Skip to main page content

• HOME
• Current Issue
• Archive
• Alerts
• About ASM
• Contact us
• Tech Support
• Journals.ASM.org

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ge, Y. Articles by Sahm, D. F. Search for Related Content PubMed PubMed Citation Articles by Ge, Y. Articles by Sahm, D. F.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2008, p. 3398-3407, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00149-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Profiling of Ceftaroline against a Collection of Recent Bacterial Clinical Isolates from across the United States

Yigong Ge,¹ Donald Biek,^1* George H. Talbot,^1, and Daniel F. Sahm²

Cerexa, Inc., Alameda, California,¹ Eurofins Medinet, Herndon, Virginia²

Received 2 February 2008/ Returned for modification 22 March 2008/ Accepted 4 July 2008

Top ABSTRACT TEXT REFERENCES

 
This study evaluated the in vitro activity of ceftaroline, a novel cephalosporin with broad-spectrum activity against gram-negative and -positive pathogens, against 4,151 recent clinical isolates collected in the United States. Ceftaroline was very potent against bacteria found in community- and hospital-acquired infections, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, and common Enterobacteriaceae spp.

Top ABSTRACT TEXT REFERENCES

 
Antimicrobial resistance is an escalating problem in both nosocomial and community-acquired bacterial infections (3, 12, 13). Pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are becoming more virulent and are increasingly found in community-acquired infections, particularly in skin and soft-tissue infections (1, 17, 18). The development of resistance to vancomycin and newer classes of antibiotics active against MRSA, such as linezolid and daptomycin, is worrisome (14, 24, 26). The prevalence of drug-resistant (including β-lactam-resistant) Streptococcus pneumoniae has increased in the United States during recent years (4, 5, 10). In addition, resistance is common among gram-negative bacteria, some of which produce β-lactamases (including extended-spectrum β-lactamases [ESBL]) and/or exhibit increased efflux activity (12, 19, 22). There is a clinical need for new antibiotics that are active against multidrug-resistant gram-positive and gram-negative pathogens (25, 27).

Ceftaroline fosamil (formerly PPI-0903, TAK-599) is a novel, parenteral, cephalosporin prodrug that is converted in vivo to the microbiologically active form, ceftaroline. Ceftaroline has broad-spectrum activity that encompasses many community- and hospital-acquired pathogens, including MRSA, multidrug-resistant S. pneumoniae (MDRSP), and common (non-ESBL-producing) gram-negative bacteria (11, 15, 23). This study evaluated the in vitro activity of ceftaroline against a collection of recent clinical isolates from the United States, including bacteria exhibiting resistance to currently available antimicrobial agents.

(A preliminary report of these results was presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago, IL, 17 to 20 September 2007.)

A total of 4,151 clinical isolates collected primarily between 2004 and 2006 at hospitals throughout the United States were analyzed. Exceptions included Providencia spp., collected from 2001 to 2002, and Pasteurella multocida, isolated from Luxembourg. Thirteen S. aureus isolates were collected before 2004, 7 of which were collected outside the United States. After being identified at a local laboratory, isolates were shipped on Copan Amies agar gel transport swabs (Copan, Brescia, Italy) to a central laboratory (Eurofins Medinet, Herndon, VA) for confirmatory identification and susceptibility testing. Confirmatory identification was accomplished using routine microbiologic methodologies in accordance with those of Murray (20) and included the use of an automated identification system (Vitek; bioMérieux, Durham, NC) as appropriate. All isolates were tested for their susceptibilities to ceftaroline and appropriate comparator antimicrobial agents as shown in Tables 1 and 2.

View this table: [in this window] [in a new window]

TABLE 1. Antimicrobial susceptibility of ceftaroline and selected comparator antimicrobial agents against gram-positive organismsb

View this table: [in this window] [in a new window]

TABLE 2. Antimicrobial susceptibility of ceftaroline and selected comparator antimicrobial agents against gram-negative organismsb

Antimicrobial susceptibility testing by broth microdilution adhered to CLSI guidelines M7-A7, employing commercially prepared frozen panels (TREK Diagnostic Systems, Cleveland, OH) (8). Susceptibility interpretative criteria for comparator antibiotics were adopted from CLSI documents M100-S16 and M45-A (7, 9). Quality control was monitored by using the following organisms: Escherichia coli ATCC 25922 and ATCC 35218, Pseudomonas aeruginosa ATCC 27853, Enterococcus faecalis ATCC 29212, S. aureus ATCC 29213, Haemophilus influenzae ATCC 49247 and ATCC 49766, and S. pneumoniae ATCC 49619. Ceftaroline (PPI-0903 M; lot no. M599-R1001) was provided by Cerexa, Inc., and other comparators were purchased from appropriate commercial sources.

