ru-66647 and Pneumonia--Pneumococcal

Streptococcus pneumoniae is the leading bacterial cause of community-acquired respiratory tract infections. Prior to the 1970s this pathogen was uniformly susceptible to penicillin and most other antimicrobials. However, since the 1990s there has been a significant increase in drug-resistant Streptococcus pneumoniae (DRSP) due, in large part, to increased use of antimicrobials. The clinical significance of this resistance is not definitely established, but appears to be most relevant to specific MICs for specific antimicrobials. Certain beta-lactams (amoxicillin, cefotaxime, ceftriaxone), the respiratory fluoroquinolones, and telithromycin are among several agents that remain effective against DRSP. Continued surveillance studies, appropriate antimicrobial usage campaigns, stratification of patients based on known risk factors for resistance, and vaccination programmes are needed to appropriately manage DRSP and limit its spread.

Topics: Anti-Infective Agents; Community-Acquired Infections; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Humans; Ketolides; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Female; Fluoroquinolones; Humans; International Cooperation; Ketolides; Longitudinal Studies; Male; Microbial Sensitivity Tests; Penicillin Resistance; Pneumonia, Pneumococcal; Retrospective Studies; Sensitivity and Specificity; Sputum; Streptococcus pneumoniae

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

The efficacy of oral telithromycin was assessed in patients with community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae with reduced susceptibility to penicillin and/or erythromycin.. Patients with CAP who had received telithromycin 800 mg once daily for 5 or 7-10 days (n = 2,289) in eight phase III clinical trials, or telithromycin 800 mg once daily for 7 days (n = 50) in a phase II study were included in this pooled analysis. Patients with S. pneumoniae as the cause of infection were identified, with particular focus on those infected with strains with reduced susceptibility to penicillin (intermediate, minimal inhibitory concentration (MIC) 0.12-1.0 mg/l; resistant, MIC >or=2.0 mg/l) and/or resistance to erythromycin (MIC >or=1.0 mg/l). Per-protocol clinical and bacteriological outcomes were assessed 7-14 days post-therapy in the phase III studies, and at 7-21 days post-therapy or at the end of therapy in the phase II study.. Of the 327 telithromycin-treated patients with S. pneumoniae infection, 61 (19%) were infected with strains with reduced susceptibility to penicillin and/or erythromycin. Clinical cure and bacterial eradication rates in these patients were 91.8% (56/61) and 93.4% (57/61), respectively. Corresponding clinical cure and bacterial eradication rates overall for all isolates of pneumococci were 94.5% (309/327) and 96.0% (314/327), respectively. All isolates with reduced susceptibility to penicillin and/or erythromycin were susceptible to telithromycin (MIC

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Community-Acquired Infections; Double-Blind Method; Erythromycin; Female; Humans; Ketolides; Male; Middle Aged; Penicillin Resistance; Pneumonia, Pneumococcal; Treatment Outcome

The efficacy of oral telithromycin 800mg once daily for 7 days was evaluated in a multicentre, multinational study in patients with community-acquired pneumonia caused by Streptococcus pneumoniae resistant to penicillin and/or erythromycin. Per-protocol clinical and bacteriological outcomes were assessed 10-17 days post-therapy. Of the 129 patients with S. pneumoniae infection, 16 were infected with strains resistant to penicillin and/or erythromycin. Fifteen of these 16 patients (93.8%) were assessed as clinically and bacteriologically cured at the post-therapy visit.

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Erythromycin; Female; Humans; Ketolides; Male; Microbial Sensitivity Tests; Middle Aged; Penicillin Resistance; Penicillins; Pneumonia, Pneumococcal; Treatment Outcome

