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Mechanism Of Action
Telithromycin is a ketolide antibacterial drug. [see Microbiology]
The pharmacokinetics of telithromycin after administration of single and multiple (7 days) once daily 800-mg doses to healthy adult subjects are shown in Table 4.
Table 4: Pharmacokinetics of Telithromycin in Healthy
|Cmax (pg/mL)||1.9 (0.80)||2.27 (0.71)|
|Tmax (h)*||1.0 (0.5-4.0)||1.0 (0.5-3.0)|
|AUC(0-24) (μg•h/mL)||8.25 (2.6)||12.5 (5.4)|
|Terminal t ½ (h)||7.16 (1.3)||9.81 (1.9)|
|C24h (μg/mL)||0.03 (0.013)||0.07 (0.051)|
|SD=Standard deviation ; Cmax =Maximum plasma
concentration ; Tmax =Time to Cmax; AUC=Area under concentration vs. time
curve; t ½ =Terminal plasma half-life; C24h =Plasma concentration at 24 hours
*Median (min-max) values
In patients, mean peak and trough plasma concentrations were 2.9 μg/mL (±1.55), (n=219) and 0.2 μg/mL (±0.22), (n=204), respectively, after 3 to 5 days of KETEK 800 mg once daily. Steady-state plasma concentrations are reached within 2 to 3 days of once daily dosing with KETEK 800 mg.
Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 – 4 hours). KETEK has an absolute bioavailability of 57% in both young and elderly subjects.
The rate and extent of absorption are unaffected by food intake, thus KETEK tablets can be given without regard to food.
Total in vitro protein binding is approximately 60% to 70% and is primarily due to human serum albumin.
Protein binding is not modified in elderly subjects or in patients with hepatic impairment.
The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg.
|Hours postdose||Mean concentration (μg/mL)||Tissue/ Plasma Ratio|
|Tissue or fluid||Plasma|
|Epithelial lining fluid||2||14.89||1.86||8.57|
|*Units in mg/kg|
In total, approximately 70% of the telithromycin dose is metabolized. In plasma, the main circulating compound after administration of an 800-mg radio-labeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin.
It is estimated that approximately 50% of its metabolism is mediated by CYP3A4 and the remaining 50% is CYP -independent.
The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver. Following oral dosing, the mean terminal elimination half-life of telithromycin is 10 hours.
Gender: There was no significant difference between males and females in mean AUC, Cmax, and elimination half-life in two studies; one in 18 healthy young volunteers (18 to 40 years of age) and the other in 14 healthy elderly volunteers (65 to 92 years of age), given single and multiple once daily doses of 800 mg of KETEK.
Hepatic impairment: Telithromycin is excreted via the liver and kidney. [see DOSAGE AND ADMINISTRATION]
In a single-dose study (800 mg) in 12 patients and a multiple-dose study (800 mg) in 13 patients with mild to severe hepatic insufficiency (Child Pugh Class A, B and C), the Cmax, AUC and t ½ of telithromycin were similar to those obtained in age- and sex-matched healthy subjects. In both studies, an increase in renal elimination was observed in hepatically impaired patients indicating that this pathway may compensate for some of the decrease in metabolic clearance.
Renal impairment: Telithromycin is excreted via the liver and kidney. [see DOSAGE AND ADMINISTRATION]
In a multiple-dose study, 36 subjects with varying degrees of renal impairment received 400 mg, 600 mg, or 800 mg KETEK once daily for 5 days. There was a 1.4-fold increase in Cmax,ss and a 1.9-fold increase in AUC (0–24)ss at 800 mg multiple doses in the severely renally impaired group (CLCR less than 30 mL/min) compared to healthy volunteers. Renal excretion may serve as a compensatory elimination pathway for telithromycin in situations where metabolic clearance is impaired. Patients with severe renal impairment are prone to conditions that may impair their metabolic clearance.
In a single-dose study in patients with end-stage renal failure on hemodialysis (n=10), the mean Cmax and AUC values were similar to normal healthy subjects when KETEK was administered 2 hours postdialysis. However, the effect of dialysis on removing telithromycin from the body has not been studied.
