In vitro antibacterial activity of telithromycin (TEL) against standard strains and freshly clinical isolates was examined in comparison with erythromycin A (EM), clarithromycin (CAM), azithromycin (AZM), roxithromycin (RXM) and josamycin (JM), as existing macrolides, ampicillin (ABPC), as a penicillin antibiotic, cefaclor (CCL), as a cephem antibiotic and ofloxacin (OFLX), as a new quinolone. Standard strains: TEL showed broad antibacterial spectrum against aerobic gram-positive bacteria (MIC: 0.006-0.1, μg/mL). The potency was equal to or more potent than those of EM, CAM, AZM, RXM and ABPC, and more potent than those of JM, CCL and OFLX. Against gram-negative bacteria, TEL was less potent than OFLX, ABPC and CCL but nearly comparable to AZM. TEL showed broad antibacterial spectrum against anaerobic gram-positive bacteria, whose MIC values ranged 0.006 to 1.56μg/mL and were not less than those in all compounds tested. Clinical isolates: The MIC₉₀s of TEL for Streptococcus pneumoniae, Streptococcus pyogens and Streptococcus agalactiae were 0.05, μg/mL, which was equal to or more than 2, 000 times smaller than those of existing macrolides. Against methicillin-susceptible Staphylococcus aureus the activity of TEL with MIC₅₀ of 0.1μg/mL was 4 to 16 times more potent than those of existing macrolides. However, TEL was inactive against methicillin-resistant S. aureus (MIC₅₀≥100 μg/mL). The MIC₉₀ (1.56-6.25μg/mL) of TEL for Enterococcus faecalis and Enterococcus faecium was markedly superior to those of other macrolides. The MIC₉₀ of TEL against Haemophilus influenzae was 3.13μg/mL, which was 2 to 16 times smaller than those of EM, CAM, RXM and JM, but twice larger than that of AZM. The MIC₉₀ of TEL for Moraxella catarrhalis was 0.2μg/mL to be similar activity to EM, CAM, AZM, RXM and OFLX. The MIC₉₀ of TEL for Peptostreptococcus anaerobius was 0.05μg/mL. The activity was superior to all reference compounds.

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Antibacterial spectrum against standard strains and antibacterial activities against clinical isolates of telithromycin (TEL) were examined in comparison with clarithromycin (CAM) and azithromycin (AZM)-existing macrolides, cefdinir (CFDN)-a cephem-and levofloxacin (LVFX)-a new quinolone-. Furthermore, influence of various factors on the antibacterial activities, influence of TEL on the growth curve and morphological changes by TEL were also investigated. TEL has a broad antibacterial spectrum covering gram-positive bacteria and some gram-negative bacteria such as Haemophilus influenzae and Hericobacter pyroli, similar to existing macrolides. The antibacterial activity of telithromycin was comparable to or more potent than all reference drugs on gram-positive bacteria and was comparable to or more potent than CAM and AZM on gram-negative bacteria. Concerning 488 strains clinically isolated in 1997, TEL exhibited excellent antibacterial activities on gram-positive bacteria. Its antibacterial activities against Streptococcus spp. and Enterococcus spp. were the most potent among test drugs, and TEL was also active against macrolide-resistant strains of Streptococcus and Enterococcus. However, antibacterial activities of TEL against methicillin-resistant Staphylococcus aureus (MRSA), new quinolones-resistant S. aureus and methicillin-resistant Staphylococcus epidermidis (MRSE) were weak as well as other reference drugs. Against gram-negative bacteria, H. influenzae, Moraxella catarrhalis and H. pylori, telithromycin was active and comparable to or more potent than AZM and CAM, but against other species were inferior to CFDN and LVFX. Influence of various factors on the antibacterial activity of telithromycin was investigated in comparison with erythromycin (EM) and CAM using standard strains of S. aureus, S. epidermidis, Enterococcus faecalis and Escherichia coli. Its antibacterial activity of telithromycin was potentiated in alkaline culture media and weakened in acidic culture media. The antibacterial activity of telithromycin became higher with the addition of horse defibrinated blood. Slight influence of inoculum size was comparable to reference drugs. As for the influence on growth curves of standard strains of S. aureus, TEL was bacteriostatic. In the concentrations not less than 2 MIC in S. pneumoniae and 1 MIC in H. influenzae, TEL was bactericidal and the action was rapid and strong. Concerning the morphological changes after TEL action observed with differential interference contrast microscope, S. aureus and S. pneumoniae became swollen in the concentrations not less than 4 MIC were lyzed in not less than 8 MIC. Further, in the transmission electron micrographs, marked hypertrophy of cell wall, vacuole-like structure and bacteriolysis were observed in S. aureus. On H. influenzae, in the concentrations not less than 1 MIC, elongation was observed and in not less than 4 MIC plasmolysis and bacteriolysis were recognized.

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Antibacterial activity of telithromycin (TEL) against 62 reference strains of anaerobes and 360 anaerobic strains clinically isolated since 1994, was examined in comparison with cefditoren (CDTR), amoxicillin/clavulanate (AMPC/CVA), clarithromycin (CAM) and clindamycin (CLDM). As for reference strains, TEL exhibited potent antibacterial activity against gram-positive bacilli. In particular, the activity of TEL against 7 strains of Lactobacillus spp. was the most potent among the compounds tested. TEL also showed antibacterial activity against gram-positive cocci except for some species. However, its antibacterial activities against gram-negative bacteria were generally not so potent. As far as clinical isolates concerns, antibacterial activity of TEL (MIC₉₀: 0.03-8μg/mL) was superior to CAM against Peptostreptococcus spp., Veillonella spp., Actinomycetes spp., Propionibacterium acnes and Clostridium perfringens. The MIC₉₀ for Prevotella intermedia and Porphyromonas spp. was 0.125μg/mL, to be somewhat inferior to CAM but still active. However, MIC₅₀ for Bacteroides fragilis was>256μg/mL, to be inactive.

