Manickam Rangaraju - Academia.edu (original) (raw)
Papers by Manickam Rangaraju
Open forum infectious diseases, Feb 5, 2024
Clinical Microbiology and Infection, 2003
Objective This open, multinational study examined the ef®cacy and tolerability of telithromycin (... more Objective This open, multinational study examined the ef®cacy and tolerability of telithromycin (HMR 3647), the ®rst ketolide antibacterial agent, at an oral dose of 800 mg once daily for seven to ten days (further validated using pharmacokinetic analysis) as an empiric therapy in adults with mild to moderate community-acquired pneumonia (CAP). Methods A total of 240 patients (aged 18±79 years; median 40 years) with clinical signs and symptoms of CAP (radiologically con®rmed) were enrolled in the study and received at least one dose of study medication. Sputum and blood samples for bacteriologic documentation were collected within 48 h prior to enrollment. Clinical and bacteriological outcomes were assessed 17±21 days (test of cure visit) and 31±36 days (late posttherapy visit) after treatment initiation. Adverse events were assessed by spontaneous reporting and investigator observation. Results At the test of cure visit, 92.9% (95% CI: 88.4±96.1; n 197) of patients achieved clinical cure in the per-protocol (PP) population. In the modi®ed intent-to-treat (mITT) population, the cure rate was 79.6% (95% CI: 73.9±84.5; n 240), including 12.5% of undetermined cases categorized as failures. Clinical cure (PP population) remained high in patients !65 years (85.7%), and in patients with a Fine score !III (92.1%). Among those patients for whom bacteriologic data were available, the majority had a satisfactory outcome (88.9% in the bacteriologic PP; n 45). Bacterial eradication rates were similarly high (85.5% and 82.7% for the mITT and PP populations, respectively). All patients with infections as a result of atypical/intracellular pathogens Chlamydophila (Chlamydia) pneumoniae, Mycoplasma pneumoniae or Legionella pneumophila had a clinical outcome of cure. Treatment was well tolerated. Adverse events were mainly gastrointestinal in origin and mild in intensity. Conclusion An oral dose of telithromycin 800 mg once daily for seven to ten days is an effective and well-tolerated ®rst-line treatment for mild to moderate CAP in adults.
International Journal of Clinical Practice, 2005
Pooled data from three randomized, double-blind, multi- centre studies evaluated the efficacy and... more Pooled data from three randomized, double-blind, multi- centre studies evaluated the efficacy and tolerability of telithromycin 800 mg once daily for 5 days vs. standard comparators (10-day amoxicillin-clavulanate 500/125 mg three times daily, clarithromycin 500 mg or cefuroxime axetil 500 mg twice daily) in the outpatient treatment for acute exacerbations of chronic bronchitis. Per-protocol clinical cure rates at post-therapy/test of cure (days 17-24) were 86.0 and 85.8% for telithromycin and comparators, respectively, and 79.1 and 78.7%, respectively, at late post-therapy (days 31-36). Clinical cure rates were comparable for patients at increased risk, including those of > or =65 years and those with severe infection or significant airway obstruction (telithromycin, > or =77.1%; comparators, > or =75.0%). Telithromycin was well tolerated. Most adverse events considered possibly related to study medication were gastrointestinal and of mild intensity. In conclusion, 5-day telithromycin therapy is as effective and well tolerated as 10-day treatment with standard comparators.
International Journal of Antimicrobial Agents, 2007
ATPase activity of these enzymes. The objective of this work was to explore the structure activit... more ATPase activity of these enzymes. The objective of this work was to explore the structure activity relationships (SAR) of the series and to progress the compounds through preclinical development towards candidate nomination. Methods: The biochemical activity of compounds was determined using an in vitro ATPase assay. Minimal inhibitory concentrations (MIC) were determined using the CLSI broth microdilution method. Resistance frequency, time-kill and post-antibiotic effect were investigated using standard microbiological methods. The ADMET profile of various compounds was evaluated using in vitro methodology. Compounds from the series were evaluated in acute systemic infection models in mice. Results: A medicinal chemistry programme to explore the SAR of the compound series resulted in the synthesis of potent derivatives that have on-target activity against a range of species. Compounds within the series have nanomolar IC50s against gyrase and topo IV ATPase and singledigit, or better, microgram/mL MICs against S. aureus, E. faecalis, S. pneumoniae, M. catarrhalis and H. influenzae. The spontaneous resistance frequency observed for the series is low, consistent with dual targeting of DNA gyrase and topo IV. The compounds have a cidal mode of action with a time, but not concentration, dependant kill and no postantibiotic effect. The protein binding, cytotoxicity, chemical, plasma and microsomal stability, Caco-2 permeability, cytochrome P450 and hERG ion channel activities of the series have been explored. Selected derivatives have been characterised in vivo. The compounds were well tolerated and there was good bioavailability following IP or oral administration. Selected compounds demonstrated efficacy in murine septicaemia models of staphylococcal infection. Conclusion: The properties of the inhibitors are consistent with a compound series capable of optimisation into an antibiotic targeting both respiratory tract and drug-resistant Gram-positive infections.
Chemotherapy, 2002
Background: The efficacy and tolerability of oral telithromycin 800 mg once daily for 5 vs. 10 da... more Background: The efficacy and tolerability of oral telithromycin 800 mg once daily for 5 vs. 10 days were assessed in patients with acute maxillary sinusitis (AMS). Methods: Adults (n = 341) with confirmed AMS diagnosed on clinical signs and symptoms and sinus X-ray showing total opacity or air-fluid level were randomized to receive oral telithromycin for 5 days (followed by placebo for 5 days; n = 170) or 10 days (n = 171). Causative pathogens were isolated by pretreatment sinus puncture (day 1). Clinical and bacteriologic outcomes, and safety and tolerability endpoints were assessed. Results: Clinical cure rates post-therapy (per-protocol; days 17–21) were comparable (91.1% in the 5-day group, n = 123; 91.0% in the 10-day group, n = 133). Bacteriologic eradication rates (per-protocol) were also similar (90.7 vs. 91.3%). Both regimens were well tolerated. Conclusions: A 5-day course of telithromycin 800 mg once daily is an effective, well-tolerated treatment for adults with AMS, com...
