| macrolide-clindamycin-streptogramine |
telithromycin (HMR 3647; RU-66647)
Moon-Hyun Chung
Sep 29, 2000
trade name in USA : Ketek
Aventis Pharma
Telithromycin, one of ketolide, add one powerful armament to battle against antibiotic-resistant bacterial infection. It is a new semi-syntetic 14-membered ring agent characterized by 3-keto group. It has an antimicrobial spectrum similar to that of erythromycin, but more potent than erythromycin in the floowing conditions ; penicillin-susceptible S. aureus; penicillin-susceptible Streptococcus pneumoniae and penicillin- and erythromycin-resistant S. pneumoniae; Enterococcus (MIC90 1-2 ug/ml irrespective of resistance to vancomycin); Corynebacterium sp. (except C. jeikeium and C. urealyticum); Bordetella pertussis; Haemophilus (less activity than other comparative antibiotics - MIC90, 2-4 micrograms/mL, but more effective than ciprofloxacin in an animal experiment. It is bacteriostatic whereas azithromycin shows a bactericidal activity); Moraxella; Neisseria sp.; Listeria monocytogenes (better than erythromycin, but its effect in human should be evaluated);
Mycoplasma species except M. hominis; Legionella; Chlamydia; Rickettsia except Ehlrhichia; anaerobic cocci and non-Bacteroides fragilis group strains; Toxoplasma gondii.
No activities against Enterobacteriaceae, nonfermentative Gram-negative bacilli, and Bacteriodes fragilis group strains; Mycobacterium tuberculosis.
a mode of action is similar to the macrolide-lincosamide-streptogramin (MLS) compounds. One difference is telithromycin binds to 2 sites on the bacteria ribosome, so even if one site becomes resistant to erythromcin, another may be still effective.
It has an beneficial effect on injuried respiratory epithelial cell.
Other new ketolide antibiotics, HMR 3004 and ABT 773, are under investigation.
adverse effects :
cardiac toxicity - raise heart rate: its magnitude is far less than that of other medications
hepatic toxicity : evidence is not enough, but serious hepatitis may occur.
interactions with other medications
this antibiotic is approved by FDA on April 27, 2001 for the treatment of community-acquired pneumonia.
In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram-positive bacteria
Malathum K, Coque TM, Singh KV, Murray BE
Antimicrob Agents Chemother 1999 Apr;43(4):930-6
The in vitro activities of two new ketolides, HMR 3647 and HMR 3004, were tested by the agar dilution method against 280 strains of gram-positive bacteria with different antibiotic susceptibility profiles, including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus spp. (group A streptococci, group B streptococci, Streptococcus pneumoniae, and alpha-hemolytic streptococci). Seventeen erythromycin-susceptible (EMs), methicillin-susceptible S. aureus strains were found to have HMR 3647 and HMR 3004 MICs 4- to 16-fold lower than those of erythromycin (MIC at which 50% of isolates were inhibited [MIC50] [HMR 3647 and HMR 3004], 0.03 microgram/ml; range, 0.03 to 0.06 microgram/ml; MIC50 [erythromycin], 0.25 microgram/ml; range, 0.25 to 0.5 microgram/ml). All methicillin-resistant S. aureus strains tested were resistant to erythromycin and had HMR 3647 and HMR 3004 MICs of > 64 micrograms/ml. The ketolides were slightly more active against E. faecalis than against E. faecium, and MICs for individual strains varied with erythromycin susceptibility. The MIC50s of HMR 3647 and HMR 3004 against Ems enterococci (MIC < or = 0.5 microgram/ml) and those enterococcal isolates with erythromycin MICs of 1 to 16 micrograms/ml were 0.015 microgram/ml. E. faecalis strains that had erythromycin MICs of 128 to > 512 micrograms/ml showed HMR 3647 MICs in the range of 0.03 to 16 micrograms/ml and HMR 3004 MICs in the range of 0.03 to 64 micrograms/ml. In the group of E. faecium strains for which MICs of erythromycin were > or = 512 micrograms/ml, MICs of both ketolides were in the range of 1 to 64 micrograms/ml, with almost all isolates showing ketolide MICs of < or = 16 micrograms/ml. The ketolides were also more active than erythromycin against group A streptococci, group B streptococci, S. pneumoniae, rhodococci, leuconostocs, pediococci, lactobacilli, and diphtheroids. Time-kill studies showed bactericidal activity against one strain of S. aureus among the four strains tested. The increased activity of ketolides against gram-positive bacteria suggests that further study of these agents for possible efficacy against infections caused by these bacteria is warranted.
