Efficacies of ABT-773, a New Ketolide, against Experimental Bacterial Infections

Abstract

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 g/ml and an area under the concentration-time curve (AUC) of 12.03 g ⅐ 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 macrolidesusceptible 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.

Failure of Macrolide Antibiotic Treatment in Patients with Bacteremia Due to Erythromycin‐ResistantStreptococcus pneumoniae

“…In the present study, treatment failures occurred in patients infected with pneumococci that had erythromycin MICs as low as 4 mg/mL, as mediated by the mef gene. These findings are in agreement with data from animal models showing that clarithromycin and azithromycin were not effective in the treatment of mice and rats infected with macrolide-resistant pneumococci (clarithromycin MIC, 4 mg/mL) that contained the mef gene [31]. They also support NCCLS criteria that categorize isolates as intermediately resistant if the MIC is 0.5 mg/ mL and resistant if the MIC is у1 mg/mL.…”

In Vivo Veritas:In Vitro Macrolide Resistance in SystemicStreptococcus pneumoniaeInfections Does Result in Clinical Failure

“…These interpretations are in agreement with numerous animal models of infections due to these pathogens as well as with bacteriologic outcome studies of acute otitis media and sinusitis in humans [30][31][32][33][34]. These studies show that macrolide-susceptible pneumococci respond to macrolide therapy, whereas macrolide-resistant pneumococci of both phenotypes, as well as all H. influenzae isolates, do not respond to therapy.…”

Ribosome affinity and the prolonged molecular postantibiotic effect of cethromycin (ABT-773) in Haemophilus influenzae

“…Cethromycin (ABT-773) is a ketolide derived from erythromycin A [2]. As it possesses significant advantages over the antimicrobial potency and spectrum of the marketed macrolide antibiotics erythromycin, clarithromycin and azithromycin [3][4][5][6][7][8][9], it may become a therapeutically useful new antibacterial agent. The greater potency may be due to its improved ribosomal binding affinity leading to more rapid accumulation and reduced efflux, which is demonstrated in S. pneumoniae [10].…”