[Skip to Content]
[Skip to Content Landing]
Figure.
CONSORT Diagram
CONSORT Diagram
Table 1.  
Demographics, Baseline, and Surgical Characteristics (Micro-ITT Population)
Demographics, Baseline, and Surgical Characteristics (Micro-ITT Population)
Table 2.  
Primary Efficacy Analysis for US Food and Drug Administration (Clinical Response at TOC Visit)
Primary Efficacy Analysis for US Food and Drug Administration (Clinical Response at TOC Visit)
Table 3.  
Reasons for Clinical Failure at TOC Visit (Micro-ITT Population)
Reasons for Clinical Failure at TOC Visit (Micro-ITT Population)
Table 4.  
Clinical Cure at the TOC Visit by Baseline Pathogen (Micro-ITT Population, With ≥10 Patients/Isolate)
Clinical Cure at the TOC Visit by Baseline Pathogen (Micro-ITT Population, With ≥10 Patients/Isolate)
1.
National Action Plan for Combating Antibiotic-Resistant Bacteria. https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf. Published 2015. Accessed March 19, 2016.
2.
Laxminarayan  R, Duse  A, Wattal  C,  et al.  Antibiotic resistance-the need for global solutions.  Lancet Infect Dis. 2013;13(12):1057-1098.PubMedGoogle ScholarCrossref
3.
Teillant  A, Gandra  S, Barter  D, Morgan  DJ, Laxminarayan  R.  Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study.  Lancet Infect Dis. 2015;15(12):1429-1437.PubMedGoogle ScholarCrossref
4.
Hawkey  PM.  Multidrug-resistant Gram-negative bacteria: a product of globalization.  J Hosp Infect. 2015;89(4):241-247.PubMedGoogle ScholarCrossref
5.
Correa  L, Martino  MD, Siqueira  I,  et al.  A hospital-based matched case-control study to identify clinical outcome and risk factors associated with carbapenem-resistant Klebsiella pneumoniae infection.  BMC Infect Dis. 2013;13:80.PubMedGoogle ScholarCrossref
6.
Frakking  FN, Rottier  WC, Dorigo-Zetsma  JW,  et al.  Appropriateness of empirical treatment and outcome in bacteremia caused by extended-spectrum-β-lactamase-producing bacteria.  Antimicrob Agents Chemother. 2013;57(7):3092-3099.PubMedGoogle ScholarCrossref
7.
Potron  A, Poirel  L, Nordmann  P.  Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: Mechanisms and epidemiology.  Int J Antimicrob Agents. 2015;45(6):568-585.PubMedGoogle ScholarCrossref
8.
Viehman  JA, Nguyen  MH, Doi  Y.  Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections.  Drugs. 2014;74(12):1315-1333.PubMedGoogle ScholarCrossref
9.
Nguyen  F, Starosta  AL, Arenz  S, Sohmen  D, Dönhöfer  A, Wilson  DN.  Tetracycline antibiotics and resistance mechanisms.  Biol Chem. 2014;395(5):559-575.PubMedGoogle ScholarCrossref
10.
Zhanel  GG, Cheung  D, Adam  H,  et al.  Review of eravacycline, a novel fluorocycline antibacterial agent.  Drugs. 2016;76(5):567-588.PubMedGoogle ScholarCrossref
11.
Sutcliffe  JA, O’Brien  W, Fyfe  C, Grossman  TH.  Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens.  Antimicrob Agents Chemother. 2013;57(11):5548-5558.PubMedGoogle ScholarCrossref
12.
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(4):1847-1854.PubMedGoogle ScholarCrossref
13.
Skrupky  LP, Tellor  BR, Mazuski  JE.  Current strategies for the treatment of complicated intraabdominal infections.  Expert Opin Pharmacother. 2013;14(14):1933-1947.PubMedGoogle ScholarCrossref
14.
Mangram  AJ, Horan  TC, Pearson  ML, Silver  LC, Jarvis  WR; Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee.  Guideline for prevention of surgical site infection, 1999.  Am J Infect Control. 1999;27(2):97-132.PubMedGoogle ScholarCrossref
15.
Mangram  AJ, Horan  TC, Pearson  ML, Silver  LC, Jarvis  WR; Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee.  Guideline for prevention of surgical site infection, 1999.  Am J Infect Control. 1999;27(2):97-132.PubMedGoogle ScholarCrossref
16.
Rahmqvist  M, Samuelsson  A, Bastami  S, Rutberg  H.  Direct health care costs and length of hospital stay related to health care-acquired infections in adult patients based on point prevalence measurements.  Am J Infect Control. 2016;44(5):500-506.PubMedGoogle ScholarCrossref
17.
Solomkin  JS, Ristagno  RL, Das  AF,  et al.  Source control review in clinical trials of anti-infective agents in complicated intra-abdominal infections.  Clin Infect Dis. 2013;56(12):1765-1773.PubMedGoogle ScholarCrossref
18.
Magiorakos  AP, Srinivasan  A, Carey  RB,  et al.  Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.  Clin Microbiol Infect. 2012;18(3):268-281.PubMedGoogle ScholarCrossref
19.
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(10):1462-1471.PubMedGoogle Scholar
20.
Mazuski  JE, Gasink  LB, Armstrong  J,  et al.  Efficacy and safety of ceftazidime-avibactam plus metronidazole vs meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program.  Clin Infect Dis. 2016;62(11):1380-1389.PubMedGoogle ScholarCrossref
21.
Broderick  RC, Fuchs  HF, Harnsberger  CR,  et al.  The price of decreased mortality in the operative management of diverticulitis.  Surg Endosc. 2015;29(5):1185-1191.PubMedGoogle ScholarCrossref
22.
Solomkin  JS, Yellin  AE, Rotstein  OD,  et al; Protocol 017 Study Group.  Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial.  Ann Surg. 2003;237(2):235-245.PubMedGoogle Scholar
23.
Lucasti  C, Jasovich  A, Umeh  O, Jiang  J, Kaniga  K, Friedland  I.  Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study.  Clin Ther. 2008;30(5):868-883.PubMedGoogle ScholarCrossref
24.
Marshall  JC, al Naqbi  A.  Principles of source control in the management of sepsis.  Crit Care Clin. 2009;25(4):753-768, viii-ix.PubMedGoogle ScholarCrossref
25.
Andersen  BR, Kallehave  FL, Andersen  HK.  Antibiotics versus placebo for prevention of postoperative infection after appendicectomy.  Cochrane Database Syst Rev. 2005;(3):CD001439.PubMedGoogle Scholar
26.
Calbo  E, Garau  J.  The changing epidemiology of hospital outbreaks due to ESBL-producing Klebsiella pneumoniae: the CTX-M-15 type consolidation.  Future Microbiol. 2015;10(6):1063-1075.PubMedGoogle ScholarCrossref
Original Investigation
March 2017

