly into respiratory tissues and fluids, a feature probably related to its ability to concentrate inside white blood cells. Pharmacodynamic studies indicate that the area under the concentration-time curve (AUC):minimum inhibitory concentration (MIC) and the peak plasma concentration (Cmax):MIC ratios are important determinants of bacteriological outcome with telithromycin. Telithromycin has a high AUC:MIC ratio compared with macrolide antimicrobials, which is expected to result in enhanced antimicrobial activity. These properties of telithromycin, combined with its good tolerability and low propensity for drug interactions, provide the basis for potent and reliable treatment of RTIs with a convenient, once-daily regimen.

Topics: Aged; Animals; Anti-Bacterial Agents; Area Under Curve; Drug Resistance, Microbial; Humans; Ketolides; Macrolides; Male; Mice; Microbial Sensitivity Tests; Respiratory Tract Infections

Atypical respiratory pathogens such as Mycoplasma pneumoniae and intracellular pathogens such as Legionella spp. and Chlamydia spp. form a significant proportion of the aetiological agents underlying community-acquired pneumonia (CAP). The clinical signs or radiological features of atypical pneumonia are generally insufficient to predict accurately the pathogen involved; in addition, high costs and a considerable length of time are involved in the identification of atypical pathogens. Treatment is, therefore, most often empirical, and it is important that the activity of antibacterial agents available to treat CAP is sufficiently broad to eradicate infection with both common and atypical bacterial pathogens. Telithromycin (HMR 3647) 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). The excellent activity of telithromycin against the respiratory tract bacterial pathogens most commonly associated with community-acquired RTIs, including resistant strains, is well established. This review examines the considerable body of evidence showing that telithromycin also has a high level of activity against atypical and intracellular respiratory tract bacterial pathogens.

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

Community-acquired respiratory tract infections (RTIs) are among the most prevalent infectious diseases in the developed world. They cause considerable morbidity, resulting in a major impact on public health both clinically and socioeconomically. The bacterial pathogens most commonly associated with community-acquired RTIs are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, with Streptococcus pyogenes predominating in pharyngitis. Over the past years, each of these pathogens has developed mechanisms to evade susceptibility to antibacterials, leading to an alarming global increase in antibacterial resistance among these pathogens. There is great concern that currently available antibacterials are insufficient to treat community-acquired RTIs and there is an urgent requirement for new agents with activity against all strains of common community-acquired RTI pathogens. Telithromycin (HMR 3647) belongs to a new family of antibacterials, the ketolides, and has been specifically designed for the treatment of community-acquired RTIs. This review covers the potent in vitro activity of telithromycin against the most common community-acquired RTI pathogens compared with other currently available antimicrobial agents.

Topics: Animals; Anti-Bacterial Agents; Community-Acquired Infections; Humans; Ketolides; Macrolides; Respiratory Tract Infections

The ketolides represent a new subclass of antibiotics among the macrolide-lincosamide-streptogramin group. Telithromycin, the first ketolide to be awarded approvable status for clinical use, demonstrates in vitro activity against community-acquired respiratory pathogens including penicillin- and erythromycin-resistant Streptococcus pneumoniae. An extended half-life permits once-daily oral administration. Telithromycin is a substrate for cytochrome P450 (CYP) 3A4 and also inhibits drugs metabolized by CYP3A4. A relatively high frequency of mild-to-moderate gastrointestinal adverse effects has been reported. Similar clinical and microbiologic efficacy has been demonstrated with oral dosing in comparative clinical trials for community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis, and pharyngitis. Although limited data on penicillin-resistant S. pneumoniae and erythromycin-resistant Streptococcus pyogenes are available from clinical trials, this drug appears promising for respiratory infections caused by these pathogens.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacteria; Clinical Trials as Topic; Drug Interactions; Drug Resistance; Humans; Ketolides; Macrolides; Respiratory Tract Infections

The aim of antibacterial chemotherapy is to achieve sufficient drug concentrations at the site of infection for an adequate length of time to ensure bacterial eradication and optimize clinical success. Whether the desired outcome is achieved or not depends on a number of pathogen-, drug- and patient-related factors. Neither microbiologic activity nor antibacterial pharmacokinetic data alone can adequately describe the complex interaction between pathogen, host and antibacterial during the disease process. A relatively new discipline - pharmacodynamics - seeks to integrate both microbiologic and pharmacokinetic data. The particular model that best predicts clinical outcome depends on the pattern of microbial killing and the persistence of antibacterial effects after plasma concentrations have fallen below the minimum inhibitory concentration (MIC) for the target pathogen (post-antibiotic effect [PAE]). The beta-lactams, for example, exhibit time-dependent bacterial killing with minimal persistent effects. Time above MIC (T(MIC)) is therefore the parameter that best correlates with clinical efficacy for these agents and that, in turn, necessitates multiple daily dosing to optimize the duration of exposure. The macrolides erythromycinA and clarithromycin exhibit a similar pharmacokinetic/pharmacodynamic relationship to that of the beta-lactams, although for clarithromycin the area under the concentration-time curve (AUC) also correlates with clinical outcome (reflecting the more prolonged PAE of this agent). Azithromycin, ketolides, such as telithromycin (HMR 3647), streptogramins and fluoroquinolones exhibit concentration-dependent killing and have prolonged persistent effects, such that the AUC:MIC or Cmax:MIC ratio correlates most closely with clinical efficacy. For these agents the aim is to maximize drug concentrations to which the target pathogen is exposed and this may require higher doses and hence enable longer dosing intervals to be used. In summary, pharmacodynamic models provide a unique approach to determining likely in vivo activity of individual antibacterial agents and prediction of clinical outcomes.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Models, Animal; Respiratory Tract Infections

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

CHANGING RESISTANCE OF GRAM-POSITIVE COCCI: Several new families of antibiotics are under development in response to the changing resistance of Gram-positive cocci. Linezolide, the leading member of the oxazolidinone family and telithromycin and ABT-773, leading members of the ketolide family have reached an advanced stage of development. INHIBITION OF PROTEIN SYNTHESIS: Oxazolidinones and ketolides inhibit protein synthesis at different levels. Oxazolidinones inhibit formation of the 70S initiation complex and ketolides block the protein elongation step by inhibiting peptidyl transferase. MECHANISMS OF RESISTANCE: To date, no cross resistance of linezolide with other antibiotic families used for the treatment of Gram-positive bacteria has been observed. It is quite difficult to obtain resistant mutants in the laboratory but two point mutations on the 23S ribosome fraction have been described in vivo. Resistance of Gram-positive cocci to macrolides occur via mechanisms altering the target (methylation of 23S rRNA or ribosome protein mutations) or via mechanisms involving active efflux. LINEZOLIDE: Linezolide is highly active in vitro against meticillin-resistant Staphylococcus aureus (MRSA), against Streptococcus including resistant pneumococcal strains, and against glycopeptide-resistant E. faecium and E. faecalis strains. TELITHROMYCIN AND ABT-773: These ketolides are active against Streptococcus and Pneumococcus strains exhibiting erythromycin-inducible resistance and resistance by active efflux. In addition, these antibiotics are highly active against other bacteria causing respiratory tract infections (Moraxella and Haemophilus), anaerobic germs and intracellular germs (Legionella).

Topics: Acetamides; Anti-Bacterial Agents; Erythromycin; Gram-Positive Bacterial Infections; Humans; Ketolides; Linezolid; Macrolides; Microbial Sensitivity Tests; Oxazolidinones; Respiratory Tract Infections; Streptococcus; Structure-Activity Relationship

Antimicrobial efficacy is dependent on the ability of the agent to reach the site of infection. To assess the bronchopulmonary drug disposition of a novel ketolide, telithromycin (TEL), the epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations were utilized as a surrogate marker for lung penetration.. Adult subjects scheduled for diagnostic bronchoscopy received oral TEL 800 mg once daily for 5 days. Plasma and bronchoalveolar lavage (BAL) samples were collected 2, 8, 12, or 24 h after the last TEL dose. TEL concentrations in the ELF and AM were determined using a validated HPLC assay. ELF drug concentrations were calculated using the urea dilution method.. Seventeen subjects with a mean age 65 +/- 13 years and a mean weight of 81 +/- 25 kg completed this open-label study. The median (range) TEL concentrations in plasma and ELF, respectively, were 1.09 mg/l (1.00-4.81) and 3.91 mg/l (2.64-9.59) at 2 h (n = 6), 0.48 and 1.09 mg/l at 8 h (n = 1), 0.65 mg/l (0.18-1.55) and 1.81 mg/l (0.61-10.0) at 12 h (n = 5), and 0.11 mg/l (0.09-0.24) and 0.69 mg/l (0.15-1.58) at 24 h (n = 5). The median AM concentrations obtained from these subjects were 53.35 mg/l at 2 h, 32.55 mg/l at 8 h, 65.96 mg/l at 12 h, and 26.43 mg/l at 24 h. Overall TEL was well tolerated. No discontinuation was required due to an adverse event.. TEL displayed high intrapulmonary penetration with ELF concentrations exceeding that of plasma at all time points. AM intracellular concentrations were multiple times higher than in the ELF and plasma. These data support the clinical efficacy of TEL against intracellular and extracellular pathogens, particularly with Streptococcus pneumoniae having an MIC(90 )well below achievable concentrations at the site of infection.

