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Antimicrobial Agents and Chemotherapy, May 2009, p. 2163-2170, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01557-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antianaerobic Activity of Sulopenem Compared to Six Other Agents {triangledown}

Lois M. Ednie and Peter C. Appelbaum*

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033

Received 21 November 2008/ Returned for modification 19 December 2008/ Accepted 9 January 2009


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ABSTRACT
 
Agar dilution MIC methodology was used to compare the activity of sulopenem with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes. Overall, MIC50/90 values were as follows: sulopenem, 0.25/1.0 µg/ml; amoxicillin/clavulanate, 0.5/2.0 µg/ml; ampicillin/sulbactam, 0.5/4.0 µg/ml; piperacillin/tazobactam, 0.25/8.0 µg/ml; imipenem, 0.06/1.0 µg/ml; clindamycin, 0.25/16.0 µg/ml; and metronidazole, 1.0/4.0 µg/ml.


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INTRODUCTION
 
Anaerobes are becoming increasingly resistant to β-lactams due to β-lactamase production and other mechanisms. Although β-lactamase production, and concomitant resistance to β-lactams, is the norm among the Bacteroides fragilis group, other anaerobic gram-negative bacilli in the genera Prevotella, Porphyromonas, and Fusobacterium have increasingly become β-lactamase positive. β-Lactamase production also has been described in clostridia. Metronidazole resistance in organisms other than non-spore-forming gram-positive bacilli has been described, as has clindamycin resistance in anaerobic gram-negative bacilli (1-5).

Although most anaerobes are susceptible to carbapenems, resistance has occurred. Quinolone resistance has developed, importantly in Clostridium difficile, necessitating development of other agents to treat pseudomembranous colitis (6, 8-10, 12, 14, 16).

CP-65,207, whose in vitro activity was published in 1989 (13), is a diastereomeric mixture of two isomers, the active component of the two being sulopenem. Sulopenem development was put on hold in the 1990s as discovery/development efforts were focused on gram-positive organisms. There is now an urgent need for drugs against gram-negative strains, and sulopenem has reentered clinical development (M. Huband, personal communication). PF-03709270 is a novel oral prodrug of sulopenem (11). The oral prodrug approach makes this compound unique among the penems and carbapenems. PF-03709270 and sulopenem both entered phase II studies in December 2008. The structures of sulopenem and its oral prodrug PF-03709270 are shown in Fig. 1 and 2, respectively.


Figure 1
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  		FIG. 1. Chemical structure of sulopenem.


Figure 2
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  		FIG. 2. Chemical structure of PF-03709270, the oral prodrug of sulopenem.

This study examined the activity of sulopenem compared with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes.

(This study was presented at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 25 to 28 October 2008 [9a].)

All anaerobes were clinical strains identified by standard procedures (16) and kept frozen in double-strength skim milk (dehydrated skim milk; BD, Sparks, MD) at –70°C until use. Prior to testing, strains were subcultured twice onto enriched brucella agar plates (7). Sulbactam and sulopenem susceptibility powders were obtained from Pfizer Central Research, Groton, CT, and other drugs were obtained from the respective manufacturers. β-Lactamase testing was performed by the nitrocefin disk method (Cefinase; BD, Sparks, MD). Agar dilution susceptibility testing was performed according to the latest method recommended by the Clinical and Laboratory Standards Institute (CLSI) (7), using brucella agar with 5% sterile laked sheep blood. Clavulanate and sulbactam were combined with amoxicillin and ampicillin, respectively, in 1:2 ratios, and tazobactam with piperacillin at a fixed concentration of 4.0 µg/ml. Breakpoint values, where CLSI approved, were as follows: amoxicillin/clavulanate, ≤4.0 µg/ml; ampicillin/sulbactam, ≤8.0 µg/ml; piperacillin/tazobactam, ≤32.0 µg/ml; imipenem, ≤4.0 µg/ml; clindamycin, ≤2.0 µg/ml; and metronidazole, ≤8.0 µg/ml. Quality control strains recommended by CLSI (Bacteroides fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741, and Eggerthella lenta ATCC 43055) were included with each run. Sulopenem MIC ranges for these strains were 0.06 to 0.125, 0.25, and 1.0 µg/ml, respectively.

Among the anaerobic gram-negative bacilli tested, 95/101 (94%) of B. fragilis group strains, 57/100 (57%) of Prevotella/Porphyromonas strains, and 3/60 (5%) of fusobacterial strains produced β-lactamase. Results of MIC testing are presented in Table 1. Overall, MIC50/90 values were as follows: sulopenem, 0.25/1.0 µg/ml; amoxicillin/clavulanate, 0.5/2.0 µg/ml; ampicillin/sulbactam, 0.5/4.0 µg/ml; piperacillin/tazobactam, 0.25/8.0 µg/ml; imipenem, 0.06/1.0 µg/ml; clindamycin, 0.25/16.0 µg/ml; and metronidazole, 1.0/4.0 µg/ml.