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In vitro antibacterial activities of telithromycin (TEL) against clinical isolates isolated from 1994 to 1998 were examined in comparison with erythromycin A (EM), clarithromycin (CAM), azithromycin (AZM), levofloxacin (LVFX), cefditoren (CDTR) and sulbactam/ampicillin (SBT/ABPC). MIC₉₀ (μg/mL) of TEL for various organisms were as follows, methicillin-resistant Staphylococcus aureus (MRSA):>128, methicillin-susceptible S. aureus (MSSA): 0.125, EM-resistant S. aureus (ERSA):>128, EM-susceptible S. aureus: 0.125, EM-resistant Staphylococcus epidermidis (ERSE):>128, EM-susceptible S. epidermidis (ESSE): 0.063, vancomycin (VCM)-resistant Enterococcus faecium: 8, EM-resistant E. faecium: 4, EM-susceptible E. faecium: 0.032, EM-resistant Enterococcus faecalis: 2, EM-susceptible E. faecalis: 0.032, EM-resistant Enterococcus avium: 1, EM-susceptible E. avium: 0.032, EM-resistant Streptococcus pneumoniae: 0.5, EM-susceptible S. pneumoniae: 0.063, penicillin-resistant S. pneumoniae (PRSP): 0.5, penicillin-susceptible S. pneumoniae (PSSP): 0.5, EM-resistant Streptococcus agalactiae: 2, EM-susceptible S. agalactiae: 0.063, EM-resistant Haemophilus influenzae: 4, EM-susceptible H. influenzae: 2, and EM-susceptible Moraxella catarrhalis: 0.125.

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In vitro antibacterial activity of telithromycin (TEL), a novel ketolide antibiotic, was examined in comparison with erythromycin A (EM), clarithromycin (CAM), rokitamycin (RKM), ampicillin (ABPC), cefpodoxime (CPDX), levofloxacin (LVFX) and teicoplanin (TEIC). The ability of TEL to induce macrolide resistance was also studied in comparison with EM, CAM and RKM. TEL showed a broad antibacterial spectrum and potent antibacterial activity against clinically isolated gram-positive cocci. TEL also exhibited excellent antibacterial activities comparable to existing macrolides against Haemophilus influenzae and Moraxella catarrhalis, gram-negative bacteria. Almost all strains of clinically isolated inducible macrolide-resistant Staphylococcus aureus and Streptococcus pneumoniae were highly susceptible to TEL. Various concentration of TEL did not induce EM resistance in S. aureus.

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The in vitro antibacterial activity of telithromycin (TEL) against clinical isolates in Japan was examined in comparison with those of erythromycin A (EM), clarithromycin (CAM) and azithromycin (AZM)-macrolide antibiotics-, amoxicillin (AMPC)-a penicillin antibiotic-, cefdinir (CFDN)-a cephem antibiotic-and levofloxacin (LVFX)-a new quinolone-.The results revealed that TEL demonstrated the most potent antibacterial activity (MIC₉₀=0.125μg/mL) among the tested compounds against not only EM-susceptible Streptococcus pneumoniae (MIC₉₀=0.008μg/mL) but also mefE-carrying (drug-excreting type) EM resistant strains and ermB-carrying (target-site mutant type) EM-resistant strains. In addition, TEL showed bactericidal activity against EM-susceptible and mefE-carrying EM-resistant strains (MBC₉₀/MIC₉₀=1), but somewhat weaker (MBC₉₀/MIC₉₀=4) activity against ermB-carrying EM-resistant strains. TEL also exhibited the most potent antibacterial activity against Streptococcus pyogenes and Streptococcus agalactiae as well as S. pneumoniae. TEL showed the most potent antibacterial activity (MIC₉₀=0.125 and 0.25μg/mL) against EM-susceptible and inducible EM-resistant Staphylococcus aureus, but its bactericidal activity was weak (MBC₉₀/MIC₉₀=16 and 8). TEL was inactive against constitutive EM-resistant strains and the similar result was also obtained on Staphylococcus epidermidis. TEL exhibited the most potent antibacterial activity against EM-susceptible Enterococcus faecalis (MIC₉₀≤0.063μg/mL), and more than 32 times stronger than EM, CAM and AZM against EM-resistant strains (MIC₉₀=4μg/mL). Furthermore, TEL showed bactericidal activity against the EM-susceptible strains (MBC₉₀/MIC₉₀=4), but its bactericidal activity was weak against the EM-resistant strains (MBC₉₀/MIC₉₀=32). TEL showed the strongest antibacterial activity against Enterococcus faecium (MIC₉₀=2μg/mL). Antibacterial activity of TEL (MIC₅₀=2μg/mL, MIC₉₀=4μg/mL) was 2 to 4 times stronger than those of EM and CAM and equal to or twice weaker than that of AZM against Haemophilus influenzae. TEL exhibited potent antibacterial activity against Moraxella catarrhalis, Bordetella pertussis, Legionella spp. and Neisseria gonorrhoeae (MIC₉₀=0.25, 0.032, 0.063 and 0.125μg/mL). These effects of TEL were comparable to or more potent than those of EM, CAM and AZM, except for inferiority to that of AZM on M. catarrhalis. However, antibacterial activity of TEL against Klebsiella pneumoniae was weak as well as those of EM, CAM and AZM. TEL showed bactericidal activity against H. influenzae and M. catarrhalis (MBC90/MIC90=1). Next, the in vivo protection effect of TEL in a systemic infection model caused by S. aureus Smith in mice was investigated in comparison with CAM, AZM, CFDN and LVFX. The results revealed that TEL and each of the reference compounds provided a protective effect in this model. The ED₅₀ values (mg/kg) were as follows, TEL=7.3, CAM=12.1, AZM=13.2, CFDN 2.1 and LVFX 5.7. In conclusion, following results became evident.
1. TEL has very potent antibacterial activity against gram-positive bacteria.
2. It especially was active against even EM-resistant S. pneumoniae
3. TEL possesses excellent activity against gram-negative causative organisms in common in bacterial community acquired pneumonia.
4. TEL has more potent protective effects than CAM and AZM in a murine model of systemic S. aureus infection.

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The in vitro antimicrobial activity of telithromycin (TEL) against reference strains of Legionella species and clinical isolates of Legionella pneumophila was evaluated in comparison with erythromycin (EM), clarithromycin CAM, azithromycin (AZM), levofloxacin and sparfloxacin. The MIC₉₀s of TEL for reference strains and clinical isolates of L. pneumophila in Japan were 0.5 and 0.25μg/mL, respectively. The activity of TEL was superior to EM and AZM, slightly less potent than CAM. Therefore, the study suggests that TEL can be effective for treatment of Legionella pneumonia.

