Telithromycin, the first ketolide, has been developed by Aventis Pharmaceuticals for the treatment of respiratory tract infections (RTIs). The proposed indications for telithromycin are:

· Community-acquired pneumonia (CAP)

· Acute exacerbation of chronic bronchitis (AECB)

· Acute sinusitis (AS)

· Tonsillitis/Pharyngitis (T/P) due to Group A beta-hemolytic streptococcus (GABHS)

RTIs are among the most frequent infectious diseases encountered in outpatients and can lead to significant morbidity and, occasionally mortality, if inadequately treated. The key pathogens associated with these infections include common bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes, as well as atypical, Mycoplasma pneumoniae, and intracellular pathogens such as Legionella pneumophila and Chlamydia pneumoniae.

The choice of antimicrobial regimens for the indications listed above is complex because of the varied classes of pathogens and the emergence of resistance to many of the older agents. Beta-lactams, a cornerstone of outpatient RTI therapy, are inactive against beta-lactamase-producing strains of H. influenzae and M. catarrhalis; they have no activity against atypical pathogens and are increasingly threatened by the emergence of penicillin G resistance among S. pneumoniae. Fluoroquinolones have variable activity against S. pneumoniae, and their widespread use for common infections poses concerns about the long-term use of these drugs due to emergent resistance.

The recently recognized increase in the prevalence of erythromycin A resistance now threatens the utility of this class [36,83]. In 1999, 20.3% of S. pneumoniae strains tested were resistant to erythromycin A in the US according to the Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network [14]@@ CDC Report (www.cdc.gov/ncidod/dbmd/abcs ). While there has been some debate about the clinical importance of this rise in in vitro resistance [6,61], there are an increasing number of reports of adverse clinical outcomes in patients with erythromycin A-resistant S. pneumoniae who were treated with macrolides [13,35,45,48,52,79]. Because most of these macrolide-resistant S. pneumoniae are resistant to most beta-lactams, cotrimoxazole, and tetracyclines, there remain few options for oral therapy in patients infected with these strains.

General characteristics of telithromycin (see Section 3, Microbiology)

Telithromycin is the first in a new chemical class of antibacterial agents, the ketolides. It is derived from erythromycin A but has three structural features which result in a unique mechanism of action. It has a 3‑keto function that replaces the alpha L-cladinose, which was long thought to be essential for antibacterial activity, a C₁₁-C₁₂ carbamate, and an aryl alkyl side chain. Telithromycin binds to domain II of the 23S rRNA of the 50S ribosomal subunit and interferes with assembly of the 30S ribosomal subunit. Telithromycin also exhibits additional ribosomal activity associated with macrolides: binding to domain V of the 23S rRNA and disruption of assembly of the 50S ribosomal subunit. This novel mechanism of action results in excellent activity against macrolide-sensitive strains and maintains activity against macrolide-resistant strains of S. pneumoniae ([40], available in Appendix 1. Relevant references). Telithromycin has an antibacterial spectrum of activity that is well suited to the treatment of outpatient RTIs. It is active against the major organisms encountered in these infections, including S. pneumoniae (regardless of resistance phenotype), H. influenzae, M. catarrhalis, S. aureus, S. pyogenes, anaerobic bacteria, and atypical pathogens such as M. pneumoniae and intracellular pathogens such as L. pneumophila and C. pneumoniae.

In vitro activity (see Section 3, Microbiology)

Activity against S. pneumoniae is crucially important for a therapy for RTIs, both because of the prevalence of this pathogen and because this pathogen is more likely to be associated with comorbid sequelae than other respiratory pathogens.

Telithromycin is highly active in vitro against strains of S. pneumoniae sensitive to erythromycin A and penicillin G, as shown in the table below. Telithromycin retains activity against penicillin G-intermediate resistant isolates, penicillin G-resistant isolates (penicillin MIC >2 mg/mL), and erythromycin A isolates with MLS_B or efflux-type resistance as well as quinolone-resistant isolates.

Table ES-1. MIC values for telithromycin against S. pneumoniae strains

Strain of S. pneumoniae:	N	MIC₅₀ range	MIC₉₀ range
Penicillin G susceptible (Pen-S)	1495	0.004 – 0.06	0.004 – 0.06
Penicillin G intermediate (Pen-I)	365	0.01 – 0.03	0.01 – 0.06
Penicillin G resistant (Pen-R) ^a	867	0.004 – 0.12	0.007 – 2.0
Erythromycin A susceptible (Ery-S)	491	0.001 – 0.06	0.001 – 0.06
Erythromycin A resistant (Ery-R)	455	0.0001 – 0.06	0.01 – 2.0
Quinolone resistant (Quinolone-R) ^b	41	0.01 – 0.03	0.03 – 0.06

^a Includes macrolide-resistant strains.

^b Includes macrolide-susceptible and macrolide-resistant strains. Telithromycin activity is independent of
quinolone MIC values.

Therapy for community-acquired RTIs must be effective against all major pathogens, including common, atypical and intracellular pathogens, associated with these infections. The table below shows the high in vitro activity of telithromycin against the pathogens most frequently causative of these infections.

Table ES-2. MIC values for telithromycin against pathogens associated with
community-acquired RTIs

Pathogen	N	MIC₅₀ range (mg/mL)	MIC₉₀ range (mg/mL)
H. influenzae	2300	0.025 – 2.0	0.5 – 4.0
M. catarrhalis	1108	0.02 – 0.25	0.03 – 0.5
S. pyogenes	1145	£0.008 – 0.03	0.01 – 0.06
S. aureus^a	2263	0.06 – 0.12	0.12 – 0.25
C. pneumoniae^b	23	0.01 – 2.0	0.03 – 2.0
L. pneumophila	136	0.01 – 0.06	0.03 – 0.12
M. pneumoniae	90	0.001 – 0.005	0.001 – 0.005

^aFor S. aureus susceptible to erythromycin A or resistant to erythromycin A by an MLS_B inducible mechanism of resistance. When a constitutive MLS_B mechanism of resistance is harbored by a S. aureus strain, the telithromyci MIC is above 16 mg/mL.

^bC. pneumoniae: MIC(mg/mL) and MCC (mg/mL)

Clinical pharmacokinetics and dose determination (see Section 5, Clinical pharmacokinetics and dose determination)

After oral administration, absorption of telithromycin is almost complete (90%), and the absolute bioavailability is 57% in both young and elderly subjects. The rate and extent of absorption are not influenced by food. Mean maximum concentration (C_max) of telithromycin in plasma is 1.9 µg/mL after a single oral dose of 800 mg, and 2.27 µg/mL at steady state, attained after 2 to 3 days of oral dosing with 800 mg once daily. The pharmacokinetics of telithromycin were comparable in RTI patients (C_max 2.89 µg/mL). Telithromycin has a terminal half-life (after multiple dosing) of 9.8 hours. It is distributed extensively in human tissues. The C_max in pulmonary epithelial lining fluid of patients with RTIs was 14.9 µg/mL, and C_max in white blood cells of healthy subjects was 83 µg/mL, with a substantial concentration, 8.9 µg/mL, at 48 hours after dosing. Telithromycin is 60 to 70% bound to serum proteins.

After oral administration of an 800 mg radiolabeled dose, the main circulating compound is unchanged telithromycin (57% of radioactivity AUC). The main plasma metabolite (RU 76363) represents 13% of the dose, and three other metabolites each represent 3% or less. None of these metabolites contribute appreciably to the clinical antibacterial activity of telithromycin.

Prior to entering the systemic circulation, about 33% of the administered telithromycin is metabolized. The absorbed telithromycin is eliminated via multiple pathways, with 7% excreted unchanged in feces by biliary and/or intestinal secretion, 13% excreted unchanged in urine by renal excretion, and 37% metabolized by the liver.

The overall metabolism of telithromycin accounts for 70% of the dose (33% presystemic, 37% systemic), and is mediated by CYP3A4- and non-CYP3A4-mediated pathways to approximately equal degrees. The multiplicity of elimination pathways for telithromycin suggests that significant impairment of a single pathway is unlikely to have a clinically relevant effect on systemic exposure to telithromycin because of the availability of compensatory pathways. This principle has been verified for a number of populations of special interest.

The observed pharmacokinetic profile in elderly patients with RTIs, in subjects with hepatic impairment, and in subjects with renal impairment was not substantially different from that of young and/or healthy subjects, as was anticipated (exposure did not exceed 2-fold in any of these populations).

Phase I studies have shown that the risk of increased telithromycin exposure due to inhibition of CYP3A4 is minimal. A potent inhibitor such as ketoconazole results in only a 1.5-fold increase in the C_max of telithromycin in plasma, and a 2-fold increase in AUC.

Telithromycin, like clarithromycin, has been shown to increase the plasma concentrations of drugs metabolized by CYP3A4, such as cisapride, simvastatin, and midazolam. Caution is therefore advised, as with macrolides, if telithromycin is administered concomitantly with CYP3A4 substrates that have a narrow therapeutic margin. As with clarithromycin, use of telithromycin with cisapride or pimozide is contraindicated. There were no clinically relevant interactions between telithromycin and theophylline or warfarin.

The mouse thigh infection model with S. pneumoniae (Craig) was used as a pharmacokinetic/ pharmacodynamic model to support selection of the telithromycin dosing regimen. Over 24 hours, the effective dose of telithromycin is independent of the dosing frequency, and the efficacy is concentration-dependent rather than time-dependent. The key parameters determining efficacy are the AUC/MIC and C_max/MIC ratios. The peak concentrations in respiratory tissue are well above the MIC₉₀ of the targeted pathogens, and the excellent tissue penetration and maintenance of tissue concentrations favor a prolonged effect at the site of infection. The favorable pharmacokinetic profile, combined with potent intrinsic antibacterial activity, permits once-daily dosing and a shortened treatment duration of 5 days in RTIs such as AECB, acute sinusitis, and tonsillitis/pharyngitis caused by GABHS.

Clinical efficacy (see Section 6, Efficacy by indication)

Thirteen Phase III clinical trials, including 9 double-blind, randomized, active controlled studies, demonstrated that telithromycin given once daily is at least as effective as a broad range of antimicrobial therapies currently used for the treatment of RTIs, most given more than once daily (see table below). In addition, the analysis of outcomes in CAP patients with erythromycin or penicillin resistant S. pneumoniae includes data obtained in a Phase II dose comparison study carried out in Japan (Study 2105). As agreed with the FDA, other data from this study will not be presented.

Table ES-3. 13 Phase III telithromycin clinical trials

	Study	Telithromycin		Comparator
Indication	No.	Dose	Duration	Drug/	Dose	Duration
CAP	3000	800 mg qd	7-10 d	-	-	-
	3001	800 mg qd	10 d	AMX	1000 mg tid	10 d
	3006	800 mg qd	10 d	CLA	500 mg bid	10 d
	3009^a	800 mg qd	7-10 d	TVA	200 mg qd	7-10 d
	3009OL^b	800 mg qd	7-10 d	-	-	-
	3010	800 mg qd	7 d	-	-	-
AECB	3003	800 mg qd	5 d	AMC	500/125 mg tid	10 d
	3007	800 mg qd	5 d	CXM	500 mg bid	10 d
AS	3002	800 mg qd	5 d/10 d	-	-	-
	3005	800 mg qd	5 d/10 d	AMC	500/125 mg tid	10 d
	3011	800 mg qd	5 d	CXM	250 mg bid	10 d
T/P	3004	800 mg qd	5 d	PEN VK	500 mg tid	10 d
	3008	800 mg qd	5 d	CLA	250 mg bid	10 d
CAP = community-acquired pneumonia, AECB = acute exacerbation of chronic bronchitis, AS = acute sinusitis, T/P = tonsillitis/pharyngitis. AMX=amoxicillin; CLA=clarithromycin; TVA=trovafloxacin; AMC=coadministration of amoxicillin and clavulanic acid; CXM=cefuroxime axetil; PEN VK=penicillin VK ^a Study 3009 was stopped prematurely after the FDA restricted trovafloxacin to inpatient use for severe infections as a result of safety concerns that arose during postmarketing surveillance. ^bNo subjects from Study 3009OL were enrolled in Study 3009.

The main analysis populations in the Phase III studies are defined as follows:

· Safety population: All subjects who received at least one dose of study medication and had at least one safety assessment following randomization.

· mITT (modified intent-to-treat population): All subjects with disease who received at least one dose of study medication.

· PPc (per-protocol population for analysis of clinical outcome): The primary analysis group. Includes all mITT subjects excluding major protocol violators and subjects with an indeterminate response.

· PPb (per-protocol population for analysis of bacteriological outcome): All PPc subjects with a causative pathogen isolated at pretherapy/entry.

A breakdown of subjects in each population in the 13 Phase III trials by indication is given in the following table.

Table ES-4. Number of telithromycin-treated subjects in 13 Phase III trial populations by indication

Indication	Population
	Safety	mITT	PPc	PPb
CAP	1415	1373	1132	344
AECB	340	342	255	64
Acute sinusitis	1083	980	731	253
Tonsillitis/pharyngitis	427	430	265	265
TOTAL	3265	3125	2383	926

mITT=modified intent-to-treat; PPc=clinically evaluable per protocol;
PPb=bacteriologically evaluable per protocol.

As shown in the following table of the 9 Phase III active-controlled trials, the clinical cure rates for clinically evaluable telithromycin-treated subjects (PPc, the primary analysis population) were equivalent to active comparators across all indications. Equivalence to active comparators was also demonstrated for clinical cure rates in the mITT population. Study 3009, was prematurely discontinued due to safety concerns about trovafloxacin, the comparator.

Table ES-5. Clinical cure rates in the PPc population of 9 Phase III active-controlled trials

Indication/	Treatment				95% confidence
Study	Telithromycin		Comparator		intervals
	n/N	(%)	n/N	(%)
CAP: 3001	141/149	(94.6)	137/152	(90.1)	[-2.1; 11.1]
3006	143/162	(88.3)	138/156	(88.5)	[-7.9; 7.5]
3009	72/80	(90.0)	81/86	(94.2)	[-13.6; 5.2]
AECB: 3003	99/115	(86.1)	92/112	(82.1)	[-6.4; 14.3]
3007	121/140	(86.4)	118/142	(83.1)	[-5.8; 12.4]
AS: 3005 (5 days Tel)	110/146	(75.3)			[-9.9; 11.7] ^a
3005 (10 days Tel)	102/140	(72.9)	102/137	(74.5)	[-12.7; 9.5] ^b
					[-8.4; 13.3] ^c
3011	161/189	(85.2)	73/89	(82.0)	[-7.1; 13.4]^c
T/P: 3004	109/115	(94.8)	112/119	(94.1)	[-6.1; 7.4]
3008	139/150	(92.7)	123/135	(91.1)	[-5.5; 8.6]
Comparators = amoxicillin (Study 3001); amoxicillin/clavulanic acid (Studies 3003 and 3005); clarithromycin (Studies 3006 and 3008); cefuroxime axetil (Studies 3007 and 3011); penicillin VK (Study 3004); trovafloxacin (Study 3009). ^aPairwise comparison between 5-day telithromycin treatment regimen and amoxicillin/clavulanic acid regimen. ^bPairwise comparison between 10-day telithromycin treatment regimen and amoxicillin/clavulanic acid regimen. ^c Pairwise comparison between 5-day and 10-day telithromycin treatment regimens.

The clinical cure rates by pathogen in the PPb population, pooled by indication, are shown in the table below.

