Eravacycline, a Newly Approved Fluorocycline

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European Journal of Clinical Microbiology & Infectious Diseases (2019) 38:1787–1794 https://doi.org/10.1007/s10096-019-03590-3

REVIEW

Eravacycline, a newly approved fluorocycline

Young Ran Lee1 & Caitlin Elizabeth Burton2

Received: 17 March 2019 /Accepted: 13 May 2019 /Published online: 7 June 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract Complicated intra-abdominal infections (cIAIs) are commonly associated with multimicroorganisms and treatment choices are becoming narrower due to developing resistance, especially in the gram-negative Enterobacteriaceae species. Eravacycline is a newly developed, fully synthetic tetracycline derivative that has shown potent broad-spectrum activity against a wide variety of microorganisms, including those such as extended spectrum β-lactamase producing Enterobacteriaceae and Acinetobacter. Eravacycline has shown activity against many gram-positive organisms such as methicillin-resistant S. aureus and vancomycin resistant Enterococcus faecalis and Enterococcus faecium (VRE), gram-negative organisms such as Escherichia coli, and anaerobic species of microorganisms such as Bacteroides. This fluorocycline has been compared to ertapenem and meropenem for the treatment of complicated intra-abdominal infections and levofloxacin for the treatment of complicated urinary tract infections. Eravacycline was shown to be noninferior to ertapenem but did not meet noninferiority criteria in comparison to levofloxacin. Oral and IV formulations on eravacycline were tested in clinical trials, but at this time, only the IV formulation is FDA approved. Eravacycline has been noted to have a half-life of 20 h with protein binding around 80%; AUC over minimum inhibitory concentration (MIC) has also been shown to be eravacycline’s best predictor of efficacy. Of note, eravacycline does not require any renal dose adjustments, as the majority of its clearance is by nonrenal pathways.

Keywords Eravacycline . Fluorocycline . Intra-abdominal infections . Drug resistance

Introduction

The rise of multidrug-resistant microorganisms not only has Key Points become a public health concern but also has complicated how • Eravacycline is a newly approved tetracycline derivate, a fluorocycline, we treat different hospital and community acquired infections which is active against gram-positive organisms, gram-negative organ- [1]. The Centers for Disease Control and Prevention (CDC) isms, anaerobes, and certain microorganisms that have developed resistance mechanisms. has stated that each year in the USA alone, approximately 2 • Eravacycline is currently only available in an IV formulation which does million people acquire an infection due to multidrug-resistant not require renal dose adjustments. bacteria and at least 23,000 people each year die from these • Eravacycline met noninferiority criteria when compared to both infections; the World Health Organization (WHO) has report- ertapenem and meropenem for the treatment of complicated intra- abdominal infections. ed that in Europe the yearly number of deaths is even higher, with an estimated 25,000 deaths due to multidrug-resistant * Young Ran Lee bacteria per year [2, 3]. In order to combat this threat, the [email protected] WHO has advocated for a global health plan that includes five objectives: enhance awareness and perception of antimicrobi- Caitlin Elizabeth Burton al resistance, increase knowledge in areas such as surveillance [email protected] and research, decrease the rate of infections, promote appro- priate use of antimicrobials, and take into account the needs of 1 Department of Pharmacy Practice, Texas Tech University Health Sciences Center School of Pharmacy, 1718 Pine St., Abilene, TX, all countries which includes the creation and expansion of USA new antimicrobial agents, diagnostic tools, and vaccines [4]. 2 Texas Tech University Health Sciences Center School of Pharmacy, In 2012, the Generating Antibiotic Incentives Now (GAIN) 1718 Pine St., Abilene, TX, USA act was passed as part of the Food and Drug Administration 1788 Eur J Clin Microbiol Infect Dis (2019) 38:1787–1794

