1.  HMR 3647
2.  Ketek(TM)
3.  RU-647
4.  RU-66647

• 1. Telithromycin tablets should be stored at 25 degrees Celsius (77 degrees Fahrenheit); excursions are permitted between 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) (Prod Info Ketek(TM), 2004).

• A. ORAL
  
  • 1. BACTERIAL SINUSITIS
    
    • a. The recommended dose of telithromycin in the treatment of acute bacterial sinusitis is 800 milligrams once daily for 5 days (Prod Info Ketek(TM), 2004; Roos et al, 2002; Tellier et al, 2000a).
    • b. In studies involving ACUTE MAXILLARY SINUSITIS patients, 5- and 10-day regimens of 800 mg daily were equally effective (Roos et al, 2002; Tellier et al, 2000a).
  • 2. CHRONIC BRONCHITIS
    
    • a. The recommended dose of telithromycin for the treatment of acute exacerbations of chronic bronchitis is 800 milligrams once daily for 5 days (Prod Info Ketek(TM), 2004; Deabate et al, 2000).
  • 3. COMMUNITY-ACQUIRED PNEUMONIA
    
    • a. The recommended dose of telithromycin for the treatment of community-acquired pneumonia is 800 milligrams once daily for 7 to 10 days (Prod Info Ketek(TM), 2004; Pullman et al, 2000; Tellier et al, 2000; Leroy & Manickam, 2000).

• A. The dosage of telithromycin in patients with severe renal impairment (creatinine clearance less than 30 millimeters/minute) or who require dialysis has not been established (Prod Info Ketek(TM), 2004).
• B. Investigators concluded that dosage adjustment is not necessary in patients with a creatinine clearance equal to or greater than 30 milliliters/minute (mL/min) and that dosage adjustment could be considered in patients with a creatinine clearance less than 10 (mL/min). A study comparing the pharmacokinetic profile of telithromycin in healthy volunteers to patients with impaired renal function was conducted after single and multiple doses. In the multiple dose study, patients with a creatinine clearance less than or equal to 10 mL/min exhibited a 2-fold higher area under the concentration-time curve and a 1.5-fold higher peak concentration. Renal clearance of telithromycin was also significantly decreased with increasing severity of renal impairment (Shi et al, 2004).

• A. Dosage adjustment is not required in patients with hepatic impairment. Pharmacokinetic studies in patients with mild to severe hepatic impairment (Child Pugh Class A, B, and C), demonstrated similar Cmax, AUC and half-lives to those obtained in age- and sex-matched health subjects (Prod Info Ketek(TM), 2004).

• A. Dosage adjustments do not appear to be necessary in elderly patients (Prod Info Ketek(TM), 2004).
• B. Peak plasma concentrations of telithromycin have been higher in elderly versus younger subjects following multiple once-daily 800-milligram (mg) doses, associated with a reduction in renal clearance (Sultan et al, 1999; Lenfant et al, 1998). However, elimination half-life data were similar. Dose adjustment does not appear warranted.

• A. ORAL
  
  • 1. Telithromycin is not approved for the use in pediatric patients as its efficacy and safety in this population has not been established (Prod Info Ketek(TM), 2004).
  • 2. In children/adolescents 13 years of age or older with group A beta-hemolytic STREPTOCOCCAL PHARYNGITIS or tonsillitis, usual adult doses (800 milligrams (mg) once daily for 5 days) were effective and fairly well-tolerated in one study (Ziter et al, 2000).

• A. THERAPEUTIC DRUG CONCENTRATION :
  
  • 1. BACTERIAL INFECTIONS :
    
    • a. Clinical correlations with in vitro data have not been adequately studied. Concentrations of 0.5 mcg/mL or less have been sufficient in vitro against most strains of Staphylococcus aureus, streptococci (including pneumococci), and some enterococci. Higher inhibitory concentrations have been required for H. influenzae, most vancomycin-resistant enterococci, and B. fragilis.
    • b. A population pharmacodynamic/pharmacokinetic study suggested that pathogens with MIC values of 2 to 4 mcg/mL can be treated effectively with telithromycin 800 mg once daily (Drusano et al, 2000).
• B. TIME TO PEAK CONCENTRATION :
  
