ru-66647 and Streptococcal-Infections

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

A pooled analysis of two double-blind, multicentre, Phase III studies compared oral telithromycin 800 mg once-daily for 5 days with penicillin V 500 mg three-times-daily or clarithromycin 250 mg twice-daily for 10 days in the treatment of Streptococcus pyogenes (group A beta-haemolytic streptococcus; GABHS) tonsillopharyngitis. Patients aged > or = 13 years with acute GABHS tonsillopharyngitis were randomised to receive telithromycin (n = 430), penicillin (n = 197) or clarithromycin (n = 231). Clinical isolates of S. pyogenes (n = 590) obtained from throat swab samples on study entry were tested for their in-vitro susceptibility to telithromycin, clarithromycin and azithromycin. Telithromycin demonstrated in-vitro activity against the clinical isolates of S. pyogenes (MIC50/90 0.03/0.06 mg/L) higher than clarithromycin or azithromycin (MIC50/90 0.06/0.06 mg/L and 0.12/0.25 mg/L, respectively), including erythromycin-resistant strains. At the post-therapy/test of cure (TOC) visit (days 16-23), satisfactory bacteriological outcome was demonstrated for 88.3% (234/265) and 88.6% (225/254) of telithromycin- and comparator-treated patients, respectively (per-protocol population). Overall, GABHS eradication rates were 88.7% (235/265) for telithromycin and 89.0% (226/254) for comparators. The clinical cure rates at the post-therapy/TOC visit were 93.6% (248/265) and 90.9% (220/242) for telithromycin and pooled comparators, respectively. Telithromycin was generally well-tolerated. Most adverse events considered to be possibly related to study medication were gastrointestinal and of mild intensity. Discontinuations as a result of adverse events were few in both treatment groups. In conclusion, telithromycin 800 mg once-daily for 5 days was as effective as penicillin V or clarithromycin for 10 days in the treatment of GABHS tonsillopharyngitis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Child; Child, Preschool; Clarithromycin; Female; Humans; Infant; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Middle Aged; Penicillin V; Pharyngitis; Streptococcal Infections; Streptococcus pyogenes; Tonsillitis; Treatment Outcome

Telithromycin, a ketolide antibacterial, has been developed for the treatment of community-acquired respiratory infections.. This study compared the efficacy and tolerability of 5-day, once-daily telithromycin with 10-day, twice-daily clarithromycin in adolescents and adults with acute tonsillitis/pharyngitis caused by group A beta-hemolytic streptococci ([GABHS] Streptococcus pyogenes).. In this multicenter, randomized, double-blind, parallel-group study, adolescent (aged > or = 13 years) and adult patients with a diagnosis of GABHS tonsillitis/pharyngitis received once-daily telithromycin 800 mg for 5 days (followed by placebo for 5 days) or twice-daily clarithromycin 250 mg for 10 days. Bacteriologic and clinical outcomes were assessed at a test-of-cure visit (days 16 to 23) and a late posttherapy visit (days 31 to 45).. A total of 526 patients were enrolled in the study, of which 463 (288 females, 175 males) were randomized to receive treatment (telithromycin, n = 232; clarithromycin, n = 231). The mean age of the telithromycin group was 30.9 years; in the clarithromycin group, it was 30.0 years. Bacterial eradication was achieved in 91.3% of telithromycin-treated patients and 88.1% of clarithromycin recipients (difference, 3.2%; 95% CI, -4.5 to 11.0). Clinical cure was achieved in 92.7% of telithromycin recipients and 91.1% of clarithromycin-treated patients (difference, 1.6%; 95% CI, -5.5 to 8.6). Bacteriologic and clinical cures for the 2 treatment groups also were similar at the late posttherapy visit. Treatment-related adverse events occurred more frequently in the telithromycin group than the clarithromycin group (67.2% vs 57.5%, respectively); diarrhea, nausea, and vomiting were significantly more common with telithromycin than with clarithromycin (P = 0.004, 0.010, and 0.001, respectively). Adverse events were generally mild.. This study demonstrates that telithromycin 800 mg once daily for 5 days was an effective and generally well-tolerated treatment for tonsillitis/pharyngitis caused by GABHS, providing similar bacteriologic and clinical efficacy to clarithromycin 250 mg twice daily for 10 days in the per-protocol population.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Clarithromycin; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Bacterial; Erythromycin; Female; Humans; Ketolides; Macrolides; Male; Middle Aged; Streptococcal Infections; Streptococcus pyogenes; Tonsillitis; Treatment Outcome