Safety and Innovation Act (FDASIA) which helped to direct class [8]. Previous studies examining structure–activity rela- attention to antimicrobial resistance by encouraging the devel- tionships of tetracycline analogs have shown that the north- opment and approval of new antimicrobials [5]. This act also west region of the tetracycline structure does not have direct allowed for new antimicrobials to be designated as qualified involvement with ribosomes; therefore, this region can be al- infectious disease products (QIDPs) which lets the FDA grant tered without risking compromising antibacterial activity. The Fast Track designation to these new agents, amongst other southeast portion of the molecule, however, is directly in- incentives [6]. volved in interactions with bacterial ribosomes, and modifica- A new, fully synthetic fluorocycline has been developed to tions here lead to loss of activity. Substitutions at C9 can lead treat infections caused by multidrug-resistant microorganisms, to improvements in both antibacterial potency and activity such as carbapenem-resistant Enterobacteriaceae, against organisms with tetracycline specific resistance mech- methicillin-resistant Staphylococcus aureus, extended spec- anisms. Eravacycline has a pyrrolidine on the C9 side chain trum β-lactamase (ESBL)-producing Enterobacteriaceae, and a fluoro group at C7, both of which grant its potent, broad- and vancomycin-resistant enterococci species; in 2014, this spectrum activity that will be discussed further in this fluorocycline was designated a QIDP by the FDA, granting manuscript. it fast track eligibility [5, 7]. Eravacycline (Xerava®), former- ly TP-434, was designed to overcome two of the main resistance mechanisms common to the tetracycline class: ribosom- Microbiological coverage al protection, commonly seen in gram-positive organisms, and active drug efflux, common in both gram-positive and gram- Table 1 details eravacycline’s microbiological coverage in negative organisms [7, 8]. Modifications at the C-7 and C-9 comparison to other agents according to Clinical Laboratory positions on the tetracycline core lead to this enhanced, broad- Standards Institute (CLSI) testing. In vitro studies have shown spectrum bacterial activity (Fig. 1)[9]. Eravaycline’smecha- that eravacycline has activity against a wide variety of organ- nism of action is similar to other members of the tetracycline isms, including multidrug-resistant Acinetobacter species and class as it inhibits protein synthesis by binding to the ESBL-producing Enterobacteriaceae [9]. ribosome. In vitro studies have evaluated eravacycline’s gram-positive

activity and found MIC90 values to be between 0.016 and 0.05 μg/mL against organisms such as methicillin-resistant Data sources S. aureus (MRSA), methicillin susceptible S. aureus, coagulase negative staphylococci, vancomycin susceptible Enterococcus faecium and Enterococcus faecalis (VSE), vancomycin resis- A search of PubMed (1945–March 2019) and International tance Enterococcus faecium and Enterococcus faecium (VRE), Pharmaceutical Abstracts (1970–March 2019) was conducted Streptococcus pneumoniae,andStreptococcus pyogenes. using the terms eravacycline, TP-434, and intra-abdominal Eravacycline’s activity also includes coverage against gram- infections. All articles available in English were reviewed. negative organisms such as Escherichia coli (including Additional sources were the Clinicaltrials.gov website, ESBL-producing strains), Salmonella species, Shigella species, International Pharmaceutical Abstracts, the Centers for Haemophilus influenzae, Moraxella catarrhalis,and Disease Control and Prevention (CDC) website, and the Acinetobacter lwoffii;MIC values for gram-negatives have Tetraphase Pharmaceuticals website. 90 beenshowntobe≤ 0.5 μg/mL. Anaerobe coverage was also noted with eravacycline as it showed activity against Clostridium difficile, Peptostreptococcus species, Actinomyces Medicinal chemistry species, Anaerococcus species, Bacteroides species, Bifidobacterium species, Eggerthella species, Lactobacillus As mentioned previously, eravacycline has modifications at species, and Propionibacterium acnes [9, 11]. key points in the tetracycline core that have enhanced its an- Additionally, compared to another tetracycline related anti- tibacterial activity in comparison to others of the tetracycline biotic, tigecycline, eravacycline has shown greater in vitro activity [9]. In an in vitro study done by Sutcliffe et al.,

eravacycline showed to have MIC90 values for a variety of gram-negative organisms, including Acinetobacter baumannii, Acinetobacter lwoffii, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Proteus mirabilis, Proteus vulgaris,andSalmonella spp., which were about 2-fold lower than those of tigecycline, a glycylcycline. The study also Fig. 1 Chemical structure of eravacycline showed that eravacycline had a 2-fold greater gram-positive Eur J Clin Microbiol Infect Dis (2019) 38:1787–1794 1789

