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Publication Date: September 2004
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TELITHROMYCIN (KETEKTM)
A NEW ANTIMICROBIAL
AGENT


Christopher Cha, Pharm.D. Candidate


Introduction
Infections that invade the lower respiratory
tract, such as community-acquired pneumonia
(CAP) and acute bacterial exacerbations of chronic
bronchitis (ABECB), comprise the more serious
respiratory tract infections (RTIs). They are associ-
ated with considerable morbidity and mortality,
particularly in groups such as the very young, the
elderly and those with co-morbid illness. Up to
80% of community-acquired RTIs are caused by
Streptococcus pneumoniae, Haemophilus influen-
zae or Moraxella catarrhalis and are usually treated
empirically. In the United States, 2-3 million cases
of CAP result in approximately 10 million physi-
cian visits, 500,000 hospitalizations, and 45,000
deaths each year.1 CAP is associated with a mortal-
ity rate of approximately 14% among patients who
require hospitalization versus a mortality rate of
<1% for patients who can be managed in an outpa-
tient setting. There is an urgent need for new agents
that are active against resistant respiratory tract
pathogens, but also exhibit a low potential to select
for resistance or induce cross-resistance to existing
antibacterial agents.
Telithromycin (Ketek*, Aventis), the first of
a new class of semi-synthetic antibiotics, the keto-
lides, was FDA-approved in April 2004. Ketolides
were designed specifically for the treatment of


community-acquired respiratory tract infections
(RTI), such as CAP, acute bacterial sinusitis, and
ABECB, including those caused by penicillin-
resistant and/or macrolide resistant Streptococcus
pneumoniae. Ketolides are members of the mac-
rolide-lincosamide-streptogramin B (MLSB) fam-
ily, and consequently execute their antibacterial ac-
tivity through the inhibition of bacterial protein
synthesis. Telithromycin differs from macrolides in
a structural modifications that allow the drug to
bind more tightly to two distinct regions of ribo-
somal RNA. This dual binding mechanism en-
hances the ability of telithromycin to overcome re-
sistance caused by modification of one of the target
sites.
This article will overview the emergence of
macrolide resistance, and the pharmacology, phar-
macokinetics, indications, dosing, clinical trials,
and safety profile of telithromycin.

Macrolide Resistance
The emergence of antibiotic-resistant bacte-
rial strains has increased at an alarming rate among
the key bacterial pathogens associated with upper
and lower RTIs. The combined percentage of peni-
cillin-intermediate and penicillin-resistant strains of
S. pneumoniae is now >40% in many regions. Re-




INSIDE THIS ISSUE:
TELITHROMYCIN (KETEKT)
A NEW ANTIMICROBIAL AGENT



,1-4


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Table 1. CAP: Clinical cure rate at post-therapy follow-up (17-24 days) 2,4,11,12

Controlled Studies Patients (n) Telithromycin Comparator

Telithromycin vs. clarithromycin 318 88.3 88.5
500 mg BID for 10 days

Telithromycin vs. trovafloxacin*
200 mg QD for 7 to 10 days

Telithromycin vs. amoxicillin 31 9.6
301 94.6% 90.1%
1000 mg TID for 10 days

Telithromycin for 7 days vs.
307 88.8% 91.8%
clarithromycin 500 mg BID for 10 days

*This study was stopped prematurely after trovafloxacin was restricted for use in hospitalized patients with severe infection.


distance has severely limited the role of penicillins
for the treatment of upper RTIs while combination
therapy is often necessary for lower RTIs due to
their lack of activity against atypical pathogens (e.
g., Chlamydia pneumoniae). The resistance and
cross-resistance of macrolides, which initially of-
fered an attractive option against a broad spectrum
of respiratory pathogens, is increasing among
agents within the class.
The most common mechanisms of resis-
tance to MLSB antimicrobials are: (i) target site
modification, (ii) reduced intracellular accumula-
tion due to decreased influx or increased efflux of
the drug and (iii) production of inactivation en-
zymes. Target site modification occurs due to me-
thylation of the 23S rRNA. Methylation is usually
governed by the acquisition of erm genes, which
are responsible for encoding methyltranferases. Ri-
bosomal methylation causes cross-resistance to all
MLSB antibacterials because there is overlap be-
tween the binding sites.5 A conformational change
is made in the ribosome due to methylation. This
results in decreased affinity for MLSB antibiotics.
Ketolides remain active against strains that harbor
the erm gene, and, compared with macrolides,
telithromycin is less likely to activate inducible erm
genes.6 Presence of erm does reduce telithromy-
cin's binding affinity; however, to a much less de-
gree as compared to other MLSB antibiotics. The
nature of the side-chain substituting the C11-C12
carbamate residue is responsible for enhancing the
in vitro and in vivo activities in comparison with


