Efficacy and Tolerability of Eravacycline in Bacteremic Patients with Complicated Intra-Abdominal Infection: A Pooled Analysis from the IGNITE1 and IGNITE4 Studies

Abstract

Background:

Eravacycline is a novel, fully synthetic fluorocycline antibiotic that was evaluated for the treatment of complicated intra-abdominal infections (cIAI) in two phase 3 clinical trials. The objective of this analysis was to evaluate the clinical cure and microbiologic response at the test-of-cure (TOC) visit and the safety of eravacycline in patients with cIAI and baseline bacteremia who received eravacycline versus comparators.

Patients and Methods:

Pooled data of patients with bacteremia from the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE) 1 and IGNITE4 studies were analyzed. All patients were randomly assigned in a one-to-one ratio to receive eravacycline 1 mg/kg intravenously every 12 hours, ertapenem 1 g intravensouly every 24 hours (IGNITE1), or meropenem 1 g intravenously every eight hours (IGNITE4) for four to 14 days. Blood and intra-abdominal samples were collected from all patients at baseline. Clinical outcome and microbiologic eradiation at the TOC visit (28 days after randomization) and safety in the microbiologic-intent-to-treat population (micro-ITT) were assessed.

Results:

Of 415 patients treated with eravacycline and 431 treated with carbapenem comparators, concurrent bacteremia was identified in 32 (7.7%) and 31 (7.2%) patients, respectively. Demographic and baseline characteristics were similar among treatment groups. In the micro-ITT population, the pooled clinical response at the TOC visit for eravacycline was 28 of 32 (87.5%) and was 24 of 31 (77.0%) for comparators among the subgroup with baseline bacteremia (treatment difference 5.9; 95% confidence interval [CI], −6.5 to 17.4). At TOC, microbiologic eradication of pathogens isolated from blood specimens occurred for 34 of 35 (97.1%) pathogens with eravacycline and 35 of 36 (97.2%) pathogens with comparators. The incidence of adverse events was comparable between treated groups and similar to that observed in the non-bacteremic population.

Conclusion:

Eravacycline demonstrated a similar clinical outcome and microbiologic eradication rate as comparator carbapenems in patients with cIAI and associated secondary bacteremia. Future clinical trials of cIAI should report outcomes of this important clinical cohort (cIAI with concurrent bacteremia) given their high risk for adverse outcomes.

Complicated intra-abdominal infection (cIAI) is a common cause of infection in hospitalized patients [1,2] and results in substantial morbidity and mortality [2,3]. The cost for treating an episode of cIAI in the hospital is approximately $44,000 [4], and the annual morbidity cost of inpatient treatment of cIAI was estimated at $731 million [5]. The risk of poor outcomes including mortality in patients with cIAI are increased further in patients receiving inappropriate empiric antimicrobial therapy [1,6,7].

Concurrent bacteremia occurs in up to 26% of patients with cIAI [8 –10], and accounts for up to 15% of the cases of bacteremia among patients in the intensive care unit (ICU) [8,11 –13]. As a complication of cIAI, bacteremia has been observed in other studies at rates of 2% to 16% [1,14,15], and is a risk factor for longer duration antibiotic therapy and worse outcomes, including mortality [1,2]. In one study, approximately 15% of the study population with secondary bacteremia had a cIAI as the primary infection, and 41% with bacteremia died [8]. Mortality was reported to approach 30% among patients with bacteremia from an abdominal source [16]. Inadequate source control and inappropriate empiric antibiotic therapy were associated with mortality in patients with cIAI and secondary bacteremia [1].

Eravacycline is a synthetic fluorocycline antibiotic that demonstrates in vitro activity against a broad spectrum of gram-negative, gram-positive, and anaerobic pathogens. Coverage includes multi-drug–resistant Enterobacteriaceae that produce extended-spectrum β-lactamases, AmpC β-lactamases, and carbapenemases as well as carbapenem-resistant Acinetobacter baumannii [17 –21]. Eravacycline maintains in vitro activity against bacteria expressing common tetracycline resistance mechanisms [22] and exhibits in vitro activity against pathogens expressing Ambler Class A–D β-lactamases [23]. Eravacycline is highly active against methicillin-susceptible or methicillin-resistant Staphylococcus aureus, vancomycin-susceptible or vancomycin-resistant Enterococcus faecium and Enterococcus faecalis, and both penicillin-susceptible and penicillin-resistant isolates of Streptococcus pneumoniae [18,24].