Table 1 Clinical Laboratory Standards Institute (CLSI) Organism Eravacycline Tigecycline Ertapenem Levofloxacin Meropenem Minimum Inhibitory Concentration (MIC) ranges [10] Gram positive Staphylococcus aureus 0.015–0.12 0.03–0.25 0.06–0.25 0.06–0.5 0.03–0.12 Enterococcus faecalis 0.015–0.06 0.03–0.12 4–16 0.25–22–8 Streptococcus pneumonia 0.004–0.03 0.015–0.12 0.03–0.25 0.5–20.03–0.25 Gram negative Escherichia coli 0.03–0.12 0.03–0.25 0.004–0.015 0.008–0.06 0.008–0.06 Pseudomonas aeruginosa 2–16 – 2–80.5–40.25–1 Haemophilus influenza 0.06–0.5 0.06–0.5 0.015–0.06 0.008–0.03 0.03–0.12 Anaerobes Bacteroides fragilis 0.06–0.25 0.12–10.06–0.25 – 0.03–0.25 Bacteroides 0.12–10.5–20.25–1 – 0.125–0.5 thetaiotaomicron Clostridium difficile 0.06–0.25 0.125–1 –– 0.5–4 and anaerobic activity than tigecycline. Gram-positives eravacycline is low, with an average around 28% [17]. assessed in this study included the following: E. faecalis Eravacycline has a half-life of 20 h that increases with repeat- (VRE and VSE), E. faecium, Enterococcus spp., MRSA, coag- ed doses and a median time to maximum plasma concentra- ulase negative staphylococci, and S. pneumoniae.When tion (Tmax) of about 30 min [18]. A dose escalation study over assessing activity against S. aureus isolates with quinolone re- 10 days showed that there is some systemic accumulation, but sistant genes, eravacycline retained its activity to these isolates, over the 10 days, the greatest amount of accumulation was while tigecycline’s activity was significantly reduced. 45% when dosed at 1 mg/kg every 12 h. Eravacycline is me- Atypical organisms that most often are implicated in com- tabolized mainly by CYP3A4 and FMO-mediated oxidation. munity acquired pneumonia include Chlamydophila It not only is primarily excreted in the feces but also has some pneumoniae, Mycoplasma pneumoniae,andLegionella spe- minor renal elimination as well. Data from the phase 1, open- cies [12, 13]. Another member of the tetracycline class, doxy- label, safety and pharmacokinetic study on eravacycline is cycline, is commonly used to treat community acquired pneu- summarized in Table 2. Data examining pharmacodynamic monia, but at this time, only in vitro studies have also evalu- (PD) parameters identified fAUC/MIC as the PK/PD index ated eravacycline against some of these pathogens. When test- that in the best associated with eravacycline efficacy [19]. ed against Legionella pneumophila, eravacycline was found Eravacycline does not require dose adjustments in renal im- to have a MIC90 between one and two, depending on the pairment or in patients with mild to moderate hepatic impair- serogroup, in comparison to tetracycline which has an ment (Child Pugh A and Child Pugh B), but in those with

MIC90 of eight for this microorganism [14]. severe hepatic impairment (Child Pugh C), it is recommended to adjust the dose [20]. The fact that eravacycline does not require renal dose adjustments is promising for its applicabil- Pharmacokinetics/pharmacodynamics ity in critically ill patients with augmented renal clearance. Additionally, eravacycline has been shown to be active Pharmacokinetic (PK) studies have shown an average protein in vitro against biofilms produced by uropathogenic E. coli, binding of 71.4–82.5% with a nonlinear, concentration- which could potentially lead to a role in treatment of urinary dependent relationship [15, 16]. Oral bioavailability of tract infections [21].

Table 2 Pharmacokinetic μ μ μ μ parameters after eravacycline Parameter Cmax ( g/ Cmin ( g/ AUC0–12 ( g·h/ CL fAUC0–12 ( g·h/ Vss (L) administration mL) mL) mL) (L/h) mL)

Mean 1.29 0.20 4.56 17.82 0.77 183.77 SD 0.40 0.05 0.94 3.41 0.14 60.38

Adapted from Connors et al., with permission

Cmax maximum plasma concentration, Cmin minimum plasma concentration, AUC0–12 area under the plasma concentration-time curve from time zero to 12 h, CL apparent clearance, fAUC0–12 free drug area under the plasma concentration-time curve from time zero to 12 h, Vss apparent volume of distribution at the terminal phase 1790 Eur J Clin Microbiol Infect Dis (2019) 38:1787–1794