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

Author Affiliations
  • 1University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 2Ohio State University School of Medicine, Columbus
  • 3Klaipeda University Hospital, Klaipeda, Lithuania
  • 4Baystate Medical Center, Springfield, Massachusetts
  • 5Tetraphase Pharmaceuticals Inc, Watertown, Massachusetts
 

Copyright 2016 American Medical Association. All Rights Reserved.

JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237
Key Points

Question  Is eravacycline a safe and effective treatment for complicated intra-abdominal infections compared with ertapenem?

Findings  This randomized clinical trial of 541 patients with complicated intra-abdominal infections requiring surgery or percutaneous drainage found a cure rate of 86.8% for the microbiological intent-to-treat population in the eravacycline treatment group and 87.6% for the microbiological intent-to-treat population in the ertapenem treatment group. The difference in clinical cure rates was −0.80%, exceeding the established noninferiority margin.

Meaning  The efficacy, microbiological activity, and safety of eravacycline support a positive risk-benefit profile for the treatment of patients with complicated intra-abdominal infections and are comparable with the known profile for ertapenem.

Abstract

Importance  Eravacycline is a novel, fully synthetic fluorocycline antibiotic of the tetracycline class with in vitro activity against clinically important gram-negative, gram-positive aerobic, and facultative bacteria including most of those resistant to cephalosporins, fluoroquinolones, β-lactam/β-lactamase inhibitors, multidrug resistant strains and carbapenem-resistant Enterobacteriaceae, and most anaerobic pathogens.

Objective  To evaluate the efficacy and safety of eravacycline compared with ertapenem in adult hospitalized patients with complicated intra-abdominal infections (cIAIs).

Design, Setting, and Participants  This was a phase III, randomized, double-blind, multicenter study that evaluated the efficacy and safety of eravacycline in comparison with ertapenem in patients with cIAI requiring surgical or percutaneous intervention. The test-of-cure evaluation was conducted 25 to 31 days after the first dose of the study drug and the follow-up visit was conducted 38 to 50 days after the first dose of the study drug. All patients recruited into this study were hospitalized. Five hundred forty-one patients were recruited for this study; 270 patients were randomized to receive eravacycline, and 271 patients were randomized to receive ertapenem. Patients had to meet all of the following criteria: hospitalized for cIAI requiring intervention; 18 years or older; evidence of systemic inflammatory response; pain caused by cIAI; able to provide informed consent; and diagnosis of cIAI with sonogram or radiographic imaging or visual confirmation. Analyses were done in intent-to-treat and evaluable populations.

Interventions  Patients received eravacycline, 1.0 mg/kg every 12 hours, or ertapenem, 1.0 g every 24 hours, for a minimum of four 24-hour dosing cycles.

Main Outcomes and Measures  Clinical outcome assessments were made at the end of treatment, test of cure, and follow-up visits and were classified as clinical cure, clinical failure, or indeterminate/missing.

