comparative efficacy of human simulated exposures of tedizolid
TRANSCRIPT
Version: May 15, 2012
Prepared for: Antimicrobial Agents and Chemotherapy
1
Comparative Efficacy of Human Simulated Exposures of Tedizolid and Linezolid against 2
Staphylococcus aureus in the Murine Thigh Infection Model 3
4
R. A. Keel1, P. R. Tessier2, J. L. Crandon2, D. P. Nicolau2 5
1California Northstate College of Pharmacy, Rancho Cordova, CA, 2Center for Anti-6
Infective Research and Development, Hartford Hospital, Hartford 7
Running title: Comparative efficacy of tedizolid and linezolid (character and space 8
count: 47/54) 9
Key words: tedizolid, linezolid, human-simulated, Staphylococcus aureus 10
Corresponding author: 11
David P. Nicolau, PharmD, FCCP, FIDSA 12
Center for Anti-Infective Research and Development 13
Hartford Hospital 14
80 Seymour Street 15
Hartford, CT 06102 16
Phone: (860) 545-3941; Fax (860) 545-3941 17
Email: [email protected]
Copyright © 2012, American Society for Microbiology. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.00122-12 AAC Accepts, published online ahead of print on 11 June 2012
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
2
ABSTRACT (252 words) 19
Objectives: Tedizolid (formally torezolid) is a second generation oxazolidinone with 20
enhanced in vitro potency against Gram-positive pathogens, including methicillin-21
susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus. The 22
efficacy of human simulated exposures of tedizolid and linezolid against S. aureus in an 23
immunocompetent mouse thigh model over 3 days were compared. 24
Methods: Four MRSA and 1 MSSA with tedizolid and linezolid MICs ranging from 25
0.25–0.5 and 2–4 µg/mL, respectively, were utilized. Tedizolid and linezolid were 26
administered as regimens simulating human steady-state 24h area under the free 27
concentration-time curve of 200mg Q24 and 600mg Q12, respectively. Thighs were 28
harvested after 4, 8, 12, 24, 36, 48 and 72h and efficacy was determined by the change 29
in bacteria density. 30
Results: The mean bacterial density in control mice increased over the 3 day period. 31
After 24h of treatment, ≥1 log CFU reduction in bacterial density was observed for both 32
tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents 33
with a reduction of ≥2.6 log CFU after 72h of treatment. Any statistical differences (p 34
≤0.05) in efficacy between agents were transient and did not persist throughout the 72h 35
treatment period. 36
Conclusions: Both tedizolid and linezolid regimens demonstrated similar in vivo 37
efficacy against the S. aureus isolates tested. Both agents were bacteriostatic at 24h 38
and were bactericidal on 3rd day of treatment. These data support the clinical utility of 39
tedizolid for skin and skin structure infections caused by S. aureus as well as the 40
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
3
bactericidal activity of the oxazolidinones after 3 days of treatment.41
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
4
INTRODUCTION 42
Acute bacterial skin and skin structure infections (ABSSSI) are frequently caused 43
by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus 44
(MRSA)35. While vancomycin is still considered the gold standard therapy for MRSA29, 45
treatment failures have been reported while the infecting pathogen is still susceptible to 46
vancomycin8,9,11,23,33. Moreover, studies have suggested the potential for a vancomycin 47
“MIC creep” or incremental increases in MIC over time22,28,34. While these increases 48
have not been noted in national or global surveillance studies to date13,30, the reported 49
clinical vancomycin failures, the advocacy for higher vancomycin exposures, and the 50
need for more aggressive concentration monitoring, highlight the need for alternative 51
therapies targeting MRSA. 52
Tedizolid (TR-700, formerly torezolid), the active moiety of tedizolid phosphate 53
(TR-701), is a novel second generation oxazolidinone with activity against Gram-54
positive pathogens26,16, including MRSA. Much interest has emerged in comparing the 55
in vitro and in vivo efficacy of TR-700 and the only other FDA approved oxazolidinone, 56