Table ES-6. Clinical cure rates for major pathogens in telithromycin-treated subjects -
PPb population (13 Phase III studies)

Key pathogen	n/N (%) Subjects
	CAP		AECB		Acute sinusitis		Tonsillitis/ pharyngitis
S. pneumoniae	165/174	(94.8)	12/14	(87.5)	82/91	(90.1)	0/0	(0)
H. influenzae	95/105	(90.5)	17/25	(68.0)	57/64	(89.1)	0/0	(0)
M. catarrhalis	26/30	(86.7)	10/10	(100)	16/18	(88.9)	0/0	(0)
S. aureus	15/19	(78.9)	2/2	(100)	22/23	(95.6)	0/0	(0)
S. pyogenes	0/0	(0)	0/0	(0)	5/5	(100)	248/265	(93.6)
C. pneumoniae	32/34	(94.1)	10/11	(90.9)	0/0	(0)	0/0	(0)
M. pneumoniae	30/31	(96.8)	1/1	(100)	0/0	(0)	0/0	(0)
L. pneumophila	12/12	(100)	0/0	(0)	0/0	(0)	0/0	(0)

In CAP (Section 6.4.1, Community-acquired pneumonia), telithromycin administered orally 800 mg once a day for 7 to 10 days has a comparable efficacy to a broad range of active comparators administered more than once daily for 10 days (amoxicillin high dosage, 1 g three times a day; clarithromycin 500 mg twice a day), and against trovafloxacin 200 mg once a day. Particularly noteworthy results are:

· Telithromycin demonstrated efficacy in the most vulnerable patients in the community: the elderly (90.3%, 139/154 cases cured) and subjects with pneumococcal bacteremia (91.5%, 43/47 cases cured). In addition, excellent results have been obtained in subjects with a diagnosis of S. pneumoniae infections (94.8%, 165/174 cases cured) and Legionella infections (100%, 12/12 cases cured), which are the infections most frequently associated with morbidity. This is particularly important because increasing numbers of elderly patients and patients at high risk are being treated as outpatients within the community.

· High efficacy was also obtained in resistant S. pneumoniae isolates: For penicillin G-resistant S. pneumoniae isolated as a single or mixed pathogen infection, the clinical outcome was cure in 16/19 isolates. For erythromycin A-resistant S. pneumoniae isolated as a single or mixed pathogen infection, the clinical outcome was cure in 21/25 isolates. When only single pathogen infections are considered, 11/12 of S. pneumoniae resistant to penicillin G and 15/17 of S. pneumoniae resistant to erythromycin A were clinically cured.

Telithromycin can therefore be used effectively in the therapy of pneumonia in outpatients.

In AECB (Section 6.4.2, Acute exacerbation of chronic bronchitis), telithromycin 800 mg given once daily for 5 days was effective and comparable to widely prescribed drugs considered the standards of care (cefuroxime axetil, amoxicillin/clavulanic acid,) given 2 to 3 times daily for 10 days. Efficacy was maintained in patients more likely to require hospitalization such as the elderly and patients with COPD, even with significant obstruction (FEV₁/FVC <60%).

In acute sinusitis (Section 6.4.3, Acute sinusitis), telithromycin 800 mg given once daily for 5 days was effective and comparable to cefuroxime axetil and amoxicillin/clavulanic acid given 2 to 3 times daily for 10 days. In this indication it was also demonstrated in two studies that 10 days of treatment with telithromycin was comparable to 5 days of telithromycin treatment. When only single pathogen infections are considered, 9/11 of S. pneumoniae resistant to penicillin G and 13/16 of S. pneumoniae resistant to erythromycin A were clinically cured. A 5 day regimen has the advantage of reducing the likelihood of missing doses at the end of a prolonged treatment period, which could promote the selection of resistant pathogens.

In tonsillitis/pharyngitis (Section 6.4.4, Tonsillitis/pharyngitis) due to Group A beta hemolytic streptococcus in patients aged 13 years or older, telithromycin 800 mg given once daily for 5 days was equivalent in clinical and bacteriological efficacy to 10 days of penicillin VK, the standard first line therapy for this indication, and to 10 days of clarithromycin treatment, the standard therapy for subjects allergic to beta-lactams.

Clinical safety (see Section 7, Safety)

A total of 4937 subjects were evaluated for safety in the 13 Phase III trials (9 controlled and 4 uncontrolled): 3265 subjects received telithromycin (2045 in comparative trials) and 1672 subjects received comparator drugs. Rates for adverse events are based on these 13 trials, with emphasis on rates for the 9 controlled studies.

Telithromycin is generally well tolerated. The rates of all treatment-emergent adverse events (TEAEs), serious adverse events and discontinuations due to adverse events were comparable between telithromycin and comparators. No specific risk was associated with age group, sex, race, or indication. Safety was assessed in 372 subjects ³65 years of age and in 95 subjects ³13 to 18 years of age.

Frequencies of possibly related TEAEs in controlled Phase III studies are summarized in the table below.

Table ES-7. Frequency of possibly related TEAEs in controlled Phase III studies ^a

		Coded Term		Number (%) of Subjects
Possibly related TEAEs
			Telithromycin N=2045		Comparator N=1672
	Total		712 (34.8)		465 (27.8)
	Diarrhea		272 (13.3)		158 (9.4)
	Nausea		166 (8.1)		64 (3.8)
	Headache		45 (2.2)		51 (3.1)
	Dizziness		73 (3.6)		26 (1.6)
	Vomiting		57 (2.8)		24 (1.4)
	Dyspepsia		39 (1.9)		20 (1.2)
	Abdominal pain		32 (1.6)		19 (1.1)
	Rhinitis		1 (0.05)		1 (0.1)
	Taste perversion		34 (1.7)		35 (2.1)
	Upper respiratory infection		1 (0.05)		3 (0.2)
	^aBased on a frequency of at least 2.0% for all TEAEs. Source data: v09/0000018t.lst

Because telithromycin, a ketolide, is derived from macrolide antibiotics, gastrointestinal safety, hepatic safety, effect on cardiac repolarization, and possible drug-drug interactions were potential safety issues. Each was thoroughly examined in the clinical development program in addition to the overall adverse event profile.

Gastrointestinal safety (see Section 7.2.4, TEAEs of special interest)

The incidences of gastrointestinal drug-related TEAEs in the 9 active-controlled Phase III studies are shown below:

Table ES-8. Frequency of severe and discontinuations due to possibly related diarrhea, nausea and vomiting TEAEs in 9 controlled Phase III studies

	Number (%) of Subjects
Coded term	Telithromycin (N=2045)	Comparator (N=1672)
Diarrhea
Possibly related TEAEs	272 (13.3)	158 (9.4)
Severe possibly related TEAEs	18 (0.9)	5 (0.3)
Discontinuation due to TEAEs	19 (0.9)	13 (0.8)
Nausea
Possibly related TEAEs	166 (8.1)	64 (3.8)
Severe possibly related TEAEs	13 (0.6)	4 (0.2)
Discontinuation due to TEAEs	18 (0.9)	9 (0.5)
Vomiting
Possibly related TEAEs	57 (2.8)	24 (1.4)
Severe possibly related TEAEs	8 (0.4)	4 (0.2)
Discontinuation due to TEAEs	19 (0.9)	6 (0.4)

The incidence of possibly related treatment-emergent diarrhea in telithromycin-treated subjects was higher (13.3%) than that for pooled-comparator subjects (9.4%); this incidence was higher than that observed for clarithromycin (7.3%) but was lower than that of subjects treated with amoxicillin/clavulanic acid (18.0%). These events were generally mild or moderate in intensity. Only 2.6% of subjects treated with telithromycin in the controlled Phase III studies discontinued their treatment due to gastrointestinal related adverse events. It is noteworthy that 0.9% of subjects treated with telithromycin discontinued treatment due to diarrhea, compared with 2.4% of subjects treated with amoxicillin/clavulanic acid alone and 0.8% of subjects treated with all active comparators (including amoxicillin/clavulanic acid).

Hepatic safety (see Section 7.4.2.2, Hepatic adverse events)

The frequency of ALT ³3 times the upper limit of the normal range (ULN) in the controlled Phase III studies at baseline and during treatment is summarized in the table below. Because patients with CAP are known to have a higher incidence of disease-related abnormal liver functions, data for CAP and non-CAP studies are presented.

Table ES-9. Frequency of subjects with normal and elevated ALT values (³3x ULN) at baseline and during treatment in the 9 controlled Phase III studies

ALT status at baseline	n/N (%) Subjects with elevated ALT during treatment
	Telithromycin	Comparator
CAP studies
Normal	5/395 (1.3)	3/388 (0.8)
Elevated	10/101 (9.9)	13/96 (13.5)
Non-CAP studies
Normal	3/1251 (0.2)	2/936 (0.2)
Elevated	14/182 (7.7)	12/130 (9.2)

The incidences of elevated ALT >3xULN were similar in the telithromycin and comparator groups. As anticipated, the frequency of patients with elevated ALT values was higher in CAP subjects than in non-CAP subjects. In the CAP and non-CAP studies, the incidence of elevated ALT values during treatment with telithromycin or comparator was higher in subjects with elevated ALT values at baseline. No subjects in either the CAP or the non-CAP studies had ALT or AST ³3xULN together in combination with total bilirubin ³1.5xULN.

One patient treated with telithromycin had a serious adverse event of hepatitis that was considered by the investigator to be possibly related to the study medication. However, this patient had a second episode of hepatitis nine months later, which occurred in the absence of telithromycin treatment. A full description of this patient can be found in Appendix 19. Narratives for subjects treated with telithromycin who experienced serious hepatic events.

Electrocardiographic QT interval (see Section 7.5, Assessment of the effects of telithromycin administration on cardiac repolarization)

Because telithromycin has structural similarities to erythromycin, a comprehensive assessment of the effects on cardiac repolarization was conducted. Data were obtained from 25 preclinical studies, 8 clinical pharmacology studies, and 10 Phase III studies, including almost 2200 subjects.

This extensive analysis revealed the following:

· In patients with RTIs, the mean change in electrocardiographic QTc interval (QT interval corrected for heart rate by the Bazett formula [see Section 7.5.3.1, Electrocardiographic QT interval findings in patients receiving telithromycin]) following treatment with telithromycin was small (~1 ms).

· A shallow relationship of telthromycin concentration to QTc interval was established across a wide range of observed plasma concentrations.

· There was no difference in the frequency of QTc outliers (>500 ms) between telithromycin and macrolide and non-macrolide antibiotics.

· An extensive analysis of at-risk subpopulations did not reveal a propensity for enhanced effect on cardiac repolarization in such patients.

· No increase in the incidence of cardiovascular adverse events was noted when compared to macrolide and non-macrolide active comparators.

Conclusions

Telithromycin is the first in a new class of antimicrobial agents, the ketolides. It has a novel mechanism of action that results in outstanding activity against sensitive strains of S. pneumoniae, as well as potent activity against macrolide- resistant strains. S. pneumoniae is the pathogen most associated with risk of morbidity and mortality in community-acquired RTIs. Reliable activity against this pathogen is the most important feature of an antibiotic for treatment of these infections. In addition to its outstanding activity against S. pneumoniae, telithromycin is active against the full spectrum of respiratory pathogens, both common and atypical, including L. pneumophila, which is associated with mortality in pneumonia. Its activity against penicillin- and erythromycin-resistant pathogens is crucial in this age of increasing resistance. As would be expected from its mechanism of action, there is no cross resistance to beta lactams or quinolones.

The pharmacokinetic profile of telithromycin, with sustained levels in tissue and therapeutic concentrations in plasma, support a brief and convenient, once-daily oral dosing regimen. This assures efficacy in infected tissues as well as in undetected bacteremia in outpatients. The brief, simple regimen will promote patient compliance, an important factor in reducing further pressure for development of resistance due to missed doses at the end of prolonged therapy [39]. @@ Guillermot, 1998.

The clinical efficacy of telithromycin was studied in 3125 patients with the following community-acquired RTIs: community acquired pneumonia (CAP, 1,373 patients), acute bacterial sinusitis (980 patients), acute exacerbation of chronic bronchitis (AECB, 342 patients), and tonsillitis/pharyngitis due to S. pyogenes (430 patients). Excellent efficacy was demonstrated in all patient populations and against all key pathogens in each of the clinical trials in the four proposed indications. Telithromycin was effective in treating CAP subjects with pneumococcal bacteremia, with Legionella pneumophila, in the elderly in both CAP and AECB, in AECB subjects with severe bronchial obstruction, and in subjects at greater risk for morbid sequelae. Telithromycin demonstrated efficacy in AECB, acute sinusitis, and tonsillitis/pharyngitis with a treatment regimen of 5 days.

Telithromycin is effective in vitro against macrolide-, beta-lactam-, and quinolone-resistant S. pneumoniae. Clinical efficacy in infections due to S. pneumoniae resistant to penicillin G or erythromycin was demonstrated with overall cure rates of 91.7% (11/12 subjects) in CAP subjects with single pathogen infections of penicillin G-resistant strains and 88.2% (15/17 subjects) for erythromycin A-resistant strains. Similarly, efficacy against penicillin G- and erythromycin A-resistant S. pneumoniae was also demonstrated in patients with acute sinusitis.

The safety of telithromycin was assessed in 3265 patients with RTIs. This population included a broad spectrum of patients with underlying diseases, who received a wide variety of concomitant medications as well as elderly patients with additional risk factors for morbidity and mortality. Telithromycin exhibited an excellent safety profile, comparable to that of other marketed outpatient antibiotics and in particular to that of the macrolides. The incidence of gastrointestinal adverse events, while slightly higher than that of the new macrolides, falls within the range of marketed antibiotics. There is no evidence of excess risk of hepatic adverse events. Treatment with telithromycin, which has a weak inhibitory effect on the cardiac Ikr channel, was associated with a small (approximately 1 ms) change in the electrocardiographic QT interval (corrected for heart rate). No excess in adverse cardiovascular events was observed with telithromycin administration.

Telithromycin is metabolized in part by cytochrome P450 (CYP3A4). Concomitant administration with a potent inhibitor of CYP3A4 (ketoconazole) was associated with a modest elevation in plasma concentrations in a clinical pharmacology study. No excess of adverse events was observed in telithromycin treated patients who received concomitant therapy with CYP3A4 inhibitors.

Thus, telithromycin is highly effective in the treatment of outpatient RTIs. It has excellent activity against S. pneumoniae, including macrolide- and penicillin G-resistant strains, and all the other major common, intracellular and atypical pathogens. Telithromycin provides an alternative to quinolones for physicians who are increasingly concerned about beta-lactam- and macrolide-resistant S. pneumoniae and atypical and intracellular pathogens in community respiratory infections. Telithromycin can be given in a convenient regimen and can be given to patients intolerant to beta lactams or quinolones. Few oral antibiotics fulfill all of these requirements. Telithromycin will therefore be an important addition to the outpatient antimicrobial therapeutic armamentarium.