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Phase II and III clinical studies of telithromycin (TEL) in Japan were conducted in 1999-2001. The susceptibilities of Streptococcus pneumoniae (103 strains) and Haemophilus influenzae (174 strains) to TEL, erythromycin A (EM), clarithromycin (CAM), azithromycin (AZM), clindamycin (CLDM), cefdinir (CFDN), levofloxacin (LVFX) and penicillin G (PCG) or ampicillin (ABPC) were investigated. S. pneumoniae strains were examined for the presence or absence of the ermAM and mefA/E resistant genes. Resistance of S. pneumoniae to CAM, AZM and clindamycin (CLDM) markedly increased (MIC₅₀: vs. 1999 isolates, 0.5, 0.5 and 0.03μg/mL; vs. 2000 isolates, 32, >16 and 32μg/mL; and vs. 2001 isolates, >64, >16 and 32μg/mL, respectively). On the other hand, against the strains isolated in the 3 years, TEL showed potent antibacterial activity irrespective of presence of the ermAM and/or mefA/E resistant genes, and its MIC range remained almost unchanged during the 3 years (0.015-0.25μg/mL). H. influenzae strains developed resistance to ABPC (MIC₉₀: 1, 8 and 8μg/mL in the 3 years, respectively). Antibacterial activity of TEL against H. influenzae including β-lactamase negative ABPC resistant isolates (BLNAR: ABPC MIC≥2μg/mL) was comparable to that of AZM and more potent than that of CAM. The result supported that S. pneumoniae and H. influenzae with resistance to TEL did not emerge during the clinical trial conducted in Japan in 1999-2001.

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MBC/MIC ratio of telithromycin (TEL) for clinical isolates of Staphylococcus aureus (19 strains), Enterococcus faecalis (20 strains), Streptococcus pneumoniae (16 strains) and Haemophilus influenzae (18 isolates) in Japan was compared with those of erythromycin A (EM), clarithromycin (CAM), azithromycin (AZM) and josamycin (JM), existing macrolide antibiotics. As a result, MBC₅₀/MIC₅₀ and MBC₉₀/MIC₉₀ ratios of all compounds tested for S. aureus and E. faecalis were more than 32, but the ratios for S. pneumoniae and H. influenzae were less than 2. Therefore, this study suggested that TEL had bacteriostatic effects against S. aureus and E. faecalis, but bactericidal effect against S. pneumoniae and H. influenzae. In addition, the bactericidal activity of TEL against standard strains of S. aureus, S. pneumoniae and H. influenzae was compared with those of EM, CAM and AZM on the basis of their killing curves. Against S. aureus Smith, TEL was slightly less potent than CAM. However, as in the case of EM and AZM, TEL inhibited the proliferation at 1/2 MIC and showed mild bactericidal activity at MIC. Against S. pneumoniae DP-1, TEL inhibited the growth at the concentration lower than MIC and showed bactericidal activity at the MIC or concentration higher than MIC as observed in other reference drugs. Against H. influenzae ATCC 49247, TEL inhibited the growth at the 1/2 MIC and showed bactericidal activity at the concentration higher than MIC. TEL showed strong short-term bactericidal activity in comparison with EM, CAM and AZM, especially against S. pneumoniae DP-1 and H. influenzae ATCC 49247. Furthermore, marked regrowth as observed in S. aureus and H. influenzae ATCC 49247 in case of EM, CAM and AZM, was not observed in TEL.

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The inability to induce resistance in Staphylococcus aureus, the 50% inhibitory concentrations (ID₅₀) for S. aureus, the inhibitory effect on protein synthesis and the affinity for ribosomes from resistant bacteria, of telithromycin (TEL), a novel ketolide antibiotic, were investigated. Macrolide resistance inducibility by TEL was compared with erythromycin A (EM) by disc diffusion method. TEL, unlike EM, did not show any resistance inducibility in macrolide (Mac)-susceptible, inducibly resistant and constitutively partial macrolide (PM) resistant S. aureus. TEL exhibited more potent antibacterial activities than EM on both susceptible and resistant strains. Fifty (50)% inhibitory activity (ID₅₀) of TEL for S. aureus was compared with EM and rokitamycin (RKM). TEL showed 5.3 to 5.5 times more potent inhibitory activity than EM and RKM against Mac-susceptible strains, and 1.5 times stronger inhibitory activity than RKM and 124 times stronger than EM against constitutively EM-resistant strains. The inhibitory effect of TEL on protein synthesis was studied using poly (A)-dependent polylysine synthesis system. TEL strongly inhibited protein synthesis in ribosome derived from susceptible strains and Mac resistant strains before resistance induction (erm (A)-arrying S. aureus and Streptococcus pneumoniae HL-3120), but did not inhibit protein synthesis in ribosome derived from Mac-resistant strains after resistance induction. As for the affinity of TEL with ribosomes derived from S. aureus and S. pneumoniae, it bound with 50S ribosome subunit but not 30S subunit as well as existing Mac. TEL also bound with ribosome derived from PM-resistant strains, though less potent than that with 50S ribosome derived from Mac-susceptible S. aureus. TEL bound with ribosome derived from susceptible S. pneumoniae and inducible-type resistant S. pneumoniae to both lincosamide and streptogramin B type antibiotic (MLS). TEL, but not existing 14-membered Macrolides, specifically bound with ribosome 50S subunit derived from S. pneumoniae after resistance induction though weaker than susceptible strains.

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The fast therapeutic effect (i. e., in vivo bactericidal activity) of telithromycin (TEL) was investigated in murine model of pneumonia caused by either an erythromycin A (EM)-susceptible strain (HL 438) or a resistant strain (HL 3523) of Streptococcus pneumoniae. During the short-term period (4 or 8 hours) after administration, TEL showed a therapeutic effect against pneumonia caused by S. pneumoniae, which was more potent than the effects of clarithromycin (CAM), azithromycin (AZM) and levofloxacin (LVFX). In vitro kill kinetic study showed that TEL expresses its bactericidal activity against S. pneumoniae HL 438 more rapidly than the reference compounds, but not against EM-resistant strain. The AUC_0-6/MIC rations of TEL, AZM, CAM and LVFX in the lung of mice with S. pneumoniae HL 438-induced pneumonia were 5, 355, 2, 178, 15, 504 and 20, respectively. These results indicates that TEL shows more rapid in vivo therapeutic effect against S. pneumoniae, because TEL shows in vitro bactericidal activity against the EM susceptible strain more rapidly and/or high AUC/MIC in lung at short-term after administration is better in comparison with the reference compounds.

