ADIS NEW DRUG PROFILE Drugs 2001; 61 (6): 815-829

0012-6667/01/0006-0815/$27.50/0

© Adis International Limited. All rights reserved.

Telithromycin
Julia A. Barman Balfour and David P. Figgitt
Adis International Limited, Auckland, New Zealand

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
1. Antimicrobial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820
3. Therapeutic Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
5. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
6. Telithromycin: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825

Abstract
h Telithromycin is the first member of a new family of the Features and properties of telithromycin
(HMR 3647, RU 66647)
macrolide-lincosamide-streptogramin-B (MLSB) class of
antimicrobials, the ketolides. It has a good spectrum of ac-
tivity against respiratory pathogens, including penicillin- Indications
and erythromycin-resistant pneumococci, as well as intra-
cellular and atypical bacteria. Furthermore, it has a low Treatment of community-acquired pneumonia, acute
potential to select for resistance or induce cross-resistance
among other MLSB antimicrobials. exacerbations of chronic bronchitis, acute bacterial maxillary
h At the recommended dosage of 800mg orally once daily, sinusitis, pharyngitis/tonsillitis
telithromycin reaches maximal plasma concentrations of
about 2 mg/L. It penetrates rapidly into bronchopulmonary, Mechanism of action
tonsillar, sinus and middle ear tissues and/or fluids and
achieves high concentrations at sites of infection. It also Ketolide antibacterial agent Inhibits bacterial 50S ribosomal
concentrates within polymorphonuclear neutrophils.
h In clinical trials in patients with community-acquired pneu-
protein synthesis and ribosome
assembly
monia (CAP), acute exacerbations of chronic bronchitis
(AECB) or pharyngitis/tonsillitis caused by group A β-
haemolytic streptococci, telithromycin 800mg once daily Dosage and administration
achieved clinical cure rates of 86 to 95%. In acute maxillary
sinusitis (AMS), cure rates were 73 to 91%. Usual dosage in clinical trials 800 mg/day (2 × 400mg tablets)
h A 7- to 10-day regimen of telithromycin was as effective
Route of administration Oral
as a 10-day course of amoxicillin 1000mg 3 times daily,
clarithromycin 500mg twice daily or a 7- to 10-day course
of trovafloxacin 200mg once daily for treating CAP. A 5- Frequency of administration Once daily
day regimen of telithromycin was as effective as a 10-day
regimen of cefuroxime axetil 500mg twice daily or Pharmacokinetic profile (800mg for 7 or 10 days)
amoxicillin/clavulanic acid 500/125mg 3 times daily in
AECB. Peak plasma concentration 1.84-2.27 mg/L
h A 5-day regimen of telithromycin was as effective as a
10-day regimen of clarithromycin 250mg twice daily or Time to peak plasma 1-2h
phenoxymethylpenicillin 500mg 3 times daily in pharyngi- concentration
tis/tonsillitis, or a 10-day regimen of amoxicillin/clavulanic
acid 500/125mg 3 times daily in patients with AMS. Terminal elimination half-life 9.81h
h Telithromycin was well tolerated across all patient popula-
tions. Adverse events associated with telithromycin were Adverse events
generally mild to moderate in intensity and seldom led to
treatment discontinuation. The most frequent adverse Most frequent Mild to moderate diarrhoea and
events were diarrhoea (13.3%) and nausea (8.1%). Other nausea, low rate of
adverse events included dizziness and vomiting.
discontinuation
816 Barman Balfour & Figgitt

H3C CH3
N N
CH3
HO
O
N CH3
H3C
N N O O O CH3

O H3C
O
O CH3
H3C
O
CH3 CH3

Telithromycin

Community-acquired respiratory pathogens are to greater than 20 times (versus both macrolides)
becoming increasingly resistant to the β-lactams, in ribosomes with domain V modifications that
erythromycin and the newer macrolides, necessi- confer MLSB resistance.[3] This is accounted for by
tating the development of alternative antimicrobi- the stronger mode of binding of telithromycin to
als. Telithromycin is the first member of a new domain II. These innovative differences in the
family of semisynthetic macrolide-lincosamide- mechanisms of action result in an extended spec-
streptogramin-B (MLSB) antimicrobials, the keto- trum of activity for telithromycin covering macro-
lides. Ketolides are 14-membered ring macrolides lide-resistant strains.
with a 3-keto structure replacing the L-cladinose
moiety of macrolides and a methoxy substituent at 1. Antimicrobial Activity
C6. In addition, telithromycin possesses a carba-
mate extension at positions C11/C12. These sub- This section focuses on the activity of telithro-
stitutions confer acid stability and enable teli- mycin against bacterial respiratory pathogens, with
a particular emphasis on the more common patho-
thromycin to overcome the most common forms of
gens associated with community-acquired respira-
macrolide resistance, thereby enhancing activity
tory tract infections (RTIs).
against erythromycin-resistant strains.[1]
In this review, in vitro antibacterial activity re-
Ketolides have a similar mechanism of action to
fers to minimum inhibitory concentrations (MICs)
the macrolides: prevention of bacterial protein syn-
determined by broth or agar dilution techniques
thesis by direct binding to the 50S subunit of bac-
(except in the case of some intracellular bacteria,
terial ribosomes and prevention of translation and which were tested in cell culture). MIC50 and
ribosome assembly.[2] However, they also exhibit MIC90 values refer to minimum concentrations re-
important differences in their mode of action which quired to inhibit the growth of 50 and 90% of
differentiate them from the macrolide class. Teli- strains, respectively. Proposed MIC breakpoints
thromycin and the macrolide erythromycin both for telithromycin indicating susceptibility, inter-
bind to bacterial ribosomes primarily through in- mediate susceptibility and resistance are ≤1, 2 and
teractions with nucleotides in domains II and V of ≥ 4 mg/L, respectively, for streptococci, staphylo-
23S ribosomal RNA. Telithromycin, however, cocci and enterococci and ≤2, 4 and ≥8 mg/L for
binds 10 times more tightly than erythromycin and Haemophilus influenzae.[4-6] The tentative phar-
6 times more tightly than clarithromycin to wild- macokinetic breakpoint predictive of successful
type ribosomes; furthermore, this difference rises clinical outcome is MIC 2 to 4 mg/L.[7]

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

Telithromycin: New Drug Profile 817

In Vitro Activity of these isolates expressing constitutive mecha-

nisms of resistance to erythromycin,[22] as S. au-
Gram-Positive Bacteria reus isolates with inducible erythromycin resis-
Streptococci tance remain highly susceptible to telithromycin
• Telithromycin has excellent activity against (MIC90 0.12 mg/L).[23]
Streptococcus pneumoniae, with reported MIC90 Gram-Negative Bacteria
values of 0.016 to 0.06 mg/L for erythromycin- • The MIC50 and MIC90 of telithromycin against
susceptible strains.[5,8-10] Telithromycin retains H. influenzae were 0.6 and 1.2 mg/L (range 0.08 to
good activity against penicillin-[8,11,12] and erythro- 2.5 mg/L), respectively.[13] MIC values were unaf-
mycin-[8,12] resistant strains, with MIC90s of 0.25 mg/ fected by β-lactamase production or ampicillin re-
L[8] and ≤0.12 to 0.5 mg/L, respectively.[5,8,9,11] Its sistance.[12,13] Telithromycin had similar activity
activity against erythromycin-resistant pneumo- to azithromycin and was 4- to 8-fold more active
cocci includes strains with erm (inducible and con- than clarithromycin against H. influenzae.[13,24]
stitutive) and mef resistance determinants.[9,13]
• The activity of telithromycin was reduced against
• In contrast, all macrolides, including azithro- 42 cefuroxime-resistant strains of H. influenzae,
mycin, were inactive against erythromycin-resistant with MIC50 and MIC90 values of 2 and 16 mg/L,
strains (MIC90 ≥32 and ≥64 mg/L for clarithro- respectively.[24]
mycin and azithromycin, respectively).[14]
• Against Moraxella catarrhalis isolates, the ma-
• S. pyogenes is also highly susceptible to jority of which were β-lactamase producers,
telithromycin with MIC90s ranging from 0.015 to telithromycin had activity similar to that of azi-
0.125 mg/L.[15-17] Telithromycin had similar activ- thromycin and clarithromycin[12,25] and levo-
ity to clindamycin (MIC90 < 0.06 mg/L) and was floxacin[24] (MIC90 ≤0.12 mg/L).
more active than azithromycin (MIC90 2 mg/L) or ery-
thromycin (MIC90 0.25 mg/L) against this spe- Atypical and Intracellular Organisms
cies.[15] Good activity has also been demonstrated • Telithromycin showed excellent activity (MICs
against erythromycin-resistant isolates of S. pyogenes ≤0.25 mg/L) against human mycoplasmas other
with the ermA (MIC90 0.06 mg/L) or mefA (MIC90 than Mycoplasma hominis.[26] It had comparable
0.5 mg/L) resistance determinants.[18] activity to erythromycin, clarithromycin, azithro-
mycin and levofloxacin against M. pneumoniae
Staphylococci
(MIC90 ≤0.015 mg/L).[26,27]
• Methicillin/oxacillin-susceptible Staphylococ-
cus aureus (MSSA) was also highly susceptible to • The activity of telithromycin also extends to in-
telithromycin (MIC90 ≤0.12 mg/L),[11] but methi- tracellular pathogens. Against Chlamydia pneu-
cillin/oxacillin-resistant strains (MRSA) were moniae isolates (n = 19) in infected human hepa-
generally resistant (MIC50 >16 mg/L).[11,19,20] tocyte cells, telithromycin had similar activity to
Telithromycin was >64-fold more active than erythromycin and azithromycin (MIC90 0.25 mg/
azithromycin or erythromycin and 2-fold more active L).[28]
than clindamycin against 66 oxacillin-susceptible • Against 30 isolates of Legionella spp. (includ-
strains.[20] ing 21 isolates of L. pneumophila), telithromycin
• The activity of telithromycin against MRSA is MIC90 was 0.03 mg/L (range ≤0.004 to 0.12
dependent on the pattern of erythromycin resis- mg/L).[29] Its activity was similar to levofloxacin
tance. Against 25 isolates of erythromycin-suscep- and higher than that of erythromycin and moxi-
tible MRSA, telithromycin MIC90 was 0.12 mg/ floxacin.[29] Telithromycin also inhibited the
L.[21] The corresponding value for erythromycin- growth of L. pneumophila serogroup 1 in guinea-
resistant MRSA was ≥128 mg/L.[21] This reduction pig alveolar macrophages.[30]
in activity against erythromycin-resistant MRSA • Mycobacterium avium, M. bovis BCG, M. para-
appears to be accounted for by the high proportion tuberculosis and M. ulcerans were moderately sus-

