ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2011, p. 583–592
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Vol. 55, No. 2
Phase 2, Randomized, Double-Blind, Dose-Ranging Study Evaluating
the Safety, Tolerability, Population Pharmacokinetics, and Efficacy
of Oral Torezolid Phosphate in Patients with Complicated
Skin and Skin Structure Infections?†‡
P. Prokocimer,1* P. Bien,1J. Surber,2P. Mehra,3C. DeAnda,1J. B. Bulitta,4and G. R. Corey5
Trius Therapeutics, Inc., 6310 Nancy Ridge Road, Suite 105, San Diego, California 921211; SERRG, Inc.,
5210 Armour Road Suite 400, Columbus, Georgia 319042; eStudy Site, 752 Medical Center Court, Suite 105,
Chula Vista, California 919113; Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 122084;
and Duke Clinical Research Institute, 2400 Pratt Street, Durham, North Carolina 277055
Received 19 January 2010/Returned for modification 9 June 2010/Accepted 2 November 2010
Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-
generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species
including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three
levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure
infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive
pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis,
and 5.9% had wound infections. S. aureus, the most common pathogen, was isolated in 90.3% of patients
(139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2%
at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of
lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated
at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No
patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic
modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of
the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters
(35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant
differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase
The incidence of drug-resistant Gram-positive organisms
such as methicillin-resistant Staphylococcus aureus (MRSA)
has reached a point where new therapeutic options are ur-
gently needed. Although MRSA infections were previously
restricted primarily to hospitals and other health care facilities,
a new MRSA clone (USA300) has spread throughout the United
States, replacing methicillin-sensitive S. aureus (MSSA) as the
dominant cutaneous pathogen in a community setting (com-
munity-associated MRSA [CA-MRSA]). Although most
commonly associated with skin and skin structure infections,
CA-MRSA can also produce more serious or life-threaten-
ing infections such as pneumonia, neonatal sepsis, osteomyeli-
tis, and bacteremia (1, 6, 28). Of particular concern is the
diagnosis of rapidly developing cutaneous infections resulting
from CA-MRSA in patients with no established health care
risk factor. This organism appears to be spreading by casual
contact or through contaminated fomites (6, 38). New commu-
nity-based clones of MRSA have also surfaced in many parts of
the world outside the United States (10, 34, 40, 41). Increasing
resistance (15) of these newly identified CA-MRSA strains is
similarly alarming. Recent reports indicate that CA-MRSA
USA300 has spread into hospital settings and may be the
dominant cutaneous pathogen in hospitals over the next de-
cade (19, 20, 32).
The efficacy of vancomycin, the parenteral antibiotic most
commonly used to treat serious MRSA infections, has been
increasingly compromised by the emergence of strains that
have intermediate sensitivity to vancomycin (vancomycin-in-
termediate S. aureus [VISA]) and others that contain subpopu-
lations of VISA strains hidden within apparently susceptible
organisms (heterogeneous VISA [hVISA]). Difficult to detect,
hVISA strains have been associated with treatment failures in
a variety of settings (2, 17, 18, 37). Currently, hVISA comprises
5 to 10% of MRSA isolates in the United States (14), and its
incidence appears to be increasing. In addition, there are well-
documented increases in vancomycin MICs, which may even-
tually compromise the continued use of vancomycin in many
locations (9, 16, 22). Other options for treating these increas-
ingly resistant Gram-positive infections are limited by newly
identified resistance, toxicity, and cost as well as the need for
parenteral administration (5, 9, 11, 13, 21, 26). For example,
* Corresponding author. Mailing address: Trius Therapeutics, Inc.,
6310 Nancy Ridge Drive, Suite 105, San Diego, CA 92121. Phone:
(858) 452-0370. Fax: (858) 677-9975. E-mail: pprokocimer@triusrx
† Supplemental material for this article may be found at http://aac
?Published ahead of print on 29 November 2010.
‡ The authors have paid a fee to allow immediate free access to this
there is growing concern about linezolid-resistant strains, es-
pecially due to the novel chloramphenicol-florfenicol resis-
tance (cfr) mechanism that leads to resistance to multiple
classes of ribosome-targeting antibiotics, including linezolid,
clindamycin, streptogramins, and pleuromutilins. This mecha-
nism of resistance is particularly troubling due to its associa-
tion with transposons and plasmids, resulting in a high proba-
bility of rapid spread (36). Clearly, new antibacterial drugs,
especially with oral formulations, are urgently needed to treat
infections due to drug-resistant Gram-positive bacteria in both
hospital and community settings.