  • 1. ORAL : 1 to 2.5 hours (Shi et al, 2004; Edlund et al, 2000; Lenfant et al, 1999; Lenfant et al, 1998).
    • a. Following single oral doses of 800 mg in healthy young subjects, mean peak plasma levels have ranged from 1.4 to 2.4 mcg/mL; 24-hour trough levels after this dose were 0.01 to 0.025 mcg/mL. With once-daily administration of this dose for 10 days, accumulation was minimal, with peak and trough levels (mean) ranging from 1.9 to 2.9 mcg/mL and 0.03 to 0.2 mcg/mL, respectively (Namour et al, 2001; Edlund et al, 2000; Drusano et al, 2000; Lenfant et al, 1998; Lenfant et al, 1999). Steady-state was reached after 2 to 3 days (Lenfant et al, 1998; Namour et al, 2001).
    • b. After 800-mg single doses and multiple doses for 10 days in elderly subjects, faster absorption and higher mean peak levels have been reported compared to young subjects. However, corresponding trough levels were similar (Sultan et al, 1999).
    • c. After single and repeated doses (once daily for 7 days) of 800 mg telithromycin in patients with hepatic impairment (Child-Pugh score between 5 and 12), mean peak plasma levels were similar to those found in healthy controls. Plasma concentration 24 hours post dose was significantly higher in patients with hepatic impairment following administration of a single dose of telithromycin (0.088 mg/L compared to 0.039 mg/L, p less than 0.01) (Cantalloube et al, 2003).
    • d. Single and multiple doses of telithromycin in healthy volunteers and in patients with varying degrees of renal impairment resulted in similar times to peak concentrations and trough concentrations. Peak concentration values after a single dose of telithromycin 800 mg were also not statistically different between patients with renal impairment and healthy volunteers. After a single 800 mg dose, mean time to peak concentrations ranged from 1.1 to 1.35 hours and mean peak concentrations ranged from 2.13 mg/L to 3.25 mg/L. After repeated once daily 800 mg doses for 5 days, mean time to peak concentrations ranged from 2.0 to 3.38 hours and mean trough levels ranged from 0.07 mg/L to 0.21 mg/L. After repeated doses, the mean peak concentration values were not statistically different between healthy volunteers and patients with mild to moderate renal impairment (creatinine clearance between 30 to 80 mL/min) with values ranging from 2.07 to 2.99 mg/L. However, in patients with a creatinine clearance less than 30 mL/min, there was a 1.5-fold increased in peak concentrations (p less than 0.05 when compared to healthy volunteers) (Shi et al, 2004).
• C. AREA UNDER THE CURVE :
  
  • 1. Values after single and multiple doses of 800 mg once daily have been 7 to 9 mcg x hr/mL and 8 to 14 mcg x hr/mL, respectively (Edlund et al, 2000; Drusano et al, 2000; Lenfant et al, 1998; Lenfant et al, 1999). Slightly higher values have been observed in elderly subjects (12 and 17 mcg x hr/mL) (Sultan et al, 1999).
  • 2. Values after single and repeated doses of 800 mg once daily were similar between healthy control subjects and patients with hepatic impairment (Child-Pugh score between 5 and 12) (Cantalloube et al, 2003).
  • 3. Area under the curve values after a single dose of telithromycin 800 mg were not statistically different between patients with renal impairment and healthy volunteers. Resulting mean area under the curve values ranged from 10.09 to 16 mg x h/L. After repeated doses, the mean area under the curve values were not statistically different between healthy volunteers and patients with mild to moderate renal impairment (creatinine clearance between 30 to 80 mL/min), with values ranging from 12.44 to 16 mg x h/L. However, patients with a creatinine clearance less than 30 mL/min, there was a 2-fold increased in area under the curve (p=0.0005 when compared to healthy volunteers) (Shi et al, 2004).

• A. BIOAVAILABILITY (F) :
  
  • 1. ORAL : 57% (Prod Info Ketek(TM), 2004)
• B. EFFECTS OF FOOD : none (Prod Info Ketek(TM), 2004; Lenfant et al, 1999).
  • 1. Administration of telithromycin 800 mg with food had no significant effect on extent or rate of oral absorption in healthy subjects (Lenfant et al, 1999).

• 2.3.2.1 DISTRIBUTION SITES
  • A. TOTAL PROTEIN BINDING : 60% to 70% (Prod Info Ketek(TM), 2004)
    • 1. In vitro total protein binding is approximately 60% to 70% and is primarily due to human serum albumin. Protein binding is not modified in elderly patients or those with hepatic impairment (Prod Info Ketek(TM), 2004).
  • B. OTHER DISTRIBUTION SITES :
    
    • 1. WHITE BLOOD CELLS, up to 40-fold higher than plasma levels (Gia et al, 1999; Bryskier, 1998; Hunter, 2000).
    • 2. BRONCHOPULMONARY TISSUE, extensive (Andrews et al, 2000; Serieys et al, 1999).
      • a. Concentrations achieved in bronchial mucosa, epithelial lining fluid, and alveolar macrophages are significantly higher than corresponding plasma levels (Andrews et al, 2000; Serieys et al, 1999; Kadota et al, 2000; Hunter, 2000). In one study, concentrations in epithelial lining fluid, alveolar macrophages, and plasma 12 hours after the last dose of a 5-day regimen of 800 mg once daily were 3.3 mcg/mL, 318 mcg/mL, and 0.2 mcg/mL, respectively, in patients undergoing fiberoptic bronchoscopy; the bronchial mucosa concentration at this time was 1.4 mcg/g (Andrews et al, 2000).
    • 3. SALIVA, exceeds plasma values (Edlund et al, 2000).
      • a. In healthy subjects, mean peak plasma/saliva concentrations after a single 800-mg oral dose were 2.4/3.1 mcg/mL; trough (24-hour) values were 0.01/0.07 mcg/mL. After 10 days of once-daily administration, corresponding values were 2/3.1 mcg/mL and 0.03/0.09 mcg/mL (Edlund et al, 2000).
• 2.3.2.2 DISTRIBUTION KINETICS
  • A. VOLUME OF DISTRIBUTION : 2.9 L/kg (Prod Info Ketek(TM), 2004)
    • 1. The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg (Prod Info Ketek(TM), 2004).

