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Antimicrobial Agents and Chemotherapy, June 2006, p. 2255-2257, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00011-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of DX-619 and Comparison Quinolones against Gram-Positive Cocci

Paul A. Wickman,* Jennifer A. Black, Ellen Smith Moland, and Kenneth S. Thomson

Creighton University School of Medicine, Department of Medical Microbiology and Immunology, Center for Research in Anti-Infectives and Biotechnology, Omaha, Nebraska

Received 4 January 2006/ Accepted 19 March 2006


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ABSTRACT
 
The in vitro activity of the novel quinolone DX-619 was compared to those of currently available quinolones against U.S. clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus spp., Streptococcus pyogenes, and Streptococcus pneumoniae. DX-619 was the most potent quinolone overall, indicating possible utility as an anti-gram-positive quinolone.


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TEXT
 
Currently available quinolones are clinically efficacious for many infections caused by gram-positive pathogens if the pathogens are wild-type in their quinolone resistance-determining regions but may lack useful activity against isolates that have developed resistance as a consequence of previous quinolone exposure (2, 7, 10). Recalcitrant gram-positive cocci, including staphylococci (4, 9), enterococci (8), and pneumococci (5, 11), may be resistant to multiple classes of antibiotics in addition to quinolones. DX-619 is a novel, des-fluoro quinolone with enhanced anti-gram-positive activity (6). The current study was designed to evaluate the in vitro activity of DX-619 against 228 clinical isolates of aerobically growing gram-positive cocci from U.S. medical centers, using gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin as comparator agents.

The isolates comprised oxacillin-susceptible and -resistant Staphylococcus aureus and coagulase-negative staphylococci, Enterococcus spp., Streptococcus pyogenes, and Streptococcus pneumoniae. Where possible, the isolates were chosen to exhibit various levels of quinolone resistance. They were not random clinical isolates. MICs were determined by the agar dilution method according to CLSI guidelines (3), using Mueller-Hinton agar (Oxoid, Basingstoke, United Kingdom) and doubling dilutions of DX-619, ciprofloxacin, moxifloxacin, gatifloxacin, and levofloxacin. Penicillin, oxacillin, and vancomycin were also tested as required to determine the resistances to these agents of isolates of S. pneumoniae, staphylococci, and enterococci, respectively. In susceptibility testing with S. pneumoniae and S. pyogenes, 5% sheep blood (Colorado Serum Co., Denver, CO) was added. Plates were inoculated with a Steers replicator to produce an inoculum of 104 CFU per spot and incubated at 37°C for 24 h. S. pneumoniae and S. pyogenes were incubated in 5% CO2. Strains were categorized as susceptible or resistant based upon CLSI criteria. Antibiotic susceptibility was also performed on the CLSI-recommended quality control strains S. pneumoniae ATCC 49619, S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 25922.

The activities of the study drugs are summarized in Table 1, which shows MIC ranges and the concentrations that inhibited 50% and 90% of the isolates. DX-619 was the most potent agent, inhibiting all isolates at 4 µg/ml, compared to moxifloxacin (32 µg/ml), gatifloxacin (64 µg/ml), levofloxacin (128 µg/ml), and ciprofloxacin (>256 µg/ml). Based on activity at the MIC90 level, DX-619 was 32- to 512-fold more potent than the comparators against oxacillin-susceptible S. aureus, 16- to 1,024-fold more potent against oxacillin-resistant S. aureus, 8- to 32-fold more potent against oxacillin-susceptible coagulase-negative staphylococci, 16- to 1,024-fold more potent against oxacillin-resistant coagulase-negative staphylococci, 16- to >128-fold more potent against vancomycin-resistant enterococci, 16- to 64-fold more potent against S. pyogenes, 32- to 512-fold more potent against all S. pneumoniae isolates, and 32- to 256-fold more potent against 18 penicillin-resistant isolates. It was particularly potent (MIC ≤ 1 µg/ml) against staphylococci that were highly resistant to ciprofloxacin (MIC > 256 µg/ml). These findings were consistent with those reported for Japanese isolates by Fujikawa et al. (6) and also those reported for staphylococci by Bogdanovich et al. (1).


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  		TABLE 1. Susceptibilities of clinical isolates to DX-619 and comparison agents

Overall, DX-619 is a novel quinolone with potent in vitro activity against a wide range of gram-positive pathogens. Its attributes of greatest potential are its high potency against oxacillin-resistant staphylococci and penicillin-resistant pneumococci. There is a growing need for effective new therapies for the increasing number of infections caused by these pathogens. Further studies, including those of toxicity, human pharmacokinetics, and therapeutic efficacy, are warranted.


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ACKNOWLEDGMENTS
 
This research was supported by a grant from Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.


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FOOTNOTES
 
* Corresponding author. Mailing address: Center for Research in Anti-Infectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178. Phone: (402) 280-2921. Fax: (402) 280-1875. E-mail: pwickman{at}creighton.edu. Back


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Antimicrobial Agents and Chemotherapy, June 2006, p. 2255-2257, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00011-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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