JAC Advance Access originally published online on November 25, 2005
Journal of Antimicrobial Chemotherapy 2006 57(1):116-121; doi:10.1093/jac/dki422
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Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function
1 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; 2 Detroit Medical Center, Detroit, MI 48201, USA; 3 School of Medicine, Wayne State University, Detroit, MI 48201, USA
* Correspondence address. Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA. Tel: +1-313-577-4376; Fax: +1-313-577-8915; E-mail: m.rybak{at}wayne.edu
Received 8 March 2005; returned 2 August 2005; revised 11 August 2005; accepted 27 October 2005
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Abstract |
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Objectives: Daptomycin is a lipopeptide antimicrobial that is primarily excreted by the kidney. We examined daptomycin bactericidal activity in an in vitro pharmacodynamic model (IVPM) under normal and simulated impaired renal function against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA).
Methods: Two clinical strains MSSA-1199 and MRSA-494 were used in an IVPM. MICs and MBCs were determined according to CLSI. Daptomycin free concentrations were simulated that corresponded to dose regimens of 4, 6 and 8 mg/kg every 24 h at 8 h t1/2 (Scheme I) and every 48 h at 30 h t1/2 (Scheme II). In addition, we simulated daptomycin free concentrations corresponding to fractional dose regimens of 2, 3 and 4 mg/kg every 24 h at 30 h t1/2 (Scheme III). The targeted Cmax free/MIC for 2, 3, 4, 6 and 8 mg/kg against MSSA-1199 ranged from 5.2 to 21.2. The targeted Cmax free/MIC for 2, 3, 4, 6 and 8 mg/kg against MRSA-494 ranged from 10.4 to 42.2. The targeted AUCfree/MIC for Schemes I, II and III against MSSA-1199 ranged from 94 to 392. The targeted AUCfree/MIC for Schemes I, II and III against MRSA-494 ranged from 188 to 581. Bactericidal activity and the potential for resistance were determined over 96 h. All models were completed in triplicate.
Results: Daptomycin MICs (MBCs) for MSSA-1199 and MRSA-494 were 0.5 (1.0) mg/L and 0.25 (0.25) mg/L, respectively. Daptomycin 6 and 8 mg/kg at both 8 and 30 h t1/2 achieved 99.9% kill as early as 1 h. Daptomycin 4 mg/kg achieved 99.9% kill as early as 1 h when given at 8 and 30 h t1/2 but was not maintained to an endpoint of 96 h (P > 0.05).
Conclusions: Overall, there was no difference in kill noted for daptomycin regimens at 4, 6 and 8 mg/kg every 24 h at 8 h t1/2 versus every 48 h at 30 h t1/2. Fractional doses of daptomycin at 30 h t1/2 were inferior to daptomycin regimens of 4, 6 and 8 mg/kg administered every 48 h (P = 0.03).
Keywords: bactericidal activity , dose fractionation , lipopeptides
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Daptomycin is a cyclic lipopeptide antibiotic derived from the fermentation product of Streptomyces roseosporus.1–7 Daptomycin was recently approved by the United States Food and Drug Administration for the treatment of complicated skin and skin structure infections caused by Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA)1–4,8,9 at a dose of 4 mg/kg every 24 h. Dosage of 6 mg/kg every 24 h is being investigated for the treatment of bacteraemia and endocarditis.
Daptomycin has a unique mechanism of action disrupting the bacterial plasma membrane function without penetrating the cytoplasmic membrane. This action results in rapid cell death.6,10–14 In addition, it exhibits rapid bactericidal activity against a broad spectrum of Gram-positive pathogens.1–3,5–7,10–12,15–22 Daptomycin is primarily excreted unchanged by the kidneys.1–3,5,12,23 Dvorchik et al. demonstrated that 80% of the drug is excreted by the kidneys with 50% of the total dose recovered in urine.1,2,5 Current dosage recommendations are for individuals with creatinine clearance <30 mL/min, including patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or haemodialysis are 4 mg/kg every 48 h.2 The pharmacodynamic impact of dosing daptomycin under a prolonged half-life condition, however, has not been evaluated.
Therefore, we conducted a study to examine the in vitro activity of daptomycin at 4, 6 and 8 mg/kg every 24 and 48 h versus fractional doses of 2, 3 and 4 mg/kg every 24 h under normal and simulated renal impaired conditions against S. aureus in an in vitro pharmacodynamic model (IVPM).
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Materials and methods |
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Bacterial strains
Two clinical strains of S. aureus were evaluated, one MSSA (MSSA-1199) and one MRSA (MRSA-494). Dr Glenn W. Kaatz (from John D. Dingell VA Medical Center in Detroit, MI, USA) provided both strains.