Eravacycline is approved for the treatment of cIAI in adult patients. The Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE) 1 and IGNITE4 trials were two double-blind, randomized phase 3 clinical studies of adult patients with cIAI. In the IGNITE1 and IGNITE4 trials, intravenous eravacycline was found non-inferior to ertapenem and meropenem, respectively, in clinical response and was generally well tolerated [25,26]. The objective of this analysis was to determine clinical and microbiologic outcomes of the subgroup of patients with cIAI and secondary bacteremia confirmed at baseline using pooled data from the IGNITE1 and IGNITE4 studies.

Patients and Methods

For the original studies, the protocol and informed consent forms were submitted to and approved by the Institutional Review Board or independent Ethics Committee at each site before initiating the study. Each study was conducted in accordance with Good Clinical Practice and the World Medical Assembly Declaration of Helsinki. All patients in this post hoc analysis had previously provided consent before any study procedures were performed.

Study design

This was a post hoc analysis of pooled results from two phase 3 studies to examine the efficacy and safety of eravacycline and comparators in patients with cIAI and baseline bacteremia. IGNITE1 and IGNITE4 were phase 3, randomized, double-blind, double-dummy, multicenter non-inferiority studies in hospitalized subjects with cIAIs requiring surgery or percutaneous drainage [25,26]. The primary objective was to assess the efficacy and safety of eravacycline 1 mg/kg intravenously every 12 hours versus ertapenem 1 g every 24 hours or meropenem 1 g every eight hours. Patients were enrolled between August 2013 and August 2014 at 66 clinical sites in 11 countries in IGNITE1 (Clinicaltrials.gov Identifier: NCT01844856). For IGNITE4, patients were enrolled between October 2016 and May 2017 at 65 sites in 11 countries (Clinicaltrials.gov identifier NCT02784704).

Selection criteria

This post hoc analysis included patients with cIAI and secondary bacteremia at baseline that was confirmed by isolation of at least one pathogen from the blood. Detailed selection criteria for IGNITE1 and IGNITE4 have been published and are summarized in this article [25,26]. Adults at least 18 years of age were eligible if they had abdominal or flank pain. Patients enrolled were diagnosed with a cIAI that required surgery or percutaneous drainage and hospitalization, including patients diagnosed with appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine or peritonitis. Patients with complicated appendicitis were limited to 30% (IGNITE1) or 50% (IGNITE4) of the total randomized population [27,28]. The enrollment criteria for both studies were consistent with Food and Drug Administration (FDA) guidance for developing drugs for treatment of cIAI at the time of trial initiation.

Patients with hepatic disease were excluded from both trials and those with end-stage renal disease were excluded from IGNITE1 only. Patients also were excluded if they received effective antibiotic therapy for their current infection for more than 24 hours during the 72 hours preceding enrollment unless they experienced prior treatment failure for documented cIAI. Additional exclusion criteria were rapidly progressing disease or immediately life-threatening illness including acute hepatic failure, respiratory failure, or septic shock, anticipated survival period shorter than the study period, or symptoms related to diagnosis of complicated appendicitis <24 hours prior to the current hospitalization. Patients who received systemic antibiotic agents for >24 hours, any carbapenem or tigecycline for the infection, or required systemic antimicrobial agents other than eravacycline were excluded.

Study treatments

Patients were randomly assigned in a one-to-one ratio to either eravacycline or a carbapenem comparator; randomization was stratified by primary site of infection (complicated appendicitis versus all other cIAI diagnoses). In IGNITE1, the comparator regimen was ertapenem 1 g intravenously every 24 hours, and in IGNITE4, the comparator regimen was meropenem 1 g intravenously every eight hours. Treatment was continued for a minimum of four days and up to 14 days. Patients remained hospitalized for the entire course of treatment with the study drug.