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

818 Barman Balfour & Figgitt

ceptible to telithromycin in vitro (MICs ≤20 mg/L activity than azithromycin and other macrolides
compared with MICs ≤1.25 mg/L for clarithro- against erythromycin-susceptible pneumococci.
mycin against the same species). M. africanum, M. At 2 × MIC, telithromycin demonstrated bacterici-
bovis, M. simiae and M. tuberculosis were resistant dal activity against erythromycin-resistant S. pneu-
to telithromycin (MICs ≥40 mg/L).[31] moniae with macrolide MICs ≥64 mg/L.[8] Macro-
lides, including azithromycin and clarithromycin,
Influence of Assay Methodology on Activity
showed bactericidal activity only against erythro-
mycin-susceptible strains.
• Broth microdilution, agar dilution, disk diffu-
sion and E-test can all be used reliably to test the • Complete killing of pneumococci (including
susceptibility of both S. pneumoniae and H. in- penicillin- and erythromycin-resistant strains) was
fluenzae to telithromycin.[5,32] However, slightly achieved within 1 to 6 hours in in vitro dynamic
higher MIC values have been reported by E-test. models which simulated the human pharmacoki-
• Telithromycin MICs against most species and netic profile achieved after administration of once
strains tested were minimally affected by an in- daily telithromycin 850mg[34] or 800mg.[35]
crease of inoculum size from 104 to 106 colony- • Telithromycin was bactericidal at 24 hours at 2
forming units (cfu)/ml or by the addition of 20 or × MIC against some strains of H. influenzae and at
70% serum, although the MIC of S. pyogenes in- MIC against M. catarrhalis.[36] In general, teli-
creased 4-fold in the presence of 70% serum.[19] thromycin and azithromycin were the most active
• Choice of media also appears to have a minimal agents evaluated against these organisms in time-
effect on telithromycin susceptibility. For Gram- kill experiments.[36,37] At 10 × MIC, telithromycin
positive cocci, Mueller–Hinton and Isosensitest was bactericidal at 24 hours against S. aureus and
agar produced similar results.[33] For H. influenzae, S. pyogenes.[38]
the use of media other than Haemophilus test me-
dium had little effect on telithromycin MICs.[32] • Telithromycin was bactericidal against M.
pneumoniae, with a minimal bactericidal concen-
• Incubation in 5 to 7% CO2 resulted in a 2-fold
tration (MBC) of ≤0.12 mg/L.[26]
increase in telithromycin MICs for H. influenzae
and a >3-fold increase in azithromycin MICs.[32] • Telithromycin demonstrated bactericidal activ-
CO2 has also been reported to affect the anti- ity against C. pneumoniae, with an MBC of 0.25
pneumococcal activity of telithromycin when de- mg/L.[28] At 10 × MIC, time-dependent killing was
termined by disk diffusion and E-test experi- observed with a maximal bactericidal effect at 72
ments.[5] Generally, zone diameters were 4 to 5mm to 96 hours’ exposure.[39] Exposure to 0.5 × MIC
smaller and MICs approximately 1 dilution higher after 12 hours’ exposure to 10 × MIC increased the
when determined in the presence of CO2. killing effect, but not to the degree seen with a
static exposure of 10 × MIC for 72 hours.[39]
Bactericidal Activity
• Telithromycin also reduced numbers of intracel-
Time-kill studies have demonstrated that lular L. pneumophila in infected guinea-pig alveo-
telithromycin has dose-dependent bactericidal ac- lar macrophages[30] and slowed regrowth for up to
tivity (defined as 99.9% killing and a 3 log10 de- 2 days. Its activity was comparable with that of
crease in cfu/ml) at 2 to 8 × MIC for key respiratory clarithromycin and erythromycin.[30] Concentra-
pathogens. tion- and time-dependent activity greater than that
• Against S. pneumoniae, telithromycin was bac- of erythromycin was demonstrated in L. pneu-
tericidal at 24 hours at 2 × MIC and showed 99% mophila-infected human monocyte cell lines. A
killing of all strains tested after 12 hours. At 4 to 8 significant (p < 0.01 vs control) antimicrobial ef-
× MIC, rapid killing was observed within 6 fect was observed at the lowest concentration of
hours.[8] Telithromycin showed higher bactericidal telithromycin evaluated (0.25 × MIC).[40]

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

Telithromycin: New Drug Profile 819

Postantibiotic Effects bly resistant isolates of S. aureus (PD50 8 and 4.5

mg/kg).[45]
• Telithromycin exhibited a significant post- • Telithromycin 30 mg/kg (2 oral doses) was ac-
antibiotic effect (PAE; >0.5 hours) at 4 and 10 × tive in reducing lung bacterial counts in experi-
MIC (0.8 to 7 and 1.2 to 8.2 hours, respectively) mental Legionella pneumonia in guinea-pigs and
against S. pneumoniae, H. influenzae, M. catar- was associated with a better survival rate than
rhalis, S. pyogenes and S. aureus.[38] erythromycin or roxithromycin (89 vs 60 vs 75%)
• Against erythromycin-susceptible strains of S. and a slightly lower survival rate than pefloxacin
aureus, S. pyogenes and S. pneumoniae, PAEs 7.5 mg/kg (2 doses; 100%).[46] An intraperitoneal
ranged from 0.5 to 3.8, 0.6 to 10.8 and 0 to 9.5 telithromycin dosage of 10 mg/kg given once or
hours, respectively, at 0.5 to 64 × MIC. Maximum twice daily for 5 days was associated with 100%
PAEs against erythromycin-resistant strains of survival in a similar model.[30]
these organisms were lower but still significant
(3.5, 3.8 and 6.6 hours, respectively).[41] Pharmacokinetic Predictors of In Vivo Activity
• Studies in the neutropenic murine thigh infec-
tion model suggest that AUC (area under the con-
In Vivo Activity
centration-time curve)/MIC is the most important
pharmacokinetic/pharmacodynamic determinant
Animal Models of Infection of in vivo activity of telithromycin.[47,48] In this
• In a murine model of pneumonia caused by β- murine model, AUC/MIC is also the best predictor
lactamase-producing H. influenzae, oral of efficacy for azithromycin; however, the 2 drugs
telithromycin 50 mg/kg (4 doses) was as active as showed differences in their pharmacodynamic
oral azithromycin or ciprofloxacin (both 100 characteristics. Telithromycin produced concen-
mg/kg) in eradicating bacteria in the lung (3/12 vs tration-dependent, whereas azithromycin exhib-
5/18 and 3/13 animals). Amoxicillin 25 mg/kg, ited time-dependent, killing against S. pneu-
erythromycin, clarithromycin and pristinamycin moniae. Maximum killing for telithromycin and
(all 100 mg/kg) failed to sterilise the lungs in any azithromycin was 4 to 5.3 and 1.5 to 2.3 log10
animal, but all test agents, except amoxicillin, re- cfu/thigh, respectively.[48]
duced lung bacterial counts (p < 0.05 vs untreated
• Results of a preliminary study in 240 patients
animals).[42]
with community-acquired pneumonia (CAP) sug-
• Telithromycin 50 or 100 mg/kg twice daily for gested that infections caused by pathogens with
3 days was more active than azithromycin 100 MICs as high as 2 to 4 mg/L may be successfully
mg/kg in a mouse model of macrolide-resistant treated with telithromycin 800mg once daily.[7]
(azithromycin MIC >128 mg/L) pneumococcal in-
fection (survival rates 47 and 71 vs 29% at 7 days
Resistance Issues
postinfection).[43] In a rabbit model of pneumococ-
cal pneumonia, telithromycin (dosed to simulate
serum concentration profiles achieved with 800mg The most clinically important resistance mech-
twice daily in humans) was active against penicillin- anism to the MLSB group of antimicrobials is tar-
resistant strains and strains with erythromycin get modification via erm genes, which encode ri-
MICs of 16 mg/L but not against highly erythro- bosome methylases (MLSB resistance). Erm genes
mycin-resistant strains (MIC >64 mg/L).[44] can be expressed constitutively or inducibly. Both
• Telithromycin has also demonstrated high ther- 14- and 15-membered ring macrolides can induce
apeutic efficacy in an animal model of infection MLSB resistance. Another common mechanism is
caused by erythromycin-susceptible S. pyogenes active efflux via mef genes.[49] Ketolides do not
[dose required to protect 50% of animals (PD50) 16 induce methylase gene expression in erythromycin-
mg/kg] and erythromycin-susceptible and induci- inducibly resistant strains.[50] Furthermore, their