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Single oral or intravenous toxicity studies of telithromycin, newly developed by Aventis Pharma as antibiotics from the ketolide family, were conducted in mice, rats and dogs. LD₅₀ values by oral administration in mice were 1, 500 mg/kg in male and 1, 000-1, 500mg/kg in female, and those by intravenous dosing were 53mg/kg in male and 49 mg/kg in female. Clinical signs mainly consisted of hypotonia and tremor at oral dosing, and polypnea, convulsion, lethargy and tremor at intravenous dosing. Gross observation of the organs revealed congested appearance of the lungs in mice dosed intravenously. LD₅₀ values by oral administration in rats were greater than 2, 000 mg/kg in both sexes, and those by intravenous dosing were 70mg/kg in male and 81 mg/kg in female. No clinical sign of intoxication observed by oral route, but dyspnea, jumping and convulsion were noted by intravenous route. Gross observation of the organs also revealed congested appearance of the lungs in rats dosed intravenously. In Beagle dogs, LD₅₀ values by oral administration were estimated than 2, 000 mg/kg in both sexes. Clinical signs mainly consisted of vomiting, diarrhea and discoloration of feces. In biochemical examination of serum at first day after dosing, elevation of ALAT activity was observed in one male dog at 2, 000mg/kg, but recovered to normal level at 7 th day after administration. No abnormalities were detected in body weight, body temperature, ECG, hematological examination and gross observations.

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In order to assess the toxicity of the test article telithromycin (TEL), we conducted a 30-day oral toxicity study with a 4-week recovery period and a 13-week oral toxicity study in male and female Sprague Dawley rats. Toxicokinetic parameters were also evaluated in these studies. In the 30-day study (0, 50, 150 and 300mg/kg/day), a slight decrease in body weight in males, increased liver enzymes in both sexes and liver weights increase in females were noted at 300mg/kg/day. At necropsy, increased size of the cecum, due to the antibacterial effect of the test article on the gut microbial flora, was observed in animals from all dosed groups. In histopathological examination, compound-associated phospholipidosis, a known class effect of macrolide molecules, were observed in the liver, lungs, bile duct, jejunum/ileum and mesenteric lymph nodes at 150 and 300 mg/kg/day and in the spleen at 300 mg/kg/day. As other liver findings, multifocal hepatic necrosis and hepatocellular hypertrophy and/or anisokaryosis were also noted. Compound-related changes were completely or partially resolved after a 4-week treatment-free period. Therefore, 50 mg/kg/day dose is considered to be the no observed adverse effect level. The variability of plasma concentrations within each subgroup was generally moderate. C_max and AUC at day 30 were increased at 150 and 300 mg/kg/day in female and at 300 mg/kg/day in male, and the accumulation ratios were 2 to 3 at the highest dose in both sexes. In the 13-week oral toxicity study at doses of 0, 20, 50 and 150 mg/kg/day, a slight decrease in body weight in males, increased liver enzymes in both sexes and increased liver weights in females were noted at 150 mg/kg/day. Phospholipidosis-related changes were observed in the liver, lungs and small intestines at 150 mg/kg/day and in the mesenteric lymph nodes and spleen at 50 and 150 mg/kg/day. In addition, focal hepatic necrosis, multinucleated hepatocytes, increased incidence and severity of mononuclear cell infiltrates and single cell necrosis at 150 mg/kg/day. Therefore in 13-week toxicity study also, 50 mg/kg dose is estimated to be the no observed adverse effect level. The variability of plasma concentrations within each subgroup was moderate and C_24h increased in a non-linear way. An increase in C_24h between day 30 and day 91 was observed at 50 and 150 mg/kg/day in female and at 150 mg/kg in male. At 150 mg/kg/day, mean C_24h in female was about 3 times higher than in the males.

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In order to assess the oral toxicity of the test article telithromycin (TEL), we conducted a 30-day toxicity study and a 13-week toxicity study with a 12-week recovery period in Beagle dogs of both sexes and a 28-day toxicity study in Cynomolgus monkeys of both sexes. Toxicokinetic parameters were also evaluated in these studies. In 30 days study (0, 50, 150 and 300 mg/kg/day), the premature euthanasia was resulted in 1/3 females at 300mg/kg/day, which was considered to be related to compound-induced phospholipidosis-associated tubular nephropathy. Compound-related in-life observations consisted of vomiting (all doses), excessive salivation, a slight reduction in body weight gain and dehydration (at 150 and 300 mg/kg/day), and a loss of reflectivity of the tapetum lucidum (at 300mg/kg/day). Nephrotoxic findings (increased serum urea and/or creatinine and histopathological changes of tubular nephropathy) were observed at 150 and 300mg/kg/day and were considered, at least in part, attributable to the premature euthanasia. Compound-related phospholipidosis-like changes characterized by tissue infiltration with enlarged macrophages in the lungs, liver, gallbladder, mesenteric lymph nodes, intestinal tract, spleen, thymus and epididymides at 150 and 300mg/kg/day and in the stomach, lymph nodes, bone marrow, trachea and urethra at 300mg/kg. The no observed adverse effect dose level in this study is estimated to be 50 mg/kg/day. The pharmacokinetic studies showed high inter-animal variability and increase not in proportion with the dose. A marked increase in AUCs and Cmax was observed between Day 1 and Day 30 at 150 and 300mg/kg/day. The 13 weeks toxicity study followed by a 12-week recovery period (0, 20, 50 or 150 mg/kg/day) resulted in the death of 1/6 males at 150mg/kg/day which was considered related to compound-induced phospholipidosis associated with tubular nephropathy. As compound-related in-life observations, vomiting (all doses), excessive salivation (50 and 150mg/kg/day) and a slight reduction in body weight gain, changes of the tapetal fundus and slight increase in liver enzyme activities were noted at 150 mg/kg/day. Compoundrelated microscopic changes compatible with phospholipidosis were observed in the lungs at 50 and 150mg/kg/day and in the kidneys, liver, gallbladder, intestinal tract, lymph nodes, spleen, thymus and bone marrow at 150mg/kg/day. All the above-mentioned findings were totally reversible after a 12-week treatment-free period, with the exception of the pathological changes in tapetal fundus, lungs, mesenteric lymph nodes, kidneys, ureter and urinary bladder at 150 mg/kg/day which were only partially reversible. The no observable adverse effect level in this study was considered to be 50 mg/kg. The pharmacokinetic parameters in this study showed moderate inter-animal variability. Compared with dosage-increases, C_max increase was lower and AUC increase was higher. AUC and C_max between day 26 and day 89 were similar, whatever sex and dose. In the 28-day toxicity study in the Cynomolgus monkeys (0, 30, 60 and 120mg/kg/day), major drug-related findings at highest dose included emesis, soft feces, poor physical condition, body weight loss and reduced food consumption, and increases of liver enzyme activities and slightly increase of liver weights. The no observable adverse effect dose-level was considered to be 60mg/kg in this study. The pharmacokinetic parameters in this study showed moderate inter-animal variability. The increase of C_max and AUCs were always higher than the ratio of the dose. C_max and AUC between day 1 and day 28 increased at most by a factor of 1.8 and 2.0 respectively. Steady state of C_24h was reached on day 8 in male or day 28 in female.