Torezolid (TR-700) is the active moiety of the prodrug
torezolid phosphate (TR-701), a novel second-generation
oxazolidinone. Torezolid is active against all clinically rele-
vant Gram-positive pathogens, some fastidious Gram-nega-
tive pathogens, and the atypical Chlamydia spp. and has dem-
onstrated 4- to 16-fold greater activity than linezolid against
Gram-positive species including MRSA (35, 36). Unlike lin-
ezolid, a bacteriostatic agent, torezolid phosphate was shown
to be bactericidal in vivo when tested in a mouse thigh infection
model (23). Moreover, torezolid retains activity against lin-
ezolid-resistant strains of S. aureus including cfr-harboring
Results of a phase 1 study of once-daily (QD) oral doses of
200, 300, or 400 mg of torezolid phosphate showed limited
dose-dependent effects on platelet and absolute neutrophil
counts over the 21-day study (4). These hematologic effects
were not seen in patients treated with 200 mg, nor were they
apparent during the first week in subjects treated with 300 mg
or 400 mg (33). Given these results, this phase 2 dose-ranging
study was performed to evaluate the safety, efficacy, and tol-
erability of 200 mg, 300 mg, and 400 mg of torezolid phosphate
once daily for 5 to 7 days in the treatment of patients with
complicated skin and skin structure infections (cSSSI). In ad-
dition, we employed a three-stage hierarchical population
pharmacokinetic (PK) modeling strategy to borrow informa-
tion from a dose-ranging study in healthy volunteers (data not
reported here) with frequent sampling during the absorption
and disposition phases. Compared with standard population
PK analyses, the three-stage hierarchical approach has the
advantage of incorporating prior information with uncertainty
for modeling of data from patients.
(Part of this research was presented at the 49th Interscience
Conference on Antimicrobial Agents and Chemotherapy, San
Francisco, CA, 12 to 15 September 2009 .)
MATERIALS AND METHODS
This phase 2 study was a dose-ranging, randomized, double-blind, noncon-
trolled study conducted at 12 sites (8 enrolled patients) in the United States.
The study was approved by institutional review boards, and informed consent
was given to all patients before enrollment. The study was conducted in
accordance with International Conference on Harmonization (ICH) and
FDA guidelines, good clinical practice (GCP), and the Declaration of Hel-
Male or female in-hospital patients or outpatients 18 to 75 years old diagnosed
with cSSSI caused by a suspected or confirmed Gram-positive pathogen were
eligible for enrollment. Infections under study were abscesses (with at least 2 cm
of surrounding induration or requiring incision and drainage), surgical or post-
traumatic wounds, and deep extensive cellulitis. All patients were required to
have at least two of the following signs and symptoms: purulent or seropurulent
drainage, erythema, fluctuance, heat or warmth, pain or tenderness, swelling or
induration, or requirement for surgical drainage. Additionally, at least one sign
of systemic infection was required: oral temperature of ?38°C, white blood cell
count of ?10,000 cells/mm3, or ?10% immature neutrophils. Systemic signs
were not required in patients with lesions greater than 5 cm in diameter.
Excluded diagnoses were diabetic foot infection, gangrene, perirectal ab-
scess, burns, decubitus or ischemic ulcers, necrotizing infection, infection at
a central catheter site or near a prosthetic device, or presence of metastatic
infection such as septic arthritis, endocarditis, or osteomyelitis. Patients were
excluded for the following reasons: creatinine clearance of ?52 ml/min esti-
mated by Cockroft-Gault formula, hepatic disease (aspartate transaminase
[AST] or alanine aminotransferase [ALT] of ?3 times the upper limit of
normal [ULN] or bilirubin of ?1.5 times the ULN or alkaline phosphatase of
?3 times the ULN), human immunodeficiency virus (HIV) infection with a
CD4 count of ?200 cells/mm3, neutropenia with absolute neutrophil counts
of ?1,000 cells/mm3, Bazett-corrected QT interval (QTCB) of ?450 ms in
males or 470 ms in females, or body mass index of ?35 kg/m2. More than 24 h
of antibiotic therapy within 96 h prior to randomization was prohibited unless
the patient was considered a failure after at least 48 h of therapy. The use of
serotonergic agents, sympathomimetic amine derivatives, chronic systemic
corticosteroids the equivalent of ?10 mg/day of prednisone, for more than 14
days, or a high-tyramine diet was prohibited. Patients with a history of
hypertensive crises, uncontrolled hypertension, migraine headaches, gastro-
intestinal resection, advanced alcohol-related disease, uncontrolled diabetes,
chronic systemic immunosuppressive therapy, known or suspected bacter-
emia, or any life-threatening condition were also excluded from enrollment.
The study drug was supplied as 200 mg of torezolid phosphate disodium salt
capsules and could be taken with or without food. Molecular weights are 370.34
for torezolid, 450.32 for torezolid phosphate-free acid, and 494.28 for torezolid
phosphate disodium salt. (Torezolid phosphate-free acid is the formulation to be
used in future clinical trials.)
Patients were randomized 1:1:1 using a central interactive voice response
system (IVRS) to receive 200, 300, or 400 mg of oral torezolid phosphate
disodium salt (equivalent to 149.9, 224.8, and 299.7 mg of torezolid) once daily
for at least 5 but not more than 7 days. Participants and investigators were blind
to treatment assignment. Duration of therapy was determined by the investigator
based on the patient’s response, including resolution or improvement of signs
and symptoms and improvement of abnormal inflammatory markers. No adjunc-
tive antimicrobial therapy was allowed. Patients enrolled before culture results
were available and found to require Gram-negative antimicrobial coverage were
discontinued from the study.