Topics: Aged; Analysis of Variance; Anti-Bacterial Agents; Area Under Curve; Biological Availability; Bronchoalveolar Lavage Fluid; Female; Humans; Ketolides; Lung; Macrophages, Alveolar; Male; Pneumococcal Infections; Prospective Studies; Respiratory Tract Infections; Statistics, Nonparametric

The incidence of community-acquired respiratory tract infections caused by Streptococcus pneumoniae exhibiting antibacterial resistance has increased dramatically in recent years. Telithromycin is the first of a new class of antibacterials, the ketolides, which have been developed specifically to provide effective treatment for these infections. Data were analysed from 3935 patients who had participated in one Japanese Phase II study and 11 US/global Phase III studies in three indications: community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute sinusitis. Patients received either telithromycin 800 mg once daily or a comparator antibacterial. S. pneumoniae isolates considered to be causative for infection were tested for susceptibility to penicillin G and erythromycin A. In per-protocol analyses, telithromycin showed a high level of clinical efficacy against S. pneumoniae, with clinical cure rates of 92.8% for all isolates, 91.7% for those with reduced susceptibility to penicillin G and 86.0% for those with reduced susceptibility to erythromycin A. Bacterial eradication rates were consistent with the clinical outcomes. High rates of clinical cure and bacterial eradication were also observed for infections caused by isolates demonstrating high-level resistance to erythro-mycin A [MICs >/= 512 mg/L: 100% (13/13) clinical cure, 100% (13/13) bacterial eradication]. These results support the use of telithromycin as a first-line oral therapy for the treatment of community-acquired respiratory tract infections caused by S. pneumoniae with reduced susceptibility to penicillin G and erythromycin A.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Female; Humans; Japan; Ketolides; Macrolides; Male; Middle Aged; Penicillin Resistance; Pneumococcal Infections; Respiratory Tract Infections; Treatment Outcome

The pharmacokinetics in plasma and saliva of a new ketolide, telithromycin (HMR 3647), and the effect on the normal oropharyngeal and intestinal microflora were studied in healthy volunteers and compared with those of clarithromycin. Ten subjects received 800 mg telithromycin perorally once daily and 10 other subjects received 500 mg clarithromycin bid for 10 days. Blood, saliva and faecal specimens were collected at defined intervals before, during and after administration for pharmacokinetic and microbiological analyses. In subjects receiving telithromycin, the mean C:(max), AUC and C:(24) (24 h) in saliva exceeded the values obtained from plasma, while saliva and serum pharmacokinetic parameters were in the same range for the clarithromycin group. The quantitative ecological disturbances in the normal microflora during administration of telithromycin were moderate and comparable to those associated with clarithromycin administration. No overgrowth of yeasts or Clostridium difficile occurred. Emergence of resistant strains was seen in both treatment groups. Administration of both telithromycin and clarithromycin was associated with significant increases in MICs for intestinal Bacteroides isolates, which persisted 2 weeks after discontinuation of treatment. In addition, a significant emergence of highly clarithromycin-resistant alpha-haemolytic streptococci, intestinal enterococci and Enterobacteriaceae was detected at day 10 in the clarithromycin group. In conclusion, administration of telithromycin resulted in high drug levels in saliva, which indicates a good therapeutic profile for throat infections. Telithromycin seems to have a more favourable ecological profile compared with clarithromycin in terms of resistance development in the normal microflora.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Area Under Curve; Bacteroides; Clarithromycin; Double-Blind Method; Feces; Female; Humans; Intestines; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Oropharynx; Respiratory Tract Infections; Saliva; Statistics, Nonparametric

Clinical pharmacokinetic profiles of clarithromycin and telithromycin in bronchopulmonary sites have not been fully characterized. This study aimed to describe in more detail the pharmacokinetics of the two macrolides in epithelial lining fluid (ELF) of human bronchi and to evaluate their pharmacodynamic target attainment at this site.. Previously reported drug concentration data for serum and ELF were simultaneously fitted to a three-compartment pharmacokinetic model using nonmem program. The model parameter estimates were used for site-specific pharmacodynamic simulation.. Population mean parameters for clarithromycin were as follows: distribution volumes of central, peripheral and ELF compartments (V1 /F, V2 /F and V3 /F) = 204·7, 168·9 and 67·1 L; clearance (CL/F) = 34·4 L/h; absorption rate constant (Ka ) = 0·680 1/h; transfer rate constants connecting compartments (K12 , K21 , K13 and K31  = 0·0193, 0·434, 0·667 and 0·260 1/h, respectively). Mean parameters for telithromycin were as follows: V1 /F, V2 /F and V3 /F = 370·3, 290·3 and 213·8 L; CL/F = 89·5 L/h; Ka  = 0·740 1/h; K12 , K21 , K13 and K31  = 0·0026, 1·044, 0·758 and 0·158 1/h, respectively. Using these parameters, the mean ELF/serum ratio in the area under drug concentration-time curve (AUC) was 7·80 for clarithromycin and 8·05 for telithromycin. Clarithromycin achieved a ≥ 90% probability of attaining a pharmacodynamic target [AUC/minimum inhibitory concentration (MIC) = 100] in ELF against bacterial isolates for which MICs were ≤0·5 and ≤1 mg/L for twice-daily doses of 250 and 500 mg, respectively. For telithromycin, once-daily doses of 600 and 800 mg achieved a ≥90% probability in ELF against Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis isolates but not Haemophilus influenzae isolates.. These results should provide a better understanding of the bronchial pharmacokinetics of clarithromycin and telithromycin, while also providing useful information about their dosages for respiratory tract infections based on site-specific pharmacodynamic evaluation. Further studies in a large number of patients are needed to confirm our findings and clarify their therapeutic implications.

Topics: Anti-Bacterial Agents; Area Under Curve; Bacteria; Bronchi; Clarithromycin; Computer Simulation; Dose-Response Relationship, Drug; Epithelium; Humans; Ketolides; Microbial Sensitivity Tests; Models, Biological; Nonlinear Dynamics; Respiratory Tract Infections; Tissue Distribution

A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These compounds showed significantly potent antibacterial activity against not only Gram-positive pathogens, including macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity against telithromycin resistant Streptococcus pneumoniae strains.

Topics: Anti-Bacterial Agents; Chemistry, Pharmaceutical; Clarithromycin; Drug Design; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Ketolides; Microbial Sensitivity Tests; Models, Chemical; Nitrogen; Respiratory Tract Infections; Streptococcus pneumoniae

We have shown that clarithromycin (CAM), a macrolide antibiotic, more highly distributes from plasma to lung epithelium lining fluid (ELF), the infection site of pathogens, than azithromycin (AZM) and telithromycin (TEL). Transporter(s) expressed on lung epithelial cells may contribute to the distribution of the compiunds to the ELF. However, distribution mechanisms are not well known. In this study, their transport characteristics in Calu-3 cell monolayers as model lung epithelial cells were examined. The basolateral-to-apical transport of CAM through Calu-3 cell monolayers was greater than that of AZM and TEL. Although verapamil and cyclosporine A as MDR1 substrates completely inhibited the basolateral-to-apical transport, probenecid as MRP1 inhibitor did not show an effect. These results suggest that the antibiotics are transported from plasma to ELF by MDR1 of lung epithelial cells. In addition, their affinity and binding rate to MDR1 was examined by ATP activity assay. The affinity and binding rate of CAM was greater than those of AZM and TEL. These corresponded with the distributions from plasma to ELF as described above. The present study suggests that the more highly distribution of CAM from plasma to ELF is due to the high affinity and binding rate to MDR1 of lung epithelial cells.

Topics: Adenosine Triphosphatases; Algorithms; Animals; Anti-Bacterial Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azithromycin; Biological Transport, Active; Cell Line; Clarithromycin; Epithelial Cells; Ketolides; Lung; Mice; Multidrug Resistance-Associated Proteins; Protein Binding; Respiratory Tract Infections

The efficacy of aerosol-based delivery of telithromycin (TEL), as a model antimicrobial agent, for the treatment of respiratory infections was evaluated by comparison with oral administration.. The aerosol formulation (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer.. The time courses of the concentration of TEL in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) following administration of an aerosol formulation to rat lungs were markedly higher than that following the administration of an oral formulation (50 mg/kg). The time course of the concentrations of TEL in plasma following administration of the aerosol formulation was markedly lower than that in ELF and AMs. These results indicate that the aerosol formulation is more effective in delivering TEL to ELF and AMs, compared to the oral formulation, despite a low dose and it avoids distribution of TEL to the blood. In addition, the antibacterial effects of TEL in ELF and AMs following administration of the aerosol formulation were estimated by pharmacokinetics/pharmacodynamics analysis. The concentrations of TEL in ELF and the AMs time curve/minimum inhibitory concentration of TEL ratio were markedly higher than the effective values.. This study indicates that an antibiotic aerosol formulation may be an effective pulmonary drug delivery system for the treatment of respiratory infections.

Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Epithelial Cells; Extracellular Fluid; Haemophilus influenzae; Ketolides; Lung; Macrophages, Alveolar; Rats; Rats, Sprague-Dawley; Respiratory Tract Infections; Streptococcus pneumoniae; Technology, Pharmaceutical

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

In an effort to find new antibiotics, a novel series of 14-membered macrolides with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains has been synthesized based on commercially available clarithromycin. Chemical transformation of hydroxy group at position C-3 afforded range of ketolides and acylides. Compared to telithromycin, compound 15a demonstrated improved in vitro activity against erythromycin-susceptible and -resistant strains.