LIST OF APPENDICES

No.	Title
1	Relevant references
2	Dose response
3	Schedule of efficacy assessments
4	ITT analyses
5	Number of telithromycin-treated subjects in populations by study
6	Flow chart of Phase III subject disposition
7	Key inclusion/exclusion criteria
8	Narratives for subjects with S. pneumoniae from single or mixed pathogen infections at entry who failed therapy
9	Listing of subjects with resistant S. pneumoniae – bmITT not PPb population
10	Listing of subjects with resistant S. pneumoniae treated with active comparators – PPb and bmITT not PPb populations
11	Narratives for subjects with S. pneumoniae positive blood cultures who failed therapy
12	Listing of subjects with pneumococcal bacteremia – bmITT but not PPb population
13	Clinical cure rates without indeterminate responses – mITT and bmITT populations
14	TEAEs in clinical pharmacology studies
15	Deaths and discontinuations for Phase III uncontrolled studies
16	Narratives for deaths in Phase III studies
17	Narratives for possibly related serious adverse events in the completed Phase III studies
18	Shift tables for ALT (SGPT)
19	Narratives for subjects treated with telithromycin who experienced serious hepatic events

LIST OF ABBREVIATIONS


AECB	Acute exacerbation of chronic bronchitis
ALT	Alanine transaminase (also referred to as SGPT)
AMC	Coadministration of amoxicillin + clavulanic acid
AS	Acute sinusitis
AST	Aspartate transaminase (also referred to as SGOT)
AMX	Amoxicillin
AUC	Area under the plasma concentration vs time curve
AUC_ss	Area under the curve at steady state
BAL	Bronchial alveolar lavage
BCYEa	Buffered charcoal yeast extract
bmITT population	Bacteriologically evaluable modified intent to treat population: all mITT subjects with a bacteriological sample at pretherapy/entry containing at least one pathogen considered by the investigator to be responsible for infection
bid	Two times daily
BYE	Buffered yeast extract agar
CAP	Community-acquired pneumonia
C/E ratio	Intracellular/extracellular ratio
cfu	Colony forming units
CHO	Chinese hamster ovary
CI	Confidence interval
CLA	Clarithromycin
CL_CR	Creatinine clearance
CL_R	Renal clearance
C_max	Maximum plasma concentration
C_max,ss	Maximum plasma concentration at steady state
CMI	Clinical Microbiology Institute, Inc
CNALV	Clinically noteworthy abnormal laboratory value
COPD	Chronic obstructive pulmonary disease
CXM	Cefuroxime axetil
CV	Coefficient of variation
CYP	Cytochrome P450
ECG	Electrocardiogram
ED₅₀	Median effective dose
ELISA	Enzyme-linked immunosorbent assay
ENT	Ear, nose, and throat
Ery-A	Erytthromycin A
Ery-R	Erythromycin A-resistant
Ery-S	Erythromycin A-susceptible
EU	European Union
FDA	Food and Drug Administration
FEV₁	Forced expiratory volume in 1 second
FVC	Forced vital capacity
GABHS	Group A beta-hemolytic streptococcus
HDL	High density lipoprotein
HTM	Haemophilus test medium
IC₅₀	50% inhibitory concentration
Ig	Immunoglobulin
INR	International normalized ratio
ITT	Intent to treat (all subjects who received at least one dose of study medication)
iv	Intravenous
K_i	Inhibition equilibrium constant
LDL	Low density lipoprotein
LFT	Liver function test
LPTV	Late posttherapy visit
MCC	Minimal chlamydicidal concentration
MIC	Minimum inhibitory concentration
MIC_50/90	Minimum inhibitory concentration at 50%/90%
mITT population	Modified intent-to-treat population: all subjects with clinical signs and symptoms of the disease who received at least one dose of study medication, as treated
MLS_B	Macrolide lincosamine streptogramine-B
MSSA	Methicillin-susceptible S. aureus
NA	Not applicable
NCCLS	National Committee for Clinical Laboratory Standards
ND	Not determined
NDA	New drug application
NOAEL	No observed adverse effect level
OL	Open label
PAE	Postantibiotic effect
PCR	Polymerase chain reaction
PD₅₀	Protective dose at 50%
PEN	Penicillin VK (comparator in study 3004)
Pen-I	Penicillin G-intermediate resistance
Pen-R	Penicillin G-resistant
Pen-S	Penicillin G-susceptible
PMN	Polymorphonuclear neutrophils
po	Oral (per os)
PP population	Per protocol population
PPb population	Bacteriologically evaluable per protocol population: all PPc subjects who had a causative pathogen isolated at pretherapy/entry
PPc population	Clinically evaluable per protocol population: all mITT subjects excluding those with major protocol violations and¤or indeterminate responses
PRSP	Penicillin G-resistant Streptococcus pneumoniae
qd	Once daily
QTc	QT interval corrected according to Bazett formula
QTf	QT interval corrected according to Fridericia formula
QTn	QT interval corrected according to new formula
rRNA	ribosomal ribonucleic acid
RTI	Respiratory tract infection
SD	Standard deviation
t_1/2	Half-life
TEAE	Treatment-emergent adverse event
TEL	Telithromycin
tid	Three times daily
t_max	Time of occurrence for maximum (peak) drug concentration
TOC	Test of cure
TVA	Trovafloxacin
UK	United Kingdom
ULN	Upper limit of normal range
US	United States
VLDL	Very low density lipoprotein
WBC	White blood cell

1. Background and medical need

Clinical background

Respiratory tract infections (RTIs) are the most common infectious diseases observed in outpatients. Treatment of community respiratory infections remains challenging in 2001 despite the availability of a variety of oral antibiotics. These infections are caused by several classes of organisms including common pathogens such as S. pneumoniae, H. influenzae, M. catarrhalis and S. pyogenes as well as the increasingly recognized atypical and intracellular microorganisms such as M. pneumoniae, C. pneumoniae, and L. pneumophila. It is challenging to find a single drug that is effective against all these organisms, particularly as many of them are becoming increasingly resistant to older agents.

The high level of beta lactamase production among H. influenzae and M. catarrhalis is well recognized as is the increasing prevalence of penicillin resistance among S. pneumoniae. These penicillin-resistant S. pneumoniae have been recently demonstrated to be resistant to other classes of antibiotics as well, including macrolides, sulfonamides, and tetracyclines giving rise to the concept of multi-drug-resistant pneumococci.

While penicillin resistance in S. pneumoniae has been acknowledged as an epidemiologic and clinical problem for at least 10 years, macrolide resistance is a more recent issue. There were few reports of in vitro macrolide resistance prior to the mid 1990’s, but in 2000, CDC reported that 20.3% of US isolates of S. pneumoniae from sterile sites were resistant to erythromycin A [14]. Of note, a large fraction of these, 61%, were also highly penicillin resistant. There is considerable regional variation in erythromycin resistance but the temporal trend is consistent in most regions. In the Atlanta area Gay et al have reported that resistance to erythromycin A increased from 13% in 1994 to 31% in 1999 [36]. Strains of S. pneumoniae which are erythromycin resistant due to an efflux mechanism generally have minimum inhibitory concentrations (MICs) in the range of 2 to 16 mg/mL for erythromycin, azithromycin and clarithromycin with an increase of MIC in the past 4 years to higher levels of MICs (16 mg/mL) in some areas [36]. Those with resistance due to methylation (macrolide-lincosamine-streptogramine-B [MLS_B]) typically have MICs ³64 mg/mL for erythromycin [36]. It is unlikely that treatment with the marketed macrolides could achieve levels exceeding these MICs in patients.

While there are numerous reports documenting the increasing prevalence of in vitro erythromycin-resistant S. pneumonia, it is more difficult to document the extent to which this constitutes a clinical problem. Because macrolide monotherapy is generally an outpatient regimen administered to patients without the benefit of bacteriologic documentation, there is limited literature about adverse outcomes in these patients. It is of interest that Lonks and Madeiros [52] were only able to identify 6 cases of adverse outcomes in macrolide-treated patients who had macrolide-resistant S. pneumoniae in their review of the literature prior to 1992. Since that time the frequency of such case reports has increased and last year, Kelley et al [48] reported that 4/41 patients hospitalized with pneumococcal bacteremia at their institution had macrolide-resistant isolates and had received prior oral macrolide therapy. Thus, recent literature supports the concept of macrolide resistance as an emerging clinical concern.

Macrolides have long been one of the mainstays of therapy for outpatient RTIs and the recent Infectious Diseases Society of America guidelines have recommended them for first-line therapy of community-acquired pneumonia (CAP) [7]. The increasing prevalence of macrolide resistance will erode the utility of these drugs. With many pneumococci resistant to erythromycin, penicillin, cefotaxime, and other drugs, there remain few classes of oral antibiotics which can be used to treat these infections.

While seeking a broadly effective drug for treatment of these infections, the physician must remain aware of safety considerations and also attempt to identify a regimen that is simple, brief, and convenient in order to facilitate patient compliance. Failure to comply with antibiotic treatment may lead to therapeutic failure in the individual and may enhance the likelihood of emergent resistance in the community.

Rationale for development

A new antibiotic for the treatment of RTIs should cover all the major pathogens mentioned above and should also be active against strains of S. pneumoniae resistant to penicillin G and/or erythromycin A. Some new quinolones that are active in vitro against resistant strains of S. pneumoniae represent one of the answers to this medical need. However, their potential for selecting resistant gram-negative strains and S. pneumoniae strains, as well as questions over the safety of some recent quinolones, justify the development of other therapeutic alternatives.

Because of its spectrum of activity, telithromycin is a suitable candidate for therapy of adults with upper and lower RTIs, including those infections caused by common, atypical, and intracellular pathogens. Unlike currently marketed macrolides, telithromycin has in vitro activity against strains of S. pneumoniae resistant to beta-lactams, erythromycin A, and quinolones. Telithromycin has in vitro activity against H. influenzae similar to that of azithromycin, but has a higher plasma concentration in vivo. As a ketolide, telithromycin does not induce resistance to macrolides by an inducible MLS_B mechanism in vitro. In addition, telithromycin’s spectrum of antibacterial activity is more tailored to respiratory tract pathogens than is the wider antibacterial spectrum of the new quinolones.

The pharmacokinetic profile of telithromycin demonstrates plasma exposures that reach or exceed the MICs of the target pathogens, particularly S. pneumoniae, the RTI pathogen most often associated with bacteremia (see Section 2, Claimed indications). It also demonstrates excellent tissue penetration and persistent therapeutic levels at the sites of infection in patients.

The balance of plasma and tissue levels achieved with telithromycin administration support a shortened treatment duration. Medical benefits of a shortened treatment duration include a shorter period of risk for drug-drug interactions and side effects, potentially improved compliance, and decreased induction of resistance, which could result from poor compliance with prolonged treatments (see [39], available in Appendix 1. Relevant references). Therefore, based on the pharmacokinetic properties of telithromycin and on the potential medical benefit of a shorter treatment duration, it was decided to test the efficacy and safety of a 5-day treatment duration in acute exacerbation of chronic bronchitis (AECB), acute sinusitis, and tonsillitis/pharyngitis caused by group A beta-hemolytic streptococci (GABHS).

Beginning in early 1998, the efficacy and safety of telithromycin administered orally have been investigated in 13 international/multicenter Phase III studies performed in subjects with CAP, AECB, acute sinusitis, or GABHS tonsillitis/pharyngitis. In addition, data from a Phase II study (Study 2105) carried out in Japan in 103 subjects with CAP have been evaluated with respect to subjects with penicillin G-resistant and erythromycin A-resistant S. pneumoniae.

The data and analyses contained in this Briefing Document have been provided to the FDA in the original NDA (submitted 28 February 2000), in the 4-month safety update (submitted 30 June 2000), in the NDA major amendment (submitted March 2001), or on request by the FDA during the assessment period.

2. Claimed indications

Approval is being sought for telithromycin 800 mg oral dose once daily dosing for the treatment of:

Community-acquired pneumonia (treatment duration: 7 to 10 days) due to S. pneumoniae, including strains resistant to penicillin G and erythromycin A, H. influenzae, M. catarrhalis, C. pneumoniae, L. pneumophila, or M. pneumoniae in patients 18 years of age or older.

Acute bacterial exacerbation of chronic bronchitis (treatment duration: 5 days) due to S. pneumoniae, including strains resistant to penicillin G and erythromycin A, H. influenzae, M. catarrhalis, S. aureus, C. pneumoniae, or M. pneumoniae in patients 18 years of age or older.

Acute sinusitis (treatment duration: 5 days) due to S. pneumoniae, including strains resistant to penicillin G and erythromycin A, H. influenzae, M. catarrhalis, or S. aureus in patients 18 years of age or older.

GABHS tonsillitis/pharyngitis (treatment duration: 5 days) due to S. pyogenes in patients 13 years of age or older.

3. Microbiology

Telithromycin, a ketolide, is two- to four-times more active than clarithromycin against gram-positive cocci susceptible to erythromycin A, and retains activity against gram-positive cocci isolates with an underlying mechanism of resistance to erythromycin A. Telithromycin is active against other pathogens involved in RTIs, including atypical pathogens (Mycoplasma pneumoniae) and intracellular pathogens (Legionella pneumophila, Chlamydia pneumoniae). The dual mechanism of action on bacterial ribosomes is responsible for telithromycin activity.

The antibacterial spectrum and activity of telithromycin have been assessed by MIC determinations and experimental infections in rodents. Reported in vitro data were mainly obtained according to National Committee for Clinical Laboratory Standards (NCCLS) recommendations (North America) or national recommendations (Europe). For each bacterial species or genus, both the wild phenotype and isolates with different phenotypes of resistance to the major antibacterial agents (penicillin G, erythromycin A, fluoroquinolones) were tested. Activities were investigated against fresh clinical isolates and against stock collections of pathogens. Numerous centers were included in these studies, with most data deriving from experimental studies carried out in North America (the US and Canada), Western Europe, South Africa, Australia, and Japan.

3.1 Ketolides: A new chemical class

The need to overcome resistance, and particularly to provide activity against penicillin G- and/or erythromycin A-resistant S. pneumoniae clinical isolates, has driven the development of new compounds designed to overcome multidrug-resistant S. pneumoniae. The ketolides are a new class of drugs resulting from intensive research to discover novel antibacterials.

Ketolides are semisynthetic derivatives of erythromycin A. The word ketolide is derived from keto (3-keto group) and olide (lactone). The defining chemical characteristic of ketolides is a 3-keto function on erythronolide A instead of L-cladinose, which confers the following novel biological properties:

· High stability in acidic media, enhancing the ability of the drug to pass through the stomach. After 6-hours of contact in a solution of pH 1.0, more than 90% of the antibacterial activity of telithromycin remains [11]. @@Bryskier et al., 2000

· Inability to induce MLS_B resistance (see Section 3.9.3, Inducible MLS_B resistance). Ketolides also exhibit antibacterial activity against inducible erm‑containing gram-positive cocci such as S. aureus and S. pneumoniae.

Substitution of the C₁₁-C₁₂ hydroxyl groups of the erythronolide A ring by a carbamate residue results in additional beneficial properties when combined with the 3-keto function, as follows:

· The C₁₁-C₁₂ carbamate residue enhances antibacterial activity when compared with erythromycin A, and confers the ability to overcome erythromycin‑A resistance due to the efflux mechanism.

· The butyl imidazolyl pyridinyl side chain attached to the C₁₁-C₁₂ carbamate residue is responsible for the antibacterial activities, mode of action, pharmacokinetics, intracellular uptake, accumulation, and efflux.

The chemical structure of telithromycin is shown below.

Figure 3-1. Chemical structure of telithromycin

3.2 Telithromycin mode of action

Erythromycin A, clarithromycin, and azithromycin prevent bacterial protein synthesis by binding to specific sites in the bacterial ribosome and interfering with the elongation of nascent polypeptide chains [56].@@Mazzei et al., 1993 In addition, these compounds interfere with a second cellular process, the formation of the 50S ribosomal subunit [16].@@Champney, 1999

Ribosomes are the functional units of translation. Bacterial ribosomes consist of ribonucleoprotein particles having a sediment coefficient of 70S. The 70S ribosome is composed of two subunits: 30S and 50S particles. The 30S subunit is made up of 16S ribosomal ribonucleic acid (rRNA) and 21 different proteins. The 50S subunit consists of 2 rRNA molecules: 23S rRNA and 5S rRNA, and 33 proteins. The main function of the 50S ribosomal subunit is to promote peptide bond formation. Six distinct structural domains have been found in the 23S rRNA, and 5S rRNA forms a structural link between domain II and domain V. Further, 5S rRNA may help in the proper juxtaposition of domain II and V in the ribosomal tertiary structure [54]. @@Mankin, 2000

3.2.1 Dual interaction of telithromycin with domain V and domain II

Interaction with domain V

The interaction with domain V of 23S rRNA (at the peptidyl transferase loop), detected by the methodology known as footprinting, is comparable for 14- and 15-membered-ring macrolides and for telithromycin. One specific nucleotide, adenine A-2058, is pivotal for the binding of macrolide-lincosamide and streptogramin B antibiotics at this site in domain V. The erythromolide A ring of ketolide docks into the same site of domain V of the 23S rRNA target through the dimethylamino group of the D-desosamine.

Interaction with domain II

The difference in affinity for the ribosome affects how 14- and 15-membered ring macrolides and telithromycin interact with A-752 in domain II of 23S rRNA. Telithromycin exhibits a strong interaction in the vicinity of the 752 hairpin of domain II, mainly due to the C₁₁-C₁₂ carbamate side chain on the erythronolide A ring [40].@@Hansen et al., 1999

In contrast, erythromycin A cannot form a strong interaction with domain II. These differences in the interactions of erythromycin A and telithromycin with domain II are determined, at least in part, by the distance the drugs span from their domain V site. Structural activity studies demonstrated that the C₁₁-C₁₂ carbamate residue in telithromycin plays an important role in the interaction at domain II.

Consequences of the dual interaction between telithromycin and domains V and II

In an erythromycin‑A susceptible strain of S. pneumoniae, both erythromycin A and telithromycin are able to bind to the A2058 residue in domain V. However, because telithromycin additionally binds to the A752 residue in domain II of the pocket, telithromycin has a higher overall binding affinity compared with erythromycin A. In an erm -containing strain of S. pneumoniae, the A2058 binding site is modified by methylation, and erythromycin A can no longer bind efficiently. This results in the strain being rendered resistant to erythromycin A, and cross resistant to other available 14- and 15‑membered ring macrolides. In contrast, the modification of A2058 by methylation does not render the strain resistant to telithromycin because, by virtue of its additional binding site at A 752 in domain II, telithromycin retains its affinity for the active site of the pocket. This explains why telithromycin retains activity against erythromycin A‑resistant strains.

