Brief Report

Clinical Pharmacology
Pharmacokinetics, Safety, and in Drug Development
2018, 00(0) 1–7
Tolerability of Tedizolid Phosphate C 2018, The American College of

Clinical Pharmacology
DOI: 10.1002/cpdd.426
in Elderly Subjects

Shawn D. Flanagan1 , Sonia L. Minassian2 , and Philippe Prokocimer1

Abstract
Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We
evaluated the pharmacokinetics of tedizolid in elderly subjects to guide dosing recommendations.In an open-label phase 1
study (ClinicalTrials.gov identifier NCT01496677), 14 elderly (65 years) and 14 younger control (18–45 years) subjects
each received a single oral dose of tedizolid phosphate 200 mg. Blood samples were collected before dose and more
than 72 hours after dose. The pharmacokinetic parameters of tedizolid after a single dose were similar in both age
groups. Geometric mean ratios (elderly/younger controls) and corresponding 90% confidence intervals were maximum
observed plasma concentration (Cmax ), 1.091 (0.917–1.297); AUC from time 0 extrapolated to infinity (AUC0– ), 1.132
(0.954–1.343). Tedizolid plasma exposure was similar in elderly and younger control subjects. The findings indicated that
after intravenous or oral administration of tedizolid phosphate 200 mg once daily, no dose adjustment was warranted in
elderly subjects to achieve therapeutic levels.

Keywords
oxazolidinone, tedizolid, ABSSSI, SSTI, population pharmacokinetics, antibacterial

