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Antimicrob Agents Chemother. Feb 2011; 55(2): 583–592.
Published online Nov 29, 2010. doi:  10.1128/AAC.00076-10
PMCID: PMC3028792
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[down-pointing small open triangle]
P. Prokocimer,1* P. Bien,1 J. Surber,2 P. Mehra,3 C. DeAnda,1 J. B. Bulitta,4 and G. R. Corey5
Trius Therapeutics, Inc., 6310 Nancy Ridge Road, Suite 105, San Diego, California 92121,1 SERRG, Inc., 5210 Armour Road Suite 400, Columbus, Georgia 31904,2 eStudy Site, 752 Medical Center Court, Suite 105, Chula Vista, California 91911,3 Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208,4 Duke Clinical Research Institute, 2400 Pratt Street, Durham, North Carolina 277055
*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/at/triusrx.com
Received January 19, 2010; Revised June 9, 2010; Accepted November 2, 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 3 trials.
The incidence of drug-resistant Gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) has reached a point where new therapeutic options are urgently 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 (community-associated MRSA [CA-MRSA]). Although most commonly associated with skin and skin structure infections, CA-MRSA can also produce more serious or life-threatening infections such as pneumonia, neonatal sepsis, osteomyelitis, 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 community-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 decade (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-intermediate S. aureus [VISA]) and others that contain subpopulations 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 eventually compromise the continued use of vancomycin in many locations (9, 16, 22). Other options for treating these increasingly 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, there is growing concern about linezolid-resistant strains, especially due to the novel chloramphenicol-florfenicol resistance (cfr) mechanism that leads to resistance to multiple classes of ribosome-targeting antibiotics, including linezolid, clindamycin, streptogramins, and pleuromutilins. This mechanism of resistance is particularly troubling due to its association with transposons and plasmids, resulting in a high probability 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 relevant Gram-positive pathogens, some fastidious Gram-negative pathogens, and the atypical Chlamydia spp. and has demonstrated 4- to 16-fold greater activity than linezolid against Gram-positive species including MRSA (35, 36). Unlike linezolid, 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 linezolid-resistant strains of S. aureus including cfr-harboring strains (36).
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 tolerability 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 addition, we employed a three-stage hierarchical population pharmacokinetic (PK) modeling strategy to borrow information 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 [39].)
This phase 2 study was a dose-ranging, randomized, double-blind, noncontrolled 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 Helsinki.
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 posttraumatic 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 abscess, 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 estimated 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, gastrointestinal resection, advanced alcohol-related disease, uncontrolled diabetes, chronic systemic immunosuppressive therapy, known or suspected bacteremia, 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 adjunctive 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 PK modeling.
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 chemistry and hematology laboratory testing were sent to the central reference laboratory (Eurofins Medinet, Chantilly, VA), and assessment of concomitant medications 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 (diagnosed 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 TOC visit.
All patients receiving the study drug were included in the modified intent-to-treat (MITT) population and evaluated for safety. Safety assessments included reviews of vital signs, physical examinations, ECG findings, laboratory evaluations, 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 populations 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 confounding 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 chromatography (HPLC)-grade deionized water; 50 μl of the resulting solution was analyzed using a validated liquid chromatographic method consisting of an isocratic step of ACN-0.05% trifluoroacetic acid (25:75, vol/vol) on a Higgins Analytical Targa C18 column and positive-ion heated nebulizer mass spectrometric detection. The analytical method was selective for torezolid and was linear (using 1/x fit with mean r2 values 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 deviation, ± 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 semiphysiological 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 variable.
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 accounting for uncertainty in the prior means and prior variability estimates. The ability to incorporate uncertainty in the prior information is the most important advantage 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 approach.
Sensitivity analysis for priors.
We assessed the impact of the extent of uncertainty 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 evaluated 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 population PK analysis).
Model selection and qualification.
The average objective function (−2 × log-likelihood) during the last 10 iterations, individual curve fits, and the standard 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 received 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 Figure11 outlines the number of patients included in each analysis population. Of the 188 patients included in the MITT population and cMITT population (same population), over 85% (164) were included in the CE population. Patients were excluded from the CE population 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 70% of patients in the MITT population were microbiologically evaluable (ME).
FIG. 1.
FIG. 1.
Populations analyzed.
The three dose groups were well balanced across all demographic data and baseline characteristics including cSSSI diagnosis, presence of systemic signs of infection, and lesion size (Table (Table1).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 procedures were surgical debridement (abscess), puncture aspiration (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%). Approximately 40% of patients (MITT) met the criteria for severe cSSSI, defined as the presence of systemic signs of infection (85%) or adjacent lymphadenopathy (15%) associated with lesions of ≥10 cm (lesion sizes ranged from 10 to 46 cm).
