Eravacycline (Xerava): A Comprehensive Pharmacological and Clinical Monograph

1.0 Executive Summary

Eravacycline, marketed under the brand name Xerava, is a fully synthetic, parenterally administered fluorocycline antibiotic, representing a novel advancement within the tetracycline class of antimicrobials.[1] Developed by Tetraphase Pharmaceuticals, its creation was a direct response to the escalating global health crisis of antimicrobial resistance, particularly among Gram-negative pathogens.[3] The drug's primary approved indication is for the treatment of complicated intra-abdominal infections (cIAI) in adult patients.[1]

The mechanism of action of Eravacycline is consistent with its parent class, involving the inhibition of bacterial protein synthesis through high-affinity binding to the 30S ribosomal subunit.[1] This action prevents the incorporation of aminoacyl-tRNA, thereby halting the elongation of peptide chains.[6] A key feature of Eravacycline is its molecular structure, which has been specifically engineered to circumvent two major mechanisms of tetracycline resistance: active drug efflux and ribosomal protection.[6] This rational drug design confers a potent and broad spectrum of activity.

Eravacycline exhibits robust in vitro activity against a wide array of clinically significant pathogens. This includes Gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), as well as a range of Gram-negative organisms, including extended-spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE).[8] It is also active against many anaerobic bacteria. A notable limitation in its spectrum is its lack of clinically relevant activity against Pseudomonas aeruginosa.[8]

Regulatory approval was granted based on the strength of two pivotal Phase 3 clinical trials, IGNITE1 and IGNITE4. These studies rigorously demonstrated the non-inferiority of Eravacycline when compared to the carbapenems ertapenem and meropenem, respectively, for the treatment of cIAI in adults.[7] This evidence firmly establishes Eravacycline as a viable alternative to carbapenems, positioning it as an important tool for antimicrobial stewardship programs seeking to implement carbapenem-sparing strategies.

The safety and tolerability profile of Eravacycline is generally favorable and consistent with the tetracycline class. The most common adverse reactions observed in clinical trials were infusion site reactions, nausea, and vomiting.[2] The drug carries the characteristic warnings of its class, including the potential for permanent tooth discoloration and enamel hypoplasia, as well as reversible inhibition of bone growth. Consequently, its use is contraindicated during the second and third trimesters of pregnancy and in children under the age of eight.[12]

In conclusion, Eravacycline represents a significant and valuable addition to the modern antimicrobial armamentarium. It offers a potent, broad-spectrum therapeutic option for the management of polymicrobial cIAI, especially in clinical settings where multidrug-resistant pathogens are a concern. Its role as an effective carbapenem-sparing agent is a cornerstone of its therapeutic value, providing a much-needed alternative to last-line beta-lactam antibiotics. Prudent clinical use requires careful patient selection, adherence to dosing guidelines, and a thorough understanding of its class-specific safety considerations.

2.0 Identification and Physicochemical Characteristics

This section provides a definitive catalog of the nomenclature, registry identifiers, and fundamental chemical and physical properties of Eravacycline, establishing a foundational reference for the compound.

2.1 Nomenclature and Identifiers

Eravacycline is identified through a comprehensive set of names and registry numbers used in chemical, pharmaceutical, and regulatory contexts.

• Generic Name: Eravacycline [2]
• Brand Name: Xerava [1]
• Synonyms/Developmental Codes: TP-434 [2]
• International Nonproprietary Names (INN):
• Eravacyclina (Spanish) [15]
• Eravacyclinum (Latin) [2]
• éravacycline (French) [15]
• Systematic (IUPAC) Name: (4S,4aS,5aR,12aS)-4-(Dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[2-(pyrrolidin-1-yl)acetamido]-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide [8]
• Registry Numbers:
• CAS Number: 1207283-85-9 [1]
• DrugBank ID: DB12329 [2]
• UNII (Unique Ingredient Identifier): 07896928ZC [1]
• European Community (EC) Number: 811-473-5 [1]

2.2 Chemical and Physical Properties

Eravacycline is a small molecule drug with distinct physicochemical characteristics that define its formulation and behavior.

• Drug Type/Modality: Small Molecule [2]
• Chemical Formula: $C_{27}H_{31}FN_{4}O_{8}$ [2]
• Molecular Weight (Average): 558.56 g/mol [2]
• Monoisotopic Mass: 558.212592137 Da [2]
• Appearance: The drug substance is a solid powder.[9] When prepared for administration, the reconstituted solution is clear and ranges from pale yellow to orange in color.[17]
• Solubility: It is reported to be soluble in DMSO and has a water solubility of 50 mg/mL.[9]
• Salt Form: The clinically available formulation is Eravacycline dihydrochloride.[14]
• Chemical Structure Identifiers:
• SMILES: CN(C)[C@H]1[C@@H]2C[C@@H]3CC4=C(C=C(C(=C4C(=O)C3=C([C@@]2(C(=O)C(=C1O)C(=O)N)O)O)O)NC(=O)CN5CCCC5)F [8]
• InChIKey: HLFSMUUOKPBTSM-ISIOAQNYSA-N [8]

The following table consolidates these key identifiers and properties for ease of reference.