Combined Renal and Hepatic Impairment: The effects of co-administration of ketoconazole in 12 subjects (age 60 years and older), with impaired renal function were studied (CLCR = 24 to 80 mL/min). In this study, when severe renal insufficiency (CLCR less than 30 mL/min, n=2) and concomitant impairment of CYP3A4 metabolism pathway were present, telithromycin exposure (AUC0-24) was increased by approximately 4- to 5-fold compared with the exposure in healthy subjects with normal renal function receiving telithromycin alone. In the presence of severe renal impairment (CLCR less than 30 mL/min), with coexisting hepatic impairment, a reduced dosage of KETEK is recommended. [see DOSAGE AND ADMINISTRATION]
Geriatric: Pharmacokinetic data show that there is an increase of 1.4-fold in exposure (AUC) in 20 patients 65 years and older with community acquired pneumonia in a Phase 3 study, and a 2.0-fold increase in exposure (AUC) in 14 subjects 65 years and older as compared with subjects less than 65 years of age in a Phase I study. No dosage adjustment is required based on age alone. [see Use In Specific Populations]
During concomitant administration of rifampin and KETEK in repeated doses, C and AUC of telithromycin were decreased by 79%, and 86%, respectively. [see DRUG INTERACTIONS]
Itraconazole: A multiple-dose interaction study with itraconazole showed that C of telithromycin was increased by 22% and AUC by 54%. [see DRUG INTERACTIONS]
Ketoconazole: A multiple-dose interaction study with ketoconazole showed that C of telithromycin was increased by 51% and AUC by 95%. [see DRUG INTERACTIONS]
Grapefruit juice: When telithromycin was given with 240 mL of grapefruit juice after an overnight fast to healthy subjects, the pharmacokinetics of telithromycin were not affected.
Simvastatin: When simvastatin was co-administered with telithromycin, there was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in simvastatin AUC, a 15-fold increase in the simvastatin active metabolite Cmax, and a 12-fold increase in the simvastatin active metabolite AUC. In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4.0-fold increase in simvastatin AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS]
Midazolam: Concomitant administration of telithromycin with intravenous or oral midazolam resulted in 2- and 6-fold increases, respectively, in the AUC of midazolam due to inhibition of CYP3A4-dependent metabolism of midazolam. [see DRUG INTERACTIONS]
The plasma peak and trough levels of digoxin were increased by 73% and 21%, respectively, in healthy volunteers when co-administered with KETEK. However, trough plasma concentrations of digoxin (when equilibrium between plasma and tissue concentrations has been achieved) ranged from 0.74 to 2.17 ng/mL. There were no significant changes in ECG parameters and no signs of digoxin toxicity. [see DRUG INTERACTIONS]
When theophylline was co-administered with repeated doses of KETEK, there was an increase of approximately 16% and 17% on the steady-state Cmax and AUC of theophylline. [see DRUG INTERACTIONS]
KETEK has been shown to decrease the Cmax and AUC of sotalol by 34% and 20%, respectively, due to decreased absorption.
When oral contraceptives containing ethinyl estradiol and levonorgestrel were co-administered with KETEK, the steady-state AUC of ethinyl estradiol did not change and the steady-state AUC of levonorgestrel was increased by 50%. The pharmacokinetic/pharmacodynamic study showed that telithromycin did not interfere with the antiovulatory effect of oral contraceptives containing ethinyl estradiol and levonorgestrel.
When metoprolol was co-administered with KETEK, there was an increase of approximately 38% on the Cmax and AUC of metoprolol; however, there was no effect on the elimination half-life of metoprolol. Telithromycin exposure is not modified with concomitant single-dose administration of metoprolol. [see DRUG INTERACTIONS]
There was no clinically relevant pharmacokinetic interaction of ranitidine or antacids containing aluminum and magnesium hydroxide on telithromycin.
There was no pharmacokinetic effect on paroxetine when KETEK was co-administered.