Study assessments

Patients were evaluated daily during treatment with study drug, at the end-of-treatment (EOT) visit (24 hours after the last dose of study drug), the test-of-cure (TOC) visit (25 to 31 days after the first dose of the study drug), and the last follow-up visit (38 to 50 days after the first dose of study drug). All patients had blood cultures collected at baseline and during hospitalization as part of source control procedures. The primary end points were clinical cure at the TOC visit in the microbiologic intent-to-treat (micro-ITT) population. The micro-ITT population included all randomly assigned patients who had one or more baseline bacterial pathogens isolated that caused cIAI, and study drug demonstrated in vitro activity against at least one of the pathogens. Clinical response was defined as complete resolution or substantial improvement of signs or symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiologic intervention was required.

Clinical failure included death related to cIAI at any time during the trials, persistence of clinical signs and symptoms of cIAI, unplanned surgical procedures or percutaneous drainage procedures, post-surgical wound infections requiring systemic antibiotic agents, and initiation of additional antibacterial drug therapy for cIAI. Patients who did not meet criteria for clinical response or clinical failure were classified as indeterminate. If the investigator did not complete an assessment or if the patient was not present for the TOC visit, the outcome was considered missing.

Statistical analysis

Data for each pooled treatment group were presented using descriptive statistics. Outcome was assessed from clinical response at the TOC visit in the micro-ITT population. Results were presented as treatment difference and 95% confidence interval calculated using the adjusted Miettinen-Nurminen method.

Results

The micro-ITT population from the pooled studies was 520 for eravacycline and 521 for comparators. At baseline, 415 and 431 patients were included in the eravacycline and comparator groups, respectively, for the micro-ITT population. Positive baseline blood cultures were identified in 32 of 415 (7.7%) patients randomly assigned to receive eravacycline and 31 of 431 (7.2%) patients randomly assigned to receive either ertapenem or meropenem. Demographic and clinical characteristics of patients in the subgroup with bacteremia at baseline and those without bacteremia in the micro-ITT population were similar between eravacycline and carbapenem comparators (Table 1).

Table 1.

Baseline Characteristics from Pooled Analysis of IGNITE1 and IGNITE 4 in Patients with Baseline Bacteremia and Those Without

	Bacteremia		No bacteremia
	Eravacycline (n = 32)	Comparator (n = 31)	Eravacycline (n = 383)	Comparator (n = 400)
Male, n (%)	18 (56.3)	22 (70.9)	217 (56.7)	215 (53.7)
Race, white, n (%)	32 (100)	31 (100)	376 (98.4)	389 (97.3)
Age <65 y, n (%)	20 (62.5)	20 (64.5)	277 (72.3)	284 (71.0)
≥65 years, n (%)	12 (37.5)	11 (35.5)	106 (27.7)	116 (29.0)
APACHE II score >10, n (%)	4 (12.5)	7 (23.3)	50 (13.1)	65 (16.3)
Complicated appendicitis, n (%)	9 (28.1)	7 (22.6)	151 (39.4)	150 (37.5)
All other cIAI, n (%)	23 (71.9)	24 (77.4)	232 (60.6)	250 (62.5)

IGNITE = Investigating Gram-Negative Infections Treated with Eravacycline; cIAI = complicated intra-abdominal infections; micro-ITT = microbiologic-intent-to-treat.

Clinical response

The overall pooled clinical response at the TOC visit for the pooled IGNITE1 and IGNITE4 micro-ITT population was 88.7% (368/415) and 89.3% (385/431) in eravacycline and comparator groups, respectively (treatment difference: −0.7, 95% CI, −4.9 to 3.6). Among patients with baseline bacteremia, clinical response at the TOC visit was 87.5% for eravacycline treated patients and 77.0% for patients treated with comparators (treatment difference: 5.9, 95% CI, −6.5 to 17.4)

Microbiologic response

At baseline, pathogens isolated from blood specimens from cIAI patients with bacteremia were widely distributed among gram-negative aerobes (43.7%), gram-positive (31.0%), and anaerobes (25.3%). Microbiologic eradication at the TOC visit occurred in 34 of 35 (97.1%) of isolates in patients treated with eravacycline and 34 of 36 (94.4%) isolates in patients treated with a carbapenem (Table 2). One patient from the eravacycline group and one patient from the comparator group who experienced microbiologic failure died during the study before the TOC visit and thus were considered indeterminate for both the per pathogen response and the primary end point. Neither death was considered related to study medication by the principal investigator.