The primary objective of the study was to determine the clinical response
rate of each dose group at the test-of-cure (TOC) visit in the clinically
evaluable (CE) and clinical modified-intent-to-treat (cMITT) populations.
Secondary objectives included cure rates at the end-of-therapy (EOT) visit,
microbiological response rates, the safety profile of each dose group, and the
characterization of absorption and disposition of torezolid using population
Directly observed therapy and clinical assessments were performed as follows:
on screening/day 1; days 2, 3, and 5; at an EOT visit; at a TOC visit (7 to 14 days
posttreatment); and at a late follow-up (LFU) visit (21 to 28 days posttreatment,
in office or by telephone). Patients were allowed to take the study drug at home
on day 4 and day 6. At each visit, a thorough examination of the cSSSI site, vital
signs assessment, and physical examination were performed; samples for chem-
istry and hematology laboratory testing were sent to the central reference labo-
ratory (Eurofins Medinet, Chantilly, VA), and assessment of concomitant med-
ications and adverse events were completed. An electrocardiogram (ECG) was
performed at screening and repeated at the EOT visit. Samples for microbiology
testing were evaluated by a local laboratory, with confirmatory identification and
susceptibility testing performed at the central laboratory.
The investigators assessed the clinical outcome at both the EOT and TOC
visits. Clinical cure was defined as resolution of the infection or improvement of
signs and symptoms of the cSSSI such that no further treatment was required. A
clinical failure was defined as either persistence or incomplete resolution of
cSSSI or development of new signs and symptoms such that further antibiotic
therapy was required, unplanned surgical intervention was necessary after 48 h
on therapy, a new diagnosis of osteomyelitis was made, a treatment-limiting
adverse event leading to discontinuation of the study drug was identified, or
death due to cSSSI was determined. An indeterminate outcome was assessed
under the following circumstances: a treatment change before at least two doses
of study medication, death unrelated to cSSSI, osteomyelitis at baseline (diag-
nosed after enrollment), or isolation of a Gram-negative organism at baseline
that required treatment or when the patient was lost to follow-up before the
All patients receiving the study drug were included in the modified intent-to-
584 PROKOCIMER ET AL.ANTIMICROB. AGENTS CHEMOTHER.
treat (MITT) population and evaluated for safety. Safety assessments included
reviews of vital signs, physical examinations, ECG findings, laboratory evalua-
tions, and adverse events. An independent cardiologist performed a blinded
overread of all ECGs.
This study was not statistically powered to determine differences between dose
groups. The sample size chosen was to provide clinically meaningful information
on safety, tolerability, and efficacy as well as the PK profile of each of three
torezolid phosphate dose levels. All safety and efficacy data for the study were
summarized using descriptive statistics for each study population. Five popula-
tions were defined for analysis: MITT, randomized patients receiving at least one
dose of study medication; cMITT, patients in the MITT population with a
diagnosis of cSSSI; microbiological modified intent-to-treat (mMITT), patients
in the cMITT with a Gram-positive bacterial pathogen isolated at baseline; CE,
patients receiving the minimum requirement of study drug, having a clinical
assessment of success or failure at the TOC visit, and having no other confound-
ing events or factors preventing assessment of outcome; and microbiologically
evaluable (ME), patients in both the CE and mMITT populations.
Blood sampling and drug assay. Serial blood samples for population PK
analysis were obtained at two time points. For the first sampling, a median of two
samples (range, one to four) per patient was obtained between 19 to 71 h after
the first dose. For the second sampling, a median of five samples (range, one to
six) per patient was obtained between 41 to 123 h after the first dose. A previous
study (3) demonstrated that torezolid phosphate was rapidly and completely
converted in vivo to torezolid, the prodrug active metabolite; therefore, only the
latter was considered in the PK analysis. Torezolid was extracted from plasma by
acetonitrile (ACN)–methanol–0.1% formic acid protein precipitation (5:4:1, vol/
vol/vol). The supernatant was diluted 1:3 with high-performance liquid chroma-
tography (HPLC)-grade deionized water; 50 ?l of the resulting solution was
analyzed using a validated liquid chromatographic method consisting of an iso-
cratic step of ACN–0.05% trifluoroacetic acid (25:75, vol/vol) on a Higgins
Analytical Targa C18column and positive-ion heated nebulizer mass spectro-
metric detection. The analytical method was selective for torezolid and was linear
(using 1/x fit with mean r2values of 0.9996 ? 0.0002) over the concentration
range of 0.16 to 1,000 ng/ml, with a lower limit of quantification (LLQ) of 0.16
ng/ml. Mean analyte recovery values ranged from 110 to 117% (standard devi-
ation, ? 4 to 18%). Intra-assay accuracy values for the quality controls ranged
from 90.4 to 98.0% with precision (coefficient of variation [CV]) values between
1.46 and 6.90%. Interassay accuracy values for the quality controls ranged from
94.9 to 102%, with CV values between 3.29 to 5.50%.
