Once-Daily Tedizolid Effective for Acute Skin Infections

Veronica Hackethal, MD

June 10, 2014

Once-daily tedizolid is noninferior and has a similar adverse effect profile to twice-daily linezolid in the treatment of acute bacterial skin infections and skin-structure infections, according to results from a phase 3 study called the TR-701 FA vs Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infections (ESTABLISH-2) trial, published online June 6 in Lancet Infectious Disease.

"Intravenous to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for patients with acute bacterial skin and skin-structure infections," write Gregory J Moran, MD, from the Department of Emergency Medicine and Division of Infectious Diseases, Olive View–University of California, Los Angeles, Medical Center, California, and colleagues. "Tedizolid could become a useful option for the treatment of acute bacterial skin and skin-structure infections in the hospital and outpatient settings."

Drug-resistant bacterial infections caused by Gram-positive bacteria have emerged as a major public health problem. Methicillin-resistant Staphylococcus aureus (MRSA) infections, in particular, have high rates of treatment failure, whereas the limitations of current antibiotics have created a need for new drugs, the authors write. Tedizolid is a new antibiotic with improved activity against Gram-positive bacteria such as MRSA, as well as vancomycin- and linezolid-resistant strains.

The ESTABLISH-2 trial used a double-blind, noninferiority design and was conducted at 58 centers in 9 countries from September 2011 to January 2013. The study included 666 patients with acute bacterial skin or skin-structure infections with a minimum lesion area of 75 cm2, suspected or documented Gram-positive bacteria, and at least 1 symptom of systemic infection. The researchers randomly assigned participants to receive intravenous tedizolid (n = 332) or linezolid (n = 334), with the option of switching to oral therapy after 2 or more intravenous doses, according to prespecified criteria. They assessed early clinical response at 48 to 72 hours after starting treatment, defining it as 20% or more reduction in lesion area, no need for rescue antibiotics, or no death from any cause within 72 hours after initiating antibiotics. They also assessed clinical response at 4 other points (day 7, day 11, 7 - 14 days after completing treatment, and 18 - 25 days after completing treatment).

Early clinical response was reached by 283 (85%) of the tedizolid group and 276 (83%) of the linezolid group (difference, 2.6%; 95% confidence interval, −3.0 to 8.2). Both groups also showed similar clinical success rates at follow-up and similar microbiological outcomes, including among those with MRSA infections.

The tedizolid group experienced fewer gastrointestinal adverse effects (diarrhea, nausea, and vomiting) than the linezolid group (52/331 [16%] vs 67/327 [20%], respectively). Likewise, the tedizolid group had fewer adverse events (n = 1 [<1%]) leading to treatment discontinuation compared with the linezolid group (n = 4 [1%]). One patient in each group died; neither death was attributed to the study drug.

Manual measurement of lesions could have introduced variability into the results, although both groups should have had similar variability, given randomization. The inability of study methodology to assess differences in clinical practice across countries could also have limited the study.

"Our results support the value of a step-down strategy with tedizolid," the authors conclude, "whereby patients treated for acute bacterial skin and skin-structure infections in an emergency department are given one intravenous dose before being discharged with oral drug after a fairly short period of observation (ie, up to 24 h)."

In an accompanying comment, Evelina Tacconelli, MD, PhD, from the Division of Infectious Diseases, University Hospital Tübingen, Germany, and Winfried V. Kern, MD, from Albert-Ludwigs-University and the Division of Infectious Diseases, Department of Medicine, and Centre for Infectious Diseases and Travel Medicine, University Hospital, Freiburg, Germany, highlighted the dire need for new antibiotics to treat skin and soft-structure infections, given the looming global threat of antibiotic resistance, limitations in trials looking at other antibiotic options, and the dearth of new antibiotics under development.

"Moran and colleagues' trial provides another piece of clear evidence of the non-inferiority of short-term treatment of bacterial skin and skin-structure infections with a new drug compared with what might be considered gold-standard in some settings," the editorialists conclude. "Thus, another new choice of A-1 drug treatment for this indication is likely to be offered to clinicians."

This study was funded by Cubist Pharmaceuticals. Multiple authors report honoraria, research support, and being a clinical trial adjudicator, scientific advisor, or consultant for 1 or more of the following companies: Cubist Pharmaceuticals, Forest Laboratories, Cerexa, Pfizer, Achaogen, Cempra, Rib-X, The Medicines Company, Theravance, Trius Therapeutics, Contrafect, Furiex, GalxoSmithKline, Durata, Nabriva, and Paratek. Three authors are employees of Cubist Pharmaceuticals.Dr. Tacconelli and Dr. Kern have disclosed no relevant financial relationships.

Lancet Infect Dis. Published online June 6, 2014. Article full text, Comment extract


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