Table 2.

Microbiologic Eradication at the TOC Visit by Baseline Pathogen from Blood Specimens in Patients with cIAI and Secondary Bacteremia (micro-ITT Population)

	Number (%) of Isolates
	Eravacycline	Comparators
	(N = 32)	(N = 31)
	n/N (%)	n/N (%)
Gram-negative	14/15 (93.3)	14/15 (93.3)
Escherichia coli	5/6 (83.3)	6/7 (85.7)
Klebsiella oxytoca	0	2/2 (100)
Klebsiella pneumoniae	1/1 (100)	1/1 (100)
Acinetobacter baumanii	1/1 (100)	0
Acinetobacter iwoffii	0	1/1 (100)
Burkholderia cepacian	1/1 (100)	1/1 (100)
Pseudomonas aeruginosa	1/1 (100)	1/1 (100)
Pseudomonas stutzeri	1/1 (100)	0
Stenotrophomonas maltophilia	2/2 (100)	0
Other non-Enterobacteraceae	3/3 (100)	2/2 (100)
Gram-positive	13/13 (100)	10/10 (100)
Staphylococcus aureus	2/2 (100)	1/1 (100)
Streptococcus spp.	8/8 (100)	4/4 (100)
Enterococcus spp.	2/2 (100)	5/5 (100)
Anaerobes	7/7 (100)	10/11 (90.9)
Bacteriodes spp.	6/6 (100)	7/7 (100)
Other anaerobes	1/1 (100)	3/4 (75.0)

n = number with microbiologic eradication; N = number with bacteremia; TOC = test of cure; micro-ITT = microbiologic-intent-to-treat.

Antibiotic treatment duration

Mean duration of treatment for the bacteremia patients was 8.5 days for eravacycline and 8.2 days for comparators, and median duration was eight days for both groups. This was comparable to the mean duration of 7.6 days in IGNITE1 and IGNITE4 across the entire cIAI study cohort [25,26].

Safety/tolerability

In the bacteremia subgroup, at least one treatment-emergent adverse event (TEAE) occurred in 11 patients in the eravacycline group and 17 patients in the comparator group (Table 3). A low rate of treatment-related, severe, and serious adverse events was reported in both treatment groups and most frequently consisted of infections/infestations, respiratory, thoracic and mediastinal disorders, or cardiac disorders. The most common adverse events with eravacycline were nausea (three patients; 10.4%) and vomiting (two patients; 5.2%), and with comparators was pyrexia (three patients; 10.4%).

Table 3.

Summary of TEAEs in Patients with Concurrent Bacteremia

	Number (%) of patients
	Eravacycline	Comparator
	N = (32)	N = (31)
Any TEAE	11 (34.4)	17 (54.8)
Treatment-related TEAE	4 (12.5)	1 (3.2)
Severe TEAE	3 (9.4)	5 (16.1)
TEAE leading to discontinuation	0	2 (6.5)
Serious TEAE	3 (9.4)	5 (16.1)
Fatal TEAE	1 (3.1)	3 (9.7)
Incidence of TEAEs by system organ class
Blood and lymphatic system disorders	1 (3.1)	2 (6.5)
Cardiac disorders	0	5 (16.1)
Gastrointestinal disorders	4 (12.5)	3 (9.7)
General disorders and administration site conditions	4 (12.5)	6 (19.4)
Infections and infestations	2 (6.3)	6 (19.4)
Injury, poisoning, and procedural complications	1 (3.1)	1 (3.2)
Investigations	3 (9.4)	2 (6.5)
Metabolism and nutrition disorders	2 (6.3)	3 (9.7)
Nervous system disorders	1 (3.1)	0
Product issues	1 (3.1)	0
Psychiatric disorders	2 (6.3)	0
Renal and urinary disorders	1 (3.1)	1 (3.2)
Respiratory, thoracic, and mediastinal disorders	4 (12.5)	2 (6.5)
Vascular disorders	1 (3.1)	2 (6.5)

TEAE = treatment-emergent adverse event.