linezolid (LZD), against clinically relevant pathogens. Against S. aureus and other 57
Gram-positive pathogens, TR-700 has shown 4- to 16-fold greater in vitro activity than 58
LZD and may have activity against LZD-resistant strains 2,15,12,31,32. Additionally, in a 59
phase 2 study evaluating the safety and efficacy of TR-700 for the treatment of ABSSSI, 60
clinical cure rates were 96.6% and 96.8% for patients with S. aureus and MRSA, 61
respectively6. Our study was undertaken to compare the in vivo efficacy of human 62
simulated exposures of TR-700 and LZD against Staphylococcus aureus in the 63
immunocompetent murine thigh infection model. 64
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
5
MATERIALS AND METHODS 65
Antimicrobial test agents. Analytical-grade tedizolid phosphate (TR-701) and LZD 66
were used for the in vivo analyses. In the in vitro analyses, analytical-grade tedizolid 67
(TR-700) and LZD were utilized. Immediately prior to each in vivo experiment, TR-701 68
and LZD were diluted in 0.025 M sodium phosphate dibasic solution and sterile water, 69
respectively, to achieve the desired concentration. The solutions were stored under 70
refrigeration and discarded 24h after reconstitution. 71
Bacterial isolates. Five clinical isolates of S. aureus, were utilized in this study. Four 72
isolates were MRSA including one community-acquired MRSA and 3 hospital-73
associated MRSA of which one was also vancomycin resistant (VRSA). The remaining 74
isolate was a methicillin-susceptible S. aureus (MSSA). MICs were determined for both 75
agents by broth microdilution according to Clinical and Laboratory Standards Institute 76
guidelines4. Isolates were stored at -80°C in double-strength skim milk (Remel, Lenexa, 77
KS), subcultured twice onto Trypticase soy agar with 5% sheep blood (Becton, 78
Dickinson, and Co., Sparks, MD) and grown for 18 to 24h at 35°C prior to use in the 79
experiments. 80
Immunocompetent thigh infection model. Specific-pathogen-free, female ICR mice 81
weighing approximately 22 g each were obtained from Harlan Sprague-Dawley, Inc. 82
(Indianapolis, IN) and utilized throughout these experiments. This study was reviewed 83
and approved by the Hartford Hospital Animal Care and Use Committee. Animals were 84
maintained and used in accordance with National Research Council recommendations 85
and were provided food and water ad libitum. 86
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
6
A suspension of each isolate was freshly prepared from the second subculture of 87
each organism and diluted in normal saline to achieve a final inoculum of 108 CFU/ml. 88
Each thigh was inoculated intramuscularly with 0.1 ml of inoculums two hours prior to 89
initiation of antimicrobial therapy. 90
Pharmacokinetic studies and determination of dosing regimen. Single doses of 91
tedizolid phosphate and LZD were administered to infected, immunocompetent mice to 92
determine a regimen that simulated the human steady state exposures of tedizolid 93
200mg PO every 24h and LZD 600mg IV every 12h. The target indices were a 24h 94
area under the free drug concentration-time curve (fAUC) of 3 µg·h/ml2,9 and 137 95
µg·h/ml 4,23,27for TR-700 and LZD, respectively. The murine protein binding values 96
utilized for TR-700 and LZD were 85%25 (data on file Trius Pharmaceuticals, San Diego, 97
CA) and 30%1,14, respectively. The fAUC for the both regimens was calculated using the 98
trapezoidal rule. Blood samples were collected via cardiac puncture from groups of six 99
mice at three to four time points over 12 to 24 h dosing interval. Plasma (TR-700) and 100
serum (LZD) samples as dictated by the analytical procedures were separated and 101
stored at -80°C until analysis. TR-700 concentrations were analyzed by Midwest 102
Bioresearch (Skokie, IL) using a validated liquid-chromatography-tandem mass 103
spectrometry (LC-MS/MS) assay26. LZD concentrations were analyzed in the Center for 104
Anti-infective Research and Development laboratory at Hartford Hospital using a 105
modified validated high performance liquid chromatography (HPLC) assay36. The 106