Antimicrobial
Daptomycin analytical powder was provided by Cubist Pharmaceuticals, Inc., Lexington, MA, USA.
Susceptibility testing and medium
MICs and MBCs were determined by broth microdilution supplemented according to CLSI guidelines.24 All samples were incubated at 37°C for 24 h. Mueller–Hinton broth (SMHB; Difco Laboratories, Detroit, MI, USA) supplemented with 12.5 mg/L magnesium and adjusted to physiological ionized calcium concentration according to CLSI guidelines was used for all IVPMs to evaluate daptomycin.24 This was owing to daptomycin dependency on calcium for its mechanism of action. Colony counts were determined using tryptic soy agar plates (TSA; Difco Laboratories).
IVPMs
The IVPM consists of a 250 mL one-compartment glass chamber with multiple ports for the removal of SMHB, delivery of antibiotics, and collection of bacterial and antimicrobial samples. All experiments were conducted over 96 h and were performed in triplicate to ensure reproducibility. Prior to each experiment, bacterial colonies from an overnight growth on TSA were added to SMHB to obtain a suspension corresponding to a 0.5 McFarland standard. Then 2.5 mL of this suspension was added to each of the pharmacodynamic models to produce a starting inoculum of 1 x 106 cfu/mL. The model was placed in a 37°C water bath for the duration of the experiment, with magnetic stir bars in the medium to allow for continuous mixing. A peristaltic pump (Masterflex; Cole-Parmer Instrument Company, Chicago, IL, USA) was used to continually replace antibiotic-containing medium with fresh SMHB at a rate to simulate the half-lives of the antibiotic. Antimicrobial was infused over 
1 min. Simulated regimens were as follows: Scheme I consisted of daptomycin 8 mg/kg every 24 h [D8-24-8 = dose-dosing interval-simulated t1/2 (Cmax free : t1/2 = 10.6 mg/L : 8 h)], daptomycin 6 mg/kg every 24 h [D6-24-8 (7.9 mg/L : 8 h)] and daptomycin 4 mg/kg every 24 h [D4-24-8 (4.6 mg/L : 8 h)]; Scheme II consisted of daptomycin 8 mg/kg every 48 h [D8-48-30 (10.6 mg/L : 30 h)], daptomycin 6 mg/kg every 48 h [D6-48-30 (7.9 mg/L : 30 h)] and daptomycin 4 mg/kg every 48 h [D4-48-30 (4.6 mg/L : 30 h)]; and Scheme III consisted of daptomycin 4 mg/kg every 24 h [D4-24-30 (4.6 mg/L : 30 h)], daptomycin 3 mg/kg every 24 h [D3-24-30 (4.0 mg/L : 30 h)] and daptomycin 2 mg/kg every 24 h [D2-24-30 (2.6 mg/L : 30 h)].2
Antibiotic assays
Daptomycin concentrations were determined by microbioassay utilizing Micrococcus luteus ATCC 9341 as the reference organism.15 Standards and samples were tested in duplicate using blank 0.25 inch discs saturated with 20 µL of the appropriate solution. The discs were then placed on Antibiotic Assay Medium #1 (AAM-1; Difco Laboratories) agar plates impregnated with 50 mg/L calcium pre-swabbed with a 0.5 McFarland suspension of the reference organism, forming a confluent lawn. The plates were incubated at 37°C for 24 h, at which time the zones of inhibition were measured. Daptomycin bioassay standard antibiotic concentrations were 12, 10, 8, 6, 4, 2, 1.0 and 0.5 mg/L, with 0.5 mg/L used as the lower limit of detection owing to the limitation of the blank disc size. The between day coefficient of variation was <10% for all daptomycin regimens.
Pharmacokinetic analysis
Antibiotic concentrations were determined from duplicate samples drawn from each model at 0, 0.5, 1, 2, 4, 6, 8, 24, 28, 32, 48, 56, 72 and 96 h. Samples were stored at –70°C until analysis. Antibiotic peak concentrations, trough concentrations and t1/2 were calculated using concentration–time plots of the model samples. The free area under the concentration–time curve from 0 to 24 h (AUC0–24 free) was calculated using the linear trapezoid method and the PKAnalyst program (Version 4.90; MicroMath Scientific Software, Salt Lake City, UT, USA).