Table 1: Key Identifiers and Physicochemical Properties of Eravacycline

Identifier/Property	Value	Source(s)
Generic Name	Eravacycline	2
Brand Name	Xerava	1
Developmental Code	TP-434	2
CAS Number	1207283-85-9	1
DrugBank ID	DB12329	2
Drug Type	Small Molecule	2
Chemical Formula	$C_{27}H_{31}FN_{4}O_{8}$	2
Average Molecular Weight	558.56 g/mol	2
Monoisotopic Mass	558.212592137 Da	2
IUPAC Name	(4S,4aS,5aR,12aS)-4-(Dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[2-(pyrrolidin-1-yl)acetamido]-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide	8
Solubility (Water)	50 mg/mL	14

3.0 Comprehensive Pharmacological Profile

This section details the molecular and physiological actions of Eravacycline, including its mechanism of action, antimicrobial spectrum, and pharmacokinetic profile.

3.1 Mechanism of Action and Resistance

Eravacycline's antibacterial effect is rooted in its ability to disrupt a fundamental process in bacterial survival, while its clinical utility is enhanced by its capacity to overcome common resistance pathways.

3.1.1 Primary Mechanism

Eravacycline is an inhibitor of bacterial protein synthesis, a mechanism it shares with other members of the tetracycline class.[1] It exerts its antimicrobial effect by binding with high affinity to the bacterial 30S ribosomal subunit.[1] This binding event physically obstructs the A-site of the ribosome, which prevents the attachment of aminoacyl-transfer RNA (tRNA) to the messenger RNA (mRNA)-ribosome complex. By blocking this crucial step, Eravacycline effectively prevents the incorporation of new amino acid residues into the elongating peptide chain, thereby arresting protein synthesis and inhibiting bacterial growth and replication.[6]

3.1.2 Bacteriostatic and Bactericidal Properties

The nature of Eravacycline's activity can vary depending on the target organism. In general, it is considered a bacteriostatic agent against Gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis, meaning it inhibits their growth without directly killing them.[1] However, a notable distinction is its demonstrated in vitro bactericidal activity against certain clinically important Gram-negative strains, including Escherichia coli and Klebsiella pneumoniae.[1] This dual activity profile is significant; while it belongs to a traditionally bacteriostatic class, its ability to exert a killing effect on key Gram-negative pathogens commonly implicated in cIAI may contribute to the high clinical cure rates observed in pivotal trials, which were comparable to those of the bactericidal carbapenem comparators. This blurs the classic distinction and may justify its use in more severe infections where a bactericidal effect is preferred.

3.1.3 Overcoming Resistance Mechanisms

A defining feature of Eravacycline is its design as a "fully synthetic" fluorocycline, a process of rational drug design aimed at overcoming the primary mechanisms of resistance that have rendered older tetracyclines less effective.[1] Its molecular structure was deliberately modified to address two well-characterized resistance pathways:

1. Evasion of Efflux Pumps: Many bacteria develop resistance by expressing transmembrane efflux pumps that actively expel antibiotics from the cell, preventing them from reaching their intracellular target at sufficient concentrations. Eravacycline's structure has been engineered to evade recognition by many of these pumps, including those of the Major Facilitator Superfamily (MFS) and Resistance-Nodulation-cell Division (RND) family. This resilience allows it to accumulate and maintain effective therapeutic concentrations inside the bacterial cell.[6]
2. Activity in the Presence of Ribosomal Protection Proteins (RPPs): Another common resistance strategy involves the production of RPPs, which bind to the ribosome and induce a conformational change that dislodges the tetracycline molecule. Eravacycline's structural modifications enable it to form more stable interactions with the 30S ribosomal subunit, allowing it to maintain high binding affinity and outcompete the protective action of these proteins.[6]

This engineered resilience is fundamental to its clinical value, allowing it to retain potent activity against many multidrug-resistant (MDR) pathogens that are resistant to older tetracyclines and other antibiotic classes.[21]

3.2 Pharmacodynamics and Spectrum of Activity

The pharmacodynamic properties of Eravacycline define the relationship between drug exposure and antimicrobial effect, while its spectrum of activity dictates its clinical utility against specific pathogens.

3.2.1 Pharmacodynamic Index

The pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of Eravacycline is the ratio of the 24-hour area under the free drug concentration-time curve to the minimum inhibitory concentration ($fAUC_{0–24}/MIC$).[23] This index integrates both the extent and duration of exposure to the unbound, biologically active fraction of the drug relative to the pathogen's susceptibility.