• 2.3.3.1 METABOLISM SITES AND KINETICS
  • A. LIVER, 37% (Prod Info Ketek(TM), 2004)
  • B. Approximately 50% is metabolized by CYP3A4 and the rest is non-P450 mediated (Cantalloube et al, 2003).
• 2.3.3.2 METABOLITES
  • A. RU 76363; 4- to 16-fold less active than telithromycin (Cantalloube et al, 2003).
    • 1. Mean peak plasma concentration of RU 76363 was 2- fold lower (p less than 0.01) and the areas under the curve were 40% lower (no p-value reported) in hepatically impaired patients (Child-Pugh score between 5 and 12) compared to healthy controls after single 800 mg doses of telithromycin. With 7 days of repeated dosing, mean peak plasma concentrations of RU 76363 and areas under the curve were approximately 50% lower than those in healthy controls at day 1 (p less than 0.01) and day 7 (p less than 0.001) (Cantalloube et al, 2003).
  • B. Three other metabolites have been identified. Each represent 3% or less of the area under the curve of telithromycin (Prod Info Ketek(TM), 2004).

• 2.3.4.1 BREAST MILK
  • A. BREASTFEEDING : unknown.
• 2.3.4.2 KIDNEY
  • A. RENAL CLEARANCE : 13 L/hr (healthy young subjects, single dose) (Lenfant et al, 1998).
    • 1. In healthy young subjects, 12% and 14% of a dose of telithromycin (800 mg) was excreted unchanged after single doses and multiple (10-day) once-daily doses, respectively (Lenfant et al, 1998). In elderly subjects (mean, 74 years), corresponding values were 10% and 16% (Sultan et al, 1999).
    • 2. A value of 7.5 L/hr has been reported in elderly subjects after single oral doses (Sultan et al, 1999).
    • 3. Renal clearance is unaltered during multiple-dose administration in both young and elderly subjects (Sultan et al, 1999; Lenfant et al, 1998).
    • 4. Renal clearance was 1.5-fold higher (p less than 0.05) in hepatically impaired patients (Child-Pugh score between 5-12) compared to healthy controls after a single 800 mg dose of telithromycin. After repeated dosing, renal clearance was not statistically different (p greater than 0.05) (Cantalloube et al, 2003).
    • 5. Renal clearance was significantly altered in patients with renal impairment after single and multiple doses of telithromycin. In a single dose study, renal clearance was 9.34 L/hr in healthy volunteers and decreased to 5.71 L/hr in patients with mild renal impairment (creatinine clearance between 41 to 80 mL/min), to 2.63 L/hr in patients with moderate renal impairment (creatinine clearance between 11 to 40 mL/min) and to 0.36 L/hr in patients with severe renal impairment (creatinine clearance less than 10 mL/min). In a multiple dose study, renal clearance was 12.71 L/hr in healthy volunteers and decreased to 7.34 L/hr in patients with mild renal impairment (p=0.0017), to 4.14 L/hr in patients with moderate renal impairment (p less than 0.0001) and to 2.08 L/hr in patients with severe renal impairment (p less than 0.001) (Shi et al, 2004).
• 2.3.4.3 OTHER
  • A. OTHER EXCRETION :
    
    • 1. FECES, about 75% (unchanged drug and metabolite)(Prod Info Ketek(TM), 2004; Hunter, 2000)
      • a. Of the drug that is excreted in the feces, 7% is excreted unchanged by biliary and/or intestinal secretion (Prod Info Ketek(TM), 2004).

• 2.3.5.1 PARENT COMPOUND
  • A. ELIMINATION HALF-LIFE : 10 to 13 hours (Lenfant et al, 1998; Lenfant et al, 1999).
    • 1. Elimination is biphasic, with the majority of the compound being eliminated during the first phase. At steady state the initial elimination half-life is 2 hours and the terminal elimination half life is 10 hours (Cantalloube et al, 2003).
    • 2. In elderly subjects, elimination half-lives of 11.5 and 14 hours were reported following single and multiple once-daily doses of 800 mg, respectively (Sultan et al, 1999).
    • 3. In patients with hepatic impairment (Child-Pugh score between 5 and 12), the terminal elimination half-life was 1.4-fold higher than in the healthy control group (p less than 0.001) after a single dose telithromycin (800 mg). After repeat dosing, the terminal elimination half-lives were similar between both groups (Cantalloube et al, 2003).
    • 4. In patients with renal impairment, the half life increased with increasing renal impairment but did not reach statistical significance. The elimination half-life was 10.66 hours in healthy volunteers compared to 11.41 hours in patients with mild renal impairment (creatinine clearance between 41 to 80 mL/min), 12.58 hours in patients with moderate renal impairment (creatinine clearance between 11 to 40 mL/min) and 14.64 hours in patients with severe renal impairment (creatinine clearance less than 10 mL/min) (Shi et al, 2004).
• 2.3.5.2 METABOLITES
  • A. ELIMINATION HALF-LIFE: 3 to 12 hours (Cantalloube et al, 2003).
  • B. In patients with hepatic impairment (Child-Pugh score between 5 and 12), the initial elimination half-life of RU 76363 was 4.52 hours compared with 3.03 hours in the healthy control group (p less than 0.01) after a single dose telithromycin (800 mg). After repeat dosing, the elimination half-lives were similar between both groups (Cantalloube et al, 2003).

• A. HEMATOLOGIC EFFECTS
  
  • 1. THROMBOCYTOSIS has been associated with the use of telithromycin (Prod Info Ketek(TM), 2004).

