AAC
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goldstein, E. J. C.
Right arrow Articles by Fernandez, H. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goldstein, E. J. C.
Right arrow Articles by Fernandez, H. T.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2003, p. 3008-3011, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.3008-3011.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of ABT-492, a New Fluoroquinolone, against 155 Aerobic and 171 Anaerobic Pathogens Isolated from Antral Sinus Puncture Specimens from Patients with Sinusitis

Ellie J. C. Goldstein,1,2* Diane M. Citron,1 C. Vreni Merriam,1 Yumi A. Warren,1 Kerin L. Tyrrell,1 and Helen T. Fernandez1

R. M. Alden Research Laboratory, Santa Monica, California 90404,1 UCLA School of Medicine, Los Angeles, California 900732

Received 5 February 2003/ Returned for modification 17 May 2003/ Accepted 10 June 2003


   ABSTRACT
Top
 Abstract
Text
 References
 
ABT-492 exhibited excellent in vitro activities against all 326 aerobic and anaerobic antral puncture sinus isolates tested with MICs (in micrograms per milliliter) at which 90% of the isolates tested were inhibited as follows: Haemophilus influenzae, 0.001; Moraxella catarrhalis, 0.008; and Streptococcus pneumoniae, 0.015. It was four- to sixfold more active than other fluoroquinolones, including against levofloxacin-resistant strains of S. pneumoniae, methicillin-resistant Staphylococcus aureus, and Prevotella species.


   TEXT
Top
 Abstract
 Text
References
 
Bacterial sinusitis affects approximately 30 million Americans yearly (14, 18). While acute sinusitis primarily involves aerobes, anaerobes are frequently isolated from patients with chronic sinusitis (1, 3, 7, 10). Quinolones have been used to treat acute sinusitis with targeted activity against pneumococci, Haemophilus spp., and Moraxella catarrhalis; however, resistance has emerged to beta-lactams (6, 15) and fluoroquinolones (2, 4, 5, 17).

In 2000 in Hong Kong 50% of Streptococcus pneumoniae isolates were highly penicillin resistant and 27% of these were fluoroquinolone resistant (8) due to a fluoroquinolone-resistant variant of the Spanish 23F-1 clone that been associated with penicillin-resistant S. pneumoniae in Canada (6). While rates of penicillin-nonsusceptible S. pneumoniae vary by geographic region (15), approximately 22% of these isolates are also multidrug resistant (2). The rate of fluoroquinolone resistance in S. pneumoniae in the United States remains low at <1.5% of isolates (2). It has been suggested that use of "less potent derivatives" of fluoroquinolones may initiate resistance, creating a need for the development of more potent fluoroquinolones.

ABT-492 (WQ-3034) is a new fluoroquinolone with a 6-amino-3,5-difluoropyridin-2-yl group at the N-1 position and a chlorine at the C-8 position. The drug has a broad spectrum of activity, including against quinolone-resistant pathogens (16; S. M. Gunderson, S. Kelkar, R. A. Hayes, J. P. Quinn, and L. H. Danziger, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-547, 2002; S. St. John, A. W. Vu, H. M. Wexler, and S. M. Finegold, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-551, 2002). It was reported to be 16 to 64 times more active than levofloxacin and gatifloxacin against S. pneumoniae isolates and quinolone-resistant methicillin-resistant Staphylococcus aureus strains (A. Yazaki, Y. Niino, Y. Kuramoto, and Y. Ohshita, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-544, 2002). Comparative studies of ABT-492 by Nilius et al. (A. M. Nilius, D. Hensey-Rudloff, L. Almer, J. Beter, and R. K. Flamm, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-546, 2002) with levofloxacin and by Zhanel et al. (G. G. Zhanel, L. Palatnick, H. Smith, K. Nichol, and D. J. Hobam, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-552, 2002) with levofloxacin, gatifloxacin, and moxifloxacin found ABT-492 to be more active against S. pneumoniae, Haemophilus influenzae, and M. catarrhalis isolates. Smith et al. (H. J. Smith, K. A. Nichol, and L. Palanick, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-549, 2002) reported that ABT-492 was more potent than levofloxacin, gatifloxacin, or moxifloxacin against 75 Canadian isolates of ciprofloxacin-resistant S. pneumoniae. Only limited data exist about the activities of ABT-492 against anaerobic bacteria (Nilius et al., 42nd ICAAC; A. L. Barry, M. M. Traczewski, and S. D. Brown, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-548, 2002). Two possible breakpoints have been proposed (Barry et al., 42nd ICAAC; L. S. Almer, V. D. Shortridge, S. Bukofzer, and R. K. Flamm, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-550, 2002): susceptible at <=1 or <=2 µg/ml and resistant at >=4 or >=8 µg/ml, depending upon further pharmacokinetic and clinical studies

