ru-66647 and Pneumococcal-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

To explore the efficacy of the ketolide telithromycin compared with azithromycin in eradicating S pneumoniae from the nasopharynx of adults with acute maxillary sinusitis. The growing resistance of Streptococcus pneumoniae to penicillin and macrolides brought about the development of a new class of antibiotics-the ketolides-that are effective against resistant pneumococci.. Otolaryngology clinic.. One-hundred five patients with acute maxillary sinusitis.. Nasopharyngeal cultures were obtained before therapy and 10 to 12 days after initiation of treatment. Fifty-nine patients were treated with 500 mg of azithromycin daily for 3 days and 46 were treated with 800 mg of telithromycin daily for 5 days.. Sixty-seven potential pathogens were recovered prior to initiation of therapy in 57 patients, 32 treated with telithromycin and 25 treated with azithromycin: S pneumoniae (31 isolates), Haemophilus influenzae (non-type b) (13), Staphylococcus aureus (8), Streptococcus pyogenes (8), and Moraxella catarrhalis (7). The distribution of the pathogens was similar in both groups. The number of S pneumoniae isolates in the azithromycin group was reduced following treatment from 14 to 8 (43% reduction), and 5 of these 8 isolates were resistant to azithromycin. In contrast, the number of S pneumoniae isolates in the telithromycin group was reduced following treatment from 17 to 1 (94% reduction) (P < .01). This isolate was susceptible to azithromycin and telithromycin. No differences were noted in the eradication rate of all of the other potential pathogens, which were all susceptible to both azithromycin and telithromycin. Development of resistance to the antimicrobial agents used (defined as increase in the minimal inhibitory concentration by at least 2 tubes) was found only in 5 isolates (4 S pneumoniae and 1 H influenzae) recovered only from patients who received azithromycin (P < .05).. These data illustrate the superiority of telithromycin to azithromycin in the eradication of S pneumoniae from the nasopharynx.

Topics: Acute Disease; Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Drug Resistance, Bacterial; Female; Humans; Ketolides; Male; Maxillary Sinusitis; Middle Aged; Pneumococcal Infections; Streptococcus pneumoniae

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

A total of 132 Streptococcus pneumoniae isolates collected between 2005 and 2006 in Japan were examined for susceptibility to telithromycin (TEL) and macrolide. The overall resistance to macrolide was 80%. Among the isolates, 128 strains had low-level TEL susceptibility (minimal inhibitory concentrations [MICs] 0.03-1 microg mL(-1)), suggesting that pneumococci with reduced susceptibility to TEL have appeared without prior exposure to the drug, although none of the isolates were assigned as TEL-resistant (breakpoint, > or = 4 microg mL(-1)). Eight of these isolates (MIC 0.5-1 microg mL(-1)) were analyzed for macrolide resistance determinants and genetic relatedness. They all carried mefE-mel, which encodes the macrolide efflux genetic assembly, and three also harbored ermB, which encodes rRNA methylase. Allele replacement mutagenesis of the corresponding genes in the clinical isolates revealed that reduced TEL susceptibility (MIC 1 microg mL(-1)) in S. pneumoniae may be caused by acquisition of the mefE-mel element only and additionally conferred by the ermB determinant.

Topics: Anti-Bacterial Agents; DNA Fingerprinting; DNA Mutational Analysis; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Genes, Bacterial; Genotype; Japan; Ketolides; Macrolides; Microbial Sensitivity Tests; Pneumococcal Infections; Recombination, Genetic; Streptococcus pneumoniae; Transformation, Bacterial

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

A rare clinical isolate of Streptococcus pneumoniae, highly resistant to telithromycin, contained erm(B) with a truncated leader peptide and a mutant ribosomal protein L4. By transformation of susceptible strains, this study shows that high-level telithromycin resistance is conferred by erm(B), wild type or mutant, in combination with a (69)GTG(71)-to-TPS mutation in ribosomal protein L4.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Culture Media; Drug Resistance, Bacterial; Genotype; Humans; Ketolides; Methyltransferases; Microbial Sensitivity Tests; Mutation; Phenotype; Pneumococcal Infections; Ribosomal Proteins; Streptococcus pneumoniae