Topics: Anti-Bacterial Agents; Chemistry, Pharmaceutical; Clarithromycin; Drug Design; Drug Resistance, Multiple, Bacterial; Erythromycin; Humans; Imidazoles; Ketolides; Macrolides; Microbial Sensitivity Tests; Models, Chemical; Respiratory Tract Infections; Staphylococcus aureus; Streptococcus pneumoniae; Sulfides; Sulfur

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Topics: Animals; Azetidines; Bacteria; Community-Acquired Infections; Disease Susceptibility; Drug Discovery; Drug Resistance, Multiple; Drug-Related Side Effects and Adverse Reactions; Humans; Ketolides; Mice; Microbial Sensitivity Tests; Respiratory Tract Infections

The increasing prevalence of resistance to established antibiotics among key bacterial respiratory tract pathogens, such as Streptococcus pneumoniae, is a major healthcare problem in the USA. The PROTEKT US study is a longitudinal surveillance study designed to monitor the susceptibility of key respiratory tract pathogens in the USA to a range of commonly used antimicrobials. Here, we assess the geographic and temporal trends in antibacterial resistance of S. pneumoniae isolates from patients with community-acquired respiratory tract infections collected between Year 1 (2000-2001) and Year 4 (2003-2004) of PROTEKT US.. Antibacterial minimum inhibitory concentrations were determined centrally using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method; susceptibility was defined according to CLSI interpretive criteria. Macrolide resistance genotypes were determined by polymerase chain reaction.. A total of 39,495 S. pneumoniae isolates were collected during 2000-2004. The percentage of isolates resistant to erythromycin, penicillin, levofloxacin, and telithromycin were 29.3%, 21.2%, 0.9%, and 0.02%, respectively, over the 4 years, with marked regional variability. The proportion of isolates exhibiting multidrug resistance (includes isolates known as penicillin-resistant S. pneumoniae and isolates resistant to > or = 2 of the following antibiotics: penicillin; second-generation cephalosporins, e.g. cefuroxime; macrolides; tetracyclines; and trimethoprim-sulfamethoxazole) remained stable at approximately 30% over the study period. Overall mef(A) was the most common macrolide resistance mechanism. The proportion of mef(A) isolates decreased from 68.8% to 62.3% between Year 1 and Year 4, while the percentage of isolates carrying both erm(B) and mef(A) increased from 9.7% to 18.4%. Over 99% of the erm(B)+mef(A)-positive isolates collected over Years 1-4 exhibited multidrug resistance. Higher than previously reported levels of macrolide resistance were found for mef(A)-positive isolates.. Over the first 4 years of PROTEKT US, penicillin and erythromycin resistance among pneumococcal isolates has remained high. Although macrolide resistance rates have stabilized, the prevalence of clonal isolates, with a combined erm(B) and mef(A) genotype together with high-level macrolide and multidrug resistance, is increasing, and their spread may have serious health implications. Telithromycin and levofloxacin both showed potent in vitro activity against S. pneumoniae isolates irrespective of macrolide resistance genotype.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Pneumococcal Infections; Respiratory Tract Infections; Streptococcus pneumoniae; United States

Haemophilus influenzae is one of the main aetiological agents of community-acquired respiratory tract infections. The primary aim of this study was to evaluate the antibacterial activity of telithromycin against H. influenzae clinical isolates showing different pattern of resistance in comparison with azithromycin and clarithromycin at 1/4 x, 1/2 x, 1 x, 2 x, 4 x minimum inhibitory concentration (MIC) and to peak concentrations in epithelial lining fluid (ELF). The secondary aim was to determine the influence of CO2 enriched atmosphere on bacterial susceptibility.. Telithromycin showed high activity against H. influenzae, including strains susceptible to beta-lactams (n = 200), beta-lactamase producer (n = 50) and beta-lactamase negative ampicillin resistant (BLNAR) (n = 10), with MIC from < or =0.03 to 4 mg/L, and MIC50/MIC90 of 1/2 mg/L with susceptibility rate of 100%, and minimum bactericidal concentrations (MBC) from 2 to 4-fold higher than the MIC. Azithromycin was the most active tested macrolide (range: 0.25 - 4 mg/L; MIC50/MIC90: 1/2 mg/L), comparable to telithromycin, while clarithromycin showed the highest MICs and MBCs (range: 0.25 - 8 mg/L; MIC50/MIC90: 2/8 mg/L). In time-kill studies, telithromycin showed a bactericidal activity at the higher concentrations (4 - 2 x MIC and ELF) against all the strains, being complete after 12 - 24 hours from drug exposition. At MIC concentrations, at ambient air, bactericidal activity of telithromycin and azithromycin was quite similar at 12 hours, and better than that of clarithromycin. Besides, telithromycin and clarithromycin at ELF concentrations were bactericidal after 12 hours of incubation for most strains, while 24 hours were needed to azithromycin to be bactericidal. Incubation in CO2 significantly influenced the MICs and MBCs, and only slightly the in vitro killing curves.. Telithromycin showed an in-vitro potency against H. influenzae comparable to azithromycin, with an in-vitro killing rate more rapid and superior to clarithromycin at 2X-MIC against beta-lactamase producers and BLNAR strains, and to azithromycin at ELF concentrations against beta-lactamase negative strains. Against all strains, MICs and MBCs were lower in the absence of CO2 for the tested antibiotics, showing an adverse effect of incubation in a CO2 environment. The in-vitro potency together with the tissue concentrations of the antimicrobial, should be considered in predicting efficacy.

Topics: Anti-Bacterial Agents; Azithromycin; beta-Lactamases; Carbon Dioxide; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Microbial Sensitivity Tests; Respiratory Tract Infections; Time Factors

Susceptibility to a range of antimicrobial agents was determined among isolates of Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae collected in 12 centers throughout Japan during years 1-5 (the respiratory seasons of 1999-2004) of the longitudinal Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin study. The most frequent source of isolates of S. pneumoniae was from patients with community-acquired pneumonia (CAP) (25.3%). Reduced susceptibility to penicillin or erythromycin resistance was common among S. pneumoniae isolates (30.9-44.5% and 77.2-81.9%, respectively). The macrolide MIC(50) for S. pneumoniae was >or=128 microg/ml (azithromycin and erythromycin) and >or=64 microg/ml (clarithromycin). The erm(B) genotype accounted for the most erythromycin-resistant isolates in each study year. H. influenzae isolates were most commonly derived from patients with CAP (26.2%). The proportion of H. influenzae isolates that were beta-lactamase positive ranged between 4.3% and 9.7%. The prevalence of beta-lactamase-negative ampicillin-resistant isolates increased from 0.4% to 2.6% between years 1 and 4 then to 19.7% in year 5. S. pyogenes isolates were highly susceptible to most antimicrobial agents except macrolides and tetracycline. Telithromycin was highly active against all three pathogens examined throughout the study.

Topics: Adult; Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Japan; Ketolides; Population Surveillance; Respiratory Tract Infections; Streptococcus pneumoniae; Streptococcus pyogenes

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

Continual monitoring of antimicrobial resistance rates is essential. Several large surveillance programmes have been established, including the international, longitudinal, multi-centre study PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin). Initiated in 1999, PROTEKT monitors the antibacterial susceptibility of common respiratory tract pathogens. This article reviews the findings from PROTEKT to date and anticipates future trends in antimicrobial resistance. Data from PROTEKT indicate that resistance patterns for Streptococcus pneumoniae and Haemophilus influenzae are changing, with an increasing prevalence of multi-drug resistant genotypes. Resistance to the ketolide telithromycin is very rare, with rates of S. pneumoniae susceptibility remaining >99%. The in vitro activity of telithromycin remains at a high level irrespective of pathogen genotype or phenotype.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Ketolides; Population Surveillance; Respiratory Tract Infections; Streptococcus pneumoniae

The in-vitro activity of telithromycin and comparator antibacterial agents was determined against clinical isolates of Legionella pneumophila collected in the PROTEKT surveillance study. In total, 133 isolates were collected between 1999 and 2004 from 13 countries (Australia, Belgium, Czech Republic, France, Germany, Hungary, Ireland, Italy, Japan, Portugal, Spain, Sweden and the USA). MICs were determined by broth microdilution. Telithromycin maintained activity between Year 1 (MIC(90) 0.015 mg/L) and Year 5 (MIC(90) 0.03 mg/L), as did the comparator antibacterial agents. Telithromycin appears to be a candidate for coverage of legionellosis in the empirical treatment of community-acquired respiratory tract infection.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Community-Acquired Infections; Female; Global Health; Humans; Ketolides; Legionella pneumophila; Legionnaires' Disease; Male; Microbial Sensitivity Tests; Middle Aged; Population Surveillance; Respiratory Tract Infections

Antibiotic-associated hepatotoxicity is rare. With widespread use of antimicrobial agents, however, hepatic injury occurs frequently, and among adverse drug reactions, idiosyncratic reactions are the most serious.. A 25-year-old male patient, with a height of 175 cm and weight of 72 kg presented to Marmara University Hospital Emergency Department, Istanbul, Turkey, with 5 days' history of jaundice, malaise, nausea, and vomiting. He had been prescribed telithromycin 400 mg/d PO to treat an upper respiratory tract infection 7 days prior. Admission laboratory tests were as follows: alanine aminotransferase, 67 U/L (reference range, 10-37 U/L); aspartate aminotransferase, 98 U/L (10-40 U/L); alkaline phosphatase, 513 U/L (0-270 U/L); gamma-glutamyltransferase, 32 U/L (7-49 U/L); amylase, 46 U/L (0-220 U/L); total bilirubin, 20.1 mg/dL (0.2-1.0 mg/dL); direct bilirubin, 14.8 mg/dL (0-0.3 mg/dL); and albumin, 4.7 mg/dL (3.5-5.4 mg/dL). No toxin, alcohol, or other drugs were reported. The patient had suffered a previous episode of "acute hepatitis of unknown origin," that occurred after telithromycin usage. Both incidents occurred within a year.. Telithromycin is the first of the ketolide antibacterials to receive US Food and Drug Administration approval for clinical use. It has been associated with infrequent and usually reversible severe hepatic dysfunction. Based on a score of 8 on the Naranjo adverse drug reaction probability scale, telithromycin was the probable cause of acute hepatitis in this patient, and pathological findings suggested drug-induced toxic hepatitis. Recurrence of hepatitis attack might have been avoided if the initial incident had been communicated to the attending physician who prescribed telithromycin the second time.. Here we report a case of acute hepatitis probably associated with the administration of telithromycin.

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Ketolides; Male; Respiratory Tract Infections

Topics: Aged; Anti-Bacterial Agents; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Japan; Ketolides; Male; Respiratory Tract Infections

A novel series of C(12) ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C(12) modification involves replacing the natural C(12) methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C(12) ethyl macrolide core, a series of C(12) ethyl ketolides were prepared and tested for antibacterial activity against a panel of relevant clinical isolates. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria, whether resistance was due to ribosome methylation (erm) or efflux (mef). In particular, the C(12) ethyl ketolides 4k,4s,4q,4m, and 4t showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. The in vivo efficacy of several C(12) ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen.