Respiratory Medicine, 2002
This randomized, double-blind study evaluated the efficacy and safety of a short, 5-day course of... more This randomized, double-blind study evaluated the efficacy and safety of a short, 5-day course of telithromycin, a new ketolide antibacterial, compared with a standard10-day course of amoxicillin/clavulanate, in the treatment of acute exacerbations of chronic bronchitis (AECB). The study enrolled 325 adult patients with AECB and a history of chronic obstructive pulmonary disease (COPD).Patients received either telithromycin 800 mg once daily (qd) for 5 days (followed by placebo for 5 days) or amoxicillin/clavulanate 500/125 mg three times daily (tid) for10 days.Clinical cure rates for telithromycin post-therapy (Days 17221, test-of-cure) and late post-therapy (Days 31236) were 86.1 and 78.1%, respectively; 82. 1 and 75.0% for amoxicillin/clavulanate. Excellent clinical cure rates were also observed for high-risk patients.Bacteriologic outcome was satisfactory for 69.2% of telithromycin recipients vs 70.0% for amoxicillin/clavulanate recipients. Both treatments were generally well tolerated, although the frequency of drug-related adverse events was almost twofold higher for amoxicillin/clavulanate (25.0 vs.13.1%).Thus, a 5-day course of telithromycin 800 mg qd is an effective and well-tolerated alternative to a standard10-day course of amoxicillin/clavulanate 500/125 mg tid for first-line empiric treatment of AECB in adults with COPD.
Journal of Medicinal Chemistry
Chest, 2002
ABSTRACT This retrospective analysis was performed to determine the clinical and bacteriologic ef... more ABSTRACT This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients 13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800 mg once daily for 7-10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800 mg once daily for 5-10 days or a comparator antimicrobial (amoxicillin 1000 mg three times daily, clarithromycin 500 mg twice daily, or trovafloxacin 200 mg once daily) for 7-10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin- or erythromycin-resistant strains of S. pneumoniae (5/7 and 8/10, respectively). In conclusion, telithromycin achieves high clinical and bacteriologic cure rates in CAP patients with pneumococcal bacteremia.
Scandinavian Journal of Infectious Diseases, 2001
This randomized, double-blind study compared the efficacy and safety of a 5-d course of the new k... more 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.
Scandinavian Journal of Infectious Diseases, 2001
This randomized, double-blind study compared the efficacy and safety of a 5-d course of the new k... more 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.
Respiratory Medicine, 2006
This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of... more This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients X13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800 mg once daily for 7-10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800 mg once daily for 5-10 days or a comparator antimicrobial (amoxicillin 1000 mg three times daily, clarithromycin 500 mg twice daily, or trovafloxacin 200 mg once daily) for 7-10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin-or erythromycin-resistant strains of S. pneumoniae (5/7 and
Journal of Hepatology, 2019
Background and aims: Long-term follow-up of phase III clinical trials has shown that reversion of... more Background and aims: Long-term follow-up of phase III clinical trials has shown that reversion of histological cirrhosis may be achieved in CHB patients after ≥ 5 years of ETV or TDF therapy. However, predictors of such reversion of cirrhosis have not been well defined, while a follow-up liver biopsy cannot be routinely performed in clinical practice. We assessed predictors of elastographic reversion of cirrhosis at 5 years of ETV/TDF in CHB patients. Method: We included 348 adult Caucasian CHB patients of the PAGE-B cohort who had compensated cirrhosis before ETV/TDF and available reliable liver elastography at 5 years of therapy. Compensated cirrhosis before ETV/TDF was diagnosed mostly by histological findings or by well accepted ultrasonographic and/or endoscopic findings. Elastographic reversion of cirrhosis at 5 years of ETV/TDF therapy was diagnosed in cases with reliable liver stiffness measurements (LSM) < 12 kPa. Results: At 5 years, LSM < 12 and ≥ 12 kPa was observed in 246 (71%) and 102 (29%) patients. In univariable analyses, elastographic reversion of cirrhosis was associated with lower BMI (p = 0.002) or BMI ≤ 30 vs > 30 kg/m 2 (77% vs 49%, p < 0.001), current alcohol use < 20 vs ≥ 20 g/day (80% vs 67%, p = 0.049), absence vs presence of diabetes (80% vs 58%, p = 0.006), higher platelets (p < 0.001) or platelets ≥ 150 vs < 150 x10 9 /L at baseline (76% vs 64%, p = 0.014), higher platelets (p = 0.001) or platelets ≥ 150 vs < 150 x10 9 /L at year 5 (75% vs 62%, p = 0.017), lower HBV DNA at baseline (p = 0.012), prior use of interferon (p = 0.001) or other nucleos (t)ide analogues (p < 0.001), normal (≤ 40 IU/L) vs elevated ALT at year 1 (74% vs 50%, p = 0.002), therapy with TDF vs ETV (74% vs 62%, p = 0.038), but not with age, gender, smoking, HBeAg status at baseline or year 5, normal ALT at baseline or year 5, baseline albumin levels, virological on-therapy remission. Logistic multivariable regression analysis showed that elastographic reversion of cirrhosis was independently associated with baseline BMI ≤ 30 kg/m 2 [OR: 2.92 (95% CI: 1.23-6.94), p = 0.015], absence of diabetes [OR: 3.16 (1.21-8.27), p = 0.019] and TDF therapy [OR: 3.21 (1.38-7.46), p = 0.007]. Conclusion: Elastographic reversion (LSM < 12 kPa) of compensated cirrhosis after long-term antiviral therapy can be achieved in > 70% of CHB patients and appears to be associated with absence of obesity and diabetes, as previously reported in clinical trials with histological follow-up, as well as with TDF compared to ETV therapy.
