JAC Advance Access originally published online on February 25, 2004
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Journal of Antimicrobial Chemotherapy (2004) 53, 669-674
© 2004 The British Society for Antimicrobial Chemotherapy
Daptomycin activity and spectrum: a worldwide sample of 6737 clinical Gram-positive organisms
1 The JONES Group/JMI Laboratories, Inc., 345 Beaver Kreek Centre, Suite A, North Liberty, Iowa 52317; 2 Tufts University School of Medicine, Boston, MA, USA
Received 21 October 2003; returned 24 November 2003; revised 8 January 2004; accepted 15 January 2004
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Abstract |
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Background: Increasing antimicrobial resistance among bacterial pathogens has prompted attempts to develop new antimicrobial agents active against multidrug-resistant Gram-positive pathogens.
Objectives: To evaluate the in vitro activity of daptomycin against a worldwide collection of clinical bacterial isolates.
Methods: Daptomycin is a novel cyclic lipopeptide recently approved by the United States Food and Drug Administration. Daptomycin and selected comparators were tested against 6737 clinical Gram-positive strains from more than 70 centres located in Europe, North America and South America.
Results: The overall distribution of daptomycin MIC values were in the range 
0.12–8 mg/L and 99.4% of all strains were inhibited at 2 mg/L. Despite resistances to other antimicrobial agents, >99.9% of staphylococcal isolates were inhibited at 1 mg/L of daptomycin (MIC90 0.5 mg/L for staphylococci). Streptococcal isolates were very susceptible to daptomycin independent of their susceptibility to penicillin. MIC50/90 values were 0.12 and 0.25 mg/L, respectively. Enterococci showed the highest daptomycin MIC values, but all isolates tested were inhibited at 4 mg/L (except for one Enterococcus faecium isolate which showed a daptomycin MIC of 8 mg/L).
Conclusions: Daptomycin exhibited excellent in vitro activity against a wide spectrum of Gram-positive organisms and may represent a therapeutic option for infections caused by multidrug-resistant pathogens worldwide.
Keywords: resistance, glycopeptides, multidrug-resistant
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Introduction |
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Increasing resistances have created a need for the development of new antimicrobial agents.1 Daptomycin, formerly LY146032, is a novel cyclic lipopeptide antibiotic naturally produced by Streptomyces rosesporus.2 Daptomycin acts at the cytoplasmic membrane of susceptible bacteria and its activity is dependent on physiological levels of free calcium ions (50 mg/L).3 However, daptomycin’s mechanism of action has not been completely elucidated. Silverman et al.3 have recently shown that daptomycin inserts into the bacterial cytoplasmic membrane in a calcium-dependent fashion, forms oligomers and disrupts the functional integrity of the cytoplasmic membrane, triggering a release of intracellular ions and rapid cell death. This mechanism of action is novel compared with classes of antimicrobial agents currently marketed and no cross-resistance with any other drug class has been demonstrated.2,3
With a half-life of 
8 h in humans, once-daily dosing trials are underway.2,4 In dosing studies in healthy volunteers, daptomycin was well tolerated at one dose of multiple concentrations (4, 6 or 8 mg/kg every 24 h).5 In addition, daptomycin has shown linear pharmacokinetics with consistent and predictable plasma concentrations.5
Daptomycin has rapid in vitro bactericidal activity against a wide spectrum of Gram-positive organisms. This spectrum includes multidrug-resistant strains—such as vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant streptococci—for which there are very few therapeutic alternatives.2 In addition, this compound has shown poor in vitro activity against Gram-negative bacteria. In the present study, we evaluated the in vitro activity of daptomycin against a contemporary worldwide collection of Gram-positive strains collected in 2002, including multidrug-resistant strains.
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Materials and methods |
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Bacterial isolates
A total of 6737 clinical Gram-positive strains were collected from more than 70 centres located in Europe, North America and South America in 2002. The collection included Staphylococcus aureus (3202 strains; 38.9% oxacillin-resistant); coagulase-negative staphylococci (CoNS; 838 strains; 79.8% oxacillin-resistant), Enterococcus faecalis (646 strains; 3.1% vancomycin-resistant), Enterococcus faecium (152 strains; 36.2% vancomycin-resistant), ß-haemolytic streptococci (247 strains); viridans group streptococci (149 strains; 20.8% penicillin-non-susceptible), Strepto- coccus pneumoniae (1424 strains; 28.5% penicillin-non-susceptible), Streptococcus bovis (16 strains) and other Gram-positive species (42). The pathogens were non-duplicate clinical isolates collected from bloodstream, respiratory tract, skin and soft tissue, and urinary tract infections.