Structural model. Models with one, two, or three disposition compartments
were assessed. Absorption of the prodrug torezolid phosphate and conversion of
torezolid phosphate to torezolid were modeled by a first-order process with or
without a lag compartment. Additionally, a previously developed semiphysiologi-
cal absorption model (8) was evaluated. As torezolid phosphate did not achieve
quantifiable concentrations in plasma, we simplified the structural model in that
we did not include the plasma concentrations of the prodrug as a dependent
To explore a potential saturation of torezolid elimination, we considered
various models for drug elimination. These included models with first-order
elimination, mixed-order (Michaelis-Menten) elimination, parallel mixed-order
and first-order elimination, and autoinhibition of clearance. Similar to the model
with penetration of drug into an inhibition compartment proposed by Plock et al.
(31) for linezolid, the model we assessed included an inhibition compartment.
The plasma concentration of torezolid was assumed to stimulate the input into
the inhibition compartment, and this compartment subsequently inhibited the
clearance of torezolid.
Parameter variability model. An exponential parameter variability model was
used to describe the between-subject variability (BSV) and between-occasion
variability (BOV) of PK parameters. The BSV was modeled by a block-diagonal
variance-covariance matrix with one block for the disposition parameters and
one block for the absorption parameters. We included BOV for the absorption
but not for the disposition parameters.
Residual error model. Residual unidentified variability was explained by an
additive plus proportional error model.
Estimation. Population PK modeling was conducted in S-ADAPT (version
1.56) using an importance sampling method (pmethod?4 in S-ADAPT) of the
Monte Carlo parametric expectation maximization (MC-PEM) algorithm. To
bridge between an intensively sampled phase 1 study in healthy volunteers
(data not shown here) and the present phase 2 study in patients but with
fewer samples, we employed a three-stage hierarchical approach (hprior?1
option in S-ADAPT). Compared to a standard population PK analysis, the
three-stage hierarchical approach has the advantage of borrowing information
from healthy volunteers for the purposes of analyzing patient data and account-
ing for uncertainty in the prior means and prior variability estimates. The ability
to incorporate uncertainty in the prior information is the most important advan-
tage of the three-stage hierarchical method compared to a maximum a posteriori
(MAP) Bayesian approach. The MAP Bayesian method assumes that the prior
means and prior variability estimates are known with certainty and are identical
between the prior data (from healthy volunteers in this case) and the patient data
to be analyzed. These assumptions are not made by the three-stage hierarchical
Sensitivity analysis for priors. We assessed the impact of the extent of uncer-
tainty for the prior means and prior variability estimates on the final parameter
estimates. As the ratio of the area under the concentration-time curve for free
drug to the MIC (fAUC/MIC) is the most predictive PK/pharmacodynamic index
for torezolid (23), this sensitivity analysis focused on clearance (CL). We eval-
uated the following cases: case A, with the uncertainty taken directly from the
estimates for healthy volunteers; case B, which is the same as case A but with
uncertainty for CL and for BSV of CL increased by 16-fold (on variance scale);
case C, which is the same as case B but with uninformative priors for the residual
error parameters; case D, which is the same as case C but with uninformative
priors on all absorption parameters; and case E, no priors (i.e., standard popu-
lation PK analysis).
Model selection and qualification. The average objective function (?2 ?
log-likelihood) during the last 10 iterations, individual curve fits, and the stan-
dard diagnostic plots were used for model selection. Predictive performance was
ensured via visual predictive checks as described previously (7).
Study population. A total of 192 patients were randomized
between September 2008 and January 2009, of which 188 re-
ceived at least one dose of study drug (63 in the 200-mg group,
63 in the 300-mg group, and 62 in the 400-mg group). No
hospitalized patients were enrolled. Figure 1 outlines the num-
ber of patients included in each analysis population. Of the 188
patients included in the MITT population and cMITT popu-
lation (same population), over 85% (164) were included in the
CE population. Patients were excluded from the CE popu-
lation due to indeterminate clinical status (n ? 16), visit
window violation (n ? 4), concomitant medication (n ? 4),
confounding medical event (n ? 1), and Gram-negative
pathogen (n ? 1); two patients had multiple reasons. Almost
FIG. 1. Populations analyzed.
VOL. 55, 2011 PHASE 2 TRIAL OF TOREZOLID PHOSPHATE FOR cSSSI 585
70% of patients in the MITT population were microbiolog-
ically evaluable (ME).