3.2.2 Inhibition of 30S and 50S ribosomal subunit formation by telithromycin

Erythromycin A has a second target for inhibition in susceptible cells. The assembly sequence leading to the formation of nascent 50S particles is interrupted by erythromycin A [17]@@Chittum et al., 1995 and telithromycin.

Antibiotic binding at a specific receptor in the 50S precursor particle site inhibits subunit formation, and the incomplete particle is subject to degradation by cellular ribonuclease activities. This leads to the gradual depletion of functional ribosomes in the cell and to the accumulation of RNA oligonucleotides in cells. Inhibition of the assembly of the 50S ribosomal subunit is a lethal event for bacterial cells because of ribonuclease degradation of the ribosomal RNAs [16]@@Champney et al., 1999.

Telithromycin reduces formation of the smaller 30S subunit. This effect is not observed with available 14- and 15‑membered ring macrolides [15]@@Champney et al., 1998. The result is an additional mechanism for the lethal disruption of ribosomal subunit formation. It is possible that this mechanism may reinforce the bactericidal action of telithromycin, which is significantly more bactericidal than members of the macrolide class.

3.2.3 Telithromycin: affinity for bacterial ribosomes

Telithromycin binds approximately 10-fold more tightly than erythromycin A to MLS_B-sensitive ribosomes of S. pneumoniae and 20-fold more tightly for S. aureus ribosomes. The higher affinity of telithromycin for the ribosome is a function of the C₁₁-C₁₂ side chain. Telithromycin binds 6-fold more tightly to ribosomes than clarithromycin and this is reflected in lower MIC values [29] (@@ Douthwaite, 2000). The presence of an A-2058 G mutation in the 23S rRNA (domain V) virtually eliminates binding of erythromycin a and clarithromycin to bacterial ribosomes. The binding of telithromycin is also lowered by this mutation, but to a smaller extent, and telithromycin remained active against these isolates while erythromycin A and clarithromycin did not.

3.2.4 Conclusion

Telithromycin acts on protein synthesis by a double interaction on the peptidyl transferase loop, allowing activity against erythromycin A-resistant gram-positive cocci due to A-2058-methylation. In addition, telithromycin inhibits the formation of the two subunits of the bacterial ribosome. This double interaction at two levels of the cellular machinery explains the enhanced in vitro activity of telithromycin against gram-positive cocci in comparison to clarithromycin and its capacity to overcome erythromycin A resistance due to A-2058-methylation.

3.3 Antipneumococcal activity

3.3.1 In vitro antipneumococcal activity

S. pneumoniae is one of the major pathogens responsible for community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, and acute bacterial maxillary sinusitis. In recent years, the penicillin G and erythromycin A susceptibilities of S. pneumoniae have rapidly decreased. As previously shown, erythromycin A resistance may occur by multiple mechanisms, including MLS_B (erm⁺), efflux (M phenotype: mef E⁺ genotype), and ribosomal mutation on protein L4.

The results of in vitro studies demonstrate that telithromycin is one of the most active antibiotics against S. pneumoniae, irrespective of sensitivity or resistance to other antibacterial agents. Telithromycin was more active than erythromycin A, clarithromycin, and azithromycin.

Comparison with clarithromycin

In vitro studies demonstrated that telithromycin is more active than clarithromycin against S. pneumoniae isolates. Telithromycin was also highly active against erythromycinA-resistant strains having an MLS_B mechanism of resistance, an efflux (mef E) mechanism of resistance, or a mutation on ribosomal protein L4. In contrast, clarithromycin was inactive against isolates that are resistant to erythromycin A due to MLS_B, efflux mechanisms, or L4 protein mutation.

Telithromycin was tested against more than 5000 isolates collected from various countries (including the US, Canada, Europe, South Africa, and Japan), using clarithromycin as the comparator. Against fully susceptible S. pneumoniae isolates, MIC₅₀ values for telithromycin were 0.004 to 0.06 µg/mL, and MIC₉₀ values were 0.004 to 0.125 µg/mL. Telithromycin was 2 to 4 times more active than clarithromycin.

Against isolates showing intermediate susceptibility to penicillin G (MIC 0.12 to 1.0 µg/mL), telithromycin MIC₅₀ values were 0.015 to 0.03 µg/mL, and MIC₉₀ values were 0.03 to 0.25 µg/mL. Telithromycin was up to 10 times more active than clarithromycin.

Telithromycin MIC₅₀ values for S. pneumoniae isolates resistant to penicillin G (MIC >1 µg/mL) were 0.015 to 0.125 µg/mL, and MIC₉₀values were 0.015 to 2.0 µg/mL. In contrast, clarithromycin and azithromycin activities delineate 2 populations of S. pneumoniae isolates: 1 population remaining sensitive and the second being totally resistant. This finding is mainly attributable to a combination of penicillin G- and erythromycin-A resistance.

Telithromycin was also active (MIC₅₀ 0.015 to 0.06 µg/mL, MIC₉₀ 0.015 to 2 µg/mL) against erythromycin A‑resistant strains harboring an MLS_B mechanism of resistance (erm B). Against isolates resistant to erythromycin A, clarithromycin and azithromycin are inactive whether the mechanism of resistance is MLS_B efflux, or a mutation in ribosomal protein L4.

In multiple studies, telithromycin activity was investigated against 114 S. pneumoniae isolates of M‑phenotype (erythromycin A-resistant and clindamycin-susceptible). MIC₅₀ values for telithromycin ranged from 0.0015 to 0.25 µg/mL, and MIC₉₀ values from 0.12 to 0.5 µg/mL. Clarithromycin exhibited a lower in vitro activity than telithromycin, with MIC₅₀ values ranging from 0.5 to 8.0 µg/mL and MIC₉₀ values from 4.0 to 16 µg/mL.

Comparisons with other antibacterial agents

It was demonstrated that telithromycin is more active against S. pneumoniae isolates (including resistant strains) than macrolides, fluoroquinolones, and other antibacterial agents tested.

In a comparative study, 400 S. pneumoniae isolates were tested for their susceptibility to 15 antibacterial agents, including telithromycin. Results for selected agents are summarized in the table below.

Table 3-1. In vitro activity of antibacterial agents against S. pneumoniae isolates USA/96/004/549

Antibacterial agent	MIC (µg/mL)
	MIC₅₀	MIC₉₀
Telithromycin	0.015	0.12
Levofloxacin	1.0	1.0
Trovafloxacin	0.06	0.12
Sparfloxacin	0.12	0.25
Quinupristin/ dalfopristin	0.25	0.5
Linezolid	1.0	1.0

Telithromycin was more active than the fluoroquinolones tested, 16 times more active than quinupristin/dalfopristin, and 60 times more active than linezolid.

Telithromycin was active against ofloxacin-resistant S. pneumoniae (MIC_50/90 0.03 µg/mL) and other fluoroquinolone-resistant strains. All the strains tested were susceptible to telithromycin, irrespective of the underlying mechanism of fluoroquinolone resistance. This included 19 multidrug‑resistant strains and 3 strains containing par C and par E mutations in topoisomerase IV. USA/00/647/676

In in vitro studies, telithromycin was compared with oral cephems against S. pneumoniae isolates Internal reports. The results showed that telithromycin was more active in vitro against S. pneumoniae than cefpodoxime, cefditoren, and cefdinir [43,44,58,60]@@.

A total of 75 S. pneumoniae clinical isolates that were penicillinG-resistant (Pen-R) or intermediately resistant (Pen-I) were tested for their susceptibilities to various oral antibacterial agents. The results are summarized in the table below.

Table 3-2. In vitro activity of antibacterial agents against S. pneumoniae Pen-R or Pen-I 98/10785/MC

Antibacterial agent	MIC (µg/mL)
	MIC₅₀	MIC₉₀	Range
Telithromycin	0.002	0.016	0.002 – 0.031
Erythromycin A	0.06	16	0.016 – 128
Clindamycin	0.03	0.06	0.016 – 128
Sparfloxacin	0.25	0.5	0.002 – 1.0
Grepafloxacin	0.12	0.25	0.008 – 1.0
Levofloxacin	0.5	1.0	0.002 – 1.0
Trovafloxacin	0.12	0.25	0.06 – 0.5
Linezolid	1.0	1.0	0.125 – 1.0
Cefprozil	8.0	16	0.12 – 16

Telithromycin showed the lowest MIC range and MIC_50/90 values of all isolates tested, and was more active than fluoroquinolones, linezolid, and cefprozil.

A total of 39 isolates of S. pneumoniae harboring different genes conferring erythromycin A resistance and 20 erythromycin A-susceptible isolates were tested for their susceptibility to telithromycin and 6 comparative compounds. Telithromycin was 4 times more active than clarithromycin against erythromycin A-susceptible S. pneumoniae isolates, and 16 times more active than clarithromycin against S. pneumoniae isolates harboring the mef E⁺ gene (efflux). Telithromycin remained active against isolates harboring an erm B⁺ gene, whereas clarithromycin was inactive. Telithromycin was 4 times more active than clarithromycin or ampicillin, and 30 times more active than cefdinir against erythromycin‑A susceptible strains. These results are summarized in the table below.

Table 3-3. In vitro activity of antibacterial agents against S. pneumoniae Ery‑S
and Ery-R (mef E⁺ and erm B⁺) LPH‑97-021

Antibacterial agent	MIC (µg/mL)
	Ery-S (N=20)		Ery-R mef E⁺ (N=21)		Ery-R erm B⁺ (N=18)
	MIC₅₀	MIC₉₀	MIC₅₀	MIC₉₀	MIC₅₀	MIC₉₀
Telithromycin	0.008	0.008	0.06	0.12	0.03	0.125
Erythromycin A	0.03	0.06	2.0	2.0	32	>128
Clarithromycin	0.016	0.03	1.0	2.0	16	>128
Azithromycin	0.12	0.125	2.0	4.0	64	>128
Ampicillin	0.03	0.25	1.0	2.0	0.03	2.0
Cefdinir	0.125	4.0	4.0	8.0	0.25	16
Levofloxacin	1.0	2.0	1.0	1.0	1.0	2.0

Note: N = number of isolates. Ery-R = erythromycin A-resistant, Ery-S = erythromycin A-susceptible.

Against 15 tetracycline‑resistant S. pneumoniae strains, the MIC_50/90 value for telithromycin was 0.0015 µg/mL.ZA/96/004/557 In this same study, the MIC₅₀ was 0.003 and theMIC₉₀ was 0.007 µg/mL against 20 cotrimoxazole‑resistant strains.

In summary, telithromycin exhibited high in vitro activity against isolates of S. pneumoniae. This was observed regardless of the underlying resistance of S. pneumoniae to penicillin G, erythromycin A, fluoroquinolones, tetracyclines, cotrimoxazole, and cefotaxime.

3.3.2 Bactericidal activity of telithromycin against S. pneumoniae

Telithromycin is bactericidal against S. pneumoniae (including strains resistant to penicillin G, erythromycin A, and cefotaxime).

Kill kinetics of telithromycin (reduction >3 log₁₀ cfu/mL) were investigated at 4 x MIC against S. pneumoniae RYC 58956 (MIC values: penicillin G 0.008 µg/mL, erythromycin A 0.03 µg/mL, clarithromycin 0.03 µg/mL, telithromycin 0.015 µg/mL) and S. pneumoniae RYC 92740 (MIC values: penicillin G 2.0 µg/mL, erythromycin A 8.0 µg/mL, clarithromycin 4.0 µg/mL, telithromycin 0.01 µg/mL).

After 2 hours of exposure to telithromycin, S. pneumoniae RYC58956 (Pen-S, Ery-S) inoculum size was reduced by 5.2 log₁₀ cfu/mL (initial inoculum size 10⁷cfu/mL) and 5.9 log₁₀ cfu/mL (initial inoculum size 10⁶ cfu/mL). After 2 hours, the reduction with clarithromycin was 2.8 and 3.8 log₁₀ cfu/mL, and at 4 hours, the reduction was 4.0 and 4.7 log₁₀ cfu/mL. Telithromycin was highly and rapidly bactericidal against this isolate.E/96/004/575 Against S. pneumoniae RYC 92740 (Pen-R, Ery-R), reductions with telithromycin after inoculum sizes of 10⁷ and 10⁶ cfu/mL were 3.1 and 3.5 log₁₀ cfu/mL at 2 hours, and 3.7 and 4.0 log₁₀ cfu/mL at 4 hours. Under the same conditions, clarithromycin showed poor bactericidal activity.

Against cefotaxime-resistant S. pneumoniae isolates, telithromycin was bactericidal at 4 x MIC and 8 x MIC. Telithromycin was rapidly bactericidal against S. pneumoniae strains that were resistant to erythromycin A and susceptible to clindamycin (M-phenotype : efflux mechanism), with a decrease in inoculum size of approximately 3 log₁₀ cfu/mL in under 2 hours.

Against erythromycin A-resistant S. pneumoniae isolates (erm B-containing strain), the rapidity of the bactericidal activity of telithromycin was strain dependent. Bactericidal activity occurred more slowly compared with erythromycin A-susceptible strains. Regrowth occurred at 2 x MIC and 4 x MIC, but not at 8 x MIC, for some isolates.

3.3.3 In vivo activity in murine infection models

Disseminated infections in mice

In disseminated murine infections, telithromycin displayed oral in vivo activity against pneumococcal infections due to erythromycin A-resistant isolates. In contrast, clarithromycin and azithromycin were inactive (Protective Dose₅₀ [PD₅₀]>50 mg/kg). Telithromycin was also more active than clarithromycin against S. pneumoniae strains susceptible to erythromycin A. 97/9551/PH

Pneumococcal murine respiratory infections

In 2 studies in mice infected intratracheally with erythromycin A-susceptible or erythromycin A-resistant S. pneumoniae strains, oral telithromycin demonstrated protective effects when administered at a dosage of 25 to 100 mg/kg twice daily over 3 days.

In the first of these studies, mice were infected with S. pneumoniae 6254 (Ery-R, MIC >128 µg/mL). Telithromycin 25, 50, and 100 mg/kg/day, begun 6 or 18 hours after bacterial challenge, demonstrated protective effects, with survival rates from 50 to 75%. All control mice developed bacteriemic pneumonia and died within 2 to 5 days. F96/004/550

A second group of mice were infected with S. pneumoniae 4241 (Ery-S, MIC 0.06 µg/mL), and telithromycin or erythromycin was administered orally at 50 mg/kg/day. Dosing started 48 or 72 hours after bacterial challenge. Survival with erythromycin was 70% (48 hours after infection) and 67% (72 hours), whereas survival for telithromycin was 100% in both regimens.

In a second study mice were infected by intranasal instillation with S. pneumoniae strains TUH 39 (Pen-S, mef E^-/erm B^-), TUM 741 (Pen-R, mef E⁺, erm B^-), and TOH 117 (erm B⁺/ mef E^-). Telithromycin and other compounds were administered by the oral route, starting 16 hours after bacterial innoculation for S. pneumoniae TUH 39, and 40 hours after bacterial instillation for the other 2 S. pneumoniae strains. Compounds were administered for 3 days. Telithromycin was administered in the following regimens: 25, 50, or 100 mg/kg every 12 hours, and 50, 100, and 200 mg/kg once daily. Lung bacterial burden was determined 16 hours after the last administration of compounds.

The results showed that the median effective dose (ED₅₀) of telithromycin (6.5 mg/kg once daily) was comparable with that of azithromycin (6.9 mg/kg once daily) for S. pneumoniae TUH 39 (susceptible). Cefdinir (ED₅₀ 46.4 mg/kg once daily) and clarithromycin (ED₅₀ 15.9 mg/kg once daily) were less active than telithromycin.

