In Vitro and In Vivo Antibacterial Activities of DC-159a, a New Fluoroquinolone

The in vitro activities of DC-159a against seven species of Mycobacterium were compared with moxifloxacin, gatifloxacin, levofloxacin, and rifampin. DC-159a was the most active compound against quinolone-resistant multidrug-resistant M. tuberculosis (MIC 90 , 0.5 g/ml) as well as drug-susceptible isolates (MIC 90 , 0.06 g/ml). The anti-tubercle bacilli activity of DC-159a was 4-to 32-fold more potent than those of currently available quinolones. DC-159a also demonstrated the highest activities against clinically important nontuberculous mycobacteria.To be effective, tuberculosis (TB) treatment with a multidrug regimen must be continued for at least 6 months. This complicated regimen makes TB control difficult because of the long treatment duration, resulting in nonadherence of treatment, the development of multidrug-resistant TB (MDR-TB), and an additional problem of TB and human immunodeficiency virus (HIV) coinfection. Consequently, new anti-TB agents are urgently needed to overcome these problems (14).Quinolones such as ofloxacin and levofloxacin are classified and used as second-line drugs for MDR-TB cases because they inhibit the supercoiling action of DNA gyrase, which is different from the target enzymes of first-line drugs; however, their bactericidal activities against Mycobacterium tuberculosis are weak in clinical use (15). Currently, moxifloxacin and gatifloxacin, which are 8-methoxy fluoroquinolones, have proven to have more potent activities and may enable the duration of treatment to be shortened. Therefore, combination regimens consisting of new quinolones are expected to improve the treatment of TB (3,11,13). However, there is a problem of cross-resistance among quinolones caused by the previous usage of old quinolones in the treatment of MDR-TB and other respiratory infections. Thus, the emergence of quinolone-resistant M. tuberculosis is a concern (4).DC-159a is a newly synthesized broad-spectrum 8-methoxy fluoroquinolone. This compound has been shown previously to have potent activities against various respiratory pathogens, including quinolone-resistant strains (2, 7). The present study was performed to compare the in vitro antimycobacterial activities of DC-159a with three currently available quinolones and also rifampin against M. tuberculosis, including quinoloneresistant MDR (QR-MDR) strains and six species of clinically important nontuberculous mycobacteria (NTM).(This work was presented in part at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 2006.) Bacterial strains were isolated from Japanese patients between 1997 and 2003. The 32 M. tuberculosis isolates included drug-susceptible isolates (n ϭ 21) and QR-MDR isolates (n ϭ 11; levofloxacin MICs, Ն2 g/ml; rifampin MICs, Ն6 g/ml; isoniazid MICs, Ն4 g/ml). The NTM isolates comprised slowly growing mycobacteria, including M. kansasii (n ϭ 22), M. avium (serovar 4 [n ϭ 10] and serovar 8 [n ϭ 23]), and M. intracellulare serovar 16 (n ϭ 17), and rapidly growing mycobacteria, includin...

supporting

confidence: 79%

In Vitro Activities of DC-159a, a Novel Fluoroquinolone, against Mycobacterium Species

Disratthakit

Doi

2010

“…Similarly, new orally active compounds in the class that retain activity against staphylococci that exhibit resistance to current fluoroquinolone agents could potentially expand the range of options for the management of MRSA and MRSE infections in the community setting. To date, medicinal chemistry efforts have yielded a series of novel 4-quinolone class agents that exhibit in vitro activities against ciprofloxacin-resistant pneumococci and staphylococci, including delafloxacin (ABT-492) (2), garenoxacin (3,25,32), DC-159a (9,29,31), and WCK-771 (5, 6). However, no members of the 4-quinolone class are currently approved for use for the treatment of infections mediated by MRSA or fluoroquinoloneresistant pathogens.…”

Section: Discussionmentioning

confidence: 99%

“…In contemporary surveillance studies of health care-associated MRSA isolates, the rate of ciprofloxacin resistance is routinely reported to be Ն50%, and currently approved fluoroquinolones are indicated for use only for the treatment of staphylococcal infections mediated by methicillin-susceptible strains. However, a series of investigational fluoroquinolones have been reported to exhibit good in vitro activities against MRSA, including ciprofloxacin-resistant strains (2,5,25,29,45), and several of these agents are reported to be undergoing clinical evaluation for the treatment of complicated skin and skin structure infections (cSSSIs), including infections caused by MRSA strains.…”

mentioning

confidence: 99%

In Vitro Antibacterial Activities of JNJ-Q2, a New Broad-Spectrum Fluoroquinolone

