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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Cubist Pharmaceuticals, Inc., Lexington, Massachusetts. Dr. Dvorchik's current affiliation is Barry Dvorchik and Associates, Inc., Tampa, Florida.
Address for reprints: Barry Dvorchik, PhD, FCP, Barry Dvorchik and Associates, Inc., 5809 Piney Lane Drive, Suite 105, Tampa, FL 33625.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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75 years) volunteers. Daptomycin was safe and well tolerated. No adverse events related to the infusion were reported. With increased age, there were increases in the area under the plasma concentration-time curve extrapolated to infinity (AUC
) and the terminal elimination half-life. Systemic (CL) and renal clearance (CLR) both decreased with increasing age. The observed changes seen in CL between the two cohorts were most likely a result of changes in renal function, as estimated by creatinine clearance. No statistically significant differences were observed between the two groups in the maximum plasma concentration (Cmax) and volume of distribution at steady state (Vdss). The confidence intervals for the arithmetic mean ratios of the fraction of the dose excreted in the urine as daptomycin (%Fe) (geriatric subjects over younger subjects) were 60% to 101%, indicating that %Fedose was lower in geriatric subjects. These results demonstrate that changes in the pharmacokinetics of daptomycin in the elderly are attributable to changes in renal function, whereas age per se is not a significant factor.
Key Words: Daptomycin • pharmacokinetics • complicated skin and skin structure infections • antibiotic therapy • elderly vs. young volunteers
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In vitro, daptomycin demonstrates rapid, concentration-dependent bactericidal activity against most clinically relevant gram-positive bacteria, including antibiotic resistant pathogens for which there are very limited therapeutic alternatives (e.g., methicillin-resistant staphylococci, vancomycin-intermediate susceptible Staphylococcus aureus, and vancomycin-resistant enterococci).1 The minimum inhibitory concentration of daptomycin (MIC90) is typically 
1 µg/mL for staphylococci and streptococci and 2 to 4 µg/mL for enterococcal species.2 In Phase III trials for the treatment of cSSSI caused by aerobic gram-positive bacteria, clinical, and microbiological outcomes of patients treated with daptomycin were comparable to those for patients receiving conventional antibiotic therapy.3,4
Daptomycin has been effective against clinical isolates in several different animal models of infection, including endocarditis, bacteremia, and renal and intramuscular infection. In a thigh soft-tissue infection model in mice, the pharmacodynamic parameter of daptomycin most closely correlated with bacterial eradication was the ratio of the area under the plasma concentration versus time curve (AUC24 h)/MIC.5 These characteristics are consistent with the concentration-dependent activity noted in vitro.
Daptomycin pharmacokinetics have been examined in healthy volunteers in both single-dose and repeated-dose studies.6,7 Its kinetics are linear over the range of 1 to 6 mg/kg, with approximately 20% accumulation following repeated once-daily doses. Daptomycin is distributed primarily to extracellular fluid, does not readily cross cell membranes, and is bound (approximately 87%-92%) to serum proteins. Elimination is primarily by renal excretion of the nonmetabolized active drug. The terminal plasma half-life (t1/2) in subjects with normal renal function is approximately 9 hours.
Several physiological changes are associated with the human aging process that can directly alter drug disposition. These include decreased plasma protein binding due to reduced serum albumin levels, reduced liver function and mass, gastrointestinal changes, and reduced kidney function.8 This study was undertaken to assess the single-dose pharmacokinetics and safety of daptomycin in healthy geriatric subjects compared with younger healthy subjects to determine if pharmacokinetic or safety differences exist between the two populations.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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75 years old and 12 who were 18-30 years old) were enrolled. Those not enrolled were excluded most often due to an out-of-range creatinine clearance or because they withdrew consent. All 24 enrolled subjects completed the study as planned. Subjects were screened within 14 days or less than 2 days prior to Study Day 1, and those meeting all inclusion/exclusion criteria were enrolled. After providing informed consent, demographic characteristics and medical/medication histories were recorded. Physical examination and vital signs assessments were performed, and blood/urine samples were obtained for routine chemistry, hematology, coagulation (PTT/INR) testing, and urinalysis. Additional testing at screening included a human immunodeficiency virus (HIV) test, a serum pregnancy test (if applicable), a urine drug/alcohol screen, and serum creatine phosphokinase (CPK) level determination. A 12-lead electrocardiogram (ECG) was also obtained.