Results  In total, 541 patients were randomly assigned to treatment: 270 in the eravacycline group and 271 in the ertapenem group. The mean ages were 54.9 years and 55.4 years for the eravacycline and ertapenem groups, respectively. Most patients were white (263 of 270 patients [97.4%] in the eravacycline group and 260 of 271 patients [95.9%] in the ertapenem group). For the microbiological intent-to-treat population, the rates of clinical cure at the test-of-cure visit were 86.8% in the eravacycline group and 87.6% in the ertapenem group. The difference in clinical cure rates between the groups was −0.80% (95% CI, −7.1% to 5.5%), meeting the prespecified noninferiority margin and allowing for statistical noninferiority of eravacycline to ertapenem to be declared for this study. Both study drugs were well tolerated.

Conclusions and Relevance  Overall, eravacycline demonstrated noninferiority to ertapenem for the treatment of patients with cIAI.

Trial Registration  Clinicaltrials.gov Identifier: NCT01844856.

Introduction

Gram-positive and gram-negative organisms with novel resistance mechanisms to commonly used antimicrobials have become a global therapeutic problem. The estimates of mortality and costs owing to antimicrobial resistance are striking, and these concerns have led to clinical and governmental action.1-3

A common resistance mechanism is the production of extended-spectrum β-lactamases (ESBLs).4 Organisms that produce ESBLs are now most commonly recognized in health care settings and are, if not appropriately treated, an independent risk factor for increased morbidity and mortality.5,6 Other important pathogens, such as those in the Acinetobacter baumanii complex, are routinely multidrug resistant.7,8

Quiz Ref IDEravacycline is a novel, fully synthetic antibiotic of the tetracycline class designed to be active against the 2 main acquired tetracycline-specific resistance mechanisms: ribosomal protection and active drug efflux.9,10 Eravacycline has potent in vitro activity against antibiotic-resistant bacteria identified as urgent or serious threats by the US Centers for Disease Control and Prevention: carbapenem-resistant Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, ESBL-producing Enterobacteriaceae, and vancomycin-resistant enterococci.11

A dose-finding phase II study supported the efficacy of eravacycline in complicated intra-abdominal infections (cIAIs),12 an important problem in clinical practice.13 Treatment failure, described as surgical site infections, may cause substantial morbidity, mortality, delayed recovery, and increased costs.14-16 For these reasons, cIAIs remain an important disease process for examining the efficacy of novel antibiotics.

Because resistant, gram-negative organisms are a documented problem in cIAIs, there is a clear need for broad-spectrum antibiotics to cover the wide range of potential pathogens seen. The objective of this study was to assess the efficacy and safety of eravacycline compared with ertapenem in the treatment of cIAIs in hospitalized adults.

Methods
Study Design

Quiz Ref IDThis was a randomized, double-blind, double-dummy, multicenter study using a 2-arm, parallel treatment group design that complied with the most recent US Food and Drug Administration (FDA) guidance.17 The study was designed to demonstrate noninferiority of eravacycline (1.0 mg/kg per 12 hours) vs ertapenem (1.0 g per 24 hours).

The protocol and all supporting information were submitted to and approved by the institutional review board or independent ethics committee at each site before the study was initiated. The study was conducted in accordance with Good Clinical Practice and the World Medical Assembly Declaration of Helsinki. Each patient of age of consent (per local requirements) signed and dated a study-specific informed consent form before any study procedures were conducted. The consent forms complied with all applicable regulations governing the protection of human participants.

Patients were enrolled between the dates of August 28, 2013, and August 24, 2014, from 66 clinical sites in 11 countries (Florence and Mobile, Alabama; Glendale, La Mesa, Los Angeles, and Torrance, California; Aurora, Illinois; Carmel, Indiana; Boston and Springfield, Massachusetts; Minneapolis, Minnesota; Las Vegas, Nevada; Camden and Teaneck, New Jersey; Cleveland, Columbus, and Weston, Ohio; Houston, Texas; and Seattle, Washington in the United States; Corboda, Argentina; Pleven, Plovdiv, Rousse, Sofia, and Varna, Bulgaria; Brno, Kladno, Melnik, Olomouc, Prague, and Usti nad Labem in the Czech Republic; Kohtla-Jarve, Tallinn, Tartu in Estonia; Paris, France; Heidelberg, Luebeck, and Magdeburg, Germany; Daugavpils, Liepaja, and Riga, Latvia; Kaunas, Klaipeda, Siauliai, and Vilnius, Lituania; Bucharest, Cluj-Napoca, Craiova, and Timisoara, Romania; Kaluga, Kemerovo, Moscow, Nizhny Novgorod, Smolensk, St Petersburg, Tomsk, Volgograd, and Vsevolozhsk of the Russian Federation; Benoni, Johannesburg, Pretoria, and Worcester, South Africa; and Dnipropetrovsk, Ivano-Frankivsk, Kharkiv, Kyiv, Odesa, Uzhhorod, and Zaporizhia in the Ukraine). The formal trial protocols for the study can be found in the Supplement.

