Division of Infectious Diseases, Geneva University Hospital, CH-1211 Geneva 14, Switzerland
Received 8 January 203; returned 14 February 2003; revised 4 March 2003; accepted 6 April 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Keywords: Gram-positive bacteria, chronic infections, antimicrobial agents
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Daptomycin is a lipopeptide antibiotic with potent in vitro bactericidal activity against a wide range of Gram-positive pathogens, including antibiotic-resistant staphylococci.1720 The mechanism of action of daptomycin is not fully understood, but seems to be distinct from that of major cell wall-active agents, such as ß-lactams and glycopeptides. Daptomycin binds in a calcium-dependent manner to Gram-positive cytoplasmic membranes,21,22 and disrupts membrane function, dissipating membrane potential and inhibiting macromolecular biosynthesis. Daptomycin is uniformly potent against S. aureus clinical isolates in large surveillance studies.2327 The in vivo activity of daptomycin is currently being evaluated in both therapeutic trials and experimental models.19,28 Optimization of daptomycin pharmacokinetics and pharmacodynamics against severe S. aureus infections17,2832 requires maximum efficacy and safety, and the maintenance of bactericidal levels in deep-seated compartments.17,19,33
We previously showed the usefulness of a rat tissue cage model of S. aureus chronic foreign body infections for evaluating various categories of antimicrobial agents such as vancomycin,34 teicoplanin,35 imipenem,36 and several fluoroquinolones including fleroxacin,34 sparfloxacin, temafloxacin, ciprofloxacin,37 levofloxacin and trovafloxacin,38 alone or in combination with rifampicin.34,35,39
In this study, we evaluate the efficacy of a once-daily dosing of daptomycin compared with a twice-a-day regimen of vancomycin in the therapy of experimental chronic foreign body infections due to S. aureus.40
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Strain Rev1 is a spontaneous methicillin-susceptible revertant of MRSA strain MRGR3, a clinical isolate from a patient with catheter-related sepsis. Strain Rev1 was found to be as virulent in the rat model of chronic S. aureus tissue cage infection as its MRSA parental strain.34,37,39 Except for the loss of the methicillin resistance element, strain Rev1 exhibits an antibiotic resistance pattern identical to its MRSA parent, including resistance to penicillin, gentamicin, chloramphenicol, erythromycin, tetracycline and polymyxin B, but susceptibility to clindamycin, rifampicin and all fluoroquinolones.34,37,39
![]() |
Antimicrobial agents |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In vitro studies
MICs of daptomycin and vancomycin for strain Rev1 were determined in cation-adjusted MuellerHinton broth (CAMHB) containing 2025 mg/L Ca2+ and 1012.5 mg/L Mg2+ by the standard broth macrodilution method, with an average inoculum of 106 cfu/mL, as described by the NCCLS.41 For daptomycin MIC, CAMHB was supplemented with additional calcium to a physiological concentration of 50 mg/L Ca2+ (CSMHB).
To screen for the possible carryover effects of each antibiotic during the MBC determinations, 100 µL portions were taken from all tubes with no visible growth. These were subcultured, either undiluted or diluted 10-fold in saline, on MuellerHinton agar (MHA) for 36 h at 37°C. The MBC was defined as the lowest concentration that killed 99.9% of the original inoculum.
Killing kinetic studies
Portions of 100 µL containing 106 cfu of strain Rev1 (obtained from exponential-phase cultures) were added to sterile plastic tubes of 1 mL of either CSMHB or CAMHB that included either daptomycin or vancomycin (4 mg/L), respectively, in a shaking waterbath at 37°C. The number of viable organisms was determined by subculturing 50 µL of 10-fold diluted portions on MHA after 0, 1, 3, 6 and 24 h of incubation. Colonies were enumerated with a laser colony counter (Spiral System) after 48 h of incubation at 37°C. The detection limit was 2 log10 cfu/mL. No significant carryover of antibiotics was observed by using these experimental conditions. To evaluate the impact of tissue cage fluid proteins on the bactericidal activity of daptomycin 4 mg/L, the rate of elimination of strain Rev1 from tubes containing 1 mL of a mixture of CSMHB and sterile tissue cage fluid (pooled from 20 different cages of uninfected animals) in a 1:1 ratio was also recorded.