TABLE 1.
TABLE 1.
Patient baseline characteristics (MITT population)
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 μg/ml for S. aureus (MIC90 of 0.25 μg/ml) and did not exceed 0.25 and 0.12 μg/ml for Streptococcus agalactiae and Streptococcus pyogenes, respectively.
Treatment.
The mean duration of therapy for all treatment groups was 6.4 days. The majority of patients (94.7%) completed 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 treatment (0.5%; 1/188 [300-mg group]), requiring i.v. antibiotic treatment (0.5%; 1/188 [400-mg group]), and insufficient therapeutic 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 cultures.
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 (Table2).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 (Tables33 and and4).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 consistent 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.
TABLE 2.
TABLE 2.
Clinical cure rates with torezolid phosphate at TOC in the MITT, CE, and ME populations
TABLE 3.
TABLE 3.
Clinical cure rates with torezolid phosphate at TOC in the CE population, by lesion type and size
TABLE 4.
TABLE 4.
Clinical cure rates with torezolid phosphate at TOC in patients with severe cSSSIa
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 abscesses (4%).
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 μg/ml for 5.1%, 0.25 μg/ml for 89.0%, and 0.5 μg/ml for 5.9% of specimens. Microbiological eradication 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 infection subgroup.
In the MITT population, only two patients (1%) had emerging pathogens. One patient had both Streptococcus acidominimus 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 provided frequent sampling. Models with one disposition compartment yielded notably worse curve fits and an objective function worse by 105 compared with a two-compartment disposition model. Addition of a third disposition compartment yielded essentially indistinguishable curve fits and did not significantly 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 elimination.
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 semiphysiological absorption model improved the individual curve fits during the absorption phase; however, this model was notably 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 compartments and two disposition compartments as the simplest model that fit data well (see supplemental material for model structure and diagnostic plots).
Parameter estimates (Table (Table5)5) were precise, with relative standard errors below 13% for all means and below 50% for variance estimates (see supplemental material for variance covariance matrix). This model yielded an excellent predictive performance for all three dose groups (Fig. (Fig.22).
TABLE 5.
TABLE 5.
Parameter estimates for the linear population PK model for torezolid in patients with severe cSSSI
FIG. 2.
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; (more ...)
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 information (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 estimation 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 excluded 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 recorded 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 later.
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 prior information).
A standard population PK analysis without prior information yielded unrealistically low BSV estimates (CV of <4%) for several PK parameters as well as high correlation coefficients between certain pairs of PK parameters. The three-stage hierarchical approach resolved this problem by borrowing information 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. Treatment-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 (Table6)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 Clostridium difficile-related diarrhea), vomiting, and headache (Table (Table7).7). No patients discontinued study drug due to an adverse event. There was no apparent dose-related toxicity.
TABLE 6.
TABLE 6.
Most common (>2% of treated subjects overall) treatment-emergent adverse events (MITT population)
TABLE 7.
TABLE 7.
Most common (>5%) investigator-identified drug-related TEAEs (MITT population)
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 laboratory abnormality.
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 baseline and 444 ms at EOT). There were no cardiac-adverse events associated with ECG findings.
Over the past decade, physicians have encountered an epidemic of S. aureus-associated complicated skin and soft tissue infections. This rapidly increasing group of resistant staphylococci has been led by the USA300 clone of MRSA. This pathogen has shown the ability to exchange genetic material with other organisms, facilitating its increasing virulence and resistance. The community onset of the majority of these infections makes the development of a robust oral antibiotic armamentarium 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.
The proposed population PK model for patients had excellent predictive performance for the range and time course of concentrations observed at all three dose levels of this study (Fig. (Fig.2).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 (Table5)5) were robust with regard to the extent of uncertainty in the priors.
One of the important outcomes of this study was the determination 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 demonstrated that torezolid phosphate was bactericidal even at 200 mg once daily (23). Population pharmacokinetic/pharmacodynamic modeling and simulation using data from mice (23, 24) and the population PK data from healthy volunteers demonstrated that a human equivalent of 164.479 mg of torezolid, corresponding to a 200-mg torezolid phosphate-free acid formulation 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.
S. aureus was responsible for approximately 90% of microbiologically 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 demonstration of the efficacy of torezolid phosphate in eradicating this pathogen. Low torezolid MIC values (MIC90 of 0.25 μg/ml) confirmed the potency of torezolid.