Inclusion Criteria

Patients were 18 years or older with clinical evidence of cIAI requiring urgent surgical or percutaneous intervention within 48 hours of diagnosis. Requirements for preoperative enrollment were sonogram or radiographic imaging results consistent with the diagnosis of cIAI; planned acute surgical or percutaneous intervention; and planned specimen collection by aspiration or tissue sample sent for culture and sensitivity. Acceptable diagnoses for cIAI were appendiceal perforation and/or periappendiceal abscess; diverticulitis abscess or peritonitis; acute gastric and duodenal perforation if operated on more than 24 hours after the perforation; traumatic perforation of the intestines if operated on more than 12 hours after the perforation; and/or abscess or peritonitis owing to perforated viscus or other focus of infection or other intra-abdominal abscess.

Exclusion Criteria

The following exclusions applied: rapidly progressing disease or immediately life-threatening illness including acute hepatic failure, respiratory failure, and/or septic shock; requirement of vasopressors at therapeutic dosages to maintain a systolic blood pressure at least 90 mm Hg or diastolic blood pressure at least 70 mm Hg; a creatinine clearance less than 50 mL/min as estimated by the Cockcroft-Gault equation (to convert to milliliters per seconds per meters squared, multiply by 0.0167); and/or possible signs of significant hepatic disease defined as alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limits of normal; greater than 5 times the upper limits of normal for patients with hepatic abscess or total bilirubin greater than 3 times the upper limits of normal; anticipated survival period shorter than the study period; symptoms related to diagnosis of complicated appendicitis for less than 24 hours prior to the current hospitalization; planned treatment of cIAI by staged abdominal repair or other open abdominal techniques; and/or known or suspected inflammatory bowel disease or associated visceral abscess. Patients were excluded if they had received systemic antibiotics for their condition for more than 24 hours, received ertapenem or any other carbapenem or tigecycline for the infection, or required systemic antimicrobial agents other than the study drug.

Randomization and Treatment

Randomization numbers were computer generated using an internet-based system and stratified based on the primary site of infection (complicated appendicitis vs all other diagnoses). No more than 30% of patients enrolled were to have complicated appendicitis. Eligible patients were assigned to receive an intravenous infusion of eravacycline, 1.0 mg/kg every 12 hours, or ertapenem, 1 g every 24 hours. The study drug was administered in 24-hour dosing cycles for a minimum of 4 dosing cycles. Drug assignment was concealed from the patient and all clinical and study staff using placebo infusions and a double-dummy design. The comparator, ertapenem, is approved by the FDA and other regulatory authorities for the treatment of cIAI.

Outcome Assessment

Patients were evaluated on day 1 through day 14 of the drug regimen and at the end-of-treatment visit, which occurred within 24 hours of the last dose of the study drug. The test-of-cure (TOC) evaluation was conducted 25 to 31 calendar days after the first dose of the study drug was administered, and the follow-up visit was performed 38 to 50 calendar days after the first dose of study drug was administered. Patients remained hospitalized for the entire course of drug therapy.

Clinical responses were classified as clinical cure, clinical failure, or indeterminate/missing. Clinical cure was defined as complete resolution or significant improvement of signs or symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Events defining clinical failure included death related to cIAI at any time, persistence of clinical signs and symptoms of cIAI, unplanned surgical procedures or percutaneous drainage procedures, postsurgical wound infections requiring systemic antibiotics, and initiation of additional antibacterial drug therapy for cIAI. Patients who did not meet criteria for clinical cure or clinical failure were listed as indeterminate. If the investigator did not complete an assessment or if the patient was not present for the TOC study visit, the outcome was considered missing.

Microbiologic Assessment

Four blood samples from at least 2 separate venipuncture sites were obtained at the time of screening for aerobe and anaerobe cultures. Surgical specimens from all sites were shipped to their respective regional laboratory at ambient temperature on the day of collection with arrival within 48 hours from the time of collection for purification and identification of isolates. All bacterial isolates cultured from aerobic and anaerobic specimens were evaluated for susceptibility to study drugs. Isolates from all studies showing resistance to carbapenems or third- and fourth-generation cephalosporins were sent to JMI Laboratories, North Liberty, Iowa, to determine uniqueness based on pulsed field gel electrophoresis and further determination of β-lactam resistance mechanisms.

Statistical Analysis

The primary efficacy end point was the clinical response at the TOC visit in the microbiological intent-to-treat (micro-ITT) population (FDA) and in the modified intent-to-treat (MITT) and clinically evaluable populations (European Medicines Agency). For the FDA, a noninferiority margin of 10% was used. The noninferiority test was based on the lower limit of the 2-sided 95% CI. If the lower limit of the 95% CI for the difference in clinical cure rates in the micro-ITT population exceeded −10%, noninferiority of eravacycline to ertapenem would be declared.