Broth microdilution MICs were determined for 14 antimicrobial agents against 296 clinical, non-duplicate isolates of Streptococcus pneumoniae collected at Methodist Hospital (Indianapolis, Indiana, USA) from January 2001 to December 2003. Isolates were categorized as susceptible, intermediate, or resistant using Clinical and Laboratory Standards Institute breakpoints. Time-kill studies were performed to evaluate the bactericidal activity of telithromycin at 1, 2, 4, and 8x MIC against 10 penicillin-nonsusceptible, levofloxacin-resistant, and macrolide-resistant (7 M-phenotype, 3 MLS(B)-phenotype) strains. Bactericidal activity was defined as a >/=3-log(10) reduction in CFU/mL. The prevalence of resistance was highest for the macrolides (32%), followed by penicillin (16.2%), clindamycin (10.8%), amoxicillin+/-clavulanate (4.4%), levofloxacin (3.0%), gatifloxacin and moxifloxacin (2.4%), ceftriaxone and cefotaxime (2.0%), and gemifloxacin (1.4%). None of the isolates tested were resistant to telithromycin. At 24h, telithromycin was bactericidal for 0/10, 2/10, 7/10, and 7/10 isolates at 1x MIC, 2x MIC, 4x MIC, and 8x MIC, respectively. At 4-8x MIC, telithromycin was bactericidal for 7/7 M-phenotype isolates and 0/3 MLS(B)-phenotype isolates. For the MLS(B)-phenotype isolates, colony counts were decreased by 1.3-2.1log(10) colony-forming units/mL after 24h at 8x MIC. Overall, telithromycin was highly active against 296 isolates of S. pneumoniae from our institution and demonstrated bactericidal activity at clinically achievable concentrations for 7 of 10 penicillin-nonsusceptible, levofloxacin-resistant, and macrolide-resistant S. pneumoniae. However, telithromycin was bacteriostatic for the MLS(B)-phenotype isolates.

Topics: Anti-Bacterial Agents; Humans; In Vitro Techniques; Ketolides; Levofloxacin; Macrolides; Microbial Sensitivity Tests; Ofloxacin; Penicillin Resistance; Pneumococcal Infections; Streptococcus pneumoniae

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

In addition to bactericidal activity, macrolide antibacterials possess clinically relevant properties such as immunomodulatory activity. Whether such activity extends to novel antibacterials that are structurally related to macrolides, such as the ketolides, remains largely unknown. The objective of this study was to evaluate the in vivo immunomodulatory profile of the first ketolide antibacterial - telithromycin in a murine neutropenic thigh infection model. Specific pathogen-free, female ICR mice were rendered transiently neutropenic with intraperitoneal cyclophosphamide. Thighs were inoculated with 10(6) colony-forming units of a single clinical isolate of Streptococcus pneumoniae. Once inoculated, mice (n=500) received single oral doses of telithromycin (10, 25 or 50 mg/kg of body weight) or no treatment (control). Blood was obtained via cardiac puncture prior to and at 2, 4, 8, and 24 h after dose administration for determination of cytokine concentrations. Significant post-inoculation elevations of interleukin (IL)-1beta, IL-6, and IL-10 were noted in untreated controls over 24 h. Telithromycin attenuated these increases and the suppression of both IL-6 and IL-10 release was observed to be dose dependent. Systemic concentrations of IL-2 and tumor necrosis factor alpha showed an upward trend over the initial 8-h post-inoculation period in the telithromycin group. These data therefore reveal novel in vivo immunomodulatory effects of telithromycin. Further studies are warranted to determine whether such effects contribute to the therapeutic efficacy of the drug in patients with acute respiratory tract infections.