The three dose groups were well balanced across all demo-
graphic data and baseline characteristics including cSSSI diag-
nosis, presence of systemic signs of infection, and lesion size
(Table 1). The majority of incision and drainage procedures
were performed between day ?2 and day 2. Of the 10 patients
with an incision and drainage procedure between day 3 and day
7, two were in the 200-mg dose group, five in the 300-mg group,
and three were in the 400-mg group; three were assessed as
clinical failures (required additional therapy). Other proce-
dures were surgical debridement (abscess), puncture aspira-
tion (abscess), and wound packing (wound) in one patient
each. Relevant comorbid conditions included diabetes mellitus
(17.4%), admitted recent intravenous (i.v.) drug use (11.7%),
and prior skin infections at the same location as the current
infection (13.8%). Of the patients tested for hepatitis B and/or
C, 1.4% and 18.4%, respectively, had positive serology. Nine
percent of patients failed prior therapy for the cSSSI under
study. Nearly all patients (98.4%) had at least four local signs
and symptoms. The most common sites of infection were the
limbs (52.6%), trunk (22.9%), and head/neck (11.7%). Ap-
proximately 40% of patients (MITT) met the criteria for
severe cSSSI, defined as the presence of systemic signs of
infection (85%) or adjacent lymphadenopathy (15%) asso-
ciated with lesions of ?10 cm (lesion sizes ranged from 10 to
S. aureus, the most common pathogen, was isolated in 90.3%
of patients (139/154) who had a baseline pathogen; 80.6% of
these strains were MRSA. Specimens of the primary lesion
were acquired via incision, needle aspirates, or deep swabs with
leukocytes present (superficial swabs were not acceptable). Of
163 S. aureus isolates, 124 were MRSA and 39 were MSSA. Of
the 124 MRSA isolates, 123 were Panton-Valentine leukocidin
(PVL) positive by PCR (1 negative), and of the 39 MSSA
isolates, 30 were PVL positive (9 negative). All tested samples
were sensitive to vancomycin. In the severe cSSSI subgroup,
almost three-quarters of patients (73.8%) had S. aureus as the
baseline pathogen (15% MSSA and 85% MRSA). Torezolid
MIC values ranged from 0.12 to 0.5 ?g/ml for S. aureus (MIC90
TABLE 1. Patient baseline characteristics (MITT population)
Value for the parameter by treatment group
200 mg (n ? 63)a
300 mg (n ? 63) 400 mg (n ? 62)All ( n ? 188)
Sex (no. of patients ?%?)
Race (no. of patients ?%?)
cSSSI diagnosis (no. of patients ?%?)
Systemic signs of infection at baseline
Longest lesion dimension (cm)
Lesion size range (no. of patients ?%?)
5 ? 10 cm
10 ? 20 cm
40 (63.5)35 (55.6) 36 (58.1) 111 (59.0)
Incision and drainage performed
(no. of patients ?%?)
Day ?2 to day 2
51 (81.0) 49 (77.8) 52 (83.9)152 (80.9)
Other procedures (no. of patients ?%?)
Debridement (day 5)
Aspiration puncture (day 4)
Wound repacking (day 3)
an, number of patients.
586PROKOCIMER ET AL.ANTIMICROB. AGENTS CHEMOTHER.
of 0.25 ?g/ml) and did not exceed 0.25 and 0.12 ?g/ml for
Streptococcus agalactiae and Streptococcus pyogenes, respec-
Treatment. The mean duration of therapy for all treatment
groups was 6.4 days. The majority of patients (94.7%) com-
pleted study drug treatment, and no patient discontinued due
to an adverse event. Reasons for discontinuing study drug were
loss to follow-up (2.7%; 5/188 [one in the 200-mg and two each
in the 300- and 400-mg groups]), withdrawal of consent (0.5%;
1/188 [200-mg group]), S. aureus bacteremia (0.5%; 1/188 [200-
mg group]), Gram-negative infection requiring antibiotic treat-
ment (0.5%; 1/188 [300-mg group]), requiring i.v. antibiotic
treatment (0.5%; 1/188 [400-mg group]), and insufficient ther-
apeutic effect (0.5%; 1/188 [200-mg group]). As a precaution in
this first study in patients, the protocol directed that patients
with bacteremia discontinue the study drug. One patient with
bacteremia discontinued the study drug after baseline blood
culture results indicated MRSA. Three additional patients with
MRSA bacteremia at screening did not discontinue treatment;
two were considered a clinical cure, and one was considered a
failure (see supplemental material for additional information).
None of these three patients had subsequent positive blood
Clinical efficacy. Clinical cure rates at TOC were similar for
all dose groups, with an overall clinical cure rate of 87.8% in
the MITT population, 95.7% in the CE population, and 96.2%
in the ME population (Table 2). Cure rates were similar not
only for all dose groups but also for subgroups based on lesion
type, lesion size, and severity of infection (Tables 3 and 4).
Clinical cure rates in patients with S. aureus isolated at baseline
(n ? 119; ME population) was 96.6% and 96.8% for patients
with MRSA (91/94 patients). End-of-therapy results were con-
sistent with the findings at the TOC visit, with an overall
clinical cure rate of 96.6% in the CE population. No relapses
were identified at the LFU visit.
Seven patients (3.7%) were assessed as clinical failures by
the investigators. One patient was classified as a failure after 2
days of treatment, and the other six had received 7 days of
therapy before being considered failures on the study drug.
The failures were identified in one patient with cellulitis (3%),
one with a wound infection (10%), and five patients with large
Microbiological outcomes. The ME population included
69% of patients in the MITT population at TOC (n ? 133). In
an analysis of specimens from these 133 patients, torezolid
MICs were ?0.12 ?g/ml for 5.1%, 0.25 ?g/ml for 89.0%, and
0.5 ?g/ml for 5.9% of specimens. Microbiological eradica-
tion rates were similar in all treatment groups, with an
overall eradication rate of 97.7%. Eradication rates ranged
from 92.6% to 100% for MRSA and 88.9% to 100% for
MSSA in the three dose groups. The microbiologic outcome
was 100% eradication for all pathogens in the severe infec-
In the MITT population, only two patients (1%) had emerg-
ing pathogens. One patient had both Streptococcus acidomini-
mus and Streptococcus sanguinis isolated from an abscess via a
needle aspiration at baseline, and on day 7 MRSA was isolated
from a deep wound swab of the abscess. The other patient had
MRSA isolated from an incision of the abscess at baseline,
with MSSA isolated from a deep wound swab of the abscess on
day 7. None of these strains was resistant to torezolid.