This study compared the resolution of symptoms in patients with group A beta-hemolytic streptococcus tonsillopharyngitis treated with 5 d of telithromycin 800 mg once daily, or 10 d of penicillin V 500 mg 3 times daily. At days 3-5 of treatment, the mean improvement in total symptom score was greater with telithromycin than with penicillin V (p = 0.042). Thus, telithromycin provided faster symptom relief than penicillin V.

Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Ketolides; Macrolides; Male; Patient Satisfaction; Penicillin V; Pharyngitis; Probability; Severity of Illness Index; Streptococcal Infections; Streptococcus pyogenes; Tonsillitis; Treatment Outcome

This randomized, double-blind study compared the efficacy and safety of a 5-d course of the new ketolide antimicrobial, telithromycin, with those of a standard 10-d course of penicillin V (phenoxymethylpenicillin) in patients with group A beta-hemolytic streptococci (GABHS) pharyngitis/tonsillitis. Patients aged 15-65 y (n = 395) with clinical signs and symptoms of pharyngitis/tonsillitis and a positive streptococcal antigen test or throat culture for GABHS were randomized to receive either telithromycin 800 mg once daily for 5 d (n = 198) or penicillin V 500 mg three times daily for 10 d (n = 197). Clinical and bacteriologic outcomes were assessed at post-therapy, test-of-cure (Days 16-20) and late post-therapy (Days 38-45) visits. Telithromycin for 5 d was equivalent to 10 d of penicillin V in terms of bacteriologic and clinical outcome (per-protocol): at post-therapy, test-of-cure visit, bacteriologic outcome was satisfactory in 84.3% and 89.1% of patients in the telithromycin and penicillin V groups, respectively, while clinical cure was achieved in 94.8% and 94.1% of patients, respectively. At late post-therapy, 82.4% of patients treated with telithromycin achieved a satisfactory bacteriologic outcome, compared with 84.7% of penicillin V recipients. The GABHS eradication rates for telithromycin and penicillin post-therapy were 85.2% and 89.1%, respectively, and 86.1% and 86.5%, respectively at late post-therapy. Both treatments were well tolerated, with a similar overall incidence of treatment-emergent adverse events. Short-course (5 d) therapy with telithromycin 800 mg once daily is comparable to a standard 10 d course of penicillin V for the treatment of GABHS pharyngitis/tonsillitis in adults and adolescents.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Double-Blind Method; Europe; Female; Humans; Ketolides; Macrolides; Male; Middle Aged; Penicillin V; Penicillins; Pharyngitis; Streptococcal Infections; Streptococcus pyogenes; Tonsillitis; Treatment Outcome