3.2.2 Spectrum of Antimicrobial Activity

Eravacycline demonstrates potent, broad-spectrum in vitro activity against a wide range of clinically important bacteria, including many MDR strains.[3]

• Gram-Positive Aerobes: It possesses excellent activity against key Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and both Enterococcus faecalis and Enterococcus faecium, including vancomycin-resistant strains (VRE).[8]
• Gram-Negative Aerobes: Eravacycline shows potent activity against a broad array of Gram-negative bacteria. This includes Enterobacteriaceae that are resistant to multiple other drug classes, such as those producing extended-spectrum β-lactamases (ESBLs) and some carbapenem-resistant Enterobacteriaceae (CRE).[7] It is also active against Acinetobacter baumannii, including carbapenem-resistant isolates (CRAB).[10]
• Anaerobes: The drug has demonstrated activity against many common anaerobic bacteria that are frequently isolated from intra-abdominal infections.[22]
• Notable Gaps in Spectrum: A critical limitation of Eravacycline's spectrum is its poor activity against Pseudomonas aeruginosa and Burkholderia cenocepacia. For both of these organisms, the concentration required to inhibit 90% of isolates (MIC90) is reported to be 32 mg/L, which is well outside the clinically achievable range.[8] This gap must be considered when selecting Eravacycline for empiric therapy in infections where P. aeruginosa is a suspected pathogen.

The following table summarizes the in vitro activity of Eravacycline against several key pathogens, as quantified by their MIC50 and MIC90 values.

Table 2: In Vitro Activity of Eravacycline Against Key Clinical Pathogens

Pathogen	MIC50 (mg/L)	MIC90 (mg/L)	Source(s)
Escherichia coli	0.12	0.5	23
Klebsiella pneumoniae	0.5	2	23
Acinetobacter baumannii	0.06	0.5	23
Staphylococcus aureus	0.03	0.12	23

3.3 Pharmacokinetics (ADME)

The pharmacokinetic profile of Eravacycline describes its absorption, distribution, metabolism, and elimination (ADME), which collectively determine the drug's exposure at the site of infection and inform its dosing regimen.

• Absorption: Eravacycline is administered exclusively via the intravenous (IV) route, resulting in 100% bioavailability.[12] Following a single 1 mg/kg IV infusion administered over 60 minutes, the maximum plasma concentration ($C_{max}$) reaches approximately 1.3 µg/mL. The time to reach this maximum concentration ($T_{max}$) occurs approximately 1.5 to 2 hours after the end of the infusion.[12]
• Distribution: Eravacycline distributes extensively into body tissues. The volume of distribution at steady-state ($V_{dss}$) is approximately 321 L.[1] This large value, far exceeding total body water, indicates significant penetration into peripheral tissues and compartments, a favorable characteristic for treating deep-seated infections such as cIAI. Plasma protein binding is nonlinear and concentration-dependent, ranging from 79% to 90% as plasma concentrations increase.[2]
• Metabolism: The drug is metabolized in the liver. The primary metabolic pathways involve oxidation mediated by two key enzyme systems: Cytochrome P450 3A4 (CYP3A4) and Flavin-containing monooxygenase (FMO).[1] The reliance on CYP3A4 for metabolism is the basis for clinically significant drug-drug interactions.
• Elimination: Eravacycline is eliminated from the body through a dual pathway involving both renal and fecal excretion. Following administration of a single radiolabeled dose, approximately 47% of the dose is recovered in the feces (with 17% as unchanged drug) and 34% is recovered in the urine (with 20% as unchanged drug).[1] The mean elimination half-life ($t_{1/2}$) is approximately 20 hours, which supports a twice-daily dosing interval.[1] With the recommended dosing regimen of 1 mg/kg every 12 hours, an accumulation of approximately 45% is observed at steady-state.[1]

The pharmacokinetic profile of Eravacycline is intrinsically linked to its clinical performance and dosing requirements. The large volume of distribution facilitates its efficacy in tissue-based infections like cIAI. Conversely, the relatively low proportion of active drug excreted unchanged in the urine (20%) likely explains its failure to meet efficacy endpoints in clinical trials for complicated urinary tract infections (cUTI), as it may not achieve sufficient concentrations at that specific site of infection.[8] Furthermore, the dual elimination pathway provides a rationale for why no dosage adjustment is needed in patients with renal impairment, as the hepatic route can compensate. However, the reliance on hepatic metabolism necessitates dose adjustments in patients with severe hepatic dysfunction and in the presence of drugs that strongly induce its primary metabolizing enzyme, CYP3A4.