Population pharmacokinetics. The choice of the structural
model was guided by the healthy volunteer data set that pro-
vided frequent sampling. Models with one disposition com-
partment yielded notably worse curve fits and an objective
function worse by 105 compared with a two-compartment dis-
position model. Addition of a third disposition compartment
yielded essentially indistinguishable curve fits and did not sig-
TABLE 2. Clinical cure rates with torezolid phosphate at TOC in
the MITT, CE, and ME populations
Cure rate by torezolid phosphate treatment group
(no. of patients in group/total no. of patients ?%?)
200 mg 300 mg 400 mg
56/63 (88.9) 56/63 (88.9) 53/62 (85.5) 165/188 (87.8)
7/63 (11.1)7/63 (11.1) 9/62 (14.5)23/188 (12.2)
55/56 (98.2) 51/54 (94.4) 51/54 (94.4) 157/164 (95.7)
1/56 (1.8)3/54 (5.6)3/54 (5.6)7/164 (4.3)
41/44 (93.2) 44/46 (95.7) 128/133 (96.2)
3/44 (6.8)2/46 (4.3) 5/133 (3.8)
aFor the MITT population, clinical failures included patients with an inde-
terminate outcome (e.g., lost to follow-up).
TABLE 3. Clinical cure rates with torezolid phosphate at TOC in
the CE population, by lesion type and size
Cure rate by torezolid phosphate dose (no. of
patients cured/total no. of patients in group ?%?)
200 mg 300 mg400 mg
5 ? 10 cm
10 ? 20 cm
TABLE 4. Clinical cure rates with torezolid phosphate at TOC in
patients with severe cSSSIa
Cure rate by torezolid phosphate dose (no. of patients
cured/total no. of patients in group ?%?)
200 mg 300 mg400 mg
aSevere cSSSI is defined as the presence of systemic signs of infection or
adjacent lymphadenopathy associated with lesions of ?10 cm.
bEOT, end of therapy; TOC, test of cure.
VOL. 55, 2011 PHASE 2 TRIAL OF TOREZOLID PHOSPHATE FOR cSSSI587
nificantly improve the objective function (P ? 0.06, likelihood
ratio test). Models with saturable elimination or autoinhibition
of clearance improved neither the objective function nor the
individual curve fits compared with a model with linear elim-
Compared with a first-order absorption model, a model with
two sequential absorption compartments linked by a first-order
process improved the objective function by 78 and yielded
notably better individual curve fits. Incorporation of the semi-
physiological absorption model improved the individual curve
fits during the absorption phase; however, this model was no-
tably more complex and affected mean CL by less than 1% and
did not affect the BSV of CL. Following the rule of parsimony,
we chose a linear model with two sequential absorption com-
partments and two disposition compartments as the simplest
model that fit data well (see supplemental material for model
structure and diagnostic plots).
Parameter estimates (Table 5) were precise, with relative
standard errors below 13% for all means and below 50% for
variance estimates (see supplemental material for variance co-
variance matrix). This model yielded an excellent predictive
performance for all three dose groups (Fig. 2).
The sensitivity analysis indicated robust parameter estimates
independent of the degree of uncertainty chosen for the priors
of cases A to D (see Materials and Methods). However, a
standard population PK analysis without use of prior infor-
mation (case E) yielded unrealistically low estimates (?4%)
for the BSV of the volume of the peripheral compartment,
intercompartmental clearance, and absorption half-life. We
chose case B for the final parameter estimates since case B
allowed CL in patients to move away more easily during esti-
mation from the prior estimates for CL in healthy volunteers
compared with case A. For case B, mean CL was 8.28 liters/h
with a coefficient of variation of 32.3% for BSV in patients. For
all cases (A to E), estimates for mean CL were within 4%, and
estimates for variance of CL were within 8% of the estimates
for case B (see supplemental material for details). We ex-
cluded 5 of 1,153 quantifiable plasma concentrations (0.43% of
observations) from the analysis since these concentrations
were implausible (i.e., a “peak-like” concentration at 24 h after
treatment). The most likely reason was an error in the re-
corded time of sampling or dosing. Exclusion of these five
observations stabilized the estimation but had essentially no
effect on the mean parameter estimates (results not shown)
since another observation was available approximately 1 to 2 h
We considered a variety of structural models and, following
the rule of parsimony, selected the simplest model that best fit
the data. Parameter estimates were determined using a state-
of-the-art three-stage hierarchical population PK approach. A
sensitivity analysis showed that the choice of uncertainty for
the prior information had only a small effect on the final
parameter estimates. The individual clearance values in each
patient differed by less than 4% between cases A to D, whereas
these differences were up to 12% for case E (without use of
A standard population PK analysis without prior informa-
tion yielded unrealistically low BSV estimates (CV of ?4%)
for several PK parameters as well as high correlation coeffi-
cients between certain pairs of PK parameters. The three-stage
hierarchical approach resolved this problem by borrowing in-
formation on the parameter estimates and model structure
with uncertainty from the data set in healthy volunteers that
provided frequent sampling.