Against S. pneumoniae TUM 741 (Pen-R, mef E⁺/erm B^-), a 3 log₁₀ cfu/g reduction of lung burden was recorded after administration telithromycin at 50 mg/kg twice a day, compared with control, and a >6 log₁₀ cfu/g reduction was recorded for 100 mg/kg telithromycin given twice a day. Results were statistically comparable for telithromycin administered at 100 mg/kg every 12 hours and at 200 mg/kg once daily. The bacterial clearance of the lung was markedly greater for telithromycin compared with clarithromycin, azithromycin, or cefdinir.

When telithromycin was administered every 12 hours at a dosage of 50 mg/kg/day against S. pneumoniae TOH 117 (Pen-R, mef E^-/erm B⁺), reduction in S. pneumoniae burden was approximately 2.5 log₁₀ cfu/g. Reduction was >6 log₁₀ cfu/g when telithromycin was administered at 100 mg/kg every 12 hours. LPH 97-023

In summary, telithromycin exhibits a good efficacy in murine models of pneumococcal pneumonia. Efficacy remained in murine pneumonia induced with S. pneumoniae strains resistant to erythromycin A and/or penicillin G. In these models, the in vivo efficacy of telithromycin was greater than that of clarithromycin, azithromycin, or cefdinir.

3.3.4 Intracellular antipneumococcal activity

The intracellular antipneumococcal activity of telithromycin was evaluated after polymorphonuclear neutrophil (PMN) phagocytosis of S. pneumoniae. Telithromycin was very active intracellularly against S. pneumoniae, irrespective of susceptibility to penicillin G or erythromycin A. Telithromycin at 4 x MIC reduced intracellular growth by 1.8 to 3.0 log₁₀ cfu at 24 hours, irrespective of the strain [46]@@Jacques Palaz et al., 1998.

It has been shown that S. pneumoniae can enter and survive within human lung alveolar carcinoma cells (Type 2 pneumocytes, A I49 cells) [73]@@Talbot U et al., 1996. S. pneumoniae isolates may persist in tissue, despite exposure to adequate antibacterial concentrations. Telithromycin killing activity was compared with that of azithromycin and 3 fluoroquinolones in human lung alveolar carcinoma cells against S. pneumoniae 14.8 and S. pneumoniae ATCC 49619 (MIC 0.002 µg/mL). It was found that moxifloxacin, trovafloxacin, and telithromycin were most active, but only telithromycin killed all intracellular pneumococci. This finding appears to be related, at least in part, to a high intracellular accumulation of telithromycin in addition to its potent bactericidal activity against S. pneumoniae. USA/98/647/56

3.4 Activity against other pathogens involved in lower respiratory tract infections

3.4.1 Activity against other common pathogens

Haemophilus influenzae

H. influenzae is involved in RTIs such as community‑acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, and acute bacterial maxillary sinusitis. In recent years, there has been an increase in the incidence of ampicillin-resistant H. influenzae isolates due to beta-lactamase production. Nonenzymatic resistance to beta-lactams is a second mechanism of resistance, with a lower incidence than beta-lactamase production.

In vitro, telithromycin is slowly bactericidal against H. influenzae.

In vitro activity against Haemophilus influenzae

MIC values against H. influenzae are strongly influenced by the experimental medium. In the US, NCCLS recommends use of the microbroth dilution technique in the Haemophilus Test Medium (HTM). The HTM medium tends to give higher MIC values than those used in other parts of the world. MIC values can also vary with incubation atmosphere, with high values occurring in 6% CO₂.

A total of 1603 H. influenzae isolates were tested in the USA using NCCLS methodology with HTM. The MIC₅₀ value for telithromycin ranged from 1.0 to 2.0 µg/mL, and the MIC₉₀ value from 2.0 to 4.0 µg/mL.

The in vitro activity of telithromycin was tested against 2300 isolates collected worldwide. Irrespective of the resistance profile to ampicillin, MIC₅₀ or MIC₉₀ values were consistent for each given investigator. The MIC₅₀ values for telithromycin ranged from 0.25 to 2.0 µg/mL, and MIC₉₀ values from 0.5 to 4.0 µg/mL.

Telithromycin was shown to be slowly bactericidal against H. influenzae. A reduction of 2.9 (2 x MIC), 3.2 (4 x MIC), and 3.9 (8 x MIC) log₁₀ cfu/mL occurred after 24 hours of contact. Results are summarized in the table below.

Table 3-4. Telithromycin bactericidal activity (kill kinetics) against H. influenzae USA/96/004/586

Concentration	Mean (range) log₁₀cfu change
Tested	at 6 hours		at 24 hours
1 x MIC	–1.1	(0.0 to –3.6)	–2.0	(+0.9 to –4.9)
2 x MIC	–1.1	(–0.1 to –2.5)	–2.9	(–0.5 to –4.8)
4 x MIC	–1.3	(–0.1 to –3.0)	–3.2	(–1.1 to –5.1)
8 x MIC	–1.5	(–0.3 to –3.0)	–3.9	(–2.0 to –4.9)
Control	+1.8	(+1.2 to +2.3)	+2.6	(+2.2 to +3.2)

MIC of telithromycin against H. influenzae in this study: 1 or 2 µg/mL.

The in vitro bactericidal activity of telithromycin against H. influenzae has been assessed by kill kinetics using the HTM medium, and was shown to be strain- and inoculum size-dependent. For some isolates, with 10⁷ cfu/mL as a starting inoculum, bacteriostatic activity was recorded (e.g., strain CI012). Telithromycin appeared to be less bactericidal against ampicillin-resistant H. influenzae type b, but variations were observed for ampicillin-resistant H. influenzae isolates producing beta‑lactamase and also for non–beta-lactamase producing strains. UK/97/647/514

Activity in Haemophilus influenzae murine lung infections

In a first study in mice, animals were infected intratracheally with ~10⁷ cfu of H. influenzae 87169. The animals developed inflammatory bronchopulmonary disease that resolved spontaneously. Kinetics of bacterial killing were recorded over a 24-hour period following a single oral dose of antibacterial agents administered 16 hours after bacterial challenge. The MIC values were 1.0 µg/mL for telithromycin, 0.25 µg/mL for azithromycin, and 2.0 µg/mL for erythromycin A. Results for kill kinetics are summarized in the table below. F/96/004/550

Table 3-5. Efficacy of telithromycin in H. influenzae lung infections in mice at
9 and 24 hours postdosing

Treatment	N	Dosage (mg/kg)	log₁₀ cfu/lungs at 9 hours (mean ± std dev.)	log₁₀ cfu/ reduction at 9 hours	log₁₀ cfu/lungs at 24 hours (mean ± std dev.)	log₁₀cfu/ reduction at 24 hours
Control (saline)	5	–	7.25 ± 0.49	0.0	6.52 ± 0.25	0.0
Erythromycin A	5	100	6.80 ± 0.25	–0.45	5.83 ± 0.60	–0.69
Telithromycin	5	50	4.45 ± 0.21*	–2.80	3.65 ± 0.38*	–2.87
	5	100	3.97 ± 0.25*	–3.28	3.42 ± 0.35*	–3.10
Azithromycin	5	50	5.15 ± 0.25*	–2.10	3.92 ± 0.15*	–2.60
	5	100	4.26 ± 0.18*	–2.99	3.88 ± 0.22*	–2.64

N = number of mice

*p £0.05 compared with control or erythromycin A.

At 24 hours, telithromycin 50 mg/kg showed comparable lung bacterial clearance compared with azithromycin 100 mg/kg, and greater clearance compared with erythromycin A. Assays at 3 hours demonstrated greater activity for telithromycin (50 mg/kg) compared with azithromycin (100 mg/kg), with a lung burden of 5.96 ± 0.45 log₁₀ cfu/lungs for telithromycin and 6.71 ± 0.39 log₁₀ cfu/lungs for azithromycin.F/96/004/550

Studies in mouse models of experimental murine pneumonia due to H. influenzae showed that telithromycin 50 mg/kg had a faster onset of activity against H. influenzae than azithromycin 100 mg/kg. Lung bacterial clearance was comparable for the 2 compounds at 24 hours.

In a second study, mice were infected intratracheally with 10⁸ cfu of H. influenzae type b. The lung clearance of H. influenzae was analyzed after oral therapy with telithromycin (50 mg/kg), azithromycin (100 mg/kg), amoxicillin (25 mg/kg), pristinamycin (100 mg/kg), clarithromycin (100 mg/kg), and erythromycin (100 mg/kg). Therapy started 4 hours after bacterial challenge and was subsequently administered every 6 hours for a total of 4 doses. The lungs were removed for analysis 6 hours after the last dose. Results are summarized below:

Table 3-6. Lung clearance of H. influenzae in murine lung tissues after therapy with telithromycin and other antibacterial agents USA/97/647/524

Treatment	Dosage (mg/kg/day)	MIC (µg/mL)	Plasma levels (µg/mL)		Sterile/ total	log₁₀ cfu/g lung
			C_{30 min}	C_{90 min}		Median	Range
Control	–	–	–	–	0/35	9.1	8.7 – 9.6
Telithromycin	50	1.0	3.2	3.9	3/12	4.3	2.1 – 5.1
Azithromycin	100	1.0	0.8	1.8	5/18	3.9	1.7 – 4.2
Erythromycin A	100	8.0	6.1	3.6	0/12	5.4	5.1 – 5.7
Clarithromycin	100	8.0	3.2	2.8	0/12	5.7	5.6 – 6.0
Pristinamycin	100	1.0	2.2	0.8	0/14	7.4	6.5 – 8.4
Amoxicillin	25	8.0	12	1.3	0/15	8.6	7.3 – 9.7

Telithromycin 50 mg/kg showed activity comparable with that of azithromycin 100 mg/kg in this model, and greater activity than other compounds tested. USA/97/647/524

Moraxella catarrhalis

Telithromycin was tested against 1108 isolates of M. catarrhalis, against which it displayed in vitro activity comparable with clarithromycin. The MIC₅₀ values for telithromycin ranged from 0.02 to 0.25 µg/mL, and MIC₉₀ values from 0.03 to 0.5 µg/mL. The MIC₅₀ values for clarithromycin ranged from 0.03 to 0.25 µg/mL, and MIC₉₀ values from 0.06 to 0.25 µg/mL. 11 internal reports

There are difficulties in performing kill kinetics experiments with M. catarrhalis, probably associated with aggregation of the organism in the test tube, particularly for high inoculum size explaining discrepancies between the different investigations.

Telithromycin, like 14- and 15-membered ring macrolides, is slowly bactericidal against M. catarrhalis. At 8 x MIC, a reduction of 3 log₁₀ cfu/mL was observed at 12 and 24 hours. USA/97/647/513. USA/96/004/515 UK/97/647/514 Another study demonstrated a reduction of approximately 4 log₁₀ cfu/mL after 12 hours of contact between M. catarrhalis and telithromycin. CDN/98/647/572

3.4.2 Bordetella species

Bordetella pertussis and B. parapertussis are the etiologic agents of whooping cough, and 14- and 15-membered ring macrolides are reference antibacterial agents for this infection. The in vitro activity of telithromycin was investigated against 133 isolates of B. pertussis. Results showed that MIC₅₀ values for telithromycin were 0.01 to 0.03 µg/mL, and MIC₉₀ values were 0.01 to 0.06 µg/mL. The MIC₅₀ values for clarithromycin were 0.01 to 0.06 µg/mL, and MIC₉₀ values were 0.03 to 0.06 µg/mL.

The MIC₅₀ and MIC₉₀ values for telithromycin against 31 B. parapertussis isolates were 0.12 µg/mL, and 0.25 µg/mL respectively.

3.5 Activity against beta-hemolytic streptococci (Streptococcus pyogenes and other streptococci)

S. pyogenes (Lancefield Group A streptococci) and Lancefield Group C and G streptococci are responsible for tonsillitis. In vitro and in vivo activities of telithromycin against S. pyogenes were investigated.

3.5.1 In vitro studies with beta-hemolytic streptococci

Telithromycin displayed good in vitro activity against b-hemolytic Lancefield Group A (N=1445), B (N=464), C and G (N=251), and F (N=41) streptococci isolates. For telithromycin, MIC₅₀ values were £0.008 to 0.03 µg/mL and MIC₉₀ values were 0.015 to 0.06 µg/mL against erythromycin A-susceptible strains. Telithromycin showed comparable in vitro activity to clarithromycin.

When an efflux mechanism of resistance to erythromycin A was present, MIC_50/90 values for telithromycin rose to 2.0 µg/mL. Against the few isolates in which an erm B gene was the underlying mechanism of resistance to erythromycin A, MIC values for telithromycin reached >16 µg/mL. For erm TR-containing S. pyogenes, MIC values ranged from 0.03 to 0.25 µg/mL; however, for one isolate, an MIC of 64 µg/mL was recorded. SF/99/647/505

Telithromycin showed bactericidal activity at 4 x MIC and at 6 hours against S. pyogenes erythromycin A-susceptible isolates and against erythromycin A-resistant (M-phenotype) isolates. Against erm B-containing S. pyogenes isolates, telithromycin was bacteriostatic. Telithromycin was highly active against other b-hemolytic streptococci (Group C, G, and F) (MIC_50/90 ≤0.015 to 0.06 µg/mL). In studies conducted at several centers, the MIC₅₀ range against Lancefield Group B streptococci was 0.008 to 0.06 µg/mL and the MIC₉₀ range was 0.015 to 0.12 µg/mL.

3.5.2 In vivo studies of activity against beta‑hemolytic streptococci

The efficacy of telithromycin in a murine model of Group A streptococcal necrotizing fasciitis/myonecrosis was compared with that of clindamycin (the reference therapy in this model) and penicillin G. Female mice were inoculated in the thigh with S. pyogenes ATCC 12384 with an inoculum size of 10⁷ to 10⁹ cfu/100 mL. The infection was 100% lethal in untreated animals. Clindamycin provided complete protection, irrespective of inoculum size. Telithromycin provided significantly greater protection compared with penicillin G for all inocula sizes.USA/97/647/509

3.6 Activity against atypical and intracellular micro-organisms

3.6.1 Intracellular concentration of telithromycin

Telithromycin (like the macrolides, fluoroquinolones, tetracycline, and clindamycin) concentrates in various types of cells. Telithromycin also exhibits a phase of steady efflux from the cells, which results in maintenance of inhibitory extracellular levels.

Polymorphonuclear neutrophils (PMN)

The in vitro uptake of [³H]-telithromycin was investigated using a velocity gradient centrifugation technique. Telithromycin (extracellular concentration of 2.5 µg/mL) was gradually concentrated by PMN with an intracellular/extracellular concentration ratio reaching 27.0 ± 8.1 at 5 minutes and 348 ± 27.1 at 180 minutes.

Telithromycin was located mainly in the granule fraction of PMN (56 ± 10.9%). Telithromycin was gradually released from drug-loaded PMN placed in a drug-free medium. In the first 5 minutes, approximately 20% of telithromycin was effluxed from the cell; after 5 minutes, the efflux slope was slower, with approximately 60% telithromycin remaining in the cell at 1 hour. The uptake of telithromycin was temperature dependent [50]@@Labro et al., 1997.

Macrophages

Uptake by peritoneal macrophages was rapid, with an intracellular/extracellular (C/E) ratio of 65 (extracellular concentration of 2 µg/mL) after 60 minutes. The intracellular penetration of telithromycin was not saturable (extracellular concentrations 2.0 to 25 µg/mL). E/96/004/582

Epithelial cells

After 20 minutes of incubation (extracellular concentration 2.0 µg/mL), the C/E ratio of telithromycin was 7 in McCoy cells and 11 in HEp-2 cells. E/96/004/582 The kinetics of telithromycin efflux were rapid. After 60 minutes of incubation in an antibacterial-free medium, the amount of cell-associated telithromycin was 10% in McCoy cells and 32% in HEp-2-cells.

3.6.2 Activity against atypical or intracellular pathogens involved in lower respiratory tract infections

Three intracellular or atypical pathogens are commonly associated with infections known as atypical parenchymal lower RTIs: Chlamydia (Chlamydophila) pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. Other intracellular pathogens are also responsible for lung parenchymal infections, but to a lower extent : Chlamydia psittaci and Coxiella burnetii.

3.6.2.1 Chlamydia pneumoniae

C. pneumoniae is an obligate intracellular pathogen. Different cell lines were used to test the in vitro activity of telithromycin against C. pneumoniae, and the results are summarized in the table below.