Topics: Animals; Anti-Bacterial Agents; Erythromycin; Ketolides; Methylation; Mice; Microbial Sensitivity Tests; Respiratory Tract Infections; Ribosomes; Streptococcus pneumoniae; Structure-Activity Relationship

In vitro activities of erythromycin A, telithromycin, and two investigational ketolides, JNJ-17155437 and JNJ-17155528, were evaluated against clinical bacterial strains, including selected common respiratory tract pathogens. Against 46 macrolide-susceptible and -resistant Streptococcus pneumoniae strains, the MIC(90) (MIC at which 90% of the isolates tested were inhibited) of the investigational ketolides was 0.25 microg/ml, twofold lower than that of telithromycin and at least 64-fold lower than that of erythromycin A. Against erm(B)-containing pneumococci, the MIC(90) of all the ketolides was 0.06 microg/ml. The MIC(90) of the investigational ketolides against mef(A)-containing pneumococci or pneumococci with both mef(A) and erm(B) was 0.25 microg/ml, two-and fourfold lower, respectively, than that of telithromycin. In contrast, the MICs of the investigational ketolides against macrolide-resistant S. pneumoniae strains with ribosomal mutations were similar to or, in some cases, as much as eightfold higher than those of telithromycin. Against Haemophilus influenzae, MICs of all the ketolides were < or =2 microg/ml. Against three Moraxella catarrhalis isolates, the MIC of the ketolides was 0.25 microg/ml. The ketolides inhibited in vitro protein synthesis, with 50% inhibitory concentrations ranging from 0.23 to 0.27 microM. In time-kill studies against macrolide-susceptible and erm- or mef-containing pneumococci, the ketolides were bacteriostatic to slowly bactericidal, with 24-h log(10) decreases ranging from 2.0 to 4.1 CFU. Intervals of postantibiotic effects for the ketolides against macrolide-susceptible and -resistant S. pneumoniae were 3.0 to 8.1 h.

Topics: Anti-Bacterial Agents; Bacteria; Colony Count, Microbial; Drug Resistance, Bacterial; Erythromycin; Haemophilus influenzae; Humans; Ketolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Naphthyridines; Respiratory Tract Infections; Staphylococcus; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Humans; Ketolides; Respiratory Tract Infections

To determine geographic and temporal trends in anti-bacterial resistance among Streptococcus pneumoniae isolated from patients with respiratory tract infections as part of the PROTEKT US surveillance study (2000-2003).. From 2000 to 2003, 31 001 isolates of S. pneumoniae were collected. Anti-bacterial minimum inhibitory concentrations were determined at a central laboratory using the CLSI broth microdilution method. Macrolide resistance genotypes were determined by PCR.. Overall, 29.4, 22.5, 0.9, and 0.02% of S. pneumoniae isolates were resistant to erythromycin, penicillin, levofloxacin, and telithromycin, respectively, with considerable regional variability. Multidrug resistance was stable at approx. 31%. Among macrolide-resistant isolates, mef(A) was the most prevalent resistance gene identified; however, the percentage of isolates with this gene decreased from 68.8% (2000) to 63.9% (2003), while the prevalence of isolates containing both the erm(B) and mef(A) genes increased (2000, 9.7%; 2003, 16.4%). Over 90% of these erm(B)+mef(A)-positive isolates were also resistant to penicillin, tetracycline, or trimethoprim-sulfamethoxazole, while 98.6% were susceptible to levofloxacin and 99.1% were susceptible to telithromycin.. Penicillin and erythromycin resistance among isolates of S. pneumoniae from the U.S.A. remained high over the 3 years of the study. Telithromycin demonstrated potent in vitro activity against pneumococcal strains.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Female; Genotype; Humans; Infant; Infant, Newborn; Ketolides; Macrolides; Male; Membrane Proteins; Methyltransferases; Microbial Sensitivity Tests; Middle Aged; Pneumococcal Infections; Respiratory Tract Infections; Streptococcus pneumoniae; United States

Telithromycin is a new ketolide antimicrobial, that can be useful for the treatment of respiratory infections.. To compare in vitro activity of telithromycin against respiratory pathogens, isolated in outpatient clinics.. Two hundred eighty strains isolated from patients with respiratory infections, were studied. The strains studied were S pneumoniae, penicillin sensitive (SPNS:57); intermediate (SPNI:35), resistant (SPNR:25); S pyogenes (SP:57); H influenzae (HIN 51); M catarrhalis (MC:25) and S aureus meticillin sensitive (SAUS:30). Minimal inhibitory concentration (MIC) by broth microdilution was studied for telitrhomycin and levofloxacin in all strains. Other antimicrobials studied, but not in all strains were erythromycin, clindamycin, trimetoprim sulphamethoxazole, oxacillin, amoxicillin-clavulanic acid and cefuroxime.. All strains were sensible to telithromycin at a concentration -4 microg/ml. MIC 90 and its range for SPNS was 0.03 microg/ml (-0.004-0.12), for SPNI was 0.03 microg/ml (-0.004-025), for SPNR was 0.06 microg/ml (-0.004-0.25), for HIN was 2 microg/ml (0.12-4), for SP was 0.5 microg/ml (-0.004-2), for MC was 0.5 microg/ml (0.06-2) and for SAU was 0.25 microg/ml (0.06-0.25).. All studied pathogens were sensible to telithromycin in vitro. This antimicrobial is an alternative for the treatment of community acquired respiratory infections.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; In Vitro Techniques; Ketolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Respiratory Tract Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes

This study was done to evaluate the in vitro activity of a new ketolide telithromycin in comparison with clarithromycin, erythromycin, moxifloxacin and levofloxacin against Streptococcus pneumoniae (n = 67), Haemophilus influenzae (n = 139), and Moraxella catarrhalis (n = 46)collected between January and June 2003 in Hong Kong. Among the H. influenzae isolates, 25.2% produced beta-lactamase, while 97.8% of M. catarrhalis isolates produced beta-lactamase. Half of the S. pneumoniae isolates were nonsusceptible to penicillin, and 90.9% of these strains were resistant to clarithromycin and erythromycin. One (1.5%) S. pneumoniae strain was resistant to levofloxacin (MIC = 8 mg/l) and all isolates were sensitive to moxifloxacin and telithromycin with MIC <1 mg/l. H. influenzae isolates were sensitive to all fluoroquinolones tested and 2.2% of H. influenzae were resistant to clarithromycin. M. catarrhalis isolates were sensitive except 1 strain which was resistant to levofloxacin (MIC = 4 mg/l) and moxifloxacin (8 mg/l). All M. catarrhalis strains were sensitive to telithromycin with MIC90 = 0.5 mg/l. Telithromycin demonstrated high activity and no resistance was found in all these major respiratory tract pathogens.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Ketolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Respiratory Tract Infections; Streptococcus pneumoniae

Telithromycin is the first ketolide anti bacterial approved for treating community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis in adults. The purpose of this article is to review the main pharmacokinetic properties of telithromycin and their application to the treatment of these infections.. Sources of information were identified through a Medline search (up to March 2005).. The absolute oral bioavailability of telithromycin is approximately 57%, which is unaffected by food intake. At the recommended 800 mg once-daily oral dosing regimen, telithromycin reaches a steady-state concentration of approximately 2 microg/mL in plasma and has an elimination half-life of approximately 10 hours. Telithromycin shows extensive tissue distribution and penetrates effectively into bronchopulmonary tissue and epithelial lining fluid. Since elimination of telithromycin occurs via multiple pathways--the highest proportion (70%) through metabolism--impairment of a single pathway has a limited impact on telithromycin exposure. Dose adjustments are unnecessary in elderly patients or in individuals with hepatic impairment or mild to moderate renal impairment. A reduced dose could be recommended in patients with severe renal impairment. Telithromycin is metabolized primarily in the liver, approximately half of which is via the cytochrome P450 (CYP) 3A4 system. Telithromycin AUC(0-24 h) increased by 1.5- to 2.0-fold in the presence of itraconazole and ketoconazole. Administration of telithromycin with drugs metabolized via CYP3A4 may result in increased exposure to the co-administered drug, as shown for simvastatin (5.3-fold) and midazolam (6-fold). Co-administration of telithromycin minimally increases (1.2- to 1.4-fold) exposure to theophylline, digoxin, and metoprolol. Although telithromycin does not affect the pharmacokinetics of warfarin, consideration should be given to monitoring prothrombin times/INR in patients receiving telithromycin and oral anticoagulants simultaneously.. Overall, the pharmacokinetic/pharmaco dynamic properties of telithromycin indicate that this ketolide antibacterial is a valuable and convenient treatment option for community-acquired respiratory tract infections.

