1576. Delaying the Start of Maintenance Vancomycin After a Loading Dose to Avoid a High 0–24h AUC

Abstract Background Vancomycin dosing guidelines recommend loading doses (LDs) (25–30 mg/kg TBW), and a maintenance regimen, usually started after a time period equal to the dosing interval. Studies of vancomycin exposure and nephrotoxicity conclude that a 0 to 24-hour area under the serum concentration–time curve (0–24AUC) > 677 mg-hour/L results in a 3- to 4-fold increased risk of nephrotoxicity (Zasowski EJ, Antimicrob Agents Chemother 2018). For vancomycin LDs we compare the calculated LD and the maintenance dose, and delay initiation of the maintenance regimen when the LD exceeds the daily maintenance dose by > 50%. This study assessed the pharmacokinetic outcomes from this technique. Methods We retrospectively reviewed 68 consecutive adult patients receiving therapeutic doses of vancomycin. Patient age, sex, height, weight, serum creatinine, and indication were used to calculate the daily dose/intervals for a steady-state 24-hr AUC of 400 or 600 mg-hour/L. The total 0–24AUC was calculated by adding the 0–24 AUC from a 25 mg/kg LD (max: 3 gm) to the 0–24AUC(s) for maintenance dose(s) within the first 24 hours. We compared the total 0-24AUC when the first maintenance dose was timed for the next dosing interval (“scheduled”) to that when the maintenance dose was delayed according to our protocol (“delayed”). We tested the proportion of patients who would be exposed to a vancomycin 0-24AUC > 677 mg-hour/L. Results 16/68 patients were diagnosed with SSTI (goal 24 hr AUC: 400 mg-hour/L) and 52/68 with sepsis, bacteremia/endocarditis, or pneumonia (24 hr AUC: 600 mg-hour/L). Median daily maintenance dose was 1750 mg (range: 875–4,000 mg). For patients with a goal AUC of 400, the 0-24AUC was > 677 mg-hour/L in one patient using the “scheduled” process and in none of the patients using the “delayed” protocol. However, for patients with a goal AUC of 600, the 0-24AUC was > 677 mg-hour/L in 22/52 patients via the “scheduled” process vs. 4/52 patients via the “delayed” protocol. Conclusion For patients with severe gram-positive bacterial infections requiring aggressive dosing of vancomycin, delaying the start of maintenance dosing following a large LD is an effective way to ensure attainment of goal therapeutic AUC within the first 24 hr without placing the patient at increased risk for nephrotoxicity. Disclosures All authors: No reported disclosures.

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Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01057-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5714-5716 ◽

Cited By ~ 24

Author(s):

David R. Andes ◽

Daniel K. Reynolds ◽

Scott A. Van Wart ◽

Alexander J. Lepak ◽

Laura L. Kovanda ◽

...

Keyword(s):

Dose Level ◽

Randomized Trials ◽

Clinical Investigation ◽

Time Curve ◽

Content Type ◽

Dosing Interval ◽

Concentration Time ◽

Dosing Regimens ◽

Dosing Strategy ◽

Current Report

ABSTRACTEchinocandins exhibit concentration-dependent effects onCandidaspecies, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P= 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.)

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Once-Weekly Micafungin Therapy Is as Effective as Daily Therapy for Disseminated Candidiasis in Mice with Persistent Neutropenia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01337-06 ◽

2006 ◽

Vol 51 (3) ◽

pp. 968-974 ◽

Cited By ~ 77

Author(s):

Tawanda Gumbo ◽

George L. Drusano ◽

Weiguo Liu ◽

Robert W. Kulawy ◽

Christine Fregeau ◽

...

Keyword(s):