Table 3-7. In vitro activity of telithromycin against C. pneumoniae

*C. pneumoniae*	N	MIC (µg/mL)	MCC (µg/mL)	Medium
Clinical isolates	5	0.12 – 0.25	–	McCoy cells
Clinical isolates	15	0.03 – 2.0	0.03 – 2.0	HEp-2 cells
TW 183	1	0.06	0.12	McCoy cells
ATCC VR1310	1	0.0156	2.5	HEp-2 cells
G954	1	0.0156	0.312	HEp-2 cells

MCC: minimum chlamydicidal concentration.

Telithromycin exhibits a good in vitro and bactericidal activity against C. pneumoniae.

3.6.2.2 Legionella pneumophila

In vitro, telithromycin was active against various strains of L. pneumophila as well as against other Legionella species. Therapeutic efficacy of telithromycin was demonstrated in animal models of L. pneumophila infection.

In vitro activity against Legionella pneumophila

· Telithromycin was tested against approximately 140 strains of L. pneumophila. The resulting MIC_50/90values were 0.015 to 0.06 µg/mL and 0.03 to 0.12 µg/mL, respectively, in buffered yeast extract agar (BYE). USA/96/004/523, UK/96/004/542 However, in buffered charcoal yeast extract (BCYE a), MIC_50/90values increased to 2 µg/mL. The presence of charcoal in BCYE a is known to impair the in vitro activity of several antibacterial agents.

· The postantibiotic effect (PAE) of telithromycin on L. pneumophila was 4.6 hours, recorded at 2 x MIC, compared with a PAE of 1.0 hours with erythromycin A.

· Using broth dilution techniques, bactericidal synergy of telithromycin was shown in combination with rifampin. USA/96/004/515

· Telithromycin was active against intracellular L. pneumophila F2111 and F889 (guinea pig alveolar macrophages). USA/95/004/503

· The bactericidal activity of telithromycin was assessed against L. pneumophila serogroup 1 (strain CB 81-13) within monocyte-derived macrophages, and the results are summarized in the table below.

Table 3-8. Intracellular bioactivity of telithromycin against L. pneumophila 98/10231A/MC

Treatment	Extracellular conc. (µg/mL)	Telithromycin cfu	Erythromycin Group cfu
Control	–	7.0 ± 0.85	7.0 ± 0.85
Telithromycin or Erythromycin A	0.0125	7.15 ± 0.28	7.65 ± 0.27
	0.025	6.15 ± 0.45	6.60 ± 0.28
	0.05	5.36 ± 0.25	5.65 ± 0.50
	0.10	4.25 ± 0.59	4.16 ± 0.35

· For a low extracellular concentration (0.05 µg/mL) of telithromycin, an inhibition of intracellular multiplication of L. pneumophila has been demonstrated.

· The antibacterial activity of telithromycin alone or in combination with rifampin has been determined against L. pneumophila L-1033 serogroup 1 within human monocytes. Telithromycin antibacterial activity was observed at 0.25 x MIC and increased with 2.5 x MIC and 10 x MIC. Combination of telithromycin with rifampin at 10 x MIC produced activity that was comparable with that of telithromycin alone.

· There is a prolonged intracellular activity of telithromycin. USA/96/004/516

In vivo activity in animal models of Legionella pneumophila infection

In vivo efficacy of telithromycin against L. pneumophila was investigated in Dunkin-Hartley strain male guinea pig models of infections.

In the first study, 16 male guinea pigs per group were infected with L. pneumophila serogroup 1 (strain F889) by the intratracheal route. Animals were completely protected by oral or intraperitoneal telithromycin 10 mg/kg administered once daily for 5 days, begun on day 1 after infection. All animals that received placebo died.

In the second study, 16 male guinea pigs per group were infected with L. pneumophila serogroup 1 (strain Paris CB81-13) by the intraperitoneal route. At 48 hours after infection, animals received 2 daily oral doses of telithromycin, erythromycin A, or placebo for 2 days. 98/10231A/MCSurvival rates are summarized in the table below.

Table 3-9. Survival of guinea pigs infected with L. pneumophila 98/10231A/MC

Treatment	Survival rate (%)
	15 mg/kg	30 mg/kg	60 mg/kg
Control	6	0	10
Telithromycin	86	89	90
Erythromycin A	14	60	67

At all dosages, telithromycin was more effective than erythromycin A.

Mycoplasma pneumoniae

In vitro activities of telithromycin against M. pneumoniae were studied by 4 investigators. Methods are not yet standardized, yielding variations in results from different laboratories.

Telithromycin was very active against M. pneumoniae. Against 90 isolates, MIC_50/90 values ranged from 0.001 to 0.005 µg/mL.

In a separate study, the comparative in vitro activity of telithromycin and 7 other antibacterial agents was investigated against M. pneumoniae. 99/11182/MCTelithromycin was more active than the 14- and 16‑membered-ring macrolides tested, and was more active than minocycline and levofloxacin, as shown in the table below.

Table 3-10. In vitro activity of antibacterial agents against
M. pneumoniae (N = 41)99/11182/MC

Antibacterial agent	MIC (µg/mL)
	MIC₅₀	MIC₉₀	Range
Telithromycin	0.00097	0.00097	0.00024 – 0.0019
Erythromycin A	0.0039	0.0078	0.0019 – 0.0078
Clarithromycin	0.0019	0.0019	0.00048 – 0.0039
Roxithromycin	0.0039	0.0078	0.0019 – 0.0078
Azithromycin	0.00024	0.00048	0.00006 – 0.00048
Josamycin	0.0078	0.0156	0.0019 – 0.0313
Minocycline	0.125	0.25	0.062 – 0.25
Levofloxacin	0.25	0.25	0.125 – 0.5

Chlamydia psittaci

Telithromycin displays in vitro activity against Chlamydia psittaci 4521UC1 strain (MIC and MCC values: 0.006 µg/mL) 97/9550/PH and against C. psittaci 1058 strain (MIC 0.25 µg/mL and MCC 0.5 µg/mL) [9]@@Boswell et al., 1998.

Coxiella burnetii

The bacteriostatic activity of telithromycin was determined against 3 strains of C. burnetii: the Nine Mile strain (reference strain in acute infections), Q-212 strain, and the Priscilla strain (reference strains in chronic infections). Assays were conducted using human fibroblasts (HEL).

Table 3-11. Susceptibility of C. burnetii to telithromycin and erythromycin A

Strain	MIC (µg/mL)
	Telithromycin	Erythromycin A
Nine Mile	1.0	>8.0
Priscilla	1.0	>8.0
Q‑212	1.0	>8.0

Telithromycin exhibited in vitro activity against C. burnetii, while erythromycin A was inactive. Telithromycin, like other antibacterials, did not exhibit bactericidal activity against the 3 strains of C. burnetii tested. F/97/647/537

3.7 In vitro activity against other pathogens

3.7.1 Staphylococcus aureus

Telithromycin demonstrated activity against 2263 S. aureus isolates with different patterns of resistance to methicillin and erythromycin A. The MIC₅₀ values ranged from 0.06 to 0.12 µg/mL, and MIC₉₀ values ranged from 0.12 to 0.25 µg/mL, irrespective of susceptibility to oxacillin (methicillin). For an S. aureus isolate harboring an inducible MLS_B mechanism of resistance, MIC₅₀ and MIC₉₀ values remained in the range 0.06 to 0.25 µg/mL. However, when an isolate of S. aureus harbored a constitutive MLS_B mechanism of resistance, MIC₅₀ values were above 16 µg/mL.

Irrespective of the species of coagulase-negative staphylococci, telithromycin MIC_50/90 values were 0.03 to 0.25 µg/mL with isolates susceptible to erythromycin A. When a constitutive MLS_B mechanism of resistance was present, the telithromycin MIC_50/90 value was above 16 µg/mL. In contrast, when an inducible MLS_B mechanism of resistance was present, MIC_50/90 values were of the same magnitude as those observed for erythromycin A‑susceptible strains.

3.7.2 Enterococcus species

Telithromycin exhibits in vitro activity against enterococci in the absence of underlying mechanisms of resistance (vancomycin, gentamicin, ampicillin). Telithromycin was active against E. faecalis (MIC₅₀ 0.12 to 1.0 µg/mL and MIC₉₀ 2.0 to 8.0 µg/mL) and Enterococcus species (MIC_50/90 £0.03 to 0.06/0.06 to 8.0 µg/mL), with a bimodal population distribution. Telithromycin also exhibited bimodal in vitro activity against E. faecium (MIC_50/90 £0.03/4.0 µg/mL).

3.7.3 Anaerobes

Telithromycin has been tested against numerous genera and species of anaerobic bacteria.

Telithromycin was active against gram‑positive cocci and bacilli. Against various Propionobacterium spp (N=66), MIC₅₀ was 0.015 mg/mL; against Peptostreptococcus spp (N=232), MIC₅₀ was 0.004 to 0.12 mg/mL; and against Clostridium difficile (N=169), MIC₅₀ was 0.06 to 1.0 mg/mL. Against C. difficile, which is a major cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis, telithromycin showed a bimodal distribution of activity.

The activity of telithromycin against gram-negative anaerobes was shown to be more species variable than against gram‑positive species. Telithromycin was active against Prevotella spp (N=753) (MIC₅₀ £0.008 to 0.25 mg/mL) and Porphyromonas spp (N=188) (MIC₅₀ 0.008 to 0.06 mg/mL). However, activity was lower against B. fragilis (N=244) (MIC₅₀ 4.0mg/mL) and Fusobacterium spp (N=261) (MIC₅₀ 1.0 to >32 mg/mL).

3.7.4 Other bacterial species

Telithromycin showed in vitro activity against a variety of other pathogens. These results are summarized in the table below.

Table 3-12. Summary of telithromycin in vitro activity against various other pathogens

Species/group studied		MIC (µg/mL)
	N	Range	MIC₅₀range	MIC₉₀range
Viridans group streptococci	1141	–	£ 0.003 - 0.25	£ 0.003 – 0.5
Corynebacterium diphtheriae	442	–	0.004	0.008
Listeria spp.	181	–	0.03 - 0.12	0.03 - 0.25
Lactobacillus spp.	124	–	0.007 - 0.03	0.03 - 0.12
Pediococcus spp.	40	–	0.007 - 0.03	£ 0.03
Leuconostoc spp.	91	–	£ 0.03	£ 0.03 - 0.25
Erysipelothrix rhusopathiae	10	£ 0.015 - 0.03	–	–
Micrococcus spp.	191	–	£ 0.03	£ 0.03
Stomatococcus spp.	63	–	£ 0.03	£ 0.03
Rhodococcus equi	31	£0.015 - 0.25	–	–
Neisseria meningitidis	448	–	0.015 - 0.12	0.03 - 0.25
Saprophytic Neisseria spp.	50	–	0.06 - 0.12	0.25 - 4.0

Telithromycin was very active against gram-positive bacilli and the other species listed above. Additionally, against Mycoplasma hominis, MIC₅₀ values for telithromycin were 2 to 32 µg/mL, and MIC₉₀ values were 4 to 32 µg/mL. The corresponding MIC₅₀ and MIC₉₀ values for clarithromycin were >32 to >64 µg/mL. Telithromycin exhibited bimodal activity against Corynebacterium jeikeium and C. urealyticum and good activity against other coryneforms.

Telithromycin was inactive against Enterobacteriaceae and nonfermentative gram-negative bacilli (e.g., Pseudomonas aeruginosa [MIC range 32 to >128 µg/mL], Acinetobacter baumannii [MIC range 2 to >128 µg/mL]).

3.8 Postantibiotic effect of telithromycin

A postantibiotic effect (PAE) is the suppression of bacterial growth that persists after short exposure to an antibacterial agent.

3.8.1 Postantibiotic effect in vitro

Several laboratories have investigated the PAE of telithromycin. Although methodology varied between laboratories (a factor that may influence the precise quantitative measurement of PAE), all studies clearly demonstrated a PAE for telithromycin. Telithromycin exhibited a PAE against S. pneumoniae of 1.5 to 3.8 hours, and a PAE of 0.3 to 2.4 hours against S. aureus and 0.4 to 2.7 hours against S. pyogenes.

Telithromycin exhibited a significant PAE against other species involved in RTIs, including H. influenzae (2.2 to 6.2 hours) and M. catarrhalis (2.5 to 5.0 hours).UK/96/004/538

3.8.2 Postantibiotic effect in vivo

Studies with S. pneumoniae ATCC10813 in mice demonstrated that telithromycin exhibits concentration-dependent killing with a prolonged in vivo PAE.R2000MIC0025 These results are shown in the table below.

Table 3-13. In vivo postantibiotic effect of telithromycin against S. pneumoniae in mice

Telithromycin	Time to grow one log₁₀ cfu/thigh (h)
dosage (mg/kg)	Control	Treated	PAE
0.29	2.81	3.69	0.88
1.17	2.81	3.44	0.63
4.69	2.81	6.05	3.24
18.8	3.03	8.82	5.79

At low dosages, the PAE was approximately 1 hour, but at higher doses, the PAE was from 3.2 to 5.8 hours.

3.9 Resistance

3.9.1 Mechanisms of resistance to erythromycin A

All 14- and 15-membered ring macrolides derived from erythromycin A share the same mechanism of resistance. The mechanisms of resistance to erythromycin A are complex and can be divided into three main patterns:

· Housekeeping

· Defensive

· Preventive.

Each of these mechanisms is described in the sections that follow.

3.9.1.1 “Housekeeping”

3.9.1.1.1 Efflux mechanism of resistance

In gram-positive cocci, efflux pumps for erythromycin A have been described for S. aureus (msrA), coagulase-negative staphylococci (msrA, msrB), S. pyogenes (mefA], S. pneumoniae (mefE), S. agalactiae(mefA and E, mreA), and viridans group streptococci (mefE and mefA). These pump proteins bind to erythromycin A and pump molecules out of the bacterial cells, resulting in reduced intracellular concentrations of erythromycin A.

3.9.1.1.1.1 The mef mechanism of efflux

The mef gene has been found in various gram-positive bacteria: Streptococcus spp, Micrococcus spp, Corynebacterium spp, and Enterococcus spp. Strains harboring a mef mechanism of resistance are also known as M-phenotype.

In streptococci, two genes encode for efflux pump proteins: mef for all streptococci and mreA for S. agalactiae [21]@@Clancy et al., 1997. The most important mef gene with respect to S. pneumoniae, and therefore telithromycin, is mefE. Telithromycin MIC₅₀ values are greater against S. pneumoniae isolates carrying a mefE gene than others, but remain within the likely therapeutic range. Against S. mitis/S. oralis isolates harboring a mefE⁺ gene, telithromycin MICs were 0.06 to 1.0 µg/mL and against 18 isolates of S. agalactiae with the M-phenotype (mefA⁺ or mefE⁺), telithromycin MICs ranged from 0.1 to 0.2 µg/mL, in comparison with MICs of 0.02 µg/mL for erythromycin A-susceptible isolates.

The mefA gene has been described in a variety of bacterial species, including S. pyogenes, S. agalactiae, viridans group streptococci (S. mitis, S. milleri), Lancefield group C, F, and G streptococci, Micrococcus spp, Listeria spp, Corynebacterium jeikeium, and Enterococcus faecium. The mef A gene appears to be inducible by 14- and 15-membered ring macrolides but not by 16‑membered ring macrolides. Further, 16-membered ring macrolides are not good substrates for Mef A protein.

For telithromycin, an analogous effect to the pneumococcal Mef E pump was shown for mefA in S. pyogenes. Strains expressing this gene exhibited higher telithromycin MICs compared with strains without the gene, nevertheless, the MICs remained within the therapeutic range.

3.9.1.1.1.2 Mre A mechanism of efflux

A putative efflux pump Mre A from a Streptococcus agalactiae strain conferred resistance to
14-, 15-, and 16-membered ring macrolides. Telithromycin retained good activity against S. agalactiae harboring the mreA gene. MIC_50/90 values for telithromycin were £0.015 mg/mL in comparison with clarithromycin, for which MIC values ranged from 0.5 to 4.0 mg/mL [84]@@Willey et al., 2000.