Topics: Aged; Anti-Bacterial Agents; Biological Availability; Bronchitis; Community-Acquired Infections; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Ketolides; Kidney Diseases; Pneumonia; Respiratory Tract Infections; Sinusitis

To determine the susceptibility of bacterial respiratory tract pathogens, isolated from children (0-12 years) as part of the global PROTEKT surveillance study (1999-2000), to a range of antibacterials, including the ketolide telithromycin.. Minimum inhibitory concentrations of the antibacterials studied were determined at a central laboratory using the NCCLS microdilution broth method. Macrolide resistance mechanisms were detected by PCR.. Of 779 Streptococcus pneumoniae isolates worldwide, 43% were non-susceptible to penicillin (18% intermediate; 25% resistant) and 37% were resistant to erythromycin, with considerable intercountry variation. Eighteen per cent of 653 Haemophilus influenzae and >90% of 316 Moraxella catarrhalis isolates produced beta-lactamase. Of 640 Streptococcus pyogenes isolates, 10% were resistant to erythromycin, with considerable intercountry variation. All S. pneumoniae and 99.8% of H. influenzae isolates were susceptible to telithromycin using breakpoints proposed to the NCCLS (

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Drug Resistance, Multiple; Female; Global Health; Humans; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Polymerase Chain Reaction; Population Surveillance; Respiratory Tract Infections

A pooled analysis of data from 13 phase III studies of telithromycin in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute sinusitis or group A beta-haemolytic streptococcal pharyngitis and tonsillitis was undertaken. Causative key respiratory tract pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pyogenes) were isolated at entry to the studies from cultures of relevant respiratory samples and tested for their susceptibility to telithromycin, penicillin and macrolides (erythromycin A). The combined clinical and bacteriological efficacy of telithromycin at the post-therapy, test-of-cure visit (days 17-24) was assessed in patients from whom a microbiologically evaluable pathogen was isolated at entry. More than 98% of key respiratory pathogens isolated, including penicillin G- and macrolide (erythromycin A)-resistant strains of S. pneumoniae, demonstrated full or intermediate susceptibility to telithromycin in vitro at the breakpoints of < or = 1.0 mg/L (susceptible) and 2.0 mg/L (intermediate) used for the purpose of evaluating the susceptibility of isolates recovered during the clinical trials. Treatment with telithromycin 800 mg once-daily for 5, 7 or 7-10 days resulted in high rates of clinical cure (88.5%) and a satisfactory bacteriological outcome (88.9%), similar to the figures seen with comparator antibacterial agents. Clinical cure and eradication rates were good for all key respiratory pathogens, including penicillin G- and macrolide (erythromycin A)-resistant S. pneumoniae. The results suggest that telithromycin will provide effective empirical therapy for community-acquired upper and lower respiratory tract infections.

Topics: Adolescent; Adult; Aged; Bacteria; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Middle Aged; Moraxella catarrhalis; Randomized Controlled Trials as Topic; Respiratory Tract Infections; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Treatment Outcome

Telithromycin is a new ketolide antimicrobial that was developed to provide good activity against resistant respiratory tract pathogens. PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) is a multicenter in vitro surveillance study that was initiated in 2000 to chart the emergence and spread of antimicrobial-resistant pathogens in patients with community-acquired respiratory tract infections (CARTIs).. This article reports first-year results from PROTEKT US pertaining to the comparative in vitro activity of telithromycin and beta-lactam antimicrobials against community-acquired bacterial respiratory tract pathogens.. Data were compiled on the comparative in vitro activity of telithromycin and beta-lactams against Streptococcus pneumoniae (10,103 isolates), Streptococcus pyogenes (3918 isolates), and Haemophilus influenzae (2706 isolates). Minimum inhibitory concentrations (MICs) and susceptibilities were determined according to National Committee for Clinical Laboratory Standards methods.. In total, 38.8% (3920/10,103) of pneumococcal isolates were not susceptible to penicillin (12.5% [1266] intermediate [MIC, > or =0.12-1.0 mg/dL], 26.3% [2654] resistant [MIC, > or =2 mg/dL]). Telithromycin was highly active against S pneumoniae (MIC required to inhibit 90% of isolates [MIC(90)], 0.5 mg/L), with 99.6% (10,062/10,103) of isolates fully susceptible (MIC, < or =1 mg/L). Based on MIC(90)s, the rank order of antimicrobial activity was telithromycin (0.5 mg/L), followed by amoxicillin/clavulanate (2 mg/L), penicillin (4 mg/L), and cefuroxime (8 mg/L). Telithromycin retained high activity (MIC(90), 1 mg/L) against penicillin-resistant penumococci that showed high levels of coresistance to beta-lactams. All isolates of S pyogenes were fully susceptible to the beta-lactams tested. Beta-lactamase production was common among H influenzae isolates (28.3% [765/2706]). Telithromycin was active against H influenzae (MIC(90), 4 mg/L), irrespective of beta-lactamase production.. Overall, these findings from the first year of PROTEKT US support the potential value of telithromycin in the treatment of CARTIs.

Topics: Anti-Bacterial Agents; beta-Lactams; Community-Acquired Infections; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; In Vitro Techniques; Ketolides; Macrolides; Microbial Sensitivity Tests; Multicenter Studies as Topic; Respiratory Tract Infections; Streptococcus pneumoniae; Streptococcus pyogenes; United States

The in vitro abilities of telithromycin, azithromycin and clarithromycin to select for resistance were compared by testing isolates of Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and beta-haemolytic streptococci.. Five strains each of beta-lactamase-positive and beta-lactamase-negative H. influenzae, beta-lactamase-positive and beta-lactamase-negative M. catarrhalis, S. pneumoniae, beta-haemolytic group A, group C and group G streptococci and three strains of beta-lactamase-negative ampicillin-resistant H. influenzae were evaluated. Development of resistance was determined by multi-step and single-step methodologies. For multi-step studies, MIC values were determined after five serial passages on antibiotic-gradient plates and after 10 serial passages on antibiotic-free plates. Acquisition of resistance was defined as an increase of >/=4-fold from the starting MIC. In single-step studies, the rate of spontaneous mutations was calculated after a passage on plates containing antibiotics at concentrations equal to the highest NCCLS breakpoints.. Azithromycin, clarithromycin and telithromycin gave a >/=4-fold increase in 20, 20 and 10 streptococcus strains, in 4, 5 and 0 H. influenzae strains and in 2, 7 and 4 M. catarrhalis strains, respectively. After 10 passages on antibiotic-free plates, 21/26 strains for azithromycin, 22/32 for clarithromycin and 1/14 for telithromycin maintained high MIC values. In single-step studies, the frequency of mutations was <10(-10) for H. influenzae and M. catarrhalis for telithromycin, azithromycin and clarithromycin. Telithromycin induced mutations at a lower rate than azithromycin and clarithromycin in streptococcal strains.. Telithromycin showed a very limited ability to select for resistance in respiratory pathogens compared with azithromycin and clarithromycin.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Drug Resistance, Bacterial; Gene Frequency; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Mutation; Respiratory Tract Infections; Streptococcus; Streptococcus pneumoniae

One of the main factors commonly associated with antibacterial resistance among Streptococcus pneumoniae is the age of the patient. The highest rates of resistance have often been reported among isolates from young children.. Data from the PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) surveillance study were examined to determine the level of antibacterial resistance among S. pneumoniae isolates collected in 2001-2002 from different patient age groups in the USA.. A total of 10 012 clinical isolates of S. pneumoniae were submitted by 242 centres across the USA and categorized into four patient age groups: infants (0-2 years, n = 1556), children (3-14 years, n=1125), adults (15-64 years, n=4058) and elderly adults (> or =65 years, n = 3067) (age unknown n=206). With the exception of the fluoroquinolones and linezolid, rates of antibacterial resistance were highest among infants and decreased with increasing patient age. Resistance to penicillin ranged from 33.6% among infants to 17.5% among elderly adults, and erythromycin resistance ranged from 41.1% among infants to 24.0% among adults. In contrast, levofloxacin resistance increased with patient age (from 0.1% to 1.6%). The highest rates of susceptibility were noted for telithromycin and linezolid (> or =99.6% and > or =99.8% susceptible isolates, respectively).. The PROTEKT US study data confirmed that the highest antibacterial resistance rates were associated with isolates collected from young children (0-2 years). Telithromycin may offer a reliable alternative to first-line drugs in the empirical treatment of community-acquired respiratory tract infections.

Topics: Adolescent; Adult; Age Factors; Aged; Anti-Infective Agents; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Infant; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Middle Aged; Phenotype; Pneumococcal Infections; Population Surveillance; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction; Specimen Handling; Streptococcus pneumoniae; United States

The Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) longitudinal global surveillance study examines the antibacterial susceptibility of community-acquired respiratory pathogens.. Data from isolates collected in Germany in 1999-2000 in the PROTEKT study show that 8.3% of pneumococcal isolates (n = 325) had reduced susceptibility to penicillin and 2.2% were fully resistant. Erythromycin resistance was 15.7% overall and particularly high in Leipzig (31.6%). All penicillin- and erythromycin-resistant strains were inhibited by telithromycin (MIC < or =0.5 mg/l) and linezolid (MIC < or =2 mg/l). Beta-lactamase was produced by 3.2% of Haemophilus influenzae (9/284) and 89.5% of Moraxella catarrhalis strains (111/124). All Streptococcus pyogenes isolates (n = 87) were susceptible to penicillin, although 9.2% were resistant to macrolides.. Penicillin resistance in Germany remains low; however, the prevalence of antimicrobial resistance among common respiratory pathogens is rising, particularly against macrolides. Continued surveillance is necessary to guide optimal empirical therapy, and new antimicrobials, like telithromycin, need to be developed with improved potency against target pathogens and low propensity for the development of resistance.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Germany; Haemophilus influenzae; Humans; Ketolides; Longitudinal Studies; Microbial Sensitivity Tests; Moraxella catarrhalis; Multicenter Studies as Topic; Penicillin Resistance; Population Surveillance; Respiratory Tract Infections; Streptococcus pneumoniae; Streptococcus pyogenes

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Controlled Clinical Trials as Topic; Drug Resistance, Bacterial; Gastrointestinal Diseases; Humans; Ketolides; Macrolides; Pneumonia, Mycoplasma; Respiratory Tract Infections; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Population Surveillance; Respiratory Tract Infections; United States

Few data exist on the distribution of Streptococcus pneumoniae serotypes in many countries and in non-invasive disease overall. Here, data are presented from 772 paediatric isolates from children with community-acquired respiratory tract infections isolated from the PROTEKT global surveillance study during 1999-2000. Overall, 60.0 % of isolates were covered by the 7-valent pneumococcal vaccine formulation (PCV7), with greater coverage in the USA compared with Europe (69.6 vs 55.5 %, P = 0.014). Geographically dispersed clones of serogroups 3, 11 and 15 accounted for most of the isolates outside PCV7 coverage. Overall, macrolide, penicillin and cotrimoxazole non-susceptibility rates were high; however, all isolates were susceptible to telithromycin. Although only 7.4 % of isolates were resistant to amoxycillin/clavulanate, a higher prevalence of resistance was found in isolates from the USA and South Korea. This study shows the feasibility and importance of serotyping antibiotic surveillance study isolates and the potential of telithromycin as an important option for empiric therapy.