The in vitro activity of ceftaroline in comparison to the activities of selected antimicrobial agents against gram-positive pathogens is summarized in Table 1. Ceftaroline was highly active in vitro against gram-positive bacteria, including resistant isolates, and had lower MICs than ceftazidime and ceftriaxone against all strains tested. Ceftaroline had an MIC at which 90% of isolates were inhibited (MIC₉₀) of 0.25 µg/ml for methicillin-susceptible S. aureus (MSSA) compared with 4 µg/ml for ceftriaxone, 1 µg/ml for vancomycin, and 0.12 µg/ml for imipenem. Ceftaroline had potent activity in vitro against methicillin-resistant strains (MIC₉₀ = 1 µg/ml), and all MRSA isolates were inhibited at an MIC of 2 µg/ml or less. Ceftaroline was the most active β-lactam antibiotic tested against MRSA. Ceftaroline also exhibited potent activity in vitro against coagulase-negative staphylococci, with an MIC₉₀ of 0.12 µg/ml for oxacillin-susceptible isolates and an MIC of 0.5 µg/ml for oxacillin-resistant isolates.

Ceftaroline exhibited high in vitro activity against all strains of streptococci tested. As with other β-lactams, MIC₉₀s were lower against penicillin-susceptible strains of S. pneumoniae (MIC₉₀ = 0.015 µg/ml) than against penicillin-resistant strains (MIC₉₀ = 0.12 µg/ml), although ceftaroline remained highly active regardless of penicillin-susceptibility status (MIC₉₀ 0.5 µg/ml). Ceftaroline was very potent against beta-hemolytic streptococci, Streptococcus pyogenes and Streptococcus agalactiae, and its activity was not affected by the macrolide-susceptibility status of the strains tested. The highest ceftaroline MICs for any isolate were 0.03 µg/ml for S. pyogenes and 0.12 µg/ml for S. agalactiae. Viridans group streptococci were susceptible to ceftaroline with an MIC₉₀ of 0.03 µg/ml for penicillin-susceptible strains and 0.5 µg/ml for penicillin-resistant strains. Against E. faecalis, ceftaroline had an MIC₉₀ of 4 µg/ml, and activity was not affected by the vancomycin-susceptibility status of the strains tested. Similarly to other β-lactam agents, ceftaroline exhibited minimal activity against Enterococcus faecium.

As shown in Table 2, the spectrum of activity of ceftaroline for Enterobacteriaceae spp. was similar to that of other extended-spectrum cephalosporins, including ceftazidime and ceftriaxone. The MIC₉₀ of 1 µg/ml for ceftaroline against the collection of cephalosporin-susceptible Enterobacteriaceae isolates was slightly higher than that for ceftazidime (0.5 µg/ml) and ceftriaxone (0.25 µg/ml). With regard to individual species of Enterobacteriaceae, ceftaroline exhibited similar activity to that of ceftazidime and ceftriaxone among cephalosporin-susceptible populations of E. coli, Citrobacter freundii, Enterobacter cloacae, and Klebsiella pneumoniae. As shown in Table 2, ceftaroline MIC₉₀s were considerably higher relative to cefepime, ceftazidime, and ceftriaxone against Proteus mirabilis, Morganella morganii, Serratia marcescens, and Providencia spp. Similarly to third-generation cephalosporins, ceftaroline was not active against ceftazidime-nonsusceptible Enterobacteriaceae spp., which included ESBL-producing or AmpC-overexpressing strains. The MIC₉₀ of ceftaroline was >16 µg/ml for imipenem-susceptible and multidrug-resistant strains of Acinetobacter, mainly Acinetobacter baumannii, which was similar to that for ceftriaxone and levofloxacin.

