Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Antimicrobial Agents and Chemotherapy
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Susceptibility

Comparative In Vitro Activity of Ceftobiprole against Staphylococci Displaying Normal and Small-Colony Variant Phenotypes

Christof von Eiff, Alexander W. Friedrich, Karsten Becker, Georg Peters
Christof von Eiff
1Institute of Medical Microbiology
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: eiffc@uni-muenster.de
Alexander W. Friedrich
2Institute of Hygiene, University of Münster Hospital and Clinics, 48149 Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karsten Becker
1Institute of Medical Microbiology
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Georg Peters
1Institute of Medical Microbiology
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/AAC.49.10.4372-4374.2005
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

The antistaphylococcal activity of ceftobiprole was compared with those of cefuroxime, linezolid, and moxifloxacin by using the agar dilution method. Apart from three strains with small-colony variant phenotypes, all Staphylococcus aureus isolates tested were inhibited by ≤2 μg/ml of ceftobiprole. This compound exhibited an excellent antistaphylococcal activity, comparable to that of linezolid.

Ceftobiprole (BPR) (formerly BAL9141) is a novel parenteral cephalosporin with activity against a broad range of pathogens, particularly against gram-positive bacteria (3, 5, 7). While the compound has been described to possess strong affinity for the mecA product PBP 2a, data on the activity of ceftobiprole against well-characterized staphylococci are limited. Therefore, aims of this study were (i) to challenge the ceftobiprole spectrum by evaluating its activity against well-defined staphylococcal strains of different species, including small-colony variants (SCVs), and (ii) to compare the in vitro antistaphylococcal activity of this cephalosporin with those of linezolid, moxifloxacin, and cefuroxime.

The 284 Staphylococcus aureus strains tested comprised 72 methicillin-susceptible S. aureus (MSSA) and 212 methicillin-resistant S. aureus (MRSA) strains, including 14 strains with stable SCV phenotypes. The 80 coagulase-negative staphylococci (CoNS) comprised 14 methicillin-susceptible and 21 methicillin-resistant Staphylococcus epidermidis strains, 17 methicillin-susceptible and 15 methicillin-resistant Staphylococcus haemolyticus strains, and 13 other CoNS belonging to eight different species.

All staphylococcal strains were freshly isolated from clinical material and were included in the testing only if they were considered etiologically relevant. Apart from isolates with SCV phenotypes, only one isolate per patient was tested. Eighty-one MRSA strains, each presenting a different spa type, were selected from our institutional collection (between 1996 and 2004). All other spa-typed MRSA isolates were collected during the course of a multicenter study in Germany also including community-acquired MRSA, with not more than five strains selected from each center. Overall, the MRSA strains tested represent more than 90 spa types and thus cover >90% of all registered European MRSA spa types within the SeqNet network (www.SeqNet.org ) (6).

If the biochemical identification of staphylococcal isolates (ATB32 Staph; bioMerieux, Marcy l'Etoile, France) was ambiguous or categorized as unacceptable, 16S rRNA gene sequencing was performed as previously described (2). Isolates      were confirmed to be methicillin resistant by supplementation of the agar with 2% NaCl (read after incubation for 48 h at 30°C by using 5-μg oxacillin disks) and by detection of the mecA gene (10).

S. aureus SCVs (n = 14) were collected from patients with persistent and/or recurrent infections, such as chronic osteomyelitis or chronic skin and soft tissue infections (11-13). Isolates were recognized as SCVs and genotyped as previously described (11-13). Strains with SCV phenotypes were confirmed as S. aureus by testing for the S. aureus-specific nuc gene (9). For comparison, 13 isolates with normal morphotypes (clonally identical to the corresponding SCVs), which were recovered in the same or subsequent clinical specimens as the SCVs, were also included in this study.

The MICs were determined by using the agar dilution technique according to CLSI (4). Ceftobiprole, cefuroxime, linezolid, and moxifloxacin were obtained from their respective manufacturers. The test range was 0.03 to 128 μg/ml (up to 32 μg/ml for ceftobiprole). The results were read after 18 h of incubation at 36°C, and the results for SCVs and their parent strains were read also after 42 h and 66 h of incubation. Several reference strains were included as controls. Additionally, sterility and growth controls were always performed.