General inclusion criteria for all subjects included age between 18 and 30 (young control) or 75 (geriatric volunteers); body weight within 30% of the ideal body weight, as defined in the 1996 Metropolitan Height and Weight Tables for men and women; body mass index between 19 and 30 kg/m2; and estimated creatinine clearance 70 mL/min (young control) or 50 mL/min (geriatric volunteers) using the Cockcroft-Gault equation9 and total body weight. Female subjects of child-bearing potential must have been nonpregnant, nonlacting, and willing to practice reliable birth control measures during and for at least 48 hours after treatment with daptomycin. Subjects taking concomitant medications that were not specifically excluded must have been on a stable dose for 2 weeks prior to administration of daptomycin. Subjects had to refrain from alcohol ingestion for the 3 days prior to admission into the clinical study and for the duration of the study. Serum CPK levels had to be 1.5 ULN. Subjects were excluded from the study if, at screening, they had anemia with a hematocrit < 27%, had used an investigational drug or participated in any experimental procedure in the 30 days proceeding study entry, had used an HMG CoA reductase inhibitor with 7 days or warfarin with 15 days of daptomycin administration, were HIV positive, had a positive drug or alcohol screen, had donated blood with the past 30 days, had a history of muscular disease or neurological disease, or had intramuscular injections or weight training within 7 days of daptomycin administration.
Study Design
This was an open-label, single-dose, parallel-design, two-center study of daptomycin pharmacokinetics and safety conducted in adult subjects who were either healthy, geriatric subjects 75 years old or healthy, younger subjects between 18 and 30 years old. Planned enrollment called for 12 geriatric subjects and 12 younger subjects; an attempt was to made to enroll an equal number of men and women in each group. The clinical portion of this study was conducted at the following two sites: Site 1 was CNS, Clinical Trials (Fort Lauderdale, FL), and Site 2 was SFBC International, Inc. (Miami, FL). Approval was received from the independent institutional review board used by each site, and the study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and its amendments, as well as in accordance with the International Conferences of Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice and local laws and regulations relevant to the use of investigational therapeutic agents.
Each subject received a single intravenous dose of 4 mg/kg daptomycin in 50 mL of saline administered as a 30-minute infusion. Subjects were required to enter the testing facility the evening prior to drug administration (Day-1) and were to remain housed in the Clinical Research Unit for the duration of the study. At the time of check-in on Day-1, subjects underwent a physical examination, including vital signs assessments and weight. Body mass index (BMI) was calculated by the Clinical Research Unit using ideal body weight (male = 50 kg + 2.3 kg per inch of height over 60 inches; female = 45.5 kg + 2.3 kg per inch of height over 60 inches). Routine laboratory testing (chemistry, hematology, coagulation, and urinalysis), a serum CPK determination, a urine drug screen, and a urine pregnancy test (for women of childbearing potential) were done. A 12-lead ECG was also obtained. Subjects were given a standardized dinner that evening and a snack at 11:00 p.m. before going to bed. Subjects were kept well hydrated by drinking at least 8 ounces of water with each meal or snack. During the study, overconsumption of food or consumption of grapefruit juice or beverages containing caffeine or alcohol was prohibited, and subjects consumed standard institutional meals. Subjects were to refrain from strenuous exercise of all types. On the dosing day (Day 1), subjects were given a standardized breakfast at least 1 hour prior to drug administration, and intravenous catheters were placed in separate arms, one for infusion of study drug and the other for blood sampling. Blood was drawn for the determination of CPK approximately 2 hours prior to dosing. A control urine sample (predose) was obtained within 2 hours before study drug administration. At approximately 8:00 a.m. on Day 1, 4 mg/kg of daptomycin was administered intravenously over 30 minutes. A 1.0-mL aliquot of the dosing solution was collected from the IV bag prior to administration, and a 5.0-mL sample was taken from the IV line after dosing. Both samples were stored frozen before being sent to the laboratory for determination of daptomycin concentration.
Sampling and Bioanalysis
Plasma concentrations of daptomycin were assessed from blood samples taken predose ( 0.5 h) and 0.25, 0.5 (end of infusion), 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours from the start of the infusion. Urine samples for the determination of daptomycin concentration were collected predose (-2h) and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 16, and 16 to 24 hours from the initiation of the infusion.