We performed a review of source control procedures for patients whose clinical outcomes were considered failures and cured patients with an unplanned second procedure.17

Results
Patient Demographics and Baseline Characteristics

In total, 541 patients were randomly assigned to treatment: 270 in the eravacycline 1.0 mg/kg every 12 hours group and 271 in the ertapenem 1.0 g every 24 hours group. The CONSORT diagram indicating different patient populations is shown in the Figure. Patients who had baseline bacterial pathogens against at least 1 of which the study drug had in vitro antibacterial activity were designated as the micro-ITT population. The demographics and baseline characteristics for this population are shown in Table 1.

Patients in the micro-ITT population displayed generally similar demographic characteristics across both treatment groups. The mean ages were 54.9 years and 55.4 years for the eravacycline and ertapenem groups, respectively. Most patients were white (263 of 270 patients [97.4%] in the eravacycline group and 260 of 271 patients [95.9%] in the ertapenem group) and men, reflecting the geographic distribution of study sites.

Approximately one-third of patients in both treatment groups (88 of 270 patients [32.6%] for eravacycline and 76 of 271 patients [28.0%] for ertapenem) were older than 65 years. We believe the paradoxically high cure rates in patients 75 years and older were owing to diseases where the infectious process could be extirpated such as pericholecystic disease.

Pathologic Processes Encountered

One hundred patients (90.0%) in the eravacycline treatment group and 189 patients (83.6%) in the ertapenem treatment group entered the study either intraoperatively or postoperatively.

Quiz Ref IDThe most common anatomic description of infection was intra-abdominal abscess(es), with 85 patients (42.9) in the eravacycline treatment group and 77 (40.7%) in the ertapenem treatment group, followed by peritonitis (62 patients [31.1%] and 65 patients [34.4%] in the eravacycline and ertapenem groups, respectively). Complicated appendicitis was the cause of infection in 62 patients (31.3%) and 60 patients (31.7) in the eravacycline and ertapenem groups, respectively. The data displayed by the presumed pathology are provided in Table 1.

Most patients in the micro-ITT population in the eravacycline group and the ertapenem group had open surgical procedures. The second most common operative approach was laparoscopic, followed by percutaneous drainage. The choices were driven by the pathology encountered; cholecystitis was most often treated by laparoscopy, as was appendicitis. Variables relating to the surgical intervention, such as average study day of intervention, number of abscesses, infection type, wound closure, and number of drains placed, were similar in both treatment groups.

Efficacy Analysis

Table 2 details the difference in clinical cure rates at the TOC visit based on a 95% CI. For the primary end point, clinical cure rates were 87.0% (235 of 270) for eravacycline and 88.8% (238 of 268) for ertapenem in the MITT population. The difference in clinical cure rates was −1.80% with a 2-sided 95% CI of −7.4% to 3.8%, meeting the statistical criteria for noninferiority. The microbiologically evaluable population also achieved statistical noninferiority, with clinical cure rates of 91.4% (181 of 198) for eravacycline and 95.0% (189 of 199) for ertapenem (difference of −3.6%; 95% CI, −8.9% to 1.5%). Clinical cure rates in the clinically evaluable population at TOC were 92.9% (222 of 239) and 94.5% (225 of 238) with a difference of −1.7% (−6.3% to 2.8%). In the micro-ITT population, cure rates were 86.8% (191 of 220) and 87.6% (198 of 226), respectively (difference −0.80%; 95% CI, −7.1% to 5.5%).

Clinical failure rates were similar in both treatment groups for the MITT population. For the micro-ITT population, the clinical failure rate was 8.6% (19 of 220) for the eravacycline treatment group and 4.9% (11 of 226) for the ertapenem treatment group, with indeterminate/missing rates of 4.5% (10 of 220) and 7.5% (17 of 226), respectively. Table 3 details all clinical failures in the micro-ITT population. The most frequent reasons for clinical failure were unplanned surgical procedure or percutaneous drainage procedure and initiation of rescue antibacterial therapy for cIAI.

There were 9 deaths in the study, 3 among patients receiving eravacycline and 6 among patients receiving ertapenem. The specific causes of death were pulmonary embolism (n = 2), respiratory failure (n = 3), multisystem organ failure (n = 1), cardiac rhythm disturbances (n = 2), and cerebrovascular accident (n = 1). None were considered related to study therapy.

Microbiologic Responses

Table 4 summarizes the number and percentage of patients from the micro-ITT population with a favorable microbiological response at the TOC visit. The percentage of favorable responses was generally similar between treatment groups for most pathogens. The baseline pathogens for which the incidence of favorable responses was at least 10% higher in the eravacycline treatment group compared with the ertapenem treatment group included Streptococcus constellatus, Citrobacter freundii, Klebsiella pneumoniae, and Bacteroides thetaiotaomicron. The baseline pathogens for which the incidence of favorable responses was at least 10% lower in the eravacycline treatment group compared with the ertapenem treatment group included Enterobacter cloacae, Bacteroides ovatus, Enterococcus faecalis, and Pseudomonas aeruginosa. Also of interest is the fact that the favorable response in patients with baseline Acinetobacter baumannii was 100% in both treatment groups (8 of 8 for eravacycline and 5 of 5 for ertapenem) at the TOC visit.