Topics: Adolescent; Anti-Bacterial Agents; Bacterial Typing Techniques; Blood; Bronchoalveolar Lavage Fluid; Child; Child, Preschool; Community-Acquired Infections; Drug Resistance, Bacterial; Heptavalent Pneumococcal Conjugate Vaccine; Humans; Infant; Infant, Newborn; Ketolides; Meningococcal Vaccines; Microbial Sensitivity Tests; Nasopharynx; Pneumococcal Infections; Pneumococcal Vaccines; Respiratory Tract Infections; Serotyping; Sputum; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Emergencies; Humans; Ketolides; Respiratory Tract Infections

Topics: Community-Acquired Infections; Drug Resistance, Bacterial; France; Humans; Ketolides; Longitudinal Studies; Microbial Sensitivity Tests; Product Surveillance, Postmarketing; Respiratory Tract Infections; Sensitivity and Specificity; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; International Cooperation; Ketolides; Longitudinal Studies; Macrolides; Male; Methods; Microbial Sensitivity Tests; Research Design; Respiratory Tract Infections; Retrospective Studies; Sensitivity and Specificity; United Kingdom

Topics: Amoxicillin; Anti-Bacterial Agents; Clavulanic Acid; Clinical Trials as Topic; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Ketolides; Macrolides; Penicillin Resistance; Penicillins; Respiratory Tract Infections; Time Factors

A total of 7,566 unique patient isolates of Haemophilus influenzae and 2,314 unique patient isolates of Moraxella catarrhalis were collected between October 1997 and June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among the 7,566 H. influenzae isolates, 22.5% produced beta-lactamase, while 92.4% of the 2,314 M. catarrhalis isolates produced beta-lactamase. The incidence of beta-lactamase-producing H. influenzae isolates decreased significantly over the 5-year study period, from 24.2% in 1997-1998 to 18.6% in 2001-2002 (P < 0.01). The incidence of beta-lactamase-producing M. catarrhalis isolates did not change over the study period. The overall rates of resistance to amoxicillin and amoxicillin-clavulanate for H. influenzae were 19.3 and 0.1%, respectively. The rank order of cephalosporin activity based on the MICs at which 90% of isolates were inhibited (MIC(90)s) was cefotaxime > cefixime > cefuroxime > cefprozil > cefaclor. On the basis of the MICs, azithromycin was more active than clarithromycin (14-OH clarithromycin was not tested); however, on the basis of the NCCLS breakpoints, resistance rates were 2.1 and 1.6%, respectively. Rates of resistance to other agents were as follows: doxycycline, 1.5%; trimethoprim-sulfamethoxazole, 14.2%; and chloramphenicol, 0.2%. All fluoroquinolones tested, including the investigational fluoroquinolones BMS284756 (garenoxacin) and ABT-492, displayed potent activities against H. influenzae, with MIC(90)s of < or = 0.03 microg/ml. The MIC(90)s of the investigational ketolides telithromycin and ABT-773 were 2 and 4 microg/ml, respectively, and the MIC(90) of the investigational glycylcycline GAR-936 (tigecycline) was 4 microg/ml. Among the M. catarrhalis isolates tested, the resistance rates derived by using the NCCLS breakpoint criteria for H. influenzae were <1% for all antibiotics tested except trimethoprim-sulfamethoxazole (1.5%). In summary, the incidence of beta-lactamase-positive H. influenzae strains in Canada is decreasing (18.6% in 2001-2002), while the incidence of beta-lactamase-positive M. catarrhalis strains has remained constant (90.0% in 2001-2002).

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Canada; Drug Resistance, Multiple, Bacterial; Erythromycin; Female; Gram-Negative Bacterial Infections; Haemophilus influenzae; Humans; Influenza, Human; Ketolides; Longitudinal Studies; Macrolides; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Moraxella catarrhalis; Respiratory Tract Infections; Tigecycline

Topics: Anti-Bacterial Agents; Humans; Inpatients; Ketolides; Macrolides; Respiratory Tract Infections

Respiratory tract infections (RTIs) remain a significant cause of morbidity and mortality. Major bacterial pathogens in RTIs, such as Streptococcus pneumoniae, have exhibited increasing resistance to a variety of antibiotics during the past decades. Telithromycin, the first ketolide, was designed especially to overcome this resistance. The present study was conducted to assess the comparative activity of telithromycin against typical RTI pathogens in Austria.. A total of 1,015 bacterial isolates was tested, including S. pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Haemophilus influenzae. MICs of the following antimicrobials: penicillin G, ampicillin (for H. influenzae), azithromycin, clarithromycin, erythromycin A and telithromycin were determined using the NCCLS broth microdilution method.. Telithromycin showed excellent activity against S. pneumoniae, with 99.8% of all isolates being susceptible. Penicillin remained active with an MIC50 and MIC90 of 0.007 mg/L. Nevertheless, a notable increase in penicillin intermediate-resistant and resistant isolates, from 4.9% in 1996 to the present rate of 10%, was observed. There was also a distinct rise in the resistance levels of S. pneumoniae against the macrolides. All tested isolates of S. pyogenes were susceptible to penicillin and telithromycin, and only low levels of resistance against telithromycin were found in S. aureus (2.2%, MIC90 of 0.5 mg/L). No telithromycin-resistant isolate of H. influenzae could be detected.. This study demonstrates the rising prevalence of resistance among S. pneumoniae not only to penicillin but also to other antimicrobials. It also shows the value of telithromycin as an attractive option for the empirical treatment of community-acquired RTIs in an era of widespread antibacterial resistance.

Topics: Anti-Bacterial Agents; Austria; Bacteria; Community-Acquired Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Respiratory Tract Infections; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes

The in vitro activity of telithromycin, a new ketolide, was compared with beta-lactam antimicrobials against pathogens commonly associated with community-acquired respiratory tract infections. These pathogens were collected during 1999-2000 as part of the ongoing PROTEKT surveillance study. Globally, penicillin nonsusceptibility among Streptococcus pneumoniae (n = 3362) was 36.3%, ranging from 21.5% (Australasia) to 68.0% (Far East). Telithromycin showed higher potency (MIC90 0.12 mg/L) than beta-lactams against S. pneumoniae; 99.9% of all and 99.6% of multi-resistant isolates were susceptible to telithromycin. Among Streptococcus pyogenes isolates (n = 1485), 100% were susceptible to beta-lactams, and the telithromycin MIC50 and MIC90 were both 0.015 mg/L. Among Haemophilus influenzae (n = 2948), 16.6% produced beta-lactamase, which reduced the activity of ampicillin, cefaclor and cefprozil. 99.9% of H. influenzae were susceptible to telithromycin and the MIC range for M. catarrhalis was 0.004-0.5 mg/L. The first year results of PROTEKT confirmed high potency for telithromycin against common respiratory tract pathogens, including beta-lactam-resistant strains.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Community-Acquired Infections; Humans; In Vitro Techniques; Ketolides; Macrolides; Microbial Sensitivity Tests; Respiratory Tract Infections

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: 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: Bacteria; Clinical Trials as Topic; Drug Design; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Respiratory Tract Infections

Respiratory tract infections are a major health problem worldwide. Streptococcus pneumoniae remains the most prevalent respiratory tract pathogen. Because of the increasing prevalence of antibiotic resistance in S pneumoniae and other respiratory tract pathogens, development of new antibacterials has become necessary to treat infections that no longer respond to commonly used agents. Telithromycin, a ketolide, is a potent new oral agent designed to treat community-acquired respiratory tract infections and is especially effective against S pneumoniae strains that are resistant to penicillins and macrolides.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Humans; Ketolides; Macrolides; Respiratory Tract Infections; Risk Assessment; Streptococcus pneumoniae

In recent years, antibacterial resistance among respiratory pathogens implicated in community-acquired respiratory tract infections (RTIs) has spread worldwide at an alarming rate. Thus, there is a pressing need for new antibacterials that retain activity against resistant organisms, have a low potential to select for resistance and do not induce cross-resistance. Telithromycin is the first of a new class of antibacterials - the ketolides - that have been designed specifically to overcome resistance among respiratory tract pathogens. This paper presents the first results of the PROTEKT study (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin), a worldwide surveillance study initiated to chart the prevalence of important resistance phenotypes and genotypes and the comparative activity of telithromycin against such strains. Analysis of over 7,000 bacterial isolates by April 2001 has confirmed the notable prevalence of strains resistant to commonly prescribed RTI antibacterials for all the pathogens studied. Telithromycin demonstrates high activity against isolates of Streptococcus pneumoniae, irrespective of penicillin G, macrolide or fluoroquinolone resistance. Telithromycin is also highly active against other respiratory tract pathogens, including Streptococcus pyogenes and beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis. These data justify the assertion that telithromycin is a promising new candidate for the empirical treatment of community-acquired RTIs, particularly in the face of increasing antibacterial resistance.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Community-Acquired Infections; Cross-Sectional Studies; Drug Resistance, Microbial; Drug Resistance, Multiple; Haemophilus influenzae; Ketolides; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Respiratory Tract Infections; Streptococcus pneumoniae; Streptococcus pyogenes