Topics: Animals; Female; Immunologic Factors; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-6; Ketolides; Mice; Mice, Inbred ICR; Pneumococcal Infections; Tumor Necrosis Factor-alpha

Telithromycin-nonsusceptible pneumococcal clinical isolates (n = 17) were analyzed for their antimicrobial susceptibility, macrolide resistance mechanisms, and genetic relatedness. All strains showed the erm(B) genotype and showed a wide range of combinations of macrolide resistance mechanisms. The predominant clone (n = 7) was serotype 14, sequence type 143.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Europe; Genotype; Humans; Ketolides; Microbial Sensitivity Tests; Molecular Sequence Data; Phenotype; Pneumococcal Infections; Reverse Transcriptase Polymerase Chain Reaction; Streptococcus pneumoniae

The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were < or =0.5 microg/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 10(5) to 10(6) CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Disease Models, Animal; Drug Resistance, Bacterial; Female; Fluoroquinolones; Ketolides; Macrolides; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pneumococcal Infections; Protein Synthesis Inhibitors; Streptococcus pneumoniae; Thigh

Incubation in CO(2) resulted in higher (> or =3 doubling dilution) MICs of telithromycin than those found in ambient air for 31.2% of 346 Streptococcus pneumoniae ermB-positive strains. An increased telithromycin MIC in CO(2) was not correlated with loss of its activity in the murine sepsis/peritonitis model.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Carbon Dioxide; Disease Models, Animal; Humans; Ketolides; Mice; Microbial Sensitivity Tests; Peritonitis; Pneumococcal Infections; Protein Synthesis Inhibitors; Streptococcus pneumoniae

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

The influence of demographic factors upon antimicrobial resistance among 3362 isolates of Streptococcus pneumoniae from 25 countries was investigated, using univariate comparison and multivariate logistic regression.. Eleven countries had significantly higher rates (Odds ratios [OR]: 2.50-64.79) of penicillin and/or erythromycin resistance than the UK. After taking country effects into account, rates of penicillin resistance (OR 1.98) and erythromycin resistance (OR 1.89) were significantly higher among infants than adults. Fewer (OR 0.69) erythromycin-resistant isolates were collected from male than female patients. There was no difference in the incidence of penicillin or erythromycin resistance among inpatients or outpatients. Penicillin resistance was more prevalent among ear swabs than blood cultures (OR 2.07). Erm(B), the predominant macrolide resistance mechanism across all age groups, was particularly prevalent among bronchoalveolar lavage (69.1%) and sinus (68.8%) isolates. Isolates possessing both erm(B) and mef(A) were generally collected from South Korea and were most common among infants and children (10.3%) and ear samples (17.3%). Telithromycin susceptibility was >99.5%, irrespective of demography.. Although demography had a significant impact on antimicrobial resistance of pneumococci, telithromycin remained highly active across all demographic groups.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Asia, Eastern; Child; Child, Preschool; Demography; Drug Resistance, Bacterial; Europe, Eastern; Female; Humans; Infant; Ketolides; Male; Mexico; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Pneumococcal Infections; Streptococcus pneumoniae; United States

In a recent study, our in vivo data suggested that clinically achievable levels of telithromycin are more effective than azithromycin against selected Streptococcus pneumoniae isolates with ribosomal mutations in 23S rRNA gene alleles and L22 region mutations. In the current study, we attempt to investigate further the antibacterial activity of telithromycin against these isolates to better delineate the disparity between isolates based on allelic differences. Four isolates of S. pneumoniae with ribosomal mutations were tested using in vitro time-kill methodology. Isolates were exposed to telithromycin at concentrations of 0.5-8 x the minimum inhibitory concentration (MIC). At these exposures, telithromycin demonstrated concentration-dependent killing for three of the four isolates. Against the fourth isolate, telithromycin affected only a 1 log decrease in colony-forming units/mL despite exposures of 8 x MIC. These data demonstrate the in vitro killing profile of telithromycin against S. pneumoniae isolates with ribosomal and L22 mutations. Whilst telithromycin did not demonstrate bactericidal activity against all isolates in these time-kill studies, the in vivo human-simulated exposures did result in a high degree of bacterial kill. Full evaluation of the potential utility of new antimicrobial agents against these emerging genotypic profiles requires both in vitro and in vivo assessments.

Topics: Ketolides; Microbial Sensitivity Tests; Mutation; Pneumococcal Infections; Protein Synthesis Inhibitors; Ribosomes; RNA, Ribosomal, 23S; Streptococcus pneumoniae; Time Factors

Streptococcus pneumoniae is a major pathogen causing community-acquired pneumonia and acute bronchitis. Macrolides, fluoroquinolones (FQs), and, recently, telithromycin (TEL) constitute primary therapeutic options, and rare cases of resistance have been reported. In this report, we describe the emergence of an S. pneumoniae clinical isolate with high-level TEL resistance (MIC, 256 microg/ml) and simultaneous resistance to FQs. Ongoing studies are oriented to elucidate the precise mechanism of resistance to TEL.