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Reproductive and developmental toxicity studies of orally administered telithromycin (TEL) were carried out in SD rats and Himalayan rabbits. At first, in studies on fertility and embryonic development to implantation in rats, TEL of 50, 150 and 300 mg/kg/day were administered orally throughout pre-mating period, mating period in males, and in females, throughout pre-mating period, mating period and during pregnancy, until implantation. Although mating was not affected at any dose-level, fertility index, testicular head sperm count and daily sperm production rate in males, and fertility index in females were reduced at 150 and 300 mg/kg/day, and the number of corpora lutea was also reduced at 300 mg/kg/day. Consequently, under our experimental conditions, it is estimated that the No Observed Adverse Effect Levels (NOAEL) on paternal and maternal tolerance are 150 mg/kg/day and NOAEL on the development and maturation of gametes is 50 mg/kg/day. It is also considered that NOAEL on mating behavior and fertilization are 300 and 50 mg/kg/day, respectively and NOAEL on pre-implantation and postimplantation loss is 300 mg/kg/day. In the studies on rat embryo-fetal development, TEL was administered orally at dose levels of 50, 150 and 300 mg/kg/day during the period of fetal organogenesis in rats. Pregnant females showed slight signs of toxicity at 150 mg/kg/day, and increased at 300 mg/kg/day. No significant disruption of development and dysmorphogeny of offspring were observed at 50 and 150 mg/kg/day. Anomalies (incomplete ossification of cranium cervical vertebrae and extremities of paws) and malformations (bent ribs) were observed in fetuses born from the group treated with 300 mg/kg/day. These effects were associated with maternal toxicity. It is considered that in terms of maternal tolerance NOAEL is 150 mg/kg/day and in terms of embryo-fetal development NOAEL is also 150 mg/kg/day. In the studies on rabbit embryo-fetal development, rabbits received daily doses of 20, 60 and 180 mg/kg/day of TEL from the 6th to the 18th day of pregnancy. Dose-dependent reduction of food intake and body weight gain was detected in the dams from doses of 60 mg/kg/day. The hematological and blood biochemical parameters were not impaired by TEL except increased ALP at 180 mg/kg/day. In addition, autopsy of the dams did not reveal any macroscopic changes in the liver and kidneys. Apart from marginally delayed growth of fetuses at 180 mg/kg/day, the embryo-fetal development was not disturbed, and the intrauterine death rate was not increased. In morphological examination of the fetuses, no effects were observed on the findings of variation, anomaly and delayed ossification, and indications of teratogenic effect. The plasma levels of TEL in mated females were apparently dose-related. Plasma concentrations declined rapidly after treatment and there was no evidence of accumulation after repeated dosing. Fetuses, too, were exposed to TEL at a low level. Based on the results of this study, it is evaluated that NOAEL on mated female andembryo-fetal rabbits are 20 and 60 mg/kg/day, respectively. In the studies on pregnant, lactating female and on the development of the conceptus and offspring, the test compound was administered to pregnant rats from implantation through lactation at dose levels of 50, 125 and 200 mg/kg/day.

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The studies on genotoxicity, antigenicity, nephrotoxicity and ototoxicity of telithromycin (TEL) were carried out. As genotoxicity studies, reverse mutation tests using Salmonella typhimurium (TA 1535, TA 1537, TA 98 and TA 100) and Eschrichia coli (WP 2 uvrA), mammalian cell gene mutation test using mouse lymphoma cells (L 5178 YTK^+/-), mammalian chromosome aberration test using cultured human lymphocytes were conducted under the conditions with and without a metabolic activation system (S 9 mix). In these studies TEL did not show any mutagenic activity and clastogenic potential. In micronucleus test in mice TEL did not also induce any damage to the chromosomes or the mitotic apparatus in bone marrow cells. As antigenicity studies, homologous active systemic anaphylaxis and passive cutaneous anaphylaxis test in guinea pigs, and IgE production test in mice using heterologous passive cutaneous anaphylaxis in rats were carried out. No positive anaphylaxis responses were observed in guinea pigs and no production of IgE antibodies against TEL were detected in mice. In order to evaluate the nephrotoxicity of TEL, the effects on renal function of normal rats and glycerol-furosemide induced renal impaired model rats were investigated by single oral dosing of the test substance and compared with the effects by single intravenous dosing of cephaloridine (CER). Clear producing and potentiating effects of renal toxicity, proximal tubular epithelium degeneration, epithelial cell vacuolation and tubular dilatation, were observed in those animals treated with CER. Although slight changes in several parameters of urine and blood biochemistry were detected in rats treated with TEL, the histopathological findings of kidneys found in rats treated with TEL were very slight similar to those of control group. TEL administered once orally to female normal and water restricted rabbits did not induce any renal impairment. In order to evaluate the potential ototoxicity of TEL, auditory thresholds test using Brainstem Evocated Responses Audiometry (BERA) and microscopic examination of the inner ear were conducted in rats orally dosed for 4 weeks and compared with the rats treated with kanamycin by intramuscular injection for the same duration. No relevant variations of the auditory thresholds were detected on BERA or at microscopic examination of the inner ear in rats treated with the test substance and also no microscopic changes in the kidneys were observed in this group. As expected, kanamycin induced functional disturbances in the inner ear, significant elevation of auditory thresholds and pathological changes in the kidneys, tubular epithelial degeneration/necrosis.