The prevalence of resistance to a range of antimicrobials was determined for isolates of Streptococcus pneumoniae examined in the PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance study (1999-2000) using NCCLS testing methods and interpretative criteria. Of 3362 pneumococcal isolates collected from 69 centres in 25 countries, 22.1% overall were resistant to penicillin G, with the highest rates of resistance found among isolates from Asia (53.4%), France (46.2%) and Spain (42.1%). Erythromycin A resistance occurred in 31.1% of isolates overall with the highest rates found in Asia (79.6%), France (57.6%), Hungary (55.6%) and Italy (42.9%). Marked geographical differences in the prevalence of both penicillin G (the Netherlands 0%; South Korea 71.5%) and erythromycin A (Sweden 4.7%; South Korea 87.6%) resistance were observed. Asia was characterized by the highest prevalence of resistance, overall, with only eight of 19 antimicrobials (co-amoxiclav, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, levofloxacin, moxifloxacin and telithromycin) retaining high activity against isolates of S. pneumoniae from this region. Notable rates of resistance to clarithromycin, azithromycin, co-trimoxazole and tetracycline were observed in the majority of countries submitting isolates of S. pneumoniae to the PROTEKT surveillance study. Fluoroquinolone resistance was low (1%), overall, although 14.3% of 70 isolates from Hong Kong were resistant to levofloxacin and moxifloxacin, all but one of these isolates belonging to a single clone of the 23F serotype. Although, at present, apparently limited to pockets of clonal spread, continued vigilance with regard to the evolution of fluoroquinolone resistance is indicated. Telithromycin (MIC(90) 0.12 mg/L; 99.9% of isolates susceptible) and lin- ezolid (MIC(90) 2 mg/L; 100% of isolates susceptible) were the two most active oral agents tested, both compounds retaining activity against isolates of fluoroquinolone-resistant S. pneumoniae. The results of the PROTEKT surveillance study 1999-2000 emphasize the widespread evolution of resistance to a variety of antimicrobials amongst isolates of S. pneumoniae and demonstrate the potential of telithromycin as a therapeutic option for the treatment of community-acquired respiratory tract infections caused by this organism.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Pneumococcal Infections; Population Surveillance; Prevalence; Respiratory Tract Infections; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Global Health; Humans; International Cooperation; Ketolides; Macrolides; Microbial Sensitivity Tests; Population Surveillance; Prospective Studies; Respiratory Tract Infections

The increasing antimicrobial resistance amongst bacterial pathogens causing community-acquired respiratory tract infections (CARTIs) necessitates surveillance at the local, regional, national and international levels to provide information to guide empiric antimicrobial therapy. PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a longitudinal, global, multicenter surveillance study designed to monitor the worldwide development of antimicrobial resistance and disseminate up-to-date information via the internet to assist in the choice of empiric therapy at the local level. In this paper, the results for the first year of PROTEKT are presented from a global perspective. Streptococcus pneumoniae, followed by Haemophilus influenzae and Moraxella catarrhalis, are the principal organisms responsible for the majority of CARTIs. The global prevalence of penicillin G resistance in S. pneumoniae has risen to an alarming 36.3% (high-level resistance 22.1%, intermediate-level 14.2%) with the highest prevalence found in Asia (68%). In all regions, macrolide resistance is greater than penicillin G resistance with a global prevalence rate of 31.2%. High resistance rates were also found for tetracycline (30.5%) and co-trimoxazole (43.9%), and multiresistance was found between penicillin G, macrolides, tetracycline and co-trimoxazole. The prevalence of beta-lactamase-producing H. influenzae and M. catarrhalis was found to be similar to previous reports. Macrolide resistance in S. pyogenes was 0.3% overall. Telithromycin demonstrated excellent in vitro activity against all organisms and is a potential new candidate for the empiric therapy of CARTIs. The first year of PROTEKT has provided valuable information on the prevalence of antimicrobial resistance of bacterial agents causing CARTIs that can be used for guiding empiric therapy and policies. The rapidly developing and geographically varying resistance observed in this study further emphasizes the need for accurate up-to-date surveillance data.

Topics: Acute Disease; Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Information Dissemination; International Cooperation; Internet; Ketolides; Longitudinal Studies; Macrolides; Microbial Sensitivity Tests; Population Surveillance; Prospective Studies; Respiratory Tract Infections; Streptococcal Infections

Because of increasing antimicrobial resistance in bacterial pathogens causing community-acquired respiratory tract infections (CARTIs), surveillance at local, regional, national and international levels is necessary to provide information to guide empiric antimicrobial therapy. PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a longitudinal, global, multicenter surveillance study designed to monitor the worldwide development of antimicrobial resistance, and disseminate up-to-date information via the internet to assist in the choice of empiric therapy at the local level. In this paper, the results for the first year of PROTEKT are presented from a local perspective. In examples from Japan, USA and Europe, great variation was observed between antimicrobial susceptibility patterns for Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae in countries and cities in close proximity to each other. Telithromycin demonstrated excellent in vitro activity against all organisms and is a potential new candidate for the empiric therapy of CARTIs. The first year of PROTEKT has provided valuable information on the prevalence of antimicrobial resistance of bacterial agents causing CARTIs that can be used for guiding empiric therapy and policies. Variation in local resistance observed in this study further emphasizes the need for accurate up-to-date surveillance data at the local level.

Topics: Anti-Bacterial Agents; Asia; Community-Acquired Infections; Drug Resistance, Bacterial; Europe; Gram-Negative Bacterial Infections; Humans; Information Dissemination; International Cooperation; Internet; Ketolides; Longitudinal Studies; Macrolides; Population Surveillance; Prevalence; Prospective Studies; Respiratory Tract Infections; Streptococcal Infections; Time Factors; United States

Resistance to macrolides is not a new phenomenon but it deserves attention because of the widespread use of these agents and their inclusion in many clinical guidelines for respiratory tract infections. The most common mechanisms by which Streptococcus pneumoniae and Streptococcus pyogenes develop resistance to macrolides is by target site modification (erythromycin ribosome methylase, erm) and efflux of the drug out of the organisms (macrolide efflux, mef). Target site modification may be of greater concern because it confers high-level resistance to all antimicrobials in the macrolide-lincosamide-streptograminB (MLSB) group. The genotype profiles of macrolide-resistant S. pneumoniae and S. pyogenes differ somewhat across regions in the US and between the US and Canada and other countries. There is some evidence for an association between macrolide resistance and treatment failure but this must be researched more fully. S. pneumoniae and S. pyogenes isolates resistant to macrolides are generally susceptible to ketolide antimicrobials because these agents bind more strongly to the relevant domain of the ribosomal subunit (withstanding erm resistance) and are less vulnerable to efflux compared to the macrolides.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; North America; Prevalence; Prospective Studies; Respiratory Tract Infections; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes; Treatment Failure

Fluoroquinolone antibiotics have been available since the 1980s when ciprofloxacin and norfloxacin were licensed. Structural revisions of the quinolone molecule have provided new compounds that were well suited to the treatment of upper and lower community-acquired respiratory tract infections, having good activity against Streptococcus pneumoniae. Nevertheless, it was only a matter of time before the pneumococcus developed effective resistance against these new agents. There are populations of fluoroquinolone-resistant S. pneumoniae and, more worryingly, many of these strains are also resistant to penicillin and to macrolides. Surveillance studies such as PROTEKT (Prospective, Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) can provide an early warning system and, with the provision of global surveillance on a local level, can assist in the selection of empirical antibiotic treatment. The new ketolide antibiotic, telithromycin, has excellent activity against the major community-acquired respiratory pathogens (including atypical/intracellular organisms), and has the advantage of retaining its activity against strains of S. pneumoniae that are resistant to penicillin, macrolides and fluoroquinolones.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Canada; Community-Acquired Infections; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Gram-Negative Bacteria; Hong Kong; Humans; International Cooperation; Ketolides; Macrolides; Mutation; Pneumococcal Infections; Population Surveillance; Prevalence; Prospective Studies; Respiratory Tract Infections; Streptococcus pneumoniae; United States

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

The activity of a new ketolide, ABT-773, was compared to the activity of the ketolide telithromycin (HMR-3647) against over 600 gram-positive clinical isolates, including 356 Streptococcus pneumoniae, 167 Staphylococcus aureus, and 136 Streptococcus pyogenes isolates. Macrolide-susceptible isolates as well as macrolide-resistant isolates with ribosomal methylase (Erm), macrolide efflux (Mef), and ribosomal mutations were tested using the NCCLS reference broth microdilution method. Both compounds were extremely active against macrolide-susceptible isolates, with the minimum inhibitory concentrations at which 90% of the isolates tested were inhibited (MIC90s) for susceptible streptococci and staphylococci ranging from 0.002 to 0.03 microg/ml for ABT-773 and 0.008 to 0.06 microg/ml for telithromycin. ABT-773 had increased activities against macrolide-resistant S. pneumoniae (Erm MIC90, 0.015 microg/ml; Mef MIC90, 0.12 microg/ml) compared to those of telithromycin (Erm MIC90, 0.12 microg/ml; Mef MIC90, 1 microg/ml). Both compounds were active against strains with rRNA or ribosomal protein mutations (MIC90, 0.12 microg/ml). ABT-773 was also more active against macrolide-resistant S. pyogenes (ABT-773 Erm MIC90, 0.5 microg/ml; ABT-773 Mef MIC90, 0.12 microg/ml; telithromycin Erm MIC90, >8 microg/ml; telithromycin Mef MIC90, 1.0 microg/ml). Both compounds lacked activity against constitutive macrolide-resistant Staphylococcus aureus but had good activities against inducibly resistant Staphylococcus aureus (ABT-773 MIC90, 0.06 microg/ml; telithromycin MIC90, 0.5 microg/ml). ABT-773 has superior activity against macrolide-resistant streptococci compared to that of telithromycin.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Erythromycin; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Respiratory Tract Infections; Ribosomes; Staphylococcus; Streptococcus

Topics: Aged; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Humans; Ketolides; Macrolides; Penicillin Resistance; Respiratory Tract Infections

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Erythromycin; Genes, Bacterial; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Respiratory Tract Infections; Streptococcus

Telithromycin is a new ketolide antimicrobial, specifically developed for the treatment of community-acquired respiratory tract infections. It has a wide spectrum of antibacterial activity against common respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes. It also has activity against atypical pathogens, such as Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae. Telithromycin maintains activity against beta-lactam and macrolide-resistant respiratory tract pathogens and does not appear to induce cross-resistance to other members of the macrolide-lincosamide-streptogramin (MLS) group of antimicrobials. It demonstrates bactericidal activity against S. pneumoniae and H. influenzae and has a prolonged concentration-dependent post-antibiotic effect (PAE) in vitro. The drug has favourable pharmacokinetics following oral administration. It is well absorbed, achieves good plasma levels and is highly concentrated in pulmonary tissues and white blood cells. In clinical trials, telithromycin given orally at a dose of 800 mg once daily for 5 - 10 days was as effective as comparator antimicrobials for the treatment of adults with community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis and group A-beta-haemolytic streptococcal pharyngitis or tonsillitis. The adverse events and safety profile were similar to comparator antimicrobials. The most common adverse events were diarrhoea, nausea, headache and dizziness. Telithromycin should provide an effective, convenient and well-tolerated once-daily oral therapy for treatment of respiratory infections.