Pharmacodynamic analysis
Samples (1.5 mL each) from each model were collected at 0, 1, 2, 4, 6, 8, 24, 28, 32, 48, 52, 56, 72, 76, 80 and 96 h and serially diluted with cold saline. Bacterial counts were determined by plating 100 µL aliquots of each diluted sample on TSA, using an automated spiral dispenser (Whitley Automatic Spiral Plater; Don Whitley Scientific Limited, West Yorkshire, UK). All samples were diluted 10–100-fold before plating in order to minimize antibiotic carryover or by plating on vacuum filtration (sample washed through a 0.45 micron filter with normal saline) if the sample had a predicted concentration close to the MIC for the experiment organisms. Plated samples were then incubated at 37°C for 24 h and colony counts (log10 cfu/mL) were determined using a laser bacteria colony counter (ProtoCOL, Version 2.05.02; Synbiosis, Cambridge, UK). The limit of detection for this method of colony count determination is 2 log10 cfu/mL. Time–kill curves were determined by plotting mean colony counts (log10 cfu/mL) from each model versus time. Bactericidal activity (99.9% kill) was defined as 
3 log10 cfu/mL reductions in colony count from the starting inoculum. Reductions in colony counts were determined over a 96 h period and were compared between regimens. Time to achieve 99.9% killing was determined by visual inspection of the model time–kill plots.
Detection of resistance
Samples (100 µL each) from each time point were plated onto TSA containing daptomycin at a concentration from four to eight times the MIC for each organism and were incubated for 48 h at 37°C in order to monitor for the development of resistance. Plates were visually inspected for growth of resistant subpopulations after 24, 32, 48, 56, 72, 80 and 96 h of incubation.
Statistical analysis
Differences between regimens (log10 cfu/mL at 96 h), time to 99.9% kill and all pharmacodynamic variables were determined using ANOVA with Tukey post-test for multiple comparisons. For all experiments, a P value of 
0.05 was considered indicative of statistical significance. All statistical analyses were performed using SigmaPlot (Version 8.0) and SPSS (Version 11.5), SPSS, Inc., Chicago, IL, USA.
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Results |
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Susceptibility testing
The microdilution MICs (MBCs) of daptomycin for MSSA-1199 and MRSA-494 were 0.5 mg/L (1.0) and 0.25 mg/L (0.25).
Pharmacokinetics
The mean half-lives (± SD) were as follows: once daily regimen (7.93 ± 0.44 h) and once every 48 h as well as fractional dose regimens (29.95 ± 2.13 h). All the achieved values for Cmax free and half-life were within 10% of the targeted value.
Pharmacodynamics
The pharmacodynamic results are graphically depicted in Figure 1. Scheme I daptomycin against MSSA-1199 achieved 99.9% kill as early as 1 h with 3.65, 3.81 and 3.70 log10 cfu/mL decreases for D8-24-8, D6-24-8 and D4-24-8, respectively. While D8-24-8 and D6-24-8 remained at the limit of detection to the 96 h endpoint, observed regrowth was noted for D4-24-8 after 8 h (P = 0.014). Scheme II daptomycin D8-48-30, D6-48-30 and D4-48-30 against MSSA-1199 produced similar affects with 4.13, 4.12 and 3.52 log10 cfu/mL decreases, respectively. Though not significant, D8-48-30 and D6-48-30 maintained bactericidal activity to 96 h whereas D4-48-30 did not. No difference in kill or regrowth was noted between any regimens in Scheme I compared with Scheme II. Scheme III daptomycin D4-24-30, D3-24-30 and D2-24-30 against MSSA-1199 achieved 99.9% kill as early as 1 h with 3.94, 3.38 and 3.09 log10 cfu/mL decreases, respectively. However, regrowth was observed after 24 h for all regimens in Scheme III. Overall kill at 96 h and regrowth for Scheme III was noted to be inferior to Scheme I and Scheme II regimens (P = 0.03).
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Against MRSA-494, Scheme I and Scheme II daptomycin D8-24-8, D6-24-8, D4-24-8, D8-48-30, D6-48-30 and D4-48-30 achieved 99.9% kill as early as 1 h with 3.91, 3.95, 4.04, 3.79, 4.07 and 3.35 log10 cfu/mL decreases, respectively. Scheme III daptomycin D4-24-30, D3-24-30 and D2-24-30 against MRSA-494 achieved 99.9% kill as early as 1 h with 3.44, 3.22 and 3.69 log10 cfu/mL decreases, respectively. The impact of fractional dose regimens for MRSA-494 was similar to the results obtained with MSSA-1199. Throughout the study, concentration-dependent activity was demonstrated for all regimens/schemes tested post initial dose and via suppression of regrowth.
Pharmacodynamic parameters with the free area under the concentration–time curve divided by MIC (AUCfree/MIC) and maximum concentration of free drug in serum divided by MIC (Cmax free/MIC) are shown in Table 1. Against MSSA-1199, the AUCfree/MIC ranges 100–212 for Scheme I, 167–402 for Scheme II and 101–168 for Scheme III. Against MRSA-494, the AUCfree/MIC ranges 200–424 for Scheme I, 335–804 for Scheme II and 202–337 for Scheme III. The Cmax free/MIC against MSSA-1199 for Schemes I, II and III ranges 9.66–21.4, 9.29–21.2 and 5.44–9.11, respectively. Against MRSA-494, the Cmax free/MIC for Schemes I, II and III ranges 19.3–42.9, 18.6–42.3 and 10.9–18.2, respectively.