Acute bacterial skin and skin structure infections
(ABSSSIs), particularly those caused by methicillin-
resistant Staphylococcus aureus, are a significant
problem in both inpatient and outpatient settings and
constitute a growing health care burden.1–3 ABSSSIs,
formerly referred to as complicated and uncomplicated
skin and skin structure infections, are primarily caused
by gram-positive pathogens and in the past decade
community-acquired methicillin-resistant Staphylo-
coccus aureus has become a predominant cause of
ABSSSIs in the United States.2 The incidence of S.
aureus ABSSSIs in the United States has nearly dou-
bled in recent years and is highest among the elderly
(65 years of age).4 Hospitalizations for S. aureus
ABSSSIs have also increased in recent years, with the
highest incidence, longest duration of hospitalization,
and highest inpatient costs observed again in the
elderly population.4 Instituting appropriate and timely
antibacterial therapy is therefore a key consideration
in older patients.
Tedizolid, the active moiety of the prodrug tedizolid
phosphate, is an oxazolidinone antibacterial that has
been approved for the treatment of ABSSSIs.5–10 Te-
dizolid phosphate is rapidly and extensively converted
by endogenous phosphatases to its microbiologically
active moiety, tedizolid, after administration.6,7 In the 2
phase 3 trials in patients with ABSSSIs, ESTABLISH-
1 and ESTABLISH-2, the percentage of patients re-
ceiving tedizolid (200 mg once daily for 6 days) who
achieved early clinical response was 79.5% and 85%,
respectively, compared with 79.4% and 83% of pa-
tients receiving linezolid (600 mg twice daily for 10
days). Both trials met their primary prespecified non-
inferiority end point and showed that tedizolid was
generally well tolerated. Noninferiority was concluded
if the lower limit of the 95% confidence interval was
greater than −10%.8–10 The pharmacokinetic (PK)
profile of tedizolid has previously been examined in
subjects aged 18–60 years, with studies demonstrat-
ing that tedizolid has a favorable PK profile, high
bioavailability, and an elimination half-life that allows
for once-daily dosing, interchangeability of oral and
1 Clinical Development, Merck & Co., Inc., Kenilworth, NJ, USA
2 Minassian Biostatistics, Inc., San Diego, CA, USA
Submitted for publication 5 June 2017; accepted 8 November 2017.
Corresponding Author:
Shawn Flanagan, PhD, 15836 Prairie Vista Road, Poway, CA 92064
(e-mail: sf.in.sd@earthlink.net)
2 Clinical Pharmacology in Drug Development 2018, 00(0)
intravenous formulations, and reduced potential for mi-
tochondrial toxicity.11–13 In vitro studies showed that
conjugation of tedizolid is mediated via multiple sul-
fotransferase (SULT) isoforms (SULT1A1, SULT1A2,
and SULT2A1).5,6 Elimination of tedizolid is primarily
hepatic as a noncirculating sulfate conjugate.7
Previously published population PK analyses based
on phase 3 trial data (ESTABLISH-1 [NCT01170221]
and ESTABLISH-2 [NCT01421511]) in patients aged
12 years (18 years in ESTABLISH-1) with a diag-
nosis of ABSSSI8,9 showed no effect of age on tedizolid
plasma exposures.14 Similarly, this analysis determined
that dose adjustment was not necessarily based on sex,
race, body size measures, and renal or hepatic function.
To guide dosing recommendations for elderly pa-
tients, who constitute a significant proportion of the
population treated with tedizolid for ABSSSIs, we com-
pared the PK profile and safety in elderly subjects
(65 years) and younger control subjects following a
single 200-mg oral dose of tedizolid phosphate.
Methods
Analysis Population
The open-label, single-center phase 1 study
(ClinicalTrials.gov identifier NCT01496677) enrolled
elderly subjects  65 years; at least 5 subjects were 75
years. Subjects were in good health, had no clinically
significant abnormalities, had body mass indexes 18.0
and 35.0 kg/m2 and estimated creatinine clearance
(CrCl; Cockcroft-Gault equation)  60.0 mL/min,
and were receiving a stable dosage of prescription or
nonprescription medications or herbal supplements.
Control subjects were matched for sex, race, and body
mass index, were 18 to 45 years of age, and had CrCl
 90.0 mL/min.
This study was conducted at Covance, Daytona
Beach, Florida, in accordance with current United
States Food and Drug Administration regulations,
International Conference on Harmonisation Good
Clinical Practice guidelines, basic principles of the
Declaration of Helsinki, and local ethical and legal
requirements. The Covance Clinical Research Unit
institutional review board approved the protocols,
amendments, and informed consent documents before
study initiation. Informed consent was obtained from
all participants included in the study.
Pharmacokinetic Sampling
Full-profile samples were collected during the phase 1
study. Twenty-eight subjects (14 elderly and 14 con-
trols) each received a single oral dose of 200 mg tedi-
zolid phosphate in the morning. Blood samples were
obtained before dose (0.5 hours before tedizolid admin-
istration) and at regular intervals up to 72 hours after
dose (0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, and
72 hours).
Samples were extracted with acetonitrile and pre-
cipitated with hydrochloric acid, followed by low-speed
(3800 g) centrifugation at room temperature for 5 min-
utes. Supernatants were evaporated to dryness and re-
constituted in methanol/water (3:7, v/v). Tedizolid and
internal standard (stable, isotopically labeled 13 CD3 -
tedizolid) were separated by high-performance
liquid chromatography (1200 series; Agilent
Technologies, Santa Clara, California) with a Hypersil
GOLD aQ column (50 × 3 mm, 5-μm particle size;
Thermo Fisher Scientific, Waltham, Massachusetts).
Samples were eluted using a gradient from 80%
20 mM ammonium phosphate (pH 9.0)/20% methanol
to 80% methanol over 4.5 minutes at a flow rate of
0.5 mL/min. The column eluent was directed to an
API 4000 triple quadrupole mass spectrometer (AB
SCIEX, Framingham, Massachusetts) for compound
quantification. Tedizolid was detected and quantified
by tandem mass spectrometry in multiple reaction-
monitoring mode (transitions: tedizolid 371→343).
The intra- and interassay precision relative standard
deviations (SDs) were 3.3% or less and 2.2% or less,