The MIC distribution data for the S. aureus strains with normal phenotypes as well as for the CoNS are shown in Table 1. Ceftobiprole exhibited excellent wide-spectrum antistaphylococcal activity. According to the MIC at which 50% of isolates were inhibited (MIC50) and MIC90 values, ceftobiprole was two- to eightfold more active than cefuroxime against methicillin-susceptible staphylococci, encompassing S. aureus and 10 different species of CoNS. While all S. aureus isolates with normal morphotypes, including MRSA isolates covering >90% of spa types registered in Europe, were inhibited by ≤2 μg/ml of ceftobiprole, cefuroxime MIC90s for methicillin-resistant staphylococci (MRS) were all greater than 128 μg/ml. By comparison, activity of ceftobiprole was similar to linezolid against MRSA; however, ceftobiprole was slightly more active than the oxazolidinone against methicillin-susceptible strains. While moxifloxacin was the most active agent against MSSA strains, the in vitro activity of the fluoroquinolone against the MRS panel was poor.

The MICs of the agents tested against stable SCVs and their isogenic parent strains with normal morphotypes are shown in Table 2. While the number of SCV isolates tested is limited, it should be stressed that eight different clonal lineages of MRSA with SCV phenotypes and six different clonal lineages of MSSA with SCV phenotypes were included in this study (9). Of interest, antimicrobials were often less active against SCVs tested than their isogenic parent strains, with consistently low MICs for ceftobiprole. This phenomenon has been clearly described for aminoglycosides but has not been demonstrated for cephalosporins, fluroroquinolones, or linezolid (1). Nevertheless, apart from three strains (MICs, 4 μg/ml), all S. aureus isolates with SCV phenotypes, including those exhibiting methicillin resistance, were inhibited by ≤2 μg/ml of ceftobiprole.

MRS, including MRSA isolates with SCV phenotypes, present a major challenge in terms of chemotherapy because effective antimicrobial treatment options for infections caused by these isolates are close to becoming exhausted. In this context, the ability of ceftobiprole to inhibit staphylococci with a methicillin resistance phenotype may be of major clinical importance. Except for three strains with SCV phenotypes, all S. aureus strains tested, including a large number of different spa types, were inhibited by ≤2 μg/ml of ceftobiprole. In fact, the antistaphylococcal activity of ceftobiprole was comparable to that of linezolid, the cephalosporin being even more active against methicillin-susceptible strains than the oxazolidinone. In previous studies testing the activity of ceftobiprole against staphylococci, smaller numbers of resistance phenotypes were tested to challenge the ceftobiprole spectrum and isolates from the same patient were not excluded (5, 7, 8). Of particular importance, multiple isolates of the same strain were not excluded by phenotypic or genomic typing. In contrast, we tested a large number of clonally unrelated strains, which is particularly important for MRSA. Furthermore, a broad spectrum of different, well-characterized staphylococcal species recovered from patients with overt infections, including isolates with SCV phenotypes, were encompassed in the testing. Thus, the range of MICs of antimicrobials documented in this study was broader than those observed in previous studies (7, 8, 14).

Overall, in our study, the newly developed agent ceftobiprole was highly active against both unrelated methicillin-susceptible and -resistant staphylococci, stimulating further evaluation of this agent for therapy of staphylococcal infections.

View this table:
  • View inline
  • View popup
TABLE 1.

Antimicrobial activities of ceftobiprole and selected comparison drugs tested against staphylococci

View this table:
  • View inline
  • View popup
TABLE 2.

Antimicrobial activities of ceftobiprole and selected comparison drugs tested against strain pairs of small-colony variants and their clonally identical parent strains with normal morphotype

ACKNOWLEDGMENTS

We sincerely thank S. Weber and A. Terliesner for expert technical assistance.

FOOTNOTES

    • Received 20 May 2005.
    • Returned for modification 19 July 2005.
    • Accepted 26 July 2005.
  • Copyright © 2005 American Society for Microbiology