Limitations are important to consider. As a phase 2 investigation, this study was limited in size and not intended to demonstrate 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 require 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 therapy 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).
Supplementary Material
[Supplemental material]
Acknowledgments
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 consultants 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.
Footnotes
[down-pointing small open triangle]Published ahead of print on 29 November 2010.
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1. Adem, P. V., et al. 2005. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children. N. Engl. J. Med. 353:1245-1251. [PubMed]
2. Bae, I.-G., et al. 2009. Heterogeneous vancomycin-intermediate susceptibility phenotype in bloodstream methicillin-resistant Staphylococcus aureus isolates from an international cohort of patients with infective endocarditis: prevalence, genotype, and clinical significance. J. Infect. Dis. 200:1355-1366. [PMC free article] [PubMed]
3. Bien, P., et al. 2008. Human pharmacokinetics of TR-700 after ascending single oral doses of the prodrug TR-701, a novel oxazolidinone antibiotic. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F1-2063.
4. Bien, P., P. Prokocimer, K. A. Munoz, and J. Bohn. 2009. Safety of multiple ascending oral doses of TR-701, a novel oxazolidinone prodrug antibiotic. Abstr. 19th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. P1089.
5. Boucher, H. W., and G. Sakoulas. 2007. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin. Infect. Dis. 45:601-608. [PubMed]
6. Boucher, H. W., and G. R. Corey. 2008. Epidemiology of methicillin-resistant Staphylococcus aureus. Clin. Infect. Dis. 46:S344-S349. [PubMed]
7. Bulitta, J. B., et al. 2007. Systematic comparison of the population pharmacokinetics and pharmacodynamics of piperacillin in cystic fibrosis patients and healthy volunteers. Antimicrob. Agents Chemother. 51:2497-2507. [PMC free article] [PubMed]
8. Bulitta, J. B., C. B. Landersdorfer, M. Kinzig, U. Holzgrabe, and F. Sorgel. 2009. New semiphysiological absorption model to assess the pharmacodynamic profile of cefuroxime axetil using nonparametric and parametric population pharmacokinetics. Antimicrob. Agents Chemother. 53:3462-3471. [PMC free article] [PubMed]
9. Butterfield, J., and T. P. Lodise, Jr. 2009. Vancomycin: is this the beginning of the end? Infect. Dis. Spec. Ed. 2009:89-95.
10. Byrd, K. K., et al. 2009. Methicillin-resistant Staphylococcus aureus-associated hospitalizations among the American Indian and Alaska native population. Clin. Infect. Dis. 49:1009-1015. [PubMed]
11. Clark, D. B., M. R. Andrus, and D. C. Byrd. 2006. Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy 26:269-276. [PubMed]
12. Corey, G. R., M. E. Stryjewski, and R. J. Everts. 2009. Short-course therapy for bloodstream infections in immunocompetent adults. Int. J. Antimicrob. Agents. 34:S44-S48.
13. Corey, G. R., M. E. Stryjewski, W. Weyenberg, U. Yasothan, and P. Kirkpatrick. 2009. Telavancin. Nat. Rev. Drug Discov. 8:929-930. [PubMed]
14. Deresinski, S. 2009. Vancomycin heteroresistance and methicillin-resistant Staphylococcus aureus. J. Infect. Dis. 199:605-609. [PubMed]
15. Diep, B. A., et al. 2008. Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men. Ann. Int. Med. 148:249-257. [PubMed]
16. Hidayat, L. K., D. I. Hsu, R. Quist, K. A. Shriner, and A. Wong-Beringer. 2006. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections. Arch. Intern. Med. 166:2138-2144. [PubMed]
17. Howden, B. P., P. D. Johnson, P. G. Charles, and M. L. Grayson. 2004. Failure of vancomycin for treatment of methicillin-resistant Staphylococcus aureus infections. Clin. Infect. Dis. 39:1544. [PubMed]
18. Howden, B. P., et al. 2004. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin. Infect. Dis. 38:521-528. [PubMed]
19. Klein, E., D. L. Smith, and R. Laxminarayan. 2009. Community-associated methicillin-resistant Staphylococcus aureus in outpatients, United States, 1999-2006. Emerg. Infect. Dis. 15:1925-1930. [PMC free article] [PubMed]
20. Klevens, R. M., et al. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298:1763-1771. [PubMed]
21. Lavery, S., H. Ravi, W. W. McDaniel, and Y. R. Pushkin. 2001. Linezolid and serotonin syndrome. Psychosomatics 42:432-434. [PubMed]
22. Lodise, T. P., et al. 2008. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob. Agents Chemother. 52:3315-3320. [PMC free article] [PubMed]
23. Louie, A., et al. 2009. Defining the impact of granulocytes on the kill of methicillin-resistant Staphylococcus aureus by the new oxazolidinone prodrug TR-701. Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother., abstr. A1-1935.