This study compared the in vitro activity of telithromycin with that of azithromycin against 438 Streptococcus pyogenes and 198 Streptococcus pneumoniae, isolated over the period 2005-2007 from specimens of different human origin obtained in three Piemonte Region's hospitals.. The determination of antimicrobial activity was evaluated by the microdilution broth method and the erythromycin-resistant (Ery-R) phenotypes by the triple-disc test. Exactly 78.8% of S. pyogenes and 69.2% of S. pneumoniae were erythromycin-susceptible (Ery-S). Concerning S. pyogenes, telithromycin was active against M and inducible MLS(B), subtype-C, phenotypes but not against constitutive MLS(B) strains. Telithromycin acted well against all S. pneumoniae, irrespective of their mechanism of macrolide-resistance. On the contrary, the Ery-R isolates, both S. pyogenes and S. pneumoniae, were resistant to azithromycin.. Our results indicate that macrolide resistance in streptococci still persist in northwest Italy (21.2% of S. pyogenes and 308% of S. pneumoniae) and that telithromycin is confirmed as being extremely active even against recent clinical Ery-R streptococcal isolates.. The present study emphasizes that an active surveillance of the phenotype distribution and antibacterial resistance in streptococci is essential in guiding the effective use of empirical treatment option for streptococcal infections, also at regional level.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Child; Drug Resistance, Bacterial; Erythromycin; Humans; Italy; Ketolides; Microbial Sensitivity Tests; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes

To test four 16-membered macrolides (josamycin, spiramycin, midecamycin and rokitamycin) along with other compounds in the same class (erythromycin, clarithromycin, roxithromycin and azithromycin) plus clindamycin and telithromycin, against Streptococcus pyogenes and Streptococcus pneumoniae isolates with well-characterized resistance genotypes.. Four hundred and eighty-six isolates of S. pyogenes and 375 isolates of S. pneumoniae were assayed for their macrolide susceptibilities and investigated by PCR to detect their different erythromycin resistance genes. All strains had been isolated over the period 2002-2003 from specimens of different human origin obtained in 14 different Italian centres.. All 16-membered macrolides showed very low MICs (MIC(50)s and MIC(90)s, < or =0.06-0.5 mg/L) for the erythromycin-susceptible isolates and for those with the M phenotype, but the telithromycin MICs for the M-type isolates were at least four times higher (MIC(90)s, 0.5 mg/L). In S. pyogenes, the MIC(50)s of 16-membered macrolides for the cMLS(B) isolates were > or = 256 mg/L, whereas that for telithromycin was 4 mg/L; the MIC(50)s of 16-membered macrolides and telithromycin ranged from < or = 0.06 to 0.5 mg/L for the iMLS(B) isolates with erm(A) and from 0.12 to > or = 256 mg/L for those with erm(B). In S. pneumoniae, the MIC(50)s of the 16-membered macrolides for the cMLS(B) isolates ranged from 0.5 to 128 mg/L, whereas for the iMLS(B) isolates their values ranged from < or = 0.06 to 4 mg/L; the MIC(50)s and MIC(90)s of telithromycin for both the cMLS(B) and the iMLS(B) isolates ranged from < or = 0.06 to 0.12 mg/L.. MICs ranged for all the drugs, except telithromycin, from < or = 0.06 to > or = 256 mg/L, with 15% to 30% resistant S. pyogenes for all drugs tested except clindamycin (8%) and telithromycin (5.4%) and 10% to 40% resistant S. pneumoniae for all drugs tested except telithromycin (0.3%). In both S. pyogenes and S. pneumoniae, erythromycin resistance related to a mef gene meant that telithromycin MICs were definitely higher than in erythromycin-susceptible isolates, although telithromycin susceptibility was preserved in all cases. In S. pyogenes, the activity of both 16-membered macrolides and telithromycin against the iMLS(B) strains proved to be dependent on the erm gene involved, being greater against isolates with erm(A).

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Erythromycin; Genotype; Humans; Italy; Ketolides; Macrolides; Microbial Sensitivity Tests; Pneumococcal Infections; Reverse Transcriptase Polymerase Chain Reaction; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes

687 isolates of Streptococcus pyogenes and 600 isolates of Streptococcus pneumoniae , isolated over the period 2002-2003 from specimens of different human origin obtained in 16 different Italian centres, were assayed for their susceptibilities to different macrolides and to telithromycin, and were investigated by PCR to detect their different erythromycin resistance genes. 25.5% of the S. pyogenes isolates proved resistant to erythromycin, as well as to clarithromycin and azithromycin. 6.6% of the isolates proved non-susceptible to clindamycin. 4.9% of the isolates were non-susceptible to telithromycin. 22.3% of all erythromycin-resistant isolates exhibited cMLS B resistance, 50.3% iMLS B resistance, and 27.4% Mtype resistance. All cMLS B strains had the erm(B) gene, all M strains had the mef (A) gene, and no resistance genes were found in the erythromycin-susceptible strains. Roughly one quarter of the iMLS(B) strains had erm(A) and roughly three quarters erm(B). 35.2% of the S. pneumoniae isolates proved resistant to erythromycin, and virtually all of them also proved resistant to clarithromycin and azithromycin, too. Only 6.0% of the pneumococcal isolates were resistant to penicillin and a further 11.0% were intermediate. Only 0.2% of the isolates were nonsusceptible to telithromycin. 65.9% of all erythromycin-resistant S. pneumoniae isolates had cMLS B resistance, 18.0% had iMLS B resistance, and 16.1% had M-type resistance. All the MLS B-resistant isolates had an erm(B) gene, and all the M-type isolates had a mef gene. We conclude that macrolide resistance of streptococci still persists in Italy with incidences as high as 40%, more often than not being characterised by the MLS B phenotype. The ketolide telithromycin, structurally related to macrolides and most likely to substitute for them in a number of clinical uses, is confirmed as being extremely active even against recent clinical streptococcal isolates.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Italy; Ketolides; Macrolides; Microbial Sensitivity Tests; Polymerase Chain Reaction; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes

Available data from the Southern Reunion Island Medical Group was processed to assess the evolution of Streptococcus pneumoniae resistance to antibiotics since 1994 when the first penicillin-non-susceptible S. pneumoniae (PNSSP) was identified. In addition, 249 strains, isolated between 1998 and 2004, were tested against telithromycin and moxifloxacin.. Between 1994 and 2004, the percentage of PNSSP increased from 0 to 59.2%. Among PNSSP, 13.9% were resistant strains in 2004 with MICs<4 microg/ml. Before 2001 the rate of resistance to penicillin was superior to 50%. In 2004, 15.8 and 8.7% of the isolated strains were of decreased susceptibility to amoxicillin and cefotaxime respectively while none were resistant to either treatment. Other antibiotics followed the pattern of resistance to penicillin. Between 1998 and 2004, resistance to erythromycin decreased from 42.5 to 35.1%, from 35.1 to 22.8% for cyclins, from 18.8 to 8.8 for chloramphenicol, and from 38.3 to 12.3% for cotrimoxazole. All tested strains were susceptible to both telithromycin and moxifloxacin.. Amoxicillin remains efficient for all strains isolated in the Reunion Island in 2004. The presence of strains with decreased susceptibility to third generation cephalosporins implies combination with vancomycin for empirical treatment of pneumococcal meningitis. Moxifloxacin can be used when using a fluoroquinolone is justified. Telithromycin is efficient even on strains resistant to erythromycin and consequently this molecule can be prescribed in the case of a required macrolide treatment.

Topics: Aza Compounds; beta-Lactams; Cephalosporin Resistance; Cephalosporins; Chloramphenicol; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Humans; Ketolides; Moxifloxacin; Penicillin Resistance; Quinolines; Retrospective Studies; Reunion; Rifampin; Streptococcal Infections; Streptococcus pneumoniae; Tetracycline; Trimethoprim, Sulfamethoxazole Drug Combination

