Introduction
Tetracyclines represent a unique class of antibiotics with broad-spectrum activity against both Gram-positive and Gram-negative pathogens.1 In light of the escalating global challenge of antimicrobial resistance, particularly against carbapenem-resistant organisms, substantial research efforts have focused on developing advanced tetracycline derivatives. This has led to the emergence of third-generation tetracyclines, including tigecycline, eravacycline, omadacycline, and sarecycline.2 Among these, tigecycline, as the prototypical glycylcycline, has emerged as a critical therapeutic option for atypical and multidrug-resistant pathogens. However, clinical application of tigecycline is significantly constrained by adverse drug reaction (ADR) including gastrointestinal toxicity (nausea, vomiting, abdominal pain, hepatic transaminitis), hematotoxicity (hypofibrinogenemia, thrombocytopenia), and metabolic disturbances (hypoglycemia).
The occurrence of moderate-to-severe adverse events frequently necessitates treatment discontinuation, thereby significantly constraining tigecycline’s clinical utility despite its important antimicrobial properties.3 Patients who develop tigecycline‑related hematologic adverse events are likely to be sicker, with a higher burden of hepatic and renal impairment, malnutrition, and hypoalbuminemia, and these same factors may influence both treatment choice and outcome.3–5
Omadacycline is a noteworthy addition to the tetracycline class.6 Of note, omadacycline has regulatory approval for community-acquired bacterial pneumonia. However, its real-world use for multidrug-resistant Gram-negative bacterial pneumonia, which is frequently encountered in clinical practice, is often off-label. Its broad-spectrum activity encompasses clinically challenging pathogens including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), β-hemolytic streptococci, and vancomycin-resistant enterococci (VRE).
Pharmacovigilance signals point to potentially reduced coagulation‑related risks for omadacycline, yet direct head‑to‑head trials evaluating hematologic tolerability versus tigecycline are absent.7,8 When tigecycline must be stopped for adverse events in MDR pneumonia, clinical alternatives are limited, but real‑world outcome data for switching to omadacycline in this intolerant subgroup remain scarce. This study was therefore designed to describe the clinical course and outcomes after switching to omadacycline in this tigecycline-intolerant subgroup.
Methods
Study Design and Participants
This single-center, retrospective observational study evaluated the clinical efficacy and safety of omadacycline as an alternative therapy for patients with tigecycline-intolerant pneumonia at Beijing Hospital in China, between Jan 1, 2023, and May 31, 2025. The study protocol received ethical approval from the Beijing Hospital Ethics Committee (2025BJYYEC-KY245-01) and complied with Declaration of Helsinki principles.
We identified all hospitalized adults (≥18 years) with pneumonia who were administered tigecycline. Among them, those who switched to omadacycline because of documented intolerance constituted the primary study cohort. A control group was formed from patients who continued tigecycline without switching.
Tigecycline intolerance was defined as the occurrence of an adverse drug reaction (ADR) that led to tigecycline discontinuation. The exclusion criteria were as follows: (1) absence of crucial data; (2) insufficient information to determine clinical efficacy.
Pneumonia was diagnosed when a patient had at least two clinical features (fever, cough, purulent sputum, dyspnea, or abnormal breath sounds), together with new or progressive infiltrates on chest imaging and supporting laboratory findings. Confirmed MDR bacterial pneumonia required compatible clinical-radiographic features plus microbiological identification of a pathogen non-susceptible to at least one agent in ≥3 antimicrobial classes. Suspected MDR bacterial pneumonia required compatible clinical-radiographic features plus high epidemiologic risk for MDR pathogens (prior intravenous antibacterial exposure within 90 days, prior documented MDR colonization or infection, hospitalization for ≥5 days, mechanical ventilation, or septic shock), prompting empirical anti-MDR therapy without microbiological confirmation.
Colonization was distinguished from infection by the treating clinician based on clinical signs, inflammatory markers, and culture context.