Clinical drug investigation, Jan 27, 2015
Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and s... more Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and some class D β-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of β-lactams, including ceftazidime, against extended-spectrum β-lactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime. The first study (NXL104-1001) was a placebo-controlled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-1002) was performed in two parts. Part 1 assessed multiple-ascending doses of avibactam. Subjec...
Journal of Infection, 2004
Objectives. To investigate the correlation between in vitro susceptibility of isolates and clinic... more Objectives. To investigate the correlation between in vitro susceptibility of isolates and clinical outcomes with telithromycin in respiratory tract infections. Methods. The activity of telithromycin was determined by in vitro susceptibility testing of key respiratory tract pathogens isolated from patients with communityacquired pneumonia, acute exacerbations of chronic bronchitis or acute maxillary sinusitis enrolled in 14 Phase III/IV clinical trials evaluating the clinical efficacy of telithromycin. Results. In this pooled analysis, telithromycin mode minimum inhibitory concentration (MIC) and MIC 90 , respectively, were: 0.016 and 0.03 mg/l against Streptococcus pneumoniae ðn ¼ 626Þ; 0.03 and 0.5 mg/l for penicillin-resistant S. pneumoniae ðn ¼ 56Þ; 0.03 and 1 mg/l for erythromycin-resistant S. pneumoniae ðn ¼ 81Þ; 2 and 4 mg/l against Haemophilus influenzae (including b-lactamase producers; n ¼ 627); both 0.12 mg/l for Moraxella catarrhalis ðn ¼ 159Þ; and both 0.25 mg/l for Staphylococcus aureus ðn ¼ 124Þ: Telithromycin (5 or 7-10 days) resulted in overall clinical and bacteriologic success rates of 88.1% (1593/1808) and 89% (1593/1789), respectively. Conclusions. High levels of in vitro susceptibility to telithromycin are paralleled by high rates of clinical cure and bacteriologic eradication.
Journal of Infection, 2005
Objectives. To compare the efficacy and tolerability of a 5-day course of telithromycin (800 mg o... more Objectives. To compare the efficacy and tolerability of a 5-day course of telithromycin (800 mg once daily) with a 10-day course of telithromycin or standard comparators (amoxicillin-clavulanate 500/125 mg three times daily or cefuroxime axetil 250 mg twice daily) in patients with acute maxillary sinusitis (AMS). Methods. Data from three randomised double blind studies were pooled. The studies included patients with clinical symptoms of AMS and sinus X-ray findings of total opacity, air-fluid levels or mucosal thickening. Results. Pooled analysis of results for 5-day telithromycin revealed overall clinical cure rates of 83.6% (383/458 patients) at post-therapy (days 17-24) and 78.9% (330/418 patients) at late post-therapy (days 31-45) in the per-protocol population. Clinical cure rates at post-therapy were equivalent to those observed with 10-day telithromycin (82.5% vs 81.7%) or comparator treatment (80.9% vs 77.4%). Moreover, clinical cure rates exceeded 80% in subgroups of patients of interest, including those with severe infection and those fulfilling more stringent criteria for bacterial AMS. A satisfactory bacteriological outcome was achieved in 87.6% of patients. The 5-day telithromycin regimen was well tolerated. Conclusions. Telithromycin once daily for 5 days offers effective treatment for AMS and is comparable to 10-day courses of standard treatments.
International Journal of Antimicrobial Agents, 2005
Increasing resistance among the key pathogens responsible for community-acquired respiratory trac... more Increasing resistance among the key pathogens responsible for community-acquired respiratory tract infections, namely Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, has the potential to limit the effectiveness of the antibacterial agents available to treat these infections. Moreover, there are regional differences in the susceptibility patterns observed and, as treatment is usually empirical, choosing an effective treatment can be challenging. Telithromycin, the first ketolide to be approved for clinical use, offers an activity profile that covers the key respiratory pathogens including penicillin- and macrolide-resistant S. pneumoniae as well as beta-lactamase-producing H. influenzae and M. catarrhalis. In a pooled analysis of three large controlled clinical trials involving patients with acute maxillary sinusitis, the bacteriological efficacy of 5- or 10-day treatment with telithromycin and 10-day treatment with comparators was evaluated. Telithromycin administered as a once-daily 800 mg dose for 5 days achieved eradication rates of 91.8, 87.5 and 92.9% for S. pneumoniae, H. influenzae and M. catarrhalis, respectively. Bacteriological eradication of 8/10 and 12/14 isolates of S. pneumoniae resistant to penicillin and erythromycin, respectively, was also reported following 5-day treatment with telithromycin. The clinical efficacy of this regimen was equivalent to that of a 10-day regimen of telithromycin or standard 10-day courses of amoxicillin-clavulanic acid or cefuroxime axetil. Telithromycin 800mg given for 5 days was well tolerated, with the majority of adverse events being of mild or moderate intensity. These data suggest that telithromycin provides effective first-line therapy for use in patients with acute maxillary sinusitis in a short and convenient once-daily dosage regimen.