erythromycin. These activities are enhanced due to
the pharmacodynamic and pharmacokinetic proper-
ties, the intracellular features, and tolerance of the
side chain.7
Efflux pumps for erythromycin A have been
described for several Gram-positive cocci. The ef-
flux-mediated resistance pattern is encoded by dif-
ferent genes: mef(A) or mef(E) in streptococci, and
msr(A) and msr(B) in staphylococci.8 The presence
of mef confers resistance to macrolides, but linco-
samides and streptogrammins remain active.
Telithromycin is a poor substrate for efflux pumps,
thus, its activity against streptococci harboring mef
genes is preserved. Production of antibiotic inacti-
vating enzymes plays a minor role in MLSB resis-
tance. Degradation is caused by hydrolysis of the
macrolide lactone ring and modification due to
macrolide phosphorylation and lincosamide nucleo-
tidylation. However, only a few strains have been
reported to have genes that produce inactivating en-
zymes.

Indications
Telithromycin is indicated for the treatment
of the following infections caused by susceptible
strains of the designated microorganisms in patients
18 years old and above: ABECB due to S. pneumo-
niae, H. influenza, or M. catarrhalis. Acute bacte-
rial sinusitis due to S. pneumoniae, H. influenza,
M. catarrhalis, or S. aureus; CAP (of mild to mod-
erate severity) due to S. pneumoniae, (including


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Table 2. Acute Sinusitis: Clinical cure rate at post-therapy follow-up (17-24 days) 4,13,14

Patients (n) Clinical cure rate

Telithromycin Comparator
Controlled Studies Telithromycin Comparator (5 day treat- (10 day treat-
ment) ment)

Telithromycin vs. amoxicillin/clavulanic 16 17 73
146 137 75.3% 74.5%
acid 500/125 mg TID

Telithromycin vs. cefuroxime axetil 189 89 85.2 82.0
250 mg89 85 82
250 mg BID


multi-drug resistant isolates [MDRSP]), H.
zae, M. catarrhalis, C. pneumoniae,
coplasma pneumoniae.4


influen-
or My-


Pharmacology and Pharmacokinetics
Ketolides have a mechanism of action simi-
lar to erythromycin A, from which they have been
derived. Bacterial protein synthesis is inhibited by
interacting near the peptidyl transferase site of the
50S ribosomal subunit.3 Telithromycin differs
chemically from macrolides by the lack of a-L-
cladinose at position 3 of the erythronolide A ring,
resulting in a 3-keto functional group.4 The main
sites of macrolide and ketolide interaction are
within domains II and V of the 23S rRNA. How-
ever, the ketolides display a higher affinity than
macrolides for ribosomal binding sites. By binding
at domain II, telithromycin remains bactericidal
against gram-positive cocci even in the presence of
resistance mediated by methylases (erm genes) that
alter the domain V binding site of telithromycin.
The ketolides also demonstrate a significant
inhibitory effect on the formation of 50S ribosomal
subunits. The ketolides were tested against Staph
aureus where the concentration inhibiting 50%
(IC50) of the 50S subunit was approximately
equivalent to that of the IC50 of the inhibition of
translation. At higher concentrations, ketolides also
inhibit protein synthesis via the 30S ribosomal sub-
unit.3
Telithromycin has other potential advan-
tages over macrolides in treating RTIs: it accumu-
lates to a greater extent in bacterial cells and it con-
centrates in human phagocytes which maintains its


