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1 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 1 ) Telithromycin 7 20 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) Telithromycin (TEL) TEL ermb mefa TEL ermb TEL PROTEKT ,864 (TEL MIC 4 mg/ml) 10 (0.07%) 10 MIC 4 8 mg/ml ermb ermb 1999 PROTEKT (PRSP: penicillin-resistant Streptococcus pneumoniae, PISP: penicillin-intermediate Streptococcus pneumoniae) (ERSP: erythromycin-resistant Streptococcus pneumoniae) 1) TEL
2 426( 2 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct. TEL TEL PROTEKT I TEL 2) (70S) 70S 30S 50S 30S 16S RNA (16SrRNA) 21 50S 5S RNA (5SrRNA) 23S RNA (23SrRNA) 2 RNA S 3,4) TEL 50S 23SrRNA I VI 5,6) TEL 50S 23SRNA V TEL V II ) 2 TEL 1 II TEL 5,10) 1
3 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 3 ) 2 Telithromycin 1 II 1 ermb 23SrRNA V 2058 (A2058) 11) B MLS B 12) efflux mefa
4 428( 4 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct B 13) 2 ermb 23SrRNA V A2058, A2059, C2611 L4, L22 PROTEKT ,103 3,053 (30.2%) mefa 70.7% ermb 17.3%, ermb mefa 9.2% 2.0% (77.2%) ermb 62.4% mefa 34.1%, ermb mefa 2.9% ermb III TEL (1) TEL 23SrRNA II V 2 V A2058 A2058 V TEL V II 6,7,14) ermb 50S TEL EM 15) EM 1 (0.271) : 0.05 (0.015) TEL 2 (0.493) : 1 (0.245) EM EM TEL 1 (0.271) : 1 (0.245) 3 50S TEL 2 1 EM TEL 50S 1 (2) TEL PROTEKT 4 ermb mefa ermb mefa TEL MIC ermb MIC 0.03 mg/ml
5 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 5 ) 3 (S. pneumoniae HL-3120) 4 Telithromycin MIC
6 430( 6 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct. 2 Telithromycin MIC MIC2 4 m g/ml mefa MIC 0.06 m g/ml ermb MIC MIC 0.5 m g/ml ermb mefa MIC MIC 0.5 m g/ml MIC 2 PROTEKT TEL 16) V A2059 A2058, C2611 TEL MIC m g/ml 16 3 A2059 L22 (G95D) TEL MIC 0.06 mg/ml TEL 3 MIC mg/ml MIC m g/ml MIC 1 mg/ml 3 L RTAHIT114 2 L4 (K68Q) 1 TEL (3) ermb 2 ermb
7 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 7 ) 3 Telithromycin 8 EM clarithromycin (CAM) 14 TEL 8 ermb ermb EM TEL TEL 8 TEL 17) ermb TEL ) TEL ermb MLS B EM TEL MIC TEL MIC EM MIC 0.5 m g/ml 18) 5 ermb TEL TEL ermb CANU 5
8 432( 8 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct. 5 Erythromycin Telithromycin MIC 10 TEL TEL MIC 4 mg/ml II A752 TEL 5 1 L22 TEL MIC 0.25 m g/ml 19) 4 TEL 5 IV TEL 6 PROTEKT ,864 MIC TEL MIC 4m g/ml 10 (0.07%) MIC 4 8 m g/ml ermb MIC 4 m g/ml F MLST (Multi Locus Sequence Typing) B, MLST902 PFGE pulsed-field gel electrophoresis
9 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 9 ) 4 MIC 5 10 ermb TEL ermb TEL 4 8 m g/ml MIC 21) TEL V TEL
10 434( 10 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct Telithromycin MIC (PROTEKT GLOBAL ) TEL MIC 4 mg/ml TEL MIC MIC 8 m g/ml TEL PÉREZ-TRALLERO MIC TEL TEL MIC 16 m g/ml L22 6 V (A2058) 21) TEL TEL 80% TEL (DPB) TEL DPB
11 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 11 ) 6 TEL 6 II V V TEL MIC PK/PD DAVIES TEL mefa 3 7 ermb ) TEL TEL TEL
12 436( 12 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct. 1) FELMINGHAM D.; R. R. REINERT, Y. HIRAKATA, et al.: Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and comparative in vitro activity of the ketolide, telithromycin. J. Antimicrob. Chemother. 50 (Sup. 1): 25 37, ) 1 Medical Practice 18: , ) BRODERSEN D. E.; J. W. M. CLEMONS, A. P. CARTER, et al.: The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30 S ribosomal subunit. Cell 103: , ) RECHT M. I. & J. D. PUGLISI: Aminoglycoside resistance with homogeneous and heterogeneous populations of antibiotic-resistant ribosomes. Antimicrob. Agents Chemother. 45: , ) PORSE B. T. & R. A. GARRETT: Sites of interaction of streptogramin A and B antibiotics in the peptidyl transferase loop of 23S rrna and the synergism of their inhibitory mechanisms. J. Mol. Biol. 286: , ) POEHLSGAARD J. & S. DOUTHWAITE: The macrolide binding site on the bacterial ribosome. Current Drug Targets-Infectious Disorders 2: 67 78, ) XIONG L.; S. SHAH, P. MAUVAIS, et al.: A ketolide resistance mutation in domain II of 23S rrna reveals the proximity of hairpin 35 to the peptidyl transferase centre. Mol. Microbiol. 31: , ) HANSEN L. H.; P. MAUVAIS & S. DOUTHWAITE: The macrolide-ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA. Mol. Microbiol. 31: , ) DOUTHWAITE S.; L. H. HANSEN & P. MAUVAIS: Macrolide-ketolide inhibition of MLS resistant ribosomes is improved by alternative drug interaction with domain II of 23S rrna. Mol. Microbiol. 