respectively, for this method for tedizolid quanti-
tation. The lower limit of quantitation for plasma
concentration values was 5 ng/mL.
Data were processed using the Analyst 1.4.1 software
package (AB SCIEX) and the Watson LIMS labora-
tory information management system (Thermo Fisher
Scientific).
Noncompartmental Pharmacokinetic Analyses
The PK analysis set consisted of subjects who received
tedizolid phosphate and for whom at least 1 valid blood
sample was collected. At least 3 quantifiable postdose
concentrations were required for calculation of any
PK parameter. Parameters of interest were maximum
observed plasma concentration (Cmax ), time to occur-
rence of Cmax (Tmax ), area under the concentration–
time curve (AUC) from time 0 to the last measurable
concentration (AUC0–t ), AUC from time 0 extrapo-
lated to infinity (AUC0– ), terminal half-life (t½ ), oral
clearance (Cl/F), and volume of distribution during the
terminal phase (Vz /F). PK calculations were performed
using WinNonlin (version 5.2 or higher; Pharsight Cor-
poration).
The parameters Cmax and AUC0– were compared
between elderly subjects and controls by calculating
the geometric mean ratio (GMR; [geometric mean
elderly]/[geometric mean younger controls]) and corre-
sponding 90% confidence intervals (CIs) using analysis
of variance (ANOVA) models. ANOVA models in-
cluded log of the PK parameter as the response and
group as a fixed factor with 2 levels (elderly and younger
Flanagan et al
Table 1. Baseline Demographic and Clinical Characteristics of
the Phase 1 Study Population
Elderly
Characteristic n = 14
Age (y), mean ± SD (range) 71.9 ± 5.08
(66–78)
Male, n (%) 7 (50)
White, n (%) 14 (100)
Non-Hispanic or Latino, n (%) 12 (85.7)
BMI (kg/m2 ), mean ± SD 28.2 ± 3.6
IBWa (kg), mean ± SD 60.1 ± 9.8
CrCl (mL/min), mean ± SD 75.0 ± 15.3
BMI, body mass index; CrCl, creatinine clearance; IBW, ideal body weight;
SD, standard deviation.
a IBW was calculated using the Devine formula: 50 + 2.3 kg for each inch
over 5 feet (men) or 45.5 + 2.3 kg for each inch over 5 feet (women).
control subjects). Relationships between age and PK
parameters such as AUC and Cmax were explored using
scatterplots and regression analyses. Linear regression
analyses were performed with PK parameters (Cmax and
AUC0– ) as the predictor and age as the response. The
study was powered to observe differences between age
groups if the GMR was outside the range of 0.7 to 1.43.
Safety Analyses
The safety population consisted of all subjects who
received the study drug. Safety parameters included
adverse events (AEs), clinical laboratory values
(hematology, chemistry, urinalysis), vital signs, electro-
cardiography (ECG) findings, physical examinations
with basic neurologic examinations, and Snellen visual
acuity examinations.
Results
Baseline Demographic and Clinical Characteristics of
Subjects
Demographic and clinical characteristics of 28 subjects
(elderly, n = 14; younger controls, n = 14) enrolled in
the phase 1 study are shown in Table 1. Mean age was
71.9 years for elderly subjects and 33.7 years for con-
trols; 6 subjects in the elderly group were 75 years of
age. Other baseline characteristics were similar between
the groups, with the exception of CrCl, which was lower
in elderly patients.
Pharmacokinetics of Tedizolid in Elderly Versus
Younger Subjects
Figure 1a,b shows the concentration–time profile of
tedizolid in older and younger subjects. Both groups
had similar t½ values for tedizolid: 12.3 hours in the
elderly group and 11.8 hours in younger controls.
Cmax and AUC0– values for individual patients are
3
plotted in Figure 1c,d; the data show greater variabil-
ity of these parameters in the elderly group. Median
Cmax and AUC0– were higher in elderly subjects than
Control
in younger controls, with extensive overlap in the range
n = 14
of exposures (ie, the entire interquartile range of the
33.7 ± 7.25 younger subjects was contained within the interquartile
(25–45) range of the elderly group). GMRs (90%CIs) for elderly
7 (50) subjects compared with younger controls were Cmax ,
14 (100) 1.091 (0.917–1.297), and AUC0– , 1.132 (0.954–1.343).
11 (78.6) Although increases of approximately 9% to 13% in
27.1 ± 2.9 these parameters were observed in elderly subjects com-
65.0 ± 10.9 pared with younger controls, all GMRs and 90%CIs
137.0 ± 31.5
were within the prespecified range of 0.7 to 1.43,
and all CIs included 1. Plasma PK parameters were
similar between elderly and younger control subjects
(Table 2).
The scatterplots in Figure 2a,b show that there was
no meaningful correlation between age, AUC0– , and
Cmax . R2 values were 0.045 for the relationship between
age and tedizolid Cmax and 0.1 for the relationship be-
tween age and AUC0– . Tedizolid exposures for the 6
patients  75 years of age were distributed across the
entire range of exposures.
Individual AUC values plotted as a function of ideal
body weight (IBW) are shown in Figure 2c,d. Unlike
age, increases in IBW showed a trend of decreased PK
exposure, with R2 values of 0.455 and 0.310 for Cmax
and AUC0– , respectively, in both the elderly and the
younger control subjects.16
Safety
There were no clinically meaningful changes in vital
sign, physical evaluation, Snellen visual acuity exam-
ination, ECG, and laboratory, hematology, or clinical
chemistry measurements in the phase 1 study. Only one
AE—a mild pretreatment headache—occurred during
the study in the elderly group. No treatment-emergent
AEs or serious AEs occurred in either group. These re-
sults support the overall good tolerability of tedizolid,
as previously reported in the phase 3 studies.8–10
Discussion
There were no clinically meaningful changes in the rate
or extent of exposure following administration of a
single oral dose of tedizolid 200 mg in elderly sub-
jects compared with younger control subjects. Tedizolid
AUC and Cmax GMRs were increased by approximately
13% and 9%, respectively, in elderly subjects, but the
90%CIs remained within the prespecified range of 0.73
and 1.43, and all CIs included 1. Regression analyses
confirmed that PK parameters were not influenced by
age.
Our analysis showed a decrease in exposure with
increasing IBW, but this relationship was observed in
4 Clinical Pharmacology in Drug Development 2018, 00(0)

