Eravacycline, the first four years: health outcomes and tolerability data for 19 hospitals in 5 U.S. regions from 2018 to 2022

ABSTRACT Eravacycline is a synthetic fluorocycline approved by the U.S. Food and Drug Administration in 2018. This study aimed to describe clinical and microbiological outcomes in addition to associated adverse effects of eravacycline used in U.S. hospitals. Real-world, observational study involving patients receiving ≥72 h of eravacycline at 19 medical centers located in all 5 regions of the United States between October 2018 and August 2022. The primary outcome was clinical success, defined as survival and absence of microbiological recurrence at 30 days from the end of eravacycline therapy and clinical improvement within 96 h of eravacycline initiation. In total, 416 patients met study criteria and were evaluated. Index culture specimens were most often isolated from the respiratory tract (24.8%, n = 103/416), wound(s) (20.9%, n = 87/416), or blood (19.5%, n = 81/416). As definitive therapy, eravacycline was most often used to treat infections caused by Enterobacterales spp. (42.3%, n = 176/416; 24.4%, n = 43/176 carbapenem-resistant), Enterococci spp. (24.0%, n = 100/416; 49.0%, 49/100 vancomycin-resistant), and Acinetobacter spp. (23.3%, n = 97/416; 47.4%, n = 46/97 carbapenem-resistant). Clinical success occurred in 75.7% of patients (n = 315/416). Thirty-nine (9.4%, n = 39/416) patients experienced a treatment emergent adverse event (TEAE) potentially related to eravacycline with the majority (51.3%, n = 20/39) being gastrointestinal intolerance. Only 27 isolates (6.5%, n = 27/416) underwent eravacycline susceptibility testing. Eravacycline is being used to treat a broad range of Gram-negative and Gram-positive bacteria in the United States including those demonstrating multidrug-resistance with consistently low reported drug-related TEAE; however, antimicrobial susceptibility testing and subsequent in vitro susceptibility data of clinical isolates was sparingly performed. IMPORTANCE The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline’s efficacy in addressing the pressing global challenge of MDR bacterial infections.

research offers pivotal insights into eravacycline's efficacy in addressing the pressing global challenge of MDR bacterial infections.KEYWORDS eravacycline, multidrug-resistant, antimicrobial stewardship F aced with the escalating challenge of antimicrobial resistance, which threatens an estimated 10 million lives annually by 2050 due to the spread of multidrug-resist ant (MDR) pathogens, novel solutions are imperative (1)(2)(3).In this context, the U.S. Food and Drug Administration (FDA) approved eravacycline in August 2018 for treating complicated intraabdominal infections (cIAI) (4).As the first fully synthetic fluorocycline, eravacycline maintains stability against the efflux pumps and ribosomal protection proteins that typically confer resistance to other members of the tetracycline antibiotic class (5).Eravacycline has shown potent in vitro activity against a wide range of Gramnegative bacteria, including carbapenem-resistant isolates.This includes bacteria such as Enterobacterales that produce an extended-spectrum beta-lactamase or carbapene mase, Acinetobacter species, and other MDR Gram-negative pathogens.Several studies have reported low minimum inhibitory concentration (MIC 90 ) values for eravacycline against these bacteria (6)(7)(8)(9)(10).Additionally, eravacycline has demonstrated activity in vitro against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), nontuberculosis mycobacteria, and anaerobic bacteria such as Clostridioides difficile (11)(12)(13).
The efficacy of eravacycline in treating cIAIs was established through two phase III multicenter clinical randomized controlled trials (RCTs) (IGNITE I/IV), demonstrat ing noninferiority to ertapenem and meropenem, respectively (14,15).Furthermore, real-world experience with eravacycline, although limited, has shown comparable clinical success and tolerability to the clinical trials (16).Retrospective studies utilizing real-world data provide valuable insights into real-world outcomes and usage, complementing RCTs by exploring long-term outcomes, rare adverse events, and complex relationships in diverse populations.The objective of this study is to describe the clinical use of eravacycline in United States hospitals in terms of clinical and microbiological response and drug-related adverse events in its first 4 years following FDA approval.