Single Dose ◽

Peak Concentration ◽

Candida Glabrata ◽

Time Curve ◽

Dosing Interval ◽

Fungal Burden ◽

Disseminated Candidiasis ◽

Time Profiles ◽

Concentration Time ◽

Versus Peak

ABSTRACT The effect of micafungin dose scheduling on the treatment of candidemia is unknown. Neutropenic mice with disseminated Candida glabrata infection were treated with single intraperitoneal micafungin doses of 0 to 100 mg/kg of body weight and sacrificed 7 days later. The maximal decline in kidney fungal burden was 5.8 log10 CFU/g. A 1-week pharmacokinetic-pharmacodynamic study revealed a micafungin serum half-life of 6.13 h. In mice treated with ≥50 mg/kg, there was maximal fungal decline without regrowth during the 1-week dosing interval. Next, doses associated with 34% (34% effective dose [ED34]) and 50% (ED50) of maximal kill were administered at one of three dose schedules: a single dose at t = 0, two equal doses at t = 0 and t = 3.5 days, and 7 equal doses daily. Some mice received a single dose of 100 mg/kg. Fungal burden was examined on days 1, 5, and 7. In mice treated with the ED34, microbial kill with the daily therapy initially lagged behind the intermittent doses but exceeded it by day 7. In mice treated with the ED50, daily and intermittent doses had equivalent day 7 effects. In mice treated with 100 mg/kg, there was no regrowth. The relative likelihoods that the area under the concentration-time curve/MIC ratio was linked to microbial kill versus peak concentration/MIC ratio or time above the MIC was 10.3 and 10,161.2, respectively. In all the experiments, no paradoxical increase in fungal burden was observed with high micafungin doses. However, only a single Candida isolate was tested. Regimens that simulated micafungin concentration-time profiles in patients treated with a single micafungin dose of 1,400 mg once a week demonstrated maximal fungal decline. Once-weekly micafungin therapy is as efficacious as daily therapy in a murine model of disseminated candidiasis.

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Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01880-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 3

Author(s):

Sean M. Stainton ◽

Marguerite L. Monogue ◽

Arlinda Baummer-Carr ◽

Ashley K. Shepard ◽

James F. Nugent ◽

...

Keyword(s):

Healthy Volunteers ◽

Subcutaneous Tissue ◽

Extracellular Fluid ◽

Pharmacokinetic Parameters ◽

Diabetic Patients ◽

Tissue Penetration ◽

Time Curve ◽

Dosing Interval ◽

Concentration Time

ABSTRACT Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (C max), 1.5 ± 0.5 versus 2.7 ± 1.1 mg/liter (P = 0.005); time to C max (T max) (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) (P = 0.003); half-life (t1/2), 9.1 ± 3.6 versus 8.9 ± 2.2 h (P = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC p ), 18.5 ± 9.7 versus 28.7 ± 9.6 mg · h/liter (P = 0.004). The tissue area under the concentration-time curve (AUC t ) for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg · h/liter (P = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) (P = 0.351). Despite lower plasma C max and delayed T max values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI.

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Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01836-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 419-423 ◽

Cited By ~ 6

Author(s):

Odin J. Naderer ◽

Keith A. Rodvold ◽

Lori S. Jones ◽

John Z. Zhu ◽

Chester L. Bowen ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Alveolar Macrophages ◽

Bacterial Infections ◽

Time Course ◽

Respiratory Pathogens ◽

Epithelial Lining ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Concentration Time

ABSTRACTGSK1322322 is a potent peptide deformylase inhibitor within vitroandin vivoactivity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC0–τ) was 66.7 μg · h/ml, and maximum concentration of drug in serum (Cmax) was 25.4 μg/ml following repeat doses of intravenous GSK1322322. The time course of epithelial lining fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC0–τfor ELF and AM were 78.9 μg · h/ml and 169 μg · h/ml, respectively. The AUC0–τratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered atClinicalTrials.govunder registration number NCT01610388.)

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Multiple-Dose Safety, Tolerability, and Pharmacokinetics of Oral Nemonoxacin (TG-873870) in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00683-09 ◽

2010 ◽

Vol 54 (1) ◽

pp. 411-417 ◽

Cited By ~ 28

Author(s):

David T. Chung ◽

Cheng-Yuan Tsai ◽

Shu-Jen Chen ◽

Li-Wen Chang ◽

Chi-Hsin R. King ◽

...

Keyword(s):