standard curve was extended from 20 µg/ml to 30 µg/ml and the extraction was 107
modified from deproteinization with 200 ml of acetonitrile to deproteinization with 150 ml 108
of 7.5% trichloroacetic acid with no drying step. The upper and lower limits of 109
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
7
quantification for the TR-700 assay were 1000 and 10 ng/ml, respectively. The upper 110
and lower limits of quantification for the LZD assay were 30 and 0.2 µg/ml, respectively. 111
The intraday percentage coefficients of variation (CV) for the LZD quality control 112
samples of 0.5 µg/ml and 20 µg/ml were 4.89% and 3.15%, respectively, and the 113
respective interday CV were 3.25% and 2.37%. 114
In vivo efficacy as assessed by bacterial density. Five clinical S. aureus isolates 115
were utilized in the immunocompetent thigh infection model to assess the efficacy of 116
humanized exposure regimens of TR-700 and LZD. Two hours after inoculation, groups 117
of three mice were administered the human simulated regimen of tedizolid as 0.2 ml 118
intraperitoneal injection and LZD as a 0.3 ml subcutaneous injection over a 72 h 119
treatment period. Control mice were administered normal saline at the same time, 120
volume, and route as the most frequent regimen. Groups of 3 untreated control mice 121
were euthanized by CO2 exposure, followed by cervical dislocation just prior to the 122
initiation of therapy (0h). A group of tedizolid-treated, LZD-treated, and control mice 123
were sacrificed at the following time points: 4, 8, 12, 24, 36, 48, and 72 h. Following 124
sacrifice, both rear thighs were removed and homogenized individually in 5 ml of normal 125
saline. Serial dilutions of thigh homogenate were subcultured onto Trypticase soy agar 126
with 5% sheep blood for determination of bacterial density. Efficacy, defined as the 127
change in bacterial density, was calculated as the change in log10 CFU/ml obtained for 128
the treated mice versus that from the control mice at the respective time point. A 129
comparison of the efficacies of TR-700 and LZD against each isolate at each time point 130
was made by using the Student t test. A P value of < 0.05 was defined a priori as 131
statistically significant. 132
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
8
RESULTS 133
Bacterial isolates. The phenotypic profiles for the 5 S. aureus isolates evaluated in 134
this study are listed in Table 1. TR-700 and LZD MICs for the isolates ranged from 0.25 135
to 0.5 µg/ml and 2 to 4 µg/ml, respectively. 136
Pharmacokinetic determination. In this study we were able to define dosing regimens 137
for both tedizolid and linezolid to attain humanized 24h fAUCs. In this model we 138
achieved exposures that simulated the human regimens of tedizolid with a fAUC0-24 of 139
2.99 µg·h/ml; and linezolid, fAUC0-24 of 144 µg·h/ml. 140
In vivo efficacy. The mean bacterial density for control mice prior to initiating dosing 141
was 6.89 log10 CFU and the mean bacterial density increased to 7.34, 6.94, and 7.08 142
log10 CFU after 24, 48, and 72 h, respectively. 143
The TR-700 human simulated regimen produced a 1.04 to 1.80, 2.13 to 2.68, 144
and 2.68 to 3.72 log10 CFU reduction from 0h control at 24, 48, and 72 h, respectively, 145
against all isolates in the immunocompetent thigh infection model (Fig 1 a-e). Similarly, 146
a reduction of 1.36 to 2.02, 2.19 to 3.11, and 2.64 to 3.76 log10 CFU was observed with 147
the LZD human simulated regimen at the respective time points (Fig 1 a-e). While both 148
agents would be defined as having bacteriostatic activity at 24 hours, this activity was 149
enhanced over time. By 72 hours, both agents showed considerable enhancement in 150
overall kill that approximated or exceeded the bactericidal target of 3 logs kill. 151
Additionally, no statistical difference (p>0.05) was observed between treatments at 24 152
hours with the exception S. aureus 152 (p=0.045); however, there was no statistical 153
difference between treatments prior to or after 24 hours for this isolate. Also, one isolate 154