Topics: Adult; Amino Acid Sequence; Bacterial Proteins; Base Sequence; Deoxyribonucleases, Type II Site-Specific; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Fluoroquinolones; Humans; Ketolides; Molecular Sequence Data; Pneumococcal Infections; Protein Synthesis Inhibitors; Sequence Alignment; Streptococcus pneumoniae

Isolates of Streptococcus pneumoniae collected over the first 4 years of the PROTEKT study were tested for susceptibility to penicillin, azithromycin and telithromycin. A total of 20,750 isolates were collected from 39 countries. Penicillin non-susceptibility rates were stable over the study period; overall, 21.8% of isolates were resistant. Azithromycin resistance increased from 31.0% in Year 1 to 36.3% in Year 4. Resistance rates for penicillin and azithromycin varied between countries and were highest in France, Spain, South Africa, USA and the Far East. Multidrug resistance in S. pneumoniae did not change significantly over the 4 years, with an overall rate of 38.6%. Telithromycin retained good activity against S. pneumoniae (0.1% of isolates resistant), including multidrug-resistant isolates.

Topics: Anti-Bacterial Agents; Azithromycin; Drug Resistance, Multiple, Bacterial; Global Health; Humans; Ketolides; Microbial Sensitivity Tests; Penicillins; Pneumococcal Infections; Streptococcus pneumoniae

The antistreptococcal activity of telithromycin and 11 different comparators was evaluated in 26 multi-drug resistant (MDR) Streptococcus pneumoniae strains collected during 2002-2003 as part of the ongoing PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) Italian Surveillance Program. The strains were characterized for their susceptibility to antibiotics both at the phenotypic and genotypic levels; furthermore, the association of erm(B), mef(A) class and tet(M) genes, as well as the mobile elements carrying them were determined. The strains in this study were resistant to penicillin (MIC > or = 2 mg/l) in 23.1% of cases, resistant to tetracycline in 88.4%, to cotrimoxazole in 34.6% and cefuroxime in 26.9% while only telithromycin and levofloxacin retained 100% activity against all microorganisms. Co-existence of different resistance determinants was found in 19.2% of all isolates collected in our laboratory, coming from southern Italy. Twenty-three isolates showing the MLSB phenotype of resistance possessing the erm(B) gene (88.5%), associated with tet(M), were carried on the same Tn1545-like element, while two isolates showing the M phenotype possessing the mef(A) gene alone, were carried on Tn1207.1. In only one strain were mef(E) and tet(M) together carried on Tn2009.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple; Genes, MDR; Genotype; Ketolides; Phenotype; Pneumococcal Infections; Streptococcus pneumoniae

Topics: Aged, 80 and over; Drug Resistance, Bacterial; Female; Humans; Ketolides; Microbial Sensitivity Tests; Pneumococcal Infections; Streptococcus pneumoniae

The in vitro activities of two investigational ketolides, cethromycin (formerly ABT-773) and telithromycin, were determined for a selected group of 312 Streptococcus pneumoniae isolates from a national surveillance program. The MIC of cethromycin at which 50% of the isolates were inhibited was 0.008 micro g/ml, and the MIC at which 90% of the isolates were inhibited was 0.06 micro g/ml; the corresponding values for telithromycin were

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Erythromycin; Genes, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; North America; Pneumococcal Infections; Reverse Transcriptase Polymerase Chain Reaction; Streptococcus pneumoniae