Discussion

Few studies have examined outcomes among patients with cIAI and secondary bacteremia. In this pooled analysis of the two pivotal studies with eravacycline [25,26], clinical response at the TOC visit in patients with cIAI was similar regardless of the presence of concurrent bacteremia. In this study, clinical cure rates were 87.5% with eravacycline and 77.0% with comparators among the subgroup with secondary bacteremia. Microbiologic eradication in the subset of patients with cIAI complicated by concurrent bacteremia occurred at comparable rates for patients randomized to eravacycline or carbapenems. These results demonstrate that eravacycline was effective as carbapenems in the treatment of cIAI complicated by secondary bacteremia.

Secondary bacteremia is observed in both community and hospitalized patients with cIAI [29,30]. Risk factors for poor outcomes with bacteremia among patients with cIAI include advanced age, impaired renal function, higher APACHE II score, and peritonitis [8]. Bacteremia in hospitalized patients, especially those in the ICU [13,31], is associated with prolonged hospitalization, a greater healthcare burden, and higher mortality rates [8,32]. Among patients admitted to an ICU, abdominal infection was an independent predictor of mortality [11], and septic shock occurring in hospitalized patients with peritonitis was associated with an increased risk of mortality [10].

The rate of concurrent bacteremia with cIAI was higher in the IGNITE1 and IGNITE4 trials than in other published cIAI clinical trials. Concurrent bacteremia was identified in 32 of 415 (7.7%) eravacycline patients and 31 of 431 (7.2%) carbapenem patients, respectively.

In the ASPECT-cIAI trial comparing ceftolozane-tazobactam plus metronidazole to meropenem, the presence of bacteremia was confirmed in eight of 389 (2.1%) and 12 of 417 (2.9%) of the groups, respectively [15]. In the RECLAIM 1 and RECLAIM 2 cIAI trials comparing ceftazidime-avibactam plus metronidazole versus meropenem, concurrent bacteremia was reported in 22 (4.2%) and 14 (2.7%) of patients, respectively [33]. Specific outcomes for the bacteremia patients in the ASPECT-cIAI or RECLAIM trials have not been reported to our knowledge. Future clinical trials of cIAI should report outcomes of this important clinical cohort (cIAI with concurrent bacteremia) given their high risk for adverse outcomes.

Treatment guidelines for patients with cIAI and secondary bacteremia recommend seven days of antibiotic therapy if patients are no longer bacteremic and have undergone adequate source control [1]. In this analysis of cIAI patients with secondary bacteremia from IGNITE1 and IGNITE4, the mean duration of antimicrobial therapy was similar (median, eight days) to the entire study cohort, and resulted in similar clinical outcomes, supporting the guideline recommendations.

Indiscriminate use of carbapenems has been associated with the increasing prevalence of resistance [34]. Rates of carbapenem resistance are 50% or higher in some geographic regions [35 − 37]. Carbapenem-resistant pathogens have been identified as critical targets by the World Health Organization and U.S. Centers for Disease Control and Prevention (CDC) and novel treatment strategies are needed [35,36,38,39]. Increased carbapenem usage is associated with an increased prevalence of carbapenem-resistant bacteria, thereby highlighting the importance of selective use of carbapenem [40,41] in preserving their utility in treating serious infections [42]. A need exists for alternative treatments that can optimize the prescribing of carbapenems, which may reduce the risk and delay a further increase in carbapenem-resistant bacteria.

Limitations of this analysis were its post hoc nature in a subgroup of patients, a small sample size, and the exclusion of other high-risk patients, including those with cardiovascular disease, malignancy, immunosuppression, and severe organ disfunction. However, data were obtained from two well-controlled phase 3 studies, which used identical study designs which were consistent with guidance from the FDA. Further data are needed in patients with secondary bacteremia and cIAI.

In summary, the results of this pooled analysis from two phase 3 studies demonstrate that eravacycline did not differ from carbapenems as empiric therapy for patients with cIAI with secondary bacteremia. Importantly, results were consistent with the overall results from the phase 3 studies and demonstrate that eravacycline is comparable to carbapenems as an empiric treatment option for cIAI. Eravacycline offers potential advantages for treating serious cIAI infections including infections caused by resistant bacterial pathogens. In addition, eravacycline has the potential to supplant the use of carbapenems for patient with cIAI especially those at risk for an infection cause by a resistant pathogen, thus supporting judicious prescribing of carbapenems in accordance with the CDC guidelines on antibiotic stewardship [43].

