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)

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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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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00197-13 ◽

2013 ◽

Vol 57 (6) ◽

pp. 2526-2534 ◽

Cited By ~ 57

Author(s):

David Oldach ◽

Kay Clark ◽

Jennifer Schranz ◽

Anita Das ◽

J Carl Craft ◽

...

Keyword(s):

Bacterial Pneumonia ◽

Clinical Success ◽

Gastrointestinal Symptoms ◽

Study Drug ◽

Comparable Efficacy ◽

Resistant Bacteria ◽

Phase 2 ◽

Double Blind ◽

Phase 2 Study ◽

Intent To Treat

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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Safety and Efficacy of Alfimeprase for Restoring Function in Occluded Central Venous Catheters: Interim Results of a Phase 2, Multicenter, Randomized, Double-Blind Study (NuCath).

Blood ◽

10.1182/blood.v104.11.1768.1768 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1768-1768 ◽

Cited By ~ 1

Author(s):

Steven R. Deitcher ◽

Stephan Moll ◽

Howard D. Homesley ◽

Luigi Bertoli ◽

Peter Kenyon ◽

...

Keyword(s):

Patency Rate ◽

Central Venous Access ◽

Study Drug ◽

Venous Access ◽

Double Blind Study ◽

Phase 2 ◽

Central Venous ◽

Bleeding Events ◽

Double Blind ◽

Safety And Efficacy

Abstract Alfimeprase, a recombinantly produced 22.6 kilodalton metalloproteinase, is a genetically modified variant of fibrolase. Alfimeprase, like fibrolase, proteolytically cleaves both the alpha and beta chains of fibrin(ogen) independent of plasminogen activation to plasmin and directly dissolves thrombi. Readily abundant alpha-2 macroglobulin acts as an endogenous circulating alfimeprase inactivator, forming a covalent, irreversible bond with alfimeprase which results in an inactive complex. Based on the direct thrombolytic effect of alfimeprase, rapid activity was hypothesized. We performed a Phase 2, randomized, double-blind, controlled, dose-ranging study to compare the safety and efficacy of one or two instillations of three intraluminal doses of alfimeprase (0.3 mg; 1.0 mg; and 3.0 mg) and Cathflo® Activase® (Genentech) 2.0 mg in reestablishing patency to occluded central venous access devices (CVADs). This report describes an interim analysis of 48 patients with CVAD withdrawal occlusion who were enrolled and randomized to treatment. Catheter patency was assessed at 5, 15, 30, and 120 minutes after each dose of study drug. Adverse events including bleeding events were assessed for a 30-day period after exposure to study drug. Cumulative patency rates are shown in the table. All study arms had similar patency rates at 120 minutes after the first dose. The alfimeprase 3.0 mg dose produced the highest patency rate at 120 minutes after the second dose. All three alfimeprase doses were more effective than Cathflo® Activase® during the first 30 minutes of treatment. The alfimeprase 1.0 mg and 3.0 mg doses resulted in ≥ 50% patency restoration rates at 15 minutes compared to 0% for Cathflo® Activase®. No intracranial hemorrhage, major hemorrhagic, or embolic events were reported in any treated patients at 5 days. Efficacy and safety results of this study support further evaluation of alfimeprase doses ranging from 1.0 mg to 3.0 mg for treatment of occluded CVADs. Cumulative Patency Rate (%) Alfimeprase 0.3 Alfimeprase 1 Alfimeprase 3 Cathflo Activase N=13 N=14 N=9 N=12 D=dose; min=minutes after dose Baseline 0 0 0 0 D 1; 5 min 15 14 44 0 D 1; 15 min 15 50 57 0 D 1; 30 min 30 50 57 25 D 1; 120 min 46 50 57 50 D 2; 5 min 46 50 57 58 D 2; 15 min 46 50 57 67 D 2; 30 min 46 50 57 67 D 2; 120 min 46 50 78 67

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124. Microbiological Outcomes With Plazomicin (PLZ) Versus Meropenem (MEM) in Patients With Complicated Urinary Tract Infections (cUTI), Including Acute Pyelonephritis (AP) in the EPIC Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy209.014 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S7-S8

Author(s):

Tiffany R Keepers ◽

Deborah S Cebrik ◽

Daniel J Cloutier ◽

Allison Komirenko ◽

Lynn Connolly ◽

...

Keyword(s):

Susceptibility Testing ◽

Study Drug ◽

Multidrug Resistant ◽

Double Blind Study ◽

In Vitro Activity ◽

Double Blind ◽

Carbapenem Resistant ◽

Days Of Therapy ◽

Tract Infections

Abstract Background PLZ is a next-generation aminoglycoside (AG) that is structurally protected from common AG-modifying enzymes (AMEs) in Enterobacteriaceae and with in vitro activity against multidrug-resistant Enterobacteriaceae, including ESBL-producing, AG-resistant, and carbapenem-resistant isolates. We report microbiological outcomes in the EPIC study, including outcomes for resistant pathogens and by the PLZ MIC. Methods EPIC was a multinational, randomized, double-blind study in hospitalized patients with cUTI or AP. Patients received IV PLZ (15 mg/kg q24h) or IV MEM (1 g q8h) for 4–7 days, followed by optional oral therapy, for a total of 7–10 days of therapy. The extended mMITT population included patients with ≥1 qualifying baseline pathogen (≥105 CFU/mL urine) who received study drug. Microbiological outcomes were assessed at TOC (day 15–19). Isolate identification and susceptibility testing were conducted by a central laboratory. Whole-genome sequencing was used to identify AME and β-lactamase genes. Results Of 609 patients enrolled, 407 (66.8%) were included in the extended mMITT population. The most common uropathogen was Escherichia coli (63.4%) followed by Klebsiella pneumoniae (19.7%). PLZ and MEM MIC50/90 for Enterobacteriaceae were 0.5/2 μg/mL (range: ≤0.06–>128 mg/mL) and 0.015/0.06 mg/mL (range: ≤0.004–128 mg/mL), respectively. ESBL and AG-NS phenotypes were found in 29% and 27% of isolates, respectively. Genotyping detected β-lactamase and AME genes in 32.5% and 36.8% of isolates, respectively, most commonly blaCTX-M-15 (n = 98), blaOXA-1/OXA-30 (n = 82), aac(6′)Ib-cr (n = 79), and aac(3)-IIa (n = 56). Rates of microbiological eradication are shown in Table 1. All Enterobacteriaceae in the PLZ group with a PLZ MIC of 4 µg/mL (6/6) were eradicated at TOC (Table 2). Across 49 patients with concurrent bacteremia, 100% (27/27) and 96% (24/25) of Enterobacteriaceae were cleared from the blood at TOC in the PLZ and MEM groups, respectively. Conclusion PLZ demonstrated comparable or higher microbiological eradication rates compared with MEM for common Gram-negative uropathogens, including resistant pathogens. The results support PLZ as a potential treatment option for cUTI, including AP, caused by Enterobacteriaceae with PLZ MICs of ≤4 mg/mL. Disclosures T. R. Keepers, Achaogen, Inc.: Employee, Salary. D. S. Cebrik, Achaogen, Inc.: Employee, Salary. D. J. Cloutier, Achaogen, Inc.: Employee and Shareholder, Salary. A. Komirenko, Achaogen, Inc.: Employee and Shareholder, Salary. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. Krause, Achaogen, Inc.: Employee, Salary.

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