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Antimicrobial Agents and Chemotherapy, May 2006, p. 1887-1889, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1887-1889.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of DX-619 and Four Comparator Agents against 376 Anaerobic Bacterial Isolates

D. Molitoris,2 M.-L. Väisänen,2 M. Bolaños,2,{dagger} and S. M. Finegold1,2,3,4*

Medical,1 Research Services, VA Greater Los Angeles Healthcare System,2 Departments of Medicine,3 Microbiology, Immunology and Molecular Genetics, UCLA School of Medicine, Los Angeles, California4

Received 3 October 2005/ Returned for modification 29 October 2005/ Accepted 9 March 2006


   ABSTRACT
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The activity of DX-619 was evaluated against 376 anaerobic isolates using the reference CLSI agar dilution method. Overall, 90% of the strains were susceptible to DX-619 at ≤1 µg/ml. It was more active than the other four compounds tested except for meropenem, which showed virtually identical overall activity.


   TEXT
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Resistance to antimicrobial agents has been observed in many if not most clinically significant pathogenic bacteria and is increasing in prevalence. New classes of antimicrobial agents and modifications of existing agents, as well as of methods of blocking bacterial resistance mechanisms, are essential for improving activity against these resistant organisms. DX-619 is a newly developed des-F(6)-quinolone (Fig. 1) that has been shown to be effective against multiresistant gram-positive bacteria including methicillin-, ciprofloxacin-, and vancomycin-resistant Staphylococcus aureus, ciprofloxacin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci (1, 4). It is currently under development for use in gram-positive infections. Garenoxacin, another desfluoroquinolone, has shown good broad-spectrum activity against gram-positive and gram-negative aerobes and anaerobes (3, 5, 8). This study compared the activity of DX-619 and that of four comparator agents (amoxicillin-clavulanate, linezolid, meropenem, and moxifloxacin, chosen from different classes of antimicrobials that are effective against anaerobes) against 376 strains of anaerobic bacteria.


Figure 1
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  		FIG. 1. Chemical structure of DX-619.

 
The bacteria included in this study were recent isolates from the Greater Los Angeles Veterans Administration Healthcare Center. Bacteria were identified according to established procedures (6), supplemented in a number of cases by 16S rRNA sequence analysis. Most of the organisms studied are involved in a great variety of infections. MICs with regard to anaerobes were determined by the Clinical and Laboratory Standards Institute (CLSI) (formerly the National Committee for Clinical Laboratory Standards)-approved Wadsworth agar dilution technique (2). A suspension of colonies taken from 48-h blood agar plates was used to achieve a final inoculum of 105 CFU/spot. The basal medium was brucella base laked-blood agar (Anaerobe Systems, Morgan Hill, CA) with hemin, vitamin K1, and 5% laked sheep blood, supplemented with pyruvic acid (1% final concentration) for the growth of Bilophila wadsworthia and formic and fumaric acids (0.3%/0.3%) for Sutterella wadsworthensis. Plates were incubated in an anaerobic chamber (Anaerobe Systems) for 48 h at 37°C. MICs were defined as the lowest concentration of antimicrobial agent resulting in no growth or a marked change in the appearance of growth compared to the control plate, as described in the CLSI protocol. Triphenyltetrazolium chloride was used as an aid in interpreting the growth endpoints of Bilophila wadsworthia (10). Reference strains of Bacteroides fragilis (ATCC 25285), Bacteroides thetaiotaomicron (ATCC 29741), and Eggerthella lenta (ATCC 43055) were used as controls in each test. The antimicrobial agents tested were obtained as powders from the following companies: amoxicillin, Sigma, St. Louis, MO.; clavulanate, GlaxoSmithKline, King of Prussia, PA; DX-619, Daiichi, Tokyo, Japan; linezolid, Pfizer, Groton, CT; meropenem, AstraZeneca, Wilmington, Del.; moxifloxacin, Bayer, West Haven, CT.