activity against intracellular (i.e., atypical) patho-
gens.3 The inflammatory response, which causes
significant morbidity and mortality during lower
RTIs due to S. pneumoniae may also be suppressed
by ketolides. In vitro and in animal models, keto-
lides decrease levels of immune mediators and neu-
trophil recruitment in response to live or heat killed
S. pneumoniae. PMN-induced phospholipid media-
tors, such as platelet activating factor, have been
shown to induce ciliary slowing and epithelial dam-
age in the airways.
A once-daily dose of telithromycin 800 mg
achieves high concentrations in both plasma and
respiratory tissues and fluids and is maintained at
effective levels throughout the 24-hour dosing pe-
riod. Telithromycin reaches maximal concentration
one hour after oral administration. It has an abso-
lute bioavailability of 57% and the rate and extent
of absorption are unaffected by food. Steady-state
plasma concentrations are reached within 2-3 days.
The mean terminal elimination half-life of telithro-
mycin is 10 hours. Total protein binding is ap-
proximately 60%-70% and is primarily due to hu-
man serum albumin. Protein binding is not
changed in elderly subjects or in patients with he-
patic impairment. The volume of distribution is ap-
proximately 2.9L/kg. Seventy percent of the drug is
metabolized, and it is estimated that 50% of
telithromycin's metabolism is by CYP 450 3A4 and
the remaining 50% is CYP 450-independent. Sys-
temically available telithromycin is eliminated as
follows: 7% is excreted unchanged in feces by bil-
iary and/or intestinal secretion; 13% is excreted un-
changed in urine by renal excretion; and 37% is


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Table 3. ABECB: Clinical cure rate at post-therapy follow-up (17-24 days)4,15,16


Patients (n)


Controlled Studies


Clinical cure rate


Telithromycin Telithromycin Comparator


Telithromycin (5 day therapy) vs.
cefuroxime axetil 500mg BID (10 day therapy)

Telithromycin (5 day therapy) vs. amoxicillin/
clavulanic acid 500/125 mg TID (10 day therapy)

Telithromycin (5 day therapy) vs.
clarithromycin 500mg BID (10 day therapy)


86.4%


86.1%


85.8%


83.1%


82.1%


89.2%


metabolized by the liver.

Clinical Trials
Telithromycin was studied in four random-
ized, double-blind, controlled studies and four
open-label studies for the treatment of CAP. Pa-
tients with mild to moderate CAP who were con-
sidered appropriate for oral outpatient treatment
were enrolled in these trials. Patients with severe
pneumonia were excluded based on any one of the
following: intensive care unit (ICU) admission,
need for parenteral antibiotics, respiratory rate >
30/minute, hypotension, altered mental status, <
90% oxygen saturation by pulse oximetry, or white
blood cell count < 4000/mm3. Total number of
clinically valuable patients in the telithromycin
group included 2016 patients. (Table 1)
Telithromycin was studied in two random-
ized, double-blind, comparative studies for the
treatment of acute sinusitis. (Table 2.)
Telithromycin was studied in three random-
ized, double-blind, controlled studies for the treat-
ment of ABECB. (Table 3)


Toxicity and Safety
Common adverse events of telithromycin
compared to other antibacterials are listed in Table
4. Most adverse events were gastrointestinal in na-
ture with diarrhea being the most prevalent at 10%.
Telithromycin may cause visual disturbances (1.1%
of treated patients), particularly in slowing the abil-


ity to accommodate and the ability to release ac-
commodation. Females and patients under 40 years
old experienced a higher incidence of telithromy-
cin-associated visual adverse events (-2%).
Telithromycin also and has the potential to prolong
the QT interval (average 3.5 msec). The safe and
effective use of telithromycin in children and ado-
lescents < 18 years of age has not been established.