Steady state peak plasma concentrations of cisapride (an agent with the potential to increase QT interval) were increased by 95% when co-administered with repeated doses of telithromycin, resulting in significant increases in QTc. [see CONTRAINDICATIONS]
OATP1B1 and OATP1B3
In vitro studies using a model compound have shown that telithromycin may act as an inhibitor for the hepatic uptake transporters OATP1B1 and OATP1B3. Although the clinical relevance of this finding is unknown, it is possible that concomitant administration of KETEK with drugs that are substrates of OATP family members could result in increased plasma concentrations of the co-administered drug.
Mechanism Of Action
Telithromycin belongs to the ketolide class of antibacterials and is structurally related to the macrolides. Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. Telithromycin may also inhibit the assembly of nascent ribosomal units.
Telithromycin concentrates in phagocytes where it exhibits activity against intracellular respiratory pathogens. In vitro, telithromycin has been shown to demonstrate concentration-dependent bactericidal activity against isolates of Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP2]).
Mechanism Of Resistance
Production of Erm dimethyltransferases may cause telithromycin resistance in some Gram-positive bacteria.
List Of Microorganisms
Telithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical settings [see INDICATIONS AND USAGE].
Streptococcus pneumoniae (including MDRSP)
The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for telithromycin. However, the safety and efficacy of KETEK in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and communityacquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods (broth or agar dilution)1,3 or equivalent with standardized inoculum and concentrations of telithromycin powder. The MIC values should be interpreted according to criteria provided in Table 6.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antibacterials. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 μg telithromycin to test the susceptibility of microorganisms to telithromycin. Disc diffusion zone sizes should be interpreted according to criteria in Table 6.
Table 6 : Susceptibility Test Result Interpretive
Criteria for Telithromycin
|Pathogen||Minimum Inhibitory Concentrations (μg/mL)||Disk Diffusion Zone Diameter (mm)|
|Streptococcus pneumoniae||≤ 1||2||≥ 4||≥ 19||16-18||≤ 15|
|Haemophilus influenzae||≤ 4||8||≥ 16||≥ 15||12-14||≤ 11|
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antibacterial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of quality control microorganisms to determine the performance of the test procedures1,2,3. Standard telithromycin powder should provide the MIC ranges for the quality control organisms in Table 7. For the disk diffusion technique, the 15-μg telithromycin disk should provide the zone diameter ranges for the quality control organisms in Table 7.
Table 7 : Acceptable Quality Control Ranges for
|Quality Control Organism||Minimum Inhibitory Concentrations (μg/mL)||Disk Diffusion (zone diameter in mm)|
|Haemophilus influenzae ATCC 49247||1.0-4.0||17-23|
|Streptococcus pneumoniae ATCC 49619||0.004-0.03||27-33|
|ATCC = American Type Culture Collection|
Animal Toxicology And/Or Pharmacology
Repeated dose toxicity studies of 1, 3, and 6 months' duration with telithromycin conducted in rat, dog and monkey showed that the liver was the principal target for toxicity with elevations of liver enzymes and histological evidence of damage. There was evidence of reversibility after cessation of treatment. Plasma exposures based on free fraction of drug at the no observed adverse effect levels ranged from 1 to 10 times the expected clinical exposure.
Phospholipidosis (intracellular phospholipid accumulation) affecting a number of organs and tissues (e.g., liver, kidney, lung, thymus, spleen, gall bladder, mesenteric lymph nodes, GI-tract) has been observed with the administration of telithromycin in rats at repeated doses of 150 mg/kg/day ( 2× the human dose on a body surface area basis) or more for 1 month, and 50 mg/kg/day (0.6× the human dose) or more for 3–6 months. Similarly, phospholipidosis has been observed in dogs with telithromycin at repeated doses of 150 mg/kg/day (6× the human dose on a body surface area basis) or more for 1 month and 50 mg/kg/day (2× the human dose) or more for 3 months. The significance of these findings for humans is unknown.