Ceftaroline had potent activity in vitro against H. influenzae, regardless of the production of β-lactamase. Ceftaroline also exhibited potent activity against all isolates of Moraxella catarrhalis, regardless of the presence of β-lactamases (93 of the 102 strains were β-lactamase positive) (data not shown), demonstrating the stability of ceftaroline to β-lactamases associated with this pathogen. Additionally, ceftaroline was very active in vitro against P. multocida.

Ceftaroline demonstrated potent in vitro activity against a wide spectrum of clinically relevant organisms, with MICs that were either lower than or similar to those of other cephalosporins. Ceftaroline was particularly active against S. aureus and beta-hemolytic streptococci, gram-positive bacteria commonly associated with skin and wound infections. Ceftaroline exhibited low MIC ranges for S. aureus, extending from 0.03 to 1 µg/ml for MSSA and 0.12 to 2 µg/ml for MRSA, which set this agent apart from currently available β-lactams. Because MRSA is becoming increasingly prevalent in hospital- and community-acquired infections (1, 18), the availability of a new cephalosporin with bactericidal activity against MRSA would have significant favorable clinical implications (16).

Ceftaroline was highly active against S. pneumoniae as well as β-lactamase-positive and -negative isolates of H. influenzae and M. catarrhalis, pathogens frequently associated with respiratory tract infections (2). There is increasing evidence that S. pneumoniae, one of the most common causes of community-acquired pneumonia, is developing resistance to many of the currently available antibiotics, including macrolides, quinolones, and older cephalosporins (6, 21). In this evaluation, ceftaroline was highly active against S. pneumoniae, regardless of penicillin-susceptibility status. In addition, ceftaroline maintained activity against many common gram-negative pathogens similar to that of other third-generation cephalosporins, a spectrum of activity that differentiates it from many newer antibiotics that are active only against gram-positive organisms.

In conclusion, ceftaroline exhibited potent in vitro activity against a broad collection of recent gram-positive and gram-negative bacterial isolates from hospitals throughout the United States. This in vitro profile suggests that ceftaroline has the potential to become an important addition to the arsenal of currently available antimicrobial therapies as a broad-spectrum antibiotic that may be used in the treatment of both nosocomial and community-acquired infections.

 
Funding for this study was provided by Cerexa, Inc. (Alameda, CA), a wholly owned subsidiary of Forest Laboratories, Inc. Funding for editorial assistance was provided by Forest Laboratories, Inc.

We acknowledge Grace E. Johnson, Scientific Therapeutics Information, Inc., Springfield, NJ, and thank her for providing editorial assistance in the development of the manuscript.

 
* Corresponding author. Mailing address: Cerexa, Inc., 1751 Harbor Bay Parkway, Alameda, California. Phone: (510) 747-3956. Fax: (510) 747-3940. E-mail: dbiek{at}cerexa.com

Published ahead of print on 14 July 2008.

Present address: Talbot Advisors, LLC, Maplewood Avenue, Wayne, Pennsylvania.

Top ABSTRACT TEXT REFERENCES

 