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

820 Barman Balfour & Figgitt

activity is not affected by inducible MLSB resis- 2. Pharmacokinetic Profile

tance or efflux mechanisms.[9,13]
• Whereas telithromycin was active against con- Absorption and Distribution
stitutive MLSB-resistant S. pneumoniae (MIC 0.25
mg/L),[9,51] its activity was affected by constitutive • The recommended telithromycin dosage (800mg
MLSB resistance in S. pyogenes (MIC90 ≥64 mg/L) once daily) produced a peak plasma concentration
and S. aureus (MIC90 ≥128 mg/L).[18,23,52] (Cmax) of 1.84 to 2.27 mg/L at 1 to 2 hours (tmax) at
• Telithromycin selected resistant mutants less steady state in healthy volunteers. AUC0-24 was 8.4
frequently than did azithromycin, clarithromycin, to 12.5 mg/L • h.[55,56]
erythromycin, roxithromycin, clindamycin and • Steady-state plasma concentrations were reached
pristinamycin after 50 passages of macrolide-sus- after 2 to 3 days of repeated administration. After
ceptible (n = 5) and -resistant (containing mefE or 7 or 10 days’ administration there was a slight ac-
ermB genes; n = 6) S. pneumoniae through sub- cumulation of telithromycin compared with single
inhibitory concentrations. Only 3 mutants resistant administration: the accumulation ratio was approx-
to telithromycin (MIC >1 mg/L) emerged, all of imately 1.2 to 1.5.[55,56]
which had MICs ≤8 mg/L. In contrast, 20 to 45 • The pharmacokinetics of telithromycin deviate
resistant mutants emerged for the other drugs.[53] modestly from dose proportionality and this is
mainly observed for AUC: for a 2-fold increase in
dose there was an approximately 3-fold increase in
Effects on Oral and Faecal Flora
AUC, whereas Cmax was approximately dose pro-
portional.[55]
• Administration of telithromycin 800mg once
• The oral absolute bioavailability of telithro-
daily (the dosage used in all clinical trials) for 10
mycin is 57%.[57] Food does not affect the bioavail-
days to 10 healthy volunteers did not result in any ability of the drug.[58]
overgrowth of yeasts or Clostridium difficile
among the oral and faecal microflora.[54] Quantita- • Telithromycin 600 or 800mg once daily for 5
days produced high concentrations in tonsillar
tive ecological disturbances in the normal micro-
tissue [59] and bronchopulmonary tissues and
flora were moderate and transient and were similar
fluids.[60-62] Concentrations at these sites remained
to those observed amongst a group of 10 healthy above telithromycin MICs for most respiratory
volunteers receiving clarithromycin 250mg twice pathogens throughout the 24-hour administration
daily. Telithromycin showed a more favourable period.
ecological profile than clarithromycin in terms of
• Concentrations in tonsils were 3-fold higher
the emergence of resistance. Salivary α-haemo-
than concurrent plasma concentrations at 3 hours
lytic streptococci remained susceptible to teli- postdose and 13-fold higher at 24 hours.[59]
thromycin (MIC ≤1 mg/L), although MICs in- Bronchopulmonary tissue or fluid : plasma ratios
creased slightly. In contrast, clarithromycin admin- over the 24-hour administration period ranged
istration was associated with the rapid emergence from 4.8 to 14.4 for epithelial lining fluid, 2.1 to
of highly resistant isolates (MIC >128 mg/ L). In 12.1 for bronchial mucosa and 37.2 to 2159.6 for
faeces, emergence of resistant enterococci (Entero- alveolar macrophages.[60-62] The penetration of
coccus faecalis; MIC90 32 mg/L) and Bacteroides telithromycin into respiratory tissues and fluids is
spp. (MIC90 >128 mg/L) were noted after shown in figure 1.
telithromycin administration. Highly resistant fae- • In 26 patients undergoing otorhinolaryngologi-
cal enterococci, enterobacteriaceae and Bacteroi- cal procedures, concentrations of telithromycin in
des spp. (MICs >128 mg/L) developed during clar- the mucous membrane of middle ear and paranasal
ithromycin administration.[54] sinuses, respectively, were 2.4- and 4-fold higher

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

Telithromycin: New Drug Profile 821

than concurrent plasma concentrations 3 to 6 hours 164 2h

after administration of telithromycin 600mg.[63] 162
24h

Telithromycin concentration (mg/L or mg/kg)

• Telithromycin Cmax, Cmin (minimum plasma 160
concentrations) and AUC values in saliva were ap- 72
proximately 1.2- to 1.5-fold, 3- to 5-fold and 1.6- 70
to 1.7-fold higher, respectively, in saliva than in 68
plasma in 10 healthy volunteers who received 16
800mg once daily for 10 days.[54] 14
12
• In 8 healthy young volunteers, the mean Cmax of
10
telithromycin in cantharidin-induced skin blister
8
fluid was 0.44 mg/L 9 hours after a single oral dose
6
of 600mg. The blister fluid : plasma AUC0-24 ratio
was 1.38.[64] In white blood cells, telithromycin 4

concentrations were approximately 100-fold 2

higher than corresponding plasma concentrations 0

2 hours after administration of a 600mg oral dose,

os l

su ar

flu l

ag lar
uc hia

g lia
m

tis sill
ea

ph eo
a

id

es
in he
as

m nc
indicating good intracellular penetration.[65]

ro lv
lin pit
Pl

To

ac A
Br

E
• An in vitro study showed that telithromycin was

m
preferentially taken up by polymorphonuclear neu-
trophils, in which it was concentrated up to 300-
Fig. 1. Penetration of telithromycin into respiratory tissues and
fold, rather than by other cell types such as periph- fluids. Concentrations of telithromycin at 3 and 24 hours after the
eral blood mononuclear cells and cell lines of fourth dose in tonsillar tissue,
[59]
and at 2 and 24 hours after the
haematopoietic and nonhaematopoietic origin. last dose in bronchial mucosa, epithelial lining fluid and alveolar
The drug was concentrated mainly within azuro- macrophages
[62]
in patients undergoing tonsillectomy (n = 20)
[59]
[62]
phil granules, suggesting that telithromycin will be or routine fibreoptic bronchoscopy (n = 19) after receiving once
effectively delivered to phagocytosed intracellular daily oral telithromycin 800mg for 5 days. Telithromycin plasma
[62]
bacteria within these cells.[66] concentrations reported by Andrews et al. are also included.
a Tonsillectomy was performed at 3, 12 or 24 hours after the fourth
dose; data are presented for the 3- and 24-hour timepoints.
Metabolism and Elimination

• Telithromycin circulates mainly (57%) in un-

changed form in the plasma. Four major meta-
bolites of telithromycin have been identified in faeces, 13% excreted unchanged in urine and 37%
humans: an alcohol, an acid, an N-desmethyl- metabolised by the liver.[68]
desosamine and an N-oxide pyridine derivative.[67]
• At steady state, the terminal elimination half- Influence of Age, Gender and Disease
life (t1⁄2z) of telithromycin in healthy volunteers on Pharmacokinetics
was 9.81 hours.[55] Renal clearance was 12.5
L/h.[55]
• Administration of telithromycin as a single
• On average, 70% of the telithromycin dose is 800mg or repeated 800mg once daily dose (for 10
metabolised (33% presystemic and 37% sys- days) to elderly patients (mean age 73.6 years) pro-
temic).[68] Among the cytochrome P450 (CYP) duced Cmax and AUC0-24 values of 3.0 or 3.6 mg/L
isoenzymes, CYP3A4 is the main enzyme in- and 11.56 or 17.17 mg/L • h, respectively. The tmax
volved in the metabolism of telithromycin.[68] in this age group was <1 hour.[69] Concentrations
• The absorbed telithromycin is eliminated via achieved in the elderly are somewhat higher than
various pathways with 7% excreted unchanged in those observed in young volunteers.