To evaluate the susceptibility to daptomycin or vancomycin of strain Rev1 recovered from infected tissue cage fluids, the bacteria were isolated from the tissue cage fluids by centrifugation, and were treated with 0.1% Triton X-100 and sonication to disrupt the host cells, as described previously.35 This procedure is used to reduce bacterial clumping, and was shown repeatedly to be harmless for ex vivo bacteria regarding their ability to multiply and their susceptibility to antibiotics.35,42 Thereafter, tissue cage bacteria were exposed to either daptomycin or vancomycin (4 mg/L each) in tubes containing 1 mL of either CSMHB or CAMHB, respectively, supplemented with 50% pooled tissue cage fluid, and their rate of elimination was compared with that of strain Rev1 grown in vitro. To make the comparison with ex vivo bacteria more relevant, bacteria grown in vitro were taken from saline-washed cultures of stationary phase organisms.35,38 The number of viable organisms after 0, 2, 4, 6 and 24 h of incubation was determined, as described above. For each group, the reductions in cfu counts from time zero to further times of incubation were expressed as log10 cfu/mL. The means ± S.E.M. of the
log10 cfu/mL of three independent determinations were analysed for significant differences by unpaired t-tests. Data were considered significant when P < 0.05 using two-tailed significance levels.
Treatment of chronic tissue cage infections
Experiments involving rats were approved by the Ethics Committee of the Faculty of Medicine, University of Geneva, and by the Veterinary Office of the State of Geneva. Four tissue cages were implanted subcutaneously, as described previously,34 in Wistar rats that had been anaesthetized with an intraperitoneal injection of a mixture of ketamine (90 mg/kg) and xylazine (5 mg/kg). At 3 weeks post-implantation, tissue cage fluid was aspirated and checked for sterility. To establish a chronic S. aureus infection, tissue cages were inoculated with 0.1 mL of saline containing 0.2 x 106 to 2 x 106 cfu of a log-phase culture of strain Rev1. Two weeks later, all tissue cages containing more than 105 cfu/mL of fluid were included in the therapeutic protocols.
Rats infected with strain Rev1 were randomized to receive (by the intraperitoneal route for 7 days) either a once-a-day regimen of daptomycin (30 mg/kg) or a twice-a-day regimen of vancomycin (50 mg/kg), or were left untreated.
At 12 h after the last injection of vancomycin or 24 h after the last injection of daptomycin, quantitative cultures of 10-fold serially diluted tissue cage fluids were performed on MHA. To optimize the yield of viable bacteria, tissue cage fluids were sonicated briefly (60 W, 1 min) to disrupt the biofilm and phagocytic cells before the serial dilutions and plating. Plates were incubated for 2448 h at 37°C. The detection limit was 2 log10 cfu/mL of tissue cage fluid. The differences in cfu counts between days 1 and 8 were determined and expressed as log10 cfu/mL. For each treatment group, results were expressed as means ± S.E.M. Comparison of bacterial counts in the different groups was performed by one-way analysis of variance and t-tests corrected for multiple groups. Data were considered significant when P <0.05 using two-tailed significance levels.
Resistance to antimicrobial agents
In initial experiments, the bacteria recovered from cage fluids on day 8 of therapy were screened for the emergence of resistance to daptomycin on MHA. Samples (of 100 µL) of 10-fold-diluted cage fluid were plated onto MHA containing daptomycin 4 mg/L. Plates were incubated for 48 h at 37°C. The detection limit was 1 log10 cfu/mL of tissue cage fluid.
Further analysis of subpopulations that grew on the daptomycin-containing agar from some tissue cages was first performed on colonies recovered from the primary antibiotic-containing plates. The identification of representative individual colonies as S. aureus was assessed by standard microbiological procedures, and their clonal relationship with strain Rev1 confirmed by pulse-field gel electrophoresis (PFGE). The overall antimicrobial susceptibility of 10 colonies isolated from each primary daptomycin-containing plate was compared with strain Rev1 by disc diffusion using MHA, according to NCCLS recommendations. The antibiotics tested were daptomycin (30 µg paper discs provided by Cubist) and 15 commercially available discs containing penicillin, oxacillin, gentamicin, norfloxacin, ciprofloxacin, trovafloxacin, clindamycin, erythromycin, fusidic acid, co-trimoxazole, fosfomycin, rifampicin, vancomycin, teicoplanin or mupirocin. Three additional colonies from each daptomycin-containing plate were tested separately for increased daptomycin MICs, compared with strain Rev1, by a standard broth microdilution test, as recommended by NCCLS, using either CAMHB or CSMBH.41 Finally, the stability of the daptomycin MICs was checked by agar dilution, broth microdilution and macrodilution assays performed on individual colonies that had been stored in skim milk for 612 months at 70°C.