Safety. Safety was evaluated in the MITT population. Treat-
ment-emergent adverse events (TEAEs) were reported in
69.1% of patients, the majority of which were graded mild
(72.3%) or moderate (24.6%) in severity. The most common
TEAEs (Table 6) reported were nausea (18.6%), secondary
abscess (11.7%), headache (11.2%), and vomiting (10.1%).
The most common (?5%) TEAEs reported as drug related by
the investigators were nausea, diarrhea (no reports of Clostrid-
ium difficile-related diarrhea), vomiting, and headache (Table
7). No patients discontinued study drug due to an adverse
event. There was no apparent dose-related toxicity.
Five patients (2.7%) experienced a serious adverse event
(SAE), none of which was considered possibly drug related.
There were no significantly abnormal values (using regulatory
criteria) involving absolute neutrophil count, platelet count,
bilirubin, or creatinine. Review of shift table analyses for signs
of toxicity found no clinically significant abnormalities. No
patients were discontinued from the study drug due to a lab-
Results from the centrally analyzed ECG data identified no
patients with a QTCB of ?500 ms and only one patient with a
QTCB increase of ?60 ms from baseline to EOT (374 ms at
TABLE 5. Parameter estimates for the linear population PK model for torezolid in patients with severe cSSSI
Parameter (unit) Symbol
Estimate (relative SE ?%?)
Apparent total clearance (liters/h)
Apparent volume of central compartment (liters)
Apparent volume of peripheral compartment (liters)
Apparent distribution clearance (liters/h)
Mean absorption time and mean lag time (min)
Proportional residual error
Additive residual error (mg/liter)
Tabs ? Tlagb
0.232 (46.7) 0.710 (15.3)
aEstimates refer to active torezolid (i.e., not to torezolid phosphate).
bTabs and Tlag were assumed to have the same value in each subject during each occasion. The Tabs is the inverse of the first-order absorption rate constant kabs
and Tlag is the inverse of klag.
cCV, coefficient of variation; BSV, between-subject variability; BOV, between-occasion variability.
588 PROKOCIMER ET AL.ANTIMICROB. AGENTS CHEMOTHER.
baseline and 444 ms at EOT). There were no cardiac-adverse
events associated with ECG findings.
Over the past decade, physicians have encountered an epi-
demic of S. aureus-associated complicated skin and soft tissue
infections. This rapidly increasing group of resistant staphylo-
cocci has been led by the USA300 clone of MRSA. This patho-
gen has shown the ability to exchange genetic material with
other organisms, facilitating its increasing virulence and resis-
tance. The community onset of the majority of these infections
makes the development of a robust oral antibiotic armamen-
tarium essential (29).
The present study is the first investigation of oral torezolid
phosphate for the treatment of patients with cSSSI. Torezolid
phosphate doses of 200, 300, or 400 mg daily showed excellent
efficacy in all populations with similar cure rates across the
three dose groups. Cure rates were not affected by underlying
disease, lesion type (i.e., abscess, cellulitis, or wound infection),
or infection severity (lesion size, the presence of systemic signs
of infection, or associated lymphadenopathy). As shown in the
supplemental material, all patients with clinical failure had an
MIC of 0.25 mg/liter if a pathogen was isolated. The ratio of
the AUC from 0 to 24 h (AUC0–24 h)/MIC of the patients in the
clinical failure group was similar to the interquartile range of
AUC0–24 h/MIC values in patients with clinical success. Given
this similarity in AUC0–24 h/MIC values in patients with clinical
success or failure, an exposure response relationship could not
be identified. The incidence of adverse events was acceptable
at all three dose levels, with no unexpected safety signals.
Importantly, no treatment-related hematologic abnormalities
were identified. Compliance with the study regimen allowed a
high clinical evaluability rate, and no patient discontinued
therapy due to adverse events.
FIG. 2. Visual predictive check for the population PK model of torezolid in patients for each dose group. Ideally, 10% of the observations
should fall outside the 80% prediction interval (10 to 90% percentile) on either side. P, predicted; q24h, every 24 h.
VOL. 55, 2011 PHASE 2 TRIAL OF TOREZOLID PHOSPHATE FOR cSSSI 589
The proposed population PK model for patients had excel-
lent predictive performance for the range and time course of
concentrations observed at all three dose levels of this study
(Fig. 2). This qualified our population PK model for its use in
Monte Carlo simulations to predict optimized dose regimens.
The estimates of the final model (Table 5) were robust with
regard to the extent of uncertainty in the priors.
