In Vitro Activity of ABT-773 against Legionella pneumophila , Its Pharmacokinetics in Guinea Pigs, and Its Use to Treat Guinea Pigs with L. pneumophila Pneumonia

Abstract

The activity of ABT-773 was studied against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia. The ABT-773 MIC at which 50% of isolates are inhibited (MIC 50 ) for 20 different Legionella sp. strains was 0.016 g/ml, whereas the MIC 50 s of clarithromycin and erythromycin were 0.032 and 0.125 g/ml, respectively. ABT-773 (1 g/ml) was bactericidal for two L. pneumophila strains grown in guinea pig alveolar macrophages. In contrast, erythromycin and clarithromycin had easily reversible static activity only. Therapy studies of ABT-773 and erythromycin were performed with guinea pigs with L. pneumophila pneumonia. When ABT-773 was given to infected guinea pigs by the intraperitoneal route (10 mg/kg of body weight), mean peak levels in plasma were 0.49 g/ml at 0.5 h and 0.30 g/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 0.55 h, and the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) was 0.65 g ⅐ h/ml. For the same drug dose, mean levels in the lung were 15.9 and 13.2 g/g at 0. ABT-773 is a novel ketolide antimicrobial agent with high levels of activity against human respiratory tract and oral bacteria, including erythromycin-sensitive and -resistant Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, Mycobacterium avium, Toxoplasma gondii, common isolates from animal and human bites, and some Staphylococcus aureus strains (1,3,4,20,22,25 , abstr. 2159, 2000). Limited studies have also shown that the compound appeared to be active against Legionella pneumophila grown in HL-60 cells (Jung et al., 39th ICAAC; Sens et al., 40th ICAAC). This study was designed to further define the extracellular and intracellular activities of ABT-773 against L. pneumophila, as well as to determine the in vivo activity of the drug for the treatment of infection in a guinea pig model of Legionnaires' disease. We demonstrate that ABT-773 is as active as erythromycin in the animal models of L. pneumophila infection and more active than erythromycin against the intracellular and extracellular bacterium. MATERIALS AND METHODSBacterial strains and growth conditions. Twenty clinical isolates of Legionella sp. bacteria were used to determine the in vitro activities of the study compounds. These bacteria were low-passage-number strains that we had isolated and comprised 13 strains of L. pneumophila (9 serogroup 1 strains and 1 strain each of serogroups 2, 4, 6, and 9); 2 strains each of Legionella micdadei, Legionella longbeachae, and Legionella dumoffii; and 1 strain of Legionella bozemanii. We have previously used these 20 strains in other studies of antimicrobial activity against Legionella spp. (11,13,15,17). Included among these strains were L. pneumophila strains F889 and F2111, which have been extensively studied in a cell model of L. pneumophila infection. We have also used strain F889 extensively in a well-validated guinea model of L. pneumophila pneumonia (5-7, 9, 1...

Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647) Administered in Ascending Single and Multiple Doses

“…820, p. 109, 1999). Telithromycin has a spectrum of activity covering most common and atypical respiratory tract pathogens, irrespective of their susceptibilities to ␤-lactams or macrolides (1,2,3,5,10,12,13).…”

In Vitro Activity of Telithromycin (HMR3647), a New Ketolide, against Clinical Isolates of Mycoplasma pneumoniae in Japan

“…Levofloxacin, a quinolone, is also known to be active against the organism. Antibacterial studies conducted outside Japan have already revealed that telithromycin (HMR3647), a new ketolide antibiotic, is highly effective against gram-positive organisms (e.g., Streptococcus pneumoniae), gram-negative organisms (e.g., Haemophilus influenzae, Moraxella catarrharis, and Legionella pneumophila), some enteric pathogens, and anaerobic bacteria (1,2,4,5,11,13).Bacteria, especially their clinical isolates, are known to differ from one country to another, but the efficacy of telithromycin against Japanese clinical isolates of M. pneumoniae has not been examined yet. This study was conducted to determine the in vitro activity of the antibiotic against 41 strains of the organism isolated in Japan, compared with those of five macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin, and josamycin), minocycline, and levofloxacin.…”

“…Levofloxacin, a quinolone, is also known to be active against the organism. Antibacterial studies conducted outside Japan have already revealed that telithromycin (HMR3647), a new ketolide antibiotic, is highly effective against gram-positive organisms (e.g., Streptococcus pneumoniae), gram-negative organisms (e.g., Haemophilus influenzae, Moraxella catarrharis, and Legionella pneumophila), some enteric pathogens, and anaerobic bacteria (1,2,4,5,11,13).…”

The chinchilla microdialysis model for the study of antibiotic distribution to middle ear fluid

“…Recently, a novel group of 14-membered macrolides, known as the ketolides, was introduced [18][19][20] exhibiting increased acid stability and antibacterial potency against erythromycinresistant bacteria. 21 , 22 This study 23 was undertaken to determine the extent of distribution of the ketolide anti biotic, cethromycin (ABT-773), into chinchilla MEF.…”