Disease relevance of Telithromycin

• Clinical isolates of Streptococcus pneumoniae with constitutive erm(B) and Streptococcus pyogenes with constitutive erm(A) subtype (TR) are resistant to macrolides, but remain susceptible to ketolides such as telithromycin [1].
• Telithromycin-resistant Streptococcus pneumoniae [2].
• The spectrum of activity of telithromycin includes common typical and atypical causative pathogens associated with community-acquired respiratory tract infections, including antibiotic-resistant strains of Streptococcus pneumoniae [3].
• Clinical trials have shown that telithromycin is as effective as traditionally used antimicrobial agents in the treatment of mild-to-moderate community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis [3].
• Effect of efflux on telithromycin and macrolide susceptibility in Haemophilus influenzae [4].

Psychiatry related information on Telithromycin

• With high efficacy and bacterial eradication rates, good tolerability and convenient once-daily administration, telithromycin therapy should result in increased patient compliance and improved outcomes, thereby minimizing the risk of developing antibacterial resistance [5].

High impact information on Telithromycin

• The lax interaction of the M. tuberculosis Erm(37) with its rRNA produces a unique methylation pattern and confers resistance to the ketolide telithromycin [6].
• Telithromycin, an antimicrobial agent, inhibits CYP3A4 in vitro and in vivo [7].
• Almost all (99.2%) dual erm(B) + mef(A) macrolide-resistant isolates exhibited multidrug resistance, whereas 98.6% and 99.0% were levofloxacin- and telithromycin-susceptible, respectively [8].
• RESULTS: ANOVA showed that telithromycin did not increase QT interval at any dose compared with placebo [9].
• CONCLUSIONS: Telithromycin administered as repeated doses of 800 mg (recommended doses) or as single doses of up to 3 times this recommended dose did not increase the QT interval at any heart rate at rest and during effort [9].

Chemical compound and disease context of Telithromycin

• Resistance to erythromycin and telithromycin in Streptococcus pyogenes isolates obtained between 1999 and 2002 from Greek children with tonsillopharyngitis: phenotypic and genotypic analysis [10].
• Efficacy of telithromycin (HMR 3647) against enterococci in a mouse peritonitis model [11].
• Time-kill studies examined the activities of telithromycin (HMR 3647), erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, pristinamycin, amoxicillin-clavulanate, and metronidazole against 11 gram-positive and gram-negative anaerobic bacteria [12].
• We evaluated the therapeutic efficacy of azithromycin, clarithromycin, and telithromycin in a lethal hamster model of leptospirosis using Leptospira interrogans serogroup Canicola serovar Portlandvere [13].
• Activities of cethromycin and telithromycin against recent North American isolates of Streptococcus pneumoniae [14].

Biological context of Telithromycin

• Clinical pharmacokinetics of telithromycin, the first ketolide antibacterial [15].
• 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 [16].
• 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 [17].
• 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 [18].
• The once-daily administration of telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure [15].

Anatomical context of Telithromycin

• The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter) [19].
• Telithromycin had immunomodulatory effects as a result of alteration of secretion of IL-1alpha and TNF-alpha by monocytes [20].
• Recovery of interfering bacteria in the nasopharynx following antimicrobial therapy of acute maxillary sinusitis with telithromycin or amoxicillin-clavulanate [21].
• By use of microdialysis we assessed the concentrations of telithromycin in muscle and adipose tissue to test its ability to penetrate soft tissues [22].
• Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages [23].

Associations of Telithromycin with other chemical compounds

• The MICs for all but eight S. pyogenes strains were < or =0.5 microg/ml, indicating that telithromycin is active in vitro against erythromycin-resistant Streptococcus strains [24].
• In vitro susceptibilities of rapidly growing mycobacteria to telithromycin (HMR 3647) and seven other antimicrobials [25].
• The potential for telithromycin to inhibit the CYP3A4 pathway is similar to that of clarithromycin [15].
• Two point mutations in domain V of 23S rRNA, C2611A and A2062G, were selected in the presence of erythromycin A, azithromycin, josamycin, quinupristin-dalfopristin, and telithromycin [26].
• Mean fecal global yeast counts increased similarly during 7 days of treatment with telithromycin (800 mg once daily) or amoxicillin-clavulanic acid (amoxiclav) (1 g of amoxicillin and 125 mg of clavulanic acid 3 times daily) in human volunteers and decreased slowly thereafter [27].

Gene context of Telithromycin

• Involvement of the drug transporters p glycoprotein and multidrug resistance-associated protein Mrp2 in telithromycin transport [28].
• Moreover, the biliary clearance of telithromycin was significantly decreased by 80% in Eisai hyperbilirubinemic mutant rats with a hereditary deficiency in Mrp2, indicating that Mrp2, as well as P glycoprotein, plays an important role in the biliary excretion of telithromycin [28].
• Secretion of each cytokine was significantly increased by LPS alone, whereas treatment with telithromycin significantly inhibited secretion of IL-1alpha and TNF-alpha but not secretion of IL-1beta, IL-6, and IL-10 [20].
• Telithromycin is metabolised via cytochrome P450 (CYP) 3A4 and non-CYP pathways [15].
• No modification of telithromycin accumulation was detected in E. aerogenes acrAB or tolC derivatives compared to that in the parental strain [29].

Analytical, diagnostic and therapeutic context of Telithromycin

• At the time of expected telithromycin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test [9].
• The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg [15].
• Telithromycin is 60-70% bound to serum proteins and has extensive diffusion into a range of target biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval [15].
• This randomized, three-period crossover study determined the dose proportionality of telithromycin pharmacokinetics after single and multiple dosing in healthy subjects [30].
• In phase III clinical trials, the telithromycin 800 mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired pneumonia [15].

References