Antipneumococcal activity of telithromycin by agar dilution, microdilution, E test, and disk diffusion methodologies
Davies TA, Kelly LM, Jacobs MR, Appelbaum PC
J Clin Microbiol 2000 Apr;38(4):1444-8
Agar dilution and microdilution (both in air) and E test and disk diffusion (both in air and CO(2)) were used to test the activity of telithromycin against 110 erythromycin-susceptible and 106 erythromycin-resistant pneumococci. The MICs at which 50 and 90% of strains are inhibited (MIC(50)s and MIC(90)s, respectively) for erythromycin-susceptible strains varied between 0.008 and 0.016 &mgr;g/ml and 0.016 and 0.03 microg/ml when the samples were incubated in air. By comparison, telithromycin MIC(50)s and MIC(90)s for erythromycin-resistant strains were in air 0.03 to 0.125 and 0. 125 to 0.5 microg/ml, respectively. When agar dilution was used as the reference method, essential agreement was found for 112 of 216 strains (51.9%) for microdilution, 168 of 216 (77.8%) for E test in air, and 132 of 216 (61.1%) for E test in CO(2). With the exception of four strains tested by E test in CO(2), all organisms were susceptible to a proposed telithromycin susceptibility breakpoint of < or =1 microg/ml. By disk diffusion with 15-microg telithromycin disks, all strains but one had zones of inhibition > or =19 mm in diameter when incubated in CO(2), while all strains had zone diameters of > or = 22 mm when incubated in air. Zone diameters in air were generally 4 to 5 mm larger than in CO(2). By all methods, MICs and zones of all erythromycin-resistant strains occurred in clusters separated from those seen with erythromycin-susceptible strains. The results for macrolide-resistant strains with erm and mef resistance determinants were similar. The results show that (i) telithromycin is very active against erythromycin-susceptible and -resistant strains irrespective of macrolide resistance mechanism; (ii) susceptibility to telithromycin can be reliably tested by the agar, microdilution, E test, and disk diffusion methods; and (iii) incubation in CO(2) led to smaller zones by disk diffusion and higher MICs by E test, but at a susceptible MIC breakpoint of < or =1 microg/ml and a susceptible zone diameter cutoff of > or =19 mm in CO(2), 215 of 216 strains were found to be susceptible to telithromycin.
In-vitro activity of HMR 3647 against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and beta-haemolytic streptococci
Wootton M, Bowker KE, Janowska A, Holt HA, MacGowan AP
J Antimicrob Chemother 1999 Oct;44(4):445-53
The in-vitro activity of HMR 3647 and seven comparators (azithromycin, clarithromycin, erythromycin A, roxithromycin, penicillin G, ciprofloxacin and levofloxacin) were tested against 207 Streptococcus pneumoniae and 200 beta-haemolytic streptococci. Ten comparators (azithromycin, clarithromycin, erythromycin A, roxithromycin, ampicillin, co-amoxiclav, cefuroxime, cefotaxime, ciprofloxacin and levofloxacin) were tested against 143 Haemophilus influenzae and 58 Moraxella catarrhalis. The MIC50 of HMR 3647 for S. pneumoniae was < or =0.008 mg/L, less than that for the macrolides or quinolones tested. Pneumococci with an erythromycin A MIC of 0.06 mg/L (n = 23) had an MIC50 of HMR 3647 < or =0.008 mg/L, whereas isolates with an erythromycin A MIC > or =1 mg/L (n = 34) had an MIC50 of HMR 3647 of 0.03 mg/L, a four-fold increase. In contrast, the difference in macrolide MIC50s for the two groups was > or =64-fold. The MIC50s foro beta-haemolytic streptococci, classified by Lancefield group, were in the range 0.015 to 0.06 mg/L for HMR 3647. H. influenzae were categorized into three groups according to cefuroxime MIC: <1 mg/L (n = 72); 2-4 mg/L (n = 29); and >4 mg/L (n = 42). The MIC50 of HMR 3647 increased two-fold with increasing cefuroxime MICs; beta-lactam MICs increased much more markedly. The MIC50 of HMR 3647 for M. catarrhalis was 0.03 mg/L. HMR 3647 has good activity against respiratory tract pathogens but in-vitro susceptibility is affected by erythromycin A susceptibility in S. pneumoniae and beta-haemolytic streptococci.