Dosing and Administration
Telithromycin is supplied as 400mg oral
tablets packaged in bottles of sixty, a Ketek* Pak
(10-tablet cards), or as unit dose package of 100.
The dose of Ketek* is 800mg (two 400mg tablets)
taken orally once every 24 hours. The duration of
therapy should be 5 days for acute bacterial exacer-
bations of chronic bronchitis and for acute bacterial
sinusitis. The duration of therapy should be 7-10
days for CAP.
Ketek* may be administered without dosage
adjustment in hepatic impairment.
The dose of Ketek* in the presence of severe renal
impairment (CrCL<30mL/min), including patients
who require dialysis, has not been established.4

Cost
The average cost, defined as the average
price at 3 retail pharmacies, is $69.07 for the Ketek*
PAK, while a 10-day course of therapy is expected
to cost $126.17.


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Table 4. Frequency of Treatment-Emergent Adverse Events Reported in Phase III Clinical Studies4

Adverse Event* All TEAEs Possibly-Related TEAEs
Telithromycin Comparatort Telithromycin Comparatort
n= 2702 n= 2139 n= 2702 n= 2139

Diarrhea 10.8% 8.6% 10.0% 8.0%

Nausea 7.9% 4.6% 7.0% 4.1%

Headache 5.5% 5.8% 2.0% 2.5%

Dizziness 3.7% 2.7% 2.8% 1.5%

Vomiting 2.9% 2.2% 2.4% 1.4%

Loose Stools 2.3% 1.5% 2.1% 1.4%

Dysgeusia 1.6% 3.6% 1.5% 3.6%

*Based on a frequency of all and possibly related treatment-emergent adverse events of > 2% in telithromycin or comparator groups.
tIncludes comparators from all controlled Phase III studies. TEAE denotes treatment-emergent adverse events.


Summary
Common pathogens responsible for com-
munity-acquired RTIs have become increasingly
resistant to antibacterial drugs. Thus, there is a
pressing need for new antibiotics with activity
against resistant respiratory tract pathogens and a
low potential to select for resistance or induce
cross-resistance to existing antibiotics. Telithromy-
cin, the first ketolide antibiotic to be FDA ap-
proved, has enhanced binding to bacterial rRNA.
Through its unique structure, telithromycin retains
activity against resistant respiratory pathogens and
has shown efficacy in the treatment of RTIs. On
the basis of phase III clinical trial experience,
telithromycin appears safe and well tolerated
across various patient populations, including high-
risk groups.9 Telithromycin represents a promising
new agent for the empirical treatment of commu-
nity-acquired RTIs.

References
1. Bartlett JG, Dowell SF, Mandell LA, et al, for the Infectious
Diseases Society of America. Practice Guidelines for the man-
agement of community-acquired pneumonia in adults. Clin
Infect Dis 2000;31:347-382.
2. Mathers Dunbar L, Hassman J, Tellier G. Efficacy and toler-
ability of once-daily oral telithromycin compared with
clarithromycin for the treatment of community-acquired pneu-
monia in adults. Clin Ther 2004;26:48-62.
3. Zhanel GG, Walters M, Noreddin A, Vercaigne LM, et al. The
Ketolides: a Critical review. Drugs 2002;62:1771-804.
4. Ketek [Package Insert]. Aventis; 2004.