Pharmacokinetics of antimicrobial agents
The pharmacokinetic properties of vancomycin in rat tissue cage fluid have been estimated previously.34 In rats treated with daptomycin, its pharmacokinetic levels in tissue cage fluids were determined at various time intervals (0, 2, 4, 6, 12 and 24 h) on days 4 and 7 of therapy. Similarly, blood levels of rats treated with daptomycin were also determined at various time intervals (0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) after single-dose intraperitoneal administration of the antimicrobial agent. The blood was collected by cardiac puncture into heparinized tubes. Plasma was collected by centrifugation and samples were stored at 20°C until analysis.
Daptomycin analytical assay
Daptomycin was detected using an internal standard of ethylparaben, and was isolated by protein precipitation with methanol, followed by HPLC. The mobile phase consisted of 90% mobile phase A (acetonitrile: 0.5% NH4H2PO4 34:66, v/v) and 10% mobile phase B (acetonitrile: 0.5% NH4H2PO4 20:80, v/v) at a flow rate of 1.5 mL/min. Serum drug concentrations were determined by reverse-phase HPLC using a Metachem Hypersil C8 analytical column and a Waters Xterra RP18 guard column (ANSYS Technologies, Inc., Lake Forest, CA, USA). At a flow rate of 1.5 mL/min, daptomycin shows a retention time of 1416 min. Samples were analysed at 214 nm. The detection of daptomycin concentrations in rat plasma was linear across the range of 7.5400 mg/L. This method has been validated for daptomycin over the concentration range of 3500 mg/L, with a lower limit of quantification equal to the lowest calibration level of 3 mg/L.
The concentrations of daptomycin in rat tissue cage fluid were estimated by a previously described microbiological assay,43 except for the use of Antibiotic medium 11 and Sarcina lutea as the test strain. To avoid a potential bias due to protein binding, all tissue cage fluids were diluted with one volume of PBS. Thus, tissue cage fluid protein concentrations of samples were equivalent to those of daptomycin standards prepared in PBS supplemented with 50% of sterile pooled tissue cage fluid. Under these experimental conditions, the limit of detection of the daptomycin assay was 1 mg/L.
The areas under the concentrationtime curve (AUC) of daptomycin in either plasma or tissue cage fluid were estimated by the linear trapezoidal rule from 024 h (AUC024) on days 4 and 7 of administration of this antimicrobial agent.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The MIC and MBC of daptomycin in CSMHB were 12 and 24 mg/L, respectively, for strain Rev1; the MIC and MBC of daptomycin in the presence of 50% tissue cage fluid added to CSMHB were 2 and 4 mg/L, respectively, for strain Rev1; the MIC and MBC of vancomycin in CAMHB were 1 and 2 mg/L, respectively, for strain Rev1.
Timekill studies performed in CSMHB showed rapid elimination of exponential-phase cultures of strain Rev1 by daptomycin 4 mg/L. The reduction in the viable counts of strain Rev1 by daptomycin exceeded 3 log10 cfu/mL after 3 h (data not shown). A similar reduction in the viable counts of strain Rev1 by daptomycin 4 mg/L was observed in CSMHB supplemented with 50% tissue cage fluid (data not shown).