Susceptibility testing
The strains were tested by NCCLS M7-A6 broth microdilution methods.6,7 Daptomycin and more than 20 comparator agents were tested in dry-form microdilution panels manufactured by TREK Diagnostics Systems (Cleveland, OH). The test medium was Mueller–Hinton broth adjusted to contain physiological levels of calcium (50 mg/L) for testing daptomycin as recommended by Fuchs et al.8 Daptomycin-susceptible breakpoints of 1 and 4 mg/L were used for S. aureus and vancomycin-susceptible E. faecalis, respectively, as recently approved by the Food and Drug Administration (FDA).9 No breakpoints have been established by the NCCLS or FDA for other organisms evaluated in the present study. The following quality control organisms were tested weekly: S. pneumoniae ATCC strain 49619, E. faecalis ATCC 29212, S. aureus ATCC 29213, Escherichia coli ATCC 25922, E. coli ATCC 35218, and Pseudomonas aeruginosa ATCC 27853.
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Results |
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The overall distribution of daptomycin MICs is shown in Table 1. Daptomycin MICs were in the range
0.12–8 mg/L, and 99.4% of isolates tested were inhibited at 2 mg/L. Only two isolates showed daptomycin MICs of 8 mg/L (one E. faecium and one Bacillus spp.), and only enterococci (38 isolates) and Listeria spp. (one isolate) showed daptomycin MICs of 4 mg/L. All other isolates were inhibited at 2 mg/L. Table 2 shows the in vitro activity of daptomycin in comparison to other antimicrobial agents against Gram-positive organisms worldwide.
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Activity against staphylococci
Daptomycin was highly active against both S. aureus and CoNS (MIC50 0.25 mg/L and MIC90 0.5 mg/L for both). Among S. aureus (3202 isolates), 38.9% of isolates were resistant to oxacillin, whereas among CoNS (838 strains), oxacillin resistance was demonstrated by 79.8% of strains. Daptomycin was equally active against both oxacillin-resistant and oxacillin-susceptible staphylococci (Table 1). Only two isolates of S. aureus (0.1%) and two isolates of CoNS (0.2%) were considered non-susceptible (MIC 2 mg/L) based on the susceptible breakpoint recently approved by the FDA (1 mg/L).9
Only vancomycin and linezolid were active against 100.0% of S. aureus (MIC90 1 and 2 mg/L, respectively) and CoNS (MIC90 2 and 1 mg/L, respectively) strains at the susceptible breakpoint.
Activity against enterococci
Daptomycin and linezolid were the most active compounds overall against enterococci. Daptomycin activity against enterococci was not affected by vancomycin resistance (Table 1). Daptomycin was the only compound that inhibited all E. faecalis isolates at the susceptible breakpoint (4 mg/L),9 and all vancomycin-resistant E. faecalis were inhibited at 1 mg/L of daptomycin (Table 1). Daptomycin was also the most active compound against vancomycin-resistant E. faecium (all isolates were inhibited at 4 mg/L) followed by linezolid (98.2% susceptible) and quinupristin/dalfopristin (90.9% susceptible; data not shown).
Activity against streptococci
These pathogens were very susceptible to daptomycin with the highest MIC value being 1 mg/L (15 strains; 0.8%). MIC50/90s were 0.12 and 0.25 mg/L, respectively, for both S. pneumoniae and ß-haemolytic streptococci, and 0.25 and 0.5 mg/L for viridans group streptococci. Among S. pneumoniae, 28.5% of strains were non-susceptible to penicillin (MIC 
0.12 mg/L), but resistance to penicillin did not affect the activity of daptomycin. Only daptomycin, vancomycin and linezolid were active against all streptococcal isolates at the susceptible breakpoint (Table 2).6,7
Activity against other Gram-positive organisms
Corynebacterium spp. were highly susceptible to daptomycin (MIC90 0.25 mg/L), whereas most Bacillus spp. (MIC90 2 mg/L) and Listeria spp. (MIC90 2 mg/L) isolates tested showed daptomycin MICs of 1–2 mg/L.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgmentsReferences |
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Antimicrobial resistance trends among bacterial pathogens have increased rapidly over the last decade. The SENTRY Program has identified an important increase in the prevalence of oxacillin-resistant S. aureus over the last 5 years. In addition, staphylococcal isolates resistant to linezolid and vancomycin—antimicrobials that have been the foundation of treating serious Gram-positive infections—have been increasingly detected.1 Trends in penicillin and erythromycin resistance among S. pneumoniae bloodstream isolates increased 6.2% and 5.8%, respectively, over a 5 year period.1 These rapid increases of antimicrobial resistance in Gram-positive pathogens has led to increased pressure for newer antimicrobial development with novel mechanisms of bactericidal activity.
Daptomycin is a novel antimicrobial agent with rapid in vitro bactericidal activity against a wide spectrum of Gram-positive pathogens.10 This drug has a unique mechanism of action that targets the bacterial membrane, and cross-resistance has not been observed with any other drug class.2,3 The in vitro activity of this compound is dependent upon the calcium ion content of the culture medium.2 The mechanism underlying this observation is poorly understood, and it has been thought that Ca2+ may aid penetration of the bacterial membrane.2,3 As the physiological concentration of calcium in the body is 45–55 mg/L, this calcium dependence is an important testing issue.