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

822 Barman Balfour & Figgitt

• Renal clearance in elderly patients (7 to 8 L/h) domised, double-blind and multicentre and all
was lower than the range reported for younger age studies were published as posters and/or abstracts.
groups and t1⁄2z was 14.23 hours after repeated ad- Clinical cure was defined as a return to the pre-
ministration, but the accumulation ratio after re- treatment state or improvement/post-infectious
peated doses (1.45) was similar to that in younger stigmata. For the purposes of this review, clinical
individuals. Gender did not affect the pharmacoki- success rates cited are those at the test-of-cure
netics of telithromycin.[69] (TOC) visit (days 17 to 21) for the per-protocol
• The pharmacokinetics of telithromycin in 12 pa- population. In contrast to other recent studies of
tients with moderate to severe hepatic impairment antimicrobial efficacy, in which TOC was mea-
(mean Child Pugh score of 9.2, range from 5 to 12) sured at the end of therapy,[72-74] the TOC visit at
were moderately modified as compared with 12 17 to 21 days after treatment initiation allowed cap-
control healthy volunteers, after administration of ture of early cases of relapse, thus representing a
a single 800mg dose. Although Cmax tended to be rigorous test of efficacy in line with US Food and
20% lower in patients with hepatic impairment, Drug Administration (FDA) guidelines. Satisfac-
AUC values were similar between patients and tory bacteriological outcome was defined as erad-
healthy controls. There was no correlation between ication or presumed eradication of the baseline
any of the pharmacokinetic parameters and the
pathogen, or was not defined.
Child Pugh score.[70]
• The elimination of telithromycin in patients Community-Acquired Pneumonia
with hepatic impairment tended to be reduced, with
a 1.4-fold higher terminal elimination half-life
compared with healthy individuals. However, this The efficacy of telithromycin has been evalu-
is not expected to contribute to further accumula- ated in a total of 1373 patients with CAP in 6 inter-
tion on multiple administration. The observed national, multicentre clinical trials: 3 uncontrolled
modest increase in half-lives is a consequence of and 3 randomised, double-blind, comparative stud-
decreased metabolic clearance of telithromycin in ies.
patients with hepatic impairment, which is par- • A 7-day or 7- to 10-day course of telithromycin
tially compensated for by a higher rate of renal was an effective treatment for patients with CAP
clearance (50% increase, p < 0.05).[70] (clinical cure rate 93 to 94%)[75-77] and was as ef-
• The pharmacokinetic parameters of telithro- fective as a 7- to 10-day regimen of trovafloxacin
mycin have also been assessed in 240 patients with 200mg once daily [telithromycin 90% vs trova-
CAP who participated in a phase III study. Mean floxacin 94%; 95% confidence interval (CI) –13.6,
Cmax, Cmin and AUC were 2.89 mg/L, 0.19 mg/L 5.2].[68] A 10-day course of telithromycin was as
and 13.9 mg/L • h, respectively, in 220 evaluable effective as a 10-day regimen of amoxicillin
patients treated with telithromycin.[7] Analysis of 1000mg 3 times daily [telithromycin 95% vs am-
pharmacokinetic data from 1590 patients with oxicillin 90% (95% CI –2.1, 11.1); fig. 2a][78] or
RTIs revealed no significant differences on ac- clarithromycin 500mg twice daily [telithromycin
count of sex, age, body size, renal function, smok- 88% vs clarithromycin 89% (95% CI –7.8, 7.5);
ing status or infection severity.[71] fig. 2b].[79] Clinical cure rates by pathogen across
the 6 CAP studies were 95% (165/174) for S. pneu-
moniae, 90% (95/105) for H. influenzae, 87%
3. Therapeutic Trials
(26/30) for M. catarrhalis and 94 to 100% for
Telithromycin 800mg once daily has been eval- atypical/intracellular pathogens in telithromycin-
uated in the treatment of RTIs, including CAP, treated patients.[68]
acute exacerbations of chronic bronchitis (AECB), • Telithromycin also demonstrated high efficacy
acute maxillary sinusitis (AMS) and pharyngi- in patients with CAP caused by penicillin- or mac-
tis/tonsillitis. All comparative studies were ran- rolide-resistant S. pneumoniae. 92% (11/12) of pa-

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

Telithromycin: New Drug Profile 823

tients who had single-pathogen S. pneumoniae a Telithromycin

with reduced susceptibility to penicillin (MIC ≥ 100 Amoxicillin
0.1 mg/L) and 88% (15/17) with erythromycin-re-
80
sistant (MIC ≥ 1 mg/L) infections achieved clinical
cure with telithromycin.[68] 60
• The efficacy of telithromycin in the treatment
40
of CAP extends to the most vulnerable patients in
the community. Analysis of data from 4 clinical 20

Rate (% of patients)
studies showed that 90% (27/30) of patients with
0
bacteraemia associated with CAP were success-
fully treated with telithromycin at the standard oral b Telithromycin
dosage of 800mg once daily for 7 to 10 days. 100 Clarithromycin

Among those with pneumococcal bacteraemia,

80
88.5% (23/26) were clinical successes.[80] In el-
derly patients (aged ≥65 years) with CAP, the clin- 60
ical cure rate was 90% (139/154).[81]
40
• A further analysis showed that among patients
with CAP caused by atypical respiratory patho- 20
gens, 93% with C. pneumoniae (28/30), 96% with
0
M. pneumoniae (27/28) and 100% with L. pneu- Clinical cure Satisfactory
mophila (4/4) were clinical successes after teli- bacteriological
outcome
thromycin treatment (n = 4 clinical trials).[82]

Acute Exacerbations of Chronic Bronchitis

Fig. 2. Clinical and bacteriological outcomes achieved with
telithromycin in the treatment of patients with community-acquired
• A 5-day regimen of telithromycin was as effec- pneumonia (CAP). Patients with CAP received (a) a 10-day course
tive as a 10-day regimen of cefuroxime axetil of telithromycin 800mg once daily (n = 149) or amoxicillin 1000mg
[78]
3 times daily (n = 152) or (b) a 10-day course of telithromycin
500mg twice daily in treating AECB: 86% (121/
800mg once daily (n = 162) or clarithromycin 500mg twice daily (n
140) versus 83% (118/142) of patients achieved = 156).
[79]
Clinical cure was defined as a return to the pretreatment
clinical cure (95% CI –5.8, 12.4).[68] Satisfactory state or improvement/post-infectious stigmata; satisfactory bacte-
bacteriological outcome was observed in 76% riological outcome was defined as eradication or presumed erad-
(19/25) and 79% (22/28) of patients, respec- ication of the causative organism. Outcomes reported are those
at the post-therapy visit (days 17 to 21) in the per-protocol popu-
tively.[83]
lation.
• A 5-day regimen of telithromycin was also as
effective as a 10-day regimen of amoxicillin/
clavulanic acid 500/125mg 3 times daily in treating
AECB in patients with chronic obstructive pulmo- Acute Maxillary Sinusitis
nary disease. 86% (99/115) versus 82% (92/112)
[95% CI –6.4, 14.3] of patients were clinical suc- • A 5-day course of telithromycin was as effective
cesses and a satisfactory bacteriological outcome as a 10-day course in treating adults with AMS.
was achieved in 69% (27/39) versus 70% (21/30) Clinical cure was achieved in 91% of patients
of patients (76 versus 81% of pathogens were erad- [112/123 and 121/133, respectively (95% CI –7.7,
icated).[84] 7.9)] in both treatment groups and a satisfactory