Plasma and urine concentrations of daptomycin were measured by high-performance liquid chromatography (HPLC) with a UV detector.7 The dynamic linear range was 3 to 500 µg/mL. For plasma, the method involved extraction of daptomycin and an internal standard; for urine, the method involved the direct analysis of daptomycin after addition of an internal standard in methanol. For further details on these methods, see Dvorchik et al.7 All dosing solutions were analyzed by HPLC with UV detection.
Safety
Safety was assessed by monitoring for adverse events, physical examination, electrocardiograms, vital signs assessments, serum CPK determinations, and standard clinical laboratory evaluations before and after study drug administration. The overall pattern and incidence of adverse events, including clinically significant abnormal laboratory values, were used to evaluate safety. Adverse events were coded using the MedDRA 3.3 Dictionary of Adverse Reaction Terms and are presented by system class and preferred term.
Pharmacokinetic Analysis
All pharmacokinetic parameters were derived by noncompartmental methods using SAS (Release 6.12; SAS Institute, Cary, NC). All statistical analyses were conducted in SAS. The pharmacokinetic parameters estimated were maximum plasma concentration (Cmax, obtained directly from the experimental plasma concentration-time data without extrapolation); time to reach Cmax (tmax, obtained directly from the experimental plasma concentration-time data without extrapolation); daptomycin terminal plasma half-life (t1/2); area under the concentration versus time curve, calculated using the linear trapezoidal rule from time 0 to the last quantifiable concentration time (AUCT); area under the concentration-time curve, calculated from the linear trapezoidal rule from 0 to 24 hours (AUC0-24); area under the concentration-time curve, calculated from time 0 to infinity (AUC0-); plasma clearance of daptomycin (CL); terminal exponential volume of distribution (Vz); mean residence time (MRT); volume of distribution at steady state following IV administration (Vss); renal clearance of daptomycin (CLR); and fraction of the dose excreted in the urine as parent drug, expressed as a percentage (Fe).
Statistics
Descriptive statistics for pharmacokinetic parameters were calculated where appropriate. Comparisons of pharmacokinetic (PK) parameters between the two cohorts were analyzed by ANOVA, and 90% confidence intervals (CI) using log-transformed AUC ratios were used to determine the equivalency of AUC, Cmax, tmax, Fu, and Fe.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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75 years old and 12 who were 18-30 years old) were enrolled; all completed the study. The baseline demographic characteristics of the groups were comparable (Table I). All younger subjects and 8 of the 12 geriatric subjects were enrolled at Site 1. The remaining 4 geriatric subjects (all Hispanic) were enrolled at Site 2.
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Most of the subjects in the study were Hispanic (18 of 24, 75%). Subjects in the geriatric group were equally divided between Caucasians and Hispanics, whereas in those in the younger group (control) all were of Hispanic origin. In the geriatric group, most subjects were men (83%), but in the younger age group, the men and women were more evenly divided (42% men, 58% women). The subjects in each group were within the specified age ranges, with a mean age of 77 years in the geriatric group and 24 years in the younger group. Subjects' heights were comparable in the two groups, but the geriatric subjects had a greater mean weight and BMI compared with younger age subjects. Mean creatinine clearance calculations were substantially different between the two groups, but each was appropriate for the respective age group.
Most subjects did not have any significant findings in their medical histories or upon physical examination at screening or baseline. Exceptions included 1 subject in the geriatric group who had Type II diabetes and mild pitting edema in both legs on physical examination, another with a heart murmur, and another with a diastolic heart murmur and bilateral leg edema up to the calves.
Pharmacokinetics
The plasma concentration profile of daptomycin, from both groups, declined consistent with a two-compartment model with first-order elimination (Figure 2). Analysis of all dosing solutions (data not shown) confirmed that 4 mg/kg total body weight was administered (mean ± SD; geriatric = 4.48 ± 0.64 mg/kg, young controls = 4.80 ± 1.20 mg/kg). One subject in the younger group was excluded from the pharmacokinetic analysis as dose analysis indicated that this subject had received 8.4 mg/kg, which was not reflected in the plasma concentration-time profile.
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Table II gives the arithmetic mean pharmacokinetic parameters and their ratios in geriatric subjects versus younger subjects. The arithmetic mean ratio indicated that the total exposure (AUC0-) was 58% higher in geriatric subjects compared with younger subjects. Cmax, AUC0-t, and AUC0- were compared using analysis of variance (ANOVA). The p-values indicated that AUC0-t and AUC0- were significantly different in geriatric subjects compared with younger subjects (p < 0.0001). No statistical differences in Cmax were observed between geriatric subjects and younger subjects (p = 0.58).
