Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function

ABSTRACT A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC24)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399 + 0.051 × CrCLCKD-EPI [creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC24/MIC ratio (≥95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (>80%) against Escherichia coli and Haemophilus influenzae, borderline against Staphylococcus aureus, and suboptimal against Pseudomonas aeruginosa. The levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of ≤0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens.

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Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01684-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 32

Author(s):

Evan J. Zasowski ◽

Kyle P. Murray ◽

Trang D. Trinh ◽

Natalie A. Finch ◽

Jason M. Pogue ◽

...

Keyword(s):

Poisson Regression ◽

Regression Tree ◽

Predictive Performance ◽

Classification And Regression Tree ◽

Therapeutic Drug ◽

Time Curve ◽

Minimum Concentration ◽

Content Type ◽

Cart Analysis ◽

Increased Risk

ABSTRACTEvidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximuma posterioriprobability Bayesian estimation. Vancomycin AUC and minimum-concentration (Cmin) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC0–48) of ≥1,218 mg · h/liter, AUC0–24of ≥677 mg · h/liter, AUC24–48of ≥683 mg · h/liter, and day 1Cmin(Cmin24) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.

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Exposure-Response Analyses for Tafenoquine after Administration to Patients with Plasmodium vivax Malaria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00718-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6188-6194 ◽

Cited By ~ 5

Author(s):

David Tenero ◽

Justin A. Green ◽

Navin Goyal

Keyword(s):

Plasmodium Vivax ◽

Regression Tree ◽

Classification And Regression Tree ◽

Radical Cure ◽

Pivotal Phase ◽

Time Curve ◽

Content Type ◽

Cart Analysis ◽

Exposure Response ◽

Time To Relapse

ABSTRACTTafenoquine (TQ), a new 8-aminoquinoline with activity against all stages of thePlasmodium vivaxlife cycle, is being developed for the radical cure of acuteP. vivaxmalaria in combination with chloroquine. The efficacy and exposure data from a pivotal phase 2b dose-ranging study were used to conduct exposure-response analyses for TQ after administration to subjects withP. vivaxmalaria. TQ exposure (i.e., area under the concentration-time curve [AUC]) and region (Thailand compared to Peru and Brazil) were found to be statistically significant predictors of clinical response based on multivariate logistic regression analyses. After accounting for region/country, the odds of being relapse free at 6 months increased by approximately 51% (95% confidence intervals [CI], 25%, 82%) for each 25-U increase in AUC above the median value of 54.5 μg · h/ml. TQ exposure was also a significant predictor of the time to relapse of the infection. The final parametric, time-to-event model for the time to relapse, included a Weibull distribution hazard function, AUC, and country as covariates. Based on the model, the risk of relapse decreased by 30% (95% CI, 17% to 42%) for every 25-U increase in AUC. Monte Carlo simulations indicated that the 300-mg dose of TQ would provide an AUC greater than the clinically relevant breakpoint obtained in a classification and regression tree (CART) analysis (56.4 μg · h/ml) in more than 90% of subjects and consequently result in a high probability of being relapse free at 6 months. This model-based approach was critical in selecting an appropriate phase 3 dose. (This study has been registered at ClinicalTrials.gov under registration no. NCT01376167.)

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Establishment of an AUC0–24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02535-16 ◽

2017 ◽

Vol 61 (5) ◽

Cited By ~ 35

Author(s):

R. Chavada ◽

N. Ghosh ◽

I. Sandaradura ◽

M. Maley ◽

S. J. Van Hal

Keyword(s):

Staphylococcus Aureus ◽

Regression Tree ◽

Kidney Injury ◽

Classification And Regression Tree ◽

Time Curve ◽

Methicillin Resistant ◽

Content Type ◽

Cart Analysis ◽

Vancomycin Trough ◽

Trough Concentrations

ABSTRACT Unlike vancomycin trough concentrations, data on the utility of vancomycin pharmacokinetic (PK) parameters, namely, the area under the concentration-time curve from 0 to 24 h (AUC0–24), in predicting acute kidney injury (AKI) are limited. Our aim was to investigate this relationship in patients receiving vancomycin therapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B). A single-center retrospective observational cohort study involving 127 consecutive MRSA-B patients was conducted to examine the incidence of AKI (defined as serum creatinine of ≥0.5 mg/liter and a 50% increase from baseline) and vancomycin exposure parameters associated with nephrotoxicity. Bayesian estimation was used to predict individual vancomycin AUC0–24. All patients received vancomycin monotherapy for a minimum of 14 days following the diagnosis of MRSA-B. AKI was observed in 15.7% of patients (20/127). Clinical characteristics were similar between patients with and without AKI. At steady state, higher vancomycin trough concentrations were associated with AKI (17.2 mg/liter versus 13.1 mg/liter; P = 0.003). A vancomycin AUC0–24 threshold for AKI of >563 mg · h/liter was detected by classification and regression tree (CART) analysis; patients with exposures above this threshold were significantly more likely to experience AKI than patients with lower vancomycin exposures (40% [8/20] versus 11.2% [12/107]; P = 0.002). This parameter remained an independent predictor of AKI on multivariate logistic regression (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.57 to 16.29; P = 0.006) and was a better predictor of nephrotoxicity than vancomycin trough concentrations. Overall, AKI is associated with higher vancomycin exposure as measured by AUC0–24. These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.

