In Vitro and In Vivo Efficacies of T-3811ME (BMS-284756) against Mycoplasma pneumoniae

126

A total of 195 Mycoplasma pneumoniae strains were isolated from 2,462 clinical specimens collected between April 2002 and March 2004 from pediatric outpatients with respiratory tract infections. Susceptibilities to six macrolide antibiotics (ML), telithromycin, minocycline, levofloxacin, and sitafloxacin were determined by the microdilution method using PPLO broth. A total of 183 M. pneumoniae isolates were susceptible to all agents and had excellent MIC 90 s in the following order: 0.00195 g/ml for azithromycin and telithromycin, 0.0078 g/ml for clarithromycin, 0.0156 g/ml for erythromycin, 0.0625 g/ml for sitafloxacin, 0.5 g/ml for minocycline, and 1 g/ml for levofloxacin. Notably, 12 ML-resistant M. pneumoniae strains were isolated from patients with pneumonia (10 strains) or acute bronchitis (2 strains). These strains showed resistance to ML with MICs of >1 g/ml, except to rokitamycin. Transition mutations of A2063G or A2064G, which correspond to A2058 and A2059 in Escherichia coli, in domain V on the 23S rRNA gene in 11 ML-resistant strains were identified. By pulsed-field gel electrophoresis typing, these strains were classified into groups I and Vb, as Mycoplasma pneumoniae is one of the main pathogens in respiratory tract infections (RTI) acquired in the community. In school-aged children and young adults with communityacquired pneumonia (CAP), M. pneumoniae accounts for as many as 10 to 30% of cases (4,6,13).In recent years, the clinical diagnosis for M. pneumoniae infection has relied on serological methods such as passive agglutination (Serodia-Myco II kit, Fujirebio, Tokyo, Japan) and complement fixation, even though a PCR method was partially applied (3,22,26). Accordingly, culture methods for this pathogen that require up to 1 week or more are rarely carried out in the laboratory. Thus, the current status of susceptibility to macrolide antibiotics (ML) used as the firstchoice agent for M. pneumoniae is unclear.In Japan, in parallel with the increase in usage of oral 14-membered ring ML (14-ML) and azithromycin for RTI, M. pneumoniae showing resistance to 14-ML has been isolated from clinical samples from pediatric outpatients with CAP (12, 16). We suspected an increase in cases with ML-resistant M. pneumoniae infection from prolonged clinical symptoms. In such cases, PCR positivity with rapid identification of M. pneumoniae persisted after the administration of clarithromycin or azithromycin for several days.We isolated causative M. pneumoniae by cultivation from clinical specimens collected from pediatric outpatients with RTI to determine susceptibilities to 10 oral antibiotics and identified a transition mutation on the 23S rRNA gene in ML-resistant isolates. MATERIALS AND METHODSMicroorganisms. M. pneumoniae was isolated from clinical specimens from patients with RTI. The specimens were collected from pediatric outpatients who visited 10 medical Japanese institutions participating in the study group on acute respiratory diseases (ARD). A total of 2,462 samples were sent to our laboratory (Kitasa...

Section: Methodsmentioning

confidence: 99%

Emergence of Macrolide-Resistant Mycoplasma pneumoniae with a 23S rRNA Gene Mutation

Morozumi

Hasegawa

Kobayashi

et al. 2005

126

“…We have evaluated the activities of garenoxacin against a large number of well-characterized clinical isolates of mycoplasmas and ureaplasmas and have shown that it is the most active quinolone tested against this group of microorganisms, results that were also apparent in three other in vitro studies that included smaller numbers of clinical isolates (8,21; Bé-béar et al, 41st ICAAC). When our data are considered in relation to the in vitro results of previously published studies that encompassed all of the newer fluoroquinolones that have enhanced potencies against gram-positive bacteria, as well as older agents such as ciprofloxacin and ofloxacin, garenoxacin is still the most active quinolone in vitro.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Susceptibilities to and Bactericidal Activities of Garenoxacin (BMS-284756) and Other Antimicrobial Agents against Human Mycoplasmas and Ureaplasmas

