IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs Meropenem in the Treatment of Complicated Intraabdominal Infections

Joseph S Solomkin, Janis Gardovskis, Kenneth Lawrence, Philippe Montravers, Angie Sway, David Evans, Larry Tsai, Joseph S Solomkin, Janis Gardovskis, Kenneth Lawrence, Philippe Montravers, Angie Sway, David Evans, Larry Tsai

Abstract

Background: Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae.

Methods: IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated.

Results: Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively.

Conclusions: Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens.

Clinical trials registration: NCT01844856.

Keywords: Enterobacteriaceae; complicated intraabdominal infection; eravacycline; gram-negative bacteria; multidrug resistance.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
CONSORT diagram. Abbreviations: CE, clinically evaluable; ME, microbiologically evaluable; micro-ITT, microbiological intent-to-treat; MITT, modified intent-to-treat; TOC, test-of-cure.

References

    1. Antimicrobial resistance threats in the United States, 2013 2013. Available at: . Accessed 14 November 2018.
    1. Antimicrobial resistance 2018. Available at: . Accessed 14 November 2018.
    1. Antimicrobial resistance 2018. Available at: . Accessed 14 November 2018.
    1. Antimicrobial resistance 2018. Available at: . Accessed 14 November 2018.
    1. Chong Y, Shimoda S, Shimono N. Current epidemiology, genetic evolution and clinical impact of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. Infect Genet Evol 2018; 61:185–8.
    1. Schwaber MJ, Carmeli Y. Mortality and delay in effective therapy associated with extended-spectrum beta-lactamase production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis. J Antimicrob Chemother 2007; 60:913–20.
    1. Thabit AK, Crandon JL, Nicolau DP. Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials. Expert Opin Pharmacother 2015; 16:159–77.
    1. Logan LK, Weinstein RA. The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J Infect Dis 2017; 215:28–36.
    1. Rodriguez-Bano J, Gutierrez-Gutierrez B, Machuca I, Pascual A. Treatment of infections caused by extended-spectrum-beta-lactamase-, AmpC-, and carbapenemase-producing enterobacteriaceae. Clinical Microbiology Reviews 2018; 31.
    1. Harris P TP, David Lye D, Mo Y.. The MERINO trial: piperacillin-tazobactam versus meropenem for the definitive treatment of bloodstream infections caused by third-generation cephalosporin nonsusceptible Escherichia coli or Klebsiella spp.: an international multi-centre open label non-inferiority randomised controlled trial. Madrid: European Congress of Clinical Microbiology and Infectious Diseases, 2018.
    1. Frère JM, Sauvage E, Kerff F. From “An Enzyme Able to Destroy Penicillin” to carbapenemases: 70 years of beta-lactamase misbehaviour. Curr Drug Targets 2016; 17:974–82.
    1. Molton JS, Tambyah PA, Ang BS, Ling ML, Fisher DA. The global spread of healthcare-associated multidrug-resistant bacteria: a perspective from Asia. Clin Infect Dis 2013; 56:1310–8.
    1. Yang Q, Xu YC, Kiratisin P, Dowzicky MJ. Antimicrobial activity among gram-positive and gram-negative organisms collected from the Asia-Pacific region as part of the tigecycline evaluation and surveillance trial: comparison of 2015 results with previous years. Diagn Microbiol Infect Dis 2017; 89:314–23.
    1. Pfaller MA, Huband MD, Streit JM, Flamm RK, Sader HS. Surveillance of tigecycline activity tested against clinical isolates from a global (North America, Europe, Latin America and Asia-Pacific) collection (2016). Int J Antimicrob Agents 2018; 51:848–53.
    1. Lob SH, Biedenbach DJ, Badal RE, Kazmierczak KM, Sahm DF. Antimicrobial resistance and resistance mechanisms of Enterobacteriaceae in ICU and non-ICU wards in Europe and North America: SMART 2011-2013. J Glob Antimicrob Resist 2015; 3:190–7.
    1. Jean SS, Hsueh PR; SMART Asia-Pacific Group Distribution of ESBLs, AmpC β-lactamases and carbapenemases among Enterobacteriaceae isolates causing intra-abdominal and urinary tract infections in the Asia-Pacific region during 2008-14: results from the study for monitoring antimicrobial resistance trends (SMART). J Antimicrob Chemother 2017; 72:166–71.
    1. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence 2017; 8:460–9.
    1. Tracking CRE 2016. Available at: . Accessed 24 June 2018.
    1. Viehman JA, Nguyen MH, Doi Y. Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections. Drugs 2014; 74:1315–33.
