Dataset Information

In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.

ABSTRACT: A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750?mg every 12 h [q12h], 1,000?mg q12h, and 1,000?mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines. Staphylococcus aureus accounted for 78/102 (76%) of Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA), and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the gepotidacin 750-mg q12h group, 89% for the 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5??g/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (?4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N, both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial agent. (This study has been registered at ClinicalTrials.gov under identifier NCT02045797.).

SUBMITTER: Scangarella-Oman NE

PROVIDER: S-EPMC7038298 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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<i>In Vitro</i> Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.

Scangarella-Oman Nicole E NE Ingraham Karen A KA Tiffany Courtney A CA Tomsho Lynn L Van Horn Stephanie F SF Mayhew David N DN Perry Caroline R CR Ashton Theresa C TC Dumont Etienne F EF Huang Jianzhong J Brown James R JR Miller Linda A LA

Antimicrobial agents and chemotherapy 20200221 3

A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12 h [q12h], 1,000 mg q12h, and 1,000 mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute gui ...[more]

PMID: 31818823

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Project description:IntroductionIntroduction of new antibiotics enabling single-dose administration, such as oritavancin may significantly impact site of care decisions for patients with acute bacterial skin and skin structure infections (ABSSSI). This analysis compared the efficacy of single-dose oritavancin with multiple-dose vancomycin in patients categorized according to disease severity via modified Eron classification and management setting.MethodsSOLO I and II were phase 3 studies evaluating single-dose oritavancin versus 7-10 days of vancomycin for treatment of ABSSSI. Patient characteristics were collected at baseline and retrospectively analyzed. Study protocols were amended, allowing outpatient management at the discretion of investigators. In this post hoc analysis, patients were categorized according to a modified Eron severity classification and management setting (outpatient vs. inpatient) and the efficacy compared.ResultsOverall, 1910 patients in the SOLO trials were categorized into Class I (520, 26.5%), II (790, 40.3%), and III (600, 30.6%). Of the 767 patients (40%) in the SOLO trials who were managed entirely in the outpatient setting 40.3% were categorized as Class II and 30.6% were Class III. Clinical efficacy was similar between oritavancin and vancomycin treatment groups, regardless of severity classification and across inpatient and outpatient settings. Class III patients had lower response rates (oritavancin 73.3%, vancomycin 76.6%) at early clinical evaluation when compared to patients in Class I (82.6%) or II (86.1%); however, clinical cure rates at the post-therapy evaluation were similar for Class III patients (oritavancin 79.8%, vancomycin 79.9%) when compared to Class I and II patients (79.1-85.7%).ConclusionSingle-dose oritavancin therapy results in efficacy comparable to multiple-dose vancomycin in patients categorized according to modified Eron disease severity classification regardless of whether management occurred in the inpatient or outpatient setting.FundingThe Medicines Company, Parsippany, NJ, USA.Trial registrationClinicalTrials.gov identifiers, NCT01252719 (SOLO I) and NCT01252732 (SOLO II).

Project description:Delafloxacin is an investigational anionic fluoroquinolone antibiotic with broad-spectrum in vitro activity, including activity against Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The in vitro activity of delafloxacin and the percent microbiological response in subjects infected with fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus isolates were determined from two global phase 3 studies of delafloxacin versus vancomycin plus aztreonam in patients with acute bacterial skin and skin structure infections (ABSSSI). Patients from 23 countries, predominately the United States but also Europe, South America, and Asia, were enrolled. The microbiological intent-to-treat (MITT) population included 1,042 patients from which 685 S. aureus isolates were submitted for identification and susceptibility testing per CLSI guidelines at the central laboratory (JMI Laboratories, North Liberty, IA). The comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Nonsusceptibility to these antibiotics was determined using CLSI breakpoints. S. aureus isolates were 33.7% levofloxacin nonsusceptible (LVX-NS). The delafloxacin MIC90 values against levofloxacin-nonsusceptible S. aureus, methicillin-resistant S. aureus (MRSA), and methicillin-susceptible S. aureus isolates were all 0.25 μg/ml. Delafloxacin demonstrated high rates of microbiological response against LVX-NS isolates as well as isolates with documented mutations in the quinolone resistance-determining region (QRDR). S. aureus was eradicated or presumed eradicated in 98.4% (245/249) of delafloxacin-treated patients. Similar eradication rates were observed for delafloxacin-treated subjects with levofloxacin-nonsusceptible S. aureus isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%). Microbiological response rates of 98.6% were observed with delafloxacin-treated subjects with S. aureus isolates with the S84L mutation in gyrA and the S80Y mutation in parC, the most commonly observed mutations in global phase 3 studies. The data suggest that delafloxacin could be a good option for the treatment of infections caused by S. aureus isolates causing ABSSSI, including MRSA isolates, where high rates of ciprofloxacin and levofloxacin nonsusceptibility are observed. (The phase 3 studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT01984684 and NCT01811732.).

Dataset Information

In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.

Publications

<i>In Vitro</i> Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.

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Dataset Information

In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.

Publications

&lt;i&gt;In Vitro&lt;/i&gt; Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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<i>In Vitro</i> Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.