Clinical Microbiology and Infection, 2004
A pooled analysis of two double-blind, multicentre, Phase III studies compared oral telithromycin... more 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 twicedaily for 10 days in the treatment of Streptococcus pyogenes (group A b-haemolytic streptococcus; GABHS) tonsillopharyngitis. Patients aged ‡ 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 (MIC 50 ⁄ 90 0.03 ⁄ 0.06 mg ⁄ L) higher than clarithromycin or azithromycin (MIC 50 ⁄ 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 telithromycinand 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.
CHEST Journal, 2005
Study objectives: To demonstrate equivalence in the clinical efficacy of telithromycin vs clarith... more Study objectives: To demonstrate equivalence in the clinical efficacy of telithromycin vs clarithromycin treatment of outpatients with acute exacerbations of chronic bronchitis (AECB), and to compare the tolerability and respiratory-related health-care resource utilization associated with these treatment regimens. Design and patients: A randomized, double-blind, multicenter, clinical study was conducted at 105 centers in 14 countries. Adult outpatients (age > 30 years) received oral telithromycin, 800 mg qd for 5 days (n ؍ 270), or oral clarithromycin, 500 mg bid for 10 days (n ؍ 282), for the treatment of AECB. Clinical and bacteriologic outcomes were assessed at the posttherapy/testof-cure (TOC) visit (days 17 to 24; per-protocol population). Health-care resource utilization data were collected for each patient by investigators blinded to study medication up to the late posttherapy visit (days 31 to 36). Results: Clinical cure rates at the posttherapy/TOC visit were comparable between the groups (telithromycin, 193 of 225 patients [85.8%]; clarithromycin, 206 of 231 patients [89.2%]); bacteriologic outcome was satisfactory for 59 of 72 telithromycin-treated patients (81.9%) vs 63 of 76 clarithromycin-treated patients (82.9%). Health-care resource utilization assessed up to the late posttherapy visit was lower in the telithromycin treatment group than the clarithromycin treatment group, with significantly fewer hospitalizations for respiratory-related causes (one hospitalization vs eight hospitalizations for a total of 4 inpatient days vs 39 inpatient days, respectively), significantly fewer AECB-related emergency department visits (0 vs 8), and fewer unscheduled outpatient visits (11 vs 18). Fewer telithromycin-treated patients reported days lost from work (21 of 91 patients [23.1%]; 133 days) compared with those receiving clarithromycin (30 of 98 patients [30.6%]; 141 days). Telithromycin was well tolerated; adverse events considered possibly related to study medication were reported by 61 of 269 patients (22.7%) and 100 of 280 patients (35.7%) receiving telithromycin and clarithromycin, respectively. Conclusions: In this study, 5-day telithromycin treatment was as effective and well tolerated as 10-day clarithromycin treatment for patients with AECB, and was associated with a reduced utilization of health-care resources.
Chemotherapy, 2005
The efficacy of telithromycin 800 mg once daily for 5 to 10 days (1 study comprised 5-or 7-day te... more The efficacy of telithromycin 800 mg once daily for 5 to 10 days (1 study comprised 5-or 7-day telithromycin) was evaluated in 8 phase III/IV studies in patients with mild to moderate community-acquired pneumonia caused by atypical/intracellular pathogens. Atypical/intracellular pathogens were identified by serology and/or polymerase chain reaction analysis of sputum. Clinical outcome was assessed at test of cure (days 17 to 24) in the per-protocol population. In total, 2289 patients received telithromycin, and 702 received comparators. Of these, 1925 (including 4.5% identified with atypical pathogens) and 540 (including 8.1% identified with atypical pathogens), respectively, were included in the analysis. The clinical success rate for telithromycin was 91.2% (1755/1925) overall and 94.4% (34/36), 97.3% (36/37), and 100% (13/13) for Chlamydophila (Chlamydia) pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila, respectively (vs. 90.7% [490/540], 94.7% [18/19], 90.9% [20/22], and 2/3, respectively, for pooled comparators). Telithromycin is clinically efficacious in patients with mild to moderate community-acquired pneumonia caused by atypical/intracellular pathogens.
Infection, 2002
Background: This randomized, double-blind study compared the efficacy and tolerability of the new... more Background: This randomized, double-blind study compared the efficacy and tolerability of the new ketolide antimicrobial telithromycin with that of high-dose amoxicillin in the treatment of community-acquired pneumonia (CAP). Patients and Methods: Adult patients (n = 404), with signs and symptoms of CAP and radiologic confirmation were randomized to receive telithromycin 800 mg once daily (n = 199) or amoxicillin 1,000 mg three times a day (n = 205) for 10 days. Clinical and bacteriologic outcomes were assessed at post-therapy test-of-cure (days 17-24) and late post therapy (days 31-36). Results: The clinical cure rate for telithromycin-treated patients (per protocol) post therapy (days 17-24) was 141/149 (94.6%) and compared well with that for amoxicillin (137/152 (90.1%)). Subset analysis of patients (per protocol) showed high clinical cure rates for patients aged ≥ 65 years (telithromycin 21/24, 87.5%; amoxicillin 22/29, 75.9%); those with documented pneumococcal bacteremia (telithromycin 10/10, 100%; amoxicillin 7/9, 77.8%); and patients with a Fine score ≥ III (telithromycin 31/34, 91.2%; amoxicillin 38/47, 80.9%). Bacterial eradication rates were comparable between treatments (telithromycin 42/48, 87.5%; amoxicillin 39/45, 86.7%), with 22/23 vs 18/21 Streptococcus pneumoniae strains 9/12 vs 11/13 Haemophilus influenzae strains and all Moraxella catarrhalis isolates (five and three patients, respectively) eradicated at the test-of-cure visit. Both treatments were generally well tolerated. Conclusion: Telithromycin 800 mg once daily is a convenient, optimal-spectrum, first-line treatment for CAP in adults, at least as effective and well tolerated as high-dose amoxicillin.