As mentioned previously, eravacycline’s half-life in- Phase 2 study creases with cumulative dosing, and in a study examining eravacycline’s antibacterial efficacy, it was shown that this A randomized phase two, double-blind, active control study, cumulative dosing leads to an enhanced killing effect, spe- published in 2014, was conducted at 19 sites in 6 countries cificallywhentestedagainstE. coli and MRSA strains [24]. Patients were included in the study if they had a BMI ≤ [22]. Pharmacokinetic studies have also shown that steady 30 kg/m2,wereaged18–75, and diagnosed with a complicat- state for eravacycline is not reached until at least day 5 of ed intra-abdominal infection (cIAI) requiring surgical inter- dosing [18]. When comparing eravacycline’s pharmacoki- vention with an anticipated antibiotic duration of 14 days or netic properties to other members of the tetracycline class less. Major exclusion criteria varied from symptoms of com- differences in volume of distribution are evident. plicated appendicitis within less than 24 h of the current hos-

Eravacycline’s volume of distribution at steady state (Vss) pitalization, previous hospitalization in the past 6 months, an is approximately 4 L/kg, which is suggestive of wide tissue Acute Physiologic Assessment and Chronic Health distribution. Comparatively, tigecycline, omadacycline, Evaluation (APACHE) II score greater than 25, requirement tetracycline, and doxycycline have volumes of distribution of vasopressors, abnormal renal or liver function, and known at steady state of 6–9 kg/L, 2.6 L/kg, 1.3 L/kg, and 0.7 L/ or suspected inflammatory bowel disease (IBD). One hundred kg, respectively [18]. forty-three eligible patients were randomized in a 2:2:1 fash- ion to receive an IV infusion of eravacycline at 1.5 mg/kg every 24 h, eravacycline at 1 mg/kg every 12 h, or 1 g of ertapenem every 24 h. Fifty-three patients received Phase 1 study eravacycline at 1.5 mg/kg, 56 received eravacycline at 1 mg/kg, 30 received ertapenem, and 4 patients do not receive A phase 1 study by Connors, et al. examined the safety and a study drug. The primary efficacy end point was clinical pharmacokinetics of eravacycline in healthy men and women response, defined as complete resolution or significant im- [16]. Twenty healthy adults participated in the study for about provement in signs and symptoms of initial infection, at the 8 weeks, which included a 30-day screening period, 6-day test of cure (TOC) visit, in the microbiologically evaluable dosing/observation period, and 20-day follow-up period. (ME) population. The ME population, a subset of the clinical- These individuals received 7 IV doses of 1 mg/kg eravacycline ly evaluable population which encompassed all randomized every 12 h as a 1 h infusion. This study evaluated plasma and patients who received any amount of drugs studied, were pulmonary pharmacokinetics as well as protein binding. Plasma those who also had a baseline pathogen identified and were samples taken immediately before and after 12 h after the sev- assessed for microbiological response. A majority of patho- enth dose showed no statistical difference, indicating steady gens identified were gram-negative aerobes (67.9%), with the state was achieved. Protein binding was found to range from most common organism being E. coli (60.3%), and approxi- 79.3 to 87.1% with an average of 82.5 ± 1.7% and steady-state mately 9% of pathogens isolated were anaerobes. A large plasma fAUC0–12 was found to be 0.77 ± 0.14 μg·h/mL. The majority of the study population’s primary site of infection calculated AUC0–12 for the epithelial lining fluid (ELF) and was appendicitis (54%). Clinical success rates were as fol- alveolar macrophages (AM) were 4.93 and 39.53 μg·h/mL, lows: 92.9% in the group receiving eravacycline 1.5 mg/kg, respectively. Previously, studies have shown concentrations in 100% in the group receiving eravacycline 1 mg/kg, and 92.3% theELFof500mglevofloxacintobe11.01±4.52μg/mL at in the ertapenem group. The difference between ertapenem 4 h and 2.5 ± 0.97 μg/mL at 12 h. Also, concentrations of and the group receiving eravacycline 1.5 mg/kg was 0.5% 500 mg levofloxacin were reported to be 83.9 ± 53.2 μg/mL (95% CI − 23.1 to 25.2%). The difference between the group at 4 h and 18.3 ± 6.7 μg/mLat12hintheAM.Ontheother receiving eravacycline 1 mg/kg and ertapenem was 7.7% hand, concentrations of 500 mg azithromycin were found to be (95% CI − 6.7 to 40.9%). Specifically, for patients with iso- 1.7 ± 0.74 μg/mL at 4 h and 1.27 ± 0.47 μg/mLat12hinthe lated ESBL-producing pathogens, there were clinical success ELF and 649.9 ± 259.1 μg/mL at 4 h and 669.4 ± 310.5 at 12 h rates of 80%, 100%, and 100% in the 1.5 mg/kg eravacycline [23]. All study participants tolerated eravacycline, and no seri- group, 1 mg/kg, and ertapenem groups, respectively. As the ous adverse effects were noted. The most common adverse results show, there was no statistically significant difference effects reported were nausea (90%), infusion related irritation between either dose of eravacycline and ertapenem, and inter- (65%), vomiting (35%), and headache (30%), but all were re- estingly, it showed that there was a higher rate of clinical ported to be mild or moderate in severity. Because this was a success in the 1 mg/kg group over the 1.5 mg/kg group, but phase 1 study, sample size was small, but this trial demonstrated this was not shown to be statistically significant. There were good tissue concentrations, with concentrations 6-fold and 50- also lower rates of total adverse effects in the 1 mg/kg fold higher in the ELF and AM, respectively, and can lead to eravacycline group when compared to the 1.5 mg/kg group, future study in respiratory infections. which will be discussed further in the safety section. Eur J Clin Microbiol Infect Dis (2019) 38:1787–1794 1791

