Susceptibilities of
            <i>Haemophilus influenzae</i>
            and
            <i>Moraxella catarrhalis</i>
            to ABT-773 Compared to Their Susceptibilities to 11 Other Agents

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The MIC at which 50% of strains are inhibited (MIC 50 ) and the MIC 90 of GW 773546, a novel macrolide, were 1.0 and 2.0 g/ml, respectively, for 223 ␤-lactamase-positive, ␤-lactamase-negative, and ␤-lactamasenegative ampicillin-resistant Haemophilus influenzae strains. The MIC 50 s and MIC 90 s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 g/ml, respectively, while the MIC 50 and MIC 90 of azithromycin were 1.0 and 2.0 g/ml, respectively. The MIC 50 and MIC 90 of erythromycin were 4.0 and 8.0 g/ml, respectively; and those of clarithromycin were 4.0 and 16.0 g/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 ؋ 10 ؊9 to 2.2 ؋ 10 ؊6 with GW 773546, 1.5 ؋ 10 ؊9 to 6.0 ؋ 10 ؊4 with GW 708408, and 7.1 ؋ 10 ؊9 to 3.8 ؋ 10 ؊4 with telithromycin, whereas the frequencies were 1.3 ؋ 10 ؊9 to 6.0 ؋ 10 ؊4 with erythromycin and azithromycin and 2.0 ؋ 10 ؊9 to 2.0 ؋ 10 ؊3with clarithromycin. Alterations in the L22 protein (which were predominant) and the L4 protein were present in mutants selected by the single-step selection process. The postantibiotic effects of GW 773546, GW 708408, and telithromycin for seven H. influenzae strains were 6.6 h (range, 5.2 to 8.8 h), 4.7 h (range, 2.6 to 6.9 h), and 6.4 h (range, 3.8 to 9.7 h), respectively. The results of in vitro studies obtained with both novel macrolides were similar to those obtained with telithromycin and better than those obtained with older macrolides.

Section: Discussionsupporting

confidence: 83%

Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Telithromycin, Erythromycin, Azithromycin, and Clarithromycin against Haemophilus influenzae

Kosowska

Credito

Pankuch

et al. 2004

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“…Credito et al determined the PAEs of ABT-773 and 11 other antibiotics against five strains of H. influenzae (5). Unlike the previously mentioned study, the antibiotic concentrations varied based upon achievable pharmacokinetic parameters.…”

mentioning

confidence: 99%

“…Limited data are available regarding the PAEs of ABT-773 against community-acquired pathogens (5,6; N. Ramer, D. McDaniel, P. Johnson, D. Shortridge, and R. K. Flamm, Abstr. 40th Intersci.…”

mentioning

confidence: 99%

Postantibiotic Effects of ABT-773 and Amoxicillin-Clavulanate against Streptococcus pneumoniae and Haemophilus influenzae

Neuhauser

Prause

Danziger

et al. 2001

This study determined the postantibiotic effect (PAE) of ABT-773 versus that of amoxicillin-clavulanate against clinical isolates of Streptococcus pneumoniae and Haemophilus influenzae. The PAEs of ABT-773 and amoxicillin-clavulanate ranged from 2.3 to 6.0 h and 0 to 2.2 h against S. pneumoniae and from 2.7 to 9.1 h and 0 to 0.8 h against H. influenzae, respectively.The ketolides represent a novel subclass of agents within the macrolide-lincosamide-streptogramin group. ABT-773, the newest member of the ketolide group, demonstrates good in vitro activity against Streptococcus pneumoniae, Haemophilus influenzae, and other community-acquired respiratory tract pathogens (2, 6, 9). Due to enhanced accumulation into cells and tighter ribosomal binding, this new ketolide maintains in vitro activity against mef-and/or ermB-containing S. pneumoniae (3). The purpose of this study was to determine the postantibiotic effect (PAE) of ABT-773 versus that of amoxicillin-clavulanate against S. pneumoniae and H. influenzae.(This work was presented in part of the poster session of the 22nd International Congress of Chemotherapy, Amsterdam, The Netherlands, 2001.) Clinical isolates of S. pneumoniae (n ϭ 4) and H. influenzae (n ϭ 4) were obtained from the microbiology laboratories at the University of Illinois at Chicago Medical Center (Chicago, Ill.) and Loyola University Medical Center (Maywood, Ill.). Two of the S. pneumoniae strains were resistant to penicillin and erythromycin (mefE gene), while the other two strains were susceptible to both agents. Half of the H. influenzae strains were beta-lactamase positive, while the other half were beta-lactamase negative. The isolates were stored at Ϫ70°C in skim milk and underwent three subcultures prior to MIC and PAE studies. Control strains (S. pneumoniae ATCC 49619 and H. influenzae ATCC 49247) were used to validate MIC results.ABT-773 (Abbott Laboratories, Abbott Park, Ill.) and amoxicillin-clavulanate (United States Pharmacopeia, Rockville, Md.) powders were prepared according to NCCLS guidelines or per the manufacturer's recommendations (8). The media for MIC and PAE studies were cation-supplemented Mueller-Hinton broth with 3% lysed horse blood (Remel, Lenexa, Kans.) and Haemophilus test medium (Remel) for S. pneumoniae and H. influenzae isolates, respectively.MIC studies were performed in duplicate per NCCLS guidelines using the microbroth dilution method (8). The organisms were freshly subcultured and incubated overnight in a 35°C incubator with 5% CO 2 . The inoculum was prepared by direct suspension and adjusted with sterile saline until the turbidity matched a 0.5 McFarland standard using a spectrophotometer at 625 nm. Each suspension was further diluted in broth media to obtain a final inoculum of approximately 5 ϫ 10 5 CFU/ml. The exact inoculum size was determined via colony counts. The microtiter plate contents were incubated at 35°C (humidified air) and read at 20 h. The MIC was defined as the lowest concentration at which there was no visible growth.The PAEs were ...

