Efficacies of ABT-773, a new ketolide, against experimental bacterial infections.
ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 microg/ml and an area under the concentration-time curve (AUC) of 12.03 microg. h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolide-susceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.
Mitten
M J
MJ
Infectious Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064-3537, USA. michael.j.mitten@abbott.com
Meulbroek
J
J
Nukkala
M
M
Paige
L
L
Jarvis
K
K
Oleksijew
A
A
Tovcimak
A
A
Hernandez
L
L
Alder
J D
JD
Ewing
P
P
Or
Y S
YS
Ma
Z
Z
Nilius
A M
AM
Mollison
K
K
Flamm
R K
RK
D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006192:Haemophilus Infections / Q000188:drug therapy / Q000378:metabolism; D006193:Haemophilus influenzae / Q000187:drug effects; D048628:Ketolides; D008088:Listeriosis / Q000188:drug therapy / Q000378:metabolism; D008171:Lung Diseases / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D012140:Respiratory Tract Diseases / Q000188:drug therapy / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism; D013290:Streptococcal Infections / Q000188:drug therapy / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects; D016896:Treatment Outcome
D048628:Ketolides; D004917:Erythromycin; C405499:cethromycin