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The confidence intervals for the least squares mean ratios of geriatric to younger subjects are shown in Table III. The lower 90% confidence intervals for the ratios were greater than 1.00 for AUC0-t and AUC0-, indicating that total exposure was higher in geriatric subjects than in younger subjects. For Cmax, the 90% confidence interval was from 93% to 116%.
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Total clearance was 35% lower in geriatric subjects compared with younger subjects. Mean values for volume of distribution (Vz and Vss) were comparable among geriatric and younger subjects. Mean tmax was found to be similar for both groups.
Renal clearance was lower in geriatric subjects compared with younger subjects. Mean fraction excreted in the urine for geriatric subjects (34.3%) was lower than the mean value for younger subjects (42.6%). While statistical comparisons using analysis of variance indicated that the differences in %Fedose were not statistically significant (p = 0.12), the confidence intervals for the arithmetic mean ratios (geriatric subjects over younger subjects) were 60% to 101%, indicating that %Fedose was lower in geriatric subjects. One geriatric subject had a twofold greater %Fe compared with the other geriatric subjects in the study (Figure 3). This led to an increase in the mean and CV for %Fedose for the geriatric treatment group and could be the reason why no differences were detected in the ANOVA comparing geriatric and younger subjects.
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Safety
Adverse events were coded using the MedDRA 3.3 Dictionary of Adverse Reaction Terms and are presented by system organ class and preferred term. Table IV presents all treatment-emergent adverse events reported during the study, where treatment emergent was defined as an event that was new in onset or aggravated in severity or frequency following administration of the investigational agent.
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One of 12 subjects in the geriatric group experienced one treatment-emergent adverse event, and 3 subjects in the younger age group experienced three adverse events. All adverse events were considered mild and were resolved with no treatment necessary. There were no deaths or serious adverse events during the study, and none of the subjects discontinued due to an adverse event.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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) of daptomycin was higher in geriatric subjects compared with the younger subjects, resulting in a decrease in daptomycin plasma clearance. Exposure to daptomycin in geriatric subjects was 58% higher compared to the younger controls. These differences are not readily ascribable to any ethnic differences between the two cohorts.7 Comparison of the pharmacokinetic data from this group of healthy geriatric subjects to historical data in young healthy volunteers following similar administration.6,7 indicates the similarity of both Cmax and AUC0-. One explanation for this may be the mean age of the volunteers. In this study, the mean age was 22 years. The mean age of the volunteers in the historical data was about 35 years, possibly reflecting lower creatinine clearances. Mean %Fe excreted in the urine was lower in geriatric subjects. While the difference did not reach statistical significance using ANOVA, the confidence interval was strongly suggestive of a lower %Fe in the geriatric population. The twofold greater %Fedose in 1 geriatric volunteer compared to the remaining 11 geriatric subjects in the study could be the reason why no differences were detected in the ANOVA comparing geriatric and younger subjects. Compared to historical data in healthy volunteers,7,10,11 %Fe in the geriatric volunteers was also lower. These differences are most likely due to the normal reduction in renal function observed in the geriatric population.
Single-dose daptomycin at 4 mg/kg was equally safe and well tolerated by the small number of geriatric and younger age subjects in this study, despite the fact that exposure to daptomycin was significantly higher in geriatric subjects. One of 12 subjects in the geriatric group experienced vomiting on the day following dosing. The event was mild in severity and was not considered to be treatment related. Three subjects in the younger age group each experienced a single adverse event. AEs among younger subjects included headache in 2 subjects and a rash on 1 subject's upper arm. Headache was mild in severity and considered possibly related to the study drug in both subjects. The headaches resolved without treatment. The rash, which persisted for approximately 48 hours, was mild in severity and considered possibly related to study treatment; it resolved without treatment. The rash occurred in the arm opposite to study drug administration, and the investigator noted that the rash was characteristic of insect bites. There were no deaths or serious adverse events during the study, and none of the subjects discontinued due to an adverse event.