3.9.1.1.1.3 The Msr A mechanism of efflux

Msr A protein is a member of the ABC superfamily of efflux pumps, and is specific to 14- and 15‑membered ring macrolides and streptogramin B. The msrA gene has been sequenced from S. epidermidis and S. aureus. The 14- and 15-membered ring macrolides and telithromycin (but not 16-membered ring macrolides) act as inducers of msr genes [30,66]@@Eady et al., 1993,@@Ross et al., 1996. However, the ketolides are poor substrates for Msr pumps.

3.9.1.1.2 Bottle brush

Erythromycin A resistance can be conferred by short pentapeptides with specific amino acid sequences. The synthesis of pentapeptides is due to translation of minigene sequences within 23S rRNA [74]@@Tenson et al., 1996. This mechanism of resistance is also known as bottle brush.

In bottle brush resistance, the newly synthesized pentapeptide actively displaces the macrolides or ketolides from the ribosome. After the macrolide is removed, the ribosome can either initiate synthesis of new polypeptides or can bind another molecule of macrolide or ketolide.

3.9.1.2 Defensive mechanism of resistance

The second mechanism of resistance for bacterial cells to xenobiotics is to render the ribosomal targets (the peptidyl transferase site) inaccessible. Two main mechanisms have been described: blockade of the binding site of erythromycin A by mono- or dimethylation (erm gene system) or transformation of the binding site by in situ mutation or indirectly by mutation on certain ribosomal proteins that modify the stereochemistry of the peptidyltransferase site.

3.9.1.2.1 Mono- or dimethylated ribosome: the erm gene system

MLS_B resistance is the consequence of induction of the synthesis of 23S rRNA methylase activity. This adds 1 or 2 methyl groups to a single adenosinyl residue (A-2058) on the N⁶ amino group of adenine, or to one of the adjacent residues A-2057 or A-2059 in the peptidyltransferase loop of domain V of the 23S rRNA. This prevents access of erythromycin A to its binding site on the ribosome [28,81]@@Douthwaite, 1993,@@Weisblum, 1995.

MLS_B resistance may be constitutively expressed or induced by subinhibitory MIC concentrations of 14- and 15-membered ring macrolides [80]@@Weisblum, 1985. MLS_B resistance is due to erm (erythromycin resistance methylase) genes.

A total of 20 different erm genes have been described [65]@@Roberts et al., 1999. S. pneumoniae isolates resistant to erythromycin A by an MLS_B mechanism of resistance harbor the ermB gene. S. pyogenes isolates resistant to erythromycin A harbor ermB or ermTR genes. The ermA and ermC genes are found in S. aureus and coagulase-negative staphylococci. The ermC gene is found mainly in animal staphylococci. Many erm genes are often associated with other antibiotic-resistant genes, especially tetracycline-resistant genes. The ermF gene is often linked with the tetQ gene.

Telithromycin retains activity against S. aureus resistant isolates when an inducible mechanism of resistance is involved (MIC_50/90 0.12 and 0.25 mg/mL), but not when MLS_B resistance is constitutively expressed (MIC >128 mg/mL).

Against S. pneumoniae, telithromycin retains good in vitro and in vivo activity, as demonstrated in animal models (lung infections) and clinical trials. There is no correlation between MIC values for telithromycin (from 0.002 to 1.0 mg/mL) and the expression of the erm gene in bacterial cells. Numerous studies investigated the influence of an underlying mechanism of resistance to erythromycin A on telithromycin antipneumococcal activity. Results, including epidemiological surveys, showed that S. pneumoniae isolates for which telithromycin exhibited MICs >2 mg/mL are rare, with an incidence of approximately 0.001%.

For S. pyogenes, two erm genes are involved: ermB and ermTR. The in vitro activity of telithromycin differs according to the gene that is expressed. For ermTR-containing S. pyogenes, MIC values for telithromycin ranged from 0.03 to 0.25 mg/mL (except for 1 strain MIC 64 mg/mL), and for ermB-containing strains, MIC values for telithromycin ranged from 0.5 to 64 mg/mL. SF/99/647/605

3.9.1.2.2 Mutations

Resistance to erythromycin A can be achieved by mutation affecting 23S rRNA sequences or the amino acid sequences of at least two ribosomal proteins, L4 and L22 [17]@@Chittum et al., 1994.

3.9.1.2.2.1 Mutations on 23S rRNA

A-2058®G mutation on 23S rRNA has been described in some bacterial species, rendering them resistant to erythromycin A and its derivatives. These mutations have been described in Helicobacter pylori [42]@@Hulten et al., 1997, Mycoplasma pneumoniae [82]@@Weisblum, 1998, Treponema pallidum [69]@@Stamm et al., 2000, Propionibacterium acnes [67]@@Ross et al., 1997, and Mycobacterium avium complex [82]@@Weisblum, 1998.

The ribosomal affinities of both erythromycin A and clarithromycin are lowered 10⁴‑fold by A‑2058®G mutation. The binding affinity of telithromycin is also lowered by the A-2058®G mutation, but to a lesser extent. Telithromycin activity remains at least 20- to 60‑fold greater than that of erythromycin A and clarithromycin [29]@@Douthwaite et al., 2000.

3.9.1.2.2.2 Mutations on protein ribosomal L4 and L22

Clinical isolates of S. pneumoniae isolates containing ribosomal mutations in proteins have been reported in Bulgaria, Slovakia, and Poland [71]@@Tait-Kamradt et al., 2000a. Against 19 S. pneumoniae isolates resistant to erythromycin A (MIC >64 mg/mL) but susceptible to clindamycin and streptogramin B, a mutation on protein L4 at ₆₉GTG ₇₁®₆₉ TPS₇₁ was reported. Footprinting experiments in ribosomes from the E. coli L4 mutants revealed that the conformation of 23S rRNA in domain II (A-789, G-799 and U-1255) and domain V (A-2572) is altered relative to the wild type strain. Telithromycin retained activity against these isolates.

3.9.1.3 Preventive mechanism of resistance

The degradative enzymes produced by micro-organisms that are known to inactivate macrolide antibiotics are the glycosylases and phosphorylases. However, this mechanism is limited to bacterial species such as Nocardia spp [57]@@Morisaki et al., 1995. These enzymes fix a glucose moiety or a phosphate on the 2′OH substituent of the D-desosamine moiety, an amino sugar at position 5 of the erythronolide A ring. By this mechanism, erythromycin A, its derivatives, and telithromycin are inactivated to various degrees. The same enzymes also render Nocardia spp resistant to telithromycin. Although of interest scientifically, these are of little relevance to the potential clinical use of telithromycin.

The erythronolide A ring may be hydrolyzed by esterases I or II from E coli, but this enzymatic activity is not known for telithromycin.

3.9.2 Resistance to telithromycin

Telithromycin is inactive against S. aureus isolates harboring an erm gene of constitutive type. MIC values for telithromycin are above 32 mg/mL. Within S. pyogenes isolates resistant to erythromycin A and harboring an ermB gene, telithromycin MIC values for some isolates are >16 mg/mL.

Other potential mechanisms of resistance have been reported from mutants obtained in the laboratory: L4 protein and L22 ribosomal mutants, 23S rRNA mutants, and K-peptide.

3.9.2.1 L4 mutants

Two types of L4 mutations have been observed. For a mutation at ₆₉GTG₇₁ leading to ₆₉TPS₇₁, 8-fold increases in telithromycin MIC values have been recorded in S. pneumoniae (MIC 0.03 to 0.1 mg/mL vs MIC 0.006 mg/mL for wild type). In type II mutants (₆₃KPW RQK GTG REK GTC RAR₇₄), increases in telithromycin MIC values up to 500-fold have been recorded (MIC 1.56 to 3.13 mg/mL vs MIC 0.006 mg/mL for the wild type) [72]@@Tait-Kamradt et al., 2000b.

3.9.2.2 L22 mutants

A mutation in ribosomal protein L22 produces an increase in telithromycin MIC values of about 10‑fold. However, the activity of telithromycin remains within the therapeutic range [12]@@Canu et al., 2000.

3.9.2.3 Mutations on 23S rRNA

Mutations of the 23S rRNA, which may increase MICs for telithromycin, have been artificially created by mutation selection in the laboratory. Summarized below are the mutations characterized to date. At this time, these remain laboratory curiosities and their likelihood of arising in the clinic is not known.

· Mutations at U 2609

A novel mutation at U 2609®C has been described, which confers resistance to telithromycin but increases bacterial cell susceptibility to erythromycin A. This mutation appears to be located within the compound binding site and may directly affect interaction of the telithromycin molecule with the ribosome.

· Mutations on domain II: A-752

One mutant selected by clarithromycin, resistant to 14- and 15-membered ring macrolides (MIC >32 mg/mL), and with decreased susceptibility to telithromycin (MIC 4 mg/mL) had a single base deletion (A-752) in domain II [12]@@Canu et al., 2000.

· Mutation at C-2611

The C-2611®U mutation confers mild macrolide-ketolide resistance that does not extend to other members of the MLS group. This has been characterized in laboratory studies [77,78]@@.

· Mutation on domain V

In laboratory studies, mutations at A-2058/2059 of domain V of 23S rRNA yielded 3 different mutations: A-2058®T, A-2059®G, A-2058®G. Telithromycin in vitro activity decreased in comparison with wild type [12]@@Canu et al., 2000.

· Mutation U 754

Mutation in the hairpin 35 at U 754®A renders bacterial cells resistant to low concentrations of erythromycin A and telithromycin [85]@@Xiong et al., 1999.

3.9.2.4 K-peptide

K-peptide, a specific pentapeptide acting as a bottle brush, which cleans the ribosome from the bound antibiotic, confers resistance to the ketolides.

3.9.3 Inducible MLS_B resistance

It has been shown that ketolides, which lack L-cladinose at position 3 of the erythronolide A ring, are unable to induce MLS_B resistance. The ability to induce MLS_B resistance was investigated for telithromycin and its L-cladinose counterpart (RU 69874), and 14-membered ring macrolides with and without L-cladinose. Erythromycin A, azithromycin, clarithromycin, and RU 69874 (all bearing a 3–a-L-cladinose moiety) were strong inducers of MLS_B resistance in erythromycin A-inducible resistance strains. In contrast, telithromycin (with no L-cladinose moiety) was unable to induce resistance to erythromycin A [55]@@Mauvais et al., 2000.

Induced bacterial cultures containing subinhibitory concentrations of erythromycin A, telithromycin, or an uninduced control were challenged with 50 mg/mL of erythromycin A. Bacterial growth was lowest for telithromycin throughout much of the assessment time. 98/10215/PH

3.9.4 Selection of resistant mutants

3.9.4.1 Serial passage experiments

Appelbaum, Davies et al examined the ability of sequential subcultures in subinhibitory concentrations of telithromycin, azithromycin, roxithromycin, clindamycin, and pristinamycin to select for resistance. The study was performed in five erythromycin A-susceptible and six erythromycin A-resistant strains of S. pneumoniae. The latter group consisted of 3 strains containing mefE genes and 3 strains containing ermB genes. The findings can be summarized as follows:

· Overall, 54 mutants were derived with increased MICs to at least one of the antibiotics. Only three of these mutants exhibited telithromycin MICs of >1 µg/mL, compared with 34 and 28 mutants exhibiting MICs of >1 µg/mL to azithromycin and clarithromycin, respectively.

· In three of the five erythromycin A-susceptible S. pneumoniae strains tested, no mutants were selected, even after 50 passages with telithromycin. In contrast, passage in erythromycin A resulted in mutants for all 5 strains, and clarithromycin and azithromycin selected for 4 mutants.

· While exposure to telithromycin did select for pneumococcal mutants with increased MICs, most remained within the proposed susceptibility range and, furthermore, telithromycin selected mutations in the least number of strains, compared to the other MLS agents.

In summary, telithromycin was shown to have good in vitro activity against strains containing mefE and ermB genes and against in vitro-selected mutants resistant to the 14- and 15-membered ring macrolides, clindamycin, and pristinamycin [24,51].

3.9.4.2 Spontaneous mutation experiments

Plating of high populations of S. pneumoniae strains onto agar containing telithromycin showed that the spontaneous mutation frequency (i.e., recovering colonies that grew at telithromycin concentrations higher than the MIC) was less than 1x10^-8, which is considered to be low.

3.10 Microbiology summary

· Telithromycin is a new medicinal chemical entity belonging to the ketolide class, with a unique chemical structure.

· Telithromycin exhibits a new mode of action, inhibiting protein synthesis by a double interaction at the 23S rRNA of bacterial ribosomes and in the formation of both ribosomal subunits.

· These properties result in superior antibacterial activity of telithromycin against the main respiratory pathogens when compared with currently available 14- and 15-membered ring macrolides, with telithromycin being two- to four-times more active than clarithromycin against S. pneumoniae and exhibiting a comparable activity to clarithromycin and azithromycin against S. pyogenes and H. influenzae, respectively.

· Telithromycin exhibits potent antibacterial activity against S. pneumoniae isolates susceptible to erythromycin A and penicillin G. In addition, telithromycin exhibits high bactericidal activity against S. pneumoniae.

· Telithromycin retains activity against penicillin G-resistant isolates of S. pneumoniae and erythromycin A-resistant isolates harboring either an MLS_B or an efflux mechanism of resistance, or protein L4 ribosomal mutation.

· Telithromycin exhibits in vitro activity against S. pneumoniae isolates resistant to fluoroquinolones, cefotaxime-ceftriaxone, cotrimoxazole and tetracycline.

· Telithromycin selects mutants of S. pneumoniae at low frequency.

· Telithromycin is active against S. pyogenes, H. influenzae, M. catarrhalis, and S. aureus.

· Telithromycin is highly concentrated in phagocytes with a moderate efflux which leads to balanced intracellular and extracellular concentrations.

· Telithromycin is active against intracellular pathogens such as Chlamydia pneumoniae and Legionella pneumophila.

· Telithromycin is highly effective against atypical microorganisms such as Mycoplasma pneumoniae.

4. Nonclinical toxicology, pharmacokinetics and pharmacology

4.1 Toxicology

Repeated-dose oral toxicity studies of up to 6 months in duration were carried out in the rat, dog, and monkey, as summarized in the table below.

Table 4-1. Repeated-dose oral toxicity studies with telithromycin

Species	Route	Duration of dosing	Recovery period	Dose levels (mg/kg/day)
Rat	Oral	15 days	-	0, 100, 200, 400
		30 days^a	28 days	0, 50, 150, 300
		13 weeks^a	-	0, 20, 50, 150
		6 months^a	-	0, 150
		6 months^a	28 days	0, 20, 50, 150
Dog	Oral	15 days^a	-	0, 100, 400, 1000
		30 days^a	-	0, 50, 150, 300
		13 weeks^a	12 weeks	0, 20, 50, 150
Monkey	Oral	14 days	-	100, 200, 300
		28 days^a	-	0, 30, 60, 120

^a Studies with toxicokinetic support

In these studies, effects typical of macrolide antibiotics, as reported, for example, for erythromycin, azithromycin, and clarithromycin, were observed. Raised levels of transaminases, some increases in liver weights, and histological correlates of foci of hepatocellular necrosis were seen at higher doses in some but not all studies. Slight phospholipidosis was evident in some rat and dog tissues, with limited distribution and intensity.

The No Observed Adverse Effect Level (NOAEL) in the rat and dog studies was 50 mg/kg/day, whatever the duration of the study. All findings were reversible. Relative to exposure levels in man, these NOAELs gave ratios of 1.6 and 14 for rat and dog, respectively, based on free fractions of drugs and levels achieved in young adult humans. Based on literature data, comparative ratios for azithromycin are 4.5 and 24, respectively [32,37,53,62,68], while for clarithromycin they are 0.5 and 1.6, respectively [1,2,20,23,49].

The NOAEL of 60 mg/kg/day in the monkey corresponded to an exposure 3.4 times that in man at the therapeutic dose, again based on levels of free drug in young adult humans.

Reproductive toxicity studies were carried out in the rat and rabbit, as summarized in the following table.