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In order to study on human pharmacokinetics of telithromycin (TEL), sensitive bioassay method, HPLC method and LC/MS/MS method were developed and the validation studies of these analytic methods were carried out. As the bioassay method, agar-well diffusion method was developed using Micrococcus luteus ATCC 9341, have high sensitivity and high specificity, as a test organism and Heart infusion agar (pH 9.0) as a test medium. The validation studies on the bioassay method resulted in good accuracy and reliability in the range of 0.002-0.032μg eq/mL in human plasma and urine samples. The lower limit of quantification were 0.002 and 0.004μg eq/mL for plasma and urine. In HPLC method, plasma samples were deproteinated by addition of acetonitrile and reconstituted in mobile phase, and urine samples was diluted directly in mobile phase composition. These mixtures were chromatographed in reverse phase conditions and detected by fluorimetry at 263 nm (excitation wavelength) and 460 nm (emission wavelength). The limit of quantification was 0.005μg/mL for a 300μL aliquot of human plasma and 0.5, u g/mL for a 50, μL aliquot of human urine, respectively. The usable range of concentrations used for the calibration was 0.005 to 1.0μg/mL in plasma and 0.5 to 100μg/mL in urine. As LC/MS/MS method, APCI ionization method was employed, and mass spectrometry was conducted after separation by HPLC under reverse phase conditions. The usable range of concentrations used for the calibration was 5 to 3, 000 ng/mL for a 50μL aliquot of human plasma and the limit of quantification was 5 ng/mL. The validation studies on these methods revealed good accuracy and reliability. The results of stability studies on TEL in clinical samples, showed that blood samples can be stored at room temperature or at 4°C for a maximum of 4 hours following collection. Plasma samples and urine samples containing TEL in clinical studies can be stored at about-20°C for 12 months and at about-25°Cc for 6 months, respectively.

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The studies on absorption, distribution, metabolism and excretion of telithromycin (TEL) were carried out in mouse, rat and dog using ¹⁴C-TEL. Absorption rates after oral dosing were 47% in mouse and rat, 83% in dog, and bioavailability in these animals were 53, 36 and 54%, respectively. The first pass effect observed was low and moderate in rat and dog respectively, but none observed in mouse. T_max of these animals were from 0.25 to 2 h, and suggested that TEL will be absorbed from small intestine to large intestine. The volume of distribution in mouse, rat and dog after intravenous dosing were 1.41, 10.62 and 4.9 L/kg, respectively, and total clearance of these animals were 0.80, 4.36 and 1.5 L/h/kg, respectively. The terminal plasma half-life of these animals were form 1.2 to 2.3 h. After single oral administration of doses ranging between 5 and 20mg/kg in rat, C_max and AUC were increased dose dependently, but these increments were more than the dose-ratio and indicated a non linear pharmacokinetic profile. In rats after oral dosing, higher concentration of radioactivity in most of the tissues was measured than that in plasma, except for central nervous system. All of the radioactivity found in tissues were rapidly decreased from 6h after administration, and almost total elimination of radioactivity from the body's tissues were observed within 24 h of administration. Throughout the study, the fact that high concentration of radioactivity was detected in intestinal wall suggested probable secretion of radioactivity from the blood compartment to the lumina of the gastrointestinal tract. In vitro serum protein binding studies, TEL was bound to mouse serum protein about 90%, but was weakly bound to that of rat and dog (less than 70%). In the studies rat and dog, TEL accounted for 70.7-72.5% of plasma radioactivity in rat and dog. Its metabolites in plasma of rat were below the limit of quantification (0.005 mg eq./L), but in dog plasma, RU 76584 (N-oxidepyridine)

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Studies on in vivo transfer of telithromycin (TEL) into infected tissue of mousewere conducted. In the infection model produced by implantation of paper-disk infiltrated with Staphylococcus aureus-suspended solution into the back-subcutis of mouse, 10mg/kg of ¹⁴C-TEL was orally administered and studied by whole body autoradiography and microautoradiography. The radioactivity was detected almost all tissues around the paper-disk implanted area, and widely distributed to the phagocytes accumulated layer, cutaneus muscle and skeletal muscle by microautoradiography. Radioactivity of most of all the tissues was decreased 8 h after dosing of TEL, on the other hands that of infected site was maintained for long time, and was detected as same level of that of the liver at 24 h after dosing. At 24 h after dosing of TEL, 72.4% of total radioactivity in infected site was remained as the unchanged form.

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In vitro human serum protein binding studies, telithromycin (TEL) was moderately bound to serum proteins. The percentage binding was 60-70% around C_max. Two binding coefficient (Nka) were estimated in all of tested serum, and these evidences suggest that albumin and α₁-acid glycoprotein could be the main protein responsible for the binding of TEL. Binding of TEL to lipoprotein (HDL, LDL and VLDL), γ-globulin and isolated erythrocytes were weak. The samples from an overseas phase I repeated dose study were examined for the in vivo protein binding rate by a centrifugal ultrafiltration method. The rate of free form of TEL ranged from 37.1% to 46.5% at the plasma concentrations of TEL ranging from 0.116 to 3.175 mg/L, the results were similar to those obtained in vitro. Among the overseas studies conducted in special populations, additionally, the protein binding rates in the elderly and the patients with hepatic disorder were similar to those obtained in healthy adults.