In order to evaluate the potential efficacy of ABT-492 in the therapy of sinusitis, we determined its in vitro activities against 326 recent aerobic and anaerobic clinical isolates from patients with sinusitis.

Strains were isolated from antral puncture specimens obtained from adult patients with sinusitis between 1994 and 2001 and were identified by standard criteria (9, 11). The numbers and species of clinical isolates tested are given in Table 1.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Comparative in vitro activities of ABT-492 against aerobic and anaerobic bacteria isolated from patients with sinusitis

 
Suppliers of standard laboratory powders were as indicated: ABT-492, Abbott Laboratories, Abbott Park, Ill.; amoxicillin-clavulanate and cefuroxime, Glaxo SmithKline, Philadelphia, Pa.; moxifloxacin, Bayer Corp., West Haven, Conn.; levofloxacin, R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J.; cefuroxime and gatifloxacin, Bristol-Myers Squibb, Princeton, N.J.; and penicillin G, Sigma Chemicals, St. Louis, Mo.

Susceptibility testing was performed according to National Committee for Clinical Laboratory Standards guidelines (12, 13) by the broth microdilution method with an inoculum of ~5 x 104 CFU per well for aerobes and by the agar dilution method with an inoculum of 105 CFU per spot for anaerobes. S. pneumoniae ATCC 49619, H. influenzae ATCC 49247, S. aureus ATCC 29213, Escherichia coli ATCC 25922, and Bacteroides fragilis ATCC 25285 were tested simultaneously with the appropriate plates and environments.

The results are presented in Table 1. ABT-492 performed well in our study with 325 of 326 (99.7%) sinus isolates, both aerobic and anaerobic, susceptible to <=4 µg of drug/ml. For only one isolate of Pseudomonas aeruginosa, which was resistant to all the quinolones tested, did ABT-492 have a MIC of 16 µg/ml. For three other isolates, two strains of Achromobacter xylosoxidans and one strain of Bacteroides uniformis, the MICs of ABT-492 were 4 µg/ml. For an additional five strains (one strain each of Acinetobacter baumannii, Bilophila wadsworthia, and Veillonella species and two strains of P. aeruginosa) the MICs of ABT-492 were 2 µg/ml.

ABT-492 was active against all pneumococci at <=0.06 µg/ml and was five- to sevenfold more active than levofloxacin, moxifloxacin, and gatifloxacin on a weight basis. Twenty percent of our pneumococcal sinus isolates were nonsusceptible to penicillin, and 10% were resistant to clindamycin. ABT-492 exhibited excellent activity against one isolate that was resistant to the other fluoroquinolones. This is in accord with the work of Nilius et al. (42nd ICAAC), who studied 30 quinolone-resistant S. pneumoniae isolates and found ABT-492 to have a MIC at which 90% of isolates tested were inhibited (MIC90) of 0.12 µg/ml compared to a levofloxacin MIC90 of 16 µg/ml. Smith et al. (42nd ICAAC) studied 75 Canadian strains of ciprofloxacin-resistant S. pneumoniae and reported a MIC90 of ABT-492 of 0.25 µg/ml compared to MIC90s of gatifloxacin, levofloxacin, and moxifloxacin of 8, 16, and 4 µg/ml, respectively. Zhanel et al. (42nd ICAAC) reported the comparative activities of ABT-492 against 850 strains of S. pneumoniae isolated from Canadian patients with lower respiratory tract infections in 2002 and found ABT-492 to be "the most powerful agent tested against respiratory isolates of S. pneumoniae," including penicillin-resistant, macrolide-resistant, doxycycline-resistant, and quinolone-resistant strains.

