1 Department of Pathology, Hershey Medical Center, PO Box 850, Hershey, PA 17033; 2 Case Western Reserve University, Cleveland, OH 44106, USA
Received 13 September 2002; returned 7 November 2002; revised 7 November 2002; accepted 19 November 2002
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Abstract |
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Keywords: pneumococci, daptomycin, MIC, timekill
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Introduction |
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Because of this worldwide increase in antibiotic resistance, there is a significant need for additional antimicrobial agents to treat infections caused by penicillin-intermediate and penicillin-resistant pneumococci.1,2 Although therapeutic modalities such as ß-lactams, macrolides and quinolones are currently available, in view of the increasing resistance described above, an agent with a unique mechanism of action compared with these three antibiotic classes is desirable.
Daptomycin is a novel lipopeptide that exhibits rapid in vitro concentration-dependent bactericidal activity against most clinically significant Gram-positive bacteria.46 Daptomycin is active against antibiotic-susceptible and -resistant strains, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and antibiotic-resistant pneumococci. The mode of action of daptomycin is unique; it is believed to kill Gram-positive bacteria by disrupting multiple aspects of bacterial plasma membrane function without penetrating into the cytoplasm.4,6
This study was designed to test the activity of daptomycin compared with that of amoxicillin, erythromycin, levofloxacin, linezolid, quinupristin/dalfopristin, penicillin G, teicoplanin and vancomycin against pneumococci using microdilution and timekill methodologies.
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Materials and methods |
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Timekill activities were measured in duplicate, as described previously, for eight pneumococcal strains: two were penicillin susceptible and six penicillin resistant (of which three were erythromycin resistant and two levofloxacin resistant).8 MuellerHinton broth was supplemented as described above, and antibiotic concentrations chosen were 4 x and 2 x MIC, and the MIC for each strain. Growth controls were included in each experiment.8 The initial inoculum for each strain was within the range of 5 x 105 to 5 x 106 cfu/mL. Viability counts of antibiotic-containing cultures were carried out at 0, 1, 6, 12 and 24 h, as described previously.8 Colony counts were carried out on plates yielding 30300 bacterial colonies. The upper limit of sensitivity of colony counts was 300 cfu/mL.8
Timekill assays were analysed by determining the number of strains yielding a log10 cfu/mL of 1 (90% killing), 2 (99% killing) and 3 (99.9% killing) at 1, 6, 12 and 24 h, compared with counts at 0 h. Results are means of two assays. Bactericidal activity was defined as the lowest antibiotic concentration that reduced the original inoculum by
3 log10 cfu/mL (99.9%) at each time period, and bacteriostatic activity was defined as a reduction of <3 log10 cfu/mL in the inoculum concentration.8 For timekill testing with erythromycin, only strains with an erythromycin MIC of
1.0 mg/L were tested. Additionally, two strains with a levofloxacin MIC of 16 mg/L were excluded from levofloxacin timekill assays.
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Results |
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Discussion |
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This study supports a possible role for daptomycin in treating infections caused by antibiotic-susceptible and -resistant pneumococci, irrespective of the susceptibility of the given strain to ß-lactams, macrolides or quinolones. Further studies are warranted on the bactericidal activity of daptomycin against S. pneumoniae, including relationship of kill kinetics with protein binding and pharmacokinetic/pharmacodynamic properties.
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Acknowledgements |
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Footnotes |
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References |
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2
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4 . Fuchs, P. C., Barry, A. L. & Brown, S. D. (2000). Daptomycin susceptibility tests: interpretive criteria, quality control, and effect of calcium on in vitro tests. Diagnostic Microbiology and Infectious Disease 38, 518.[CrossRef][ISI][Medline]
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8 . Pankuch, G. A., Lichtenberger, C., Jacobs, M. R. & Appelbaum, P. C. (1996). Antipneumococcal activities of RP 59500 (quinupristin/dalfopristin), penicillin G, erythromycin, and sparfloxacin determined by MIC and rapid timekill methodologies. Antimicrobial Agents and Chemotherapy 40, 16536.[Abstract]
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Henwood, C. J., Livermore, D. M., Johnson, A. P., James, D., Warner, M., Gardiner, A. et al. (2000). Susceptibility of Gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid. Journal of Antimicrobial Chemotherapy 46, 93140.
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