• A. CARDIOVASCULAR EFFECTS
  
  • 1. ATRIAL ARRYTHMIAS, BRADYCARDIA, flushing, and HYPOTENSION have rarely been associated with the use of telithromycin (Prod Info Ketek(TM), 2004).
  • 2. Although telithromycin has the potential to prolong the QTc interval, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with telithromycin in 4780 patients in clinical trials, including 204 patients with prolonged QTc at baseline (Prod Info Ketek(TM), 2004).

• A. CENTRAL NERVOUS SYSTEM EFFECTS
  
  • 1. HEADACHE and DIZZINESS have been reported in 4% and 2 to 6% of patients treated with 800 mg once daily in unpublished clinical studies (Tellier et al, 2000; Pullman et al, 2000; Ziter et al, 2000). Dizziness tended to occur more often with telithromycin than clarithromycin in one study (Ziter et al, 2000).
  • 2. SOMNOLENCE, INSOMNIA and VERTIGO have been reported with the use of telithromycin (Prod Info Ketek(TM), 2004).

• A. ENDOCRINE/METABOLIC EFFECTS
  
  • 1. INCREASED SWEATING has been reported with the use of telithromycin (Prod Info Ketek(TM), 2004).

• A. GASTROINTESTINAL EFFECTS
  
  • 1. Diarrhea (10.8%), nausea (7.9%), vomiting (2.9%), loose stools (2.3%) and DYSGEUSIA (1.6%) have been reported in association with telithromycin in phase III clinical trials (Prod Info Ketek(TM), 2004).
  • 2. DIARRHEA, NAUSEA, and vomiting have been relatively common during therapy (Anon, 2001; Tellier et al, 2000; Pullman et al, 2000). In unpublished clinical trials employing 800-mg once-daily doses, diarrhea has occurred in 11 to 20% of patients; nausea was observed in 8 to 12% (Pullman et al, 2000; Tellier et al, 2000; Tellier et al, 2000a; Deabate et al, 2000; Ziter et al, 2000).
  • 3. Diarrhea has been significantly more frequent with telithromycin than with oral trovafloxacin (Pullman et al, 2000); it tended to occur more often with telithromycin than clarithromycin in a further study (Ziter et al, 2000). Both diarrhea and nausea were more frequent with telithromycin than with penicillin V (Norrby et al, 2000). Nausea tended to be more common with telithromycin compared to cefuroxime axetil in one study (Deabate et al, 2000).

• A. HEPATIC EFFECTS
  
  • 1. Reversible HEPATITIS occured in 0.07% of patients treated with telithromycin in phase III clinical studies. Abnormal liver function tests were also reported. Post-marketing surveillance has also produced reports of infrequent hepatocellular and/or cholestatic hepatitis with or without jaundice (Prod Info Ketek(TM), 2004).

• A. OCULAR EFFECTS
  
  • 1. BLURRED VISION, DIPLOPIA, and difficulty focusing have been reported during telithromycin therapy. Although events were reported at various times during treatment, most events occurred after the first or second dose. Visual effects lasted several hours and recurred upon subsequent dosing in some patients (Prod Info Ketek(TM), 2004).

• A. RESPIRATORY EFFECTS
  
  • 1. Rapid onset, life-threatening acute respiratory failure has been reported in patients with myasthenia gravis treated for respiratory tract infections with telithromycin. Telithromycin is not recommended in this patient population (Prod Info Ketek(TM), 2004).

• A. DERMATOLOGIC EFFECTS
  
  • 1. RASH has been associated with telithromycin use (Prod Info Ketek(TM), 2004).

• A. MUSCULOSKELETAL EFFECTS
  
  • 1. Exacerbation of disease symptoms in patients with MYASTHENIA GRAVIS has been reported (10 cases) in association with telithromycin therapy (Anon, 2003). This may occur within a few hours of the first dose of telithromycin (Prod Info Ketek(TM), 2004).

• A. OVERDOSE
  

• 1. U.S. Food and Drug Administration's Pregnancy Category C (Prod Info Ketek(TM), 2004).