Pharmacology/toxicology studies showed an effect both in prolonging QTc interval in dogs in vivo and in vitro action potential duration (APD) in rabbit Purkinje fibers. These effects were observed at concentrations of free drug at least 8.8 (in dogs) times those circulating in clinical use. In vitro electrophysiological studies (hERG assays) suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr) as an underlying mechanism.
KETEK was studied in four randomized, double-blind, controlled studies and four open-label studies for the treatment of community-acquired pneumonia (CAP). Patients with mild to moderate CAP who were considered appropriate for oral outpatient treatment were enrolled in these trials. Patients with severe pneumonia were excluded based on any one of the following: ICU admission, need for parenteral antibacterials, respiratory rate greater than 30 per minute, hypotension, altered mental status, less than 90% oxygen saturation by pulse oximetry, or white blood cell count less than 4000 per mm³. There were 2016 clinically evaluable patients in the KETEK group.
Table 8: CAP: Clinical Cure Rate at Post-Therapy
Follow-Up (17–24 days)
|Controlled Studies||Patients (n)||Clinical Cure Rate|
|KETEK vs. clarithromycin 500 mg twice a day for 10 days||162||156||88.3%||88.5%|
|KETEK vs. trovafloxacin* 200 mg daily for 7 to 10 days||80||86||90.0%||94.2%|
|KETEK vs. amoxicillin 1000 mg three times a day for 10 days||149||152||94.6%||90.1%|
|KETEK for 7 days vs. clarithromycin 500 mg twice a day for 10 days||161||146||88.8%||91.8%|
|*This study was stopped prematurely after trovafloxacin was restricted for use in hospitalized patients with severe infection.|
Clinical cure rates by pathogen from the four CAP controlled clinical trials in microbiologically evaluable patients given KETEK for 7–10 days or a comparator are displayed in Table 9.
Table 9: CAP: Clinical Cure Rate by Pathogen at Pos
t-Therapy Follow-Up (17–24 days )
|Streptococcus pneumoniae||73/78 (93.6%)||63/70 (90%)|
|Haemophilus influenzae||39/47 (83%)||42/44 (95.5%)|
|Moraxella catarrhalis||12/14 (85.7%)||7/9 (77.8%)|
|Chlamydophila pneumoniae||23/25 (92%)||18/19 (94.7%)|
|Mycoplasma pneumoniae||22/23 (95.7%)||20/22 (90.9%)|
Clinical cure rates for patients with CAP due to Streptococcus pneumoniae were determined from patients in controlled and uncontrolled trials. Of 333 evaluable patients with CAP due to Streptococcus pneumoniae, 312 (93.7%) achieved clinical success. Blood cultures were obtained in all patients participating in the clinical trials of mild to moderate community-acquired pneumonia. In a limited number of outpatients with incidental pneumococcal bacteremia treated with KETEK, a clinical cure rate of 88% (67/76) was observed. KETEK is not indicated for the treatment of severe community-acquired pneumonia or suspected pneumococcal bacteremia.
Clinical cure rates for patients with CAP due to multi-drug resistant Streptococcus pneumonia (MDRSP3) were determined from patients in controlled and uncontrolled trials. Of 36 evaluable patients with CAP due to MDRSP, 33 (91.7%) achieved clinical success.
Table 10: Clinical Cure Rate for 36 Evaluable KETEK-Treated
Patients with MDRSP in Studies of Community-Acquired Pneumonia
|Screening Susceptibility||Clinical Success in Evaluable MDRSP Patients|
|2nd generation cephalosporin-resistant||20/22||90.9|
|*n = the number of patients successfully treated; N = the
number with resistance to the listed drug of the 36 evaluable patients with CAP
due to MDRSP.
†Includes isolates tested for resistance to either tetracycline or doxycycline.
2MDRSP=Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antimicrobials: penicillin, 2 generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
3MDRSP: Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibacterials: penicillin, 2 generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07- A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S24, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014.
Last reviewed on RxList: 5/19/2016
This monograph has been modified to include the generic and brand name in many instances.
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