Figure 1. Tedizolid plasma concentration–time profile and exposure parameters in elderly and younger control subjects. (a) Plasma
concentration–time profile, linear scale. (b) Plasma concentration–time profile, semilogarithmic scale. (c) Cmax . (d) AUC0– . AUC0– ,
area under the plasma concentration–time curve from time 0 extrapolated to infinity based on the apparent terminal rate constant;
Cmax , maximum observed concentration. Solid lines represent the median and interquartile ranges; dotted lines represent the mean.

both age groups. In a previous population PK anal-
ysis of intravenous and oral tedizolid, IBW had a
statistically significant, but not clinically meaningful,
effect on PK, with only a 38% higher AUC at steady
state in patients at the 5th percentile of IBW than in
those at the 95th percentile of IBW.14 As expected,
alanine transaminase and aspartate transaminase were
not important covariates in the population PK anal-
ysis. Total bilirubin was a statistically significant co-
variate but did not account for variability in PK. The
mean total bilirubin values in this study were com-
parable in the 2 groups (elderly, 0.65 ± 0.27 mg/dL;
control, 0.54 ± 0.24 mg/dL).14 Population PK results
were not available at the time of this PK study, but in
hindsight, control subjects should have been matched
by IBW. Fortunately, given the relatively small influ-
ence of this covariate on PK, this was not a significant
limitation.
Of note, although both groups were in the nor-
mal range, the CrCl was reduced by 50% in elderly
subjects compared with younger control subjects in
our analysis. Although age-related declines in renal
plasma flow and glomerular filtration rates (GFR) have
been observed, these changes are neither uniform nor
consistent.17 Furthermore, the true GFR of healthy el-
derly remains within the normal range and is likely un-
derestimated by CrCl and calculated Cockcroft-Gault
clearance; therefore, the PK of renally excreted drugs
are not affected to a clinically significant extent in the
elderly.18
The single oral dose of tedizolid 200 mg was well
tolerated by both elderly and younger control subjects.
Only a mild AE was reported in an elderly subject; no
patient discontinued because of an AE. Once-daily dos-
ing, high protein binding, and lack of significant accu-
mulation after multiple dosing may all contribute to a
Flanagan et al 5