• A. ADENOSINE
  
• B. ANTIPSYCHOTICS
  
• C. ARSENIC TRIOXIDE
  
• D. ASTEMIZOLE
  
• E. BEPRIDIL
  
• F. CHLORAL HYDRATE
  
• G. CHLOROQUINE
  
• H. CISAPRIDE
  
• I. CLARITHROMYCIN
  
• J. CLASS I ANTIARRHYTHMIC AGENTS
  
• K. CLASS IA ANTIARRHYTHMIC AGENTS
  
• L. CLASS III ANTIARRHYTHMICS
  
• M. CLINDAMYCIN
  
• N. COTRIMOXAZOLE
  
• O. DOLASETRON
  
• P. DROPERIDOL
  
• Q. ENFLURANE
  
• R. ERGOT DERIVATIVES
  
• S. ERYTHROMYCIN
  
• T. ERYTHROMYCIN/SULFISOXAZOLE
  
• U. ETHINYL ESTRADIOL
  
• V. FLUCONAZOLE
  
• W. FLUOXETINE
  
• X. FOSCARNET
  
• Y. HALOFANTRINE
  
• Z. HALOTHANE
  
• AA. ISOFLURANE
  
• AB. ISRADIPINE
  
• AC. LEVOMETHADYL
  
• AD. LIDOFLAZINE
  
• AE. MEFLOQUINE
  
• AF. MESORIDAZINE
  
• AG. MESTRANOL
  
• AH. NORETHINDRONE
  
• AI. NORGESTREL
  
• AJ. OCTREOTIDE
  
• AK. ONDANSETRON
  
• AL. PENTAMIDINE
  
• AM. PHENOTHIAZINES
  
• AN. PIMOZIDE
  
• AO. PROBUCOL
  
• AP. SPIRAMYCIN
  
• AQ. SULFAMETHOXAZOLE
  
• AR. TERFENADINE
  
• AS. THIORIDAZINE
  
• AT. TRICYCLIC ANTIDEPRESSANTS
  
• AU. TRIMETHOPRIM
  
• AV. VASOPRESSIN
  
• AW. VENLAFAXINE
  
• AX. WARFARIN
  
• AY. ZIPRASIDONE
  

• A. LABORATORY PARAMETERS
  
  • 1. C/S pre- and posttherapy
  • 2. Plasma level monitoring in selected patients
• B. PHYSICAL EXAMINATION
  
  • 1. Temperature; white-cell counts with differential
  • 2. Other clinical symptoms/signs of infection

• A. LABORATORY PARAMETERS
  
  • 1. Liver function tests, particularly in patients with preexisting hepatic disease
• B. PHYSICAL EXAMINATION
  
  • 1. Signs of hypersensitivity (eg, rash, facial swelling, difficulty breathing)
  • 2. Other adverse-effect monitoring (eg, persistent or severe diarrhea, dizziness)
  • 3. Telithromycin may cause prolonged QT interval and torsade de pointes; monitor EKG in high risk patients

• 1. The mechanism of action of telithromycin (and ketolides in general) is similar to that of macrolides, and is related to 50S-ribosomal subunit binding with inhibition of bacterial protein synthesis (Piper et al, 2999; Malathum et al, 1999; Soriano et al, 1998); however, telithromycin appears to have greater affinity for the ribosomal binding site than macrolides (Hunter, 2000).

• 1. Telithromycin is a ketolide antimicrobial agent. Ketolides are semisynthetic derivatives of 14-membered ring macrolides, and represent a new class of antibiotics with enhanced activity against multidrug-resistant gram-positive pathogens and Haemophilus influenzae (Soriano et al, 1998; Wootton et al, 1999; Bryskier, 1998; Barry et al, 1998a).
• 2. Compared to erythromycin A or clarithromycin, telithromycin is characterized by substitution of a 3-keto group for the L-cladinose moiety (neutral sugar) on the erythronolide ring, and a C11-C12 carbamate link to imidazolyl and pyridinyl rings via a C-4 alkyl side chain (Bryskier, 1998; Malathum et al, 1999). The 3-keto substitution purportedly reduces or eliminates macrolide-lincosamide-streptogramin (MLS-B) resistance (gram-positive cocci), efflux (mef) resistance (Streptococcus pyogenes, S. pneumoniae), and inducible resistance to macrolides, and increases stability in acidic environments (Bryskier, 1998; Bryskier, 2000; Descheemaeker et al, 2000; Davies et al, 2000; Hamilton-Miller et al, 2000); strains of pneumococci and S. pyogenes with these resistance mechanisms have been sensitive to low concentrations of telithromycin in some in vitro studies (Davies et al, 2000; Hoban et al, 2000; Davies et al, 2000a; Descheemaeker et al, 2000). The C11-C12 carbamate residue appears to support activity against mef-containing pathogens, promote stability to esterase hydrolysis, and increased affinity for the ribosomal binding site (and an attendant increase in potency) (Hunter, 2000; Bryskier, 2000; Bryskier, 1998).
• 3. The antibacterial spectrum of telithromycin resembles that of macrolides, with additional activity against multiresistant Streptococcus pneumoniae (including penicillin-resistant isolates and strains resistant to 2 or more of the following antibiotics: penicillin, second generation cephalosporins, macrolides, tetracyclines and trimethoprim/sulfamethoxazole), Staphylococcus aureus (methicillin and erythromycin susceptible isolates only), Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae and Mycoplasma pneumoniae (Prod Info Ketek(TM), 2004; Boswell et al, 1998; Wootton et al, 1999; Malathum et al, 1999; Barry et al, 1998; Hoban et al, 1999a; Karlowsky et al, 1999; Okamoto et al, 2000). In vitro activity greater than that of erythromycin or clarithromycin has been observed against gram-positive pathogens susceptible to macrolides in some studies (Boswell et al, 1998; Malathum et al, 1999). The activity of telithromycin against H. influenzae is similar to that of azithromycin (Barry et al, 1998a). Good in vitro activity against some anaerobes has been observed (Edlund et al, 1998). However, telithromycin is inactive against the Enterobacteriaceae and Pseudomonas aeruginosa.
• 4. Telithromycin show high penetration into human polymorphonuclear cells (Miossec-Bartoli et al, 1999; Piper et al, 1999; Bryskier, 1998; Vazifeh et al, 1998) and has shown good activity against intracellular pathogens, including Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila (Bryskier, 1998; Sens et al, 2000; Roblin & Hammerschlag, 1998; Yamaguchi et al, 2000; Schulin et al, 1998a).
• 5. Telithromycin has been effective in treating experimental H. influenzae pneumonia (Piper et al, 1999) and B. fragilis intraabdominal abscess (Thadepalli et al, 2001) in animal models.