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  		TABLE 1. MICs of the agents tested in this study

With the exception of six strains of lactobacilli, sulopenem and imipenem both had MICs of ≤4.0 µg/ml against all strains tested in this study. Clindamycin resistance was found in all of the Bacteroides species tested as well as 5 of the 15 different species of Prevotella and Porphyromonas tested. Eighteen of the 21 strains of Fusbacterium varium showed resistance to clindamycin, while all other fusobacteria were clindamycin susceptible. For all anaerobic gram-positive cocci tested, clindamycin resistance was observed in only one strain of Finegoldia magna and one strain of Peptoniphilus asaccharolyticus. All groups of anaerobic non-spore-forming gram-positive rods except Propionibacterium acnes had some degree of clindamycin resistance. All Clostridium tertium strains as well as some strains in 5 of the 11 other Clostridium species were clindamycin resistant. Most gram-positive non-spore-forming rods (with the exception of Eggerthella) were metronidazole resistant, while all anaerobic gram-negative rods, gram-positive cocci, and clostridia were metronidazole susceptible. Pipercillin/tazobactam was active against all strains tested, with MICs of ≤16 µg/ml. Resistance to amoxicillin/clavulanate was found in four of seven species of Bacteroides as well as two strains of Fusobacterium mortiferum. All other strains of fusobacteria as well as all strains of Prevotella, Porphyromonas, Clostridium, and gram-positive non-spore-forming rods were amoxicillin/clavulanate susceptible. Two of the 10 Peptostreptococcus anaerobius strains showed amoxicillin/clavulanate resistance, while all other gram-positive cocci were susceptible. Ampicillin/sulbactam was active against all strains of Clostridium, anaerobic gram-positive non-spore-forming rods, Prevotella, and Porphyromonas tested. Gram-negative rods showing ampicillin/sulbactam resistance included some strains in three of the seven Bacteroides species tested and two strains of Fusobacterium mortiferum, while other species of fusobacteria were susceptible.

While 413 of 431 strains (95.8%) tested had sulopenem MICs of ≤2 µg/ml, 18 strains (4.2%) had MICs of ≥4.0 µg/ml. These included 7 Lactobacillus species (6 strains with >8.0 µg/ml and 1 strain at 4.0 µg/ml), 10 strains of Clostridium (4 C. difficile, 1 C. innocuum, and 5 unspeciated) (MICs all 4.0 µg/ml), and 1 strain of Peptostreptococcus anaerobius (MIC of 4.0 µg/ml). Until pharmacokinetic/pharmacodynamic breakpoints for sulopenem can be established, the clinical significance of these relatively higher sulopenem MICs cannot be established.

Gootz and coworkers (13) in their 1989 study on CP-65,207, reported on its activity against 84 anaerobes, many of which have since been reclassified. Excluding Peptococcus spp., which are no longer included among clinically significant anaerobic gram-positive cocci in standard manuals (16), their results were similar to those obtained in our study. In a study of the comparative activity of sulopenem against a collection of recently isolated gram-positive and -negative aerobic organisms, sulopenem MIC90s ranged between 0.03 and 1 µg/ml against all clinically significant bacterial species tested. This high in vitro potency was also confirmed by in vitro time-kill studies (15). Our study adds anaerobes to the activity spectrum for this drug and suggests a potential place for sulopenem in treatment of mixed anaerobic infections. Pharmacokinetic/pharmacodynamic and experimental animal studies are necessary to further delineate the clinical role of these compounds in treatment of anaerobic infections.


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ACKNOWLEDGMENTS
 
This study was supported by a grant from Pfizer Central Research, Groton, CT.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psu.edu Back