Additional measures of safety, including hematology, clinical chemistry, coagulation testing, and urinalysis, did not show clinically meaningful changes from baseline or differences between geriatric and younger age subjects. For most hematology, chemistry, coagulation testing, and urinalysis parameters, the mean and median changes from baseline were minor in both treatment groups. Changes in vital signs during the study were not clinically meaningful, and there were no changes in the results of the physical examinations other than the single subject who developed a rash. In ECG results, changes from normal at baseline to abnormal at Days 1 or 2 were noted in 1 subject in the geriatric group and 3 subjects in the younger age group, but the changes were not considered by the investigator to be clinically significant in any subject. Overall, no safety concerns were raised from the results of adverse events, laboratory tests, vital signs measurements, physical examinations, or ECGs in geriatric or younger age subjects.
Of the 534 patients treated with daptomycin in Phase III controlled clinical trials of cSSSI, 27% were 65 years of age or older, and 12.4% were 75 years or older. Current guidelines for the optimization of antimicrobial therapy are based on drug concentrations measured in serum/plasma. However, for most infections, the target is the infecting microorganisms that are located outside the blood in the interstitial space of tissues and organs. Wise et al11 determined the penetration of daptomycin into inflammatory fluid produced by cantharidin induced blisters in healthy male volunteers. The AUC in the inflammatory fluid averaged 68% of that in plasma, with a range of 224 to 447 µg•h/mL (mean = 318.2 µg•h/mL). This is well within the AUC required for efficacy based on modeling studies using Monte Carlo simulation.12 Perhaps there is a difference in the rate and extent of daptomycin tissue distribution in the elderly, as has been demonstrated for pipercillin and imipenem in severely ill patients.13,14
In conclusion, the results of this single-dose Phase I study demonstrate that changes in the pharmacokinetics of daptomycin in the elderly are attributable to changes in renal function, whereas age per se is not a significant factor.
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FOOTNOTES |
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Submitted for publication January 26, 2004; Revised version accepted March 22, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Fuchs PC, Barry AL, Brown SD: In vitro bactericidal activity of daptomycin against staphylococci. J Antimicrob Chemother 2002;49: 467-470.
2. Critchley IA, Draghi DC, Sahm DF, Thornsberry C, Jones ME, Karlowsky JA: Activity of daptomycin against susceptible and multidrug resistant gram-positive pathogens collected in the SECURE study (Europe) during 2000-2001. J Antimicrob Chemother 2003; 51: 639-649.
3. Wesson KM, Lerner DS, Silverberg NB, Weinberg JM: Linezolid, quinupristin/dalfopristin, and daptomycin in dermatology. Clin Dermatol 2003;21: 64-69.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI, and Daptomycin 98-01 and 99-01 Investigators: The safety and efficacy of daptomycin in the treatment of complicated skin and skin structure infections. Clin Infect Dis; in press.
5. Louie A, Kaw P, Liu W, Jumbe N, Miller MH, Drusano GL: Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection. Antimicrob Agents Chemother 2001;45: 845-851.
6. Woodworth JR, Nyhart EH, Brier GL, Wolny JD, Black HR: Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy subjects. Antimicrob Agents Chemother 1992;36: 318-325.
7. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD: Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother 2003;47: 1318-1323.
8. Woodhouse K: The pharmacology of aging, in: Tallis R, Fillit H, Brochlehurst J (eds.), Geriatric Medicine and Gerontology. London: Harcourt Brace, 1998; 169-178.
9. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1978;16: 31-41.
10. Dvorchik B, Arbeit R, Chung J, Liu S, Knebel W, Kastrissios H: Population pharmacokinetic analysis of daptomycin. Antimicrob Agents Chemother; submitted for publication, 2003.
11. Wise R, Gee T, Andrews JM, Dvorchik B, Marshall G: Pharmacokinetic and inflammatory fluid penetration of intravenous daptomycin in volunteers. Antimicrob Agents Chemother 2002; 46: 31-33.
12. Use of population modeling to determine the tissue penetration of daptomycin and Monte Carlo simulation for determining the target attainment rate for a dose suitable for treatment of skin and skin structure infections. Cubist Internal Report, 2003.
13. Joukhadar C, Frossard M, Mayer BX, Brunner M, Klein N, Siostrzonek P, Eicer HG, et al: Impaired target site penetration of ß-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 2001;29(2): 385-391.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Tegeder I, Schmidtko A, Bräutigam L, Kirschbaum A, Geisslinger G, Lötsch J: Tissue distribution of imipenem in critically ill patients. Clin Pharmacol Ther 2002;71: 325-333.[CrossRef][Web of Science][Medline]
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