• 1. The recommended ranges for telithromycin susceptibility are as follows (Prod Info Ketek(TM), 2004):

  
  PATHOGEN             MINIMUM INHIBITORY CONCENTRATIONS
                           (microgram/milliliter)
  --------------------------------------------------------
                    Susceptible   Intermediate   Resistant
  --------------------------------------------------------
  Staphylococcus
     aureus*          lt= 0.25
  Streptococcus
     pneumoniae       lt= 1             2          gt= 4
  Haemophilus
     influenzae       lt= 4             8          gt= 16
  --------------------------------------------------------
  * absence of data precludes definitions other than
    susceptible
  lt= less than or equal to
  gt= greater than or equal to
  --------------------------------------------------------
  

• 2. Minimum inhibitory concentrations in vitro against 90% of strains (MIC-90) are usually 0.5 mcg/mL or less for methicillin-sensitive or -resistant S. aureus, oxacillin-susceptible S. aureus, most streptococci including multidrug resistant pneumococci (S. pneumoniae), and some enterococci (particularly E. avium, E. gallinarum); most pneumococci are inhibited by less than 0.25 mcg/mL (Schulin et al, 1998; Karlowsky et al, 1999; Boswell et al, 1998; Dubois & St-Pierre, 2000; Verhaegen & Verbist, 2000; Barry et al, 1998; Hoban et al, 1999a; Mittermayer et al, 2000; Willey et al, 2000; Malathum et al, 1999). In 1 study, the MIC- 90 of telithromycin is 0.25 mg/L in quinolone-resistant pneumococci (Nagai et al, 2001). Oxacillin-resistant S. aureus and methicillin-resistant S. aureus resistant to erythromycin have been resistant to telithromycin (Malathum et al, 1999; Boswell et al, 1998; Barry et al, 1998a).
• 3. MIC-90 values for vancomycin-sensitive and vancomycin-resistant Enterococcus faecalis have been 0.25 to 8 mcg/mL and 16 mcg/mL, respectively (Schulin et al, 1998; Barry et al, 1998a; Malathum et al, 1999); vancomycin-sensitive and -resistant E. faecium are somewhat more resistant (Barry et al, 1998a; Malathum et al, 1999).
• 4. Ampicillin-/erythromycin-resistant H. influenzae is usually susceptible to 4 mcg/mL or less (Barry et al, 1998a; Boswell et al, 1998; Hoban et al, 1999). Most strains of Bacteroides fragilis are inhibited by 4 mcg/mL, whereas concentrations of less than 1 or 2 mcg/mL have been sufficient for other Bacteroides spp., Prevotella spp., Peptostreptococcus, and Porphyromonas spp.; clostridia have demonstrated species/strain variability, with MIC-90 values of 0.125 to 32 mcg/mL, and Fusobacterium spp. are relatively resistant (4 to 32 mcg/mL) (Edlund et al, 1998; Goldstein et al, 1999; Goldstein et al, 1998).
• 5. An MIC-90 of less than 0.2 mcg/mL has been reported for M. catarrhalis (including beta-lactamase-producing strains), similar to that of azithromycin (Wootton et al, 1999; Saez-Nieto & Vazquez, 1999).

• 1. Telithromycin has shown good in vitro and in vivo (murine model) activity against Toxoplasma gondii (Araujo et al, 1997).

• 1. The postantibiotic effect (PAE) observed with S. pyogenes ranged from 0.4 to 2.7 hours in vitro. S. aureus and S pneumoniae demonstrated PAEs ranging from 0.3 to 2.4 hours and 1.5 to 3.8 hours, respectively. The post-antibiotic sub-MIC effects (PA-SME) observed ranged from 0.8 to 4.5 hours, 1.9 to 3.5 hours and 1.5 to 5.2 hours for S. pyogenes, S aureus and S pneumoniae, respectively (Jacobs et al, 2003).
• 2. A postantibiotic effect (PAE) of at least 4 hours has been observed against S. pyogenes, most pneumococci, and H. influenzae in vitro (Dubois & St-Pierre, 1999).

• 1. OVERVIEW :

  
  FDA APPROVAL:  Adult, yes; pediatric, no
  EFFICACY:  Adult, effective
  DOCUMENTATION:  Adult, good
  

• 2. SUMMARY :

  
   - Telithromycin is indicated in the treatment of
     acute bacterial exacerbations of chronic
     bronchitis due to susceptible strains of
     Streptococcus pneumoniae, Haemophilus influenzae
     or Moraxella catarrhalis (Prod Info Ketek(TM), 
     2004)
  
   - Telithromycin once daily for 5 days has been 
     effective in treating acute exacerbations of
     chronic bronchitis, comparing well with 10-day 
     regimens of amoxicillin/clavulanic acid and 
     cefuroxime
  

• 3. ADULT :
  
  • a. In relatively large but unpublished double-blind studies, clinical cure at follow-up (up to one month) was reported in 86 to 89% of patients with ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS treated with oral doses of 800 milligrams (mg) once daily for 5 days; bacteriologic cure rates ranged from 69 to 88%. Efficacy of the drug was similar to that of 10-day courses of amoxicillin/clavulanic acid and cefuroxime axetil (Deabate et al, 2000; Aubier et al, 2000).
  • b. In the largest trial (n=496), clinical cure rates at days 17 to 21 were 89% and 86% with 5-day regimens of telithromycin and 10-day cefuroxime axetil, respectively; corresponding bacteriologic eradication rates (when organism isolated pretherapy) were 88% and 86%. The incidence of adverse effects was similar, although nausea tended to occur more often with telithromycin (Deabate et al, 2000).
  • c. In these studies, at least one author/investigator was employed by Aventis Pharmaceuticals. Inclusion of 5-day comparator treatment groups would have been useful in placing results in perspective.