Table 4-2. Reproduction toxicity studies with telithromycin

Study type	Species	Dosing period^a	Dose levels (mg/kg/day)
Fertility	Rat	M – Day 29 pm to Day 27 pc^c	0, 50, 150, 300
		F – Day 15 pm to Day 7 pc
Embryotoxicity	Rat	Days 6 to 17 pc^b	0, 50, 150, 300
		Days 6 to 17 pc^c	0, 50, 150, 300
	Rabbit	Days 6 to 18 pc^b	0, 30, 100, 300
		Days 6 to 18 pc^c	0, 20, 60, 180
		Days 6 to 18 pc^c	0, 20, 60, 180
Pre/post natal	Rat	Day 6 pc to Day 21 pp^c	0, 50, 125, 200

^a pm = premating; pc = post coitum; pp = post partum

^b Preliminary studies

^c Studies with toxicokinetic support

Telithromycin induced maternal toxicity at the high doses in both rats and rabbits; consequent delayed fetal growth and maturation was observed in both species, with a small number of malformations in rats at a maternally toxic dose of 300 mg/kg/day. No evidence of a direct teratogenic effect was observed. In the fertility study, fertility indices were slightly reduced at parentally toxic doses, but histological examination of testes at these dose levels in the 1, 3 and 6 month repeated dose studies in the rat did not show any adverse effects.

Telithromycin was not genotoxic in a standard battery of tests.

4.2 Pharmacokinetics

The pharmacokinetics of telithromycin have been investigated in the mouse, rat, dog, and monkey, the species used for pharmacology and toxicology studies.

Telithromycin was rapidly absorbed after oral administration to mice, dogs, and rats with bioavailabilities in the range of 36 to 54%. Volumes of distribution were large. Half-lives after intravenous administration were in the range of 1.2 to 2.3 hours.

Radioactivity was widely distributed in the rat after oral and intravenous administration, although levels in the central nervous system were low, indicating poor passage through the blood–brain barrier. Levels of radioactivity in tissue decreased in parallel to plasma levels with almost complete elimination of radioactivity by 24 hours after dosing.

In vivo metabolism studies showed that the main circulating metabolites in man were also seen in rats, dogs, and monkeys, in plasma or in urine.

Fecal elimination of radioactivity predominated in rats and dogs, as in humans. Studies in the rat confirmed biliary excretion and indicated a moderate enterohepatic circulation as well as the involvement of direct secretion of telithromycin into the gut lumen.

At concentrations of approximately 1 μg/mL, binding to serum proteins was approximately 90%, 60%, 45%, 50%, and 70% in mouse, rat, dog, monkey, and man respectively.

4.3 Safety pharmacology

Telithromycin has been subjected to a range of tests designed to evaluate its general pharmacological effect on body systems. In vivo tests were carried out by both the oral (doses up to 300 mg/kg) and intravenous routes (doses up to 15 mg/kg), while in vitro studies used concentrations of 0.1 to 500 µM. A concentration of 100 µM corresponds to 81.2 μg/mL. Few effects were observed apart from isolated findings at high doses.

Telithromycin was slightly emetic in the dog with a potency similar to that of clarithromycin but the effect was less pronounced than that of azithromycin or erythromycin. Telithromycin, unlike azithromycin or erythromycin, did not induce diarrhea in these animals. A delay in gastric emptying was seen in rats after oral doses of 100 and 300 mg/kg, but there was no action on intestinal transit and only a slight effect in reducing acidity of gastric contents. Telithromycin showed very weak binding to the human motilin receptor (23% at 100 µM) as compared to erythromycin (60% at 3 µM).

Cardiovascular effects of telithromycin have been investigated in the rat and dog, as well as in relevant in vitro procedures. In addition, observations on blood pressure, heart rate and ECG were included in the repeated-dose toxicity studies in the dog. These data are reported and discussed in the context of clinical safety (see Section 7.5, Assessment of the effects of telithromycin administration on cardiac repolarization).

5. clinical pharmacokinetics and dose determination

The clinical pharmacology of telithromycin was investigated in an extensive program involving 847 subjects. Twenty-three studies investigated pharmacokinetics, bioavailability and metabolism. Thirteen studies investigated interactions, 7 studies investigated special populations (30 subjects with renal impairment, 12 subjects with hepatic impairment, 58 elderly subjects ³65 years, 18 adolescents with RTIs, 24 subjects with cardiovascular disease).

The clinical pharmacokinetics of telithromycin were investigated in young and elderly healthy subjects at oral doses of 50 to 3200 mg, and at intravenous doses of 120 to 2000 mg (infused over 1.5 to 2.5 hours). Most of the studies in special populations, tissue penetration studies, and drug interaction studies were conducted using the oral therapeutic dose of 800 mg telithromycin once daily.

5.1 Absorption, distribution, metabolism, and elimination

5.1.1 Absorption/Bioavailability

The absorption of telithromycin in humans is estimated to be almost complete (90%). Prior to entering the systemic circulation, telithromycin undergoes first-pass due to metabolism mainly by the liver and to some extent by the intestine. The absolute bioavailability of an 800 mg oral dose of telithromycin was 57% in both young and elderly subjects (Study 1044).

A crossover food-interaction study was performed with a single oral 800 mg dose of telithromycin after an overnight fast and immediately after a standard high-fat breakfast (Study 1003). The rate and extent of telithromycin absorption were not modified by food, indicating that telithromycin may be administered with or between meals.

5.1.2 Distribution

Protein binding

Telithromycin was 60 to 70% bound to serum proteins in healthy young subjects, elderly subjects, and subjects with hepatic impairment. Albumin was the major serum fraction responsible for binding (25%), with minor contributions from acid a1-glycoprotein (11%) and the lipoproteins LDL, VLDL, and HDL (10% each). Binding was not saturable across the range of concentrations that arise from the therapeutic dose of telithromycin. This moderate level of binding, and the absence of significant saturation at therapeutic levels, mean that clinically relevant interactions by protein-binding displacement of telithromycin are unlikely.

Tissue distribution

The volume of distribution of telithromycin after intravenous infusion was high (2.9 L/kg) (Study 1044), and extensive tissue distribution was confirmed in various biological tissues after multiple dosing, as summarized in the table below.

Table 5-1. Concentrations of telithromycin in respiratory tissues and white blood cells after
oral dosing with telithromycin (800 mg)

Tissue	Subjects	Mean concentration (µg/mL)
		2-3h	6-8h	12h	24h	48h
Epithelial lining fluid	Healthy	5.4^a	4.2^d	–	1.17	0.30
	RTI patients	14.9^a	–	3.27	0.84	–
Alveolar macrophages	Healthy	65^a	100^d	–	41	2.15
	RTI patients	69^a	–	318	162	–
Bronchial tissue ^e	Healthy	0.68^a	2.2^d	–	3.5	LOQ
	RTI patients	3.88^a	–	1.41	0.78	–
Tonsils ^e	Tonsillitis	3.95^b	–	0.88	0.72	–
White blood cells (Day 5)	Healthy^f	64.6^a	72.1^c	39.4	14.1	–
(Day 10)	Healthy^f	83^a	60.9^c	40.6	20.9	8.9

^a 2h, ^b 3h, ^c 6h, ^d 8h, ^econcentrations in µg/g.

^f600 mg once a day; all other studies used 800 mg once a day.

LOQ = Below the lower limit of quantification; NC = not calculated; – = No data collected

The concentrations of telithromycin observed in tissues are high compared to the MIC values for telithromycin against the main pathogens encountered in RTIs. High concentrations in epithelial lining fluid and alveolar macrophages persisted for up to 48 hours after dosing.

In the case of epithelial lining fluid, the difference in concentrations measured 2 to 3 hours after dosing in the 2 studies can be attributed to differences between RTI patients and healthy subjects. In addition, small differences in sampling times at around the time of peak concentrations may have resulted in differences. The higher peak concentration measured in the RTI patients is considered more representative, and samples were obtained closer to the expected C_max. It is also relevant to note that the study in RTI patients was conducted in the unit of Prof. Wise at the Birmingham Chest Clinic, UK, with the same methodology used for other compounds, thereby enabling direct comparisons to be made.

At the dose of 800 mg telithromycin, the maximum concentration of telithromycin in saliva (3.1 µg/mL on days 1 and 10 of dosing) was higher than in plasma, and the concentrations were above the MIC₅₀ for group A, C, and G beta-hemolytic streptococci (0.008 to £0.06 µg/mL) (Study 1014). The same was also true for concentrations of telithromycin in the tonsils (Study 1028).

5.1.3 Metabolites of telithromycin

In plasma, the main circulating compound after administration of an 800 mg radiolabelled dose was telithromycin, representing 56.7% of the total AUC of radioactivity. The main metabolite, RU 76363, represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin (see table below). The antibacterial activities of the metabolites have been studied and are also summarized in the table below.

Table 5-2. Antibacterial activity of telithromycin and its main metabolites (Study 1009)

Analyte	AUC metabolite / AUC telithromycin	S. pneumoniae (Ery-R)		S. pyogenes (Ery-R)
	(%)	MIC₅₀ (µg/mL)	AUC/ MIC₅₀	MIC₅₀ (µg/mL)	AUC/ MIC₅₀
Telithromycin	–	0.03	247	0.06	123
RU 72365	2.97	0.03	7.4	0.5	0.44
RU 76584	2.03	0.12	1.2	1.0	0.15
RU 76363	12.6	0.12	7.3	1.0	0.87
RU 78849	2.22	>16	<0.01	>16	<0.01

The AUC/MIC ratios for all metabolites indicate that they contribute little to the antibiotic activity of telithromycin.

5.1.4 Pathways of elimination

The elimination pathways of telithromycin in humans have been investigated in a series of studies, from which the following conclusions can be drawn:

· After oral administration, approximately 90% of the dose is absorbed.

· Prior to entering the systemic circulation, telithromycin undergoes a first-pass effect (33% of dose). This effect is due to presystemic metabolism mainly by the liver, but also to some extent by the intestine.

· The 57% of dose reaching the systemic circulation as unchanged drug is eliminated by multiple pathways as follows:

- 7% is excreted unchanged in feces by biliary and/or intestinal secretion

- 13% is excreted unchanged in urine by renal excretion

- 37% is metabolized by the liver.

· Overall metabolism accounts for approximately 70% of the dose (33% pre-systemic and 37% systemic). About half of this metabolism is mediated by CYP3A4 and about half is non-CYP3A4 dependent.

The multiple elimination pathways of telithromycin limit the risk of increased exposure when any one pathway is impaired.

5.2 Pharmacokinetic characteristics of telithromycin 800 mg (single and multiple dose)

The pharmacokinetics of single and multiple once-daily dosing for 7 days with telithromycin were assessed in young healthy subjects (18 to 29 years) in a crossover study (Study 1008). The mean pharmacokinetic parameters for the 800 mg doses of telithromycin (the therapeutic dose) in this study are summarized in the table below.

Table 5-3. Pharmacokinetic parameters of telithromycin in young subjects after single and multiple (qd) oral dosing with telithromycin 800 mg (Study 1008)

Parameter	Mean (CV%)
	SD N = 18	MD₇ N = 18
Plasma
C_max (µg/mL)	1.90 (42)	2.27 (31)
t_max (h)	1.0 ^a [0.5-4.0]^b	1.0^a [0.5-3.0]^b
C_24h (µg/mL)	0.030 (45)	0.070 (72)
AUC(0-24h) (µg·h/mL)	8.25 (31)	12.5 (43)
t_1/2,_l1 (h) ^c	2.43 (41)	2.87 (50)
t_1/2,_lz (h)^c	7.16 (19)	9.81 (20)

SD = single dose, MD₇ = Day 7 of multiple dose (once daily for 7 days)

^aMedian

^b[min-max]

^cElimination half-lives calculated using a compartmental model.

The maximum concentration (C_max) after the first dose was similar to the value seen after seven days of dosing. AUC and C24h increased upon multiple dosing, and steady state (based on C24h) was achieved by the 2nd or 3rd dose. Plasma concentrations of telithromycin showed a biphasic decrease over time. The terminal elimination half-life of telithromycin is about 10 hours after multiple dosing.

These pharmacokinetic characteristics are consistent with those seen in patients with RTIs.

There are no pharmacokinetic differences between men and women (Studies 1031, 1042, 1005, 1030, 3000).

5.3 Pharmacokinetics in RTI patients from clinical trials

Two hundred and twenty patients with CAP (mean age 42.6 years) in Study 3000 (Phase III) were included in the investigation of pharmacokinetics in patients from clinical trials. At the on-therapy visit (Day 3 to 5 of dosing), blood samples were taken before dosing and at 1, 2, 4, 6, and 8 hours after dosing for analysis of telithromycin concentrations in plasma. The C_max and AUC values in these patients were 2.89 µg/mL and 13.9 µg·h/mL, respectively, compared to values of 2.27 µg/mL and 12.5 µg·h/mL in healthy subjects (see Section 5.2, Pharmacokinetic characteristics of telithromycin 800 mg (single and multiple dose)).

A multiple-dose (800 mg qd) pharmacokinetic study (Study 1054) was conducted in adolescent patients with bacterial RTIs, which confirmed that the pharmacokinetics of telithromycin in these patients were similar to those in healthy adults.

5.4 Pharmacokinetics in populations of special interest

5.4.1 Elderly subjects

The pharmacokinetics of telithromycin after multiple dosing with telithromycin 800 mg have been investigated in elderly healthy subjects and elderly patients with CAP, as summarized in the table below.

Table 5-4. Comparison of pharmacokinetics between elderly and young subjects (healthy and patients with CAP) after multiple oral dosing with telithromycin (800 mg qd)

Parameter	Mean (CV%)
	Healthy subjects ^a		Patients with CAP ^b
	Elderly (N=14)	Young (N=12)	Elderly (N=20)	Young (N=142)
Age (years)	73.6 (11) ^c	21.3 (15)	69.8 (5.1)	39.0 (34)
C_max (µg/mL)	3.6 (40)	1.8 (62)	3.53 (63)	2.80 (50)
AUC(0-24h) (µg.h/mL)	17.2 (32)	8.5 (31)	25.9 (70)	18.1 (63)
^a Treatment for 10 days ^b Treatment for 7 to 10 days ^c N=16

The pharmacokinetics in elderly patients (³65 years) with CAP compared to young subjects (<65 years) indicate that there is a 1.3-fold increase in C_max and a 1.4-fold increase in AUC in the elderly patients at the therapeutic dose of telithromycin (800 mg qd). A similar magnitude of change was also observed in healthy elderly subjects.

The unbound fraction of telithromycin is similar between elderly and young patients.

5.4.2 Subjects with renal impairment

The pharmacokinetics of a single oral dose of 800 mg telithromycin were examined in subjects with various degrees of renal impairment or end-stage renal failure (N = 30), and in control subjects with normal renal function (N = 10) (Study 1016). The results are summarized in the table below.

Table 5-5. Comparison of pharmacokinetics between subjects with differing degrees of renal function after a single oral dose of 800 mg telithromycin

Parameter	Renal function group
Creatinine clearance (mL/min)	>80 N=10	41 to 80 N=10	11 to 40 N=10	£10 N=10
C_max (mg/mL)	2.25	3.00	3.25	2.13
AUC(0-¥) (mg·h/mL)	10.09	14.31	16.00	10.79
t_½,_lz (h)	10.66	11.41	12.58	14.64

Plasma concentrations of telithromycin in subjects with mild to severe impairment were 1.4-fold higher for C_max, and 1.4 to 1.5-fold higher for AUC, than those of control subjects. When telithromycin was given to subjects with end-stage renal failure (CL_CR £10 mL/min) 2 hours after dialysis, C_max and AUC were similar to the control group. Pharmacokinetic parameters of telithromycin were similar between the subgroups of subjects with renal impairment, despite a significant linear relationship between creatinine clearance and renal clearance of telithromycin. The elimination half-life of telithromycin did not increase markedly in subjects with renal impairment or end-stage renal failure compared to the control subjects. The results in the end-stage renal failure group could be explained by the short interval of time between dialysis and administration of telithromycin.

Overall, these changes are consistent with the limited role played by renal excretion in the elimination of telithromycin. Renal excretion may play a more important role because it may serve as a compensatory elimination pathway in those patients whose metabolism of telithromycin is impaired.

5.4.3 Subjects with hepatic impairment

The pharmacokinetics of a single oral dose of 800 mg telithromycin were examined in subjects with hepatic impairment (median Child Pugh score of 9, range 5 to 12) in a study that was pair-matched to control healthy subjects in terms of demographic characteristics. (Study 1015) The results are summarized in the table below.

Executive summary