Open forum infectious diseases, Feb 5, 2024
Clinical Microbiology and Infection, 2003
Objective This open, multinational study examined the ef®cacy and tolerability of telithromycin (... more Objective This open, multinational study examined the ef®cacy and tolerability of telithromycin (HMR 3647), the ®rst ketolide antibacterial agent, at an oral dose of 800 mg once daily for seven to ten days (further validated using pharmacokinetic analysis) as an empiric therapy in adults with mild to moderate community-acquired pneumonia (CAP). Methods A total of 240 patients (aged 18±79 years; median 40 years) with clinical signs and symptoms of CAP (radiologically con®rmed) were enrolled in the study and received at least one dose of study medication. Sputum and blood samples for bacteriologic documentation were collected within 48 h prior to enrollment. Clinical and bacteriological outcomes were assessed 17±21 days (test of cure visit) and 31±36 days (late posttherapy visit) after treatment initiation. Adverse events were assessed by spontaneous reporting and investigator observation. Results At the test of cure visit, 92.9% (95% CI: 88.4±96.1; n 197) of patients achieved clinical cure in the per-protocol (PP) population. In the modi®ed intent-to-treat (mITT) population, the cure rate was 79.6% (95% CI: 73.9±84.5; n 240), including 12.5% of undetermined cases categorized as failures. Clinical cure (PP population) remained high in patients !65 years (85.7%), and in patients with a Fine score !III (92.1%). Among those patients for whom bacteriologic data were available, the majority had a satisfactory outcome (88.9% in the bacteriologic PP; n 45). Bacterial eradication rates were similarly high (85.5% and 82.7% for the mITT and PP populations, respectively). All patients with infections as a result of atypical/intracellular pathogens Chlamydophila (Chlamydia) pneumoniae, Mycoplasma pneumoniae or Legionella pneumophila had a clinical outcome of cure. Treatment was well tolerated. Adverse events were mainly gastrointestinal in origin and mild in intensity. Conclusion An oral dose of telithromycin 800 mg once daily for seven to ten days is an effective and well-tolerated ®rst-line treatment for mild to moderate CAP in adults.
International Journal of Clinical Practice, 2005
Pooled data from three randomized, double-blind, multi- centre studies evaluated the efficacy and... more Pooled data from three randomized, double-blind, multi- centre studies evaluated the efficacy and tolerability of telithromycin 800 mg once daily for 5 days vs. standard comparators (10-day amoxicillin-clavulanate 500/125 mg three times daily, clarithromycin 500 mg or cefuroxime axetil 500 mg twice daily) in the outpatient treatment for acute exacerbations of chronic bronchitis. Per-protocol clinical cure rates at post-therapy/test of cure (days 17-24) were 86.0 and 85.8% for telithromycin and comparators, respectively, and 79.1 and 78.7%, respectively, at late post-therapy (days 31-36). Clinical cure rates were comparable for patients at increased risk, including those of > or =65 years and those with severe infection or significant airway obstruction (telithromycin, > or =77.1%; comparators, > or =75.0%). Telithromycin was well tolerated. Most adverse events considered possibly related to study medication were gastrointestinal and of mild intensity. In conclusion, 5-day telithromycin therapy is as effective and well tolerated as 10-day treatment with standard comparators.
International Journal of Antimicrobial Agents, 2007
ATPase activity of these enzymes. The objective of this work was to explore the structure activit... more ATPase activity of these enzymes. The objective of this work was to explore the structure activity relationships (SAR) of the series and to progress the compounds through preclinical development towards candidate nomination. Methods: The biochemical activity of compounds was determined using an in vitro ATPase assay. Minimal inhibitory concentrations (MIC) were determined using the CLSI broth microdilution method. Resistance frequency, time-kill and post-antibiotic effect were investigated using standard microbiological methods. The ADMET profile of various compounds was evaluated using in vitro methodology. Compounds from the series were evaluated in acute systemic infection models in mice. Results: A medicinal chemistry programme to explore the SAR of the compound series resulted in the synthesis of potent derivatives that have on-target activity against a range of species. Compounds within the series have nanomolar IC50s against gyrase and topo IV ATPase and singledigit, or better, microgram/mL MICs against S. aureus, E. faecalis, S. pneumoniae, M. catarrhalis and H. influenzae. The spontaneous resistance frequency observed for the series is low, consistent with dual targeting of DNA gyrase and topo IV. The compounds have a cidal mode of action with a time, but not concentration, dependant kill and no postantibiotic effect. The protein binding, cytotoxicity, chemical, plasma and microsomal stability, Caco-2 permeability, cytochrome P450 and hERG ion channel activities of the series have been explored. Selected derivatives have been characterised in vivo. The compounds were well tolerated and there was good bioavailability following IP or oral administration. Selected compounds demonstrated efficacy in murine septicaemia models of staphylococcal infection. Conclusion: The properties of the inhibitors are consistent with a compound series capable of optimisation into an antibiotic targeting both respiratory tract and drug-resistant Gram-positive infections.
Chemotherapy, 2002
Background: The efficacy and tolerability of oral telithromycin 800 mg once daily for 5 vs. 10 da... more Background: The efficacy and tolerability of oral telithromycin 800 mg once daily for 5 vs. 10 days were assessed in patients with acute maxillary sinusitis (AMS). Methods: Adults (n = 341) with confirmed AMS diagnosed on clinical signs and symptoms and sinus X-ray showing total opacity or air-fluid level were randomized to receive oral telithromycin for 5 days (followed by placebo for 5 days; n = 170) or 10 days (n = 171). Causative pathogens were isolated by pretreatment sinus puncture (day 1). Clinical and bacteriologic outcomes, and safety and tolerability endpoints were assessed. Results: Clinical cure rates post-therapy (per-protocol; days 17–21) were comparable (91.1% in the 5-day group, n = 123; 91.0% in the 10-day group, n = 133). Bacteriologic eradication rates (per-protocol) were also similar (90.7 vs. 91.3%). Both regimens were well tolerated. Conclusions: A 5-day course of telithromycin 800 mg once daily is an effective, well-tolerated treatment for adults with AMS, com...