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

824 Barman Balfour & Figgitt

bacteriological outcome was achieved in 93% across the phase III clinical programme. Amongst
(65/70) versus 90% (62/69) of patients.[85] telithromycin-treated patients, eradication and
• These 2 telithromycin regimens were as effec- clinical cure rates for resistant isolates of S. pneu-
tive as a 10-day regimen of amoxicillin/clavulanic moniae were both 53/57 (93%). Corresponding
acid 500/125mg 3 times daily in patients with values for the comparator-treated patients were
AMS. Clinical cure rates were almost identical in 7/10 (70%; clinical cure) and 8/10 (80%; eradica-
the 3 treatment groups [73 to 75%; n = 423 evalu- tion).[88]
able patients (95% CI –9.9, 11.7 for 5-day
telithromycin vs 10-day amoxicillin/clavulanic
acid)].[68] 4. Tolerability

• Most adverse events in patients receiving teli-

Pharyngitis/Tonsillitis
thromycin 800mg once daily for up to 10 days were
• In adults and adolescents with pharyngitis/ton- mild to moderate in intensity and treatment dis-
sillitis caused by group A β-haemolytic strepto- continuation because of treatment-related adverse
cocci (GAS), a 5-day regimen of telithromycin was events was uncommon (4%). In 8 comparator-
as effective as a 10-day regimen of clarithromycin controlled studies, the incidence and profile of ad-
250mg twice daily. Clinical success was achieved verse events was similar for telithromycin and
in 93 versus 91% of patients (95% CI –5.5, 8.6) and comparators.[68,78,79,86,87,89]
a satisfactory bacteriological outcome in 91% • The most frequent treatment-related events re-
(137/150) versus 88% (119/135) of patients (95% ported by telithromycin-treated patients (n = 2045)
CI –4.5, 11.0).[86]
in 9 controlled phase III studies were diarrhoea
• In adults with pharyngitis/tonsillitis caused by (13.3%), nausea (8.1%), dizziness (3.6%) and
GAS, a 5-day regimen of telithromycin was as ef- vomiting (2.8%).[68] The overall incidence of diar-
fective as a 10-day regimen of phenoxymethyl- rhoea was slightly higher in the telithromycin
penicillin 500mg 3 times daily, each regimen group than for pooled comparators (13.3 vs 9.4%),
achieving clinical cure in >94% of patients. A sat-
although within the range observed for individual
isfactory bacteriological outcome was achieved in
comparators [7.3% (clarithromycin) to 18%
84% (97/115) versus 89% (106/119) of patients
(95% CI –14.2, 4.8) and >85% of pretreatment (amoxicillin/clavulanic acid)]. Furthermore, the
pathogens were eradicated in each group.[87] majority of cases of diarrhoea were mild (69%) or
moderate (25%) in severity and resulting treatment
Pooled Eradication Rates discontinuations (0.9% of all telithromycin-treated
patients) were similar to pooled comparators
• Analysis of eradication rates of typical respira- (0.8%) and lower than for amoxicillin/clavulanic
tory pathogens from 10 clinical trials showed that acid (2.4%).[90]
105/111 S. pneumoniae (95%), 65/82 H. influenzae • In double-blind, comparative studies, there was
(79%), 24/26 M. catarrhalis (92%), 218/247 S.
no significant difference in QT effects for teli-
pyogenes (88%), 12/14 H. parainfluenzae (86%)
thromycin versus clarithromycin or non-macrolide
and 12/12 S. aureus (100%) infections were eradi-
cated after telithromycin treatment.[4] comparators, and no increase in the incidence of
cardiovascular adverse events.[68]
• Clinical cure and bacteriological eradication
rates were similar amongst patients with infections • Consistent with this observation, single (800 to
caused by penicillin- (MIC ≥2 mg/L) and/or mac- 2400mg) or repeated once daily (800mg) doses of
rolide-resistant (MIC ≥1.0 mg/L) S. pneumoniae telithromycin did not have any effect on the QT
(as sole pathogen or part of a mixed infection) to interval in healthy volunteers (n = 34) in a double-
the overall rates for all S. pneumoniae infections blind, placebo-controlled, crossover study.[91]

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

Telithromycin: New Drug Profile 825

5. Drug Interactions formulation of telithromycin are also in develop-

ment. The convenience of the short, once daily
• Although it is a competitive inhibitor of CYP3A4, dosage regimen (5 days for AECB, AMS and
telithromycin did not form inhibitory complexes pharyngitis/tonsillitis, and 7 to 10 days for CAP)
with CYP in hepatic microsomes in vitro since it and its activity against resistant pathogens (partic-
is metabolised partially by this isoenzyme.[92] ularly penicillin- and/or macrolide-resistant pneu-
Ketoconazole and itraconazole (strong CYP3A4 mococci) make it a promising new empirical ther-
inhibitors) have been shown to increase teli- apy for community-acquired RTIs.
thromycin AUC by 2 and 1.5 times, respec-
tively.[93]
References
• As with macrolides, concomitant administra-
1. Bryskier A. New research in macrolides and ketolides since
tion of telithromycin with drugs that are metabo- 1997. Expert Opin Invest Drug 1999; 8 (8): 1171-94
lised by CYP3A4 results in increased plasma con- 2. Champney WS, Tober CL. Inhibition of translation and 50S
centrations of the latter, including cisapride, ribosomal subunit formation in Staphylococcus aureus cells
by 11 different ketolide antibiotics. Curr Microbiol 1998; 37
simvastatin and midazolam.[93] (6): 418-25
• Coadministration of telithromycin with the 3. Douthwaite S, Hansen LH, Mauvais P. Macrolide-ketolide in-
hibition of MLS-resistant ribosomes is improved by alterna-
CYP2D6 inhibitor paroxetine had no significant tive drug interaction with domain II of 23S rRNA. Mol
effect on the pharmacokinetic parameters of Microbiol 2000; 36 (1): 183-93
paroxetine.[94] 4. Leroy B, Rangaraju M. High in vitro susceptibility of the ketol-
ide telithromycin (HMR 3647) in clinical isolates of key re-
• Telithromycin 800mg once daily for 7 days did spiratory pathogens [abstract no. 2224]. 40th Interscience
not affect the pharmacokinetics or pharmacody- Conference on Antimicrobial Agents and Chemotherapy;
2000 Sep 17-20; Toronto
namic action of warfarin 25mg when the 2 drugs 5. Davies TA, Kelly LM, Jacobs MR, et al. Antipneumococcal
were given concurrently to 24 healthy volun- activity of telithromycin by agar dilution, microdilution, E-
teers.[95] test, and disk diffusion methodologies. J Clin Microbiol 2000;
38: 1444-8
• Similarly, telithromycin (800mg once daily on 6. Barry AL, Fuchs PC, Brown SD. Tentative interpretive criteria
for HMR 3647 disk diffusion susceptibility tests [abstract no.
days 3 to 12 of the menstrual cycle) did not com- 1.01]. 4th International Congress on the Macrolides,
promise the efficacy of low dose triphasic contra- Azalides, Streptogramins and Ketolides; 1998 Jan 21-23;
ceptives containing ethinylestradiol/levonorgestrel Barcelona
7. Drusano GL, Preston SL, Decosta P, et al. Pharmacokinetics
in preventing ovulation in 38 women of child- (PK) and pharmacodynamics (PD) of telithromycin in the
bearing potential. The pharmacokinetics of ethinyl- treatment of community-acquired pneumonia (CAP) [ab-
estradiol were not affected by concurrent telithro- stract no. 1388]. 40th Interscience Conference on Antimicro-
bial Agents and Chemotherapy; 2000 Sep 17-20; Toronto, 28
mycin administration. Although plasma concen- 8. Pankuch GA, Visalli MA, Jacobs MR, et al. Susceptibilities of
trations of levonorgestrel increased, this was not penicillin- and erythromycin-susceptible and -resistant pneu-
considered likely to affect contraceptive efficacy.[96] mococci to HMR 3647 (RU 66647), a new ketolide, com-
pared with susceptibilities to 17 other agents. Antimicrob
• Coadministration of the gastric pH altering Agents Chemother 1998 Mar; 42: 624-30
agents ranitidine or aluminium hydroxide/magne- 9. Morosini MI, Cantón R, Loza E, et al. Distribution of erythro-
mycin A resistance determinants in Spanish Streptococcus
sium hydroxide had no effect on the bioavailability pneumoniae isolates and comparative activity of telithro-
of telithromycin.[97] mycin (HMR 3647) [abstract no. 2157]. 40th Interscience
Conference on Antimicrobial Agents and Chemotherapy;
2000 Sep 17-20; Toronto
6. Telithromycin: Current Status 10. Barry AL, Fuchs PC, Brown SD. Antipneumococcal activities
of a ketolide (HMR 3647), a streptogramin (quinupristin-
dalfopristin), a macrolide (erythromycin), and a lincosamide
Telithromycin, the first member of a new MLSB (clindamycin). Antimicrob Agents Chemother 1998 Apr; 42:
antimicrobial family called ketolides, is currently 945-6
awaiting registration in the US and Europe for the 11. Barry AL, Fuchs PC, Brown SD. In vitro activities of the ketol-
ide HMR 3647 against recent gram-positive clinical isolates
treatment of CAP, AECB, AMS and pharyngitis/ and Haemophilus influenzae. Antimicrob Agents Chemother
tonsillitis. An adult intravenous and a paediatric 1998 Aug; 42: 2138-40