The increase in resistance to macrolides has been linked with increasing use of these agents as empirical therapy for community-acquired respiratory tract infections (CARTIs). As part of the ongoing PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance program, over 7600 Streptococcus pneumoniae isolates were collected worldwide from 1999-2001 and evaluated for macrolide resistance. Globally, macrolide resistance was 31-33%, with considerable inter-country variation (<10-88%) and particularly high prevalence in the Far East (>71%). In Europe, France had the most resistant isolates (>53%). The highest rates of macrolide resistance were seen in 0-2 year olds. Co-resistance to clindamycin (64%) and all beta-lactams (14-79%) was seen among macrolide-resistant isolates, but >99% of these isolates were susceptible to telithromycin, vancomycin and linezolid. There was considerable variation in the prevalence of erm(B) (56-64%) and mef(A) (30-35%): erm(B) was prevalent in Europe and mef(A) in North America. Globally, 5-7% isolates carried both mechanisms (erm(B)+mef(A)); of these, 47-65% were from South Korea. These double resistance isolates were >90% resistant to the beta-lactams, except amoxicillin-clavulanate. Clindamycin was active against >98% mef(A) but poorly active against erm(B) and erm(B)+mef(A) isolates. Telithromycin, vancomycin and linezolid were highly active (>99.5%) across all three genotypes.. In vitro, telithromycin, vancomycin and linezolid are highly active against antibiotic-resistant strains of S. pneumoniae. Telithromycin may be a useful therapeutic alternative to macrolides for the treatment of CARTIs.

Topics: Acetamides; Anti-Bacterial Agents; Anti-Infective Agents; Drug Resistance, Bacterial; Humans; Ketolides; Linezolid; Macrolides; Oxazolidinones; Pneumococcal Infections; Population Surveillance; Streptococcus pneumoniae; Vancomycin

Telithromycin MICs for 13,874 Streptococcus pneumoniae isolates collected in the first 3 years of the global PROTEKT study (1999 to 2003) were studied. There was no change in the distribution of telithromycin MICs over this period, even in countries where telithromycin is in use. The telithromycin MICs for 10 isolates (0.07%) were >/=4 micro g/ml, and these 10 isolates contained erm(B); there was no evidence of reproducible clonal spread between centers.

Topics: Anti-Bacterial Agents; DNA-Binding Proteins; Drug Resistance, Bacterial; Genotype; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Pneumococcal Infections; Population Surveillance; Streptococcus pneumoniae; Transcription Factors

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

To date, 86 of 7,746 macrolide-resistant Streptococcus pneumoniae isolates from 1999 to 2002 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance studies were negative for methylase and efflux mechanisms. Mutations in 23S rRNA or the genes encoding riboprotein L4 or L22 were found in 77 of 86 isolates. Six isolates were resistant to quinupristin-dalfopristin and two were resistant to linezolid, while telithromycin demonstrated good activities against all isolates.

Topics: Acetamides; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Humans; Ketolides; Linezolid; Macrolides; Mutation; Oxazolidinones; Pneumococcal Infections; Ribosomes; RNA, Ribosomal, 23S; Streptococcus pneumoniae; Virginiamycin

Of 595 isolates of Streptococcus pneumoniae from outpatients with respiratory tract infections, collected from 17 microbiology laboratories, 14.1% were resistant to erythromycin. Eighty-three erythromycin-resistant isolates were genetically analyzed, 83.1% of which harbored the ermB gene. Only four isolates (4.8%) harbored the mefA gene. Telithromycin exhibited potent activity against all isolates.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Erythromycin; Genotype; Germany; Ketolides; Macrolides; Membrane Proteins; Methyltransferases; Pneumococcal Infections; Reverse Transcriptase Polymerase Chain Reaction; Streptococcus pneumoniae

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

A telithromycin (TEL) kill-kinetics study was conducted with 120 clinically significant Streptococcus pneumoniae isolates (60 susceptible and 60 highly resistant to erythromycin). Time-kill curves were performed using different antibiotic concentrations. The minimum inhibitory concentrations (MICs) of TEL were low for both erythromycin-susceptible (MIC < or = 0.016 mg/L) and erythromycin-resistant strains (MIC < or = 0.25 mg/L). TEL showed 99.9% killing of all erythromycin resistant strains at 18-24 h of incubation. Even for strains with erythromycin MICs > or = 64.0 mg/L, TEL was uniformly bactericidal at 0.25 mg/L.