1
1. Baba, T., F. Takeuchi, M. Kuroda, H. Yuzawa, K. Aoki, A. Oguchi, Y. Nagai, N. Iwama, K. Asano, T. Naimi, H. Kuroda, L. Cui, K. Yamamoto, and K. Hiramatsu. 2002. Genome and virulence determinants of high virulence community-acquired MRSA. Lancet 359:1819-1827.[CrossRef][Medline]
2
2. Bartlett, J. G., and L. M. Mundy. 1995. Community-acquired pneumonia. N. Engl. J. Med. 333:1618-1624.[Free Full Text]
3
3. Burke, J. P. 2003. Infection control: a problem for patient safety. N. Engl. J. Med. 348:651-656.[Free Full Text]
4
4. Centers for Disease Control and Prevention. 2007. Active bacterial core surveillance (ABCs) report, emerging infections program network, Streptococcus pneumoniae, 2006. http://www.cdc.gov/ncidod/dbmd/abcs/survreports/spneu06.pdf.
5
5. Centers for Disease Control and Prevention. 2005. Active bacterial core surveillance (ABCs) report, emerging infections program network, Streptococcus pneumoniae, 2004. http://www.cdc.gov/ncidod/dbmd/abcs/survreports/spneu04.pdf.
6
6. Chiu, C. H., L. H. Su, Y. C. Huang, J. C. Lai, H. L. Chen, T. L. Wu, and T. Y. Lin. 2007. Increasing ceftriaxone resistance and multiple alterations of penicillin-binding proteins among penicillin-resistant Streptococcus pneumoniae isolates in Taiwan. Antimicrob. Agents Chemother. 51:3404-3406.[Abstract/Free Full Text]
7
7. Clinical and Laboratory Standards Institute. 2006. Methods for antimicrobial dilution and disk susceptibility testing of infrequently isolated or fastidious bacteria. CLSI M45-A. Clinical and Laboratory Standards Institute, Wayne, PA.
8
8. Clinical and Laboratory Standards Institute. 2007. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard, 7th ed. Clinical and Laboratory Standards Institute, Wayne, PA.
9
9. Clinical and Laboratory Standards Institute. 2007. Performance standards for antimicrobial susceptibility testing; sixteenth informational supplement. CLSI M100-S16. Clinical and Laboratory Standards Institute, Wayne, PA.
10
10. Draghi, D. C., M. E. Jones, D. F. Sahm, and G. S. Tillotson. 2006. Geographically-based evaluation of multidrug resistance trends among Streptococcus pneumoniae in the USA: findings of the FAST surveillance initiative (2003-2004). Int. J. Antimicrob. Agents 28:525-531.[CrossRef][Medline]
11
11. Ge, Y., R. S. Blosser, D. F. Sahm, and J. A. Karlowsky. 2004. In vitro activity of PPI-0903 (TAK-599), a new anti-MRSA cephalosporin, against gram-positive and gram-negative clinical isolates, abstr. A-139. Abstr. 104th Gen. Meet. Am. Soc. Microbiol. American Society for Microbiology, Washington, DC.
12
12. Giamarellou, H. 2005. Multidrug resistance in Gram-negative bacteria that produce extended-spectrum beta-lactamases (ESBLs). Clin. Microbiol. Infect. 11(Suppl. 4):S1-S16.
13
13. Herrero, I. A., N. C. Issa, and R. Patel. 2002. Nosocomial spread of linezolid-resistant, vancomycin-resistant Enterococcus faecium. N. Engl. J. Med. 346:867-869.[Free Full Text]
14
14. Howe, R. A., A. Monk, M. Whootton, T. R. Walsh, and M. C. Enright. 2004. Vancomycin susceptibility within methicillin-resistant Staphylococcus aureus lineages. Emerg. Infect. Dis. 10:855-857.[Medline]
15
15. Iizawa, Y., J. Nagai, T. Ishikawa, S. Hashiguchi, M. Nakao, A. Miyake, and K. Okonogi. 2004. In vitro antimicrobial activity of T-91825, a novel anti-MRSA cephalosporin, and in vivo anti-MRSA activity of its prodrug, TAK-599. J. Infect. Chemother. 10:146-156.[Medline]
16
16. Ishikawa, T., N. Matsunaga, H. Tawada, N. Kuroda, Y. Nakayama, Y. Ishibashi, M. Tomimoto, Y. Ikeda, Y. Tagawa, Y. Iizawa, K. Okonogi, S. Hashiguchi, and A. Miyake. 2003. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg. Med. Chem. 11:2427-2437.[CrossRef][Medline]
17
17. Jones, R. N., A. M. Nilius, B. K. Akinlade, L. M. Deshpande, and G. F. Notario. 2007. Molecular characterization of Staphylococcus aureus isolates from a 2005 clinical trial of uncomplicated skin and skin structure infections. Antimicrob. Agents Chemother. 51:3381-3384.[Abstract/Free Full Text]
18
18. Klevens, R. M., M. A. Morrison, J. Nadle, S. Petit, K. Gershman, S. Ray, L. H. Harrison, R. Lynfield, G. Dumyati, J. M. Townes, A. S. Craig, E. R. Zell, G. E. Fosheim, L. K. McDougal, R. B. Carey, and S. K. Fridkin. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298:1763-1771.[Abstract/Free Full Text]
19
19. Lockhart, S. R., M. A. Abramson, S. E. Beekmann, G. Gallagher, S. Riedel, D. J. Diekema, J. P. Quinn, and G. V. Doern. 2007. Antimicrobial resistance among gram-negative bacilli causing infections in intensive care unit patients in the United States between 1993 and 2004. J. Clin. Microbiol. 45:3352-3359.[Abstract/Free Full Text]
20
20. Murray, P. R. 2007. Manual of clinical microbiology, 9th ed. ASM Press, Washington, DC.
21
21. Niederman, M. S. 2007. Recent advances in community-acquired pneumonia: inpatient and outpatient. Chest 131:1205-1215.[CrossRef][Medline]
22
22. Pagès, J. M., M. Masi, and J. Barbe. 2005. Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol. Med. 11:382-389.[CrossRef][Medline]
23
23. Sader, H. S., T. R. Fritsche, K. Kaniga, Y. Ge, and R. N. Jones. 2005. Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob. Agents Chemother. 49:3501-3512.[Abstract/Free Full Text]
24
24. Skiest, D. J. 2006. Treatment failure resulting from resistance of Staphylococcus aureus to daptomycin. J. Clin. Microbiol. 44:655-656.[Abstract/Free Full Text]
25
25. Talbot, G., J. Bradley, J. Edwards, D. Gilbert, M. Scheld, J. Bartlett, and Antimicrobial Availability Task Force of the Infectious Diseases Society of America. 2006. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin. Infect. Dis. 42:657-668.[CrossRef][Medline]
26
26. Tsiodras, S., H. S. Gold, G. Sakoulas, G. M. Eliopoulos, C. Wennersten, L. Venkataraman, R. C. Moellering, and M. J. Ferraro. 2001. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 358:207-208.[CrossRef][Medline]
27
27. Wright, G., and A. Sutherland. 2007. New strategies for combating multidrug-resistant bacteria. Trends Mol. Med. 13:260-267.[CrossRef][Medline]

