Telithromycin in the treatment of acute bacterial sinusitis, acute exacerbations of chronic bronchitis, and community-acquired pneumonia

Figures & data

Figure 1 Chemical structure of telithromycin.

Table 1 In vitro activities of telithromycin, erythromycin, and azithromycin against key respiratory pathogens collected in the USA as part of the PROTEKT US study 2001–2002a

	Telithromycin				Erythromycin			Azithromycin
Organism	MIC90 (μg/mL)	Range (μg/mL)	%S	MIC90 (μg/mL)	Range (μg/mL)	%S	MIC90 (μg/mL)	Range (μg/mL)	%S
Streptococcus pneumoniae
All (n = 10,012)	0.25	≤ 0.015–4	99.9	16	≤ 0.06–> 256	71.9	32	≤ 0.03–> 256	71.9
Pen-I (n = 1424)b	0.25	≤ 0.015–2	99.9	> 256	≤ 0.06–> 256	50.1	> 256	≤ 0.03–> 256	50.2
Pen-R (n = 2124)c	0.5	≤ 0.015–4	99.4	> 256	≤ 0.06–> 256	19.4	> 256	≤ 0.03–> 256	19.6
Ery-R (n = 2793)d	0.5	≤ 0.015–4	99.5	> 256	1–> 256	0	> 256	0.5–> 256	0.1
Pen-R and Ery-R (n = 1709)	1	≤ 0.015–4	99.3	> 256	1–> 256	0	> 256	0.5–> 256	0.2
Haemophilus influenzae
All (n = 3296)	4	≤ 0.12–>16	96.3	ND	ND	ND	2	≤ 0.12–> 256	98.9
β-lactamase positive (n = 905)	4	≤ 0.12–>16	97.3	ND	ND	ND	2	≤ 0.12–128	99.2
β-lactamase negative (n = 2391)	4	≤ 0.12–>16	95.9	ND	ND	ND	2	≤ 0.12–> 256	98.8
Streptococcus pyogenes (n = 4508)	0.03	≤ 0.015–16	—	0.12	≤ 0.06–> 256	94	0.25	≤ 0.03–> 256	94.1

a Adapted from Brown and Rybak (2004).

b Pen-I, penicillin-intermediate (MIC 0.12–1 μg/mL).

c Pen-R, penicillin-resistant (MIC ≥ 2 μg/mL).

d Ery-R, erythromycin-resistant (MIC ≥ 1 μg/mL).

Abbreviations: MIC, minimum inhibitory concentration; ND, not determined; S, susceptible.

Table 2 Tissue distribution of telithromycin 24 hours after administration of final dose

Target tissue/fluid/cell	Dose regimen	Mean tissue/fluid/cell to plasma concentration ratio	Reference
Multiple-dose studies
White blood cells	600 mg once daily for 10 days	1383	Pham Gia et al (1999)
Alveolar macrophages	800 mg once daily for 5 days	2160	Khair et al (2001)
Epithelial lining fluid	800 mg once daily for 5 days	14.41	Khair et al (2001)
Bronchial mucosa	800 mg once daily for 5 days	12.11	Khair et al (2001)
Tonsillar tissue	800 mg once daily for 5 days	13.10	Gehanno et al (2003)
Saliva	800 mg once daily for 10 days	1.60a	Edlund et al (2000)
Sputum	600 mg once daily for 7 days	4.80	Watanuki et al (2001)
Single-dose studies
Sinus fluid	600 mg dose administered 3–6 hours before tissue collection	4.00	Miyamoto et al (2000)
Middle-ear fluid	600 mg dose administered 3–6 hours before tissue collection	2.40	Miyamoto et al (2000)

a Results reported as a ratio of AUC_saliva/AUC_plasma

Abbreviations: AUC, area under the concentration–time curve.