Safety group and the ertapenem group was Enterobacteriaceae,with 168 isolates in the eravacycline group (76.36% of the study The percentage of patients who experienced a treatment– population) and 171 in the ertapenem group (75.66% of the emergent adverse effect was 35.8% in the group receiving study population). A total of 12.5% of the Enterobacteriaceae eravacycline 1.5 mg/kg, 28.6% in the group receiving were confirmed to be ESBL-producing in the eravacycline eravacycline 1 mg/kg, and 26.7% in the ertapenem group. group, and 10.5% were ESBL-producing in the ertapenem The most commonly reported adverse effects were nausea group. A total of 90.5% of the patients with ESBL- and vomiting and were of mild severity. No serious adverse producing Enterobacteriaceae in the eravacycline group had effects, such as death, life threatening events, or events that a favorable response, while 83.3% in the ertapenem group had lead to significant disability, were reported to be related to the a favorable response. About 8% of the patients receiving study drug. Nausea occurred in 1.9% of those in the 1.5 mg/kg eravacycline had Pseudomonas isolates and 8.8% of the eravacycline group and 10.7% of the 1 mg/kg eravacycline ertapenem group has Pseudomonas isolates, but the group as compared to 6.7% in the ertapenem group and when ertapenem group had a higher favorable response rate with comparing these results to previous studies of tigecycline this pathogen (90.0% to 83.3%). As mentioned previously, which show much higher rates of nausea, 24.4% of patients, eravacycline is not known to have reliable coverage to eravacycline has a favorable side effect profile [25]. Pseudomonas species, so this favorable response rate was critiqued to be due to pre-operative antipseudomonal β- lactams used for source control [26]. Both treatment groups Phase 3 study—IGNITE1 had similar durations of therapy (average 7.6 days for each). Table 3 compares data from the phase 1, phase 2, and phase 3 In 2016, a randomized phase 3 study was conducted to eval- studies. uate the safety and efficacy of eravacycline [7]. The Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE1) trial was a randomized, double- blind, double dummy, multicenter study that compared Phase 3 study—IGNITE4 eravacycline to ertapenem in the management of cIAI which required surgical or percutaneous intervention plus antibiotics. A recently published study discussed results from the Five hundred and forty-one patients were randomized to re- IGNITE4 trial which compared eravacycline to meropenem ceive either eravacycline 1 mg/kg IVevery 12 h or ertapenem for the treatment of cIAI [27]. This study was a randomized, 1 g IVevery 24 h. The primary efficacy end point was clinical double-blind, double-dummy, multicenter, prospective trial response at the TOC visit. A noninferiority margin of 10% aimed to address the safety and efficacy of eravacycline com- was implemented. Clinical cure rates 87.0% for the pared to meropenem. Five hundred patients from 65 sites in 11 eravacycline group and 88.8% for the ertapenem group in countries were randomized to receive either 1 mg/kg the modified intent to treat (MITT) population. Noninferiority eravacycline IV every 12 h or 1 g meropenem daily. The pri- criteria was met with a 95% CI of − 7.4 to 3.8% for this popu- mary end point for this study was similar to the INGITE1 lation. The microbiologically evaluable population also met study, which was clinical response at the TOC visit. As noninferiority; 91.4% of the eravacycline group and 95% of eravacycline had demonstrated noninferiority in the the ertapenem group had clinical cure (95% CI − 8.9 to IGNITE1 trial with a 10% margin, the noninferiority margin 1.5%). There were 3 deaths in the eravacycline group and 6 for this study was set at 12.5%. The primary disease for each in the ertapenem group, but none were considered related to group was complicated appendicitis, with 48.2% in the study therapy. More treatment emergent adverse events oc- eravacycline group and 43.9% in the meropenem group. At curred in the eravacycline group (113 of 270 versus 75 of 268 the TOC visit, 92.4% of the eravacycline group and 91.6% of in the ertapenem group); nausea and phlebitis occurred more the meropenem group met the criteria for clinical cure (95% frequently in the eravacycline group. Study results show that CI, − 4.1 to 5.8), indicating noninferiority. Gram-negative aer- eravacycline did meet the Food and Drug Administration obes were the most common pathogen isolated at baseline, (FDA) and European Medicines Agency (EMA) criteria for with 89.2% of the eravacycline group and 92.2% of the noninferiority and that the microbiology in this study was typ- meropenem group reporting these pathogens. Additionally, ical of the larger population of patients seen in clinical practice 90% of the eravacycline group and 93.7% of the meropenem with these types of infections. However, the average patient in group had anaerobes isolated at baseline; polymicrobial infec- this study was under 65 years of age and had a low risk of tions occurred in 71% of total patients. Treatment emergent mortality as evidence by a low APACHE score. adverse events occurred in 37.2% of the eravacycline group When comparing the study populations in the IGNITE1 compared to 30.9% of the meropenem group, with the major- trial, the most common pathogen in both the eravacycline ity of side effects being gastrointestinal in nature; nausea was 1792

