ABSTRACT
Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). In a pooled analysis of 1,333 ABSSSI patients from the ESTABLISH clinical trials, treatment with tedizolid or linezolid demonstrated similar early and posttherapy clinical responses in nonsevere and severe disease, irrespective of the parameters used to measure ABSSSI severity. Shorter 6-day treatment of ABSSSI, including those that were severe, with tedizolid phosphate demonstrated efficacy comparable to that of 10-day treatment with linezolid. (The ESTABLISH studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01170221 and NCT01421511.)
KEYWORDS: ABSSSI, clinical response, linezolid, severity, tedizolid phosphate
TEXT
Acute bacterial skin and skin structure infections (ABSSSI) are among the most common infections in clinical practice and are caused primarily by Gram-positive pathogens, including Staphylococcus aureus and Streptococcus pyogenes (1). Tedizolid phosphate, the prodrug of the antibacterial oxazolidinone tedizolid, has been approved in the United States and other countries for the treatment of patients with ABSSSI (2, 3). Tedizolid has potent activity against a wide range of Gram-positive pathogens, such as S. aureus, including methicillin-resistant S. aureus (MRSA), Streptococcus spp., and Enterococcus spp. (including vancomycin-resistant enterococci) (4, 5).
Although the optimal duration of treatment for skin infections remains to be established, it is generally recommended that antimicrobial therapy be given for the shortest effective duration (6). Research has indicated that treatment durations vary considerably in practice (7); however, data from a previous randomized controlled trial comparing 5 days and 10 days of levofloxacin treatment in patients with cellulitis indicated no difference between outcomes based on treatment duration (8). More recently, two phase 3 trials, ESTABLISH-1 (ClinicalTrials.gov registration no. NCT01170221) and ESTABLISH-2 (registration no. NCT01421511), demonstrated the noninferior efficacy of tedizolid (200 mg once daily for 6 days) compared with that of linezolid (600 mg twice daily for 10 days) in patients with ABSSSI (9, 10). These trials were conducted according to recent U.S. Food and Drug Administration guidance, which defined ABSSSI as having the following inclusion criteria: cellulitis/erysipelas, wound infections, major cutaneous abscess, and regional or systemic signs of infection (1, 11, 12).
Although there is no consensus on the definition of disease severity in ABSSSI, a number of baseline markers have been proposed as disease severity criteria in clinical trials, among which are lesion size, fever, leukocytosis, sepsis criteria (systemic inflammatory response syndrome [SIRS] plus known or suspected infection), lymphadenopathy, and presence of immature neutrophils (bands) (11–13). In this pooled subgroup analysis of tedizolid phase 3 studies, we assessed the effect of the different measures of disease severity at baseline on clinical response in patients with ABSSSI.
In ESTABLISH-1, patients 18 years of age or older received oral therapy exclusively; in ESTABLISH-2, patients 12 years of age or older first received intravenous therapy for 24 h and could be switched to oral study drug at the investigator's discretion if prespecified clinical improvement criteria were met. The study designs and patient inclusion criteria of both trials have been described (9, 10). These two studies excluded patients who received systemic or topical antibiotics with Gram-positive activity within 96 h before the first dose of study drug. The primary endpoint was a reduction in lesion area of ≥20% at 48 to 72 h after start of the study drug (without the use of rescue antibiotics); a key secondary endpoint was investigator-assessed clinical response at the posttherapy evaluation (PTE) (7 to 14 days after the end of therapy). Efficacy data from both studies were pooled, and the effect of the following measures of disease severity at baseline on the primary and secondary endpoints were evaluated: lesion area, fever (≥38°C), abnormal white blood cell (WBC) count (≥10,000 or <4,000 cells/mm3), SIRS (2 or more of the following: temperature of <36°C or >38°C; heart rate of >90 beats per minute; respiratory rate >20 breaths per min; WBC of <4,000 or >12,000 cells/mm3 or >10% bands), lymphadenopathy, presence of immature neutrophils (>10% bands), visual analog scale score (<75 mm or ≥75 mm), and Faces Rating Scale score (<7 or ≥7).
In the current analysis, 1,333 patients in the intent-to-treat (ITT) population (tedizolid, n = 664; linezolid, n = 669) were included. Disease severity measures at baseline were comparable between both treatment arms (Table 1). High proportions of patients in the tedizolid and linezolid treatment groups had lymphadenopathy (78.9% [524/664] and 78.3% [524/669], respectively). Approximately half the patients in each treatment group had an abnormal WBC count. Lesion areas >300 cm2 were observed in 34.3% (228/664) of tedizolid patients and 32.9% (220/669) of linezolid patients. Smaller proportions of patients in the two treatment groups had fever, SIRS, or immature neutrophils (bands) (Table 1).