24. Louie, A., et al. 2009. In vivo pharmacodynamics of TR-701, a new oxazolidinone antibiotic against methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains. Abstr. 19th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. O28.
25. Mandell, L. A., and T. M. File. 2003. Short course treatment of community-acquired pneumonia. Clin. Infect. Dis. 39:761-763. [PubMed]
26. Mangili, A., I. Bica, D. R. Snydman, and D. H. Hamer. 2005. Daptomycin-resistant, methicillin-resistant Staphylococcus aureus bacteremia. Clin. Infect. Dis. 40:1058-1060. [PubMed]
27. Micek, S. T., T. J. Heuring, J. M. Hollands, R. A. Shah, and M. H. Kollef. 2006. Optimizing antibiotic treatment for ventilator-associated pneumonia. Pharmacotherapy 26:204-2013. [PubMed]
28. Miller, L. G., et al. 2005. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N. Engl. J. Med. 352:1444-1453. [PubMed]
29. Moran, G. J., et al. 2006. Methicillin-resistant S. aureus infections among patients in the emergency department. N. Engl. J. Med. 355:666-674. [PubMed]
30. Munoz, K. A., P. Bien, P. Prokocimer, M. Berry, and C. R. Bethune. 2009. Effect of food on the pharmacokinetics of TR-701, a novel oxazolidinone antibiotic prodrug, in healthy adult subjects. Abstr. 19th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. A-1091.
31. Plock, N., C. Buerger, C. Joukhadar, S. Kljucar, and C. Kloft. 2007. Does linezolid inhibit its own metabolism? Population pharmacokinetics as a tool to explain the observed nonlinearity in both healthy volunteers and septic patients. Drug Metab. Dispos. 35:1816-1823. [PubMed]
32. Popovich, K. J., and R. A. Weinstein. 2009. The graying of methicillin-resistant Staphylococcus aureus. Infect. Control Hosp. Epidemiol. 30:9-12. [PubMed]
33. Prokocimer, P., P. Bien, K. A. Munoz, and R. Aster. 2008. Hematological effects of TR-701, linezolid and placebo administered for 21 days in healthy subjects. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F1-2069.
34. Reyes, J., et al. 2009. Dissemination of methicillin-resistant Staphylococcus aureus USA300 sequence type 8 lineage in Latin America. Clin. Infect. Dis. 49:1861-1867. [PMC free article] [PubMed]
35. Schaadt, R., D. Sweeney, D. Shinabarger, and G. Zurenko. 2009. In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent. Antimicrob. Agents Chemother. 53:3236-3239. [PMC free article] [PubMed]
36. Shaw, K. J., et al. 2008. In vitro activity of TR-700, the antibacterial moiety of the prodrug TR-701, against linezolid-resistant strains. Antimicrob. Agents Chemother. 52:4442-4447. [PMC free article] [PubMed]
37. Steinkraus, G., R. White, and L. Friedrich. 2007. Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001-05. J. Antimicrob. Chemother. 60:788-794. [PubMed]
38. Stryjewski, M. E., and H. F. Chambers. 2008. Skin and soft-tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Clin. Infect. Dis. 46:S368-S377. [PubMed]
39. Surber, J., et al. 2009. Efficacy and safety of torezolid phosphate (TR-701) in a dose-ranging phase 2 randomized, double-blind study in patients with severe complicated skin and skin structure infections (cSSSI). Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L1-335.
40. Tinelli, M., M. Monaco, M. Vimercati, A. Ceraminiello, and A. Pantosti. 2009. Methicillin-susceptible Staphylococcus aureus in skin and soft tissue infections, Northern Italy. Emerg. Infect. Dis. 15:250-257. [PMC free article] [PubMed]
41. Tong, S. Y. C., M. I. McDonald, D. C. Holdt, and B. J. Currie. 2008. Global implications of the emergence of community-associated methicillin-resistant Staphylococcus aureus in indigenous populations. Clin. Infect. Dis. 46:1871-1878. [PubMed]
42. Weigelt, J., et al. 2005. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob. Agents Chemother. 49:2260-2266. [PMC free article] [PubMed]
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