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

826 Barman Balfour & Figgitt

12. Hoban DJ, Zhanel GG, Karlowsky JA. In vitro activity of the influenzae, Moraxella catarrhalis and β-haemolytic strepto-
novel ketolide HMR 3647 and comparative oral antibiotics cocci. J Antimicrob Chemother 1999 Oct; 44: 445-53
against Canadian respiratory tract isolates of Streptococcus 25. Biedenbach DJ, Barrett MS, Jones RN. Comparative antimicro-
pneumoniae, Haemophilus influenzae, and Moraxella bial activity and kill-curve investigations of novel ketolide
catarrhalis. Diagn Microbiol Infect Dis 1999 Sep; 35: 37-44 antimicrobial agents (HMR 3004 and HMR 3647) tested
13. Agouridas C, Bonnefoy A, Chantot JF. In vitro antibacterial against Haemophilus influenzae and Moraxella catarrhalis
activity of HMR 3647, a novel ketolide highly active against strains. Diagn Microbiol Infect Dis 1998 Jun; 31: 349-53
respiratory pathogens [abstract no. 1.11]. 4th International 26. Bebear CM, Renaudin H, Bryskier A, et al. Comparative activ-
Conference on the Macrolides, Azalides, Streptogramins and ities of telithromycin (HMR 3647), levofloxacin, and other
Ketolides; 1998 Jan 21-23; Barcelona antimicrobial agents against human mycoplasmas. Anti-
14. Felmingham D, Harding I. Telithromycin is highly active microb Agents Chemother 2000; 44: 1980-2
against clinical isolates of Streptococcus pneumoniae col- 27. Yamaguchi T, Hirakata Y, Izumikawa K, et al. In vitro activity
lected in the PROTEKT study, irrespective of penicillin, mac- of telithromycin (HMR3647), a new ketolide, against clinical
rolide or fluoroquinolone resistance [abstract no. P1253]. isolates of Mycoplasma pneumoniae in Japan. Antimicrob
11th European Congress on Clinical Microbiology and Infec- Agents Chemother 2000 May; 44: 1381-2
tious Diseases; 2001 Apr 1-4; Istanbul. Clin Microbiol Infect 28. Roblin PM, Hammerschlag MR. In vitro activity of a new ketol-
2001; 7 Suppl. 1: 263 ide antibiotic, HMR 3647, against Chlamydia pneumoniae.
15. Mittermayer H, Jebelean C, Bocksrucker A, et al. Activity of Antimicrob Agents Chemother 1998 Jun; 42: 1515-6
telithromycin (HMR 3647) against erythromycin-susceptible 29. Schülin T, Wennersten CB, Ferraro MJ, et al. Susceptibilities
and -resistant isolates of Streptococcus pneumoniae and of Legionella spp. to newer antimicrobials in vitro. Anti-
Streptococcus pyogenes from Austria [abstract no. 2145]. microb Agents Chemother 1998 Jun; 42: 1520-3
40th Interscience Conference on Antimicrobial Agents and 30. Edelstein PH, Edelstein MA. In vitro activity of the ketolide
Chemotherapy; 2000 Sep 17-20; Toronto
HMR 3647 (RU 6647) for Legionella spp., its pharmacoki-
16. Appelbaum PC, Kelly LM, Hryniewicz W, et al. Activity of netics in guinea pigs, and use of the drug to treat guinea pigs
telithromycin (HMR 3647) against 599 S. pyogenes from ten
with Legionella pneumophila pneumonia. Antimicrob Agents
central and eastern European countries [abstract no. 2153].
Chemother 1999 Jan; 43: 90-5
40th Interscience Conference on Antimicrobial Agents and
31. Rastogi N, Goh KS, Berchel M, et al. In vitro activities of the
Chemotherapy; 2000 Sep 17-20; Toronto
ketolides telithromycin (HMR 3647) and HMR 3004 com-
17. Morrissey I, Trezise E, Tsa N, et al. The comparative in vitro
pared to those of clarithromycin against slowly growing
activity of telithromycin (HMR 3647) against isolates of
mycobacteria at pHs 6.8 and 7.4. Antimicrob Agents Chem-
Streptococcus pyogenes (Lancefield Serogroup A) circulating
in Great Britain, Northern Ireland and the Republic of Ireland other 2000; 44 (10): 2848-52
during late 1999 [abstract no. 2149]. 40th Interscience Con- 32. Fuchs PC, Barry AL, Brown SD. Influence of variations in test
ference on Antimicrobial Agents and Chemotherapy; 2000 methods on susceptibility of Haemophilus influenzae to am-
Sep 17-20; Toronto picillin, azithromycin, clarithromycin, and telithromycin. J
18. Nagai K, Davies TA, Appelbaum PC, et al. Mechanism of mac- Clin Microbiol 2001; 39 (1): 43-6
rolide resistance in Streptococcus pneumoniae and Strepto- 33. Soussy CJ, Goldstein F, Bryskier A, et al. Telithromycin (TEL):
coccus pyogenes from central and eastern European countries assessment of susceptibility testing [abstract no. 321]. 40th
[abstract no. 0138]. 40th Interscience Conference on Antimi- Interscience Conference on Antimicrobial Agents and Che-
crobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto motherapy; 2000 Sep 17-20
19. Boswell FJ, Andrews JM, Ashby JP, et al. The in-vitro activity 34. Zinner SH, Gilbert D, Simmons K, et al. HMR 3647 activity
of HMR 3647, a new ketolide antimicrobial agent. J Anti- against penicillin- and erythromycin-sensitive and -resistant
microb Chemother 1998 Dec; 42: 703-9 Streptococcus pneumoniae in a two-compartment in vitro dy-
20. Jones RN, Biedenbach DJ. Antimicrobial activity of RU-66647, namic model that mimics human pharmacokinetics [abstract
a new ketolide. Diagn Microbiol Infect Dis 1997 Jan-Feb; 27: no. M 302]. Antiinfect Drugs Chemother 1998; 16 Suppl. 1:
7-12 51
21. Felmingham D, Robbins MJ, Leakey A, et al. The comparative 35. Odenholt I, Löwdin E, Cars O. Pharmacodynamics of telithro-
in vitro activity of HMR 3647, a ketolide antimicrobial, mycin in vitro against respiratory tract pathogens. Antimicrob
against clinical bacterial isolates [abstract no. F-116 and Agents Chemother 2001; 45 (1): 23-9
poster]. 37th Interscience Conference on Antimicrobial 36. Pankuch GA, Hoellman DB, Lin G, et al. Activity of HMR 3647
Agents and Chemotherapy; 1997 Sep 28 - Oct 1; Toronto, 166 compared to those of five agents against Haemophilus in-
22. Schmitz F-J, Sadurski R, Kray A, et al. Prevalence of macro- fluenzae and Moraxella catarrhalis by MIC determination
lide-resistance genes in Staphylococcus aureus and Entero- and time-kill assay. Antimicrob Agents Chemother 1998
coccus faecium isolates from 24 European university Nov; 42: 3032-4
hospitals. J Antimicrob Chemother 2000; 45 (6): 891-4 37. Felmingham D, Clark S, Robbins MJ, et al. In vitro bactericidal
23. Kitzis MD, Goldstein FW, Bismuth R, et al. Comparative in activity of HMR 3647 against respiratory tract pathogens [ab-
vitro activity of HMR 3647, a new ketolide antibiotic, against stract E-133]. 38th Interscience Conference on Antimicrobial
S. aureus (SA) and coagulase negative staphylococci (CNS) Agents and Chemotherapy; 1998 Sep 24-27; San Diego, 207
[abstract no. F-111 and poster]. 37th Interscience Conference 38. Boswell FJ, Andrews JM, Wise R. Pharmacodynamic proper-
on Antimicrobial Agents and Chemotherapy; 1997 Sep 28- ties of HMR 3647, a novel ketolide, on respiratory pathogens,
Oct 1; Toronto, 165 enterococci and Bacteroides fragilis demonstrated by studies
24. Wootton M, Bowker KE, Janowska A, et al. In-vitro activity of of time-kill kinetics and postantibiotic effect. J Antimicrob
HMR 3647 against Streptococcus pneumoniae, Haemophilus Chemother 1998 Feb; 41: 149-53