Ketolide treatment of Haemophilus influenzae experimental pneumonia
Piper KE, Rouse MS, Steckelberg JM, Wilson WR, Patel R
Antimicrob Agents Chemother 1999 Mar;43(3):708-10
The MICs of HMR 3004 and HMR 3647 at which 90% of beta-lactamase-producing Haemophilus influenzae isolates were inhibited were 4 and 2 micrograms/ml, respectively. Both HMR 3004 and HMR 3647 were active against beta-lactamase-producing H. influenzae in a murine model of experimental pneumonia. As assessed by pulmonary clearance of H. influenzae, HMR 3004 was more effective (P < 0.05) than was azithromycin, ciprofloxacin, clarithromycin, erythromycin A, pristinamycin, or HMR 3647 in this model.
In vitro activities of ketolides HMR 3647 [correction of HRM 3647] and HMR 3004 [correction of HRM 3004], levofloxacin, and other quinolones and macrolides against Neisseria spp. and Moraxella catarrhalis
Saez-Nieto JA, Vazquez JA
Antimicrob Agents Chemother 1999 Apr;43(4):983-4
In vitro activities of the ketolides HMR 3647 [corrected] and HMR 3004 [corrected] against pathogenic Neisseria gonorrhoeae and N. meningitidis, saprophytic Neisseria isolates, and Moraxella catarrhalis were determined. The comparison of ketolide activities with those of the other macrolides shows a much better activity in the majority of species, with macrolide MICs at which 90% of the isolates are inhibited between 8- and 10-fold higher.
In vitro activities of ketolide HMR3647, macrolides, and other antibiotics against Lactobacillus, Leuconostoc, and Pediococcus isolates
Zarazaga M, Saenz Y, Portillo A, Tenorio C, Ruiz-Larrea F, Del Campo R, Baquero F, Torres C
Antimicrob Agents Chemother 1999 Dec;43(12):3039-41
Testing of susceptibility to 13 antibiotics was performed with 90 isolates of Lactobacillus, Leuconostoc, and Pediococcus. MICs at which 90% of the isolates tested were inhibited by HMR3647, erythromycin, and ciprofloxacin were 0.015, 0.125 and 32 microg/ml, respectively. The penicillin MIC was > or = 16 microg/ml against 26.2% of the studied Lactobacillus sp. isolates and 50% of Lactobacillus plantarum. HMR3647 showed excellent activity against these genera.
In vitro pharmacodynamics of the new ketolides HMR 3004 and HMR 3647 (Telithromycin) against Chlamydia pneumoniae
Gustafsson I, Hjelm E, Cars O
Antimicrob Agents Chemother 2000 Jul;44(7):1846-9
The ketolides HMR 3004 and HMR 3647 (telithromycin) are a new class of macrolides that have a potential clinical efficacy against intracellular pathogens. The objectives of this study were to investigate the MIC, minimum bactericidal concentration, and time-dependent killing of two Chlamydia pneumoniae strains of the two ketolides. The killing effect was also studied with a newly developed intracellular in vitro kinetic model. Furthermore, HMR 3647 was studied for the effect of a subinhibitory concentration of 0.5 times the MIC after a preexposure of 10 times the MIC during 12 h. The MICs for both strains were 0.0039 and 0.0156 mg/liter for HMR 3004 and HMR 3647, respectively. Killing with 10 times the MIC was time dependent, increasing from a 1-log-unit decrease in the number of inclusions per well at 48 h to a maximal effect of 2.8-log-unit decrease after 96 h. A preexposure of 10 times the MIC of HMR 3647 for 12 h followed by a subinhibitory concentration of 0.5 times the MIC increased the killing effect to a 1.2-log-unit reduction in inclusions per well. An exposure for 12 h gave poor reduction of inclusions, while a static dose of 10 times the MIC for 72 h showed a 2.2-log-unit reduction in inclusions per well. In the kinetic model, a small number of inclusions were detected after 72 h by one exposure of 10 times the MIC. Regrowth could not be detected after 120 h. The ketolides HMR 3004 and HMR 3647 have bactericidal activity and show a significant sub-MIC effect on the intracellular pathogen C. pneumoniae.