Since the late 1990s, the prevalence of erythromycin-resistant Streptococcus pyogenes has significantly increased in several European countries. Between January 1999 and December 2002, 1,577 isolates of S. pyogenes were recovered from children with tonsillopharyngitis living in various areas of Western Greece. Erythromycin resistance was observed in 379 (24%) of the 1,577 isolates. All erythromycin-resistant strains along with 153 randomly selected erythromycin-susceptible S. pyogenes isolates were tested for their antimicrobial susceptibility, resistance phenotypes, and genotypes. Representative isolates underwent emm gene sequence typing. Isolates with reduced susceptibility to telithromycin (MIC, > or = 2 microg/ml) were studied for multilocus sequence type, L22, L4, and 23S rRNA mutations. Of the total 379 erythromycin-resistant isolates, 193 (50.9%) harbored the mef(A) gene, 163 (43%) erm(A), 1 (0.3%) mef(A) plus erm(A), and 22 (5.8%) the erm(B) gene. Among the erythromycin-susceptible isolates, emm 1 (25%), emm 2 (12.5%), and emm 77 (12.5%) predominated. Furthermore, among the erythromycin-resistant isolates, emm 4 (30.6%), emm 28 (22.2%), and emm 77 (12.5%) prevailed. Resistance to telithromycin was observed in 22 (5.8%) of the erythromycin-resistant isolates. Sixteen (72.7%) of the 22 isolates appeared to be clonally related, since all of them belonged to emm type 28 and multilocus sequence type 52. One of the well-known mutations (T2166C) in 23S rRNA, as well as a new one (T2136C), was detected in erythromycin- and telithromycin-resistant isolates. High incidence of macrolide resistance and clonal spread of telithromycin resistance were the characteristics of the Greek S. pyogenes isolates obtained from 1999 to 2002.

Topics: Acute Disease; Child; Child, Preschool; Drug Resistance, Bacterial; Erythromycin; Genotype; Greece; Humans; Ketolides; Pharyngitis; Phenotype; Streptococcal Infections; Streptococcus pyogenes; Tonsillitis

To evaluate the effects of subinhibitory concentrations of penicillin and telithromycin on capsular formation by Streptococcus pneumoniae.. A total of 60 isolates of S. pneumoniae, 20 susceptible, 20 intermediately resistant and 20 resistant to penicillin, were studied. All isolates were susceptible to telithromycin.. All isolates were capsulate when grown without antibiotics. Encapsulation was lower after incubation with telithromycin as compared with penicillin in isolates susceptible to penicillin (20% versus 75%), in those intermediately resistant to penicillin (25% versus 95%) and in isolates fully resistant to penicillin (15% versus 100%) (P < 0.01).. Telithromycin appears to be superior to penicillin in reducing the expression of the capsule by S. pneumoniae.

Topics: Anti-Bacterial Agents; Bacterial Capsules; Humans; Ketolides; Maxillary Sinusitis; Microbial Sensitivity Tests; Penicillin Resistance; Streptococcal Infections; Streptococcus pneumoniae

The in vitro activities of penicillin, erythromycin, clindamycin, and telithromycin were determined against 155 viridans group streptococci (VGS) and 18 Streptococcus bovis blood isolates. Heterogeneity in the susceptibility patterns and macrolide resistance phenotypes and genotypes in the different groups of VGS was detected. We found seven telithromycin-resistant S. bovis isolates all harboring the erm(B) gene.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Cattle; Drug Resistance, Bacterial; Humans; Ketolides; Membrane Proteins; Methyltransferases; Microbial Sensitivity Tests; Phenotype; Species Specificity; Streptococcal Infections; Streptococcus bovis; Viridans Streptococci

Macrolide, lincosamide, and ketolide mechanisms of resistance and clonal relationships were characterized in a collection of 79 resistant group B streptococcus isolates obtained from neonates or pregnant women. The erm(B), erm(TR), and mef(A) genes were present in 62%, 30.4%, and 3.8% of the isolates, respectively. There was considerable clonal diversity among them.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Erythromycin; Female; Humans; Infant, Newborn; Ketolides; Lincosamides; Macrolides; Microbial Sensitivity Tests; Pregnancy; Pregnancy Complications, Infectious; Spain; Streptococcal Infections; Streptococcus agalactiae