Table 2. Plasma Pharmacokinetics of Tedizolid in Elderly Given that the elderly have a high incidence of
and Younger Control Subjects ABSSSIs caused by S. aureus and of hospital admis-
sions because of S. aureus–associated skin and soft-
Elderly Control
tissue infections,4 they are a significant population that
Parametera n = 14 n = 14
may require antibiotic treatment. In the 2 phase 3 tri-
Cmax , μg/mL 2.6 ± 0.7 2.4 ± 0.5 als in patients with ABSSSIs, the efficacy of tedizolid
Tmax , h 3.0 (1.5–8.0) 3.1 (1.5–8.0) (200 mg once daily for 6 days) was noninferior to that
t½ , h 12.3 ± 1.3 11.8 ± 1.0 of linezolid (600 mg twice daily for 10 days). In these
AUC0–t , μg·h/mL 34.2 ± 10.3 29.5 ± 5.7 trials, early clinical response to tedizolid 48–72 hours
AUC0– , μg·h/mL 34.7 ± 10.6 29.9 ± 5.9 after the initiation of dosing was slightly lower in pa-
CL/F, L/h 5.2 ± 1.6 5.7 ± 1.3 tients at least 65 years (73.6%) than in those younger
Vz /F, L 91.6 ± 28.2 96.6 ± 21.0 than 65 years (82.6%); however, clinical success rates as
AUC0–t , area under the plasma concentration–time curve from time 0 assessed by the investigator at the posttherapy evalua-
to the last measurable concentration; AUC0– , area under the plasma tion were similar in patients older and younger than 65
concentration–time curve from time 0 extrapolated to infinity based on
years (95.4% vs 93.3%; data on file). Age will be eval-
the apparent terminal rate constant; CL/F, oral clearance, calculated as
dose/AUC0– ; Cmax , maximum observed concentration; SD, standard uated as a covariate for both safety and efficacy in an
deviation; Tmax , time to occurrence of Cmax ; t½, apparent terminal half- ongoing study in ventilator subjects with pneumonia, a
life; Vz /F, volume of distribution during the terminal phase. population that has been historically much older than
a Arithmetic mean ± SD are reported for all parameters except T
max ,
which reports median (range).
subjects with skin infections.19,20
A single-dose study, which is often more sensitive at
detecting differences, was considered appropriate for
this analysis because the PK of tedizolid is generally
reduced potential with tedizolid for side effects related similar for single- and multiple-dose administration
to higher oxazolidinone exposure.13 and because tedizolid accumulation at steady state

Figure 2. Relationship between PK parameters. (a) Tedizolid and age, Cmax . (b) Tedizolid and age, AUC0– . (c) Tedizolid and ideal
body weight, Cmax . (d) Tedizolid and ideal body weight, AUC0– . AUC0– , area under the plasma concentration–time curve from time
0 extrapolated to infinity based on the apparent terminal rate constant; Cmax , maximum observed concentration. Line represents a
linear regression line with either AUC0– or Cmax as the predictor and age as the response.
6 Clinical Pharmacology in Drug Development 2018, 00(0)
is minimal.12 Values for PK parameters obtained in
the younger control population were consistent with
previous findings11,12 and validate the methods used
in and the findings of this study. Inclusion of a con-
currently tested younger control group for comparison
increases the reliability of the findings compared with
use of historical controls. Although the phase 3 studies
enrolled only a small number of older patients, the PK
data from patients with ABSSSIs support the phase
1 study findings. There was no clinically meaningful
relationship between tedizolid plasma exposure and
age in the phase 3 studies of tedizolid in patients
with ABSSSIs.14 Collectively, these data suggest that
tedizolid dose adjustment is not warranted to achieve
therapeutic drug levels in older patients.
In conclusion, the similarity in tedizolid PK between
elderly and younger control subjects and the absence of
an age effect on tedizolid PK in patients with ABSSSIs
suggest that the 200-mg dose can be used in elderly pa-
tients without the need for dose adjustment.
Acknowledgments
The authors thank Julie A. Passarell and Jill Fiedler-Kelly
(Cognigen Corporation, a SimulationsPlus company, Buffalo,
New York) for valuable discussions and comments on an
earlier version of this article. Medical writing and editorial
assistance were provided by Sally Mitchell, PhD, and Anna
Battershill, MSc (ApotheCom, Yardley, Pennsylvania). This
assistance was funded by Merck & Co., Inc., Kenilworth, New
Jersey.
Declaration of Conflicting Interests
Shawn D. Flanagan and Philippe Prokocimer were employ-
ees of Merck & Co., Inc., Kenilworth, New Jersey, at the
time of the study. Sonia L. Minassian was a consultant to
Merck and was compensated for supporting this research.
The authors have no other funding or conflicts of interest to
disclose.
Funding
Funding for this research was provided by Merck & Co., Inc.,
Kenilworth, New Jersey.
Author Contributions
Shawn D. Flanagan contributed to the conception and design
of the study, the acquisition and analysis of data, and the writ-
ing and critical review or revision of the manuscript. Sonia L.
Minassian contributed to the analysis of data and the writ-
ing and critical review or revision of the manuscript. Philippe
Prokocimer contributed to the conception and design of the
study, the interpretation of results, and the writing and critical
review or revision of the manuscript.
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