Topics: Anti-Bacterial Agents; Drug Interactions; Drug Resistance, Microbial; Humans; Ketolides; Macrolides; Respiratory Tract Infections

Telithromycin (HMR 3647) is a ketolide suitable for the treatment of respiratory infections. The aim of this study was to demonstrate its antibacterial efficacy against an erythromycin-susceptible Staphylococcus aureus, an erythromycin-resistant Streptococcus pneumoniae and Haemophilus influenzae. The free serum concentrations of telithromycin, produced by repeated oral administration of 800 mg to adults for 10 days, was simulated in an in vitro system. The ketolide displayed bacteriostatic activity against all three strains tested. This study supported the observation that an 800 mg po dose of telithromycin demonstrated antibacterial efficacy against respiratory tract pathogens.

Topics: Administration, Oral; Anti-Bacterial Agents; Computer Simulation; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Respiratory Tract Infections; Staphylococcus aureus; Streptococcus pneumoniae

Macrolide-resistance was assessed in 216 consecutive Streptococcus pyogenes isolates from throat infections in the region of Aachen, Germany. Seventeen isolates were resistant to erythromycin: 12 isolates revealed a macrolide (M) phenotype and harbored mefA, and five strains expressed an inducible macrolide-lincosamide-streptogramin B (MLSB) phenotype of which four strains harbored ermA(TR) and one strain contained ermB(AM). Telithromycin (HMR 3647) and quinupristin/dalfopristin remained active particularly against the ermA(TR)-containing S. pyogenes isolates studied. Random amplified polymorphic DNA analysis identified multiple clones among erythromycin-resistant strains, but did not discriminate beyond the emm-type. mefA was present in three isolates either with emm2, emm12, or emm75, and in nine isolates with emm4. All four strains with ermA(TR) contained emm77, and the single strain with ermB(AM) harbored emm1. Despite the relative low rate of macrolide-resistance, these data suggest that at least three different macrolide-resistance determinants are prevalent in Germany and that mefA has spread rapidly into multiple clones of S. pyogenes.

Topics: Anti-Bacterial Agents; Drug Resistance; Erythromycin; Genotype; Germany; Ketolides; Macrolides; Microbial Sensitivity Tests; Pharynx; Phenotype; Polymorphism, Restriction Fragment Length; Regulon; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction; Streptococcal Infections; Streptococcus pyogenes; Streptogramins; Virginiamycin

The in vivo activity of telithromycin against erythromycin A- and penicillin G-resistant Streptococcus pneumoniae was superior to that of azithromycin, clarithromycin, cefdinir, and levofloxacin. In respiratory tract infections caused by erythromycin A-susceptible S. pneumoniae or Haemophilus influenzae in mice, telithromycin was more effective than clarithromycin and comparable to azithromycin.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Half-Life; Ketolides; Macrolides; Male; Mice; Mice, Inbred CBA; Mice, Inbred ICR; Microbial Sensitivity Tests; Pneumococcal Infections; Respiratory Tract Infections; Streptococcus pneumoniae

Topics: Adolescent; Adult; Anti-Bacterial Agents; Bacteria; Child; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Penicillin Resistance; Penicillins; Pneumococcal Infections; Pneumonia, Pneumococcal; Respiratory Tract Infections; Streptococcus pneumoniae; Time Factors

Telithromycin was the first ketolide to be approved in Europe and is in the approval process in the United States. It is structurally related to the macrolides; it has a keto group in the C3 position rather than cladinose. A carbamate group is also present at C11-C12. As a result, it has a reduced induction of the MLSB resistance mechanism (erm gene), it is not affected by the flux mechanism (mef gene), it has higher stability at low pH and has increased intrinsic activity compared with clarithromycin and azithromycin. Phase III studies have shown telithromycin to be effective in the treatment of community-acquired upper and lower respiratory tract infections. Its long half-life allows for oral once-daily dosing. From a pharmacokinetic point of view, its activity has been shown to be AUC(24h)/MIC dependent. It is active against bacteria involved in atypical pneumonia. The aim of our study was to determine the activity of telithromycin in isolates with defined resistance phenotypes obtained from community-acquired respiratory tract infections. Twelve centers in Argentina, Chile, Paraguay and Uruguay participated in the study. Each center collected three strains of the following species and resistance patterns: S. pyogenes, S. pneumoniae with resistance or intermediate resistance to oxacillin, erythromycin-resistant S. pneumoniae, clindamycin-resistant S. pneumoniae, oxacillin-susceptible S. aureus, erythromycin-resistant S. aureus, ampicillin-susceptible and -resistant M. catarrhalis and H. influenzae. Agar diffusion susceptibility tests with NeoSensitabs tablets (Rosco, Denmark) were carried out at each center. Isolates were sent to the coordinating center, where MICs were determined using agar microdilution and the Seppala test was used to determine the resistance mechanism to macrolides. The 327 isolates received were susceptible to telithromycin. Eighty percent of the erythromycin-resistant S. pneumoniae isolates were likely resistant due to a flux mechanism, and all those resistant to clindamycin were resistant due to the erm inducible mechanism. Only 20 out of 36 strains of clindamycin-resistant S. pneumoniae and 25 of the 36 ampicillin-resistant H. influenzae strains could be collected, thereby showing that these resistance patterns are less common in the participating South American countries than in other areas. The in vitro activity of telithromycin suggests that it is a promising antibacterial drug for the treatment of community-acquired respira

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Microbial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Phenotype; Respiratory Tract Infections; South America

The in vitro activities (MIC and MBC) of telithromycin (HMR 3647) against clinical isolates in Japan were investigated in comparison with those of erythromycin A, clarithromycin, azithromycin, amoxycillin, cefdinir and levofloxacin. Telithromycin was more potent than the reference compounds against erythromycin A-susceptible or resistant Streptococcus pneumoniae isolates possessing either mef (mefA or mefE) genes or the ermB gene. Against erythromycin A-susceptible or inducibly resistant Staphylococcus aureus and erythromycin A-susceptible and intermediate Enterococcus faecalis, telithromycin was highly active.

Topics: Amoxicillin; Anti-Bacterial Agents; Cefdinir; Cephalosporins; Community-Acquired Infections; Drug Resistance, Microbial; Erythromycin; Gram-Positive Bacteria; Humans; Japan; Ketolides; Levofloxacin; Macrolides; Microbial Sensitivity Tests; Ofloxacin; Penicillins; Respiratory Tract Infections; Staphylococcus aureus

KETOLIDES: The principal advantage of this series of original compounds elaborated from macrolides is their activity against pneumococci and against macrolide-resistant streptococci while preserving the remainder of the macrolide spectrum of activity, particularly for intracellular germs. TELITHROMYCIN: To date, the main indications have been assessed in adults: pneumonia, super-infection of chronic bronchitis, sinusitis and pharyngitis. The recommended dose is 800 mg once a day. The safety of this dose has been validated for patients treated for 7 to 10 days for community-acquired pneumonia. CONTRIBUTION TO CURRENT STRATEGIES: Should telithromycin be proposed as first line treatment for community-acquired respiratory tract infections or should it be used as an alternative treatment for situations where no other antibiotic can be used?

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Microbial; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Respiratory Tract Infections

The in vitro activities of HMR 3647, erythromycin A, clarithromycin, azithromycin, roxithromycin, penicillin G, ampicillin, cefuroxime, trimethoprim/sulfamethoxazole, tetracycline, ciprofloxacin, and levofloxacin were determined for 1179 Streptococcus pneumoniae, 1438 Haemophilus influenzae, and 428 Moraxella catarrhalis isolated from respiratory tract specimens by 18 medical centers across Canada during 1997-1998. On a per weight basis, HMR 3647 was the most active agent tested against S. pneumoniae with MIC90s of < or = 0.12 microgram/mL for both penicillin susceptible and penicillin intermediate isolates and 0.25 microgram/mL for penicillin-resistant isolates. HMR 3647 was also highly active against M. catarrhalis (MIC90, < or = 0.12 microgram/mL), but less active against H. influenzae (MIC90, 4 micrograms/mL).

Topics: Administration, Oral; Anti-Bacterial Agents; Canada; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Neisseriaceae Infections; Respiratory Tract Infections; Streptococcal Infections; Streptococcus pneumoniae

The pharmacodynamic properties of a novel ketolide (a new class of macrolide), HMR 3647, were investigated by studying time-kill kinetics and postantibiotic effect (PAE). The time-kill kinetics were studied at two inocula against three strains each of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium and Bacteroides fragilis. The PAEs of HMR 3647 were also investigated on these organisms at concentrations equivalent to 1, 4 and 10 x MIC. The time-kill kinetic data demonstrated that HMR 3647 is predominantly bacteriostatic and only slowly bactericidal at higher concentrations. HMR 3647 exhibited a significant PAE with all strains studied, ranging from 1.2 h to 8.2 h at 10 x MIC. The bacteriostatic activity and significant PAE demonstrated by HMR 3647 are similar to those previously obtained with other macrolides.

Topics: Anti-Bacterial Agents; Bacteroides fragilis; Enterococcus; Haemophilus influenzae; Ketolides; Kinetics; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Respiratory Tract Infections; Staphylococcus aureus; Streptococcus pneumoniae; Time Factors