Respiratory Medicine, 2002
This randomized, double-blind study evaluated the efficacy and safety of a short, 5-day course of... more This randomized, double-blind study evaluated the efficacy and safety of a short, 5-day course of telithromycin, a new ketolide antibacterial, compared with a standard10-day course of amoxicillin/clavulanate, in the treatment of acute exacerbations of chronic bronchitis (AECB). The study enrolled 325 adult patients with AECB and a history of chronic obstructive pulmonary disease (COPD).Patients received either telithromycin 800 mg once daily (qd) for 5 days (followed by placebo for 5 days) or amoxicillin/clavulanate 500/125 mg three times daily (tid) for10 days.Clinical cure rates for telithromycin post-therapy (Days 17221, test-of-cure) and late post-therapy (Days 31236) were 86.1 and 78.1%, respectively; 82. 1 and 75.0% for amoxicillin/clavulanate. Excellent clinical cure rates were also observed for high-risk patients.Bacteriologic outcome was satisfactory for 69.2% of telithromycin recipients vs 70.0% for amoxicillin/clavulanate recipients. Both treatments were generally well tolerated, although the frequency of drug-related adverse events was almost twofold higher for amoxicillin/clavulanate (25.0 vs.13.1%).Thus, a 5-day course of telithromycin 800 mg qd is an effective and well-tolerated alternative to a standard10-day course of amoxicillin/clavulanate 500/125 mg tid for first-line empiric treatment of AECB in adults with COPD.
Journal of Medicinal Chemistry
Chest, 2002
ABSTRACT This retrospective analysis was performed to determine the clinical and bacteriologic ef... more ABSTRACT This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients 13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800 mg once daily for 7-10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800 mg once daily for 5-10 days or a comparator antimicrobial (amoxicillin 1000 mg three times daily, clarithromycin 500 mg twice daily, or trovafloxacin 200 mg once daily) for 7-10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin- or erythromycin-resistant strains of S. pneumoniae (5/7 and 8/10, respectively). In conclusion, telithromycin achieves high clinical and bacteriologic cure rates in CAP patients with pneumococcal bacteremia.
Scandinavian Journal of Infectious Diseases, 2001
This randomized, double-blind study compared the efficacy and safety of a 5-d course of the new k... more 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.
Scandinavian Journal of Infectious Diseases, 2001
This randomized, double-blind study compared the efficacy and safety of a 5-d course of the new k... more 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.
Respiratory Medicine, 2006
This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of... more This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients X13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800 mg once daily for 7-10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800 mg once daily for 5-10 days or a comparator antimicrobial (amoxicillin 1000 mg three times daily, clarithromycin 500 mg twice daily, or trovafloxacin 200 mg once daily) for 7-10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin-or erythromycin-resistant strains of S. pneumoniae (5/7 and
Journal of Hepatology, 2019
Background and aims: Long-term follow-up of phase III clinical trials has shown that reversion of... more Background and aims: Long-term follow-up of phase III clinical trials has shown that reversion of histological cirrhosis may be achieved in CHB patients after ≥ 5 years of ETV or TDF therapy. However, predictors of such reversion of cirrhosis have not been well defined, while a follow-up liver biopsy cannot be routinely performed in clinical practice. We assessed predictors of elastographic reversion of cirrhosis at 5 years of ETV/TDF in CHB patients. Method: We included 348 adult Caucasian CHB patients of the PAGE-B cohort who had compensated cirrhosis before ETV/TDF and available reliable liver elastography at 5 years of therapy. Compensated cirrhosis before ETV/TDF was diagnosed mostly by histological findings or by well accepted ultrasonographic and/or endoscopic findings. Elastographic reversion of cirrhosis at 5 years of ETV/TDF therapy was diagnosed in cases with reliable liver stiffness measurements (LSM) < 12 kPa. Results: At 5 years, LSM < 12 and ≥ 12 kPa was observed in 246 (71%) and 102 (29%) patients. In univariable analyses, elastographic reversion of cirrhosis was associated with lower BMI (p = 0.002) or BMI ≤ 30 vs > 30 kg/m 2 (77% vs 49%, p < 0.001), current alcohol use < 20 vs ≥ 20 g/day (80% vs 67%, p = 0.049), absence vs presence of diabetes (80% vs 58%, p = 0.006), higher platelets (p < 0.001) or platelets ≥ 150 vs < 150 x10 9 /L at baseline (76% vs 64%, p = 0.014), higher platelets (p = 0.001) or platelets ≥ 150 vs < 150 x10 9 /L at year 5 (75% vs 62%, p = 0.017), lower HBV DNA at baseline (p = 0.012), prior use of interferon (p = 0.001) or other nucleos (t)ide analogues (p < 0.001), normal (≤ 40 IU/L) vs elevated ALT at year 1 (74% vs 50%, p = 0.002), therapy with TDF vs ETV (74% vs 62%, p = 0.038), but not with age, gender, smoking, HBeAg status at baseline or year 5, normal ALT at baseline or year 5, baseline albumin levels, virological on-therapy remission. Logistic multivariable regression analysis showed that elastographic reversion of cirrhosis was independently associated with baseline BMI ≤ 30 kg/m 2 [OR: 2.92 (95% CI: 1.23-6.94), p = 0.015], absence of diabetes [OR: 3.16 (1.21-8.27), p = 0.019] and TDF therapy [OR: 3.21 (1.38-7.46), p = 0.007]. Conclusion: Elastographic reversion (LSM < 12 kPa) of compensated cirrhosis after long-term antiviral therapy can be achieved in > 70% of CHB patients and appears to be associated with absence of obesity and diabetes, as previously reported in clinical trials with histological follow-up, as well as with TDF compared to ETV therapy.