MATERIALS AND METHODS
Retrospective cohort study using inpatient data from October 2018 to August 2022 of adult patients admitted to a participating medical center and receipt of ≥72 consec utive hours of eravacycline therapy for any pathogen within the spectrum of eravacy cline activity isolated from any infectious source.Participating centers encompassed a diverse range of medical institutions including academic/university-affiliated centers and community hospitals situated in both urban and suburban locales.Exclusion criteria included patients who were pregnant or nursing, prisoners, and those that received subsequent eravacycline courses not separated by at least 90 days from the end of the index eravacycline treatment course.
The primary outcome was clinical success, defined as survival with absence of microbiological recurrence at 30 days from the end of eravacycline therapy and clinical improvement within 96 hours of eravacycline initiation.Microbiological recurrence was defined as a positive culture for the same organism and infectious source within 30 days from the end of eravacycline therapy.Clinical improvement was defined as the resolution of infectious signs and symptoms including infection-related abnormal white blood cell count/temperature or as documented by the physician in clinical notes.Key secondary clinical, microbiological, and tolerability endpoints including hospital readmission, infection-related readmission, and possible eravacycline-related adverse effects using the common terminology criteria for adverse events were also evaluated (17).The relationship of possible treatment emergent adverse events (TEAEs) related to eravacycline was determined based on adverse event onset in relation to the initiation and possible discontinuation of eravacycline using medical record documentation.Concomitant therapy was defined as any therapy used in conjunction with eravacycline for ≥48 continuous hours for the primary organism that eravacycline therapy was used for.
To obtain information on patient demographics and baseline characteristics, we accessed the electronic health record (EHR) and recorded the data in Research Electronic Data Capture (REDCap) (18).The Charlson Comorbidity Index was used to estimate comorbidity burden, while measures of organ function and illness severity were assessed based on the highest Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) score within 48 h of index culture collection.Index culture was defined as the culture collected closest to eravacycline initiation.Immunosuppressive factors were defined as neutropenia (absolute neutrophil count <500), splenectomy (functional or surgical), or high dose corticosteroids (>pre dnisone 20 mg/day or equivalent).All cultures, bacterial identifications, and antibiotic susceptibilities were conducted according to local procedures at each center.Clinical Laboratory Standards Institute (CLSI) breakpoints were used to interpret MIC results, where applicable (19).
Descriptive statistics were employed to evaluate baseline characteristics.Frequen cies and percentages were used to report discrete data, while continuous data were described using median and interquartile range (IQR) or mean and standard deviation (SD), depending on the normality of the distribution.IBM SPSS Statistics version 29 (IBM Corp., Armonk, NY) was used to carry out the analyses.