Pharmacokinetics of antimicrobial agents in tissue cage fluid
At day 4 of therapy, the mean levels of daptomycin in tissue cage fluids (n = 6) of animals treated with daptomycin were 5.4 at time zero, 6.6 at 2 h, 9.8 at 4 h, 11.8 at 6 h, 10.0 at 12 h and 3.4 mg/L at 24 h, respectively, after administration of a 30 mg/kg once-daily regimen (Figure 1). Similar concentrations of daptomycin were recorded at day 7 of therapy (data not shown). Since residual levels of daptomycin were nearly equivalent to the MBC of this antimicrobial agent for strain Rev1, recorded in CSMHB containing 50% tissue cage fluid, the daptomycin once-daily regimen yielded bactericidal levels of daptomycin in infected tissue cage fluids throughout therapy. At day 4 of therapy, the tissue cage fluid AUC024 of daptomycin was 195.8 mgh/L.
|
The average peak and trough tissue cage fluid levels of vancomycin determined in a previous study34 were 12 and 2 mg/L at 4 and 12 h, respectively.
Treatment of chronic tissue cage infections
At the onset of therapy, average bacterial counts for cages infected with strain Rev1 were 6.87 ± 0.28 cfu/mL for controls (n = 24), 6.25 ± 0.17 log10 cfu/mL for animals receiving daptomycin once a day (n = 28), and 6.43 ± 0.13 log10 cfu/mL for animals receiving vancomycin twice a day (n = 35). At the end of the 7 day treatment period, bacterial counts in the tissue cages of control animals showed a slight and non-significant increase of 0.24 ± 0.23 log10 cfu/mL (n = 24). In contrast, both the daptomycin and vancomycin regimens (Figure 2) led to significant reductions in bacterial counts in tissue cage fluids of 1.11 ± 0.25 (n = 28; P = 0.001) and 0.80 ± 0.31 log10 cfu/mL (n = 35; P = 0.02), respectively, compared with tissue cage fluids of control animals. The higher average reduction in cfu counts of rats treated with daptomycin compared with that of vancomycin-treated animals did not reach statistical significance (P = 0.45).
|
To evaluate the bactericidal activity of daptomycin compared with vancomycin against tissue cage fluid organisms of strain Rev1 in conditions relevant to therapy, we assayed, in parallel, the elimination rates of tissue cage and in vitro grown bacteria by 4 mg/L of either antimicrobial agent in the presence of 50% sterile tissue cage fluid in CSMHB. Stationary-phase were preferred to log-phase organisms to make the comparison with ex vivo bacteria more relevant.35,38 Figure 3 shows a significantly (P < 0.001) higher elimination rate of stationary-phase organisms by daptomycin 4 mg/L, compared with vancomycin, during the initial 4 h period of drug exposure, which led to >3 log10 reductions in viable counts at 4 versus 6 h, respectively. However, the most impressive differences in the bactericidal activities of daptomycin compared with vancomycin were seen with bacteria freshly removed from infected cages. During the initial 6 h period of drug exposure, the average reductions in viable counts of tissue cage bacteria by daptomycin 4 mg/L were 2.1 and 2.6 log10 cfu/mL at 4 and 6 h, respectively, compared with 0.3 and 0.6 log10 cfu/mL with vancomycin 4 mg/L (Figure 3). The presence of 50% tissue cage fluid, yielding average protein concentrations of 1015 mg per mL of CSMHB, did not significantly impair the bactericidal activity of daptomycin against bacteria grown in vitro or in vivo. Since tissue cage fluid was uniformly present in all assay conditions, this protein supplement was therefore not responsible for the markedly different elimination of tissue cage bacteria by daptomycin compared with vancomycin.
|
After exclusion of six cages that contained undetectable numbers of bacteria (2 log10 cfu/mL), daptomycin resistance was screened in 22 cage fluids by direct plating of post-therapy tissue cage bacteria on MHA containing daptomycin 4 mg/L. This low concentration of daptomycin, equivalent to its MBC for strain Rev1 in the presence of tissue cage fluid, was selective enough to prevent bacterial growth of post-therapy isolates in 19 of 22 cages of daptomycin-treated animals, whose average viable counts at day 8 were 5.05 ± 0.25 log10 cfu/mL. In contrast, three of the 22 cages whose average viable counts (6.86 ± 0.13 log10 cfu/mL) at day 8 were relatively high, yielded bacterial subpopulations on daptomycin-supplemented MHA with an average frequency of 2.2 x 104. The number of colonies that grew on daptomycin-supplemented MHA from these three cages were 6, 23 and 31 cfu, respectively, yielding an average concentration of 3.21 ± 0.21 log10 cfu/mL. Phenotypical properties (haemolysis, coagulase) and the PFGE pattern of the bacteria grown on daptomycin-supplemented MHA were identical to those of the parental strain Rev1. Further studies of daptomycin resistance phenotypes were performed with the two cages yielding the highest viable counts (>20 cfu per plate) of daptomycin-supplemented MHA.