One of the important outcomes of this study was the deter-
mination of the lowest effective dose of torezolid phosphate in
the treatment of cSSSI. A daily dose of 200 mg was found to be
as effective as higher doses. In addition, a previous study has
shown that a daily dose of 200 mg of torezolid phosphate
disodium is safe through 21 days of therapy (3). The dose of
200 mg per day is also supported by murine models that dem-
onstrated that torezolid phosphate was bactericidal even at 200
mg once daily (23). Population pharmacokinetic/pharmacody-
namic modeling and simulation using data from mice (23, 24)
and the population PK data from healthy volunteers demon-
strated that a human equivalent of 164.479 mg of torezolid,
corresponding to a 200-mg torezolid phosphate-free acid for-
mulation dose, is expected to provide a maximal killing effect
(23). These results support the clinical finding of high clinical
and microbiological cure rates in all three dose groups.
TABLE 6. Most common (?2% of treated subjects overall) treatment-emergent adverse events (MITT population)
No. of patients positive (%) by torezolid phosphate treatment group
200 mg (n ? 63)a
300 mg (n ? 63)400 mg (n ? 62) All ( n ? 188)
Any adverse event42 (66.7)44 (69.8) 44 (71.0) 130 (69.1)
General disorders and administration site conditions
Infections and infestations
Blood pressure increased
Metabolism and nutrition disorders
Nervous system disorders
Respiratory, thoracic, and mediastinal disorders
Skin and subcutaneous tissue disorders
an, number of patients in group.
TABLE 7. Most common (?5%) investigator-identified drug-
related TEAEs (MITT population)
No. of patients positive (%) by torezolid phosphate
(n ? 63)a
(n ? 63)
(n ? 62)
(n ? 188)
an, number of patients in group.
590PROKOCIMER ET AL.ANTIMICROB. AGENTS CHEMOTHER.
S. aureus was responsible for approximately 90% of micro-
biologically documented infections, of which approximately
80% were caused by MRSA. This high incidence of MRSA is
consistent with recent reports (6, 9, 20) and allowed demon-
stration of the efficacy of torezolid phosphate in eradicating
this pathogen. Low torezolid MIC values (MIC90of 0.25 ?g/
ml) confirmed the potency of torezolid.
Limitations are important to consider. As a phase 2 investi-
gation, this study was limited in size and not intended to dem-
onstrate noninferiority but rather a proof of concept, safety,
and dose selection evaluation. In this dose-ranging study of
torezolid, the value of including a comparator was considered
of lesser value than investigating a broader range of dose
levels. Additionally, the efficacy and safety profiles of the likely
comparator, linezolid, in the same clinical setting are well
characterized (42), and the complications of using drugs with
different treatment durations (torezolid, 5 to 7 days; linezolid,
10 days) could confound the intended analyses.
The high rates of clinical and microbiological success at all
three dose levels in the large abscess population may call into
question whether these infections were severe enough to re-
quire systemic antibiotic treatment in addition to local care.
However, the cure rate did not vary by size of lesion, severity
of infection, or infection type (i.e., abscess, cellulitis, or wound
infection). Finally, the duration of therapy was short, making
assessment of long-term safety risk difficult. However, the high
rates of clinical and microbiological successes further confirm
that, as seen in other types of infections (12, 25, 27), there
appears to be limited value in extending the duration of ther-
apy beyond 7 days. Shorter courses of therapy have the benefits
of improving compliance, reducing development of resistant
pathogens, and improving the safety profile due to a lower
cumulative dose of drug. Results from this study show that a 5-
to 7-day duration of therapy is efficacious in cSSSI and merits
further investigation in phase 3 clinical trials.
In conclusion, torezolid phosphate was found to be safe and
well tolerated when tested in a 200-, 300-, or 400-mg QD
regimen for 5 to 7 days of therapy for the treatment of cSSSI.
The PK of torezolid was linear over the studied dose range.
Clinical cure rates were very high for each infection type and at
all dose levels, and the 200-mg daily dose was found to be the
lowest efficacious dose. Efficacy, safety, and pharmacokinetic/
pharmacodynamic results support the selection of 200 mg QD
of torezolid phosphate for the oral treatment of patients with
cSSSI. Torezolid phosphate provides optimal characteristics
for the treatment of cSSSI including high efficacy and safety
across patient and infection characteristics, once-daily therapy,
digestive tolerability, and absorption unaffected by food (30).
This study was supported and conducted under the direction of
Trius Therapeutics, Inc. J. Surber and P. Mehra received a clinical
investigator grant, and J. B. Bulitta received research funding from
Trius Therapeutics, Inc.
P. Prokocimer, P. Bien, and C. DeAnda are employees of or con-
sultants for Trius Therapeutics, Inc. J. Surber is an employee of
SERRG, Inc., P. Mehra is an employee of eStudy Site, J. B. Bulitta is
an employee of Ordway Research Institute, and G. R. Corey is an
employee of Duke Clinical Research Institute.
We give special thanks to all the study investigators, P. Manos, J.
Winetz, M. Mascolo, D. Green, D. Young, J. Vazquez, B. Heller, K.
Shriner, J. Jones, and D. Graham, as well as other staff, and to the
patients for their participation in the study. We thank M. Stryjewski, K.
Bartizal, and K. Shaw for editorial contributions to the manuscript,
G. L. Drusano for scientific guidance, and R. Weaver for medical
writing assistance in preparing the manuscript.
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