Topics: Adult; Drug Resistance, Bacterial; Erythromycin; Humans; Ketolides; Microbial Sensitivity Tests; Pneumococcal Infections; Streptococcus pneumoniae

There is a high prevalence of beta-lactam- and macrolide-resistant Streptococcus pneumoniae in Taiwan. To understand the in vitro susceptibilities of recent isolates of S. pneumoniae to fluoroquinolones and telithromycin (which is not available in Taiwan), the MICs of 23 antimicrobial agents for 936 clinical isolates of S. pneumoniae isolated from different parts of Taiwan from 2000 to 2001 were determined by the agar dilution method. Overall, 72% of isolates were not susceptible to penicillin (with 61% being intermediate and 11% being resistant) and 92% were resistant to erythromycin. Telithromycin MICs were >or=1 microg/ml for 16% of the isolates, and for 99% of these isolates the MICs of all macrolides tested were >or=256 microg/ml; all of these isolates had the constitutive macrolide-lincosamide-streptogramin B phenotype. Eighty-eight percent of the isolates were resistant to three or more classes of drugs. The ciprofloxacin MICs were >or=4 microg/ml for six (0.6%) isolates from five patients collected in 2000 and 2001, and the levofloxacin MICs were >or=8 microg/ml for five of these isolates. Seven isolates for which ciprofloxacin MICs were >or=4 microg/ml, including one isolate recovered in 1999, belonged to three serotypes (serotype 19F, five isolates; serotype 23A, one isolate; and serotype 23B, one isolate). The isolates from the six patients for which ciprofloxacin MICs were >or=4 microg/ml had different pulsed-field gel electrophoresis profiles and random amplified polymorphic DNA patterns, indicating that no clonal dissemination occurred over this time period. Despite the increased rate of fluoroquinolone use, the proportion of pneumococcal isolates for which ciprofloxacin MICs were elevated (>or=4 microg/ml) remained low. However, the occurrence of telithromycin resistance is impressive and raises concerns for the future.

Topics: Adult; Anti-Bacterial Agents; Anti-Infective Agents; beta-Lactam Resistance; Ciprofloxacin; Erythromycin; Genotype; Humans; Incidence; Ketolides; Macrolides; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pneumococcal Infections; Prevalence; Streptococcus pneumoniae; Taiwan

We compared the activities of telithromycin, erythromycin, azithromycin, josamycin, penicillin G, amoxicillin, cefpodoxime, and ceftriaxone against invasive and noninvasive non-penicillin-susceptible Streptococcus pneumoniae isolates recovered from children. Of the 186 isolates tested, 89% were positive for erm(B) by PCR. Telithromycin had the lowest MICs, with MICs at which 90% of the isolates tested are inhibited of 0.032 and 0.25 micro g/ml for erythromycin-sensitive and -resistant isolates, respectively.

Topics: Amoxicillin; Anti-Bacterial Agents; Azithromycin; Cefpodoxime; Ceftizoxime; Ceftriaxone; Child; Drug Resistance, Bacterial; Erythromycin; France; Humans; In Vitro Techniques; Josamycin; Ketolides; Macrolides; Penicillin G; Penicillin Resistance; Penicillins; Pneumococcal Infections; Streptococcus pneumoniae

Topics: Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Pneumococcal Infections; Streptococcus pneumoniae

ABT-773 is a new 3-keto macrolide antibiotic that has been shown to be very effective against infections by Gram-positive microorganisms. This work examines its inhibitory effects in cells of Streptococcus pneumoniae. ABT-773 caused a proportional decline in cell growth rates and viability with an IC(50) of 5 ng/ml. Protein synthesis in these cells was reduced by 50% at an antibiotic concentration of 2.5 ng/ml. This compound was also found to be a very effective inhibitor of the formation of the 50S ribosomal subunit in growing cells. Pulse and chase labeling assays revealed a reduced rate of 50S synthesis in antibiotic-treated cells. At 2 ng/ml, the rate was reduced to 33% of the control synthesis rate. An IC(50) of 5 ng/ml was found for the effect on this process, indicating an equal effect of the drug on translation and assembly. Synthesis of the 30S ribosomal subunit was unaffected by this antibiotic. The effects of ABT-773 in S. pneumoniae are compared with those of the related ketolide antibiotic telithromycin in S. pneumoniae and in Staphylococcus aureus.