The stability and homogeneity of the daptomycin resistance phenotypes were evaluated on 10 colonies randomly selected from each daptomycin-supplemented primary plate. We compared their overall antimicrobial susceptibility with that of strain Rev1, using disc diffusion on MHA. Each daptomycin-selected colony exhibited a consistent 34 mm reduction in zone sizes around the daptomycin discs (1920 mm) compared with those recorded around the parental strain Rev1 (23 mm). In contrast, all other zone sizes around 15 additional antibiotic discs were identical for all daptomycin-selected colonies and Rev1, which further confirmed their respective clonal identity.
The resistance phenotypes of six daptomycin-selected colonies were found to be stable after 1 year of storage at 70°C, since the viable counts of all subclones on MHA supplemented with daptomycin 4 mg/L were nearly equivalent to those enumerated on antibiotic-free MHA. In contrast, the cfu counts of strain Rev1 plated on the same daptomycin-containing MHA medium represented only 108 of those on daptomycin-free MHA, thus confirming the low spontaneous emergence of daptomycin resistance in the parental strain.
When tested by the broth microdilution or macrodilution methods in CAMHB adjusted to 50 mg/L Ca2+ or non-adjusted, daptomycin-selected colonies showed average 4-fold and 8-fold increases in daptomycin MICs, respectively, compared with strain Rev1. Similar values were found after 1 year of storage at 70°C, or after repeated passages in daptomycin-free MHB (data not shown).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A useful property of subcutaneous tissue cage models of implant-associated infections due to S. aureus3437,39 or Staphylococcus epidermidis 45,46 is the possibility of the direct assessment of the levels of each antimicrobial agent in tissue cage fluids. This allows direct estimates to be made of the tissue cage concentrationtime profile of each antimicrobial agent in tissue cage fluids. In recent years, pharmacodynamic modelling of the therapeutic efficacies of antimicrobial agents has been developed, and is a powerful tool that combines the pharmacokinetic properties of each agent with the antimicrobial susceptibilities of their microbial targets.47,48 These pharmacodynamic concepts were applied recently to daptomycin in a murine thigh model of S. aureus infection, which indicated that the plasma AUC/MIC ratio was an important predictor of successful microbiological outcome.28 The plasma AUC024 of daptomycin recorded in our tissue cage rat model (which was slightly higher than the average AUC024 of human volunteers receiving a clinical dose of 4 mg/kg)44 falls within the AUC024 values leading to bactericidal activities in the murine thigh S. aureus infection model.28 Despite being 65% lower than that recorded in rat plasma, the tissue cage fluid AUC024 of daptomycin was still sufficient to exert a significant bactericidal effect in the locally infected cage fluids, even against strain Rev1. The efficacy of daptomycin, compared with that of several other antimicrobial agents tested in the hard-to-treat rat model of chronic foreign body infection,3439 was at least equivalent to a larger daily regimen of vancomycin, and is an indication for its good bactericidal activity in vivo. This assumption was confirmed by in vitro testing demonstrating bactericidal activity of daptomycin at 4 mg/L, equivalent to its MBC against strain Rev1. Daptomycin is 90% bound by serum proteins.44 However, in vitro testing indicated that the presence of tissue cage fluid components, which contain serum-derived proteins, did not significantly affect the bactericidal activity of daptomycin at a concentration of 4 mg/L against organisms, collected from either a stationary-phase culture or even freshly removed from infected cage fluids.
Tissue cage grown bacteria frequently express in vivo-induced tolerance to different antibiotics.34,35,42 This in vivo-induced tolerance, which is either not expressed or rapidly disappears under in vitro conditions, is referred to as phenotypical tolerance.49 In contrast to the previously described high level of phenotypical tolerance expressed by tissue cage bacteria against teicoplanin,35 daptomycin still demonstrates a high level of bactericidal activity against the potentially tolerant bacteria.