The ranges and the MICs at which 50% (MIC50) and 90% (MIC90) of isolates were inhibited are presented in Table 1. DX-619 demonstrated potent activity against a broad spectrum of gram-negative and gram-positive anaerobes, inhibiting 340 of 376 strains (90%) at ≤1 µg/ml; MICs ranged from ≤0.12 µg/ml to 8 µg/ml. On a weight basis (no breakpoint has been set as yet), DX-619 was comparable to meropenem in overall activity and at least three dilutions more active than the other three compounds tested. DX-619 and meropenem had the same MIC90s against the B. fragilis group of organisms (MIC90, 2 µg/ml), Fusobacterium species (MIC90, 0.25 µg/ml), and Porphyromonas species (MIC90, 0.12 µg/ml). Within the B. fragilis group DX-619 was most effective against Bacteroides caccae, Bacteroides distasonis/merdae, B. fragilis, and an unspeciated group of 8 B. fragilis group strains (MIC90, 0.5 µg/ml) and was least active against Bacteroides vulgatus (MIC90, 8 µg/ml). Meropenem showed strongest activity (MIC90, 0.5 µg/ml) versus B. fragilis, Bacteroides stercoris, and Bacteroides uniformis. Amoxicillin-clavulanate, linezolid, and moxifloxacin had overall MIC90s of 16, 8, and 32 µg/ml, respectively, against the B. fragilis group. Twenty-two strains of B. fragilis group organisms that were resistant to moxifloxacin (MICs, 16 to 64 µg/ml) had MICs of 1 to 4 µg/ml with DX-619 and ≤0.12 to 2 µg/ml with meropenem. Two strains of B. vulgatus with moxifloxacin MICs of 128 µg/ml were more susceptible to DX-619 (MICs, 8 µg/ml) and meropenem (MICs, 0.5 and 1 µg/ml). Amoxicillin-clavulanate was equivalent to DX-619 and meropenem when tested against Porphyromonas species (MIC90, ≤0.12 µg/ml); the MIC90s for linezolid and moxifloxacin were 2 µg/ml. DX-619 inhibited 100% of Bilophila wadsworthia, Campylobacter gracilis, and Sutterella wadsworthensis strains and 93% of Prevotella strains at 2 µg/ml. However, meropenem showed the strongest activity against these organisms (all strains inhibited by ≤0.25 µg/ml). Moxifloxacin was also effective against Bilophila wadsworthia (MIC90, 0.5 µg/ml) and Sutterella wadsworthensis (MIC90, 1 µg/ml).


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  		TABLE 1. In vitro activities of DX-619 and four other antimicrobial agents against 376 anaerobic bacteria

 
Among gram-positive anaerobic organisms, DX-619 was the most potent antimicrobial agent tested. DX-619 was the most effective agent against clostridia; at a concentration of 0.25 µg/ml, all 39 strains were inhibited. MIC90s for amoxicillin-clavulanate, linezolid, meropenem, and moxifloxacin against clostridia were 2, 4, 4, and 8 µg/ml, respectively. DX-619 was 2 to 4 dilutions more active than the other compounds tested against Clostridium difficile (n = 6). Against non-spore-forming gram-positive rods, amoxicillin-clavulanate, DX-619, and meropenem demonstrated very similar activities; MICs ranged from ≤0.12 to 4 µg/ml. Linezolid and moxifloxacin were less potent than the other agents, with an MIC50 of ≤1 µg/ml, but inhibited all strains of non-spore-forming gram-positive rods at ≤8 µg/ml. DX-619 had the most potent activity against anaerobic gram-positive cocci (MIC90, ≤0.25 µg/ml); amoxicillin-clavulanate, linezolid, meropenem, and moxifloxacin had MIC90s of 0.5, 2, 0.5, and 4 µg/ml, respectively.

Overall, DX-619 performed comparably to meropenem and was more active than amoxicillin-clavulanate, linezolid, and moxifloxacin against the diverse group of anaerobic organisms tested. Most notably, DX-619 inhibited all clostridia at an MIC of ≤0.25 µg/ml, besting all the other drugs by 4 to 5 dilutions. These results are in accordance with and perhaps somewhat surpass (in the case of Clostridium and Fusobacterium spp.) those obtained from studies of garenoxacin, another desfluoroquinolone. Animal studies of garenoxacin (7, 9) found it to produce less joint cartilage damage than the other quinolones tested. Additional studies are needed to assess the clinical utility and possible toxicity of drugs, such as DX-619, which show good in vitro activity against clinically important gram-positive and gram-negative anaerobic organisms.


   ACKNOWLEDGMENTS
 
This study was supported, in part, by a grant from Daiichi, Tokyo, Japan.


   FOOTNOTES
 
* Corresponding author. Mailing address: Greater Los Angeles VAMC, 11301 Wilshire Blvd., Bldg. 304, Rm. E3-237, Los Angeles, CA 90073. Phone: (310) 268-3678. Fax: (310) 268-4458. E-mail: sidfinegol{at}aol.com. Back

{dagger} Present address: Monseñor Sanabria Hospital, Puntarenas, Costa Rica. Back


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Antimicrobial Agents and Chemotherapy, May 2006, p. 1887-1889, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1887-1889.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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