Topics: Anti-Bacterial Agents; Erythromycin; Humans; In Vitro Techniques; Ketolides; Macrolides; Pneumococcal Infections; Protein Biosynthesis; Ribosomes; Staphylococcus aureus; Streptococcus pneumoniae

Increasing resistance of Streptococcus pneumoniae to macrolides represents a challenge for clinicians. New ketolides have an enhanced activity against macrolide-resistant strains. Four hundred and seventy-four strains of S. pneumoniae were collected during the 2000-2001 season in Quebec through a surveillance network. Macrolide resistance was 20.2%, and significantly higher in non-invasive strains versus invasive ones (22.4% versus 14.8%), and in children (30%) versus adults (14.8%). For susceptible strains, MIC(90)s of ABT-773 and telithromycin were 0.008 and 0.015 mg/L. Among the 96 macrolide-resistant strains, 56 (58%) were erm(B), 35 (37%) carried the mef(A) gene, four were carrying both genes and one none. ABT-773 and telithromycin were very active against all these resistant strains irrespective of the resistance mechanism, with MIC(90)s of 0.25 and 0.5 mg/L, respectively.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Drug Resistance, Bacterial; Erythromycin; Female; Genes, Bacterial; Genotype; Humans; Ketolides; Macrolides; Male; Microbial Sensitivity Tests; Pneumococcal Infections; Quebec; Streptococcus pneumoniae

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

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

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

Agar dilution and microdilution (both in air) and E test and disk diffusion (both in air and CO(2)) were used to test the activity of telithromycin against 110 erythromycin-susceptible and 106 erythromycin-resistant pneumococci. The MICs at which 50 and 90% of strains are inhibited (MIC(50)s and MIC(90)s, respectively) for erythromycin-susceptible strains varied between 0.008 and 0.016 microg/ml and 0.016 and 0.03 microg/ml when the samples were incubated in air. By comparison, telithromycin MIC(50)s and MIC(90)s for erythromycin-resistant strains were in air 0.03 to 0.125 and 0. 125 to 0.5 microg/ml, respectively. When agar dilution was used as the reference method, essential agreement was found for 112 of 216 strains (51.9%) for microdilution, 168 of 216 (77.8%) for E test in air, and 132 of 216 (61.1%) for E test in CO(2). With the exception of four strains tested by E test in CO(2), all organisms were susceptible to a proposed telithromycin susceptibility breakpoint of < or =1 microg/ml. By disk diffusion with 15-microg telithromycin disks, all strains but one had zones of inhibition > or =19 mm in diameter when incubated in CO(2), while all strains had zone diameters of > or = 22 mm when incubated in air. Zone diameters in air were generally 4 to 5 mm larger than in CO(2). By all methods, MICs and zones of all erythromycin-resistant strains occurred in clusters separated from those seen with erythromycin-susceptible strains. The results for macrolide-resistant strains with erm and mef resistance determinants were similar. The results show that (i) telithromycin is very active against erythromycin-susceptible and -resistant strains irrespective of macrolide resistance mechanism; (ii) susceptibility to telithromycin can be reliably tested by the agar, microdilution, E test, and disk diffusion methods; and (iii) incubation in CO(2) led to smaller zones by disk diffusion and higher MICs by E test, but at a susceptible MIC breakpoint of < or =1 microg/ml and a susceptible zone diameter cutoff of > or =19 mm in CO(2), 215 of 216 strains were found to be susceptible to telithromycin.

Topics: Anti-Bacterial Agents; Colony Count, Microbial; Drug Resistance, Microbial; Erythromycin; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Pneumococcal Infections; Streptococcus pneumoniae

Four different compounds belonging to the macrolide-lincosamide-streptogramin B (MLSb) class of antimicrobial agents were tested against 611 Streptococcus pneumoniae strains. The ketolide (HMR 3647, previously RU66647) and the streptogramin (quinupristin-dalfopristin) were both active against pneumococci with high-level MLSb resistance (clindamycin-resistant strains) as well as those with low-level macrolide resistance (clindamycin-susceptible strains).

Topics: Anti-Bacterial Agents; Clindamycin; Erythromycin; Humans; Ketolides; Macrolides; Penicillin Resistance; Phenotype; Pneumococcal Infections; Streptococcus pneumoniae; Virginiamycin