In our study, 45% of H. influenzae and other Haemophilus species isolates were beta-lactamase producers and all were susceptible to all the fluoroquinolones tested, with ABT-492 being 4- to 10-fold more active. Against Haemophilus species and M. catarrhalis, ABT-492 had a MIC90 of 0.008 µg/ml. Zhanel et al. (42nd ICAAC) noted ABT-492 to have excellent activities against 630 strains of H. influenzae and 430 strains of M. catarrhalis. ABT-492 was also active at <=0.5 µg/ml against two strains of methicillin-resistant S. aureus tested.

Studies of the anaerobic activity of ABT-492 have been extremely limited to date. Nilius et al. (42nd ICAAC) studied the activities of ABT-492 against 16 strains of B. fragilis and 12 strains of Clostridium difficile and found MIC90s of 0.12 and <=0.015 µg/ml, respectively. Barry et al. (42nd ICAAC) reported the activities of ABT-492 against 20 isolates of B. fragilis (MIC90, 1 µg/ml), 11 isolates of Prevotella species (MIC90, 1 µg/ml), 12 isolates of Clostridium perfringens (MIC90, 0.008 µg/ml), and 10 isolates of C. difficile (MIC90, 2 µg/ml). In our study, ABT-492 performed well against the anaerobes tested, with one isolate of B. uniformis requiring 4 µg of ABT-492/ml for inhibition and all other isolates being inhibited by <=2 µg/ml.

Amoxicillin-clavulanate performed well against all the anaerobes and many of the aerobes studied with the exception of the Enterobacteriaceae and nonfermenting gram-negative bacilli as previously reported (5). Levofloxacin showed good activity against most aerobic and many anaerobic sinus isolates with the exception of 8% of anaerobes (especially Prevotella melaninogenica). Moxifloxacin and gatifloxacin had similar activities against both aerobes and anaerobes.

ABT-492 was the most active agent tested with an improved and broader spectrum of activity compared with those of currently available quinolones. It merits further evaluation as a therapeutic alternative in both acute and chronic sinusitis.


   ACKNOWLEDGMENTS
 
This study was supported, in part, by a grant from Abbott Laboratories.

We thank Judee H. Knight and Alice E. Goldstein for assistance.


   FOOTNOTES
 
* Corresponding author. Mailing address: 2021 Santa Monica Blvd., Suite 740 East, Santa Monica, CA 90404. Phone: (310) 315-1511. Fax: (310) 315-3662. E-mail: EJCGMD{at}aol.com. Back