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Detection of resistance
There was no evidence of daptomycin resistance observed for any of the samples at the 24, 32, 48, 56, 72, 80 and 96 h time points.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Daptomycin is a lipopeptide with a unique mechanism of action that was recently approved for the treatment of complicated skin and skin structure infections cause by Gram-positive pathogens. It possesses potent concentration-dependent bactericidal activity against multidrug-resistant Gram-positive pathogens, including MRSA as well as vancomycin-resistant S. aureus.1,3,11,25
Dvorchik et al.2 using population pharmacokinetic analysis demonstrated that renal function was the most significant interindividual factor that contributed to the variability observed with daptomycin concentrations. They concluded that dosage adjustment is necessary for patients with severe renal disease as well as those on dialysis owing to the reduced clearance of daptomycin.
Our study attempted to determine the impact of a simulated prolonged half-life on the pharmacodynamics of daptomycin against MSSA and MRSA over a 4 day period. We observed equivalent bactericidal killing with daptomycin at 4, 6 and 8 mg/kg every 24 and 48 h delivered at 8 and 30 h t1/2 against both strains. The fractional dose Scheme III, although initially bactericidal, demonstrated inferior and more variable killing activity with regrowth observed shortly after 24 h compared with Schemes I and II (P < 0.05).
Daptomycin exhibits linear pharmacokinetics in vivo as demonstrated from previous studies.3,21,23 Studies evaluating doses of 4–8 mg/kg in healthy volunteers have observed AUC0–24 ranging from 425 to 1127 µg·h/mL.2,3,23 Both Cmax/MIC and AUC0–24/MIC have been demonstrated to be the pharmacodynamically linked parameters for daptomycin.7,12,16,26 In a neutropenic murine thigh infection model examining the efficacy of daptomycin against S. aureus, Streptococcus pneumoniae and Enterococcus, Safdar et al.7 reported that Cmax/MIC ratios of 59–94 and AUC/MIC ratios of 388–537 were correlated with successful outcome. Investigators examining a range of dosing regimens against S. aureus and Enterococcus isolates determined that an AUCfree/MIC ratio of 189 achieved 80% maximal kill (ED80).27 A Monte Carlo prediction model determined that the probability of achieving this ratio in a clinical setting was 80.4, 91.1 and 95.6% for doses of 4, 6 and 8 mg/kg every 24 h in patients with normal renal function.27 Louie et al.26 described the pharmacodynamics of daptomycin in a neutropenic mouse thigh model using fractionated doses administered every 6, 12 and 24 h. Their data suggested that 80% maximal kill could be achieved with AUC/MIC ratios of 245.5 and 516.5 and that these targets would be readily exceeded in most patients by a dose of 6 mg/kg every 24 h.
In our study, we observed Cmax free/MIC of 5.44–42.9 and AUC0–24 free/MIC ranging from 100 to 804 that appeared to be adequate to cover S. aureus susceptible to daptomycin. Despite extreme differences in simulated half-lives of 8 and 30 h, no appreciable differences in bactericidal activity or endpoints were noted between full dose daptomycin delivered either every 24 h for simulated normal or every 48 h for simulated impaired renal function. However, smaller fractionated doses delivered every 24 h produced inferior results despite achieving AUC0–24 free/MIC values that were approximately equal to daptomycin at 4, 6 and 8 mg/kg every 24 h with 8 h t1/2. These results emphasize the importance of the Cmax/MIC and the concentration-dependent properties of daptomycin. A limitation of our study was that we only evaluated two simulated half-lives that would have resulted from an average normal renal function and one that approximates a creatinine clearance of 30 mL/min. Since the model design targeted current dosing recommendations, we did not attempt to perfectly match equivalent AUC exposures at the various dosing intervals that would have been a more rigorous test of AUC/MIC exposure and bactericidal activity as a function of half-life.
In conclusion, our IVPM simulation of current dosing recommendations for renal impairment indicates that there is little difference in bactericidal activity when daptomycin is delivered at 4, 6 and 8 mg/kg once daily or every other day administration in the presence of simulated reduced renal clearance. Further in vivo and in vitro verification of these results is warranted.
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Footnotes |
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Present address. Department of Clinical and Administrative Sciences, Southern School of Pharmacy, Mercer University, Atlanta, GA 30341, USA 
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Acknowledgements |
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A portion of this work was presented at the Eleventh International Symposium on Staphylococci & Staphylococcal Infections, Charleston, SC, 2004. This work was supported by Cubist Pharmaceuticals, Inc.
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