Plasma Concentration ◽

Healthy Volunteers ◽

Bacterial Infections ◽

Maximum Plasma Concentration ◽

Maximum Plasma ◽

Time Curve ◽

Once Daily ◽

Concentration Time ◽

Atypical Pathogens ◽

Plasma Concentration Time Curve

ABSTRACT Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with broad-spectrum activities against Gram-positive and Gram-negative aerobic, anaerobic, and atypical pathogens, as well as against methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus, and multiple-resistant bacterial pathogens. We conducted a randomized, double-blind, placebo-controlled, dose-escalating study to ascertain the safety, tolerability, and pharmacokinetics of nemonoxacin. We enrolled 46 healthy volunteers and used a once-daily oral-dosing range of 75 to 1,000 mg for 10 days. Additionally, the food effect was evaluated in subjects in the 500-mg cohort. Nemonoxacin was generally safe and well tolerated, with no significant changes in the clinical laboratory tests or electrocardiograms. Adverse effects, including headache, contact dermatitis, and rash, were mild and resolved spontaneously. Nemonoxacin was rapidly absorbed within 2 h postdosing, and generally, a steady state was reached after 3 days. The maximum plasma concentration and the area under the plasma concentration-time curve were dose proportional over the dosing range. The elimination half-life was approximately 7.5 h and 19.7 h on days 1 and 10, respectively. Approximately 37 to 58% of the drug was excreted in the urine. Food affected the pharmacokinetics, with decreases in the maximum plasma concentration and area under the plasma concentration-time curve of 46% and 27%, respectively. However, the free AUC/MIC90 of nemonoxacin was more than 100 under both the fasting and fed conditions, predicting the efficacy of nemonoxacin against most of the tested pathogens. In conclusion, the results support further clinical investigation of once-daily nemonoxacin administration for antibiotic-sensitive and antibiotic-resistant bacterial infections.

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Optimizing the Initial Amikacin Dosage in Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01032-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 7094-7096 ◽

Cited By ~ 13

Author(s):

Bryan P. White ◽

Ben Lomaestro ◽

Manjunath P. Pai

Keyword(s):

Body Weight ◽

Standard Deviation ◽

Therapeutic Drug Monitoring ◽

Drug Concentration ◽

Drug Monitoring ◽

Maintenance Dose ◽

Therapeutic Drug ◽

High Dose ◽

Time Curve ◽

Concentration Time

ABSTRACTWe report on the pharmacokinetics (PK) and pharmacodynamics (PD) of high-dose (>15 mg/kg of body weight per day) amikacin. A mean (standard deviation [SD]) maximum drug concentration in the serum (Cmax) and 24-h area under the concentration-time curve (AUC24) of 101 (49.4) mg/liter and 600 (387) mg · h/liter, respectively, were observed (n= 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2,500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK and PD.

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Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer

Biology ◽

10.3390/biology10101054 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1054

Author(s):

Hayato Yokota ◽

Kazuhiro Sato ◽

Sho Sakamoto ◽

Yuji Okuda ◽

Mariko Asano ◽

...

Keyword(s):

Single Point ◽

Plasma Concentrations ◽

Small Cell ◽

Therapeutic Drug ◽

Small Cell Lung ◽

Time Curve ◽

Concentration Time ◽

Kaplan Meier ◽

Daily Dose ◽

Plasma Concentration Time Curve

We evaluated the area under the plasma concentration–time curve (AUC) of afatinib required to avoid the onset of grade 2 or higher diarrhea. The C0 and AUC0–24 of afatinib were significant higher in patients with grade 2 diarrhea than in those with grade 0–1 diarrhea. The areas under the receiver operator curves were 0.795 with the highest sensitivity (89%) and specificity (74%) at an AUC0–24 threshold of 823.5 ng·h/mL, and 0.754 with the highest sensitivity (89%) and specificity (74%) at a C0 threshold of 28.5 ng/mL. In Kaplan–Meier analysis based on these cut-off AUC0–24 and C0 values, the median time to the incidence of grade 2 diarrhea was 16 days. The predicted AUC0–24 of afatinib from the single point of C6 showed the highest correlation with the measured AUC0–24 (r2 = 0.840); however, a significant correlation between the AUC0–24 and C0 was also observed (r2 = 0.761). C0 could be used as a marker of therapeutic drug monitoring because afatinib C0 was related to AUC0–24. Therefore, afatinib C0 should be monitored on day 8 after beginning therapy, and the daily dose of afatinib should be adjusted as an index with a cut-off value of 28.5 ng/mL.

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Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01723-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 4

Author(s):

Julian Lindsay ◽

Stuart Mudge ◽

George R. Thompson

Keyword(s):

Steady State ◽

Maximum Concentration ◽

Healthy Adults ◽

Plasma Exposure ◽

Open Label ◽

Time Curve ◽

Dosing Interval ◽

Fasted State ◽

Concentration Time ◽

Bioavailability Study

ABSTRACT To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

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A reduced pazopanib dose with food: Is it more patient-friendly and does it reduce drug costs?