TABLE 1.
Measures of disease severity at baseline in the tedizolid and linezolid treatment groups
| Measure of disease severity | No. (%) of tedizolid patients (n = 664) | No. (%) of linezolid patients (n = 669) |
|---|---|---|
| Lesion area | ||
| >300 cm2 | 228 (34.3) | 220 (32.9) |
| ≤300 cm2 | 436 (65.7) | 449 (67.1) |
| Fever (≥38°C) | ||
| Yes | 159 (23.9) | 160 (23.9) |
| No | 505 (76.1) | 509 (76.1) |
| WBC count (≥10,000 or <4,000 cells/mm3) | ||
| Yes | 316 (47.6) | 284 (42.5) |
| No | 348 (52.4) | 385 (57.5) |
| Presence of SIRS | ||
| Yes | 163 (24.5) | 128 (19.1) |
| No | 501 (75.5) | 541 (80.9) |
| Lymphadenopathy | ||
| Yes | 524 (78.9) | 524 (78.3) |
| No | 140 (21.1) | 145 (21.7) |
| Presence of immature neutrophils (bands) | ||
| >10% | 65 (9.8) | 48 (7.2) |
| ≤10% | 599 (90.2) | 621 (92.8) |
| Visual analog scale | ||
| ≥75 mm | 245 (36.9) | 246 (36.8) |
| <75 mm | 403 (60.7) | 403 (60.2) |
| Faces rating scale | ||
| ≥7 | 345 (52.0) | 340 (50.8) |
| <7 | 305 (45.9) | 308 (46.0) |
Clinical response at the early and posttherapy time points was assessed for each disease severity measure. Early clinical response rates were similar between the tedizolid and linezolid treatment groups across all disease severity measures. The weighted (by study) treatment difference and weighted 95% confidence intervals (CI) of the early clinical response rate between the two groups were comparable across the subgroups (Fig. 1A). For each severity measure, response rates were similar between the tedizolid and linezolid treatment groups (i.e., treatment difference was similar), and response rates were similar across the severity measures. Investigator-assessed clinical response rates at the PTE between tedizolid and linezolid were also similar across all evaluated measures of disease severity (Fig. 1B). These findings suggest that the type of disease severity criteria used at baseline did not impact clinical response for either treatment.
FIG 1.
(A) Early clinical response (reduction in lesion area of ≥20%) at 42 to 72 h by severity measure. Difference is the weight treatment difference (weighted by study), and the CI was adjusted for the study. (B) Investigator-assessed clinical response at the posttherapy evaluation by severity measures. Difference is the weight treatment difference (weighted by study), and the CI was adjusted for the study. FRS, Faces Rating Scale; LZD, linezolid; TZD, tedizolid; VAS, visual analog scale.
In conclusion, this subgroup analysis of pooled efficacy data from ESTABLISH-1 and ESTABLISH-2 demonstrated comparable clinical response rates (at 48 and 72 h after the start of study drug) and investigator-assessed outcomes (7 to 14 days after the end of therapy) between tedizolid (200 mg once daily for 6 days) and linezolid (600 mg twice daily for 10 days) across all disease severity criteria evaluated. These findings confirm the activity of a shorter 6-day course of tedizolid with regard to early clinical response.
ACKNOWLEDGMENTS
T.S. substantially contributed to interpretation of the results and drafting and revising the manuscript for important intellectual content. C.D.A. substantially contributed to the conception of this article, data acquisition, analysis and interpretation of the results, and revising the manuscript for important intellectual content. E.F. substantially contributed to the conception of this article, data acquisition, analysis and interpretation of the results, and revising the manuscript for important intellectual content. A.F.D. substantially contributed to the conception of this article, data analysis and interpretation of the results, and revising the manuscript for important intellectual content. P.P. substantially contributed to the conception of this article, interpretation of the results, and revising the manuscript for important intellectual content. All authors have provided final approval of the version to be published, and all authors had access to the relevant data and agree to be accountable for all aspects of the work.
Funding for this research was provided by Merck & Co., Inc. (Kenilworth, NJ, USA).
Medical writing and editorial assistance was provided by Sally A. Mitchell, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck & Co., Inc.
C.D.A is a current employee of Merck & Co., Inc. T.S., E.F., and P.P. are former employees of Merck & Co., Inc. A.F.D. was an employee of InClin and a consultant to Cubist Pharmaceuticals (now Merck & Co., Inc.) when this article was conceived and was compensated for supporting this research; she is also a consultant to Achaogen, Cempra, Cerexa, Contrafect, Durata, Melinta, Nabriva, Paratek, Tetraphase, Theravance, Wockhardt, and Zavante.
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