36: , ) SCHLUNZEN F.; R. ZARIVACH, J. HARMS, et al.: Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413: ) TRIEU-CUOT P., et al.: Nucleotide sequence of the erythromycin resistance gene of the conjugative transposon Tn1545. Nucleic Acids 18: 3660, ) KAIEDA S.; H. YANO, N. OKITSU, et al.: In vitro isolation of a Streptococcus pneumoniae mutant constitutively resistant to macrolide-lincosamide (ML) and characteroization of its altered attenuator of the ermb gene. In program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego Abstract C , p. 72. American Society for Microbiology, Washington, DC, USA 13) TAIT-KOMARDT A., et al.: mefe is necessary for the erythromycin-resistant M phenotype in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 41: ) Telithromycin 51: , ) telithromycin 51(S-1): 83 93, ) FARRELL D. J.; S. DOUTHWAITE, I. MORRISSEY, et al.: Macrolide resistance by ribosomal mutation in clinical isolates of Streptococcus pneumoniae from the PROTEKT study. Antimicrob. Agents Chemother. 47: , ) CLAREBOUT G.; C. HUET & R. LECLERCQ: A convenient fluorescence assay to study the capacity of macrolides and related antimicrobials to induced resistance by ribosomal methylation. In program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Abstract 1924, p American Society for Microbiology, Washington, DC, USA 18) KAIEDA S.; N. OKITSU, H. YANO, et al.: Induction of telithromycin resistance in Streptococcus pneumoniae. J. Antimicrob. Chemother. 52: ) CANU A.; B. MALBRUNY, M. L. COQUEMONT, et al.: Diversity of ribosomal mutations conferring resistance to macrolides, clindamycin, streptogramin, and telithromycin in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 46: , ) FARRELL D. J. & D. FELMINGHAM: Activities of telithromycin against 13,874 Streptococcus pneumoniae isolates collected between 1999 and Antimicrob. Agents Chemother. 48: , 21) PÉREZ-TRALLERO E.; J. M. MARIMON, L. IGLESIAS, et al.: Fluoroquinolone and macrolide treatment failure in pneumococcal pneumonia and selection of multidrug-resistant isolates. Emerging Infectious Diseases 9: , ) DAVIES T. A.; B. E. DEWASSE, M. R. JACOBS, et al.: In vitro development of resistance to telithromycin (HMR 3647), four macrolides, clindamycin, and pristinamycin in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 44: , 2000
13 THE JAPANESE JOURNAL OF ANTIBIOTICS ( 13 ) MOLECULAR ANALYTICAL EVALUATION OF MACROLIDE- AND KETOLIDE-RESISTANT Streptococcus pneumoniae MECHANISM OF ACTION OF TELITHROMYCIN AND RESISTANCE TO IT MATSUHISA INOUE, KENICHI KANEKO, RYUICHI NAKANO, YOSHINORI SATO and SUSUMU ARAI Department of Microbiology, Kitasato University School of Medicine PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a worldwide epidemiologic survey for investigating drug susceptibility against major bacterial pathogens in respiratory tract infections, and that is also designed to identify the action mechanism of telithromycin (TEL), a ketolide antibacterial agent, on the resistant Streptococcus pneumoniae and the resistance mechanism for TEL on the TEL-resistant S. pneumoniae strain, in addition to determine macrolide/ketolide resistant S. pneumoniae activities of TEL using molecular analysis. TEL exerted the antibacterial action on the macrolide-resistant S. pneumoniae regardless maintaining the macrolide-resistant mechanism and exhibited the potent antibacterial activity against all of ermb gene-positive strains, mefa gene-positive strains and ribosome variants. This result was considered to reflect the fact that TEL did not induce resistance to ermb and had extremely low ability to select resistant strain by mutation. These actions of TEL were considered to be derived from its novel chemical structure and might be characteristics of ketolides not possessed by macrolides. In the survey of PROTEKT in 1999 to 2002, among 13,864 strains of S. pneumoniae isolated worldwide, ketolide-resistant strain (TEL MIC 4 m g/ml) was observed in 10 strains (0.07%). MIC of these 10 strains was 4 or 8 m g/ml and all of these strains were ermb-positive strains. Based on this fact, potential involvement of adenine demethylase (ermb gene product) was considered in the background of development of ketolide-resistant S. pneumoniae.
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