Organisms Present in Treatment Failures

Fifteen patients in the eravacycline arm and 11 in the ertapenem arm had failed clinical outcomes because of need for a second unplanned procedure or wound infection. Ten patients receiving eravacycline had persisting isolates. These included 6 Escherichia coli and 1 each Bacteroides species, Clostridia perfringens, Enterococcus durans, Hemophilus parainfluenzae, and Pseudomonas aeruginosa. In the ertapenem-treated patients, there was 1 E coli, 2 Bacteroides species, and 2 streptococci.

In patients whose outcomes were classified as clinical failures and who underwent a second surgical procedure that allowed for repeated culture, the susceptibility to eravacycline of the pathogens isolated at the follow-up procedure was compared with the susceptibility of the original baseline pathogens. Only 1 patient in the eravacycline group exhibited decreasing susceptibility.

Safety

There were more treatment-emergent adverse events in the eravacycline treatment group (113 of 270) than the ertapenem treatment group (75 of 268). The number of severe or life-threatening treatment-emergent adverse events was the same for both groups (n = 13). The number of patients who experienced treatment-emergent adverse events by preferred term in each treatment group was similar for vomiting, anemia, pyrexia, and diarrhea. Nausea and phlebitis were the exceptions: nausea was recorded for 22 patients (8.1%) in the eravacycline group and 2 patients (0.7%) in the ertapenem group, and phlebitis was recorded for 8 patients (3.0%) in the eravacycline group and 1 patient (0.4%) in the ertapenem group. The number and percentage of patients who experienced severe treatment-emergent adverse events, including life-threatening and fatal events, were similar between both treatment groups: 15 (5.6%) for eravacycline and 16 (6.0%) for the ertapenem.

Discussion

Quiz Ref IDIn this phase III trial comparing eravacycline with ertapenem for complicated intra-abdominal infections, eravacycline met both the FDA and EMA primary end points of noninferior clinical efficacy vs ertapenem.

The patients entered in this trial were somewhat different from those in 2 trials performed in 2015 and 2016. We limited the percentage of patients with appendicitis, an infection with high cure rates, to 30%. In the trial with ceftolozane/tazobactam, 46% of the patients had appendicitis with a cure rate of 96%.19 In the ceftazidime/avibactam trial, 41% of patients had appendicitis with a similarly high success rate.20

There has been considerable improvement in clinical outcomes in trials conducted in the past decade compared with those reported 10 or more years ago. For example, in a 2003 study, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam.19 We noted a considerable increase in the use of laparoscopic and percutaneous procedures compared with open operations in previous trials. The movement to less invasive procedures has been associated with reduced treatment failure.21-23

Source control, the physical steps taken to drain abscesses and correct any underlying intestinal discontinuity, is an essential element of treatment.24 Because of the dependency of infection rates on the type of procedure performed and because the procedure is typically dictated by the organ of origin, we would like to highlight the importance of documenting the organ of origin rather than only the presence of abscess/peritonitis because this may obscure the clinical details of infection and the source control procedure performed.

Quiz Ref IDThe microbiology encountered in this trial is similar to that seen in other clinical trials in cIAI. Most infections (>90%) were polymicrobial, and gram-negative facultative or aerobic organisms were isolated in 82% of patients. Clinical cure rates by organism were equivalent between eravacycline and ertapenem across all types of organisms. Patients with cephalosporin-resistant isolates and the large subset of those expressing ESBLs were cured at rates equivalent to cephalosporin-susceptible and non-ESBL–producing organisms.

The presence of ESBLs in 9% of the patients is of concern. Placebo-controlled randomized clinical trials have demonstrated a critical role for antibiotics targeting the range of organisms encountered in these mixed flora infections, with a substantial effect size.16 Whether, in the presence of resistance, empirical treatment active against the gram-negative organisms resistant to β-lactams prior to incision would provide even lower surgical site infections is not known. For 90% of the patients, perioperative antibiotics were β-lactams, and study-driven therapy was not given until the postoperative period. Given the small numbers of failures with ESBLs, a case for empirical treatment for these isolates cannot be made until studies with higher background ESBL rates are done.

This and other protocols exclude patients with rapidly fatal background disease or septic shock. The outcome of interest is the ability of the study agents to resolve the local infection and prevent recurrent surgical site infections. Mortality confounds an antibiotic efficacy study because death is typically multifactorial, primarily driven by background disease and septic shock.