---

Antimicrobial Agents and Chemotherapy, September 2008, p. 3398-3407, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00149-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Jacqueline, C., Caillon, J., Le Mabecque, V., Miegeville, A.-F., Ge, Y., Biek, D., Batard, E., Potel, G. (2009). In Vivo Activity of a Novel Anti-Methicillin-Resistant Staphylococcus aureus Cephalosporin, Ceftaroline, against Vancomycin-Susceptible and -Resistant Enterococcus faecalis Strains in a Rabbit Endocarditis Model: a Comparative Study with Linezolid and Vancomycin. Antimicrob. Agents Chemother. 53: 5300-5302 [Abstract] [Full Text]  
• Vidaillac, C., Leonard, S. N., Rybak, M. J. (2009). In Vitro Activity of Ceftaroline against Methicillin-Resistant Staphylococcus aureus and Heterogeneous Vancomycin-Intermediate S. aureus in a Hollow Fiber Model. Antimicrob. Agents Chemother. 53: 4712-4717 [Abstract] [Full Text]  
• Pankuch, G. A., Appelbaum, P. C. (2009). Postantibiotic Effect of Ceftaroline against Gram-Positive Organisms. Antimicrob. Agents Chemother. 53: 4537-4539 [Abstract] [Full Text]  
• Patel, S. N., Pillai, D. R., Pong-Porter, S., McGeer, A., Green, K., Low, D. E. (2009). In vitro activity of ceftaroline, ceftobiprole and cethromycin against clinical isolates of Streptococcus pneumoniae collected from across Canada between 2003 and 2008. J Antimicrob Chemother 64: 659-660 [Full Text]  
• Vidaillac, C., Leonard, S. N., Sader, H. S., Jones, R. N., Rybak, M. J. (2009). In Vitro Activity of Ceftaroline Alone and in Combination against Clinical Isolates of Resistant Gram-Negative Pathogens, Including {beta}-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 53: 2360-2366 [Abstract] [Full Text]  
• McGee, L., Biek, D., Ge, Y., Klugman, M., du Plessis, M., Smith, A. M., Beall, B., Whitney, C. G., Klugman, K. P. (2009). In Vitro Evaluation of the Antimicrobial Activity of Ceftaroline against Cephalosporin-Resistant Isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 53: 552-556 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ge, Y. Articles by Sahm, D. F. Search for Related Content PubMed PubMed Citation Articles by Ge, Y. Articles by Sahm, D. F.