Table 3 Phase III/IV clinical trials of telithromycin for the treatment of patients with acute bacterial sinusitis, acute exacerbations of chronic bronchitis, or community-acquired pneumonia

Study	Design	Patient age range, years (mITT population)	Total nr patientsa	Regimen	Length of treatment	Clinical response, n/N (%)b		Bacteriologic outcome, n/N (%)c
Acute bacterial sinusitis
3002 (Roos et al 2002)	Randomized	18–66		335 (256) T 800 mg od	5 days	mITT	138/167 (82.6)	80/97 (82.5)
						PP	112/123 (91.1)	65/70 (92.9)
				T 800 mg od	10 days	mITT	147/168 (87.5)	93/104 (89.4)
						PP	121/133 (91.0)	62/69 (89.9)
3005 (Luterman et al 2003)	Randomized, double-blind, parallel-group	16–84	607 (423)	T 800 mg od	5 days	mITT	nd	nd
						PP	110/146 (75.3)	6/7 (85.7)
				T 800 mg od	10 days	mITT	nd	nd
						PP	102/140 (72.9)	6/7 (85.7)
				A/C 500/125 mg tid	10 days	mITT	nd	nd
						PP	102/137 (74.5)	8/10 (80.0)
3011 (Buchanan et al 2003)	Randomized, double-blind, parallel-group	14–84	356 (278)	T 800 mg od	5 days	mITT	193/240 (80.4)	102/126 (81.0)
						PP	161/189 (85.2)	84/100 (84.0)
				CA 250 mg bid	10 days	mITT	84/116 (72.4)	44/60 (73.3)
						PP	73/89 (82.0)	39/49 (79.6)
4017 (Ferguson et al 2004)	Randomized, double-blind, parallel-group	18–85	322 (272)	T 800 mg od	5 days	mITT	128/159 (80.5)	36/41 (87.8)
						PP	118/135 (87.4)	32/34 (94.1)
				MOX 400 mg od	10 days	mITT	125/163 (76.7)	31/43 (72.1)
						PP	119/137 (86.9)	31/33 (93.9)
Acute exacerbations of chronic bronchitis
3003 (Aubier et al 2002)	Randomized, double-blind, parallel-group	18–84	320 (227)	T 800 mg od	5 days	mITT	130/160 (81.3)	30/50 (60.0)
						PP	99/115 (86.1)	27/39 (69.2)
				A/C 500/125 mg tid	10 days	mITT	125/160 (78.1)	24/55 (56.8)
						PP	92/112 (82.1)	21/30 (70.0)
				T 800 mg od	5 days	mITT	142/182 (78.0)	nd
3007 (Zervos et al 2003)	Randomized, double-blind, parallel-group	19–97	373 (282)			PP	121/140 (86.4)	19/25 (76.0)
				CA 500 mg bid	10 days	mITT	138/191 (72.3)	nd
						PP	118/142 (83.1)	22/28 (78.6)
3013 (Fogarty, de Wet, et al 2005)	Randomized, double-blind, parallel-group	18–95	552 (456)	T 800 mg od	5 days	mITT	224/270 (83.0)	nd
						PP	193/225 (85.8)	59/72 (81.9)
				C 500 mg bid	10 days	mITT	236/282 (83.7)	nd
						PP	206/231 (89.2)	63/76 (82.9)
Community-acquired pneumonia
3000 (Carbon, Moola,et al 2003)	Non-blinded, non-comparative	18–79	240 (197)	T 800 mg od	7–10 days	mITT	191/240 (79.6)	49/67 (73.1)
						PP	183/197 (92.9)	40/45 (88.9)
3009OL (van Rensburg et al 2002)	Non-blinded, non-comparative	18–89	212 (187)	T 800 mg od	7–10 days	mITT	182/212 (85.8)	80/98 (81.6)
						PP	175/187 (93.6)	61/68 (89.7)
3010 (Fogarty, Patel, et al 2005)	Non-blinded, non-comparative	13–92	418 (357)	T 800 mg od	7 days	mITT	357/418 (85.4)	215/255 (84.3)
						PP	332/357 (93.0)	137/149 (91.9)
3012 (Aventis, data on file)	Non-blinded, non-comparative	13–90	538 (473)	T 800 mg od	7 days	mITT	447/538 (83.1)	229/265 (86.4)
						PP	424/473 (89.6)	161/179 (89.9)
3001 (Hagberg et al 2002)	Randomized, double-blind, parallel-group	16–88	404 (301)	T 800 mg od	10 days	mITT	171/199 (85.9)	49/62 (79.0)
						PP	141/149 (94.6)	36/40 (90.0)
				A 1000mg tid	10 days	mITT	161/205 (78.5)	46/63 (73.0)
						PP	137/152 (90.1)	35/40 (87.5)
3006 (Mathers,Dunbar, et al 2004)	Randomized, double-blind, parallel-group	18–92	416 (318)	T 800 mg od	10 days	mITT	161/204 (78.9)	36/48 (75.0)
						PP	143/162 (88.3)	25/28 (89.3)
				C 500 mg bid	10 days	mITT	171/212 (84.6)	37/45 (82.2)
						PP	138/156 (88.5)	27/28 (96.4)
3009 (Pullman et al 2003)	Randomized, double-blind, parallel-group	17–99	204 (166)	T 800 mg od	7–10 days	mITT	82/100 (82.0)	27/32 (84.4)
						PP	72/80 (90.0)	13/14 (92.9)
				TR 200 mg od	7–10 days	mITT	89/104 (85.6)	30/34 (88.2)
						PP	81/86 (94.2)	22/22 (100)
4003 (Tellier, Niederman, et al 2004)	Randomized, double-blind, parallel-group	15 –88	559 (466)	T 800 mg od	5 days	mITT	154/187 (82.4)
						PP	142/159 (89.3)	57/65 (87.7)
				T 800 mg od	7 days	mITT	157/191 (82.2)	nd
						PP	143/161 (88.8)	52/65 (80.0)
				C 500 mg bid	10 days	mITT	147/181 (81.2)	nd
						PP	134/146 (91.8)	45/54 (83.3)
4015 (Mouton et al 2005)	Non-blinded, comparative, Parellel-group	nd	482 (438)	T 800 mg od	7–10 days	mITT	208/242 (86.0)	nd
						PP	191/219 (87.2)	nd
				Pooled COMP	nd	mITT	189/240 (78.8)	nd
						PP	175/219 (79.9)	nd