We noted high success rates in this study with organisms known to be resistant to one or the other agent used in this study. This is of particular relevance for ertapenem and eravacycline activity against P aeruginosa and for ertapenem against Acinetobacter. This phenomenon is observed in most randomized clinical trials in cIAI. The most common explanation is that the source control procedure reduces the inoculum density substantially, so that ongoing invasive infection is terminated. However, multiple placebo-controlled trials in perforated appendicitis demonstrate significant benefit of organism-specific therapy.25 Another possibility is that in polymicrobial infections, the requirement for microbial synergy may mean cure rates would be increased if only part of the infecting flora were killed. To support this, we noted that 97% of cases harboring P aeruginosa also had coinfecting susceptible isolates. It would appear that the best evidence for an agent’s activity against a specific organism is the demonstration of clinical eradication combined with in vitro susceptibility. The causes of failure were similar between the treatment groups and are consistent with findings in clinical practice and in other trials.

Limitations

Trials of antimicrobial therapy in cIAIs are at risk of confounding by the various factors that affect the outcome. These factors include patients with varying premorbid conditions, clinical details of the acute disease process varying significantly in their prognostic importance, and perioperative care practices that may alter outcomes if not standardized. Finally, the timing and nature of the procedure performed may vary within specific disease states. These individual outcome determinants may have stronger effects than the antimicrobial agent given and thus may confound the statistical analysis. To avoid these problems, this study enrolled a large number of patients and limited the wide range of premorbid conditions such as terminal cancer and other life-threatening diseases allowed for study entry, controlled the timing of study drug initiation to maximize effectiveness, and used objective end points, such as death or surgical site infection, as the outcome determinants.

Conclusions

In this study, intravenous eravacycline, 1.0 mg/kg every 12 hours, was found to be noninferior to ertapenem in patients with cIAIs. The microbiology and patients encountered in this trial were representative of the broader group of patients seen in clinical practice with such infections.

Back to top
Article Information

Corresponding Author: Joseph S. Solomkin, MD, Department of Surgery, University of Cincinnati College of Medicine, 6005 Given Rd, Cincinnati, OH 45243 (solomkjs@ucmail.uc.edu).

Accepted for Publication: July 26, 2016.

Published Online: November 16, 2016. doi:10.1001/jamasurg.2016.4237

Author Contributions: Drs Solomkin and Horn had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Solomkin, Slepavicius, Lee, Horn.

Acquisition, analysis, or interpretation of data: Solomkin, Evans, Slepavicius, Tsai, Sutcliffe, Horn.

Drafting of the manuscript: Solomkin, Evans, Slepavicius, Sutcliffe, Horn.

Critical revision of the manuscript for important intellectual content: Evans, Slepavicius, Lee, Tsai, Sutcliffe, Horn.

Statistical analysis: Slepavicius, Lee, Tsai.

Administrative, technical, or material support: Solomkin, Evans, Sutcliffe, Horn.

Conflict of Interest Disclosures: Dr Solomkin reports personal fees and nonfinancial support from Tetraphase Pharmaceuticals Inc during the conduct of the study and personal fees from Cubist Pharmaceutical, Merck, Pfizer, GlaxoSmithKline, and Melinta outside of the submitted work. Dr Evans reports grants from Tetraphase during the conduct of the study and grants from Cubist Pharmaceutical and Merck outside of the submitted work. Dr Slepavicius reports grants from Tetraphase Pharmaceuticals Inc for his role as Principal Investigator. Drs Sutcliffe, Horn, and Tsai and Mr Marsh are full-time employees of Tetraphase. No other disclosures are reported.

Funding/Support: This study was sponsored by Tetraphase Pharmaceuticals Inc.

Role of the Funder/Sponsor: The sponsor provided the authors with the Clinical Study Report, which was generated by the contract research organization from the original case report forms and contained all of the necessary information on the design and conduct of the study. The sponsor had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Angie Sway, BA, Oasis Global Inc and Johns Hopkins University, and Kimberley Severin, MS, Johnson and Johnson, contributed to the writing and revision of the manuscript. No compensation from a funding sponsor was received by either contributor.