    1. van Harten RM, Willems RJL, Martin NI, Hendrickx APA. Multidrug-resistant enterococcal infections: new compounds, novel antimicrobial therapies? Trends Microbiol 2017; 25:467–79.
    1. Mazuski JE, Solomkin JS. Intra-abdominal infections. Surg Clin North Am 2009; 89:421–37, ix.
    1. Mazuski JE, Tessier JM, May AK, et al. . The Surgical Infection Society revised guidelines on the management of intra-abdominal infection. Surg Infect (Larchmt) 2017; 18:1–76.
    1. Solomkin JS, Mazuski JE, Bradley JS, et al. . Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:133–64.
    1. Chukwudi CU. rRNA binding sites and the molecular mechanism of action of the tetracyclines. Antimicrob Agents Chemother 2016; 60:4433–41.
    1. Grossman TH, Starosta AL, Fyfe C, et al. . Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother 2012; 56:2559–64.
    1. Zhang Y, Lin X, Bush K. In vitro susceptibility of β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE) to eravacycline. J Antibiot (Tokyo) 2016; 69:600–4.
    1. Seifert H, Stefanik D, Sutcliffe JA, Higgins PG. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents 2018; 51:62–4.
    1. Zhanel GG, Baxter MR, Adam HJ, Sutcliffe J, Karlowsky JA. In vitro activity of eravacycline against 2213 gram-negative and 2424 gram-positive bacterial pathogens isolated in Canadian hospital laboratories: CANWARD Surveillance Study 2014-2015. Diagn Microbiol Infect Dis 2018; 91:55–62.
    1. Newman JV, Zhou J, Izmailyan S, Tsai L. Randomized, double-blind, placebo-controlled studies of the safety and pharmacokinetics of single and multiple ascending doses of eravacycline. Antimicrob Agents Chemother 2018; 62.
    1. Solomkin JS, Ramesh MK, Cesnauskas G, et al. . Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections. Antimicrob Agents Chemother 2014; 58:1847–54.
    1. Schein M, Marshall J. Source control for surgical infections. World J Surg 2004; 28:638–45.
    1. Solomkin J, Hershberger E, Miller B, et al. . Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 2015; 60:1462–71.
    1. Mazuski JE, Gasink LB, Armstrong J, et al. . Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis 2016; 62:1380–9.
    1. Solomkin J, Evans D, Slepavicius A, et al. . Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE 1) Trial: a randomized clinical trial. JAMA Surg 2017; 152:224–32.
    1. Mazuski JE, Gasink LB, Armstrong J, et al. . Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection—results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis 2016; 62:1380–89.
    1. Berne TV, Yellin AW, Appleman MD, Heseltine PN. Antibiotic management of surgically treated gangrenous or perforated appendicitis. Comparison of gentamicin and clindamycin versus cefamandole versus cefoperazone. Am J Surg 1982; 144:8–13.
    1. Heseltine PN, Yellin AE, Appleman MD, et al. . Perforated and gangrenous appendicitis: an analysis of antibiotic failures. J Infect Dis 1983; 148:322–9.
    1. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis. J Antimicrob Chemother 2012; 67:2793–803.
    1. Girometti N, Lewis RE, Giannella M, et al. . Klebsiella pneumoniae bloodstream infection: epidemiology and impact of inappropriate empirical therapy. Medicine (Baltimore) 2014; 93:298–309.
    1. Harris PNA, Tambyah PA, Lye DC, et al. ; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E. coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 2018; 320:984–94.
    1. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E; Tigecycline 301 Study Group; Tigecycline 306 Study Group The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis 2005; 41 (Suppl 5):S354–67.
    1. Lauf L, Ozsvár Z, Mitha I, et al. . Phase 3 study comparing tigecycline and ertapenem in patients with diabetic foot infections with and without osteomyelitis. Diagn Microbiol Infect Dis 2014; 78:469–80.
    1. Matthews P, Alpert M, Rahav G, et al. ; Tigecycline 900 cSSSI Study Group A randomized trial of tigecycline versus ampicillin-sulbactam or amoxicillin-clavulanate for the treatment of complicated skin and skin structure infections. BMC Infect Dis 2012; 12:297.
    1. O’Riordan W, Mehra P, Manos P, Kingsley J, Lawrence L, Cammarata S. A randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin-structure infections. Int J Infect Dis 2015; 30:67–73.
    1. Towfigh S, Pasternak J, Poirier A, Leister H, Babinchak T. A multicentre, open-label, randomized comparative study of tigecycline versus ceftriaxone sodium plus metronidazole for the treatment of hospitalized subjects with complicated intra-abdominal infections. Clin Microbiol Infect 2010; 16:1274–81.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する