a Number of patients in the mITT population, with the number of patients that were clinically evaluable at the end of treatment (PP) in parentheses.

b Proportion of patients clinically cured at the post-therapy test of cure visit.

c Proportion of patients with a satisfactory bacteriologic outcome (presumed or documented eradication of the causative pathogen) at the post-therapy test of cure visit.

Abbreviations: A, amoxicillin; A/C, amoxicillin–clavulanic acid; bid, twice daily; C, clarithromycin; CA, cefuroxime axetil; COMP, comparators; mITT, modified intent to treat; MOX, moxifloxacin; nd, no data presented; od, once daily; PP, per-protocol; T, telithromycin; tid, three-times daily; TR, trovafloxacin.

Table 4 Treatment-emergent adverse events (TEAEs) possibly related to study medication reported by >1% of patients in 11 comparator-controlled trials of telithromycin

	Number (%) of patients
Possibly related TEAE	Telithromycin (n = 2702)	Comparators (n = 2139)
Diarrhea	270 (10.0)	171 (8.0)
Nausea	190 (7.0)	87 (4.1)
Headache	54 (2.0)	53 (2.5)
Dizziness (excluding vertigo)	75 (2.8)	33 (1.5)
Vomiting	64 (2.4)	30 (1.4)
Loose stools	58 (2.1)	30 (1.4)
Dyspepsia	36 (1.3)	21 (1.0)
Dysgeusia	40 (1.5)	76 (3.6)
Total nr of patients	861 (31.9)	606 (28.3)
with possibly related
TEAEs