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
9
at both 48 h (S. aureus 433; p=0.002) and 72 h (S. aureus 456; p=0.012) had a 155
statistical difference noted between treatments in favor of LZD; however, this difference 156
was not identified consistently throughout therapy. When considering the reduction in 157
bacterial density for the 5 S. aureus isolates as a whole, both regimens produced similar 158
reduction in CFU over the 72h treatment period regardless of genotype or phenotype. 159
DISCUSSION 160
Tedizolid, the active moiety of the prodrug tedizolid phosphate, is an 161
oxazolidinone, which has activity against Gram-positive pathogens including MRSA. In 162
addition to its spectrum of activity, tedizolid has been postulated to have a lower 163
potential to induce resistance than the only FDA approved oxazolidinone, LZD16,17,18,. In 164
the present analysis, we evaluated the efficacy of human simulated exposures of TR-165
700 and LZD against a number of S. aureus strains including MRSA in an 166
immunocompetent mouse thigh infection model. No sustained statistical difference in 167
efficacy was observed between the human simulated exposures of TR-700 once daily 168
and LZD twice daily against the five tested S. aureus isolates. Additionally, as treatment 169
continued past the initial 24 hours, enhanced antibacterial activity was observed for both 170
agents with an overall reduction of approximately 3 logs over the 72h treatment period. 171
Similar to LZD, the pharmacodynamic target associated with efficacy for TR-700 172
is the AUC to MIC ratio (AUC/MIC)19. A previous study has noted that a lower AUC/MIC 173
ratio is required for efficacy in immunocompetent mice compared with neutropenic 174
mice20. In the current study using immunocompetent animals, the human simulated 175
regimen of TR-700 achieved a mean total drug AUC0-24/MIC of 79.7 and 39.8 for the 176
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
10
isolates with TR-700 MICs of 0.25 and 0.5 µg/ml, respectively. For LZD, the 177
pharmacodynamic index associated with efficacy is an AUC0-24/MIC of ≥ 831,21,27 and 178
our human simulated LZD regimen attained a mean AUC0-24/MIC ratio of 102.9 and 51.4 179
for those isolates with LZD MICs of 2 and 4 µg/ml, respectively. While having isolates 180
with higher MICs for both agents would have helped identify the in vivo therapeutic 181
breakpoint, the TR-700 MIC90 for S. aureus is 0.5 µg/ml while the LZD MIC90 is 4 µg/ml 182
thus the isolates in the present study represent the upper end of the MIC distribution 183
that would be encountered clinically.31 184
In a phase 2 clinical trial using TR-700 in patients with ABSSSI, S. aureus was 185
the most common pathogen with TR-700 MIC values ranging from 0.12 to 0.5 µg/ml at 186
baseline.26 For those with S. aureus identified at baseline, clinical cure rates were > 187
96% and pathogen eradication occurred between 88.9 and 100% depending on the 188
dose of TR-700 (doses ranged from 200mg to 400mg daily). These data, in conjunction 189
with our murine data, support the continued development of TR-700 for the treatment of 190
complicated skin and skin structure infections. The exposure of TR-700 and its 191
reductions in CFU noted herein provide pharmacodynamic support for the clinical 192
efficacy observed with this compound. Moreover, the accumulative bactericidal activity 193
that TR-700 displayed over the 72h in this model provides additional pharmacodynamic 194
sustenance for its Day 3 efficacy (i.e. cessation of lesion spread and resolution of fever) 195
as observed in the clinical trials of acute bacterial skin and skin structure infections 196
(ABSSI)6. 197
Tedizolid is a novel second generation oxazolidinone with in vitro potency against 198
S. aureus, including MRSA and has shown positive clinical outcomes in setting of 199
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
11
ABSSI. In the immunocompetent murine thigh model, human simulated exposures of 200
tedizolid and linezolid resulted in similar efficacy against both methicillin-susceptible and 201
resistant S. aureus. Furthermore, the antibacterial activity for both agents was 202