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In an attempt to investigate the safety, the effect on intestinal bacterial flora and the pharmacokinetics of telithromycin (TEL), a novel ketolide oral antimicrobial agent, phase I clinical studies were performed using 76 subjects (52 in a single administration study and 24 in a multiple administration study) of Japanese healthy male adult volunteers. In the single oral administration study of TEL at doses of 50, 100, 200, 400, 600, 800 and 1, 200 mg under fasting condition, there were no serious or clinically significant adverse events, indicating that TEL was well tolerated at these doses. TEL was rapidly absorbed after oral administration and the plasma level of TEL reached maximum (C_max) 1.8 to 2.5 hours after administration. After single oral administration of 600mg, which is presumed to be clinically optimal dose in Japanese, the plasma TEL level reached C_max 2.5 hours after administration and plasma elimination half-life in β phase (T_1/2β) was 9.6 hours. C_max, area under the plasma concentration-time curve (AUC_0-24h) and the concentration 24 hours after administration (C_24h) in the above condition were 0.91μg/mL, 4.00μg·h/mL and 0.012μg/mL respectively. The apparent systemic clearance (CL/F) and renal clearance (CL_R) up to 24 hours after administration were 163.4 L/h and 11.3 L/h respectively. When TEL was orally administered at doses of 400, 600 and 800 mg once daily for 10 days, no serious or clinically significant adverse events were observed, indicating that TEL was well tolerated at these doses. As for the influence of TEL multiple administration on intestinal bacterial flora, TEL caused a transient reduction in the total counts of aerobes, but little changes in the total counts of anaerobes. And Clostridium difficile was not found and the toxin was not detected. C_max, AUC_0-24h, C_24h and CL/F at day 10 after administration of 600 mg were 1.18μg/mL, 7.47μg·h/mL, 0.039μg/mL and 86.1 L/h respectively. C_max at day 10 was increased up to about 1.4 times and AUC at day 10 up to about 1.5 times compared with those values at day 1. The TEL levels in WBC at day 10 were 53.05 and 53.94μg/mL 2 and 6 hours after administration respectively. Those values were about 73 times and 99 times higher than the plasma levels respectively. After administration of 600 mg of TEL at day 10, the cumulative urinary excretion rate of TEL up to 24 hours after administration (A_c(0-24h)) was 12.8% and CL_R was 9.6 L/h. In the phase I clinical studies described above by single administration of TEL (50-1, 200mg) and multiple administration of TEL (400, 600 and 800 mg) once daily for 10 days in healthy adult male volunteers, there were no problems of clinical concern in the safety of TEL, and pharmacokinetic characteristics of TEL were elucidated.

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The efficacy, safety and pharmacokinetics of telithromycin (TEL), a new ketolide antibiotic, were evaluated by three clinical studies in patients with respiratory infections. The efficacy and safety in 7 days treatment duration with 600 mg once daily were assessed in the Phase II open labelstudy (open study of 7 days). In the Phase II open label clinical pharmacology study (PK study), sputum concentrations of TEL in 7 days treatment duration with 600 mg once daily were determined periodically for 7 days and the propriety of TEL 600 mg treatment was primarily investigated. Furthermore, in the Phase III open label study (open study of 5 days) the treatment method was the same as in 7 days treatment but treatment duration period was shortened to 5 days, and the efficacy, safety and newly additional final assessment were investigated.
1. Clinical efficacy/final assessment
The efficacy rates in 7 days-open study, pharmacology study and 5 days-open study were respectively 92.0%(23/25), 6/7 and 92.7%(89/96). The final assessment in 5 days treatment study (treatment cure rate) was 85.6%(83/97). The clinical efficacy in 10 cases whose causative organism was judged as penicillin or macrolide-resistant Streptococcus pneumoniae in 3 studies was every “effective”.
2. Bacteriological efficacy
The eradication rates in 7 days-open study, pharmacology study and 5 days-pen study were respectively 75.0%(6/8), 1/3 and 86.0%(37/43).
3. Pharmacokinetics (PK)
The maximum concentrations (mean values) of TEL in the spectrum and plasma were respectively 8.45μg/mL and 1.78μg/mL, and the mean transfer rate into sputum (the maximum sputum concentration/the maximum plasma concentration) was 4.75.
4. Safety
The incidence rates of side effects in 7 days and 5 days open studies were respectively 44.8%(13/29) and 34.5%(41/119). In the pharmacology study, there were no side effects. Side effects with relatively higher incidence rates were gastro-intestinal tract disturbances and hepato-biliary tract related disturbances. They were all mild to moderate and recovered or improved without any sequela. In there 3 studies, TEL was recognized to be highly effective against respiratory tract infections and to be well transferred into sputum. From above findings, it was suggested that TEL could exhibit sufficient usefulness with 600mg once daily treatment for 5 days against respiratory tract infections.

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In an attempt to confirm the appropriateness of the expected clinical dose of telithromycin (TEL), a ketolide antibiotic, in Japan, the clinical efficacy and safety of TEL 600 mg once daily (600 mg group) and TEL 800 mg once daily (800 mg group) against community-acquired pneumonia were investigated in a double-blind, randomized, two-arm parallel-group, non-inferiority, comparative study. Obtained results were as follows,
1. Clinical efficacy
The number of subjects in population for analysis was 91 cases. The efficacy rate excluding 1 indeterminate case was respectively 92.9%(39/42) in 600 mg group and 95.8%(46/48) in 800 mg group, and there was no significant difference between groups. The ratio of “not-relapsed/not reinfected” who did not receive a subsequent antibiotic after completion of study drug treatment to 87 cases who did undergo “relapse/infection” investigation was respectively 85.0%(34/40) in 600 mg group and 85.1% (40/47) in 800 mg group, and no significant difference was observed between groups.
2. Bacteriological efficacy
The number of subjects in population for analysis of bacteriological efficacy was 90 cases. The eradication rate excluding 53 indeterminate cases was 92.9%(13/14) in 600 mg group and 95.7%(22/23) in 800 mg group. Streptococcus pneumoniae including penicillin-or erythromycin-resistant strains were all eradicated in either treatment group.
3. Safety
The number of subjects in population for safety analysis was 103 cases. The incidence rate of adverse events (including abnormal changes in clinical laboratory variables) was 41.3% (19/46) in 600 mg group and 57.4%(27/47) in 800 mg group. The incidence for which a causal relationship to study medication could not be ruled out (excluding indeterminate 10 cases) was 34.8%(16/46) in 600 mg group and 50.0 %(23/46) in 800 mg group.
The clinical and bacteriological efficacy in pneumonia was nearly comparable between both groups and no significant difference was not observed between groups. In the “non-relapse/non-reinfection” rate after the confirmation of final cure assessment, no significant difference was observed between groups. On the other hand, the incidence rate of adverse events (including abnormal change of clinical laboratory variables) was 41.3%(19/46) in 600 mg group and 57.4%(27/47) in 800 mg group, and there was no significant difference between groups. However, the incidence rate of side effects in 800 mg group was higher than that of 600 mg group by 15% or more, and so 600 mg was to be recommended from the aspect of safety. In conclusion, based on the efficacy and safety results, it was suggested that the appropriate recommended optimum clinical dose of TEL in Japan was 600 mg once daily.

