THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 425( 1 ) Telithromycin 7 20 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) Telithromycin (TEL) TEL ermb mefa TEL ermb TEL PROTEKT 1999 2002 13,864 (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
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 31 1 30S 3,4) TEL 50S 23SrRNA I VI 5,6) TEL 50S 23SRNA V 2058 2059 1 TEL V II 752 2 7 9) 2 TEL 1 II TEL 5,10) 1
THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 427( 3 ) 2 Telithromycin 1 II 1 ermb 23SrRNA V 2058 (A2058) 11) 14 15 16 B MLS B 12) efflux mefa
428( 4 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct. 14 15 16 B 13) 2 ermb 23SrRNA V A2058, A2059, C2611 L4, L22 PROTEKT 2000 2001 10,103 3,053 (30.2%) mefa 70.7% ermb 17.3%, ermb mefa 9.2% 2.0% 627 484 (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
THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 429( 5 ) 3 (S. pneumoniae HL-3120) 4 Telithromycin MIC
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) 2000 2001 16 V A2059 A2058, C2611 TEL MIC 0.015 0.25 m g/ml 16 3 A2059 L22 (G95D) TEL MIC 0.06 mg/ml 1999 2002 86 TEL 3 MIC 0.004 1 mg/ml MIC 90 0.25 m g/ml MIC 1 mg/ml 3 L22 6 109RTAHIT114 2 L4 (K68Q) 1 TEL (3) ermb 2 ermb
THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 431( 7 ) 3 Telithromycin 8 EM clarithromycin (CAM) 14 TEL 8 ermb ermb EM TEL TEL 8 TEL 17) ermb TEL 10 10 12) 10 6 10 8 TEL ermb MLS B EM TEL MIC TEL MIC EM MIC 0.5 m g/ml 18) 5 ermb TEL TEL ermb CANU 5
432( 8 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct. 5 Erythromycin Telithromycin MIC 10 TEL 5 5 3 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 1999 2002 13,864 MIC TEL MIC 4m g/ml 10 (0.07%) MIC 4 8 m g/ml ermb MIC 4 m g/ml 2 1 23F MLST (Multi Locus Sequence Typing) 242 1 6B, MLST902 PFGE pulsed-field gel electrophoresis 2001 2002 2 2002 2003
THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 433( 9 ) 4 MIC 5 10 ermb TEL ermb TEL 4 8 m g/ml MIC 21) TEL V TEL
434( 10 ) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 Oct. 6 13864 Telithromycin MIC (PROTEKT GLOBAL 1999 2002) 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
THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 435( 11 ) 6 TEL 6 II V V TEL MIC PK/PD DAVIES TEL 2 24 44 mefa 3 7 ermb 3 3 6 22) TEL TEL TEL
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, 2002 2) 1 Medical Practice 18: 1244 1249, 2001 3) 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: 1143 1154, 2000 4) RECHT M. I. & J. D. PUGLISI: Aminoglycoside resistance with homogeneous and heterogeneous populations of antibiotic-resistant ribosomes. Antimicrob. Agents Chemother. 45: 2414 2419, 2001 5) 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: 375 387, 1999 6) POEHLSGAARD J. & S. DOUTHWAITE: The macrolide binding site on the bacterial ribosome. Current Drug Targets-Infectious Disorders 2: 67 78, 2002 7) 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: 633 639, 1999 8) 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: 623 631, 1999 9) 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: 183 193, 2000 10) SCHLUNZEN F.; R. ZARIVACH, J. HARMS, et al.: Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413: 814 821 2001 11) TRIEU-CUOT P., et al.: Nucleotide sequence of the erythromycin resistance gene of the conjugative transposon Tn1545. Nucleic Acids 18: 3660, 1990 12) 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. 2002. Abstract C 1-1580, 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: 2251 2255 1997 14) Telithromycin 51: 511 514, 2003 15) telithromycin 51(S-1): 83 93, 2003 16) FARRELL D. J.; S. DOUTHWAITE, I. MORRISSEY, et al.: Macrolide resistance by ribosomal mutation in clinical isolates of Streptococcus pneumoniae from the PROTEKT 1999 2000 study. Antimicrob. Agents Chemother. 47: 1777 1783, 2003 17) 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, 2000. Abstract 1924, p. 117. 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: 736 737 2003 19) 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: 125 131, 2002 20) FARRELL D. J. & D. FELMINGHAM: Activities of telithromycin against 13,874 Streptococcus pneumoniae isolates collected between 1999 and 2003. Antimicrob. Agents Chemother. 48: 1882 1884, 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: 1159 1162, 2003 22) 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: 414 417, 2000
THE JAPANESE JOURNAL OF ANTIBIOTICS 57 5 437( 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.