5. Ackermann G, RodloffAC. Drugs of the 21st century: telithro-
mycin (HMR 3647)--the first ketolide. J Antimicrob Chemother
2003;51:497-511.
6. Champney WS, Tober CL. Inhibition of translation and 50S
ribosomal subunit formation in Staphylococcus aureus cells by
11 different ketolide antibiotics. Curr Microbiol 1998;37:418-
25.
7. Bryskier A. Ketolides-telithromycin, an example of a new class
of antibacterial agents. Clin Microbiol Infect 2000;6:661-9.
8. Bryskier, A. & Denis, A. Ketolides: novel antibacterial agents
designed to overcome resistance to erythromycin A within
Gram-positive cocci. In Macrolide Antibiotics (Schonfeld, W.
& Kirst, H. A., Eds), pp. 97-140. 2002, Birkhauser Verlag,
Basel, Switzerland.
9. Clark JP, Langston E. Ketolides: a new class of antibacterial
agents for treatment of community-acquired respiratory tract
infections in a primary care setting. Mayo Clin Proc
2003;78:1113-24.
10. Dipiro JT et al. Pharmacotherapy: A Pathophysiological Ap-
proach, 5th ed.; McGraw-Hill; 2002.
11. Pullman J, Champlin J, Vrooman PS Jr. Efficacy and tolerabil-
ity of once-daily oral therapy with telithromycin compared with
trovafloxacin for the treatment of community-acquired pneumo-
nia in adults. Int J Clin Pract 2003;57:377-84.
12. Hagberg L, Torres A, van Rensburg D, Leroy B, Rangaraju M,
Ruuth E. Efficacy and tolerability of once-daily telithromycin
compared with high-dose amoxicillin for treatment of commu-
nity-acquired pneumonia. Infection 2002;30:378-86.
13. Buchanan PP, Stephens TA, Leroy B. A comparison of the effi-
cacy of telithromycin versus cefuroxime axetil in the treatment
of acute bacterial maxillary sinusitis. Am J Rhinol 2003;17:369-
77.
14. Luterman M, Tellier G, Lasko B, Leroy B. Efficacy and toler-
ability of telithromycin for 5 or 10 days vs amoxicillin/
clavulanic acid for 10 days in acute maxillary sinusitis. Ear
Nose Throat J2003;82:576-80, 82-4.
15. Zervos MJ, Heyder AM, Leroy B. Oral telithromycin 800 mg
once daily for 5 days versus cefuroxime axetil 500 mg twice


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daily for 10 days in adults with acute exacerbations of chronic
bronchitis. J Int Med Res 2003;31:157-69.
16. Aubier M, Aldons PM, Leak A, et al. Telithromycin is as effec-
tive as amoxicillin/clavulanate in acute exacerbations of chronic
bronchitis. Respir Med 2002;96:862-71.



VytorinTM, a combination product containing
the cholesterol-lowering agents ezetimibe
and simvastatin was approved in July. It is
indicated for adjunctive therapy to diet in
patients with primary hypercholesterolemia,
mixed hyperlipidemia, and homozygous
familial hypercholesterolemia (HoFH).
VytorinTM tablets are available in 4 strengths,
each containing 10 mg of ezetimibe and
either 10 mg, 20 mg, 40 mg, or 80 mg of
simvastatin. The combination of ezetimibe
and 10-80 mg of simvastatin achieves LDL
reductions of > 51%. The adverse effect
profile of VytorinTM is similar to station
monotherapy, except for an increase in the
incidence of hepatic enzyme elevations
(3.6% with 80 mg dose). Liver function tests
should be monitored at baseline, before
titrating to the 80 mg dose, in 12 weeks, and
thereafter when clinically indicated.




New Dosage Forms

Extended-release lovastatin will no
longer be marketed as AltocorTM. Instead,
the proprietary name will be AltoprevTM.




Labeling Changes

Atorvastatin (Lipitor) labeling will
now include an indication for the
prevention of MI, angina, or the risk of
coronary revascularization. The new
indications apply to patients with normal
or only mildly elevated cholesterol levels
who have other features indicating
increased risk for coronary disease.


Duloxetine (Cymbalta) was approved in
August for the treatment of major
depression. Like venlafaxine and
clomipramine, Cymbalta inhibits the
reuptake of both serotonin and
norepinephrine and is often referred to as a
'dual' inhibitor. It has been shown to be
effective for treating symptoms of depression
and improving painful physical symptoms
(e.g., back pain, shoulder pain) associated
with depression. Cymbalta should be
administered at a total dose of 40 mg/day
(given as 20 mg BID) to 60 mg/day (given
either once a day or as 30 mg BID) without
regard to meals. Cymbalta is a substrate for
CYP 1A2 and 2D6; inhibitors of these
enzyme systems increase plasma
concentrations of Cymbalta. No dosage
adjustments are available. Common adverse
reactions include nausea, dry mouth
constipation, and decreased appetite. It
should be used with caution in patients with
hepatic disease; in clinical trials, liver
transaminase elevations resulted in the
discontinuation of Cymbalta in 0.3% of
patients.





The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.


~
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PharmaNote


Volume 19, Issue 12 September 2004




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