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Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00794-17 ◽

2017 ◽

Vol 61 (10) ◽

Cited By ~ 18

Author(s):

Piergiorgio Cojutti ◽

Assunta Sartor ◽

Elda Righi ◽

Claudio Scarparo ◽

Matteo Bassetti ◽

...

Keyword(s):

Monte Carlo ◽

Renal Function ◽

Klebsiella Pneumoniae ◽

Monte Carlo Simulations ◽

Continuous Infusion ◽

Population Pharmacokinetics ◽

University Hospital ◽

Therapeutic Drug ◽

High Dose ◽

Content Type

ABSTRACT We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients with Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with a ≤10% to 15% likelihood of meropenem steady-state concentrations (C ss) of >100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T>1×MIC, 100% T>2×MIC, 100% T>3×MIC, and 100% T>4×MIC, where “T>MIC” represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 (n = 169). Ninety-seven meropenem C ss were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (>80%) of 100% T>1×MIC against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of <130 ml/min. Dosages of 8 g/day were needed for achieving the same target in patients with CrCL at levels of 130 to 200 ml/min. In dealing with pathogens with a meropenem MIC of 64 mg/liter, HDCI regimens using meropenem at higher than licensed levels should be considered. In these cases, real-time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

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Population Pharmacokinetic and Pharmacodynamic Analysis of Linezolid and a Hematologic Side Effect, Thrombocytopenia, in Japanese Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01185-10 ◽

2011 ◽

Vol 55 (5) ◽

pp. 1867-1873 ◽

Cited By ~ 57

Author(s):

Tomohiro Sasaki ◽

Hiroshi Takane ◽

Katsuhiro Ogawa ◽

Sayaka Isagawa ◽

Takeshi Hirota ◽

...

Keyword(s):

Renal Function ◽

Liver Cirrhosis ◽

Creatinine Clearance ◽

Side Effect ◽

Population Pharmacokinetic ◽

Severe Liver ◽

Time Curve ◽

Content Type ◽

Platelet Counts ◽

The Relationship

ABSTRACTLinezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillin-resistantStaphylococcus aureus(MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h) = 2.85 × (creatinine clearance/60.9)0.618× 0.472CIR(CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, ≤30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.

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Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01647-17 ◽

2018 ◽

Vol 62 (4) ◽

pp. e01647-17 ◽

Cited By ~ 10

Author(s):

Sheng-Hsuan Tseng ◽

Chuan Poh Lim ◽

Qi Chen ◽

Cheng Cai Tang ◽

Sing Teang Kong ◽

...

Keyword(s):

Steady State ◽

Trough Concentration ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Vancomycin Trough ◽

Trough Concentrations ◽

The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

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Effects of Delayed Antibiotic Therapy on Outcomes in Children with Streptococcus pneumoniae Sepsis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00623-19 ◽

2019 ◽

Vol 63 (9) ◽

Cited By ~ 1

Author(s):

Qinyuan Li ◽

Jie Cheng ◽

Yi Wu ◽

Zhili Wang ◽

Siying Luo ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Antibiotic Therapy ◽