Table 3: Summary of Key Pharmacokinetic Parameters of Eravacycline

Parameter	Value	Clinical Significance/Implication	Source(s)
Administration Route	Intravenous	100% bioavailability, rapid onset of action	12
$C_{max}$ (1 mg/kg dose)	~1.3 µg/mL	Peak concentration achieved after infusion	12
Volume of Distribution ($V_{dss}$)	~321 L	Extensive tissue penetration, suitable for deep-seated infections like cIAI	1
Plasma Protein Binding	79% to 90% (concentration-dependent)	High degree of binding; only the unbound fraction is active	2
Metabolism	Hepatic; primarily CYP3A4- and FMO-mediated oxidation	Potential for drug-drug interactions with CYP3A4 inducers/inhibitors	1
Elimination Half-Life ($t_{1/2}$)	~20 hours	Supports a twice-daily (q12h) dosing interval	1
Route of Elimination	Fecal (47%) and Renal (34%)	Dual pathway allows for use without dose adjustment in renal impairment	1

4.0 Clinical Efficacy in Complicated Intra-Abdominal Infections (cIAI)

The clinical efficacy of Eravacycline for its primary indication of cIAI has been established through a robust clinical development program, highlighted by two pivotal Phase 3, randomized, double-blind, non-inferiority trials: IGNITE1 and IGNITE4. These trials were strategically designed to compare Eravacycline against standard-of-care carbapenems, setting a high bar for demonstrating efficacy.

4.1 The IGNITE1 Trial: Non-Inferiority vs. Ertapenem

The IGNITE1 trial was designed to evaluate the efficacy and safety of Eravacycline compared to ertapenem, a commonly used carbapenem for community-acquired cIAI.

• Study Design: This was a multinational, multicenter, randomized, double-blind study involving 541 hospitalized adult patients with cIAI requiring intervention. Patients were randomized to receive either intravenous Eravacycline at a dose of 1.0 mg/kg every 12 hours or intravenous ertapenem at 1.0 g every 24 hours.[8]
• Primary Endpoint: The primary efficacy outcome was the clinical cure rate at the Test-of-Cure (TOC) visit, which occurred 25 to 31 days after the initiation of therapy. The analysis was conducted in the microbiological intent-to-treat (micro-ITT) population, which included all randomized patients who had at least one baseline bacterial pathogen identified. The pre-specified non-inferiority margin was 10%.[7]
• Results: Eravacycline successfully met the primary endpoint, demonstrating non-inferiority to ertapenem. In the micro-ITT population, the clinical cure rate was 86.8% for patients treated with Eravacycline, compared to 87.6% for those treated with ertapenem.[21] The statistical analysis yielded a difference in cure rates of -0.80%, with a 95% confidence interval (CI) of -7.1% to 5.5%. The lower bound of this confidence interval was well above the pre-defined -10% margin, confirming non-inferiority.[25]
• Conclusion: The IGNITE1 trial concluded that Eravacycline was non-inferior to ertapenem for the treatment of cIAI in hospitalized adults, establishing its efficacy as comparable to a first-line carbapenem therapy.[25]

4.2 The IGNITE4 Trial: Non-Inferiority vs. Meropenem

To further solidify the efficacy data and satisfy regulatory requirements, the IGNITE4 trial was conducted. This study compared Eravacycline to meropenem, a carbapenem with a broader spectrum of activity than ertapenem, representing an even more stringent test of efficacy.

• Study Design: IGNITE4 was a second pivotal Phase 3, randomized, double-blind trial that enrolled approximately 500 adult patients with cIAI. Patients were randomized to receive either intravenous Eravacycline (1.0 mg/kg every 12 hours) or intravenous meropenem (1 g every 8 hours).[7]
• Primary Endpoint: The primary endpoint was again the clinical cure rate at the TOC visit in the micro-ITT population. For this trial, the non-inferiority margin was set at 12.5%.[7]
• Results: Eravacycline once again met its primary endpoint, demonstrating non-inferiority to meropenem. The clinical cure rate in the micro-ITT population was 90.8% for the Eravacycline group and 91.2% for the meropenem group.[7] The calculated difference was -0.5% (95% CI, -6.3% to 5.3%), with the lower bound of the CI (-6.3%) clearly exceeding the -12.5% non-inferiority margin.[8] Consistent results were observed in secondary analyses of the modified intent-to-treat (MITT) population (92.4% vs. 91.6%) and the clinically evaluable (CE) population (96.9% vs. 96.1%).[7]
• Conclusion: The IGNITE4 trial confirmed that Eravacycline was non-inferior to the broad-spectrum carbapenem meropenem, providing robust and consistent evidence of its efficacy in treating patients with cIAI.[7]

4.3 Pooled and Subgroup Analyses

Further analyses of the data from these pivotal trials provide deeper context on Eravacycline's efficacy in specific patient populations and against challenging pathogens.