References
1.
National Action Plan for Combating Antibiotic-Resistant Bacteria. https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf. Published 2015. Accessed March 19, 2016.
2.
Laxminarayan  R, Duse  A, Wattal  C,  et al.  Antibiotic resistance-the need for global solutions.  Lancet Infect Dis. 2013;13(12):1057-1098.PubMedGoogle ScholarCrossref
3.
Teillant  A, Gandra  S, Barter  D, Morgan  DJ, Laxminarayan  R.  Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study.  Lancet Infect Dis. 2015;15(12):1429-1437.PubMedGoogle ScholarCrossref
4.
Hawkey  PM.  Multidrug-resistant Gram-negative bacteria: a product of globalization.  J Hosp Infect. 2015;89(4):241-247.PubMedGoogle ScholarCrossref
5.
Correa  L, Martino  MD, Siqueira  I,  et al.  A hospital-based matched case-control study to identify clinical outcome and risk factors associated with carbapenem-resistant Klebsiella pneumoniae infection.  BMC Infect Dis. 2013;13:80.PubMedGoogle ScholarCrossref
6.
Frakking  FN, Rottier  WC, Dorigo-Zetsma  JW,  et al.  Appropriateness of empirical treatment and outcome in bacteremia caused by extended-spectrum-β-lactamase-producing bacteria.  Antimicrob Agents Chemother. 2013;57(7):3092-3099.PubMedGoogle ScholarCrossref
7.
Potron  A, Poirel  L, Nordmann  P.  Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: Mechanisms and epidemiology.  Int J Antimicrob Agents. 2015;45(6):568-585.PubMedGoogle ScholarCrossref
8.
Viehman  JA, Nguyen  MH, Doi  Y.  Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections.  Drugs. 2014;74(12):1315-1333.PubMedGoogle ScholarCrossref
9.
Nguyen  F, Starosta  AL, Arenz  S, Sohmen  D, Dönhöfer  A, Wilson  DN.  Tetracycline antibiotics and resistance mechanisms.  Biol Chem. 2014;395(5):559-575.PubMedGoogle ScholarCrossref
10.
Zhanel  GG, Cheung  D, Adam  H,  et al.  Review of eravacycline, a novel fluorocycline antibacterial agent.  Drugs. 2016;76(5):567-588.PubMedGoogle ScholarCrossref
11.
Sutcliffe  JA, O’Brien  W, Fyfe  C, Grossman  TH.  Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens.  Antimicrob Agents Chemother. 2013;57(11):5548-5558.PubMedGoogle ScholarCrossref
12.
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(4):1847-1854.PubMedGoogle ScholarCrossref
13.
Skrupky  LP, Tellor  BR, Mazuski  JE.  Current strategies for the treatment of complicated intraabdominal infections.  Expert Opin Pharmacother. 2013;14(14):1933-1947.PubMedGoogle ScholarCrossref
14.
Mangram  AJ, Horan  TC, Pearson  ML, Silver  LC, Jarvis  WR; Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee.  Guideline for prevention of surgical site infection, 1999.  Am J Infect Control. 1999;27(2):97-132.PubMedGoogle ScholarCrossref
15.
Mangram  AJ, Horan  TC, Pearson  ML, Silver  LC, Jarvis  WR; Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee.  Guideline for prevention of surgical site infection, 1999.  Am J Infect Control. 1999;27(2):97-132.PubMedGoogle ScholarCrossref
16.
Rahmqvist  M, Samuelsson  A, Bastami  S, Rutberg  H.  Direct health care costs and length of hospital stay related to health care-acquired infections in adult patients based on point prevalence measurements.  Am J Infect Control. 2016;44(5):500-506.PubMedGoogle ScholarCrossref
17.
Solomkin  JS, Ristagno  RL, Das  AF,  et al.  Source control review in clinical trials of anti-infective agents in complicated intra-abdominal infections.  Clin Infect Dis. 2013;56(12):1765-1773.PubMedGoogle ScholarCrossref
18.
Magiorakos  AP, Srinivasan  A, Carey  RB,  et al.  Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.  Clin Microbiol Infect. 2012;18(3):268-281.PubMedGoogle ScholarCrossref
19.
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(10):1462-1471.PubMedGoogle Scholar
20.
Mazuski  JE, Gasink  LB, Armstrong  J,  et al.  Efficacy and safety of ceftazidime-avibactam plus metronidazole vs meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program.  Clin Infect Dis. 2016;62(11):1380-1389.PubMedGoogle ScholarCrossref
21.
Broderick  RC, Fuchs  HF, Harnsberger  CR,  et al.  The price of decreased mortality in the operative management of diverticulitis.  Surg Endosc. 2015;29(5):1185-1191.PubMedGoogle ScholarCrossref
22.
Solomkin  JS, Yellin  AE, Rotstein  OD,  et al; Protocol 017 Study Group.  Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial.  Ann Surg. 2003;237(2):235-245.PubMedGoogle Scholar
23.
Lucasti  C, Jasovich  A, Umeh  O, Jiang  J, Kaniga  K, Friedland  I.  Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study.  Clin Ther. 2008;30(5):868-883.PubMedGoogle ScholarCrossref
24.
Marshall  JC, al Naqbi  A.  Principles of source control in the management of sepsis.  Crit Care Clin. 2009;25(4):753-768, viii-ix.PubMedGoogle ScholarCrossref
25.
Andersen  BR, Kallehave  FL, Andersen  HK.  Antibiotics versus placebo for prevention of postoperative infection after appendicectomy.  Cochrane Database Syst Rev. 2005;(3):CD001439.PubMedGoogle Scholar
26.
Calbo  E, Garau  J.  The changing epidemiology of hospital outbreaks due to ESBL-producing Klebsiella pneumoniae: the CTX-M-15 type consolidation.  Future Microbiol. 2015;10(6):1063-1075.PubMedGoogle ScholarCrossref
×