Since the relatively low concentrations of daptomycin reached in the chronically infected cage fluids, varying only from the MBC to three times the MBC levels, already showed therapeutic efficacy, these data suggest that optimization of the pharmacokinetic and pharmacodynamic parameters to this particular infection model potentially might lead to significantly improved therapeutic responses by reaching higher local levels of daptomycin, as suggested by a recent preliminary report.50
The emergence, in three infected cages, of subpopulations exhibiting decreased susceptibility to daptomycin, compared with the parental strain Rev1, was an interesting microbiological finding whose real clinical significance is still uncertain. A single previous study mentioned the emergence of S. aureus subpopulations exhibiting diminished susceptibility during daptomycin therapy of experimental endocarditis in rabbits.31 These rabbits were treated with suboptimal dosages of daptomycin, which yielded isolates with an increase in MIC value in 13% of rabbits. Trough levels of daptomycin in tissue cage fluid were just equivalent to the MBC for strain Rev1. Animal-to-animal variability cannot exclude that daptomycin levels fell below the MBC in these three rats, allowing emergence of resistant subpopulations.
In conclusion, daptomycin showed an encouraging in vivo efficacy in the rat model of chronic foreign body infections due to S. aureus Rev1, and was equivalent to that of vancomycin. Daptomycin produced significant reductions in the bacterial burden of S. aureus. High tissue levels of daptomycin seem to be required to minimize emergence of subpopulations exhibiting decreased susceptibility to daptomycin. Prediction of the therapeutic efficacies of various antibiotics against foreign body infections may be difficult by relying exclusively on in vitro pharmacodynamic models derived from pharmacokinetic data in the plasma compartment. Our data further emphasize the value of performing experiments in animals for the primary evaluation of new therapeutic agents.
![]() |
Acknowledgements |
---|
This work was supported in part by research grant from Cubist Pharmaceuticals, Inc., Lexington, Mass., and grants 4049063250, 320063710.00 (to P.V.) and 63257950.99 (to J.S.) from the Swiss National Science Foundation.
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2
.
Zimmerli, W., Widmer, A. F., Blatter, M. et al. (1998). Role of rifampin for treatment of orthopedic implant-related staphylococcal infectionsa randomized controlled trial. Journal of the American Medical Association 279, 153741.
3 . Drancourt, M., Stein, A., Argenson, J. N. et al. (1993). Oral rifampin plus ofloxacin for treatment of Staphylococcus-infected orthopedic implants. Antimicrobial Agents and Chemotherapy 37, 121418.[Abstract]
4 . Drancourt, M., Stein, A., Argenson, J. N. et al. (1997). Oral treatment of Staphylococcus spp. infected orthopaedic implants with fusidic acid or ofloxacin in combination with rifampicin. Journal of Antimicrobial Chemotherapy 39, 23540.[Abstract]
5 . Hooper, D. C. (2002). Fluoroquinolone resistance among Gram-positive cocci. Lancet Infectious Diseases 2, 5308.[CrossRef][ISI][Medline]
6 . Norden, C. W. & Shaffer, M. (1983). Treatment of experimental chronic osteomyelitis due to Staphylococcus aureus with vancomycin and rifampin. Journal of Infectious Diseases 147, 3527.[ISI][Medline]
7 . Faville, R. J., Jr, Zaske, D. E., Kaplan, E. L. et al. (1978). Staphylococcus aureus endocarditis. Combined therapy with vancomycin and rifampin. Journal of the American Medical Association 240, 19635.[Abstract]
8 . Bayer, A. S. & Lam, K. (1985). Efficacy of vancomycin plus rifampin in experimental aortic- valve endocarditis due to methicillin-resistant Staphylococcus aureus: in vitroin vivo correlations. Journal of Infectious Diseases 151, 15765.[ISI][Medline]
9 . Acar, J. F., Goldstein, F. W. & Duval, J. (1983). Use of rifampin for the treatment of serious staphylococcal and gram-negative bacillary infections. Reviews of Infectious Diseases 5, Suppl. 3, S5026.[ISI][Medline]
10 . Hiramatsu, K., Aritaka, N., Hanaki, H. et al. (1997). Dissemination in japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 350, 16703.[CrossRef][ISI][Medline]
11
.
Tenover, F. C., Lancaster, M. V., Hill, B. C. et al. (1998). Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides. Journal of Clinical Microbiology 36, 10207.