• Efficacy Against Resistant Pathogens: A key strength demonstrated in these trials was Eravacycline's efficacy against resistant bacteria. In the IGNITE4 trial, among the subgroup of patients with infections caused by ESBL-producing Enterobacteriaceae, the clinical cure rates were high and comparable between the two arms: 87.5% (14/16) for Eravacycline and 84.6% (11/13) for meropenem.[7] Pooled analyses from both trials reinforced these findings, showing favorable microbiological and clinical responses against MDR Enterobacteriaceae and Acinetobacter baumannii.[28]
• Efficacy in Obese Patients: A post-hoc pooled analysis of IGNITE1 and IGNITE4 was conducted to evaluate efficacy in patients stratified by Body Mass Index (BMI). The results showed that clinical cure rates remained consistently high across all BMI categories, including for patients with Class III obesity (BMI ≥40 kg/m²). This analysis supports the recommended dosing strategy of using actual body weight, demonstrating its effectiveness even in obese populations.[30]
• Network Meta-Analysis: To place Eravacycline in a broader context, a network meta-analysis was performed comparing it to seven other commonly used antibiotic regimens for cIAI, including piperacillin/tazobactam, imipenem/cilastatin, and tigecycline. This analysis found no statistically significant differences in clinical response rates among the various treatments.[10] Importantly, the analysis revealed that the microbiological response rate for Eravacycline was significantly superior to that of tigecycline, its structural predecessor in the glycylcycline class.[10] This suggests a potential advantage for Eravacycline in achieving pathogen eradication compared to tigecycline, a point of differentiation for clinicians choosing between these two broad-spectrum agents.

The successful demonstration of non-inferiority against two different first-line carbapenems solidifies Eravacycline's role as a reliable alternative for cIAI. This is particularly relevant in the context of antimicrobial stewardship, as it provides a potent, non-beta-lactam option that can be used as part of a "carbapenem-sparing" strategy to help reduce the selective pressure that drives the emergence of carbapenem resistance.

Table 4: Comparative Summary of Pivotal Phase 3 Trials for cIAI (IGNITE1 & IGNITE4)

Feature	IGNITE1	IGNITE4
Comparator Drug	Ertapenem (1 g q24h)	Meropenem (1 g q8h)
Primary Population	Microbiological Intent-to-Treat (micro-ITT)	Microbiological Intent-to-Treat (micro-ITT)
Non-Inferiority Margin	10%	12.5%
Eravacycline Cure Rate (%)	86.8%	90.8%
Comparator Cure Rate (%)	87.6%	91.2%
Difference (95% CI)	-0.80% (-7.1% to 5.5%)	-0.5% (-6.3% to 5.3%)
Source(s)	7	7

5.0 Safety and Tolerability Profile

The safety profile of Eravacycline has been characterized through its clinical development program. While generally well-tolerated, it is associated with specific adverse events and carries important class-specific warnings and precautions inherent to all tetracycline antibiotics.

5.1 Clinical Trial Adverse Events

Data pooled from the Phase 3 cIAI clinical trials provide a clear picture of the most common adverse reactions associated with Eravacycline therapy.

• Most Common Adverse Reactions: In the integrated analysis of cIAI trials, the most frequently reported adverse reactions, occurring in 3% or more of patients, were infusion site reactions (7.7%), nausea (6.5%), and vomiting (3.7%).[2]
• Less Common Adverse Reactions: Other adverse effects reported in at least 1% of patients included diarrhea (2%), hypotension (1%), and wound dehiscence (1%).[2] Adverse events occurring in less than 1% of patients included acute pancreatitis, hypocalcemia, dizziness, dysgeusia (taste disturbance), anxiety, and rash.[2]
• Discontinuation Rates: The rate of treatment discontinuation due to adverse events was low. In a pooled safety analysis, 1.6% (9 of 576) of patients receiving Eravacycline discontinued treatment due to an adverse event, compared to 2.2% (12 of 547) of patients in the comparator arms.[13] The most common adverse reactions leading to discontinuation were gastrointestinal in nature.[11]
• Comparison to Comparators: While the incidence of serious adverse events and all-cause mortality was found to be similar between Eravacycline and its carbapenem comparators, some meta-analyses have suggested that Eravacycline is associated with a statistically higher risk of overall treatment-emergent adverse events (TEAEs). This difference appears to be driven primarily by a higher incidence of nausea and vomiting in the Eravacycline groups.[32]

5.2 Warnings, Precautions, and Contraindications

The use of Eravacycline is governed by several important warnings and contraindications, many of which are characteristic of the entire tetracycline class.