Comparative activities of telithromycin (HMR 3647), levofloxacin, and other antimicrobial agents against human mycoplasmas
Bebear CM, Renaudin H, Bryskier A, Bebear C
Antimicrob Agents Chemother 2000 Jul;44(7):1980-2
The activities of telithromycin and levofloxacin against 99 mycoplasma strains were compared to those of several macrolides, ofloxacin, and doxycycline. Telithromycin MICs of less than or equal to 0.25 microgram/ml were found for all isolates, except for Mycoplasma hominis, while levofloxacin was active at concentrations of less than or equal to 1 microgram/ml against all species studied.
Activities of antimicrobial agents against intracellular pneumococci
Mandell GL, Coleman EJ
Antimicrob Agents Chemother 2000 Sep;44(9):2561-3
Pneumococci can enter and survive inside human lung alveolar carcinoma cells. We examined the activity of azithromycin, gentamicin, levofloxacin, moxifloxacin, penicillin G, rifampin, telithromycin, and trovafloxacin against pneumococci inside and outside cells. We found that moxifloxacin, trovafloxacin, and telithromycin were the most active, but only telithromycin killed all intracellular organisms.
In vitro activity of the ketolide HMR 3647 (RU 6647) for Legionella spp., its pharmacokinetics in guinea pigs, and use of the drug to treat guinea pigs with Legionella pneumophila pneumonia
Edelstein PH, Edelstein MA
Antimicrob Agents Chemother 1999 Jan;43(1):90-5
The activities of HMR 3647, HMR 3004, erythromycin, clarithromycin, and levofloxacin for 97 Legionella spp. isolates were determined by microbroth dilution susceptibility testing. Growth inhibition of two Legionella pneumophila strains grown in guinea pig alveolar macrophages was also determined. The concentrations required to inhibit 50% of strains tested were 0.06, 0.02, 0.25, 0.03, and 0.02 microg/ml for HMR 3647, HMR 3004, erythromycin, clarithromycin, and levofloxacin, respectively. BYEalpha broth did not significantly inhibit the activities of the drugs tested, as judged by the susceptibility of the control Staphylococcus aureus strain; however, when Escherichia coli was used as the test strain, levofloxacin activity tested in BYEalpha broth was fourfold lower. HMR 3647, HMR 3004, erythromycin, and clarithromycin (0.25 and 1 microg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 0.5 to 1 log10, but regrowth occurred over a 2-day period. HMR 3647, erythromycin, and clarithromycin appeared to have equivalent intracellular activities which were solely static in nature. HMR 3004 was more active than all drugs tested except levofloxacin. In contrast, levofloxacin (1 microg/ml) was bactericidal against intracellular L. pneumophila and significantly more active than the other drugs tested. Therapy studies with HMR 3647 and erythromycin were performed in guinea pigs with L. pneumophila pneumonia. When HMR 3647 was given (10 mg/kg of body weight) by the intraperitoneal route to infected guinea pigs, mean peak plasma levels were 1.4 microg/ml at 0.5 h and 1.0 microg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.4 h. All 16 L. pneumophila-infected guinea pigs treated with HMR 3647 (10 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days after antimicrobial therapy, as did all 16 guinea pigs treated with the same dose of HMR 3647 given twice daily. Fourteen of 16 erythromycin-treated (30 mg/kg/dose given intraperitoneally twice daily) animals survived, whereas 0 of 12 animals treated with saline survived. HMR 3647 is effective against L. pneumophila in vitro, in infected macrophages, and in a guinea pig model of Legionnaires' disease. HMR 3647 given once daily should be evaluated as a treatment for Legionnaires' disease in humans.