• 1. OVERVIEW :

  
  FDA APPROVAL:  Adult, no; pediatric, no
  EFFICACY:  Adult, effective; pediatric, effective
  DOCUMENTATION:  Adult, good; pediatric, good
  

• 2. SUMMARY :

  
   - Once-daily therapy for 5 days has been effective 
     in group A beta-hemolytic streptococcal 
     pharyngitis/tonsillitis in adults and children
  

• 3. ADULT :
  
  • a. With oral doses of 800 milligrams (mg) once daily for 5 days, satisfactory bacteriologic outcome (undefined criteria) and clinical cure at follow-up (17 to 21 days) was achieved in 84% and 95% of adult patients , respectively, with group A beta-hemolytic streptococcal pharyngitis and/or tonsillitis in an unpublished double-blind study; efficacy was similar to that of penicillin V given for 10 days (Norrby et al, 2000). In this study, half of the authors/investigators were employees of Aventis Pharmaceuticals. Inclusion of a 5-day penicillin V treatment group would have been useful in placing results of this study in perspective.
• 4. PEDIATRIC :
  
  • a. Oral telithromycin 800 mg once daily for 5 days was effective in treating adolescents with group A beta-hemolytic streptococcal pharyngitis or tonsillitis (13 years or older) in an unpublished double-blind comparison with clarithromycin (10-day course). Satisfactory bacteriologic outcome (pathogen eradication or appearance of a new group A beta-hemolytic streptococcal serotype without clinical signs) was achieved in 91% and 88% of patients randomized to telithromycin and clarithromycin, respectively; clinical cure rates were similar (about 92%) (Ziter et al, 2000). One investigator in this study was an employee of Aventis Pharmaceuticals. Inclusion of a 5-day clarithromycin treatment group would have been useful in placing results in perspective.

• 1. OVERVIEW :

  
  FDA APPROVAL:  Adult, yes; pediatric, no
  EFFICACY:  Adult, effective
  DOCUMENTATION:  Adult, good
  

• 2. SUMMARY :

  
   - Telithromycin is indicated in the treatment of
     mild to moderate community-acquired pneumonia 
     due to susceptible strains of Streptococcus
     pneumoniae (including multi-drug resistant
     isolates), Haemophilus influenzae, Moraxella
     catarrhalis, Chlamydophila pnuemoniae or
     Mycoplasma pneumoniae (Prod Info Ketek(TM), 
     2004)
  
   - Oral telithromycin once daily has been 
     effective in community-acquired pneumonia in 
     controlled studies, comparing well with oral 
     amoxicillin (high-dose), clarithromycin, and 
     trovafloxacin
  
   - Efficacy in bacteremia complicating 
     community-acquired pneumonia has been reported
  

• 3. ADULT :
  
  • a. Oral doses of 800 milligrams (mg) once daily for 7 to 10 days have been reported effective in the treatment of adult COMMUNITY-ACQUIRED PNEUMONIA in relatively large open and controlled comparative studies (Carbon et al, 2000; Tellier et al, 2000; Hagberg et al, 2000; Pullman et al, 2000). Clinical cure rates (per protocol basis) at 17 to 24 days ranged from 88 to 95%; bacteriologic eradication rates (when isolated pretherapy) were usually assessed on posttreatment days 17 to 21, and ranged from 88 to 94%. On a modified intention-to-treat basis, clinical cure rates at 17 to 21 days were 80 to 86%. One study provided early (days 17 to 21) and late follow-up data (days 31 to 36), and cure rates at these times were 93% and 91%, respectively (Carbon et al, 2000). Telithromycin was compared to oral trovafloxacin, oral clarithromycin, and oral high-dose amoxicillin in these studies, and efficacy against each was comparable. The most common pathogen in two of these studies was pneumococcus, whereas the type of pathogen was not provided in others.
  • b. Telithromycin 800 milligrams (mg) once daily is as effective as clarithromycin 500 mg twice daily in the treatment of community- acquired pneumonia in adults. In a multicenter, double-blind study, patients with a confirmed community acquired pneumonia diagnosis were randomized to receive either telithromycin (n=204) or clarithromycin (n=212) for 10 days. Per protocol assessment demonstrated that 88.3% of telithromycin patients and 88.5% of clarithromycin achieved clinical cure status at the test-of-cure visit on days 17 to 24 with the 2-sided 95% CI for the between group difference suggesting therapeutic equivalence (-0.2%; 95% CI, -7.8% to 7.5%). Rates of cure on days 31 to 45 were also similar between the 2 arms with 1.3% of telithromycin patients presenting with relapses or reinfections compared to 2.8% of clarithromycin patients. Both antibiotics were equally effective in patient equal to or older than 65-years, smokers or ex- smokers, and patients with bacteremia, multilobar disease, or pleural effusion. Documented eradication of the causative pathogen and presumed eradication based on the absence of culturable sputum was attained in 89.3% of telithromycin patients and 96.4% of clarithromycin patients by days 17 to 24. By days 31 to 45, the eradication rates were 88.5% in both arms. Adverse effects were reported in 57% of telithromycin patients and 49.1% of clarithromycin patients and were primarily gastrointestinal in nature (Dunbar et al, 2004).
  • c. In patients with community-acquired pneumonia caused by atypical/intracellular pathogens, clinical cure rates at days 17 to 21 were over 90% in those with documented Chlamydia pneumoniae, Mycoplasma pneumoniae, or Legionella pneumophila infection in one study; an 80% cure rate was reported in patients with Coxiella burnetti infection (Leroy & Manickam, 2000). The small number of patients evaluated (n=67) precludes definitive efficacy assessment.
  • d. BACTEREMIA accompanying community-acquired pneumonia has been successfully treated with telithromycin 800 mg once daily (Leroy & Manickam, 2000a). In this small series (n=30), a clinical and bacteriologic cure rate of 90% was observed, with the predominant pathogen being pneumococcus. Several pneumococcal strains were resistant to penicillin or erythromycin.