• Contraindications: Eravacycline is strictly contraindicated in patients with a known hypersensitivity to Eravacycline, any of its excipients, or any other tetracycline-class antibacterial drug.[4]
• Hypersensitivity Reactions: Life-threatening anaphylactic reactions have been reported with Eravacycline. Due to its structural similarity to other tetracyclines, it should be avoided in patients with a history of serious hypersensitivity to any drug in this class. Treatment must be discontinued immediately if an allergic reaction occurs.[12]
• Tetracycline-Class Warnings: Eravacycline carries the potential for adverse reactions common to the tetracycline class, which are primarily related to developmental effects [2]:
• Tooth Discoloration and Enamel Hypoplasia: The use of Eravacycline during periods of tooth development—specifically, the last half of pregnancy, infancy, and childhood up to the age of 8 years—may lead to permanent (yellow-gray-brown) discoloration of the teeth and enamel hypoplasia. This risk is higher with long-term use but has been observed after repeated short-term courses.[12]
• Inhibition of Bone Growth: During the same developmental periods (second and third trimesters of pregnancy, infancy, and childhood up to age 8), Eravacycline use may cause a reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue, which can lead to a decrease in fibula growth rate in premature infants, a reaction shown to be reversible upon discontinuation of the drug.[12]
• Clostridioides difficile-Associated Diarrhea (CDAD): As with nearly all systemic antibacterial agents, treatment with Eravacycline can alter the normal flora of the colon, leading to an overgrowth of C. difficile. This can result in a spectrum of illness ranging from mild diarrhea to life-threatening or fatal colitis.[12]
• Other Class Effects: Other potential adverse reactions reported with the tetracycline class that may occur with Eravacycline include photosensitivity (increased sensitivity to sunlight), pseudotumor cerebri (benign intracranial hypertension), and anti-anabolic actions that can lead to increased blood urea nitrogen (BUN), azotemia, acidosis, and hyperphosphatemia.[2]

The safety profile of Eravacycline thus presents a notable dichotomy. For its indicated adult population, the primary risks are related to acute, generally manageable tolerability issues such as infusion reactions and gastrointestinal upset. However, for specific populations—namely developing fetuses and children under eight—the risks involve the potential for significant and irreversible developmental harm. This duality underscores that while Eravacycline is a modern, engineered antibiotic, it cannot escape the fundamental class-specific toxicities of its tetracycline heritage, which strictly define the populations in which it can be safely used.

5.3 Use in Special Populations

Dosing and safety considerations for Eravacycline vary significantly across different patient populations.

• Pediatric Use: Eravacycline is not recommended for use in children under 8 years of age due to the established risks of permanent tooth discoloration and inhibition of bone growth.[12] The U.S. FDA waived the requirement for pediatric studies in this age group on safety grounds. Studies in older children (ages 8 to <18 years) have been deferred.[35]
• Pregnancy: Use of Eravacycline should be avoided during the second and third trimesters of pregnancy due to the same potential risks to the developing fetus (tooth and bone effects).[12]
• Lactation: The manufacturer officially recommends that breastfeeding is not advised during treatment with Eravacycline and for 4 days following the final dose. However, other sources note that due to its high plasma protein binding (79-90%) and the likelihood that absorption by the infant would be inhibited by calcium in breastmilk, short-term use may be acceptable. If used, close monitoring of the infant for potential gastrointestinal effects (e.g., diarrhea, candidiasis) is recommended.[16]
• Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B). However, a dose reduction is necessary for patients with severe hepatic impairment (Child-Pugh Class C) due to reduced metabolic clearance.[4]
• Renal Impairment: No dosage adjustment is necessary for patients with any degree of renal impairment, including those with end-stage renal disease requiring hemodialysis.[4]

6.0 Dosage, Administration, and Drug Interactions

This section provides practical clinical guidance on the appropriate dosing, preparation, administration, and management of drug interactions for Eravacycline.

6.1 Dosing and Administration Guidelines

Adherence to standardized dosing and administration procedures is essential for achieving optimal efficacy and safety.

• Standard Adult Dosage: The recommended dosage for adults (18 years of age and older) is 1 mg/kg of actual body weight, administered as an intravenous (IV) infusion over approximately 60 minutes, every 12 hours.[4]
• Duration of Therapy: The total duration of treatment should be guided by the severity and location of the infection, as well as the patient's clinical response. The recommended duration is between 4 and 14 days.[4]
• Preparation and Administration: Eravacycline is supplied as a sterile, preservative-free, yellow to orange lyophilized powder in single-dose vials (50 mg or 100 mg) that must be reconstituted and diluted prior to administration.[17]

1. Reconstitution: Using aseptic technique, each vial should be reconstituted with 5 mL of either Sterile Water for Injection, USP, or 0.9% Sodium Chloride Injection, USP. The vial should be gently swirled until the powder is completely dissolved. The resulting solution will have a concentration of 10 mg/mL (for the 50 mg vial) or 20 mg/mL (for the 100 mg vial).[17]
2. Dilution: The required volume of the reconstituted solution, based on the patient's weight-based dose, must be withdrawn and further diluted in an infusion bag of 0.9% Sodium Chloride Injection, USP. The final concentration of the infusion solution should be targeted to 0.3 mg/mL (within an acceptable range of 0.2 to 0.6 mg/mL).[17]
3. Stability: The reconstituted solution in the vial is stable for 1 hour at room temperature. The final diluted infusion solution is stable for up to 12 hours if stored at room temperature (not to exceed 25°C/77°F) or for up to 8 days if stored under refrigeration (2°C to 8°C or 36°F to 46°F).[17]
4. Compatibility: Eravacycline is compatible with 0.9% Sodium Chloride Injection. It should not be mixed with or co-infused with other drugs, as compatibility has not been established.[17] If a common IV line is used, it should be flushed with 0.9% Sodium Chloride before and after the Eravacycline infusion.[33]

6.2 Dosage Adjustments

Dosage adjustments are required in specific clinical scenarios to account for altered drug metabolism.