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

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

In order to modify lincomycin at the C-6 and C-7 positions, we prepared target molecules, which have substituted pipecolinic acid at the 6-amino group and a para-substituted phenylthio group at the C-7 position, in application of palladium-catalyzed cross-coupling as a key reaction. As the result of structure-activity relationship (SAR) studies at the 6-position, analogs possessing 4'-cis-(cyclopropylmethyl)piperidine showed significantly strong antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with an erm gene. On the basis of SAR, we further synthesized novel analogs possessing 4'-cis-(cyclopropylmethyl)piperidine by transformation of a C-7 substituent. Consequently, novel derivatives possessing a para-heteroaromatic-phenylthio group at the C-7 position exhibited significantly strong activities against S. pneumoniae and S. pyogenes with an erm gene even when compared with those of telithromycin. Finally, in vivo efficacy of selected two derivatives was evaluated in a rat pulmonary infection model with resistant S. pneumoniae with erm + mef genes. One of them exhibited strong and constant in vivo efficacy in this model, and both compounds showed strong in vivo efficacy against resistant S. pneumoniae with a mef gene.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Ketolides; Lincomycin; Membrane Proteins; Microbial Sensitivity Tests; Neutropenia; Pneumonia, Pneumococcal; Rats; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship

As we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds. In vivo efficacy was assessed in a murine model of S. pneumoniae-induced pneumonia, and pharmacokinetic (PK) profiles in mice were determined. The in vitro antibacterial profiles of macrolones were superior to those of marketed macrolide antibiotics, including the ketolide telithromycin, and the compounds did not induce the expression of inducible erm genes. They acted as typical protein synthesis inhibitors in an Escherichia coli transcription/translation assay. Macrolones were characterized by low to moderate systemic clearance, a large volume of distribution, a long half-life, and low oral bioavailability. They were highly efficacious in a murine model of pneumonia after intraperitoneal application even against an S. pneumoniae strain with constitutive resistance to macrolide-lincosamide-streptogramin B antibiotics. Macrolones are the class of macrolide antibiotics with an outstanding antibacterial profile and reasonable PK parameters resulting in good in vivo efficacy.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Disease Models, Animal; Drug Resistance, Bacterial; Escherichia coli; Haemophilus influenzae; Ketolides; Lincosamides; Macrolides; Male; Methyltransferases; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal; Protein Biosynthesis; Protein Synthesis Inhibitors; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Streptogramin B; Structure-Activity Relationship

To compare the probability of target attainment (PTA) for macrolides and ketolides against penicillin-susceptible, intermediate, and resistant Streptococcus pneumoniae in both serum and epithelial lining fluid (ELF) of patients with community-acquired pneumonia (CAP).. Monte Carlo simulations were used to assess the attainment of the bacterial eradication-linked pharmacodynamic index of the free drug area under the concentration-time curve over 24 hours to minimum inhibitory concentration (fAUC(0-24)/MIC90) by azithromycin, clarithromycin, and telithromycin, at therapeutic doses, against penicillin-susceptible, intermediate, and resistant S. pneumoniae.. In serum, azithromycin and clarithromycin were found to have a probability of attaining the recommended fAUC(0-24)/MIC90 ratio of 30 in 50.2% and 74.6%, respectively, of CAP patients with penicillin-intermediate strains, and a probability of 36.9% and 60.7%, respectively, in cases of penicillin-resistant strains. Telithromycin maintained a probability of reaching the fAUC(0-24)/MIC90 ratio of 30 in serum and ELF in 89.1% of CAP patients, regardless of the penicillin resistance of the strain.. Clarithromycin results in a higher PTA than azithromycin in the treatment of penicillin-susceptible S. pneumoniae, but both of these agents exhibit a decreasing efficacy as S. pneumoniae penicillin resistance increases. When compared to clarithromycin and azithromycin, telithromycin maintains higher PTA in CAP patients with penicillin-resistant strains of S. pneumoniae.

