KETEK^ä (telithromycin)

 

 

Briefing Document
for the FDA Anti-Infective Drug Products
Advisory Committee Meeting

March 2001

 

 

Executive summary 5

TABLE OF CONTENTS 12

LIST OF APPENDICES 16

LIST OF ABBREVIATIONS 17

1.   Background and medical need 20

2.   Claimed indications 22

3.   Microbiology 23

3.1   Ketolides:  A new chemical class 23

3.2   Telithromycin mode of action 24

3.2.1   Dual interaction of telithromycin with domain V and domain II 24

3.2.2   Inhibition of 30S and 50S ribosomal subunit formation by telithromycin 25

3.2.3   Telithromycin:  affinity for bacterial ribosomes 25

3.2.4   Conclusion 25

3.3   Antipneumococcal activity 25

3.3.1   In vitro antipneumococcal activity 25

3.3.2   Bactericidal activity of telithromycin against S. pneumoniae 27

3.3.3   In vivo activity in murine infection models 27

3.3.4   Intracellular antipneumococcal activity 28

3.4   Activity against other pathogens involved in lower respiratory tract infections 28

3.4.1   Activity against other common pathogens 28

3.4.2   Bordetella species 30

3.5   Activity against beta-hemolytic streptococci (Streptococcus pyogenes and other streptococci) 30

3.5.1   In vitro studies with beta-hemolytic streptococci 30

3.5.2   In vivo studies of activity against beta‑hemolytic streptococci 31

3.6   Activity against atypical and intracellular micro-organisms 31

3.6.1   Intracellular concentration of telithromycin 31

3.6.2   Activity against atypical or intracellular pathogens involved in lower respiratory tract infections 31

3.7   In vitro activity against other pathogens 33

3.7.1   Staphylococcus aureus 33

3.7.2   Enterococcus species 33

3.7.3   Anaerobes 34

3.7.4   Other bacterial species 34

3.8   Postantibiotic effect of telithromycin 34

3.8.1   Postantibiotic effect in vitro 34

3.8.2   Postantibiotic effect in vivo 35

3.9   Resistance 35

3.9.1   Mechanisms of resistance to erythromycin A 35

3.9.2   Resistance to telithromycin 37

3.9.3   Inducible MLS_B resistance 38

3.9.4   Selection of resistant mutants 38

3.10   Microbiology summary