Waites

Crabb

Xue

et al. 2003

The in vitro susceptibilities to garenoxacin (BMS-284756), an investigational des-fluoroquinolone, and eight other agents were determined for 63 Mycoplasma pneumoniae, 45 Mycoplasma hominis, 15 Mycoplasma fermentans, and 68 Ureaplasma sp. isolates. Garenoxacin was the most active quinolone, inhibiting all isolates at <1 g/ml. The garenoxacin MIC at which 90% of isolates are inhibited (MIC 90 s; <0.008 g/ml) was at least 4-fold less than those of moxifloxacin and clindamycin, 8-fold less than that of sparfloxacin, and 64-fold less than those of levofloxacin and ciprofloxacin for M. pneumoniae. For M. hominis, the garenoxacin MIC 90 (<0.008 g/ml) was 4-fold less than those of clindamycin and moxifloxacin, 8-fold less than that of sparfloxacin, and 64-fold less than those of levofloxacin and ciprofloxacin. All 15 M. fermentans isolates were inhibited by garenoxacin at concentrations <0.008 g/ml, making it the most active drug tested against this organism. For Ureaplasma spp., the garenoxacin MIC 90 (0.25 g/ml) was equivalent to those of moxifloxacin and doxycycline, 4-fold less than those of levofloxacin and sparfloxacin, 8-fold less than that of azithromycin, and 32-fold less than that of ciprofloxacin. Garenoxacin and the other fluoroquinolones tested were demonstrated to have bactericidal activities against M. pneumoniae and M. hominis by measurement of minimal bactericidal activities and by time-kill studies. Further study of garenoxacin is required, as it has great potential for use in the treatment of infections due to mycoplasmas and ureaplasmas.Garenoxacin (also known as BMS 284756 and T-3811ME) is a new des-F(6)-quinolone that differs from other quinolones approved for use in the United States in that it lacks fluorine at the C-6 position (8). It has a broad spectrum of activity against a wide array of gram-positive and gram-negative bacteria, anaerobes, and fastidious organisms such as Haemophilus influenzae, legionellae, and chlamydiae (6,8,18,19). Earlier studies have also shown promising results with respect to the activity of garenoxacin against mycoplasmas and ureaplasmas (8, 21; C. M. Bébéar et al., Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., p. 179, abstr. E-725, 2001). We present here the results of the largest evaluation to date of garenoxacin against mycoplasmas and ureaplasmas obtained from humans, comparing the MIC of garenoxacin with those of other fluoroquinolones, macrolides, clindamycin, and doxycycline. The bactericidal activities of these agents for a subgroup of organisms were determined by measuring minimal bactericidal concentrations (MBCs) for a single isolate of Mycoplasma hominis and Mycoplasma pneumoniae by time-kill studies.(This work was presented at the 102nd General Meeting of the American Society for Microbiology, Salt Lake City, Utah, May 2002.) MATERIALS AND METHODSOrganisms. The M. pneumoniae isolates studied included 63 strains collected from the respiratory tracts of individuals with proven respiratory disease from six different countries between 1987 and ...

“…Quinolones have attracted interest as therapy for community-acquired respiratory tract infections because they are active against a wide range of pathogens responsible for these diseases, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Mycoplasma pneumoniae (1,3,9,11). We previously reported that quinolones, including ofloxacin, levofloxacin, grepafloxacin, gatifloxacin, gemifloxacin, sparfloxacin, trovafloxacin, and moxifloxacin, have good activity against Chlamydia trachomatis and C. pneumoniae in vitro (4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

In Vitro Activities of BMS-284756 against Chlamydia trachomatis and Recent Clinical Isolates of Chlamydia pneumoniae

Malay

Roblin

Reznik

et al. 2002

The in vitro activities of BMS-284756 (a novel des-fluoroquinolone), levofloxacin, moxifloxacin, and clarithromycin were tested against 5 strains of Chlamydia trachomatis and 20 isolates of Chlamydia pneumoniae. The MIC at which 90% of the isolates were inhibited and the minimal bactericidal concentration at which 90% of the isolates were killed by BMS-284756 for all isolates of C. pneumoniae and C. trachomatis was 0.015 g/ml (range, 0.015 to 0.03 g/ml). BMS-284756 was the most active quinolone tested.Chlamydia pneumoniae is a frequent cause of communityacquired respiratory tract infection, including pneumonia and bronchitis, in adults and children. Quinolones have attracted interest as therapy for community-acquired respiratory tract infections because they are active against a wide range of pathogens responsible for these diseases, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Mycoplasma pneumoniae (1, 3, 9, 11). We previously reported that quinolones, including ofloxacin, levofloxacin, grepafloxacin, gatifloxacin, gemifloxacin, sparfloxacin, trovafloxacin, and moxifloxacin, have good activity against Chlamydia trachomatis and C. pneumoniae in vitro (4-8). BMS-284756 is a novel des-fluoro(6) quinolone, which differs from recently approved quinolones in that it lacks fluorine at the C-6 position. BMS-284756 has antibacterial activity similar to that of other fluorinated quinolones against most bacteria (3). We compared the in vitro activity of BMS-284756, levofloxacin, moxifloxacin, and clarithromycin against 5 strains of C. trachomatis and 20 recent clinical isolates of C. pneumoniae. Strains of C. trachomatis included E-BOUR (ATCC VR-384B), F-IC-CAL3 (ATCC VR-346), C-HAR32 (ATCC VR-572), J-UW-36 (ATCC VR-886), and L 2 434 (ATCC VR-902B).Isolates of C. pneumoniae tested included one reference isolate; TW183 (ATCC VR-2282; Washington Research Foundation, Seattle, Wash.); CM-1, a clinical isolate from the Centers for Disease Control and Prevention (ATCC VR-1360); and 18 recent clinical isolates from adults and children enrolled in multicenter community-acquired pneumonia treatment studies conducted in the United States: T2023 (ATCC VR-1356), 124, 453, 490, 493, 600, 08002, 08016, 21001, 21002, 2212, 24013, 25001, MC16005, MC01016, MT57001, PDS07015, and RR57002. BMS-284756 (Bristol-Myers Squibb, Wallingford, Conn.), levofloxacin (Ortho Pharmaceuticals, Raritan, N.J.), moxifloxacin (Bayer Pharmaceuticals, West Haven, Conn.), and clarithromycin (Abbott Laboratories, Abbott Park, Ill.) were supplied as powders and were solubilized according to the manufacturers' instructions. Susceptibility testing of C. trachomatis and C. pneumoniae was performed in cell culture with HEp-2 cells grown in 96-well microtiter plates as previously described (5). Each experiment was set up in duplicate plates. Each well was inoculated with 0.1 ml of the test organism diluted to yield 10 3 to 10 4 inclusion-forming units (IFU) per ml for a multiplicity of infection of 1:1, was centrifuged at ...