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The clinical efficacy and safety of telithromycin (TEL), a new ketolide antibiotic, were evaluation in community-acquired pneumonia in a double-blind, randomized, drug-controlled, two-groups parallelgroup, non-inferiority comparative study versus levofloxacin (LVFX). The dose and dosage of TEL was 600mg once daily (TEL group) and those of LVFX was 100mg 3 times daily (LVFX group). The treatment period was either 7 days. The following results were obtained in this trial.
1. Clinical efficacy
Two hundred seven patients were evaluated for clinical efficacy. The clinical efficacy rates against pneumonia were 93.6% (102/109) in TEL group and 87.8%(86/98) in LVFX group. The difference of clinical efficacy rate (TEL group-LVFX group) was 5.8% and its 2-sided 95%% confidence interval was [-3.1, 14.7]. The lower limit of the confidence interval provided by the clinical trial protocol was not less than-15%, and so the fact that TEL is not inferior to LVFX was verified.
2. Bacteriological efficacy
The eradication rate excluding indeterminate 119 cases out of 205 cases for bacteriological efficacy analysis was respectively 73.9%(34/46) in TEL group and 100.0% (40/40) in LVFX group. Bacterial species not eradicated in TEL group was mainly Haemophilus influenzae, but clinical efficacy rates of TEL and LVFX against cases whose causative organism was this bacteria were respectively 96.8% (30/31) and 86.7% (13/15). In TEL group, resistant Streptococcus pneumoniae strains were all eradicated except for 1 strain of erythromycin-resistant S. pneumoniae.
3. Safety
Case number for the safety analysis was 244. The incidence rates of side effects excluding uncertain 4 cases were respectively 33.6% (42/125) in TEL group and 33.9% (39/115) in LVFX group. No significant difference was found between the groups with respect to the incidence rate of side effects.
Considering from above results, it was suggested that 600mg TEL administered once a day for 7 days could be expected to be clinically very useful in the treatment of community-acquired pneumonia.

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The transferability into tissues of telithromycin (TEL), a novel ketolide antibiotic, in the otorhinolaryngological field was investigated. And, the efficacy and safety of TEL 600 mg once daily for 7 days against patients suffered from sinusitis were investigated. Subsequently, the efficacy and safety of TEL were also investigated by the oral treatment once daily for 5 days.
1. Pharmacokinetic study: The mean drug concentration value after the single oral treatment of TEL 600 mg in the middle ear mucosa, sinus mucosa and palatine tensile was 1.35μg/g, 1.68μg/g and 2.62μg/g, respectively. The ratio against simultaneous plasma concentration was 2.36, 3.97 and 7.81, respectively.
2. 7 days' treatment study: The clinical efficacy by the oral treatment of TEL 600 mg once daily for 7 days against sinusitis was 76.5%(13/17), and the side effects occurred in 3 cases out of 17 cases (17.6%) though all mild.
3. 5 days' treatment study: The clinical efficacy by the oral treatment of TEL 600 mg once daily for 5 days against sinusitis was 85.4%(35/41). The clinical efficacy at treatment termination time in 8 cases whose causative bacteria before treatment was penicillin-moderately resistant-Streptococcus pneumoniae (MIC in benzylpenicillin: 0.12-1μg/mL) or macrolide-resistant S. pneumoniae (MIC in erythromycin:≥1μg/mL) was either “excellent” or “good”. The bacteriological efficacy was 84.0%(21/25). As for the safety, the side effects were observed in 8 cases out of 41 cases (19.5%), but there were no serious cases.
In conclusion, based on the above results, it was suggested that TEL was well transferred into tissues in the otorhinolaryngological field and the oral treatment of TEL 600 mg once daily for 5 days against sinusitis including patients whose causative bacteria was penicillin-resistant or macrolide-resistant S. pneumoniae exhibited an excellent clinical usefulness.

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A clinical pharmacology study to investigate the transferability of telithromycin (TEL), a novel ketolide oral antibiotic, into oral cavity tissues, and a phase II clinical study by TEL 600 mg once daily for 7 days (7 days' treatment study) and a phase III clinical study by TEL 600 mg once daily for 3 days (3 days'treatment study) against infectious patients in the field of dentistry and oral surgery were performed. Following results were obtained.
1. Transferability into oral cavity tissues (clinical pharmacology study)
The oral cavity tissue concentration 3 to 6 hours after the single treatment of TEL 600 mg in 11 cases for the data analysis was 1.72, ug/g in gingiva, 1.13, ug/mL in the wound exudate after exodontia, and so the transfer rate was 3.33 in gingiva and 2.20 in wound exudate after exodontia, respectively.
2. Clinical efficacy
The clinical efficacy rate by rating ratio after 7 days in 7 days' treatment study against 31 cases for the data analysis was 100%(31/31). The clinical efficacy rate by rating ratio after 3 days' in 3 days' treatment study against 24 cases for the data analysis was 91.7%(22/24).
3. Bacteriological efficacy
The eradication rate after 7 days in 7 days' treatment study against 29 cases for the data analysis of bacteriological efficacy was 100%(29/29). The eradication rate after 3 days in 3 days' treatment study against 22 cases for the data analysis of bacteriological efficacy was 95.5%(21/22).
4. Safety
The adverse events undeniable the causal relationship with TEL were not observed in the clinical pharmacology study, and occurred in 7 cases (21.9%, 10 events) out of 32 cases for the data analysis in 7 days' treatment study and in 3 cases (11.1%, 3 events) out of 27 cases for the data analysis in 3 days' treatment study.
Considering from above results, it was suggested that TEL was well transferred into oral cavity tissues after TEL 600 mg oral treatment and TEL 600 mg once daily for 3 days' treatment exhibited sufficient efficacy against infectious patients in the field of dentistry and oral surgery and there were no problems in the safety and further the good drug-intake compliance was expected owing to the once daily treatment.

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