Antibacterial effect of telithromycin (HMR 3647) and comparative antibiotics against intracellular legionella pneumophila
Baltch AL, Smith RP, Ritz WJ, Franke MA, Michelsen PB
J Antimicrob Chemother 2000 Jul;46(1):51-5
The activity of the ketolide telithromycin (HMR 3647) against intracellular Legionella pneumophila strain L-1033 was compared with the activities of erythromycin and levofloxacin. To assay intracellular antibacterial activity, human monocytes were allowed to adhere to wells in 24-well tissue culture plates and were then exposed to L. pneumophila cells for 1 h to allow phagocytosis to occur. Antibiotics were added to the wells after removal of unphagocytosed bacteria. Quantitative bacterial cell counts were made from lysed monocytes at 0, 24, 48, 72 and 96 h. The antibacterial effects of antibiotics against intracellular L. pneumophila L-1033 were concentration and time dependent; at 10 x MIC the activity of telithromycin was greater than that of erythromycin and was less than that of levofloxacin (P < 0.01); telithromycin-rifampicin combinations showed no synergy or interference; and removal of telithromycin from assays at 24 h did not affect its intracellular antibacterial activity. In conclusion, the ketolide telithromycin has excellent activity against intracellular L. pneumophila strain L-1033 and should be evaluated for therapy of legionnaires' disease.
In vitro activity of HMR 3647 against anaerobic bacteria
Edlund C, Sillerstrom E, Wahlund E, Nord CE
J Chemother 1998 Aug;10(4):280-4
The aim of the present investigation was to determine the in vitro activity of HMR 3647 compared with other antimicrobial agents against anaerobic bacteria. The activity of HMR 3647 was determined against 342 clinical isolates of anaerobic bacteria by the agar dilution method and was compared with azithromycin, clarithromycin, roxithromycin, erythromycin, cefoxitin, imipenem, clindamycin and metronidazole. Among the macrolides HMR 3647 and among the beta-lactams imipenem were the most active agents tested. Anaerobic cocci (50 strains) had the following minimum inhibitory concentrations (MICs): HMR 3647, range 0.016-0.125 mg/l; imipenem, range 0.016-0.064 mg/l. Propionibacterium acnes (30 strains): HMR 3647, 0.016-1.0 mg/l; imipenem, 0.032-0.064 mg/l. Clostridium perfringens (30 strains): HMR 3647, 0.125 mg/l; imipenem, 0.016-0.5 mg/l. Clostridium difficile (50 strains): HMR 3647, 0.125-256 mg/l; imipenem, 4.0-8.0 mg/l. Bacteroides fragilis (102 strains): HMR 3647, 0.032-16 mg/l; imipenem, 0.064-0.25 mg/l. Bacteroides and Prevotella species (50 strains): HMR 3647, 0.016-4.0 mg/l; imipenem, 0.016-0.25 mg/l. Fusobacterium nucleatum (30 strains): HMR 3647, 0.016-8.0 mg/l; imipenem, 0.008-0.064 mg/l. HMR 3647 may be useful as treatment and prophylaxis for infections due to anaerobic bacteria.
In vitro activity of telithromycin (HMR 3647) and seven other antimicrobial agents against anaerobic bacteria
Ackermann G, Schaumann R, Pless B, Claros MC, Rodloff AC
J Antimicrob Chemother 2000 Jul;46(1):115-9
We assessed the in vitro activity of telithromycin (HMR 3647) and seven other antimicrobials against 292 strains of obligately anaerobic bacteria. MICs were determined with the microdilution technique and Wilkins-Chalgren broth according to DIN 58940-83. MIC50/MIC90s (mg/L) for telithromycin were 4/4 for Bacteroides fragilis, Bacteroides ovatus and Bacteroides thetaiotaomicron, 2/4 for FUSOBACTERIUM: spp. and Bilophila wadsworthia, 2/2 for Bacteroides caccae, 1/4 for Bacteroides vulgatus, 0.25/4 for PREVOTELLA: spp., >/=0.03/0.5 for CLOSTRIDIUM: spp. and 0.125/4 for PEPTOSTREPTOCOCCUS: spp.