REFERENCES

  1. 1.↵
    Baumert, N., C. von Eiff, F. Schaaff, G. Peters, R. A. Proctor, and H. G. Sahl. 2002. Physiology and antibiotic susceptibility of Staphylococcus aureus small colony variants. Microb. Drug Resist.8:253-260.
    OpenUrlCrossRefPubMedWeb of Science
  2. 2.↵
    Becker, K., D. Harmsen, A. Mellmann, C. Meier, P. Schumann, G. Peters, and C. von Eiff. 2004. Development and evaluation of a quality-controlled ribosomal sequence database for 16S ribosomal DNA-based identification of Staphylococcus species. J. Clin. Microbiol.42:4988-4995.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    Chambers, H. F. 2005. Evaluation of ceftobiprole in a rabbit model of aortic valve endocarditis due to methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. Antimicrob. Agents Chemother.49:884-888.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    CLSI (formerly NCCLS). 2005. Performance standards for antimicrobial susceptibility testing; 15th informational supplement (M100-S15). CLSI, Wayne, Pa.
  5. 5.↵
    Deshpande, L., P. R. Rhomberg, T. R. Fritsche, H. S. Sader, and R. N. Jones. 2004. Bactericidal activity of BAL9141, a novel parenteral cephalosporin against contemporary gram-positive and gram-negative isolates. Diagn. Microbiol. Infect. Dis.50:73-75.
    OpenUrlCrossRefPubMedWeb of Science
  6. 6.↵
    Harmsen, D., H. Claus, W. Witte, J. Rothganger, H. Claus, D. Turnwald, and U. Vogel. 2003. Typing of methicillin-resistant Staphylococcus aureus in a university hospital setting by using novel software for spa repeat determination and database management. J. Clin. Microbiol.41:5442-5448.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    Hebeisen, P., I. Heinze-Krauss, P. Angehrn, P. Hohl, M. G. Page, and R. L. Then. 2001. In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci. Antimicrob. Agents Chemother.45:825-836.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    Jones, R. N., L. M. Deshpande, A. H. Mutnick, and D. J. Biedenbach. 2002. In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci. J. Antimicrob. Chemother.50:915-932.
    OpenUrlCrossRefPubMedWeb of Science
  9. 9.↵
    Kipp, F., K. Becker, G. Peters, and C. von Eiff. 2004. Evaluation of different methods to detect methicillin resistance in small-colony variants of Staphylococcus aureus. J. Clin. Microbiol.42:1277-1279.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    Murakami, K., W. Minamide, K. Wada, E. Nakamura, H. Teraoka, and S. Watanabe. 1991. Identification of methicillin-resistant strains of staphylococci by polymerase chain reaction. J. Clin. Microbiol.29:2240-2244.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    Proctor, R. A., D. M. Bates, and P. J. McNamara. 2001. Electron transport-deficient Staphylococcus aureus small-colony variants as emerging pathogens, p. 95-110. In W. M. Scheld, W. A. Craig, and J. M. Hughes (ed.), Emerging infections 5. ASM Press, Washington, D.C.
  12. 12.
    von Eiff, C., K. Becker, D. Metze, G. Lubritz, J. Hockmann, T. Schwarz, and G. Peters. 2001. Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with Darier's disease. Clin. Infect. Dis.32:1643-1647.
    OpenUrlCrossRefPubMedWeb of Science
  13. 13.↵
    von Eiff, C., D. Bettin, R. A. Proctor, B. Rolauffs, N. Lindner, W. Winkelmann, and G. Peters. 1997. Recovery of small colony variants of Staphylococcus aureus following gentamicin bead placement for osteomyelitis. Clin. Infect. Dis.25:1250-1251.
    OpenUrlCrossRefPubMedWeb of Science
  14. 14.↵
    von Eiff, C., and G. Peters. 1999. Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinupristin/dalfopristin and linezolid against staphylococci. J. Antimicrob. Chemother.43:569-573.
    OpenUrlCrossRefPubMedWeb of Science
PreviousNext
Back to top
Download PDF
Citation Tools
Comparative In Vitro Activity of Ceftobiprole against Staphylococci Displaying Normal and Small-Colony Variant Phenotypes
Christof von Eiff, Alexander W. Friedrich, Karsten Becker, Georg Peters
Antimicrobial Agents and Chemotherapy Sep 2005, 49 (10) 4372-4374; DOI: 10.1128/AAC.49.10.4372-4374.2005

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Antimicrobial Agents and Chemotherapy article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Comparative In Vitro Activity of Ceftobiprole against Staphylococci Displaying Normal and Small-Colony Variant Phenotypes
(Your Name) has forwarded a page to you from Antimicrobial Agents and Chemotherapy
(Your Name) thought you would be interested in this article in Antimicrobial Agents and Chemotherapy.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Comparative In Vitro Activity of Ceftobiprole against Staphylococci Displaying Normal and Small-Colony Variant Phenotypes
Christof von Eiff, Alexander W. Friedrich, Karsten Becker, Georg Peters
Antimicrobial Agents and Chemotherapy Sep 2005, 49 (10) 4372-4374; DOI: 10.1128/AAC.49.10.4372-4374.2005
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

Anti-Bacterial Agents
cephalosporins
Genetic Variation
Phenotype
staphylococcal infections
Staphylococcus

Related Articles

Cited By...

About

  • About AAC
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • AAC Podcast
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #AACJournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0066-4804; Online ISSN: 1098-6596