12 . Hiramatsu, K. (1998). Vancomycin resistance in staphylococci. Drug Resistance Updates 1, 13550.[ISI]
13
.
Johnson, A. P. & Woodford, N. (2002). Glycopeptide-resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 50, 6213.
14 . Centers for Disease Control and Prevention. (2002). Staphylococcus aureus resistant to vancomycinUnited States, 2002. Morbidity Mortality Weekly Report 51, 5657.
15 . Hiramatsu, K. (2001). Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet 1, 14755.
16 . Geisel, R., Schmitz, F. J., Fluit, A. C. et al. (2001). Emergence, mechanism, and clinical implications of reduced glycopeptide susceptibility in Staphylococcus aureus. European Journal of Clinical Microbiology and Infectious Diseases 20, 68597.[CrossRef][ISI][Medline]
17
.
Tally, F. P. & DeBruin, M. F. (2000). Development of daptomycin for Gram-positive infections. Journal of Antimicrobial Chemotherapy 46, 5236.
18
.
Akins, R. L. & Rybak, M. J. (2001). Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrobial Agents and Chemotherapy 45, 4549.
19 . Tally, F. P., Zeckel, M. L., Wasilewski, M. et al. (2001). Daptomycin: a novel agent for Gram-positive infections. Experimental Opinion on Investigational Drugs 8, 122338.
20
.
Fuchs, P. C., Barry, A. L. & Brown, S. D. (2002). In vitro bactericidal activity of daptomycin against staphylococci. Journal of Antimicrobial Chemotherapy 49, 46770.
21
.
Silverman, J. A., Oliver, N., Andrew, T. et al. (2001). Resistance studies with daptomycin. Antimicrobial Agents and Chemotherapy 45, 17991802.
22 . 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]
23
.
King, A. & Phillips, I. (2001). The in vitro activity of daptomycin against 514 Gram-positive aerobic clinical isolates. Journal of Antimicrobial Chemotherapy 48, 21923.
24
.
Snydman, D. R., Jacobus, N. V., McDermott, L. A. et al. (2000). Comparative In vitro activities of daptomycin and vancomycin against resistant gram-positive pathogens. Antimicrobial Agents and Chemotherapy 44, 344750.
25
.
Fuchs, P. C., Barry, A. L. & Brown, S. D. (2001). Evaluation of daptomycin susceptibility testing by Etest and the effect of different batches of media. Journal of Antimicrobial Chemotherapy 48, 55761.
26
.
Wise, R., Andrews, J. M. & Ashby, J. P. (2001). Activity of daptomycin against Gram-positive pathogens: a comparison with other agents and the determination of a tentative breakpoint. Journal of Antimicrobial Chemotherapy 48, 5637.
27
.
Barry, A. L., Fuchs, P. C. & Brown, S. D. (2001). In vitro activities of daptomycin against 2,789 clinical isolates from 11 North American medical centers. Antimicrobial Agents and Chemotherapy 45, 191922.
28
.
Louie, A., Kaw, P., Liu, W. et al. (2001). Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection. Antimicrobial Agents and Chemotherapy 45, 84551.
29 . Kennedy, S. & Chambers, H. F. (1989). Daptomycin (LY146032) for prevention and treatment of experimental aortic valve endocarditis in rabbits. Antimicrobial Agents and Chemotherapy 33, 15225.[ISI][Medline]
30 . Cantoni, L., Glauser, M. P. & Bille, J. (1990). Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination. Antimicrobial Agents and Chemotherapy 34, 234853.[ISI][Medline]
31 . Kaatz, G. W., Seo, S. M., Reddy, V. N. et al. (1990). Daptomycin compared with teicoplanin and vancomycin for therapy of experimental Staphylococcus aureus endocarditis. Antimicrobial Agents and Chemotherapy 34, 20815.[ISI][Medline]
32 . Voorn, G. P., Kuyvenhoven, J., Goessens, W. H. et al. (1994). Role of tolerance in treatment and prophylaxis of experimental Staphylococcus aureus endocarditis with vancomycin, teicoplanin, and daptomycin. Antimicrobial Agents and Chemotherapy 38, 48793.[Abstract]
33
.