This compound has been recently approved by the FDA for the treatment of complicated skin and skin structure infections caused by susceptible strains of S. aureus (methicillin-susceptible and -resistant), vancomycin-susceptible E. faecalis, Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus dysgalactiae subsp. equisimiles.9 All MRSA (1247 isolates tested) and >99.9% of methicillin-susceptible S. aureus (MSSA) isolates tested in the present study were considered susceptible based on the FDA-approved susceptible breakpoint for these organisms (1 mg/L). Two out of 1955 MSSA isolates showed a daptomycin MIC of >1 mg/L (MIC 2 mg/L for both strains). Among the E. faecalis, all isolates tested (n = 646) were considered susceptible to daptomycin (MIC 4 mg/L), including the vancomycin-resistant strains. E. faecium (MIC90 4 mg/L) isolates showed slightly higher daptomycin MICs when compared to E. faecalis (MIC90 1 mg/L), but only one E. faecium isolate (0.6%) showed daptomycin MIC at >4 mg/L. In addition, all streptococcal isolates tested were very susceptible to daptomycin, including penicillin-resistant strains.
Daptomycin has displayed linear pharmacokinetics, long half-life (8–9 h) and high protein binding (92%), which allows for once-daily dosing. This compound [4 mg/kg intravenously (iv) every 24 h] showed similar results to both vancomycin (1 g iv every 12 h) or semi-synthetic penicillin (i.e. nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4–12 g iv per day) for the treatment of complicated skin and skin structure infection.4,5,9 In addition, daptomycin seems to be well tolerated with only mild adverse effects.5,9 The most frequent adverse event reported in the Phase III clinical trials were gastrointestinal disorders, especially constipation.5,9 Pre-clinical studies indicated that skeletal muscle is the primary target of dose-related toxicity. Muscle weakness, myalgia and creatinine kinase elevation has been reported after 7–12 days of treatment. However, these effects reversed rapidly and completely following discontinuation of the drug.5
The data presented show excellent daptomycin in vitro activity against a wide spectrum of Gram-positive pathogens and its activity against enterococci, staphylococci and streptococci was not affected by resistance to vancomycin, quinupristin/dalfopristin, oxacillin or penicillin. The results of the present study, coupled with the results of previous microbiology, pharmacology and clinical investigations indicate that this compound represents an acceptable therapeutic option for infections caused by Gram-positive cocci, especially multiresistant strains that have appeared worldwide.
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Acknowledgments |
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We would like to thank Kay Meyer and Mondell Beach for their technical help. This study was supported by an educational/research grant from Cubist Pharmaceuticals.
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Footnotes |
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* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; Email: helio-sader{at}jmilabs.com
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References |
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1 . Jones, R. N. (2003). Global epidemiology of antimicrobial resistance among community-acquired and nosocomial pathogens: a five-year summary from the SENTRY Antimicrobial Surveillance Program (1997–2001). Seminars in Respiratory and Critical Care Medicine 24, 121–33.
2 . Thorne, G. M., & Alder, J. (2002). Daptomycin: a novel lipopeptide antibiotic. Clinical Microbiology Newsletter 24, 33–9.[CrossRef]
3
.
Silverman, J. A., Perlmutter, N. G. & Shapiro, H. M. (2003) Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 47, 2538–44.
4
.
Dandekar, P. K., Tessier, P. R., Williams, P. et al. (2003). Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model. Journal of Antimicrobial Chemotherapy 52, 405–11.
5
.
Dvorchik, B. H., Brazier, D., DeBruin, M. F. et al. (2003). Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrobial Agents and Chemotherapy 47, 1318–23.
6 . National Committee for Clinical Laboratory Standards. (2003). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Approved Standard M7-A6. NCCLS, Wayne, PA, USA.
7 . National Committee for Clinical Laboratory Standards. (2003). Performance Standards for Antimicrobial Susceptibility Testing—13th Information Supplement M100-S13. NCCLS, Wayne, PA, USA.
8 . 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, 51–8.[CrossRef][Web of Science][Medline]
9 . Package insert. (2003). Cubicin (daptomycin for injection). Lexington MA. [Cubist Pharmaceuticals, Inc.] Available at http://www.cubist.com/shared/cubicin_label.pdf. (22 September 2003, date last accessed).
10
.
Critchley, I. A., Blosser-Middleton, R. S., Jones, M. E. et al. (2003). Baseline study to determine in vitro activities of daptomycin against Gram-positive pathogens isolated in the United States in 2000–2001. Antimicrobial Agents and Chemotherapy 47, 1689–93.
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