Activities of telithromycin (HMR 3647, RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and other antimicrobial agents against unusual anaerobes
Goldstein EJ, Citron DM, Merriam CV, Warren Y, Tyrrell K
Antimicrob Agents Chemother 1999 Nov;43(11):2801-5
The comparative activity of telithromycin (HMR 3647) against 419 human anaerobic isolates was determined by the agar dilution method. At concentrations of
In vitro activities of the ketolides telithromycin (HMR 3647) and HMR 3004 compared to those of clarithromycin against slowly growing mycobacteria at pHs 6.8 and 7.4
Rastogi N, Goh KS, Berchel M, Bryskier A
Antimicrob Agents Chemother 2000 Oct;44(10):2848-52
The in vitro activities of HMR 3647 (telithromycin) and HMR 3004, two novel semisynthetic ketolides, were investigated and compared with that of the reference macrolide drug, clarithromycin, against 34 strains of slowly growing mycobacteria at pHs 6.8 and 7.4, as determined radiometrically. The MICs at pH 7.4 were about 1 to 2 dilutions lower than those observed at pH 6.8. In terms of the highest to the lowest activity, the three antibiotics could be classified as follows: clarithromycin > HMR 3004 > HMR 3647. Among the species tested, Mycobacterium bovis BCG, M. ulcerans, M. avium, and M. paratuberculosis were moderately susceptible to HMR 3004 and HMR 3647 (MICs at pH 7.4, /=10.0 and >/=40.0 &mgr;g/ml, respectively, at pH 7.4). Although not more active than clarithromycin in vitro, the high level of intracellular accumulation of the two ketolides inside phagocytes warrants further screening in experimental animal models.
In vitro susceptibilities of rapidly growing mycobacteria to telithromycin (HMR 3647) and seven other antimicrobials
Fernandez-Roblas R, Esteban J, Cabria F, Lopez JC, Jimenez MS, Soriano F
Antimicrob Agents Chemother 2000 Jan;44(1):181-2
The antimicrobial activities of telithromycin (HMR 3647) and seven other antimicrobials against 94 strains of rapidly growing mycobacteria were determined. Telithromycin at a concentration of 1 microg/ml inhibited Mycobacterium peregrinum (100%), Mycobacterium chelonae (80%), Mycobacterium abscessus-Mycobacterium mucogenicum (44.4%), and Mycobacterium fortuitum (2.1%). All or most strains of M. peregrinum, M. fortuitum, and M. mucogenicum were inhibited by 2 microg of quinolones per ml.
In vitro activities of telithromycin (HMR 3647) against Rickettsia rickettsii, Rickettsia conorii, Rickettsia africae, Rickettsia typhi, Rickettsia prowazekii, Coxiella burnetii, Bartonella henselae, Bartonella quintana, Bartonella bacilliformis, and Ehrlichia chaffeensis
Rolain JM, Maurin M, Bryskier A, Raoult D
Antimicrob Agents Chemother 2000 May;44(5):1391-3
In vitro activities of telithromycin compared to those of erythromycin against Rickettsia spp., Bartonella spp., Coxiella burnetii, and Ehrlichia chaffeensis were determined. Telithromycin was more active than erythromycin against Rickettsia, Bartonella, and Coxiella burnetii, with MICs of 0.5 microg/ml, 0.003 to 0.015 microg/ml, and 1 microg/ml, respectively, but was inactive against Ehrlichia chaffeensis.
