Randomized, Double-Blind, Multicenter Phase 2 Study Comparing the Efficacy and Safety of Oral Solithromycin (CEM-101) to Those of Oral Levofloxacin in the Treatment of Patients with Community-Acquired Bacterial Pneumonia

ABSTRACTSolithromycin, a new macrolide, and the first fluoroketolide in clinical development, with activity against macrolide-resistant bacteria, was tested in 132 patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP) in a multicenter, double-blind, randomized phase 2 study. Patients were enrolled and randomized (1:1) to either 800 mg solithromycin orally (PO) on day 1, followed by 400 mg PO daily on days 2 to 5, or 750 mg levofloxacin PO daily on days 1 to 5. Efficacy outcome rates of clinical success at the test-of-cure visit 4 to 11 days after the last dose of study drug were comparable in the intent-to-treat (ITT) (84.6% for solithromycin versus 86.6% for levofloxacin) and microbiological-intent-to-treat (micro-ITT) (77.8% for solithromycin versus 71.4% for levofloxacin) populations. Early response success rates at day 3, defined as improvement in at least two cardinal symptoms of pneumonia, were also comparable (72.3% for solithromycin versus 71.6% for levofloxacin). More patients treated with levofloxacin than with solithromycin experienced treatment-emergent adverse events (TEAEs) during the study (45.6% versus 29.7%). The majority of TEAEs were mild or moderate gastrointestinal symptoms and included nausea (1.6% for solithromycin; 10.3% for levofloxacin), diarrhea (7.8% for solithromycin; 5.9% for levofloxacin), and vomiting (0% for solithromycin; 4.4% for levofloxacin). Six patients, all of whom received levofloxacin, discontinued the study drug due to an adverse event. Solithromycin demonstrated comparable efficacy and favorable safety relative to levofloxacin. These findings support a phase 3 study of solithromycin for the treatment of CABP. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168713.)

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1477. A Randomized Phase 2 Study of Cefepime Combined with the Novel Extended Spectrum β-Lactamase Inhibitor Enmetazobactam in Hospitalized Adults with Complicated Urinary Tract Infections (cUTI) Including Acute Pyelonephritis (AP)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1341 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S539-S539

Author(s):

Yehuda Carmeli ◽

Philipp Knechtle ◽

Jeff Hardenberg ◽

Mathias Knecht

Keyword(s):

Study Drug ◽

Generation Cephalosporin ◽

Double Blind Study ◽

The Novel ◽

Phase 2 ◽

Double Blind ◽

Extended Spectrum ◽

Phase 2 Study ◽

Dosing Regimens ◽

Tract Infections

Abstract Background Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae has been classified as critical priority pathogens. The novel extended-spectrum β-lactamase (ESBL) inhibitor enmetazobactam (formerly AAI101; EMT) in combination with cefepime (FEP) is currently being developed as a carbapenem-sparing treatment of serious Gram-negative infections in settings with a high prevalence of 3GC-resistant Enterobacteriaceae. We report here the results from a phase 2 study that assessed safety, tolerability, and pharmacokinetics of FEP-EMT in patients with cUTI/AP. Methods Forty-five patients were enrolled in a randomized, multicenter, double-blind study of hospitalized adults with cUTI/AP. Patients received dosing regimens of FEP or FEP-EMT IV therapy q8h by 2 hours infusion (table) for 7 to 10 days with a 28-day follow-up. Efficacy was evaluated in the microbiological-modified ITT (µMITT) population. Safety was monitored in patients who received at least 1 dose of study drug. Clinical cure was designated as the resolution of cUTI symptoms present at study entry. Plasma and urine PK were determined from all patients. Results The study drugs were well tolerated in each cohort, with similar % adverse events and no new or unexpected safety concerns (table). Two discontinuations were due to allergic dermatitis. The microbiological- and clinical responses at test-of-cure for the combined FEP-EMT group were 83.3% (20/24) and 95.8% (23/24) compared with responses in the combined FEP group of 73.3% (11/15) and 93.3% (14/15), respectively (table). The most common baseline pathogens were Escherichia coli (66.7%) and Klebsiella pneumoniae (23.1%): 28.2% of isolates produced ESBLs with eradication rates for the combined FEP-EMT group of 85.7% (6/7) and for the combined FEP group of 75.0% (3/4). FEP and EMT PK were best described by a 2-compartment, linear PK model. Both agents exhibited half-lives of 2.3 hours. Creatinine clearance had a significant covariate effect on FEP and EMT, consistent with predominant renal excretion of both agents. Conclusion Results from this phase 2 study justify advancement to phase 3 studies to evaluate the safety and efficacy of FEP-EMT in patients with cUTI/AP. Disclosures All authors: No reported disclosures.

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1687. Omadacycline in Female Adults With Acute Pyelonephritis: Results from a Randomized, Double-Blind, Adaptive Phase 2 Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1865 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S827-S827

Author(s):

J Scott Overcash ◽

Evan Tzanis ◽

Amy Manley ◽

Courtney Kirsch ◽

Alisa W Serio ◽

...