Table 5 Interactions between telithromycin and commonly prescribed drugsa

Drug	Interaction	Comments/recommendations
CYP3A4 inhibitors
Ketoconazole	Increase in TEL exposure: Cmax by 51%; AUC by 95%	No clinically significant interaction
Itraconazole	Moderate increase in TEL exposure: Cmax by 22%; AUC by 54%	No clinically significant interaction
CYP3A4 inducers
Rifampicin	Reduction in TEL exposure: Cmax by 79%; AUC by 86%	Co-administration not recommended
CYP3A4 substrates
Cisapride/pimozide	Not tested: potential for TEL to increase pimozide exposure	Use of TEL contraindicated with cisapride and pimozide
Midazolam Statins (simvastatin, lovastatin, atorvastatin)	6-fold increase in midazolam exposure (AUC) Simvastatin exposure increased 5.3-fold (Cmax)/8.9-fold (AUC). Lovastatin and atorvastatin not tested	Midazolam dose adjustment may be necessary Suspension of simvastatin, lovastatin, or atorvastatin therapy recommended if TEL is prescribed
CYP2D6 substrates
Metoprolol	Moderate increase in exposure to metoprolol: and AUC, but no effect on elimination ∼38% on Cmax half-life of metoprolol	Co-administration in patients with heart failure should be considered with caution
Others
Theophylline	Moderate increase in exposure to theophylline: and AUC ∼17% on Cmax	To reduce GI side-effects of theophylline, drugs should be administered 1 hour apart
Digoxin	Moderate increase in exposure to digoxin (plasma peak and trough levels increased by 73% and 21%, respectively) but no changes in ECG or signs of digoxin toxicity	Monitor digoxin side-effects or serum levels
Warfarin	No significant effects on racemic warfarin. Post-marketing reports suggest TEL may increase exposure to oral anticoagulants	Consider monitoring prothrombin times/INR
Antacids or other agents containing multivalent cations	No interactions
Oral contraceptives	Anti-ovulatory effects of oral contraceptives containing ethinylestradiol or levonorgestrel unaffected by TEL

a Adapted from (Ciervo and Shi (2005).

Abbreviations: AUC, area under the concentration–time curve; C_max, peak plasma concentration; CYP, cytochrome P450; ECG, electrocardiogram; GI, gastrointestinal; INR, international normalized ratio; TEL, telithromycin.

BrownSDRybakMJAntimicrobial susceptibility of Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae collected from patients across the USA, in 2001–2002, as part of the PROTEKT US studyJ Antimicrob Chemother200454Suppl 1i71515265831

 PubMed Web of Science ®Google Scholar

Pham GiaHRoederVNamourFThe new ketolide, HMR 3647, achieves high and sustained concentrations in white blood cells in man [Abstract]J Antimicrob Chemother199944Suppl A57P79

 Google Scholar

KhairOAAndrewsJMHoneybourneDLung concentrations of telithromycin after oral dosingJ Antimicrob Chemother2001478374011389116

 PubMed Web of Science ®Google Scholar

GehannoPSultanEPassotVTelithromycin (HMR 3647) achieves high and sustained concentrations in tonsils of patients undergoing tonsillectomyInt J Antimicrob Agents200321441512727077

 PubMed Web of Science ®Google Scholar

EdlundCAlvanGBarkholtLPharmacokinetics and comparative effects of telithromycin (HMR 3647) and clarithromycin on the oropharyngeal and intestinal microfloraJ Antimicrob Chemother200046741911062193

 PubMed Web of Science ®Google Scholar

WatanukiYOdagiriSOguraTA new ketolide antibacterial, telithromycin, achieves high and sustained concentrations in sputum in patients [Abstract]2001Abstracts of the 22nd International Congress of ChemotherapyJune 2001Amsterdam, The Netherlands P9.007