enhanced as therapy continued out to 72 hours. Human simulated dosages of tedizolid 203
200 mg once daily resulted in efficacy against these S. aureus isolates with MICs, up to 204
and including 0.5 µg/ml. These data support the clinical utility and further development 205
of tedizolid against S. aureus for the treatment of ABSSI. 206
207
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
12
Acknowledgements 208
We authors wish to thank Deborah Santini, Lindsay Tuttle, Jennifer Hull, Henry 209
Christensen, Mary Banevicius, Christina Sutherland, Mao Hagihara and Seth Housman 210
for technical assistance in the performance of this study. This study was sponsored by a 211
grant from Trius Therapeutics, San Diego, CA. 212
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
13
Table 1. Phenotypic and genotypic profiles of the Staphylococcus aureus test isolates 213
for TR-700 and LZD. 214
MIC (µg/ml) (Range)
S. aureus isolate Genotype TR-700 LZD
152 HA-MRSA 0.5 4 (2 – 4)
156 CA-MRSA 0.5 4 (2 – 4)
426 HA-MRSA 0.25 2
433 MSSA 0.5 4
456 HA-MRSA,VRSA 0.25 2
TR-700, tedizolid; LZD, linezolid; HA-MRSA, hospital-acquired methicillin-resistant S. 215
aureus; CA-MRSA, community-acquired methicillin-resistant S. aureus; MSSA, 216
methicillin-susceptible S. aureus; VRSA, vancomycin-resistant S. aureus. 217
218
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
14
Figure 1. Change in log10 CFU for human simulated TR-700 (black bars) and LZD (grey 219
bars) at selected time points relative to the 0h controls for (A) Staphylococcus aureus 220
152, (B) S. aureus 156, (C), S. aureus 426, (D) S. aureus 433, (E) S. aureus 456. Data 221
is expressed as means ± SD for 3 mice per group. 222
223
224
225
226
227
228
229
230
231
232
233
234
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
15
References: 235
1. Andes, D., M. L. van Ogtrop, J. Peng, and W. A. Craig. 2002. In vivo 236 pharmacodynamics of a new oxazolidinone (Linezolid). Antimicrob Agents 237 Chemother. 46(11):3484-3489. 238
2. Bien P., K. A. Munoz, J. Bohn, R. Wright, C. Bethune, and P. Prokocimer. 239 2008. Human Pharmacokinetics of TR-700 after ascending single oral doses 240 of the prodrug TR-701, a novel oxazolidinone antibiotic. Abstr., 48th Intersci. 241 Conf. Antimicrob. Agents Chemother. Abstr F1-2063. 242
3. Brown, S. D., and M. M. Traczewski. 2010. Comparative in vivo 243 antimicrobial activities of torezolid (TR-700), the active moiety of a new 244 oxazolidinone, torezolid phosphate (TR-701), determination of tentative disk 245 diffusion interpretative criteria, and quality control ranges. Antimicrob. Agents 246 Chemother. 54(5):2063-2069. 247
4. Buerger C., N. Plock, P. Dehghanyar, C. Joukhadar, and C. Kloft. 2006. 248 Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of 249 critically ill patients after multiple dosing using microdialysis. Antimicrob. 250 Agents Chemother. 50:2455-2463. 251
5. Clinical and Laboratory Standards Institute (CLSI). 2009. Methods for 252 dilution antimicrobial susceptibility tests for bacteria that grow aerobically 253 approved standard, 8th edition. M07-A8. Clinical and Laboratory Standards 254 Institute, Wayne, PA. 255
6. De Anda, C., Das, A., Fang, E. and P. Prokocimer. 2011. Acute Bacterial 256 Skin and Skin Structure Infection (ABSSI) Dose-Ranging Phase 2 Tedizolid 257 Phosphate (TR-701) Study: Assessment of Efficacy with New FDA Guidance. 258 Abstr 51st Intersci. Conf. Antimicrob Agents Chemother. abstr L1-1496. 259
7. Drusano, G. L., C. Fregeau, W. Liu, H. Conde, R. Kulawy, and Louie, A. 260 2011. Impact of granulocytes on the antimicrobial effect of Tedizolid in a 261 mouse thigh infection model. Antimicrob. Agents Chemother. 55(11):5300-262 5305. 263
8. Hidayat, L. K., H. Dl, R. Quist, K. A. Shriner, and A. Wong-Beringer. 264 2006. Highdose vancomycin therapy for methicillin-resistant Staphylococcus 265 aureus infections: efficacy and toxicity. Arch Intern Med. 166:2138–2144. 266
9. Housman, S. T., J. S. Pope, J. Russomanno, E. Salerno, E. Shore, J. L. 267 Kuti, and D. P. Nicolau. 2011. Pulmonary disposition of torezolid following 268 200mg once-daily oral tedizold phosphate in healthy volunteers. Abstr. 51st 269 Intersci. Conf. Antimicrob. Agents Chemother. Abstr.A1-1747. 270