Topics: Anti-Bacterial Agents; Area Under Curve; Azithromycin; Clarithromycin; Community-Acquired Infections; Drug Resistance, Bacterial; Humans; Ketolides; Microbial Sensitivity Tests; Monte Carlo Method; Pneumonia, Pneumococcal; Probability; Streptococcus pneumoniae

Telithromycin (TEL) is a ketolide antimicrobial agent with in vitro activity against Streptococcus pneumoniae (SPN), including macrolide resistant strains. The purpose of this study was to assess the efficacy of TEL against clinical SPN isolates with various genotypic mutations including the newly recognized ribosomal mutations. Pneumonia was induced in either immunocompetent and immunosuppressed mice. Six isolates were included in the study and all were resistant to azithromycin (AZI) by MIC testing. Three oral regimens of TEL were chosen to simulate the human pharmacokinetic (PK) exposures observed in young healthy, healthy elderly (> or =65 years), and infected subjects. An additional group was given AZI in human simulated doses. Bacterial density in lung was determined after each treatment. Telithromycin administered simulating infected patients showed greater efficacy (i.e., change in logCFU) than the azithromycin treated group for all isolates except P1660008. The immune system was responsible for increased efficacy (ranging from 45-146%) for all but one of the telithromycin treatment regimens. Unlike other isolates studied in this in vivo model, P1660008 displayed a highly variable response to therapy, such that the reductions in CFU were not consistent with the microbiological and PK profiles of either compound. For all other isolates, the activity of AZI was comparable with untreated controls. Human simulated exposures of TEL displayed 0.5-3.4 log kill in vivo despite the ribosomal mutations studied. These data support the in vivo efficacy of TEL against a variety of genotypic resistance profiles observed in pneumococci, however, additional studies are required to fully characterize the killing profile of the compound against these recently determined ribosomal mutations.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Azithromycin; Colony Count, Microbial; Disease Models, Animal; Drug Resistance, Bacterial; Genes, rRNA; Ketolides; Lung; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Mutation; Pneumonia, Pneumococcal; Streptococcus pneumoniae

A total of 486 Streptococcus pneumoniae isolates were collected in 2003 and 2004 in Germany and revealed the following resistance rates: penicillin G (7.2%) and erythromycin A (18.9%). Telithromycin exhibited good in vitro activity (MIC at which 90% of the isolates tested were inhibited, 0.125 microg/ml). However, one erm(B)-positive isolate was found to be telithromycin resistant (MIC, 8 microg/ml).

Topics: Aged; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Erythromycin; Germany; Humans; Ketolides; Macrolides; Membrane Proteins; Microbial Sensitivity Tests; Pneumonia, Pneumococcal; Streptococcus pneumoniae

An experimental Streptococcus pneumoniae pneumonia model in rabbits was used to assess the efficacy of amoxycillin, erythromycin and a new ketolide, telithromycin (HMR 3647). The MICs of amoxycillin, erythromycin and HMR 3647 for the three clinical S. pneumoniae strains used were, respectively, (mg/L): 0.01, 16 and 0.02 (strain 195); 2, 0.25 and 0.02 (strain 16089); 8, >64 and 0.02 (strain 11724). Antibiotic therapy reproduced human serum pharmacokinetics (amoxycillin 1 g iv tds or erythromycin 500 mg qds or HMR 3647 800 mg bd). Forty-eight hours of therapy with HMR 3647 and amoxycillin resulted in significant bacterial clearance in the lungs and spleen of rabbits infected by S. pneumoniae strain 195 and strain 16089 (at least 3 log(10) cfu/g decrease, P < 0.001). Erythromycin was active against only the erythromycinsusceptible strain (3 log(10) cfu/g decrease at 48 h, P < 0.001). None of the antibiotics showed significant efficacy with strain 11724. All agents produced significant bacterial clearance when time above MBC was >33%, and microbiological failure when it was <25%, whereas MIC was not correlated with microbiological outcome with HMR 3647. Our findings suggest that pharmacodynamic data integrating MBC may be predictive of microbiological success or failure with greater accuracy than with MIC. HMR 3647 produced significant bacterial clearance in both penicillin- and erythromycin-resistant pneumonia, but was less effective against the highly erythromycin-resistant S. pneumoniae strain.

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Disease Models, Animal; Erythromycin; Humans; Ketolides; Macrolides; Male; Penicillins; Pneumonia, Pneumococcal; Rabbits; Streptococcus pneumoniae; Treatment Outcome

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Humans; Ketolides; Macrolides; Pneumonia, Pneumococcal

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