• Renal Impairment: No dosage adjustment is required for patients with any degree of renal impairment, including those on hemodialysis.[4]
• Hepatic Impairment:
• Mild to Moderate (Child-Pugh Class A and B): No dosage adjustment is necessary.[4]
• Severe (Child-Pugh Class C): The dosage should be modified. On Day 1, the standard dose of 1 mg/kg every 12 hours should be administered. Starting on Day 2, the frequency should be reduced to 1 mg/kg every 24 hours for the remainder of the treatment course.[4]
• Concomitant Use of Strong CYP3A Inducers: When Eravacycline is co-administered with a strong inducer of the CYP3A enzyme system, its metabolism is accelerated, leading to lower drug exposure. To compensate, the dose of Eravacycline should be increased to 1.5 mg/kg IV every 12 hours.[4]

The following table provides a consolidated guide to these dosage adjustments.

Table 5: Dosage Adjustments in Special Populations and Drug Interactions

Condition	Recommended Eravacycline Dosage	Rationale
Normal Renal and Hepatic Function	1 mg/kg IV every 12 hours	Standard dose based on clinical trials
Renal Impairment (any degree, including hemodialysis)	No adjustment required	Dual (renal and hepatic) elimination pathway compensates for reduced renal clearance
Mild-to-Moderate Hepatic Impairment (Child-Pugh A/B)	No adjustment required	Sufficient hepatic metabolic capacity remains
Severe Hepatic Impairment (Child-Pugh C)	Day 1: 1 mg/kg IV q12h Day 2 onward: 1 mg/kg IV q24h	Significantly reduced hepatic metabolism leads to increased drug exposure, requiring a frequency reduction
Concomitant Use of a Strong CYP3A Inducer	1.5 mg/kg IV every 12 hours	Increased metabolic clearance by the inducer necessitates a higher dose to maintain therapeutic exposure

6.3 Clinically Significant Drug Interactions

Eravacycline has several clinically important drug interactions that require careful management.

• Strong CYP3A Inducers: Co-administration with strong inducers of the CYP3A4 enzyme, such as rifampin, carbamazepine, phenytoin, fosphenytoin, phenobarbital, and St. John's Wort, can significantly decrease plasma concentrations of Eravacycline, potentially leading to reduced efficacy and treatment failure. An increased Eravacycline dose of 1.5 mg/kg every 12 hours is recommended.[4]
• Anticoagulant Drugs: Tetracycline-class antibiotics have been shown to depress plasma prothrombin activity. Therefore, patients receiving concomitant therapy with warfarin or other anticoagulants may be at increased risk of bleeding and may require a downward adjustment of their anticoagulant dosage and more frequent monitoring of coagulation parameters.[33]
• Bacteriostatic/Bactericidal Antagonism: As a primarily bacteriostatic agent, Eravacycline has the potential to interfere with the bactericidal action of beta-lactam antibiotics, such as penicillins (e.g., amoxicillin, ampicillin). This antagonism is a theoretical concern, and concurrent use should be approached with caution, particularly in severe infections where rapid bactericidal activity is desired.[2]
• Retinoids: The concurrent use of tetracyclines and systemic retinoids (e.g., acitretin, isotretinoin) is generally not recommended. This combination has been associated with an increased risk of developing pseudotumor cerebri (benign intracranial hypertension).[31]
• Photosensitizing Agents: Eravacycline may cause photosensitivity. Co-administration with other known photosensitizing agents (e.g., systemic or topical aminolevulinic acid) could potentially enhance this effect, increasing the risk of severe sunburn or skin reactions upon sun exposure.[21]

The table below summarizes these key interactions and provides management recommendations.

Table 6: Summary of Clinically Significant Drug Interactions with Eravacycline

Interacting Drug/Class	Potential Effect	Clinical Management/Recommendation	Severity
Strong CYP3A Inducers (e.g., rifampin, carbamazepine, phenytoin)	Decreased Eravacycline exposure and potential for reduced efficacy.	Increase Eravacycline dose to 1.5 mg/kg IV every 12 hours.	Severe
Anticoagulants (e.g., warfarin)	Increased anticoagulant effect and risk of bleeding.	Monitor coagulation parameters closely. A downward adjustment of the anticoagulant dose may be required.	Moderate
Bactericidal Beta-Lactams (e.g., amoxicillin, ampicillin)	Potential for antagonistic effect, reducing the efficacy of the beta-lactam.	Avoid combination if possible, especially in severe infections where bactericidal activity is critical.	Serious
Systemic Retinoids (e.g., acitretin, isotretinoin)	Increased risk of pseudotumor cerebri (benign intracranial hypertension).	Combination is not recommended.	Serious
Photosensitizing Agents (e.g., aminolevulinic acid)	Enhanced photosensitivity, increasing the risk of skin reactions.	Avoid combination if possible. Advise patient on strict sun protection measures.	Moderate

7.0 Regulatory Landscape and Place in Therapy

This section situates Eravacycline within its global regulatory context and provides an expert perspective on its established therapeutic role and clinical niche.