10. Howden, B. P., P. B. Ward, P. G. Charles, T. M. Korman, A. Fuller, P. du 271 Cros, E. A. Grabsch, S. A. Roberts, J. Robson, K. Read, N. Bak, J. 272 Hurley, P. D. Johnson, A. J. Morris, B. C. Mayall, and M. L. Grayson. 273 2004. Treatment outcomes for serious infections caused by methicillin-274 resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin 275 Infect Dis 38:521–528. 276
11. Hsu, D.I., L. K. Hidayat, R. Quist, J. Hindler, A. Karlsson, A. Yusof, and A. 277 Wong-Beringer. 2008. Comparison of method-specific vancomycin minimum 278 inhibitory concentration values and their predictability for treatment outcome 279
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
16
of methicillin-resistant Staphylococcus aureus(MRSA) infections. Int J 280 Antimicrob Agents. 32:378–385. 281
12. Jones, R. N., G. J. Moet, H. S. Sader, R. E. Mendes, and M. Castanheira. 282 2009. TR-700 in vitro activity against and resistance mutation frequencies 283 among Gram-positive pathogens. J. Antimicrob. Chemother. 63:716-720. 284
13. Jones, R. N. 2006. Microbiological features of vancomycin in the 21st 285 century: minimum inhibitory concentration creep, bactericidal/static activity, 286 and applied breakpoints to predict clinical outcomes or detect resistant 287 strains. Clin. Infect. Dis. 42:S13–S24. 288
14. LaPlante, K. L., S. L. Leonard, D. R. Andes, W. A. Craig, and M. J. Rybak. 289 2008. Activities of clindamycin, daptomycin, doxycycline, linezolid, 290 trimethoprim-sulfamethoxazole, and vancomycin against community-291 associated methicillin-resistant Staphylococcus aureus with inducible 292 clindamycin resistance in murine thigh infection and in vitro 293 pharmacodynamic models. Antimicrob Agents Chemother. 52(6):2156-2162. 294
15. Livermore, D. M., S. Mushtaq, M. Warner, and N. Woodford. 2009. Activity 295 of oxazolidinone TR-700 against linezolid –susceptible and –resistant 296 staphylococci and enterococci. J. Antimicrob Chemother. 63:713-715. 297
16. Locke, J. B., M. Hilgers, and K. J. Shaw. 2009. Novel ribosomal mutations 298 in Staphylococcus aureus strains identified through selection with the 299 oxazolidinones linezolid and torezolid (TR-700). Antimicrob. Agents 300 Chemother. 53(12):5265-5274. 301
17. Locke, J. B., M. Hilgers, and K. J. Shaw. 2009. Mutations in ribosomal 302 protein L3 are associated with oxazolidinone resistance in Staphylococci of 303 clinical origin. Antimcrob. Agents Chemother. 53(12):5275-5278. 304
18. Locke, J. B., J. Finn, M. Hilgers, G. Morales, S. Rahawi, G. C. Kedar, J. J. 305 Picazo, W. Im, K. J. Shaw, and J. L. Stein. 2010. Structure-activity 306 relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus 307 aureus strains possessing the cfr methyltransferase gene or ribosomal 308 mutations. Antimicrob. Agents. Chemother. 54(12):5337-5343. 309
19. Louie, A., W. Lui, R. Kulawy, and G. L. Drusano. 2011. In vivo 310 pharmacodynamics of torezolid phosphate (TR-701), a new oxazolidinone 311 antibiotic, against methicillin-susceptible and methicillin-resistant 312 Staphylococcus aureus strains in a mouse thigh infection model. Antimicrob. 313 Agents Chemother. 55(7):3453-3460. 314
20. Louie, A., C. Fregeau, W. Liu, H. Conde, R. Kulawy, and G. L. Drusano. 315 2009. Defining the impact of granulocytes on the kill of methicillin-resistant 316 Staphyloccocus aureus (MRSA) by the new oxazolidinone prodrug TR-701. 317 Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother. Abstr. A1-1935. 318
21. MacGowan, A. P. 2003. Pharmacokinetic and pharmacodynamic profile of 319 linezolid in healthy volunteers and patients with Gram-positive infections. J. 320 Antimicrob. Chemother. 51(S2):ii17-ii25. 321
22. Mason, E. O., L. B. Lamberth, W. A. Hammerman, K. G. Hulten, J. 322 Versalovic, and S. L. Kaplan. 2009. Vancomycin MICs for Staphylococcus 323 aureus vary by detection method and have subtly increased in a pediatric 324 population since 2005. J Clin. Microbiol. 47:1628–1630. 325