Footnotes

Acknowledgments

The authors also acknowledge Richard Perry for editorial assistance with preparation of the manuscript and Dr. Maria-Stephane A. Hughes for her careful review of the manuscript.

Poster presented at IDWeek, October 3–7, 2018, San Francisco, California.

Authors' Contributions

Dr. Grant-Di Felice, Dr. Efimova, and Mr. Izmailyan performed data analysis and interpretation, as well as manuscript review and approval. Dr. Napolitano and Dr. Chopra reviewed and approved the manuscript.

Funding Information

This work was supported by Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts.

Author Disclosure Statement

Dr. Grant-Di Felice, Dr. Efimova, and Mr. Izmailyan were paid employees or consultants of Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, at the time of this work. The remaining authors have nothing to disclose.

References

Mazuski

, Tessier

, May

, et al. The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection. Surg Infect, 2017; 18:1–76.

Solomkin

, Mazuski

, Bradley

, 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. Surg Infect, 2010; 11:79–109.

Solomkin

, Ramesh

, Cesnauskas

, 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; 58:1847–1854.

Prabhu

, Solomkin

, Medic

, et al. Cost-effectiveness of ceftolozane/tazobactam plus metronidazole versus piperacillin/tazobactam as initial empiric therapy for the treatment of complicated intra-abdominal infections based on pathogen distributions drawn from national surveillance data in the United States. Antimicrob Resist Infect Control, 2017; 6:107.

Sertkaya

, Eyraudd

, Birkenbach

, et al. Analytical framework for examining the value of antibacterial products. U.S. Department of Health and Human Services, 2014. https://aspe.hhs.gov/report/analytical-framework-examining-value-antibacterial-products (Last accessed June 21, 2020).

De Pascale

, Carelli

, Vallecoccia

, et al. Risk factors for mortality and cost implications of complicated intra-abdominal infections in critically ill patients. J Crit Care, 2019; 50:169–176.

Edelsberg

, Berger

, Schell

, et al. Economic consequences of failure of initial antibiotic therapy in hospitalized adults with complicated intra-abdominal infections. Surg Infect, 2008; 9:335–347.

Alqarni

, Kantor

, Grall

, et al. Clinical characteristics and prognosis of bacteraemia during postoperative intra-abdominal infections. Crit Care, 2018; 22:175.

Montravers

, Augustin

, Grall

, et al. Characteristics and outcomes of anti-infective de-escalation during health care-associated intra-abdominal infections. Crit Care, 2016; 20:83.

10.

Riche

, Dray

, Laisne

, et al. Factors associated with septic shock and mortality in generalized peritonitis: Comparison between community-acquired and postoperative peritonitis. Crit Care, 2009; 13:R99.

11.

Boncagni

, Francolini

, Nataloni

, et al. Epidemiology and clinical outcome of healthcare-associated infections: A 4-year experience of an Italian ICU. Minerva Anestesiol, 2015; 81:765–775.

12.

Havey

, Fowler

, Daneman

. Duration of antibiotic therapy for bacteremia: A systematic review and meta-analysis. Crit Care, 2011; 15:R267.

13.

Tabah

, Koulenti

, Laupland

, et al. Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: The EUROBACT international cohort study. Intensive Care Med, 2012; 38:1930–1945.

14.

Harris

PNA

, Tambyah

, Lye

, et al. 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; 320:984–994.

15.

Solomkin

, Hershberger

, Miller

, 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; 60:1462–1471.

16.

Tellor

, Skrupky

, Symons

, et al. Inadequate source control and inappropriate antibiotics are key determinants of mortality in patients with intra-abdominal sepsis and associated bacteremia. Surg Infect, 2015; 16:785–793.

17.

Goldstein

EJC

, Citron

, Tyrrell

. In vitro activity of eravacycline and comparator antimicrobials against 143 recent strains of Bacteroides and Parabacteroides species. Anaerobe, 2018; 52:122–124.

18.