Clinical drug investigation, Jan 27, 2015
Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and s... more Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and some class D β-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of β-lactams, including ceftazidime, against extended-spectrum β-lactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime. The first study (NXL104-1001) was a placebo-controlled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-1002) was performed in two parts. Part 1 assessed multiple-ascending doses of avibactam. Subjec...
Journal of Infection, 2004
Objectives. To investigate the correlation between in vitro susceptibility of isolates and clinic... more Objectives. To investigate the correlation between in vitro susceptibility of isolates and clinical outcomes with telithromycin in respiratory tract infections. Methods. The activity of telithromycin was determined by in vitro susceptibility testing of key respiratory tract pathogens isolated from patients with communityacquired pneumonia, acute exacerbations of chronic bronchitis or acute maxillary sinusitis enrolled in 14 Phase III/IV clinical trials evaluating the clinical efficacy of telithromycin. Results. In this pooled analysis, telithromycin mode minimum inhibitory concentration (MIC) and MIC 90 , respectively, were: 0.016 and 0.03 mg/l against Streptococcus pneumoniae ðn ¼ 626Þ; 0.03 and 0.5 mg/l for penicillin-resistant S. pneumoniae ðn ¼ 56Þ; 0.03 and 1 mg/l for erythromycin-resistant S. pneumoniae ðn ¼ 81Þ; 2 and 4 mg/l against Haemophilus influenzae (including b-lactamase producers; n ¼ 627); both 0.12 mg/l for Moraxella catarrhalis ðn ¼ 159Þ; and both 0.25 mg/l for Staphylococcus aureus ðn ¼ 124Þ: Telithromycin (5 or 7-10 days) resulted in overall clinical and bacteriologic success rates of 88.1% (1593/1808) and 89% (1593/1789), respectively. Conclusions. High levels of in vitro susceptibility to telithromycin are paralleled by high rates of clinical cure and bacteriologic eradication.
Journal of Infection, 2005
Objectives. To compare the efficacy and tolerability of a 5-day course of telithromycin (800 mg o... more Objectives. To compare the efficacy and tolerability of a 5-day course of telithromycin (800 mg once daily) with a 10-day course of telithromycin or standard comparators (amoxicillin-clavulanate 500/125 mg three times daily or cefuroxime axetil 250 mg twice daily) in patients with acute maxillary sinusitis (AMS). Methods. Data from three randomised double blind studies were pooled. The studies included patients with clinical symptoms of AMS and sinus X-ray findings of total opacity, air-fluid levels or mucosal thickening. Results. Pooled analysis of results for 5-day telithromycin revealed overall clinical cure rates of 83.6% (383/458 patients) at post-therapy (days 17-24) and 78.9% (330/418 patients) at late post-therapy (days 31-45) in the per-protocol population. Clinical cure rates at post-therapy were equivalent to those observed with 10-day telithromycin (82.5% vs 81.7%) or comparator treatment (80.9% vs 77.4%). Moreover, clinical cure rates exceeded 80% in subgroups of patients of interest, including those with severe infection and those fulfilling more stringent criteria for bacterial AMS. A satisfactory bacteriological outcome was achieved in 87.6% of patients. The 5-day telithromycin regimen was well tolerated. Conclusions. Telithromycin once daily for 5 days offers effective treatment for AMS and is comparable to 10-day courses of standard treatments.
International Journal of Antimicrobial Agents, 2005
Increasing resistance among the key pathogens responsible for community-acquired respiratory trac... more Increasing resistance among the key pathogens responsible for community-acquired respiratory tract infections, namely Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, has the potential to limit the effectiveness of the antibacterial agents available to treat these infections. Moreover, there are regional differences in the susceptibility patterns observed and, as treatment is usually empirical, choosing an effective treatment can be challenging. Telithromycin, the first ketolide to be approved for clinical use, offers an activity profile that covers the key respiratory pathogens including penicillin- and macrolide-resistant S. pneumoniae as well as beta-lactamase-producing H. influenzae and M. catarrhalis. In a pooled analysis of three large controlled clinical trials involving patients with acute maxillary sinusitis, the bacteriological efficacy of 5- or 10-day treatment with telithromycin and 10-day treatment with comparators was evaluated. Telithromycin administered as a once-daily 800 mg dose for 5 days achieved eradication rates of 91.8, 87.5 and 92.9% for S. pneumoniae, H. influenzae and M. catarrhalis, respectively. Bacteriological eradication of 8/10 and 12/14 isolates of S. pneumoniae resistant to penicillin and erythromycin, respectively, was also reported following 5-day treatment with telithromycin. The clinical efficacy of this regimen was equivalent to that of a 10-day regimen of telithromycin or standard 10-day courses of amoxicillin-clavulanic acid or cefuroxime axetil. Telithromycin 800mg given for 5 days was well tolerated, with the majority of adverse events being of mild or moderate intensity. These data suggest that telithromycin provides effective first-line therapy for use in patients with acute maxillary sinusitis in a short and convenient once-daily dosage regimen.