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
17
23. Meager A. K., A. Forrest, C. R. Rayner, M. C. Birmingham, and J. J. 326 Schentag. 2003. Population pharmacokinetics of linezolid in patients treated 327 in a compassionate-use program. Antimicrob. Agents Chemother. 47:548-328 553. 329
24. Neoh, H., S. Hori, M. Komatsu, T. Oguri, F. Takeuchi, L. Cui, and K. 330 Hiramatsu. 2007. Impact of reduced vancomycin susceptibility on the 331 therapeutic outcome of MRSA bloodstream infections. Ann Clin Microbiol 332 Antimicrob. 6:13. 333
25. Pichereau, S., J. Bohrmuller, K. Marchillo, T. Stamstad, W. Craig, and D. 334 Andes. 2009. Comparative pharmacodynamics of novel oxazolidinone, 335 torezolid phosphate (TR-701), against S. aureus in the neutropenic murine 336 pneumonia model. Abstr 49th Instersci. Conf. Antimicrob Agents Chemother. 337 abstr A1-1939. 338
26. Prokocimer P., P. Bien, J. Surber, P. Mehra, C. DeAnda, J. B. Bulitta, and 339 G. R. Corey. 2011. Phase 2, randomized, double-blind, dose-ranging study 340 evaluating the safety, tolerability, population pharmacokinetics, and efficacy of 341 oral torezolid phosphate in patients with complicated skin and skin structure 342 infections. Antimicrob Agents Chemother. 55(2):583-592. 343
27. Rayner, C. R., A. Forrest, A. K. Meagher, M. C. Birmingham, and J. J. 344 Schentagg. 2003. Clinical pharmacodynamics of linezolid in seriously ill 345 patients treated in a compassionate use programme. Clin. Pharmacokinet. 346 42(15):1411-1423. 347
28. Rhee, K. Y., D. F. Gardiner, and M. Charles. 2005. Decreasing in-vitro 348 susceptibility of clinical Staphylococcus aureus isolates to vancomycin at the 349 New York Hospital: quantitative testing redux. Clin. Infect. Dis. 40:1705–1706. 350
29. Rybak, M., B. Lomaestro, J. C. Rotschafer, R. Moellering, W. Craig, M. 351 Billeter, J. R. Dalovisio, and D. P. Levine. 2009. Therapeutic monitoring of 352 vancomycin in adult patients: a consensus review of the American Society of 353 Health-System Pharmacists, the Infectious Diseases Society of America, and 354 the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 355 66:82–98. 356
30. Sader, H. S.,P. D. Fey, D. N. Fish, A. P. Limaye, G. Pankey, J. Rahal, M. 357 J. Rybak, D. R. Snydman, L. L. Steed, K. Waites, and R. N. Jones. 2009. 358 Evaluation of vancomycin and daptomycin potency trends (MIC creep) 359 against methicillin-resistant Staphylococcus aureus isolates collected in nine 360 U.S. medical centers from 2002 to 2006. Antimicrob. Agents Chemother. 361 53:4127–4132. 362
31. Schaadt, R., D. Sweeney, D. Shinabarger, and G. Zurenko. 2009. In vitro 363 activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a 364 novel oxazolidinone antibacterial agent. Antimicrob. Agents Chemother. 365 53(8):3236-3239. 366
32. Shaw, K. J., S. Poppe, R. Schaadt, V. Brown-Driver, J. Finn, C. M. Pillar, 367 D. Shinabarger, G. Zurenko. 2008. In vitro activity of TR-700, the 368 antibacterial moiety of the prodrug TR-701, against linezolid-resistant strains. 369 Antimicrob. Agents Chemother. 52(12):4442-4447. 370
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
18
33. Soriano, A., F. Marco, J. A. Martinez, E. Pisos, M. Almela, V. P. Dimova , 371 D. Alamo, M. Ortega, J. Lopez, and J. Mensa. 2008. Influence of 372 vancomycin minimum inhibitory concentration on the treatment of methicillin 373 resistant Staphylococcus aureus bacteremia. Clin Infect Dis 46:193–200. 374
34. Steinkraus, G., R. White, L. Friedrich. 2007.Vancomycin MIC creep in non–375 vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin 376 susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 377 2001–05. J. Antimicrob. Chemother. 60:788–794. 378
35. Stevens, D. L., et al. 2005. Practice guidelines for the diagnosis and 379 management of skin and soft-tissue infections. Clin. Infect. Dis. 41:1373–380 1406. 381
36. Tobin, C. M., Sunderland, J., White, L. O. and A. P. MacGowan. 2001. A 382 Simple, Isocratic High-Performance Liquid Chromatography Assay for 383 Linezolid in Human Serum. J Antimicrob. Chemother. 48:605-608. 384
385
386
387
388
on March 25, 2018 by guest
http://aac.asm.org/
Dow
nloaded from
