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Reversible daptomycin tolerance of adherent staphylococci in an implant infection model

John, A. K. and Schmaler, M. and Khanna, N. and Landmann, R.. (2011) Reversible daptomycin tolerance of adherent staphylococci in an implant infection model. Antimicrobial agents and chemotherapy, Vol. 55, H. 7. pp. 3510-3516.

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Official URL: http://edoc.unibas.ch/dok/A6005194

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Abstract

Daptomycin (DAP) is bactericidal against methicillin-resistant Staphylococcus aureus (MRSA) in vitro, but it failed to eradicate MRSA in an experimental model of implant-associated infection. We therefore investigated various factors which could explain treatment failure by evaluating DAP activity, including the role of different cell wall components, adherence, biofilm, and calcium ions (Ca(2+)) in vitro and in vivo. In the tissue cage infection model, DAP was active only prophylactically and against low inocula. To identify the mechanisms of treatment failure, the in vitro activity of DAP against planktonic and adherent growing S. aureus and S. epidermidis mutants, differing in their capacity of biofilm formation and adherence, was determined. For planktonic staphylococci, the MIC was 0.625 ?g/ml. For adherent staphylococci, DAP reduced biofilms at 30 ?g/ml. However, it did not kill adherent bacteria up to 500 ?g/ml, independent of biofilm biosynthesis (the ica mutant strain), nuclease (the nuc1/nuc2 mutant strain), LPXTG-anchored adhesin (the srtA mutant strain), autolysin (the atl mutant strain), or alanyl-LTA (the dltA mutant strain). Resistance of adherent staphylococci was not due to mutations of adherent bacteria, since staphylococci became DAP susceptible after detachment. Phenotypic tolerance was not explained by inactivation of DAP or inability of initial Ca(2+)-DAP complex formation. However, the addition of up to 100 mg/liter (2.5 mmol/liter) Ca(2+) gradually improved bactericidal activity toward adherent staphylococci in vitro and increased the prevention rate in the cage model from 40% to 60%. In summary, adherent staphylococci are resistant to DAP killing unless Ca(2+) is supplemented to physiologic concentrations.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Infektiologie
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Infektiologie
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Infection Biology (Khanna)
UniBasel Contributors:Khanna, Nina
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 May 2015 08:44
Deposited On:06 Dec 2013 09:36

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