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4564 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4564-4564 ◽

Cited By ~ 2

Author(s):

Floor Lubberman ◽

Hans Gelderblom ◽

Paul Hamberg ◽

Walter Vervenne ◽

Sasja F. Mulder ◽

...

Keyword(s):

Cost Reduction ◽

Geometric Mean ◽

Bioequivalence Study ◽

Geometric Mean Ratio ◽

Advanced Soft Tissue Sarcoma ◽

Time Curve ◽

Concentration Time ◽

Daily Dose ◽

Gi Toxicity ◽

Clinical Trial Information

4564 Background: Pazopanib has been licensed for advanced soft tissue sarcoma and metastatic renal cell carcinoma in a fixed oral daily dose of 800mg taken fasted. We hypothesized that ingesting pazopanib with food may improve patients’ comfort and reduce gastro-intestinal adverse events. Moreover, a food intervention, resulting in a better absorption, can lead to a lower dose, which could significantly reduce treatment costs. Methods: Part 1 of the study was performed to determine whether 600mg pazopanib taken with a continental breakfast was bioequivalent to 800mg pazopanib taken fasted. In part 2, differences in GI-toxicity and patient satisfaction were assessed by the cancer-therapy-satisfaction-questionnaire after both intake regimens. Finally, patient’s preference for either intake regimen was asked. Results: 16 patients were included in the bioequivalence study. The geometric mean ratio (fed/fasted) of the area under the plasma concentration time curve was 1.10 (90% CI 1.00-1.19), maximum peak concentration was 1.12 (90% CI 1.02-1.22) and pazopanib trough concentration was 1.10 (90% CI 1.02-1.18). In part 2, 60 patients were included. No differences were seen in the occurrence of GI-toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects (72.3(95% CI 68.1-76.5) vs 68·2 (62.7-73.6); p=.092) and satisfaction with therapy scores were higher (84.7(95% CI 81.4-87.9) vs 81.9 (78.7-85.2); p= .059) when pazopanib was taken with food. 41 (68%) of the patients preferred the intake with continental breakfast. Conclusions: Intake of 600mg pazopanib with food results in bioequivalent exposure and was preferred over a standard pazopanib dose without food. Moreover, with this simple food intervention a large cost reduction can be realized in patients treated with pazopanib. Clinical trial information: NCT02138526.

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Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02355-14 ◽

2014 ◽

Vol 58 (6) ◽

pp. 3162-3167 ◽

Cited By ~ 20

Author(s):

Manjunath P. Pai ◽

Alessandro Russo ◽

Andrea Novelli ◽

Mario Venditti ◽

Marco Falcone

Keyword(s):

Healthy Volunteers ◽

Critically Ill ◽

Critically Ill Patients ◽

Antimicrobial Agents ◽

Population Pharmacokinetic ◽

Good Precision ◽

Time Data ◽

Time Curve ◽

Dosing Interval ◽

Concentration Time

ABSTRACTThe effects of several antimicrobial agents are predicted by the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). Peak (Cp) and trough (Ct) concentrations are often measured clinically as surrogates of AUC because actual computation of AUC from 1 or 2 samples requires sophisticated mathematical methods. Given that the effects of daptomycin are predicted by AUC/MIC, our objective was to compare simple equation calculated AUC based onCpandCtto model integrated AUC. A standard population pharmacokinetic model was used to simulate 5,000 daptomycin concentration-time profiles after 5 doses of 6 mg/kg of body weight/day (0.5-h infusions). The AUC for the 24-h period was computed by integration and by equations with 110Cp-Ctcombination pairs. TheCptime points were in 15-min increments between 0.5 h and 3 h andCtin 15-min increments within an hour of the end of the dosing interval for each dose. The precision and bias of the calculated AUC relative to the integrated AUC were determined to identifyCp-Ctpairs associated with the lowest bias and highest precision. The equations were further validated using two daptomycin concentration-time data sets from healthy volunteers and critically ill patients. The precision and bias of calculated AUC were based primarily onCp, and use of a daptomycinCp1.5 h to 3 h from the start of infusion was associated with a bias of <10% and anR2of >0.95. Data from the healthy volunteers and critically ill patients also demonstrated declining bias with use ofCp≥1.5 h from the start of infusion with relatively good precision. Simplified equations using a daptomycinCpapproximately 2 h from the start of infusion and aCtwithin an hour of the end of the dosing interval should yield precise and unbiased estimates of daptomycin AUC.

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