Morrissey

, Olesky

, Hawser

, et al. In vitro activity of eravacycline against gram-negative bacilli isolated in clinical laboratories worldwide from 2013 to 2017. Antimicrob Agents Chemother. 2020; 64:e01699–19.

19.

Seifert

, Stefanik

, Sutcliffe

, Higgins

. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents, 2018; 51:62–64.

20.

Snydman

, McDermott

, Jacobus

, et al. Evaluation of the in vitro activity of eravacycline against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother, 2018; 62:e02206–17.

21.

Zhanel

, Baxter

, Adam

, et al. 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.

22.

Grossman

, Starosta

, Fyfe

, et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother, 2012; 56:2559–2564.

23.

Livermore

, Mushtaq

, Warner

, Woodford

. In Vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother, 2016; 60:3840–3844.

24.

Morrissey

, Hawser

, Lob

, et al. In vitro activity of eravacycline against Gram-positive bacteria isolated in clinical laboratories worldwide from 2013 to 2017. Antimicrob Agents Chemother. 2020; 64:e01715–19.

25.

Solomkin

, Evans

, Slepavicius

, 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; 152:224–232.

26.

Solomkin

, Gardovskis

, Lawrence

, et al. IGNITE4: Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections. Clin Infect Dis, 2019; 69:921–929.

27.

Food and Drug Administration. Complicated Intra-Abdominal Infections: Developing drugs for treatment. Guidance for Industry. Silver Spring, MD: 2015.

28.

Food and Drug Administration. Complicated Intra-Abdominal Infections: Developing Drugs for Treatment. Guidance for Industry. Revision 1. Silver Spring MD: 2018.

29.

Blot

, Antonelli

, Arvaniti

, et al. Epidemiology of intra-abdominal infection and sepsis in critically ill patients: “AbSeS,” a multinational observational cohort study and ESICM Trials Group Project. Intensive Care Med, 2019; 45:1703–1717.

30.

De Waele

, Hoste

, Blot

. Blood stream infections of abdominal origin in the intensive care unit: Characteristics and determinants of death. Surg Infect, 2008; 9:171–177.

31.

Vincent

, Rello

, Marshall

, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA, 2009; 302:2323–2329.

32.

Payá-Llorente

, Martínez-López

, Sebastián-Tomás

, et al. The impact of age and comorbidity on the postoperative outcomes after emergency surgical management of complicated intra-abdominal infections. Sci Rep, 2020; 10:1631.

33.

Mazuski

, Gasink

, Armstrong

, 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; 62:1380–1389.

34.

Mikamo

, Yuasa

, Wada

, et al. Optimal treatment for complicated intra-abdominal infections in the era of antibiotic resistance: A systematic review and meta-analysis of the efficacy and safety of combined therapy with metronidazole. Open Forum Infect Dis, 2016; 3:ofw143.

35.

Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services; 2019.

36.

World Health Organization (WHO). Antimicrobial resistance: global report on surveillance, 2014. www.who.int/drugresistance/documents/surveillancereport/en/ (Last accessed June 23, 2016).

37.

Nordmann

, Naas

, Poirel

. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011; 17:1791–1798.

38.

Corcione

, Lupia

, Maraolo

, et al. Carbapenem-sparing strategy: Carbapenemase, treatment, and stewardship. Curr Opin Infect Dis, 2019; 32:663–673.

39.

Wagner

, Rhodes

, Scheetz

, et al. Opportunities for antimicrobial stewardship among carbapenem-treated patients in 18 North American hospitals. Int J Antimicrob Agents, 2020; 55:105970.

40.

van Loon

, Voor In 't Holt

, Vos

. A systematic review and meta-analyses of the clinical epidemiology of carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother, 2017; 62:e01730–17.

41.

, Duan

, Wu

, Zhou

. Surveillance and correlation of antimicrobial usage and resistance of Pseudomonas aeruginosa: A hospital population-based study. PLoS One, 2013; 8:e78604.

42.

Sartelli

, Chichom-Mefire

, Labricciosa

, et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg, 2017; 12:29.

43.

Centers for Disease Control and Prevention. Core elements of antibiotic stewardship. Atlanta, GA: U.S. Department of Health and Human Services; 2019.