Time Window ◽

Classification And Regression Tree ◽

Antibiotic Administration ◽

Content Type ◽

Cart Analysis ◽

Administration Time ◽

Appropriate Therapy ◽

Poor Outcomes

ABSTRACT Delayed antimicrobial therapy is associated with poor outcomes in sepsis, but the optimal antibiotic administration time remains unclear. We aimed to investigate the effects of the time of antimicrobial administration on outcomes and evaluate an optimal empirical antibiotic administration time window for children with Streptococcus pneumoniae sepsis. This retrospective study enrolled children with S. pneumoniae sepsis who presented to the Children’s Hospital of Chongqing Medical University from May 2011 to December 2018. Classification and regression tree (CART) analysis was used to determine the time-to-appropriate-therapy (TTAT) breakpoint. Outcomes were compared between patients receiving early or delayed therapy, defined by CART-derived TTAT breakpoint. During the study period, 172 patients were included. The CART-derived TTAT breakpoint was 13.6 h. After adjustment for confounding factors, a TTAT of ≥13.6 hours was found to be an independent predictor of sepsis-related in-hospital mortality (odds ratio [OR] = 39.26; 95% confidence interval [CI] = 6.10 to 252.60), septic shock (OR = 4.58; 95% CI = 1.89 to 11.14), and requiring mechanical ventilation (OR = 2.70; 95% CI = 1.01 to 7.35). A Pediatric Risk of Mortality (PRISM) III score of ≥10 was independently associated with delayed therapy. Delayed antibiotic therapy was associated with poor outcomes in children with S. pneumoniae sepsis. The optimal empirical antibiotic administration time window in children with S. pneumoniae sepsis was within 13.6 h. Efforts should be made to ensure timely and appropriate therapy.

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Development and validation of a screening tool for early identification of bloodstream infection in older patients – a retrospective case-control study

BMC Geriatrics ◽

10.1186/s12877-019-1402-x ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Sandra A. N. Walker ◽

Heather Bannerman ◽

Nathan Ma ◽

Christine Peragine ◽

Marion Elligsen ◽

...

Keyword(s):

Bloodstream Infection ◽

Early Identification ◽

Older Patients ◽

Screening Tool ◽

Performance Metrics ◽

Classification And Regression Tree ◽

Maximum Temperature ◽

Controlled Study ◽

Cart Analysis ◽

Matched Case

Abstract Background Delayed diagnosis of bloodstream infection (BSI) occurs in > 20% of older patients, with misdiagnosis in 35%. Our objective was to develop and validate a clinically useful screening tool to identify older patients with a high probability of having a BSI. Methods Hospitalized patients > 80 years old with BSI (n = 105/group) were evaluated for the tool development in this retrospective matched case-controlled study (learn cohort). The tool was validated in different retrospectively matched case and control patients > 80 years old (n = 120/group) and 65 to 79 years old (n = 250/group) (test cohort). Binary logistic regression was used to develop a screening tool using laboratory and clinical parameters that were significantly associated with BSI (P < 0.05; adjusted odds ratio (OR) > 1); and Classification and Regression Tree (CART) analysis was used to identify parameter breakpoints. Performance metrics were used to evaluate and validate the tool. Results The significant parameters associated with BSI were maximum temperature (Tmax)(> 37.55C)(OR = 42.575), neutrophils (> 7.95)(OR = 1.923), a change in level of consciousness (LOC) (Yes = 1, No = 0)(OR = 1.571), blood urea nitrogen (BUN)(> 10.05)(OR = 1.359), glucose (> 7.35)(OR = 1.167), albumin (< 33.5)(OR = 1.038) and alanine aminotransferase (ALT) (> 19.5)(OR = 1.005). The optimal screening tool [Ln (odds of BSI) = − 150.299 + 3.751(Tmax) + 0.654(neutrophils) + 0.452(change in LOC) + 0.307(BUN) + 0.154(glucose) + 0.038(albumin) + 0.005(ALT)] had favorable performance metrics in the learn and test cohorts (sensitivity, specificity and accuracy of 95% in the learn cohort and 77, 89, and 81% in the total test cohort); and performed better than using only temperature and neutrophil count. Conclusions The validated tool had high predictive value which may improve early identification and management of BSI in older patients.

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Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01653-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 309-316 ◽

Cited By ~ 179

Author(s):

Michael N. Neely ◽

Gilmer Youn ◽

Brenda Jones ◽

Roger W. Jelliffe ◽

George L. Drusano ◽

...

Keyword(s):

Renal Function ◽

Trough Concentration ◽

Pharmacokinetic Data ◽

Full Model ◽

Full Data ◽

Time Curve ◽

Data Set ◽

Content Type ◽

Vancomycin Trough ◽

Trough Concentrations

ABSTRACTThe current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults withStaphylococcus aureusinfections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%;P= 0.0001) and 14% (7 to 19%;P< 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%;P= 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.

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Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03423-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6462-6470 ◽

Cited By ~ 52

Author(s):

S. Flanagan ◽

J. Passarell ◽

Q. Lu ◽

J. Fiedler-Kelly ◽

E. Ludwig ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Coefficient Of Variation ◽

Safety Data ◽

Absolute Bioavailability ◽

Optimum Dose ◽

Target Attainment ◽

Time Curve ◽

Unbound Fraction ◽

Once Daily ◽

Content Type

ABSTRACTTedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0–24)], 7 to 50 μg · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against aStaphylococcus aureusstrain for which the MIC was ≤0.5 μg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.

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