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

We found a 13% macrolide resistance in 3,866 Streptococcus pyogenes isolated from tonsillopharyngitis patients; 59% macrolide-resistant isolates were distributed in 5 clones, suggesting the importance of both resistance gene transfer and clonal dissemination in the spread of these organisms. We also report one of the largest collections of telithromycin-resistant isolates.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Child, Preschool; Drug Resistance, Bacterial; Humans; Infant; Ketolides; Macrolides; Microbial Sensitivity Tests; Middle Aged; Population Surveillance; Streptococcal Infections; Streptococcus pyogenes

To study the antimicrobial susceptibility and prevalence of the different phenotypes and genotypes of macrolide resistance in group A streptococci isolated in Spain in 2004, and to compare the results with those obtained in 1998 and 2001 using the same methodology and centres.. A total of 530 unique isolates of Streptococcus pyogenes collected in 21 laboratories from 16 geographic areas (regions) in Spain were used. Antimicrobial susceptibility testing was performed using the agar dilution method. Discs containing erythromycin or clindamycin were used to recognize the phenotypes of macrolide-lincosamide-streptogramin (MLS) resistance. Genes encoding macrolide-lincosamide resistance were detected by PCR.. Resistance to erythromycin was 21.7% [95% confidence interval (CI) 16.5-26.3]. The resistance to azithromycin was 21.5%, whereas the resistance to miocamycin and to clindamycin was 6.6% (95% CI 3.0-8.9). Thirty-one (5.8%) of the isolates were resistant to telithromycin. Of the 115 erythromycin-resistant isolates, 67.8% had the M phenotype, representing 14.7% of all the isolates tested. Thirty-five isolates (30.5% of the erythromycin-resistant strains and 6.6% of all the isolates) had the MLS(B) constitutive phenotype. There was a high prevalence of resistance to telithromycin (88.6%) among the 35 strains with the MLS(B) constitutive phenotype. When we compared these results with those from previous studies (1998 and 2001), we found a significant increase in the MLS(B) constitutive phenotype (P < 0.001), and a significant decrease in the M phenotype (P < 0.005) was noted.. The significant increase in the prevalence of resistance to clindamycin and miocamycin, and the prevalence of resistance to telithromycin reached in a short period of time from the introduction of its use, underscore the need for continuous surveillance of antimicrobial resistance in S. pyogenes in Spain.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Clindamycin; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Humans; Ketolides; Macrolides; Membrane Proteins; Methyltransferases; Spain; Streptococcal Infections; Streptococcus pyogenes

We studied the telithromycin, erythromycin, azithromycin, and clindamycin susceptibilities of serotype III macrolide-resistant group B streptococci, together with genetic mechanisms of resistance and genomic diversity. ermB, ermA, and mefA were found in, respectively, 57, 32, and 9% of isolates. The telithromycin MIC at which 90% of isolates were inhibited was 0.5 micro g/ml. Macrolide resistance was associated with dissemination of resistance determinants among isolates of different genetic backgrounds.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Erythromycin; Female; Genes, Bacterial; Humans; Infant, Newborn; Ketolides; Macrolides; Membrane Proteins; Methyltransferases; Microbial Sensitivity Tests; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Streptococcal Infections; Streptococcus agalactiae

The increase detected in macrolide resistance in streptococci in various parts of the world has brought into question the usefulness of macrolides as first line therapy for respiratory tract infections. In a nationwide study, a total of 3012 Streptococcus pneumoniae and 499 Streptococcus pyogenes isolates were collected from 1996 to 2002 and tested for their susceptibility to penicillin, azithromycin, clarithromycin and telithromycin (2002 only). Penicillin-intermediate and -resistant isolates of S. pneumoniae comprised 4.9% (2.9 and 2.0%, respectively) of all isolates in 1996; macrolide resistance was also comparatively low at 3.2%. In the following years the rate of penicillin-resistant pneumococci increased steadily, reaching the 10% mark in 2002. A similar trend was recorded for the macrolides. No penicillin-resistant strain of S. pyogenes was found during the observation period. The prevalence of macrolide-resistance in S. pyogenes climbed from 4.7% in 1996 to the present rate of 7.2% (clarithromycin) and 9.4% (azithromycin). Telithromycin showed excellent activity against both S. pneumoniae and S. pyogenes with 99.8 and 100% strains sensitive, respectively.