DISCUSSION
This study provides valuable insight into the real-world use of eravacycline for the treatment of various infections in U.S. hospitals in the 4 years following its FDA appro val.The data herein suggest that eravacycline is predominantly used as consolidation therapy for monomicrobial infections from a variety of sources.The broad activity and low MIC 90 values of eravacycline against an array of Gram-negative and Gram-posi tive bacteria, including those demonstrating multidrug resistance, make eravacycline a therapeutic option in such challenging clinical scenarios.These data also identified that eravacycline was commonly used as definitive therapy for infections caused by carbapenem-resistant A. baumannii and Enterobacterales spp., which make up greater than one-fifth of the study cohort.The use of eravacycline for carbapenem-resistant Acinetobacter spp.infections in the study cohort is particularly noteworthy since eravacycline has not yet earned an indication specifically for Acine tobacter spp., nor has it been assigned a CLSI or U.S. Food & Drug Administration breakpoint despite demonstrating in vitro activity against MDR A. baumannii isolates (20).Similarly, eravacycline does not have an approved indication for the treatment of respiratory or acute bacterial skin and skin structure infections, the two most common sites of positive culture attainment in this cohort (21).Additionally, compared to patients in the eravacycline IGNITE I/IV clinical trials, our study population required a significantly higher level of care.Almost half were admitted to the ICU, those on ventilators received eravacycline therapy for an average of over 3 weeks, and eravacycline was often used to treat pathogens that have historically been challenging to manage.Therefore, these findings enrich limited data suggesting that eravacycline could be a potential treatment for challenging cases, such as infections caused by CRE, carbapenem-resistant Acineto bacter spp., and Stenotrophomonas maltophilia even though recent therapeutic guidance does not currently recommend eravacycline for these conditions (22,23).Additional data is warranted to establish the effectiveness of eravacycline in these specific patient and clinical scenarios.
The incidence of eravacycline-related adverse events and subsequent eravacycline discontinuation are like that reported in the IGNITE I/IV clinical trials with the most common being gastrointestinal disorders.While gastrointestinal disorders are more common with the tetracycline class of antibiotics, available RCT and observational data demonstrate that the incidence of drug-related gastrointestinal disorders is approxi mately two to five-fold lower than that reported for the other tetracyclines including omadacycline, minocycline, and tigecycline (24)(25)(26)(27)(28).
While this study is the largest report of eravacycline use in U.S. hospitals to date, it has important limitations including its retrospective, observational design, and a lack of control group to validate the role of eravacycline in reported clinical effectiveness and tolerability.Furthermore, this study highlights the limited antimicrobial susceptibility testing of eravacycline occurring in U.S. hospital-affiliated microbiology laboratories.Limited testing may be due to a lack of eravacycline breakpoints for most organisms including Acinetobacter and Stenotrophomonas maltophilia and/or limited available antimicrobial susceptibility tests for eravacycline.There are only two FDAcleared commercial automated antimicrobial susceptibility tests (AST) with eravacycline on-panel (e.g., VITEK 2 AST Gram-Negative Panel Assay and MicroScan Neg Urine Combo 90) (29, 30), and other available AST are limited to HardyDisk, Liofilchem MTS, Thermo Scientific Sensititre, and bioMerieux ETEST (31)(32)(33)(34).Unfortunately, there remains scant in vitro susceptibility data comparing isolate eravacycline MIC data to that of other novel and standard of care antibiotics.In the current study, approximately half of participating centers used the isolate tigecycline MIC to guide eravacycline use for Acinetobacter spp.and carbapenem-resistant K. pneumoniae infections, which may be problematic since tigecycline breakpoints are not established for eravacycline.Surveillance data of eravacycline in vitro activity against Gram-negative bacilli aligns with limited MIC data presented herein; however, more data are needed to elucidate the appropriateness of this practice at an organism and infectious source level.
In conclusion, eravacycline is being used in real-world clinical settings to treat a broad range of Gram-negative and Gram-positive aerobic and anaerobic bacteria in the United States, including those demonstrating multidrug-resistance, with consistently low reported drug-related TEAEs.This study adds to the growing body of evidence that supports the clinical success and tolerability of eravacycline in the treatment of complicated infections.However, the limited availability of antimicrobial susceptibil ity data highlights the need for continued monitoring and surveillance of antibiotic resistance patterns.Further studies are warranted to evaluate the long-term safety and efficacy of eravacycline in different patient populations and clinical settings.

FIG 1 FIG 2
FIG 1 Microbiological isolates and culture specimen source.
(Continued on next page) median (IQR) time from index culture collection to the first administration of eravacycline was 4 (2, 8) days.

TABLE 2
Clinical course and treatment characteristics (n = 416) a,f,g (Continued) a Data presented as number (%) or median (IQR), as appropriate.b Hospital-acquired infection: Index positive culture collected ≥48 h from hospital admission (includes time accrued at previous institution if the patient transferred from an outside hospital).c Surgical intervention: Incision and drainage (n = 68), debridement (n = 51), amputation (n = 10), valvular replacement (n = 2), invasive device removal (n = 6), other (n = 82).d Total may exceed n of 416 due to receipt of multiple antibiotics.e Active therapy: Demonstrated in vitro susceptibility.f Concomitant therapy: Antibiotic administered for ≥48 continuous hours while the patient received eravacycline.g ICU, intensive care units; ID, infectious diseases; ERV, eravacycline; CRE, carbapenem-resistant Enterobacterales; LTAC, long-term acute care.

TABLE 3
Definitive eravacycline therapy a Total may exceed n of 416 due to polymicrobial infections.b spp., species; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus.c Data are presented as number (%), as appropriate.

TABLE 4
Eravacycline MIC distribution by organism c
b c d e Patients with a 30-day readmission were muted from 60-day readmission total.f g Gastrointestinal intolerance defined as nausea, vomiting, and/or diarrhea.microbiological