• 1. OVERVIEW :

  
  FDA APPROVAL:  Adult, yes; pediatric, no
  EFFICACY:  Adult, effective
  DOCUMENTATION:  Adult, good
  

• 2. SUMMARY :

  
   - Telithromycin is indicated in the treatment of 
     acute bacterial sinusitis due to susceptible strains
     of Streptococcus pneumoniae, Haemophilus influenzae
     Moraxella catarrhalis or Staphylococcus aureus (Prod
     Info Ketek(TM), 2004)
  
   - A 5-day and 10-day once-daily regimen has been 
     effective in acute maxillary sinusitis, comparing 
     well with amoxicillin/clavulanic acid and cefuroxime
  

• 3. ADULT :
  
  • a. In a randomized, double-blinded, active-controlled trial, 5-day telithromycin therapy and 10-day cefuroxime therapy demonstrated similar efficacy in the treatment of acute bacterial maxillary sinusitis (ABMS). Patients were randomized in a 2 to 1 ratio to receive telithromycin 800 milligrams (mg) once daily (n=260) or cefuroxime axetil 250 mg twice daily (n=125). Per protocol assessment of clinical cure rates at the test of cure visit (days 16 to 24) demonstrated an 85.2% cure rate for the telithromycin arm and 82% in the cefuroxime axetil arm (difference in proportions, 3.2%; 95% CI, -7.1% to 13.4%). Cure was defined as a return to preinfection state with no signs or symptoms of ABMS, a sinus x-ray or CT scan confirming no worsening of infection or the presence of only residual symptoms indicative of a normal course of infection clearance with no need for additional antibiotic therapy. Bacterial outcomes at the test of cure visit were also similar with 84% of telithromycin patients and 77.6% of cefuroxime axetil patients demonstrating the eradication or presumed eradication of the pathogen or the detection of a new bacterial strain with no signs or symptoms of active disease (difference in proportions, 4.4%; 95% CI, -10.4% to 19.3%). Bacterial outcomes were again similar at the late posttherapy visit (days 31 to 45) with 79.3% of telithromycin patients and 73.9% of cefuroxime patients demonstrating satisfactory bacteriologic outcomes (difference in proportions 5.4%; 95% CI, - 11.3% to 22.2%). The most commonly reported adverse events reported with telithromycin and cefuroxime use were nausea, diarrhea, dizziness, vomiting and decreased creatinine clearance (Buchanan et al, 2003).
  • b. Investigators concluded that there is no significant difference in efficacy and tolerability between 5- or 10-day telithromycin therapy and 10-day amoxicillin/clavulanate therapy in the treatment of acute maxillary sinusitis. In a double-blinded, multicenter study, 754 patients were randomized to receive telithromycin 800 milligrams (mg) once daily for 5-days or 10- days or amoxicillin/clavulanate 500/125 mg three times daily for 10-days. Only per-protocol-analyses were reported (n=423). Patients were excluded from analysis due to insufficient duration of therapy, an incorrect diagnosis or missing post-treatment information. Clinical outcome was measured on days 17 to 24 and 31 to 45. On days 17 to 24, 75.3% of the telithromycin 5-day arm (n=146), 72.9% of the telithromycin 10-day arm (n=250) and 74.5% of the amoxicillin clavulanate arm (n=137) had achieved clinical cure. Clinical cure was defined as the disappearance of infection, an improvement or resolution of the signs and symptoms of sinusitis, a sinus x-ray that had not worsened and the lack of need for additional antibiotics. On days 31 to 45, 69.9% of the telithromycin 5-day arm, 67.7% of the telithromycin 10-day arm and 70.8% of the amoxicillin/clavulanate arm did not require additional antibiotics or did not relapse and develop signs and symptoms of new infections. The use of telithromycin was associated with adverse events in 42.2% and 46.9% of the 5-day and 10-day arm patients, respectively. The more serious effects were allergy, gastroenteritis and pseudomembranous colitis. Amoxicillin/clavulanate related adverse events occurred in 42.9% of patients with the most serious being pseudomembranous colitis (Luterman et al, 2003; Tellier et al, 2000a).
  • c. Oral telithromycin 800 milligrams (mg) once daily has shown efficacy in acute maxillary sinusitis in unpublished and published double-blind studies. Efficacy was similar after treatment for either 5 or 10 days, with clinical and bacteriologic cure rates of approximately 90% at follow-up assessments (Roos et al, 2002).