Telithromycin (KETEK ™)

 

Brand Name: KETEK™

Generic Name: Telithromycin

Manufacturer: Aventis

Drug Class: Ketolides

 

Uses:                     

                                                Labeled:

Acute bacterial exacerbation of chronic bronchitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis

 

Acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae,  Moraxella catarrhalis, or Staphylococcus aureus

 

Community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae

 

                                                Unlabeled:

The tonsillitis/pharyngitis indication has a Anot approvable@ letter

Mechanism of Action:

                                Telithromycin is a ketolide antimicrobial agent. The ketolides differ from the 14-membered ring macrolides (erythromycin and clarithromycin) by the replacement of the erythronolide A ring alpha-L-cladinose moiety with a 3-keto group. While the mechanism remains the same, the substitution of the 3-keto group confers greater stability in an acid environment, eliminates the induction of macrolide-liconsamide-streptogramin B (MLS) resistance, and may increase bactericidal activity compared to the macrolides. 

 

Activity against isolates:

Streptococcus pneumoniae (Penicillin sensitive) – activity is similar or less than azithromycin, clarithromycin, and penicillin and lower than erythromycin.1,3,4,5  

Penicillin intermediate and resistant isolates: telithromycin > PCN, erythromycin, azithromycin, clarithromycin, roxithromycin, cefuroxime, trimethoprim/sulfamethoxazole, tetracycline, ciprofloxacin, levofloxacin, and ofloxacin. 1,5,6

 

Beta-hemolytic streptococci: telithromycin > erythromycin, azithromycin, clarithromycin4

 

Staphylococcus aureus telithromycin > erythromycin, azithromycin, clarithromycin, and roxithromycin; active against methicillin-sensitive and some methicillin-resistant isolates.7,9

 

Haemophilus influenzae- more active than clarithromycin or roxithromycin, and similar in activity or less than erythromycin and azithromycin. 1,4,6,9,10

 

Moraxella catarrhalis – comparable or less activity than azithromycin, clarithromycin, and erythromycin. 1,4,9,10,11

Telithromycin also has activity against viridans group streptococci, Streptococcus agalactiae, Enterococcus faecalis, Neisseria gonorrhoeae, Neisseria meningitides, Chlamydia pneumoniae, Peptostreptococcus magnus, some Corynebacterium spp., Listeria spp., Mycoplasma pneumoniae, Ureaplasma urealyticum, Helicobacter pylori, Legionella spp., Bartonella spp., Rickettsia spp., and Coxiella burnetii.6,7,9,11,12,13,14,15,16,17,18,19,20,21,22,23,24 Telithromycin also has activity against a number of anaerobic pathogens similar to that observed with the macrolides.25,26,27,28

In general, against gram-positive organisms such as S. aureus, Enterococcus faecalis, Enterococcus faecium, and Streptococcus spp., telithromycin is more active than erythromycin although its activity appears to reflect that of erythromycin. Some erythromycin resistant enterococci were susceptible to telithromycin. S. pneumonia strains with reduced erythromycin susceptibility retained telithromycin susceptibility.3,29,30,31,32,33

Pharmacokinetics:

                Pharmacokinetic profile following a 800mg oral dose

                Peak concentrations are reached in 1 – 3 hours. Mean peak concentrations of 1.9 to 2.89

mg/L and mean trough concentrations of 0.07 to 0.19 mg/L. 38,39,40

Volume of Distribution (Vd)  
Clearance (Cl) 11-13L/hr
Half-life (t1/2) Biphasic: Initial – 2.87hours

                 Terminal – 9.81 hours

Telithromycin is 70 % metabolized with the CYP 3A4 isoenzyme. 43 Telithromycin and its main hepatic metabolite, RU 76363, reach steady state within 2 –3 days with QD dosing. Some accumulation occurs after 7 days. The metabolite is 4 – 16fold less active than telithromycin in vitro. 38 Routine adjustments in the elderly or those with hepatic impairment are not recommended by the manufacturer. 40

Telithromycin has good penetration into the middle ear, paranasal sinus, pulmonary tissue, and tonsil, and ahieves drug levels in the saliva higher than those in the plasma. 39,45,46,47,48

Efficacy:

Community-acquired pneumonia:

Telithromycin  800mg once daily x 10 days vs. clarithromycin 500mg twice daily x 10 days. Clinical cure rate = 88.3% vs. 88.5%49

Telithromycin  800mg once daily for 7-10days vs. trovafloxicin 200mg once daily for 7-10days. Clinical cure rate = 91.1% vs. 94.8%50

Telithromycin 800mg once daily for 10 days vs. amoxicillin 1000mg three times daily for 10 days. Clinical cure rate = 94.6% vs. 90.1%51

The eradication rates of baseline pathogens between telithromycin and the comparator are further summarized in Table 2 based on pathogen.