7.1 Global Regulatory Approvals

Eravacycline has received marketing authorization from major regulatory bodies in North America and Europe based on the strength of its clinical trial data.

• U.S. Food and Drug Administration (FDA): Eravacycline (as Xerava) was approved by the FDA on August 28, 2018. The approved indication is for the treatment of complicated intra-abdominal infections (cIAI) in patients 18 years of age and older.[4] The New Drug Application was reviewed without referral to an external advisory committee, indicating that the agency did not identify issues requiring outside expertise.[35] As part of the approval, the FDA mandated a significant post-marketing requirement: a five-year surveillance study in the United States to monitor for the development of resistance to Eravacycline in pathogens specific to the cIAI indication.[35] This requirement underscores a modern regulatory approach focused not only on immediate drug safety and efficacy but also on the long-term public health imperative of preserving the utility of new antibiotics in an era of increasing resistance.
• European Medicines Agency (EMA): Following a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) in July 2018, the European Commission granted a marketing authorization valid throughout the European Union on September 20, 2018.[43] The indication is consistent with the FDA approval, for the treatment of cIAI in adults.[45]
• Therapeutic Goods Administration (TGA), Australia: The provided documentation does not contain evidence that Eravacycline has been registered on the Australian Register of Therapeutic Goods (ARTG).[46] In Australia, medicines that are not registered on the ARTG can sometimes be accessed for individual patients through specific pathways, such as the Special Access Scheme (SAS), which is designed to provide access to unapproved therapeutic goods for patients with a clinical need.[46]

7.2 Comparative Assessment and Therapeutic Niche

Eravacycline's place in therapy is defined by its spectrum of activity, its demonstrated efficacy against standard-of-care agents, and its specific limitations.

• Positioning vs. Carbapenems: The successful demonstration of non-inferiority to both ertapenem (IGNITE1) and the broader-spectrum meropenem (IGNITE4) positions Eravacycline as a legitimate and potent alternative for the treatment of cIAI.[11] Its most significant value proposition lies in its role as a carbapenem-sparing agent. In an effort to combat the rise of carbapenem-resistant organisms (CROs), a central goal of antimicrobial stewardship is to reduce the selective pressure exerted by the overuse of carbapenems. Eravacycline provides a non-beta-lactam option with a comparable efficacy profile, allowing clinicians to reserve carbapenems for situations where they are absolutely necessary.[3]
• Positioning vs. Tigecycline: Eravacycline is a fluorocycline and is structurally related to tigecycline, the first-in-class glycylcycline.[8] While both offer a broad spectrum of activity, Eravacycline may hold advantages. A network meta-analysis suggested a significantly better microbiological response rate for Eravacycline compared to tigecycline in cIAI.[10] Furthermore, in vitro data indicates that Eravacycline is two- to eight-fold more potent than tigecycline against certain pathogens like Acinetobacter baumannii.[50] These findings, combined with the absence of the mortality concerns that have been associated with tigecycline, position Eravacycline as a potentially more reliable option within this subclass of tetracyclines.
• Therapeutic Niche: The optimal therapeutic niche for Eravacycline is well-defined by its strengths and weaknesses. It is best suited for the empiric or targeted treatment of moderate-to-severe cIAI in hospitalized adults, particularly in the following scenarios:
• When infections are suspected or confirmed to be caused by multidrug-resistant pathogens, including ESBL-producing Enterobacteriaceae, CRE, MRSA, or VRE.
• As part of a deliberate carbapenem-sparing strategy to promote antimicrobial stewardship.
• In patients with a documented severe beta-lactam allergy (e.g., anaphylaxis) that precludes the use of carbapenems or piperacillin/tazobactam.[42]
• Limitations and Exclusions: The therapeutic role of Eravacycline is equally defined by what it is not suited for. Its lack of reliable activity against P. aeruginosa makes it an inappropriate choice for monotherapy in infections where this pathogen is a significant risk, such as in certain healthcare-associated or post-operative infections.[8] The failure to meet efficacy endpoints in cUTI trials clearly delineates its use for intra-abdominal infections and not for urinary tract infections, a distinction driven by its pharmacokinetic profile.[8] Finally, its class-specific developmental toxicities strictly exclude its use in pregnant women (second and third trimesters) and children under the age of eight.[12] Therefore, its appropriate use requires a precise clinical diagnosis that considers the likely pathogens, the site of infection, and the specific patient population.

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