Oleson, F. B., Jr, Berman, C. L., Kirkpatrick, J. B. et al. (2000). Once-daily dosing in dogs optimizes daptomycin safety. Antimicrobial Agents and Chemotherapy 44, 294853.
34 . Lucet, J. C., Herrmann, M., Rohner, P. et al. (1990). Treatment of experimental foreign body infection caused by methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 34, 231217.[ISI][Medline]
35 . Schaad, H. J., Chuard, C., Vaudaux, P. et al. (1994). Teicoplanin alone or combined with rifampin compared with vancomycin for prophylaxis and treatment of experimental foreign body infection by methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 38, 170310.[Abstract]
36 . Schaad, H. J., Chuard, C., Vaudaux, P. et al. (1994). Comparative efficacies of imipenem, oxacillin and vancomycin for therapy of chronic foreign body infection due to methicillin- susceptible and -resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 33, 11911200.[Abstract]
37 . Cagni, A., Chuard, C., Vaudaux, P. et al. (1995). Comparison of sparfloxacin, temafloxacin, and ciprofloxacin for prophylaxis and treatment of experimental foreign-body infection by methicilin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 39, 165560.[Abstract]
38
.
Vaudaux, P., Francois, P., Bisognano, C. et al. (2002). Comparison of levofloxacin, alatrofloxacin, and vancomycin for prophylaxis and treatment of experimental foreign-body-associated infection by methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 46, 15039.
39 . Chuard, C., Herrmann, M., Vaudaux, P. et al. (1991). Successful therapy of experimental chronic foreign-body infection due to methicillin-resistant Staphylococcus aureus by antimicrobial combinations. Antimicrobial Agents and Chemotherapy 35, 261116.[ISI][Medline]
40 . Vaudaux, P., Bisognano, C., Francois, P. et al. (2001). Comparative efficacy of daptomycin and vancomycin in the therapy of experimental foreign body infection due to Staphylococcus aureus. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract 790. American Society for Microbiology, Washington, DC, USA.
41 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA, USA.
42 . Chuard, C., Lucet, J. C., Rohner, P. et al. (1991). Resistance of Staphylococcus aureus recovered from infected foreign body in vivo to killing by antimicrobials. Journal of Infectious Diseases 163, 136973.[ISI][Medline]
43 . Bouchenaki, N., Vaudaux, P., Huggler, E. et al. (1990). Successful single-dose prophylaxis of Staphylococcus aureus foreign body infection in guinea pigs by fleroxacin. Antimicrobial Agents and Chemotherapy 34, 214.[ISI][Medline]
44
.
Wise, R., Gee, T., Andrews, J. M. et al. (2002). Pharmacokinetics and inflammatory fluid penetration of intravenous daptomycin in volunteers. Antimicrobial Agents and Chemotherapy 46, 313.
45 . Widmer, A. F., Frei, R., Rajacic, Z. et al. (1990). Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections. Journal of Infectious Diseases 162, 96102.[ISI][Medline]
46
.
Schwank, S., Rajacic, Z., Zimmerli, W. et al. (1998). Impact of bacterial biofilm formation on in vitro and in vivo activities of antibiotics. Antimicrobial Agents and Chemotherapy 42, 8958.
47 . Karabalut, N. & Drusano, G. L. (1993). Pharmacokinetics of the quinolone antimicrobial agents. In Quinolone Antimicrobial Agents (Hooper, D. C. & Wolfson, J. S., Eds), pp. 195223. American Society for Microbiology, Washington, DC, USA.
48 . Turnidge, J. D. (1990). Prediction of antibiotic dosing intervals from in vitro susceptibility, pharmacokinetics and post-antibiotic effect: theoretical considerations. Scandinavian Journal of Infectious Diseases. Supplementum 74, 13741.
49 . Vaudaux, P. (1998). Phenotypic antibiotic tolerance of Staphylococcus aureus in implant-related infections: relationship with in vitro colonization of artificial surfaces. Drug Resistance Updates 1, 3527.[ISI]
50 . Vaudaux, P., Schaad, H., Francois, P. et al. (2003). Efficacy of a high dose regimen of daptomycin compared with oxacillin and vancomycin in the therapy of experimental foreign body infection due to methicillin-susceptible Staphylococcus aureus. In Program and Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Abstract B-274, p. 32. American Society for Microbiology, Washington, DC, USA.