Table 2: Eradication Rates with Telithromycin and Comparator in Community-Acquired Pneumonia Studies:40

Pathogen

Telithromycin

Comparator

Total

90.3%
(392/494)

89.4%
(101/113)

S. pneumoniae

95.4%
(166/174)

88%
(44/50)

H. influenzae

89.5%
(94/105)

92.8%
(26/28)

M. catarrhalis

90%
(27/30)

100%
(6/6)

H. parainfluenzae

88.3%
(53/60)

90%
(9/10)

S. aureus

79%
(15/19)

100%
(3/3)

Other

80.4%
(37/46)

81.2%
(13/16)

 

Acute Exacerbation of Chronic Bronchitis:

Telithromycin 800mg once daily for 5 days vs. amoxicillin/clavulanic acid 500/125mg three times daily for 10 days. Clinical cure rate =86.1% vs. 82.1%. 55

Telithromycin 800mg once daily for 5 days vs. cefuroxime axetil 500mg twice daily for 10 days. Clinical cure rate = 89.2% vs. 86.3%56

Table 3: Eradication Rates with Telithromycin and Comparator in Acute Exacerbation of Chronic Bronchitis Studies:40

Pathogen

Telithromycin

Comparator

Total

77%
(54/70)

77.9%
(53/68)

S. pneumoniae

92.8%
(13/14)

75%
(9/12)

H. influenzae

60%
(15/25)

88.2%
(15/17)

H. parainfluenzae

83.3%
(5/6)

0%
(0/1)

M. catarrhalis

100%
(10/10)

87.5%
(14/16)

S. aureus

100%
(2/2)

66.6%
(2/3)

Other

69.2%
(9/13)

68.4%
(13/19)

 

Acute Maxillary Sinusitis:

Telithromycin 800mg once daily for 5 or 10 days vs. amoxicillin/clavulanic acid 500/125mg three times daily for 10 days. Clinical cure rate= 75.8%(5 days); 74.1% (10days) vs. 74.6%.57

Pharyngitis/Tonsillitis: (caused by group A b-hemolytic streptococci)

Telithromycin 800mg once daily for 5 days vs. clarithromycin 250mg twice daily for 10 days. Clinical cure rate =92.7% vs. 91.1%.59

Telithromycin 800mg once daily for 5 days vs. penicillin V 500mg three times daily for 10 days. Clinical cure rate= 94.8% vs. 94.1%.60

Adverse Reactions:

The most commonly observed adverse effects seen in clinical trials included diarrhea (10.9% - 19.1%), nausea (8.3% - 11.7%), headache (4.1% - 9.2%), dizziness (1.7% - 6.1%), vomiting (3.3% ), dyspepsia (2.4%), and abdominal pain (2%). 40,49,50,56,57,59,60 Other adverse effects that occur less frequently included taste perversion, gastrointestinal pain, flatulence, and blurred vision. 40 1.6% of patients had abnormal liver function tests. 40

Telithromycin was associated with concentration-dependent increases in the QTc interval in Phase I studies, and an effect on mean QTc duration was observed in Phase III studies. Overall, the patients in Phase III trials with EKG data available, the mean change in the QTc was 2msec among telithromycin treated patients.40

Warnings/Precautions:

Contraindicated in those allergic to the drug or any of its components

Drug Interactions:

Ketoconazole and itraconazole (CYP 3A4 inhibitors) increased telithromycin exposure by 2 and 1.5 times. 40

Telithromycin is a competitive inhibitor of CYP 3A4 and results in increased plasma concentrations of cisapride, simvastatin, and midazolam. 43 Levels of theophylline and digoxin have been increased with use of telithromycin. 40

There were no interactions documented with concomitant use with CYP2D6 inhibitors such as paroxetine, warfarin, ranitidine, aluminum hydroxide/magnesium hydroxide, triphasic oral contraceptive, or grapefruit juice.40

 

 

Dosing/Administration:

The recommended telithromycin dose is 800mg once daily. The duration of therapy is 5 days in the treatment of acute sinusitis and acute bacterial chronic bronchitis, and 7-10 days in the treatment of community-acquired pneumonia.

Conclusions:

Telithromycin is the first of the ketolide class of antimicrobials with FDA approval. Telithromycin is similar to the macrolide antibiotics, and may show some benefit against pencillin and erythromycin resistant pathogens. It appears to be as effective as the therapies routinely used in the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, and acute sinusitis. The recommended dose is 800mg once daily for 5 –10 days depending upon indication.

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