Chemical modification of erythromycins. III. In vitro and in vivo antibacterial activities of new semisynthetic 6-O-methylerythromycins A, TE-031 (clarithromycin) and TE-032.
The in vitro and in vivo antibacterial activities of 6-O-methylerythromycin A (TE-031, A-56268, or clarithromycin) and 6,11-di-O-methylerythromycin A (TE-032) have been compared with those of erythromycin A (EM) and josamycin (JM). TE-031 and TE-032, having the same antibacterial spectra as EM, are active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, L-form bacteria and Mycoplasma pneumoniae. The activity of TE-031 against clinical isolates is equal to or two times more potent than that of EM, whereas TE-032 is slightly less active than EM. The activities of TE-031 and TE-032 are pH dependent (more active at pH 8 than at 5) and are increased by adding serum to medium. TE-031 and TE-032 show dose-related bactericidal activities against Haemophilus influenzae. The therapeutic efficacies of TE-031 and TE-032 against systemic and subcutaneous infections provoked by Gram-positive bacteria in mice are 4- to 35-fold superior to those of EM and JM. TE-031 and TE-032 have demonstrated higher and longer-lasting plasma levels than EM when administered orally to mice, rats or dogs.
Morimoto
S
S
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Nagate
T
T
Sugita
K
K
Ono
T
T
Numata
K
K
Miyachi
J
J
Misawa
Y
Y
Yamada
K
K
Omura
S
S
D000818:Animals; D001419:Bacteria / Q000187:drug effects*; D017291:Clarithromycin / Q000031:analogs & derivatives; D004285:Dogs; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006863:Hydrogen-Ion Concentration; D015570:Josamycin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013203:Staphylococcal Infections / Q000188:drug therapy; D013290:Streptococcal Infections / Q000188:drug therapy
C040935:6,11-di-O-methylerythromycin A; D004917:Erythromycin; D017291:Clarithromycin; D015570:Josamycin