Disease relevance of ABT-773

• Recent semi-synthetic studies of erythromycin A culminated in the discovery of two ketolide drug candidates, HMR-3647 and ABT-773, for the treatment of community-acquired bacterial infections caused by both macrolide- and beta-lactam-susceptible and -resistant S. pneumoniae, gram negative bacteria, and intracellular atypical pathogens [1].
• Efficacy of cethromycin, a new ketolide, against Streptococcus pneumoniae susceptible or resistant to erythromycin in a murine pneumonia model [2].
• ABT-773 was also effective against Haemophilus influenzae lung infections in rats [3].
• In acute systemic infections in mice, ABT-773 showed efficacy against macrolide-susceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes [3].
• Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections [3].

High impact information on ABT-773

• METHODS: Healthy volunteers given 3 different oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1 polymorphisms [4].
• ABT-773 plasma levels did not trend with MDR-1 genotypes [4].
• The serum protein binding levels of cethromycin were 94.8 and 88.5% after doses of 12.5 and 25 mg/kg, respectively [2].
• The U2609C mutation, which renders E. coli resistant to the previously studied ketolides telithromycin and cethromycin, barely affected cell susceptibility to the bridged macrolides used in this study [5].
• In this mouse model, treatment with cethromycin significantly reduced M. pneumoniae culture titers in BAL samples, cytokine and chemokine concentrations in BAL samples, histologic inflammation in the lungs, and disease severity as defined by AO and AHR [6].

Chemical compound and disease context of ABT-773

• Against Haemophilus influenzae, ABT-773 and azithromycin were similar in their antibacterial potency (MIC(90), 4.0 and 2.0 microg/ml, respectively) [7].
• The ABT-773 MIC at which 50% of isolates are inhibited (MIC(50)) for 20 different Legionella sp. strains was 0.016 microg/ml, whereas the MIC(50)s of clarithromycin and erythromycin were 0.032 and 0.125 microg/ml, respectively [8].
• In conclusion, ABT-773 showed in vivo efficacy and considerably greater activity than ERY in a mouse peritonitis model [9].
• The MICs of ABT-773 were also lower than those of quinupristin-dalfopristin (Q-D) for methicillin-susceptible Staphylococcus aureus, Rhodococcus spp., and Streptococcus spp., while the MICs of Q-D were lower than those of ABT-773 for methicillin-resistant S. aureus and Enterococcus faecium, including vancomycin-resistant isolates [10].
• In vitro bactericidal activity of ABT-773 and amoxicillin against erythromycin-susceptible and -resistant strains of Streptococcus pyogenes [11].

Biological context of ABT-773

• CYP3A5 genotype has a dose-dependent effect on ABT-773 plasma levels [4].
• Steady-state plasma and intrapulmonary pharmacokinetics and pharmacodynamics of cethromycin [12].
• We also showed that ABT-773 (i) accumulated in macrolide-sensitive S. pneumoniae at a higher rate than erythromycin, (ii) was able to bind with methylated ribosomes, though at lower affinities than with wild-type ribosomes, and (iii) accumulated in S. pneumoniae strains with the efflux-resistant phenotype [13].
• We concluded that the C(max)/MIC(90) ratios, AUC/MIC(90) ratios, %T > MIC(90) values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections [12].
• Sucralfate had no impact on the bioavailability of ABT-773 [14].

Anatomical context of ABT-773

• Studies of the novel ketolide ABT-773: transport, binding to ribosomes, and inhibition of protein synthesis in Streptococcus pneumoniae [13].
• Interaction of the new ketolide ABT-773 (cethromycin) with human polymorphonuclear neutrophils and the phagocytic cell line PLB-985 in vitro [15].
• ABT-773 (1 microg/ml) was bactericidal for two L. pneumophila strains grown in guinea pig alveolar macrophages [8].
• ABT-773 is as effective as erythromycin against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease [8].
• Whatever the cell type and in contrast to the results obtained with HMR 3004, ABT-773 was mainly located in the cytosol (about 75%) and was rapidly released from loaded cells (about 40% at 5 min), followed by a plateau, likely owing to avid reuptake [15].

Associations of ABT-773 with other chemical compounds

• Both compounds were extremely active against macrolide-susceptible isolates, with the minimum inhibitory concentrations at which 90% of the isolates tested were inhibited (MIC90s) for susceptible streptococci and staphylococci ranging from 0.002 to 0.03 microg/ml for ABT-773 and 0.008 to 0.06 microg/ml for telithromycin [16].
• Therapy studies of ABT-773 and erythromycin were performed with guinea pigs with L. pneumophila pneumonia [8].
• The ketolide ABT-773, which has a 3-keto group and no L-cladinose sugar, represents a new class of drugs with in vitro activity against a variety of resistant bacteria [13].
• In vitro bactericidal activity and post-antibiotic effect of ABT-773 versus co-amoxiclav against anaerobes [17].

Gene context of ABT-773

• Against 78 ermB- and 44 mefE-containing strains, ABT-773 MICs at which 50% of the isolates tested were inhibited (MIC(50)s) and MIC(90)s were 0.016 to 0.03 and 0.125 microgram/ml, respectively [18].
• ABT-773 showed excellent activity against macrolide, azalide, lincosamide (MAL) inducible S. aureus producers but was inactive against constitutive producers [19].

Analytical, diagnostic and therapeutic context of ABT-773

• A classical velocity centrifugation technique was used to study the in vitro uptake of the new ketolide ABT-773 by human polymorphonuclear neutrophils (PMNs) and a myelomonoblastic cell line, PLB-985, which can be differentiated into PMNs under certain culture conditions, compared to that of HMR 3004 [15].
• Serum ABT-773 concentrations were measured using a validated HPLC assay with fluorescence detection (excitation at 324 nm and emission at 364 nm) [20].
• Cethromycin (ABT-773) is a new ketolide currently in clinical trials, for treatment of community acquired respiratory tract infections [21].
• A method is developed for the specific and sensitive determination of cethromycin concentrations in plasma, bronchoalveolar lavage (BAL), and alveolar cells (AC), using a high-performance liquid chromatographic-tandem mass spectrometry (MS) method [22].

References