 Google Scholar

MiyamotoNMurakamiSYajinKPharmacokinetic study of a new ketolide antimicrobial telithromycin (HMR 3647) in otorhinolaryngology [Abstract]2000Abstracts of the 40th Interscience Conference on Antimicrobial Agents and ChemotherapySeptember 2000Toronto, Canada 2144

 Google Scholar

RoosKBrunswig-PitschnerCKostricaREfficacy and tolerability of once-daily therapy with telithromycin for 5 or 10 days for the treatment of acute maxillary sinusitisChemotherapy200248100812011543

 PubMed Web of Science ®Google Scholar

LutermanMTellierGLaskoBEfficacy and tolerability of telithromycin for 5 or 10 days vs amoxicillin/clavulanic acid for 10 days in acute maxillary sinusitisEar Nose Throat J2003825768014503094

 PubMedGoogle Scholar

BuchananPPStephensTALeroyBA comparison of the efficacy of telithromycin versus cefuroxime axetil in the treatment of acute bacterial maxillary sinusitisAm J Rhinol2003173697714750614

 PubMedGoogle Scholar

FergusonBJGuzzettaRVSpectorSLEfficacy and safety of oral telithromycin once daily for 5 days versus moxifloxacin once daily for 10 days in the treatment of acute bacterial rhinosinusitisOtolaryngol Head Neck Surg20041312071415365537

 PubMed Web of Science ®Google Scholar

AubierMAldonsPMLeakATelithromycin is as effective as amoxicillin/clavulanate in acute exacerbations of chronic bronchitisRespir Med2002968627112418583

 PubMed Web of Science ®Google Scholar

ZervosMJHeyderAMLeroyBOral telithromycin 800 mg once daily for 5 days versus cefuroxime axetil 500 mg twice daily for 10 days in adults with acute exacerbations of chronic bronchitisJ Int Med Res2003311576912870368

 PubMed Web of Science ®Google Scholar

FogartyCde WetRMandellLFive-day telithromycin once daily is as effective as 10-day clarithromycin twice daily for the treatment of acute exacerbations of chronic bronchitis and is associated with reduced healthcare resource utilizationChest20051281980816236845

 PubMed Web of Science ®Google Scholar

CarbonCMoolaSVelancsicsITelithromycin 800 mg once daily for seven to ten days is an effective and well-tolerated treatment for community-acquired pneumoniaClin Microbiol Infect2003969170312925111

 PubMed Web of Science ®Google Scholar

van RensburgDJMatthewsPALeroyBEfficacy and safety of telithromycin in community-acquired pneumoniaCurr Med Res Opin20021839740012487505

 PubMed Web of Science ®Google Scholar

FogartyCMPatelTCDunbarLMEfficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter studyBMC Infect Dis2005c54315927060

 PubMed Web of Science ®Google Scholar

HagbergLTorresAvan RensburgDEfficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumoniaInfection2002303788612478329

 PubMed Web of Science ®Google Scholar

Mathers DunbarLHassmanJTellierGEfficacy and tolerability of once-daily oral telithromycin compared with clarithromycin for the treatment of community-acquired pneumonia in adultsClin Ther200426486214996517

 PubMed Web of Science ®Google Scholar

PullmanJChamplinJVroomanPSJrEfficacy and tolerability of once-daily oral therapy with telithromycin compared with trovafloxacin for the treatment of community-acquired pneumonia in adultsInt J Clin Pract2003573778412846341

 PubMed Web of Science ®Google Scholar

TellierGNiedermanMSNusratRClinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumoniaJ Antimicrob Chemother2004545152315269191

 PubMed Web of Science ®Google Scholar

MoutonYThamlikitkulVNiemanRBTelithromycin versus other first-line single-agent antibiotics in the treatment of community-acquired pneumonia: a randomized superiority trialClin Microbiol Infect Dis200511Suppl 2S267

 Google Scholar

CiervoCAShiJOutline Pharmacokinetics of telithromycin: application to dosing in the treatment of community-acquired respiratory tract infectionsCurr Med Res Opin20052116415016238904

 PubMed Web of Science ®Google Scholar