Clinical Microbiology and Infection, 2004
A pooled analysis of two double-blind, multicentre, Phase III studies compared oral telithromycin... more 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 twicedaily for 10 days in the treatment of Streptococcus pyogenes (group A b-haemolytic streptococcus; GABHS) tonsillopharyngitis. Patients aged ‡ 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 (MIC 50 ⁄ 90 0.03 ⁄ 0.06 mg ⁄ L) higher than clarithromycin or azithromycin (MIC 50 ⁄ 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 telithromycinand 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.
CHEST Journal, 2005
Study objectives: To demonstrate equivalence in the clinical efficacy of telithromycin vs clarith... more Study objectives: To demonstrate equivalence in the clinical efficacy of telithromycin vs clarithromycin treatment of outpatients with acute exacerbations of chronic bronchitis (AECB), and to compare the tolerability and respiratory-related health-care resource utilization associated with these treatment regimens. Design and patients: A randomized, double-blind, multicenter, clinical study was conducted at 105 centers in 14 countries. Adult outpatients (age > 30 years) received oral telithromycin, 800 mg qd for 5 days (n ؍ 270), or oral clarithromycin, 500 mg bid for 10 days (n ؍ 282), for the treatment of AECB. Clinical and bacteriologic outcomes were assessed at the posttherapy/testof-cure (TOC) visit (days 17 to 24; per-protocol population). Health-care resource utilization data were collected for each patient by investigators blinded to study medication up to the late posttherapy visit (days 31 to 36). Results: Clinical cure rates at the posttherapy/TOC visit were comparable between the groups (telithromycin, 193 of 225 patients [85.8%]; clarithromycin, 206 of 231 patients [89.2%]); bacteriologic outcome was satisfactory for 59 of 72 telithromycin-treated patients (81.9%) vs 63 of 76 clarithromycin-treated patients (82.9%). Health-care resource utilization assessed up to the late posttherapy visit was lower in the telithromycin treatment group than the clarithromycin treatment group, with significantly fewer hospitalizations for respiratory-related causes (one hospitalization vs eight hospitalizations for a total of 4 inpatient days vs 39 inpatient days, respectively), significantly fewer AECB-related emergency department visits (0 vs 8), and fewer unscheduled outpatient visits (11 vs 18). Fewer telithromycin-treated patients reported days lost from work (21 of 91 patients [23.1%]; 133 days) compared with those receiving clarithromycin (30 of 98 patients [30.6%]; 141 days). Telithromycin was well tolerated; adverse events considered possibly related to study medication were reported by 61 of 269 patients (22.7%) and 100 of 280 patients (35.7%) receiving telithromycin and clarithromycin, respectively. Conclusions: In this study, 5-day telithromycin treatment was as effective and well tolerated as 10-day clarithromycin treatment for patients with AECB, and was associated with a reduced utilization of health-care resources.
Chemotherapy, 2005
The efficacy of telithromycin 800 mg once daily for 5 to 10 days (1 study comprised 5-or 7-day te... more The efficacy of telithromycin 800 mg once daily for 5 to 10 days (1 study comprised 5-or 7-day telithromycin) was evaluated in 8 phase III/IV studies in patients with mild to moderate community-acquired pneumonia caused by atypical/intracellular pathogens. Atypical/intracellular pathogens were identified by serology and/or polymerase chain reaction analysis of sputum. Clinical outcome was assessed at test of cure (days 17 to 24) in the per-protocol population. In total, 2289 patients received telithromycin, and 702 received comparators. Of these, 1925 (including 4.5% identified with atypical pathogens) and 540 (including 8.1% identified with atypical pathogens), respectively, were included in the analysis. The clinical success rate for telithromycin was 91.2% (1755/1925) overall and 94.4% (34/36), 97.3% (36/37), and 100% (13/13) for Chlamydophila (Chlamydia) pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila, respectively (vs. 90.7% [490/540], 94.7% [18/19], 90.9% [20/22], and 2/3, respectively, for pooled comparators). Telithromycin is clinically efficacious in patients with mild to moderate community-acquired pneumonia caused by atypical/intracellular pathogens.
Infection, 2002
Background: This randomized, double-blind study compared the efficacy and tolerability of the new... more Background: This randomized, double-blind study compared the efficacy and tolerability of the new ketolide antimicrobial telithromycin with that of high-dose amoxicillin in the treatment of community-acquired pneumonia (CAP). Patients and Methods: Adult patients (n = 404), with signs and symptoms of CAP and radiologic confirmation were randomized to receive telithromycin 800 mg once daily (n = 199) or amoxicillin 1,000 mg three times a day (n = 205) for 10 days. Clinical and bacteriologic outcomes were assessed at post-therapy test-of-cure (days 17-24) and late post therapy (days 31-36). Results: The clinical cure rate for telithromycin-treated patients (per protocol) post therapy (days 17-24) was 141/149 (94.6%) and compared well with that for amoxicillin (137/152 (90.1%)). Subset analysis of patients (per protocol) showed high clinical cure rates for patients aged ≥ 65 years (telithromycin 21/24, 87.5%; amoxicillin 22/29, 75.9%); those with documented pneumococcal bacteremia (telithromycin 10/10, 100%; amoxicillin 7/9, 77.8%); and patients with a Fine score ≥ III (telithromycin 31/34, 91.2%; amoxicillin 38/47, 80.9%). Bacterial eradication rates were comparable between treatments (telithromycin 42/48, 87.5%; amoxicillin 39/45, 86.7%), with 22/23 vs 18/21 Streptococcus pneumoniae strains 9/12 vs 11/13 Haemophilus influenzae strains and all Moraxella catarrhalis isolates (five and three patients, respectively) eradicated at the test-of-cure visit. Both treatments were generally well tolerated. Conclusion: Telithromycin 800 mg once daily is a convenient, optimal-spectrum, first-line treatment for CAP in adults, at least as effective and well tolerated as high-dose amoxicillin.