{triangledown} Published ahead of print on 17 February 2009. Back


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REFERENCES
 
    1
  1. Appelbaum, P. C., A. Philippon, M. R. Jacobs, S. K. Spangler, and L. Gutmann. 1990. Characterization of β-lactamases from non-Bacteroides fragilis group Bacteroides spp. belonging to seven species and their role in β-lactam resistance. Antimicrob. Agents Chemother. 34:2169-2176.[Abstract/Free Full Text]
    2. 2
  2. Appelbaum, P. C., S. K. Spangler, and M. R. Jacobs. 1990. Evaluation of two methods for rapid testing for beta-lactamase production in Bacteroides and Fusobacterium. Eur. J. Clin. Microbiol. Infect. Dis. 9:47-50.[CrossRef][Medline]
    3. 3
  3. Appelbaum, P. C., S. K. Spangler, and M. R. Jacobs. 1990. β-Lactamase production and susceptibilities to amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavulanate, cefoxitin, imipenem, and metronidazole of 320 non-Bacteroides fragilis Bacteroides isolates and 129 fusobacteria from 28 U.S. centers. Antimicrob. Agents Chemother. 34:1546-1550.[Abstract/Free Full Text]
    4. 4
  4. Appelbaum, P. C., S. K. Spangler, and M. R. Jacobs. 1993. Susceptibility of 539 gram-positive and -negative anaerobes to new agents, including RP 59500, biapenem, trospectomycin and piperacillin/tazobactam. J. Antimicrob. Chemother. 32:223-231.[Abstract/Free Full Text]
    5. 5
  5. Appelbaum, P. C., S. K. Spangler, G. A. Pankuch, A. Philippon, M. R. Jacobs, R. Shiman, E. J. C. Goldstein, and D. Citron. 1994. Characterization of a β-lactamase from Clostridium clostridioforme. J. Antimicrob. Chemother. 33:33-40.[Abstract/Free Full Text]
    6. 6
  6. Bauernfeind, A. 1997. Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J. Antimicrob. Chemother. 40:639-651.[Abstract/Free Full Text]
    7. 7
  7. Clinical Laboratory Standards Institute. 2007. Methods for antimicrobial susceptibility testing of anaerobic bacteria, 7th ed. Approved standard M11-A7. CLSI, Wayne, PA.
    8. 8
  8. Credito, K. L., and P. C. Appelbaum. 2004. Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species. Antimicrob. Agents Chemother. 48:4430-4434.[Abstract/Free Full Text]
    9. 9
  9. Credito, K. L., L. M. Ednie, and P. C. Appelbaum. 2008. Comparative antianaerobic activities of doripenem determined by MIC and time-kill analysis. Antimicrob. Agents Chemother. 52:365-373.[Abstract/Free Full Text]
    10. 9
  10. Ednie, L. M., and P. C. Appelbaum. 2008. Anti-anaerobic activity of sulopenem compared to other agents, abstr. F1-347, p. 282. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC.
    11. 10
  11. Ednie, L. M., M. R. Jacobs, and P. C. Appelbaum. 1998. Activities of gatifloxacin compared to those of seven other agents against anaerobic organisms. Antimicrob. Agents Chemother. 42:2459-2462.[Abstract/Free Full Text]
    12. 11
  12. Forrest, A., A. Hazra, D. Girard, S. Finegan, J. O'Donnell, and K. Soma. 2008. Use of PK/PD analysis to select PF-03709270 doses, with and without probenecid (P), for phase 2b trials, abstr. A-034, p. 9. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC.
    13. 12
  13. Goldstein, E. J. C., and D. M. Citron. 1992. Comparative activity of ciprofloxacin, ofloxacin, sparfloxacin, temafloxacin, CI-960, CI-990, and Win 57273 against anaerobic bacteria. Antimicrob. Agents Chemother. 36:1158-1162.[Abstract/Free Full Text]
    14. 13
  14. Gootz, T., J. Retsema, A. Girard, E. Hamanaka, M. Anderson, and S. Sokolowski. 1989. In vitro activity of CP-65,207, a new penem antimicrobial agent, in comparison with those of other agents. Antimicrob. Agents Chemother. 33:1160-1166.[Abstract/Free Full Text]
    15. 14
  15. Hoellman, D. B., L. M. Kelly, M. R. Jacobs, and P. C. Appelbaum. 2001. Comparative antianaerobic activity of BMS 284756. Antimicrob. Agents Chemother. 45:589-592.[Abstract/Free Full Text]
    16. 15
  16. Huband, M. D., T. D. Gootz, M. A. Cohen, L. M. Mullins, S. P. McCurdy, L. A. Brennan, J. M. Duignan, P. J. Pagano, and R. W. Murray. 2008. In vitro antibacterial activity of sulopenem: a new oral penem antimicrobial versus recent bacterial isolates, abstr. F1-344, p. 281. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC.
    17. 16
  17. Jousimies-Somer, H. R., P. Summanen, D. M. Citron, E. J. Baron, H. Wexler, and S. M. Finegold. 2002. Wadsworth-KTL anaerobic bacteriology manual. Star Publishing Co., Belmont, CA.

Antimicrobial Agents and Chemotherapy, May 2009, p. 2163-2170, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01557-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.




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