Topics: Anti-Bacterial Agents; Austria; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Streptococcal Infections; Streptococcus; Streptococcus pneumoniae; Streptococcus pyogenes

The rates of resistance to erythromycin and clindamycin among Streptococcus agalactiae strains isolated in our hospital increased from 4.2 and 0.8% in 1993 to 17.4 and 12.1%, respectively, in 2001. Erythromycin resistance was mainly due to the presence of an Erm(B) methylase, while the M phenotype was detected in 3.8% of the strains. Telithromycin was very active against erythromycin-resistant strains, irrespective of their mechanisms of macrolide resistance.

Topics: Anti-Bacterial Agents; Clindamycin; Cross Infection; Drug Resistance, Bacterial; Erythromycin; Humans; Infant, Newborn; Ketolides; Macrolides; Microbial Sensitivity Tests; Spain; Streptococcal Infections; Streptococcus agalactiae; Tetracycline Resistance

The in vitro activities of telithromycin and cethromycin (ABT-773) against 412 Streptococcus pyogenes isolates, consecutively collected in 17 Spanish hospitals from different geographical areas, were evaluated and compared with those of erythromycin A, penicillin G, clindamycin and quinupristin-dalfopristin. With a susceptibility testing breakpoint of < or = 1 mg/L for both compounds, 96.1% of isolates were susceptible to telithromycin and 99.8% to cethromycin. Erythromycin non-susceptible isolates (intermediate plus resistant, MIC > or = 0.5 mg/L) comprised 23% of those tested, and were analysed for the genetic basis of their resistance by PCR. Among these isolates (n = 95), 72.6% harboured mef(A), 8.4%, erm(B), and 3.2%, erm(A), as sole macrolide resistance gene, whereas the presence of mef(A) plus erm(A) (11.6%) or mef(A) plus erm(B) (4.2%) was also observed. Both ketolides displayed a significant in vitro activity against S. pyogenes regardless of the macrolide resistance mechanisms. Nevertheless, in the case of telithromycin, 11 out of 19 of the erm(B)-positive isolates (2.7% of total population) exhibited an MIC range of 4-32 mg/L. According to the present results, telithromycin and cethromycin offer a wide coverage against S. pyogenes isolates in a geographic area with a high incidence of resistance to currently used macrolides.

Topics: Anti-Bacterial Agents; Drug Resistance; Erythromycin; Genes, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Spain; Streptococcal Infections; Streptococcus pyogenes

This study evaluated the current status of antimicrobial resistance in clinical isolates of Streptococcus pyogenes in Taiwan as part of the SMART (Surveillance from Multicenter Antimicrobial Resistance in Taiwan) program. In 2001, 419 different isolates of S. pyogenes, including 275 from respiratory secretions, 87 from wound pus, and 31 from blood, were collected from nine hospitals in different parts of Taiwan. MICs of 23 antimicrobial agents were determined at a central location by the agar dilution method. All of the isolates were susceptible to penicillin (MIC at which 90% of the isolates were inhibited [MIC(90)], moxifloxacin > ciprofloxacin = levofloxacin = gatifloxacin > gemifloxacin) demonstrated potent activity against nearly all of the isolates of S. pyogenes tested. Thirty-two isolates (8%) were not susceptible to quinupristin-dalfopristin. Seventeen percent of isolates had telithromycin MICs of >or=1 microg/ml, and all of these isolates exhibited erythromycin MICs of >or=32 microg/ml. The high prevalence of resistance to telithromycin (which is not available in Taiwan) limits its potential use in the treatment of S. pyogenes infections, particularly in areas with high rates of macrolide resistance.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Erythromycin; Genes, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Phenotype; Streptococcal Infections; Streptococcus pyogenes; Taiwan; Virginiamycin