Morrow

Amsler

et al. 2010

JNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae, including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC 90 value for JNJ-Q2 of 0.12 g/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillinresistant Staphylococcus aureus (MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC 90 value was 0.25 g/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2؋ and 4؋ MIC levels against clinical isolates of S. pneumoniae and MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA, parC, or gyrA plus parC mutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2؋ and 4؋ MICs in S. pneumoniae, MRSA, and Escherichia coli were indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitro that is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections.

“…This agent has been shown previously to have potent in vitro activity against other bacterial pathogens causing diseases in the respiratory tract, including Streptococcus pneumoniae, S. pyogenes, S. agalactiae, Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, and Bordetella pertussis (5,6). The only susceptibility data available for DC-159a thus far are those in a report providing MICs for 10 strains of M. pneumoniae (4). The present study was undertaken to investigate the comparative in vitro inhibitory and bactericidal activities of DC-159a against a collection of mycoplasma and ureaplasma species that are known to cause disease in humans.…”

Section: Mycoplasmal Species Of Human Origin Including Mycoplasma Pnmentioning

confidence: 99%

Comparative In Vitro Activities of the Investigational Fluoroquinolone DC-159a and Other Antimicrobial Agents against Human Mycoplasmas and Ureaplasmas

Waites

Crabb

Duffy

2008

The in vitro susceptibilities of 151 unique clinical isolates of Mycoplasma pneumoniae, Mycoplasma hominis, Mycoplasma fermentans, Mycoplasma genitalium, and Ureaplasma species to DC-159a, an investigational fluoroquinolone, in comparison with those to other agents were determined. Macrolides were the most active agents against M. pneumoniae and M. genitalium, whereas clindamycin was most active against M. hominis. DC-159a MICs were <0.5 g/ml for all Mycoplasma species and <4 g/ml for ureaplasmas. DC-159a was the most active fluoroquinolone tested against M. pneumoniae and M. fermentans, and it was second to moxifloxacin against the other species. It was bactericidal against 10 M. pneumoniae isolates and demonstrated killing of >99.9% of the inoculum at 24 h for 2 isolates. The excellent in vitro activity of DC-159a demonstrates its potential for use in the treatment of infections due to mycoplasmas and ureaplasmas.Mycoplasmal species of human origin, including Mycoplasma pneumoniae, M. genitalium, M. hominis, M. fermentans, and Ureaplasma spp., can be responsible for infections in the respiratory and urogenital tracts. In some cases, these organisms can cause severe, systemic disease, especially in the setting of a debilitated or immunocompromised host (11). Current treatment alternatives are limited primarily to drugs in the macrolide, lincosamide, tetracycline, and fluoroquinolone classes, and various agents in these classes exhibit differential in vitro activities against these organisms.Fluoroquinolones are useful treatment options for mycoplasmal and ureaplasmal infections because they have the advantages of being well tolerated in oral formulations; they have long half-lives, allowing once-daily dosage; they possess bactericidal activity; they are not affected by resistance mechanisms that affect other drug classes, such as tetracyclines and macrolides; and documented in vitro resistance is uncommon (3,8,9,11). The broad spectrum of activity against many other microorganisms that may cause clinically similar illnesses makes fluoroquinolones attractive for empirical treatment since most mycoplasmal and ureaplasmal infections are rarely confirmed by microbiological testing.DC-159a is an investigational fluoroquinolone being developed by Daiichi Sankyo Pharmaceuticals Co., Ltd., Tokyo, Japan. This agent has been shown previously to have potent in vitro activity against other bacterial pathogens causing diseases in the respiratory tract, including Streptococcus pneumoniae, S. pyogenes, S. agalactiae, Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, and Bordetella pertussis (5, 6). The only susceptibility data available for DC-159a thus far are those in a report providing MICs for 10 strains of M. pneumoniae (4). The present study was undertaken to investigate the comparative in vitro inhibitory and bactericidal activities of DC-159a against a collection of mycoplasma and ureaplasma species that are known to cause disease in humans.(Results of this work were presented at the 47th Interscience ...