title: Safety, tolerability, and efficacy of GSK1322322 in the treatment of acute bacterial skin and skin structure infections.
abstract: GSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a ≥20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with ≥20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01209078 and at http://www.gsk-clinicalstudyregister.com [PDF113414].).
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Corey
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA odin.j.naderer@gsk.com.
authors.forename: Odin J
authors.initials: OJ
authors.lastname: Naderer
authors.affiliation: eStudySite, San Diego, California, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: O'Riordan
authors.affiliation: GlaxoSmithKline, Upper Providence, Pennsylvania, USA.
authors.forename: Etienne
authors.initials: E
authors.lastname: Dumont
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Jones
authors.affiliation: GlaxoSmithKline, Upper Providence, Pennsylvania, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Kurtinecz
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: John Z
authors.initials: JZ
authors.lastname: Zhu
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects* / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects; D065692:Cytochrome P-450 CYP3A Inhibitors; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects* / Q000627:therapeutic use*; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D023303:Oxazolidinones / Q000009:adverse effects / Q000627:therapeutic use; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000382:microbiology; D016896:Treatment Outcome; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065692:Cytochrome P-450 CYP3A Inhibitors; C583947:GSK1322322; D006877:Hydroxamic Acids; D023303:Oxazolidinones; D051544:Cytochrome P-450 CYP3A; D000581:Amidohydrolases; C084507:peptide deformylase; D001618:beta-Lactamases; D000069349:Linezolid