Table 3 Summary of clinical studies on eravacycline

Author, year Phase/design Population Study intervention Outcomes (size)

Connors, et al., Phase1,P,OL,R, Healthy volunteers Seven IV doses of 1.0 mg of eravacycline Protein binding: 9.3 to 87.1%; mean 82.5% ± 1.7% 2014 [15] PK and safety 1 mg/kg Q12H as a 1-h infusion over an Steady-state plasma fAUC0–12 : 0.77 ± 0.14 g h/ml (n = 20) study 8-week period Solomkin, et al., Phase2,R,DB, Adults diagnosed with a cIAI requiring Eravacycline 1.5 mg/kg IV Q24H, Clinical success rates: 92.9% in the group receiving 1.5 mg/kg 2014 [19] AC study surgical or percutaneous intervention eravacycline 1 mg/kg IV Q12H, or eravacycline, 100% in the group receiving 1 mg/kg eravacycline, (n = 143) and antibacterial therapy ertapenem 1 g Q24H and 92.3% in the ertapenem group. for a range of 4–14 days Difference in clinical success rates: 1.5 mg/kg eravacycline and ertapenem = 0.5%; 95% CI of −23.1 to 25.2%; 1 mg/kg eravacycline and ertapenem = 7.7%; 95% CI of − 6.7 to 40.9% TEAE: 35.8% in the group receiving 1.5 mg/kg eravacycline, 28.6% in the group receiving 1 mg/kg eravacycline, and 26.7% in the ertapenem group Solomkin, et al., Phase3,R,DB, Adults with a cIAI requiring surgical Eravacycline 1 mg/kg IV Q12H or Clinical success rates (MITT population): 87.0% in the eravacycline 2016 [7] DD, MC study or percutaneous intervention and ertapenem 1 g IV Q24H for a range group and 88.8% in the ertapenem group (n = 541) antibacterial therapy of 4–14 days (95% CI − 7.4to3.8) Clinical success rates (ME population): 91.4% in eravacycline group and 95% in the ertapenem group (95% CI − 8.9to1.5) TEAE: 41.9% in the eravacycline group and 30% in the ertapenem group Solomkin, et al., Phase3,R,DB, Adults with a cIAI requiring surgical or Eravacycline 1 mg/kg IV Q12H or Clinical success rates (micro-ITT): 90.8% in the eravacycline group and