Of 500 group A streptococci isolated from pharyngeal swabs, 72 (14.4%) were macrolide resistant, compared to 2.1% in 1997. Of these, 66 (92%) were of the M phenotype and 6 (8.3%) were of the MLS phenotype. Pulsed-field gel electrophoresis found that two clones, with patterns identical to those of serotypes M1 and M4, accounted for 19.4 and 68.1% of the macrolide-resistant isolates, respectively.

Topics: Anti-Bacterial Agents; Clindamycin; Drug Resistance, Bacterial; Erythromycin; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Ontario; Pharynx; Prevalence; Streptococcal Infections; Streptococcus pyogenes

In total, 1039 pediatric Streptococcus pyogenes isolates from Bulgaria, Croatia, the Czech Republic, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia and Slovenia were studied. All strains were susceptible to penicillin G, levofloxacin, and quinupristin-dalfopristin, 91-100% to telithromycin, and 82-100% to erythromycin, azithromycin, and clarithromycin, and 90-100% to clindamycin. Macrolide resistance occurred mainly in Slovakia (25%), the Czech Republic (17.3%), and Croatia (15.8%). Overall, 9.7% of S. pyogenes isolates were erythromycin resistant due to erm(B)- or erm(A)-encoded methylases (72.3%) or to a mef(A)-encoded efflux pump (25.7%). One strain had alterations of both 23S rRNA (A2058G Escherichia coli numbering) and ribosomal protein L22 (G95D).

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Drug Resistance, Bacterial; Europe; Humans; Infant; Infant, Newborn; Ketolides; Macrolides; Methylation; Ribosomes; Streptococcal Infections; Streptococcus pyogenes

The susceptibilities of 468 recent Russian clinical Streptococcus pneumoniae isolates and 600 Streptococcus pyogenes isolates, from 14 centers in Russia, to telithromycin, erythromycin, azithromycin, clarithromycin, clindamycin, levofloxacin, quinupristin-dalfopristin, and penicillin G were tested. Penicillin-nonsusceptible S. pneumoniae strains were rare except in Siberia, where their prevalence rate was 13.5%: most were penicillin intermediate, but for three strains (two from Smolensk and one from Novosibirsk) the MICs of penicillin G were 4 or 8 micro g/ml. Overall, 2.5% of S. pneumoniae isolates were resistant to erythromycin. Efflux was the prevalent resistance mechanism (five strains; 41.7%), followed by ribosomal methylation encoded by constitutive erm(B), which was found in four isolates. Ribosomal mutation was the mechanism of macrolide resistance in three isolates; one erythromycin-resistant S. pneumoniae isolate had an A2059G mutation in 23S rRNA, and two isolates had substitution of GTG by TPS at positions 69 to 71 in ribosomal protein L4. All S. pyogenes isolates were susceptible to penicillin, and 11% were erythromycin resistant. Ribosomal methylation was the most common resistance mechanism for S. pyogenes (89.4%). These methylases were encoded by erm(A) [subclass erm(TR)] genes, and their expression was inducible in 96.6% of isolates. The rest of the erythromycin-resistant Russian S. pyogenes isolates (7.6%) had an efflux resistance mechanism. Telithromycin was active against 100% of pneumococci and 99.2% of S. pyogenes, and levofloxacin and quinupristin-dalfopristin were active against all isolates of both species.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance; Genes, Bacterial; Ketolides; Macrolides; Methylation; Methyltransferases; Microbial Sensitivity Tests; Ribosomes; Russia; Streptococcal Infections; Streptococcus

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Streptococcal Infections; Streptococcus pyogenes; Tetracycline Resistance

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

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 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