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

Telithromycin: New Drug Profile 827

39. Gustafsson I, Hjelm E, Cars O. In vitro pharmacodynamics of pneumoniae. Antimicrob Agents Chemother 2000 Feb; 44:
the new ketolides HMR 3004 and HMR 3647 (telithromycin) 414-7
against Chlamydia pneumoniae. Antimicrob Agents Chemo- 54. Edlund C, Alván G, Barkholt L, et al. Pharmacokinetics and
ther 2000; 44: 1846-9 comparative effects of telithromycin (HMR 3647) and clar-
40. Baltch AL, Smith RP, Ritz WJ, et al. Antibacterial effect of ithromycin on the oropharyngeal and intestinal microflora. J
telithromycin (HMR 3647) and comparative antibiotics Antimicrob Chemother 2000; 46: 741-9
against intracellular Legionella pneumophila. J Antimicrob 55. Namour F, Wessels DH, Pascual MH, et al. Pharmacokinetics
Chemother 2000; 46: 51-5 of the new ketolide telithromycin (HMR 3647) administered
41. Munckhof WJ, Borlace G, Turnidge J. Postantibiotic suppres- in ascending single and multiple doses. Antimicrob Agents
sion of growth of erythromycin A-susceptible and -resistant Chemother 2001; 45 (1): 170-5
gram-positive bacteria by the ketolides telithromycin (HMR 56. Lenfant B, Sultan E, Wable C, et al. Pharmacokinetics of 800-
3647) and HMR 3004. Antimicrob Agents Chemother 2000; mg once-daily oral dosing of the ketolide, HMR 3647, in
44: 1749-53 healthy young volunteers [abstract no. A-49]. 38th Intersci-
42. Piper KE, Rouse MS, Steckelberg JM, et al. Ketolide treatment ence Conference on Antimicrobial Agents and Chemother-
of Haemophilus influenzae experimental pneumonia. Anti- apy; 1998 Sep 24-27; San Diego, 16
microb Agents Chemother 1999 Mar; 43: 708-10 57. Perret C, Wessels DH. Oral bioavailability of the ketolide
43. Rajagopalan-Levasseur P, Vallee E, Agouridas C, et al. HMR telithromycin (HMR 3647) is similar in both elderly and
3647: activity against erythromycin-resistant pneumococci young subjects [abstract no. MoP250]. Clinical Microbiology
and Haemophilus influenzae in murine pneumonia models and Infection 2000 May; 6 Suppl. 1: 203-4
[abstract no. F-260]. 37th Interscience Conference on Anti- 58. Lenfant B, Perret C, Pascual M-H. The bioavailability of HMR
microbial Agents and Chemotherapy; 1997 Sep 28-Oct 1; 3647, a new once-daily ketolide antimicrobial, is unaffected
Toronto, 190 by food [abstract no. P69]. J Antimicrob Chemother 1999; 44
44. Piroth L, Desbiolles N, Mateo-Ponce V, et al. HMR 3647 hu- Suppl. A: 55
man-like treatment of experimental pneumonia due to peni- 59. Gehanno P, Passot V, Nabet P, et al. Telithromycin (HMR
cillin-resistant and erythromycin-resistant Streptococcus 3647) penetrates rapidly into tonsillar tissue achieving high
pneumoniae. J Antimicrob Chemother 2001; 47: 33-42 and prolonged tonsillar concentrations. Clinical Microbiol-
ogy and Infection 2000; 6 Suppl. 1: 204
45. Agouridas C, Bonnefoy A, Chantot JF. In vivo antibacterial
activity of HMR 3647, a novel ketolide highly active against 60. Muller-Serieys C, Cantalloube C, Soler P, et al. HMR 3647
achieves high and sustained concentrations in broncho-pul-
respiratory pathogens [abstract F-257]. 4th International Con-
monary tissues [abstract no. P78]. J Antimicrob Chemother
gress on the Macrolides, Azalides, Streptogramins and
1999; 44 Suppl. A: 57
Ketolides; 1998 Jan 21-23; Barcelona, 189
61. Kadota J, Ishimatsu Y, Iwashita T, et al. The ketolide antimi-
46. Rajagopalan-Levasseur P, Vallee E, Bonnefoy A, et al. HMR
crobial, telithromycin (HMR 3647) achieves high and sus-
3647: activity against Legionella pneumophila serogroup 1
tained concentration in alveolar macrophages and
(Lp1) in monocyte-derived macrophages and in experimental
bronchoalveolar epithelial lining fluid in healthy Japanese
guinea pig infection models [abstract no. B-47]. 38th Inter-
volunteers [abstract no. 2143]. 40th Interscience Conference
science Conference on Antimicrobial Agents and Chemother- on Antimicrobial Agents and Chemotherapy; 2000 Sep 17-
apy; 1998 Sep 24-27; San Diego, 58 20; Toronto: 32
47. Vesga O, Bonnat C, Craig WA. In vivo pharmacodynamic ac- 62. Andrews J, Honeybourne D, Khair O, et al. Penetration of
tivity of HMR 3647, a new ketolide [abstract no. F-255]. 37th telithromycin (HMR 3647) into bronchial mucosa (BM), ep-
Interscience Conference on Antimicrobial Agents and Che- ithelial lining fluid (ELF) and alveolar macrophages (AM)
motherapy; 1997 Sep 28-Oct 1; Toronto, 189 following multiple oral doses [abstract no. 658]. 40th Inter-
48. Craig WA, Andes DR. Differences in the in vivo pharmacody- science Conference on Antimicrobial Agents and Chemother-
namics of telithromycin and azithromycin against Streptococ- apy; 2000 Sep 17-20; Toronto
cus pneumoniae [abstract no. 2141]. 40th Interscience 63. Miyamoto N, Murakami S, Yajin K, et al. Pharmacokinetic
Conference on Antimicrobial Agents and Chemotherapy; study of a new ketolide antimicrobial telithromycin (HMR
2000 Sep 17-20; Toronto, 32 3647) in otorhinolaryngology [abstract no. 2144]. 40th Inter-
49. Chu DTW. Recent developments in macrolides and ketolides. science Conference on Antimicrobial Agents and Chemother-
Current Opinion in Microbiology 1999; 2 (5): 467-74 apy; 2000 Sep 17-20; Toronto
50. Bonnefoy A, Girard AM, Agouridas C, et al. Ketolides lack 64. Sultan E, Namour F, Pascual MH, et al. Penetration of the ketol-
inducibility properties of MLS resistance phenotype. J Anti-
B ide, HMR 3647, in cantharidin-induced blister fluid [abstract
microb Chemother 1997; 40: 85-90 no. A-47]. 38th Interscience Conference on Antimicrobial
51. Reinert RR, Bryskier A, Lütticken R. In vitro activities of the Agents and Chemotherapy; 1998 Sep 24-27; San Diego, 15
new ketolide antibiotics HMR 3004 and HMR 3647 against 65. Pham Gia H, Roeder V, Namour F, et al. HMR 3647 achieves
Streptococcus pneumoniae in Germany. Antimicrob Agents high and sustained concentrations in white blood cells in man
Chemother 1998 Jun; 42: 1509-11 [abstract no. P79]. J Antimicrob Chemother 1999; 44 Suppl.
52. Hamilton-Miller JM, Shah S. Comparative in-vitro activity of A: 57-8
ketolide HMR 3647 and four macrolides against gram-posi- 66. Miossec-Bartoli C, Pilatre L, Peyron P, et al. The new ketolide
tive cocci of known erythromycin susceptibility status. J HMR3647 accumulates in the azurophil granules of human
Antimicrob Chemother 1998 Jun; 41: 649-53 polymorphonuclear cells. Antimicrob Agents Chemother
53. Davies TA, Dewasse BE, Jacobs MR, et al. In vitro develop- 1999 Oct; 43: 2457-62
ment of resistance to telithromycin (HMR 3647), four mac- 67. Sultan E, Namour F, Mauriac C, et al. HMR 3647, a new ketol-
rolides, clindamycin, and pristinamycin in Streptococcus ide antimicrobial, is metabolised, and excreted mainly in fae-

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)