Keyword(s):

Acute Pyelonephritis ◽

Clinical Success ◽

Asymptomatic Bacteriuria ◽

Data Monitoring Committee ◽

Panel Member ◽

Phase 2 ◽

Standard Regimen ◽

Double Blind ◽

Once Daily ◽

Phase 2 Study

Abstract Background Omadacycline (OMC) is a novel intravenous (IV) and oral aminomethylcycline, approved in the USA for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in adults. We present data from a randomized, adaptive dose–response phase 2 study of OMC in adult females with acute pyelonephritis (AP). Methods Females aged ≥ 18 y with acute uncomplicated pyelonephritis were initially randomized to 1 of 4 once-daily regimens of OMC vs once-daily standard regimen of IV-to-oral levofloxacin (LEV) (total therapy: 7–10 days) (NCT03757234); the randomization algorithm was subsequently adapted by the data monitoring committee (DMC; blinded to the investigators) following interim analyses of efficacy in the microbiological-intent-to-treat (micro-ITT) population (Table 1). Efficacy was assessed for noninferiority according to investigator’s assessment of clinical response (IACR) and microbiological response at post-therapy evaluation (PTE; Day 21) and end of therapy (EOT). Treatment-emergent adverse events (TEAEs) were assessed. Results were reviewed by the DMC. Table 1 Results 201 patients were randomized. Baseline characteristics were similar across groups (Table 2). Among patients with an identified pathogen, the most common species was E. coli. For IACR at both EOT and PTE, no OMC group met noninferiority to LEV (Figure 1), as the lower limit of the 95% CI for the treatment difference exceeded −10% (range −12.4% to −34.8%). Responses at PTE were consistent with those at EOT. Microbiological responses in each OMC group were generally lower than LEV. OMC was well tolerated; 36.2% and 32.4% of OMC- and LEV-treated patients had ≥ 1 TEAE. The most frequently reported TEAEs (≥ 5%) in the OMC the LEV groups, respectively, were headache (10.2% vs 6.8%), asymptomatic bacteriuria (6.3% vs 1.4%), diarrhea (2.4% vs 6.8%), and nausea (5.5% vs 6.8%). Table 2 Figure Conclusion In this adaptive, phase 2 study, clinical success was high for both groups, although no OMC group met criteria for noninferiority to levofloxacin in AP, potentially due to pharmacokinetic/pharmacodynamic drivers of efficacy for AP. Omadacycline was well tolerated, with a safety profile consistent with its current labeling. Further evaluation is warranted to further understand the outcomes of this study. Disclosures J. Scott Overcash, MD, FACEP, Paratek Pharmaceuticals, Inc. (Scientific Research Study Investigator) Evan Tzanis, BS, Paratek Pharmaceuticals, Inc. (Employee, Shareholder) Amy Manley, BS, Paratek Pharmaceuticals, Inc. (Employee) Courtney Kirsch, BS, Paratek Pharmaceuticals, Inc. (Employee) Alisa W. Serio, PhD, Paratek Pharmaceuticals, Inc. (Employee, Shareholder) Tiffany White, PhD, ContraFact Corporation (Consultant, (ended Feb 2020))Facile Therapeutics (Consultant)Paratek Pharmaceuticals, Inc. (Employee) Kelly Wright, PharmD, Paratek Pharmaceuticals, Inc. (Employee, Shareholder) Surya Chitra, PhD, Paratek Pharmaceuticals, Inc. (Consultant) Paul B. Eckburg, MD, AN2 Therapeutics (Consultant)Bugworks Research (Consultant)Curza (Advisor or Review Panel member)Paratek Pharmaceuticals, Inc. (Consultant)SNIPR Biome (Consultant)Spero Therapeutics (Consultant)

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A Phase-3 Study to Compare Delafloxacin to Moxifloxacin for the Treatment of Adults with Community-acquired Bacterial Pneumonia (DEFINE-CABP)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz514 ◽

2019 ◽

Cited By ~ 2

Author(s):

Juan P Horcajada ◽

Robert A Salata ◽

Rodolfo Álvarez-Sala ◽

Floarea Mimi Nitu ◽

Laura Lawrence ◽

...

Keyword(s):

Clinical Response ◽

Bacterial Pneumonia ◽

Study Drug ◽

The United States ◽

Efficacy And Safety ◽

Success Rates ◽

Phase 3 ◽

Double Blind ◽

Atypical Pathogens ◽

Intent To Treat

Abstract Background The clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is anticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin’s shape and charge profile uniquely impacts its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin to moxifloxacin for the treatment of CABP. Methods A randomized, double-blind, comparator-controlled, multicenter, global Phase 3 study compared the efficacy and safety of delafloxacin 300 mg BID or moxifloxacin 400 mg QD in adults with CABP. The primary endpoint was early clinical response (ECR) defined as improvement at 96 (± 24) hours after first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed. Results In the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group. Conclusions IV/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for grampositive, gramnegative, and atypical pathogens.

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