Use of ketolides in combination with other drugs to treat experimental toxoplasmosis
Araujo FG, Khan AA, Bryskier A, Remington JS
J Antimicrob Chemother 1998 Nov;42(5):665-7
Because combination therapy is required to treat human toxoplasmosis, we examined combinations of the ketolides HMR 3004 and HMR 3647 with atovaquone, clindamycin or sulphadiazine in a murine model of toxoplasmosis. An oral dose of 50 mg/kg/day of HMR 3004 protected 30% of mice lethally infected with Toxoplasma gondii. The same dose protected 100% of infected mice when administered in combination with non-protective doses of atovaquone, clindamycin or sulphadiazine. Similar results were noted with 25 mg/kg/day of HMR 3647. These results demonstrate that these drug combinations are highly effective for treating toxoplasmosis in mice.
In vitro development of resistance to telithromycin (HMR 3647), four macrolides, clindamycin, and pristinamycin in Streptococcus pneumoniae
Davies TA, Dewasse BE, Jacobs MR, Appelbaum PC
Antimicrob Agents Chemother 2000 Feb;44(2):414-7
The ability of 50 sequential subcultures in subinhibitory concentrations of telithromycin (HMR 3647), azithromycin, clarithromycin, erythromycin A, roxithromycin, clindamycin, and pristinamycin to select for resistance was studied in five macrolide-susceptible and six macrolide-resistant pneumococci containing mefE or ermB. Telithromycin selected for resistance less often than the other drugs.
The effects of ketolides on bioactive phospholipid-induced injury to human respiratory epithelium in vitro
Feldman C, Anderson R, Theron A, Mokgobu I, Cole PJ, Wilson R
Eur Respir J 1999 May;13(5):1022-8
The potential of the novel ketolide antimicrobial agents, HMR 3004 and HMR 3647, to antagonize the injurious effects of the bioactive phospholipids (PL), platelet-activating factor (PAF), lyso-PAF, and lysophosphatidylcholine (LPC) on the ciliary beat frequency and structural integrity of human ciliated respiratory epithelium in vitro was investigated, in the presence or absence of polymorphonuclear leukocytes (PMNL). The ciliary beat frequency of human nasal respiratory epithelium, obtained by nasal brushing of healthy volunteers, was measured using a photo-transistor technique, while superoxide generation by activated human PMNL and membrane-stabilizing activity were measured by lucigenin-enhanced chemiluminescence and haemolytic procedures, respectively. All three PL, at concentrations of 2.5 microg x mL(-1), caused significant (p<0.005) ciliary slowing and epithelial damage, while treatment of the epithelial strips with the ketolides, in particular HMR 3004, caused dose-related attenuation of these direct adverse effects of the PL on ciliated epithelium, apparently by a membrane-stabilizing mechanism. When epithelial strips were exposed to the combination of PMNL (1 x 10(6) cells x mL(-1)) and PAF (1 microg x mL(-1)), significant ciliary dysfunction and epithelial damage were also observed, which were mediated predominantly by neutrophil-derived oxidants. These injurious effects of PAF were antagonized by preincubation of the epithelial strips or the PMNL with HMR 3004 (10 microg x mL(-1)). The ketolide antimicrobial agents, in particular HMR 3004, antagonize the direct and polymorphonuclear leukocyte-mediated injurious effects of phospholipids on human ciliated epithelium and may have beneficial effects in inflammatory disorders of the airways, such as asthma, chronic bronchitis, diffuse panbronchiolitis and bronchiectasis.
Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils
Vazifeh D, Preira A, Bryskier A, Labro MT
45: Antimicrob Agents Chemother 1998 Aug;42(8):1944-51
HMR 3647, a new ketolide, is active upon intracellular pathogens. We previously demonstrated that HMR 3004 (RU 64004), another ketolide, is highly concentrated by human polymorphonuclear neutrophils (PMNs). This prompted us to evaluate whether the presence of a 3-keto group instead of an L-cladinose, a neutral sugar characteristic of erythromycin A derivatives, confers peculiar pharmacokinetic properties with regard to cellular accumulation and efflux. After incubation with the radiolabelled drug, HMR 3647 uptake was determined by a velocity gradient centrifugation technique. HMR 3647 was avidly concentrated by PMNs, without saturation, over a 3-h incubation period, with cellular-to-extracellular concentration ratios of 31 +/- 4.2 at 5 min and up to 348 +/- 27.1 at 180 min. About 60% of HMR 3647 was located in the granular compartment; less than 6% was associated with the membranes. HMR 3647 gradually egressed from loaded cells placed in drug-free medium. Uptake was dependent on environmental temperature (activation energy, 128 +/- 9. 4 kJ/mol) but not on extracellular pH. HMR 3647 displayed Michaelis-Menten saturation kinetics with a mean Vmax of 2315 ng/2.5 x 10(6) PMNs/5 min and a mean Km of 117 mg/liter (144 microM). As already observed with erythromycin A-derived macrolides, extracellular Ca2+ was necessary for optimal uptake of HMR 3647. Interestingly, verapamil increased the uptake of HMR 3647 at 5 min, but this was followed by gradual inhibition at later incubation times, a phenomenon probably related to stimulation of drug efflux. The impact of intracellular accumulation of HMR 3647 on PMN functions was also investigated. In contrast to other erythromycin A derivatives, HMR 3647 only weakly triggered granule exocytosis, but it inhibited superoxide anion production in a time- and concentration-dependent manner, with concentrations which inhibited 50% of control response of 55 (67 microM) (5 min) and 30 (36 microM) (30 min) mg/liter for formyl-methionyl-leucyl-phenylalanine stimulation and 117 (143 microM) (5 min) and 44 (54 microM) (30 min) mg/liter for phorbol myristate acetate stimulation.
The new ketolide HMR3647 accumulates in the azurophil granules of human polymorphonuclear cells
Miossec-Bartoli C, Pilatre L, Peyron P, N'Diaye EN, Collart-Dutilleul V, Maridonneau-Parini I, Diu-Hercend A
Antimicrob Agents Chemother 1999 Oct;43(10):2457-62
HMR3647 is a semisynthetic representative of a new group of drugs, the ketolides, derived from erythromycin A. Since macrolides have been shown to accumulate in human polymorphonuclear cells (PMNs), we have investigated the ability of the molecule HMR3647 to enter human PMNs as well as other cell types, such as peripheral blood mononuclear cells and cell lines of hematopoietic and nonhematopoietic origin. In these experiments, HMR3647 was compared to erythromycin A, azithromycin, clarithromycin, and roxithromycin. Our results show that HMR3647 is specifically trapped in PMNs, where it is concentrated up to 300 times . In addition, it is poorly released by these cells, 80% of the compound remaining cell associated after 2 h in fresh medium. By contrast, it is poorly internalized and quickly released by the other cell types studied. This differs from the results obtained with the macrolide molecules, which behaved similarly in the different cells studied. In addition, subcellular fractionation of PMNs allowed us to identify the intracellular compartment where HMR3647 was trapped. In PMNs, more than 75% of the molecule was recovered in the azurophil granule fraction. Similarly, in NB4 cells differentiated into PMN-like cells, almost 60% of the molecules accumulated in the azurophil granule fraction. In addition, when HMR3647 was added to disrupted PMNs, 63% accumulated in the azurophil granules. Therefore, this study shows that the ketolide HMR3647 specifically accumulates in PMN azurophil granules, thus favoring its delivery to bacteria phagocytosed in these cells.
Postantibiotic suppression of growth of erythromycin A-susceptible and -resistant gram-positive bacteria by the ketolides telithromycin (HMR 3647) and HMR 3004
Munckhof WJ, Borlace G, Turnidge JD
Antimicrob Agents Chemother 2000 Jun;44(6):1749-53
We investigated the in vitro postantibiotic effects (PAEs) of the ketolides telithromycin (HMR 3647) and HMR 3004 and analyzed the results using the sigmoid E(max) model. Mean maximum telithromycin PAEs against erythromycin A-susceptible strains of Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae were 3. 7, 8.9, and 9.7 h, respectively, while maximum PAEs for erythromycin A-resistant strains were much shorter. Mean maximum HMR 3004 PAEs were 3.2 to 4.4 h for all species.
|
|