828 Barman Balfour & Figgitt

ces in man [abstract no. P63]. J Antimicrob Chemother 1999; 82. Leroy B, Rangaraju M. Efficacy of telithromycin (HMR 3647),
44 Suppl. A: 54 a new once-daily ketolide, in community-acquired pneumo-
68. Aventis Pharma. Data on file. Ketek™ (telithromycin). Briefing nia caused by atypical pathogens [abstract no. 2225]. 40th
document for the FDA Anti-infective Drug Products Advi- Interscience Conference on Antimicrobial Agents and Che-
sory Committee Meeting. Aventis Pharma, Bridgewater, New motherapy; 2000 Sep 17-20; Toronto
Jersey, US; Executive summary, 2001 March 83. Aventis Pharma. Data on file. Ketek™ (telithromycin). Briefing
69. Sultan E, Lenfant B, Wable C, et al. Pharmacokinetic profile of document for the FDA Anti-infective Drug Products Advi-
HMR 3647 800 mg once-daily in elderly volunteers [abstract sory Committee Meeting. Aventis Pharma, Bridgewater, New
no. P66]. J Antimicrob Chemother 1999; 44 Suppl. A: 54 Jersey, US; Section 6.4.2 Acute exacerbations of chronic
70. Sultan E, Cantalloube C, Patat A, et al. Telithromycin (HMR bronchitis, 2001 March: 94
3647), the first ketolide antimicrobial, does not require dosage 84. Aubier M, Aldons PM, Leak A, et al. Efficacy and tolerability
adjustment in individuals with hepatic impairment [abstract of a 5-day course of a new ketolide antimicrobial,
no. MoP249]. Clinical Microbiology and Infection 2000; 6 telithromycin (HMR 3647), for the treatment of acute exac-
Suppl. 1: 203 erbations of chronic bronchitis in patients with COPD [ab-
71. Pluim J. Population pharmacokinetics support the convenient stract no. 2241]. 40th Interscience Conference on Antimicrobial
once-daily 800 mg dosage of telithromycin in patients with Agents and Chemotherapy; 2000 Sep 17-20; Toronto
upper and lower RTIs, including special populations [abstract 85. Roos K, Brunswig-Pitschner C, Kostrica R, et al. Efficacy and
no. P1263]. 11th European Congress of Clinical Microbiol- tolerability of a 5-day course of a new ketolide antimicrobial,
ogy and Infectious Diseases; 2001 Apr 1-4; Istanbul. Clin telithromycin (HMR 3647), for the treatment of acute sinusitis
Microbiol Infect 2001; 7 Suppl. 1: 266 [abstract no. 2243]. 40th Interscience Conference on Antimi-
72. Trémolières F, de Kock F, Pluck N, et al. Trovafloxacin versus crobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto
high-dose amoxicillin (1 g three times daily) in the treatment 86. Quinn J, Ziter P, Leroy B, et al. Oral telithromycin (HMR 3647)
of community-acquired bacterial pneumonia. Eur J Clin 800 mg once daily for 5 days is well tolerated and as effective
Microbiol Infect Dis 1998; 17: 447-53 as oral clarithromycin 250 mg twice daily for 10 days in group
73. O’Doherty B, Dutchman DA, Pettit R, et al. Randomized, dou- A-hemolytic streptococcal (GABHS) pharyngitis/tonsillitis
ble-blind, comparative study of grepafloxacin and amoxycil- [abstract no. 2229]. 40th Interscience Conference on Antimi-
lin in the treatment of patients with community-acquired crobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto
pneumonia. J Antimicrob Chemother 1997; 40 Suppl. A: 73- 87. Norrby SR, Rabie W, Bacart P, et al. Efficacy of 5 days’
81 telithromycin (HMR 3647) vs 10 days’ penicillin V in the
74. Genné D, Siegrist HH, Humair L, et al. Clarithromycin versus treatment of pharyngitis in adults [abstract no. 2242]. 40th
amoxicillin-clavulanic acid in the treatment of community- Interscience Conference on Antimicrobial Agents and Che-
acquired pneumonia. Eur J Clin Microbiol Infect Dis 1997; motherapy; 2000 Sep 17-20; Toronto
16 (11): 783-8 88. Rangaraju M, Leroy B. Clinical and bactriological efficacy of
75. Carbon C, Moola S, Velancsics I, et al. Efficacy of telithromycin (HMR 3647) in the treatment of community-ac-
telithromycin (HMR 3647), a new once-daily antimicrobial, quired RTIs caused by S. pneumoniae with reduced suscepti-
in the treatment of community-acquired pneumonia [abstract bility to penicillins or macrolides [abstract no. P1261]. 11th
no. 2245]. 40th Interscience Conference on Antimicrobial European Congress of Clinical Microbiology and Infectious
Agents and Chemotherapy; 2000 Sep 17-20; Toronto Diseases; 2001 Apr 1-4; Istanbul. Clin Microbiol Infect 2001;
76. Aventis Pharma. Data on file. Aventis Pharma study synopsis 7 Suppl. 1: 265-6
A/3009 Open-label. 2000 May 89. Tellier G, Lasko B, Leroy B, et al. Oral telithromycin (HMR
77. Aventis Pharma. Data on file. Aventis Pharma study synopsis 3647) 800 mg once daily for 5 days and 10 days is well toler-
A/3010. 2001 Jan ated and as effective as amoxicillin/clavulanic acid 500/125
78. Hagberg L, Torres A, Van Rensburg DJ, et al. Efficacy and mg three-times daily for 10 days in acute maxillary sinusitis
tolerability of telithromycin (HMR 3647) vs high-dose am- (AMS) in adults [abstract no. 2226]. 40th Interscience Con-
oxicillin in the treatment of community-acquired pneumonia ference on Antimicrobial Agents and Chemotherapy; 2000
[abstract no. 2244]. 40th Interscience Conference on Antimi- Sep 17-20; Toronto
crobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto 90. Aventis Pharma. Data on file. Ketek™ (telithromycin). Briefing
79. Tellier G, Hassman J, Leroy B, et al. Oral telithromycin (HMR document for the FDA Anti-infective Drug Products Advi-
3647) 800 mg once daily is well tolerated and as effective as sory Committee Meeting. Aventis Pharma, Bridgewater, New
oral clarithromycin 500 mg twice daily in community-ac- Jersy, US; Section 7.2.4.1 Diarrhea, 2001 March: 121-4
quired pneumonia (CAP) in adults [abstract no. 2227]. 40th 91. Démolis JL, Cardus S, Vacheron F, et al. Effect of telithromycin
Interscience Conference on Antimicrobial Agents and Che- on ventricular repolarization in healthy subjects [abstract no.
motherapy; 2000 Sep 17-20; Toronto 651]. 7th World Conference on Clinical Pharmacology and
80. Leroy B, Rangaraju M. Efficacy of telithromycin (HMR 3647) Therapeutics IUPHAR - Division of Clinical Pharmacology,
in the treatment of bacteremia associated with community-ac- and 4th Congress of the European Association for Clinical
quired pneumonia [abstract no. 2223]. 40th Interscience Con- Pharmacology and Therapeutics (EACPT); 2000 Jul 15-20;
ference on Antimicrobial Agents and Chemotherapy; 2000 Florence, 168
Sep 17-20; Toronto 92. Labbe G, Flor M, Lenfant B. HMR 3647, a new ketolide anti-
81. Aventis Pharma. Data on file. Ketek™ (telithromycin). Briefing microbial, does not inhibit cytochrome P450 activity in vitro
document for the FDA Anti-infective Drug Products Advi- [abstract no. P95]. J Antimicrob Chemother 1999; 44 Suppl.
sory Committee Meeting. Aventis Pharma, Bridgewater, New A: 61
Jersey, US; Section 6.4.1 Community-acquired pneumonia, 93. Aventis Pharma. Data on file. Ketek™ (telithromycin). Briefing
2001 March: 90 document for the FDA Anti-infective Drug Products Advi-

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Telithromycin: New Drug Profile 829

sory Committee Meeting. Aventis Pharma, Bridgewater, Interscience Conference on Antimicrobial Agents and Chemo-
New Jersey, US; Section 5.5 Drug interactions, 2001 March: therapy; 1999 Sep 26-29; San Francisco, 3
59-62 97. Lippert C, Leese PT, Sultan E. Effect of gastric pH on the bio-
94. Lippert C, Leese PT, Sultan E. Telithromycin (HMR 3647) availability of telithromycin (HMR 3647) [abstract no.
does not interact with the CYP2D6 substrate paroxetine [ab- P1269]. 11th European Congress of Clinical Microbiology
stract no. P1268]. 11th European Congress of Clinical Micro- and Infectious Diseases; 2001 Apr 1-4; Istanbul. Clin
biology and Infectious Diseases; 2001 Apr 1-4; Istanbul. Clin Microbiol Infect 2001; 7 Suppl. 1: 267
Microbiol Infect 2001; 7 Suppl. 1: 267
95. Scholtz HE, Pretorius SG, Wessels DH, et al. HMR 3647, a new
ketolide antimicrobia, does not affect the pharmacodynamics
or pharmacokinetics of warfarin in healthy adult males [ab-
stract no. 81]. Clin Infect Dis 1999 Oct; 29 (4): 976 Correspondence: David P. Figgitt, Adis International Lim-
96. Scholtz HE, Sultan E, Wessels D, et al. HMR 3647, a new ited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
ketolide antimicrobial, does not affect the reliability of low- Auckland 10, New Zealand.
dose, triphasic oral contraceptives [abstract no. 10]. 39th E-mail: [email protected]

© Adis International Limited. All rights reserved. Drugs 2001; 61 (6)