“…The incidence of ␤-lactamase-negative ampicillin-resistant (BLNAR) strains is currently Ͻ1% in the United States (11) but is significantly higher in Japan (23). Among members of the macrolide and azalide groups, azithromycin has the lowest MICs against these organisms, followed by ketolides such as telithromycin, erythromycin A, and clarithromycin (1,5,6,10,14,17). Of available streptogramins, oral pristinamycin and parenteral quinupristin/ dalfopristin have MICs for H. influenzae and H. parainfluenzae which are several dilutions higher than those for pneumococci (8,12,15).…”

mentioning

confidence: 99%

“…The major bacterial pathogens responsible for communityacquired respiratory tract infections comprise Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis (6,7,(9)(10)(11)24). Pneumococcal resistance to penicillin G and other ␤-lactam and non-␤-lactam compounds has increased worldwide at an alarming rate, including in the United States.…”

mentioning

confidence: 99%

Activities of a New Oral Streptogramin, XRP 2868, Compared to Those of Other Agents against Streptococcus pneumoniae and Haemophilus Species

Pankuch

Kelly

Lin

et al. 2003

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MIC methodology was used to test the antibacterial activity of XRP 2868, a new oral combination of two semisynthetic streptogramins, RPR 132552A and RPR 202868, compared to activities of other antibacterial agents against pneumococci, Haemophilus influenzae, and Haemophilus parainfluenzae. For 261 pneumococci, XRP 2868 and pristinamycin MICs were similar, irrespective of penicillin G and erythromycin A susceptibilities (MIC at which 50% of isolates were inhibited [MIC 50 ], 0.25 g/ml; MIC 90 , 0.5 g/ml), while quinupristin/ dalfopristin had MICs which were 1 to 2 dilutions higher. Single components of both XRP 2868 and quinupristin/dalfopristin had higher MICs. Erythromycin A, azithromycin, clarithromycin, and clindamycin MICs were higher for penicillin G-intermediate and -resistant than -susceptible pneumococci. Against 150 H. influenzae strains, all compounds tested had unimodal MIC distributions. XRP 2868 had an overall MIC 50 of 0.25 g/ml and an MIC 90 of 1.0 g/ml, with no differences between ␤-lactamase-positive, ␤-lactamase-negative, and ␤-lactamase-negative ampicillin-resistant strains. Of note was the similarly low activity of one of its components, RPR 132552A. Pristinamycin and quinupristin/dalfopristin had MICs of 0.125 to 8.0 g/ml; quinupristin alone had MICs of 8.0 to >64.0 g/ml, and dalfopristin had MICs of 1.0 to >64.0 g/ml. Erythromycin A, azithromycin, and clarithromycin had modal MICs of 4.0, 1.0, and 8.0 g/ml, respectively. MICs of all compounds against H. parainfluenzae were 1 to 2 dilutions higher than against H. influenzae. XRP 2868 showed potent activity against pneumococci and Haemophilus strains irrespective of their susceptibility to other agents.