2018 [27] DD, MC study percutaneous intervention and meropenem 1 g IV daily for a range of 91.2% in the meropenem group (95% CI − 6.3to5.3) 38:1787 (2019) Dis Infect Microbiol Clin J Eur (n = 500) antibacterial therapy 4–14 days Clinical success rates (MITT population): 92.4% in the eravacycline group and 91.6% in the meropenem group (95% CI − 4.1to5.8) TEAE: 37.2% in the eravacycline group and 30.9% in the meropenem group

P prospective, OL open-label, R randomized, DB double-blind, AC active control, DD double dummy, MC multicenter, cIAI complicated intra-abdominal infection, TEAE treatment emergent adverse effects, MITT modified intent-to-treat, ME microbiologically evaluable – 1794 Eur J Clin Microbiol Infect Dis (2019) 38:1787–1794 1793 only reported in 4.8% of patients in the eravacycline group 4. Global action plan on antimicrobial resistance. World Health and 0.8% of the meropenem group. Organization website. http://www.who.int/antimicrobial- resistance/global-action-plan/en/. Accessed 6 Sept 2018 5. Generating antibiotic incentives now. Food and Drug Administration website. https://www.fda.gov/downloads/ Additional studies AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/ CDER/UCM595188.pdf.Accessed6Sept2018 6. FDA awards fast track status to tetraphase pharmaceuticals for IV IGNITE2, a trial studying IV to PO regimens of eravacycline, and oral formulations of eravacycline [news release]. Tetraphase compared eravacycline to levofloxacin in the treatment of Pharmaceuticals, Watertown, MA. April 2, 2014. https://ir.tphase. complicated UTIs (cUTIs). The maker of eravacycline, com/news-releases/news-release-details/fda-awards-fast-track- Tetraphase Pharmaceuticals, announced results of the trial, status-tetraphase-pharmaceuticals-iv-and#. Accessed 6 Sept 2018 7. Solomkin J, Evans D, Slepavicius A et al (2017) Assessing the but results showed eravacycline to be inferior to levofloxacin. efficacy and safety of eravacycline vs ertapenem in complicated Those in the study who remained on IV therapy alone had a intra-abdominal infections in the investigating gram-negative infec- higher response rate, so it was hypothesized that the problem tions treated with eravacycline (IGNITE 1) trial: a randomized clin- – lay with the oral formulation due to low oral bioavailability as ical trial. JAMA Surg 152(3):224 232 8. Xiao XY,Hunt DK, Zhou J et al (2012) Fluorocyclines. 1. 7-fluoro- mentioned previously [28]. IGNITE3, a trial again studying 9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, eravacycline, compared IVeravacycline to IV levofloxacin for broad spectrum antibacterial agent. J Med Chem 55(2):597–605 the treatment of cUTIs. Eravacycline again failed to meet the 9. Sutcliffe JA, O’Brien W, Fyfe C, Grossman TH (2013) FDA’s criteria for noninferiority [29]. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother 57(11):5548–5558 10. CLSI (2016) Performance Standards for Antimicrobial Conclusion Susceptibility Testing, 26th edn. CLSI Supplement M100S. Clinical and Laboratory Standards Institute, Wayne Eravacycline, a newly approved tetracycline derivative, has 11. Goldstein EC, Citron DM, Tyrrell KL (2018) In vitro activity of eravacycline and comparator antimicrobials against 143 recent shown broad-spectrum activity for gram-positive, gram-nega- strains of Bacteroides and Parabacteroides species. Anaerobe 52: tive, anaerobic, and multidrug-resistant microorganisms. 122–124 Eravacycline also does not require renal dose adjustments, 12. 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