   REFERENCES
Top
 Abstract
 Text
 References
 

  1. Brook, I. 2002. Anaerobic bacteria in upper respiratory tract and other head and neck infections. Ann. Otol. Rhinol. Laryngol. 111:430-440.[Medline]
  2. Brueggemann, A. B., S. L. Coffman, P. Rhomberg, H. Huynh, L. Almer, A. Nilius, R. Flamm, and G. V. Doern. 2002. Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994-1995. Antimicrob. Agents Chemother. 46:680-688.[Abstract/Free Full Text]
  3. Finegold, S. M., M. J. Flynn, F. V. Rose, H. Jousimies-Somer, C. Jakielaszek, M. McTeague, H. M. Wexler, E. Berkowitz, and B. Wynne. 2002. Bacteriologic findings associated with chronic bacterial maxillary sinusitis in adults. Clin. Infect. Dis. 35:428-433.[CrossRef][Medline]
  4. Goldstein, E. J. C., and S. M. Garabedian-Ruffalo. 2002. Widespread use of fluoroquinolones versus emerging resistance of pneumococci. Clin. Infect. Dis. 35:1505-1511.[CrossRef][Medline]
  5. Goldstein, E. J. C., D. M. Citron, and C. V. Merriam. 1999. Comparative in vitro activities of amoxicillin-clavulanate against aerobic and anaerobic bacteria isolated from antral puncture specimens from patients with sinusitis. Antimicrob. Agents Chemother. 43:705-707.[Abstract/Free Full Text]
  6. Greenberg, D., D. P. Speert, E. Mahenthiralingam, D. A. Henry, L. E. Campbell, D. W. Scheifele, and the CPS/LCDC IMPACT Monitoring Network. 2002. Emergence of penicillin-nonsusceptible Streptococcus pneumoniae invasive clones in Canada. J. Clin. Microbiol. 40:68-74.[Abstract/Free Full Text]
  7. Grollier, G., G. Le Moal, R. Robert, C. Bernard, and J. M. Klossek. 2000. Role des bacteries anaerobies strictes dans les sinusitis. Med. Mal. Infect. 30(Suppl. 2):109-113.
  8. Ho, P. L., R. W. H. Yung, D. N. C. Tsang, T. L. Que, M. Ho, W. H. Seto, T. K. Ng, W. C. Yam, and W. W. S. Ng. 2001. Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicenter study in 2000. J. Antimicrob. Chemother. 48:659-665.[Abstract/Free Full Text]
  9. Jousimies-Somer, H. R., P. Summanen, D. M. Citron, E. J. Baron, H. M. Wexler, and S. M. Finegold. 2002. Wadsworth-KTL anaerobic bacteriology manual, 6th ed. Star Publishing Company, Belmont, Calif.
  10. Jousimies-Somer, H. R., S. Savolainen, and J. S. Ylikoski. 1988. Bacteriological findings of acute maxillary sinusitis in young adults. J. Clin. Microbiol. 26:1919-1925.[Abstract/Free Full Text]
  11. Murray, P. R., E. J. Baron, M. A. Pfaller, F. C. Tenover, and R. H. Yolken. 1999. Manual of clinical microbiology, 7th ed. ASM Press, Washington, D.C.
  12. National Committee for Clinical Laboratory Standards. 2001. Methods for antimicrobial susceptibility testing of anaerobic bacteria, 5th ed. Approved standard. NCCLS publication no. M11-A5. National Committee for Clinical Laboratory Standards, Wayne, Pa.
  13. National Committee for Clinical Laboratory Standards. 2000. Method for dilution antimicrobial susceptibility testing for bacteria that grow aerobically: approved standard, 5th ed. NCCLS publication no. M7-A5. National Committee for Clinical Laboratory Standards, Wayne, Pa.
  14. Sinus and Allergy Health Partnership. 2000. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol. Head Neck Surg. 123(Suppl. 1, Part 2):S1-S32.[CrossRef]
  15. Thornsberry, C., P. Ogilvie, H. P. Holley, Jr., and D. F. Sahm. 1999. Survey of susceptibilities of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates to 26 antimicrobial agents: a prospective U.S. study. Antimicrob. Agents Chemother. 43:2616-2623.
  16. Tomioka, H., K. Sato, H. Kajitani, T. Akaki, and S. Shishido. 2000. Comparative antimicrobial activities of the newly synthesized quinolone WQ-3034, levofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex. Antimicrob. Agents Chemother. 44:283-286.[Abstract/Free Full Text]
  17. Urban, C., N. Rahman, X. Zhao, N. Mariano, S. Segal-Maurer, K. Drlica, and J. J. Rahal. 2001. Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. J. Infect. Dis. 184:794-798.[CrossRef][Medline]
  18. U.S. Department of Health and Human Services. 1987. National health survey. Prevalence of selected chronic conditions. United States, 1983-1985. U.S. Department of Health and Human Services, Hyattsville, Md.

Antimicrobial Agents and Chemotherapy, September 2003, p. 3008-3011, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.3008-3011.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goldstein, E. J. C.
Right arrow Articles by Fernandez, H. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goldstein, E. J. C.
Right arrow Articles by Fernandez, H. T.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Clin. Vaccine Immunol. Clin. Microbiol. Rev.
J. Clin. Microbiol. ALL ASM JOURNALS