Time zero was defined as the date of tigecycline initiation for both groups. For the switch group, the timing of tigecycline initiation, ADR onset, tigecycline discontinuation, and omadacycline initiation was recorded. Clinical effectiveness was assessed at the end of treatment for both groups.
Data Collection and Outcome Definitions
Patient data were retrospectively extracted from the hospital’s electronic medical records system, including: (1) demographic characteristics (age, gender, underlying comorbidities, CURB-65 score (Confusion, Urea nitrogen, Respiratory rate, Blood pressure, age ≥65 years), and clinical outcomes; (2) microbiological results (specimen type, identified pathogens, and antimicrobial susceptibility profiles); (3) treatment details of both TGC and OMC regimens (dosage, duration, concomitant medications, and clinical outcome); and (4) specific adverse drug reactions to TGC that prompted the switch to OMC, including their severity grading and subsequent management approaches.
ADR was defined and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 developed by the National Cancer Institute (NCI).9 The coagulation disorders assessed in this study included decreased fibrinogen levels, elevated international normalized ratio (INR), prolonged prothrombin time (PT), and prolonged activated partial thromboplastin time (APTT). Causality between tigecycline and each reported adverse event was assessed using the Naranjo Adverse Drug Reaction Probability Scale.10 Only events with a score of ≥5 (probable or definite) were included as tigecycline-related ADRs.
Clinical outcomes were defined as clinical effective or ineffective. The effective category required: (1) complete resolution or clinically significant improvement of infection-related signs and symptoms; (2) normalization or substantial improvement in laboratory parameters and radiographic findings; and (3) either successful antimicrobial de-escalation or no need for additional antibiotic therapy. Clinically significant improvement was defined as clear improvement of infection-related signs and symptoms together with improvement in laboratory parameters or radiographic findings.
Ineffective was considered when the efficacy criteria were not satisfied or were indeterminate for any reason. Clinical effectiveness was assessed retrospectively at the end of treatment by two clinicians, with the identical assessment time window applied for both groups. Blinding to treatment group was not feasible, as the assessment was based on review of electronic medical records.
Statistical Analysis
Continuous data with normal distribution were expressed as mean ± standard deviation (mean ± SD), and categorical data were presented using frequencies and percentages. For comparisons between patients who switched to omadacycline and those who were not, we employed independent samples t-tests (for continuous variables) or Chi-square tests (for categorical variables). Paired t-tests were used for within-group comparisons of treatment duration in the switch group.
Propensity score matching (PSM) was performed at a 1:5 ratio without replacement, where each patient in the omadacycline-switch group was matched to up to five controls using the closest propensity score. A caliper value of 0.2 was set to ensure the quality of matching. The propensity score model included age, sex, and CURB-65 score.
Hepatic disease, renal disease, malnutrition, and hypoalbuminemia were not included because adding them compromised the balance of CURB-65, a core prognostic factor. We then compared the standardized mean differences (SMD) of covariates between groups before and after matching to assess balance. Covariate balance was considered adequate when SMD < 0.1.
After matching, the efficacy rates between the two groups were compared using Fisher’s exact test, because of the small sample size and low event counts in the matched sample. A P-value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software, version 27.0.
Results
Demographic and Clinical Characteristics
During the study period, a total of 694 adult patients received tigecycline during hospitalization. Of these, 32 (4.6%) were switched to omadacycline due to adverse events. After applying the exclusion criteria, 26 patients formed the study cohort, while the remaining 622 patients constituted the final control group, as shown in Figure 1.
The two groups were compared in Table 1. Comparative analysis revealed that the omadacycline-switch cohort had a significantly higher burden of major comorbidities, including hepatic dysfunction, renal impairment, malnutrition, and hypoalbuminemia.Table 1Comparison of Baseline Characteristics Between Omadacycline-Switch and Tigecycline GroupsCharacteristicsOmadacycline-Switched Group (n=26)Tigecycline Group (n=622)χ2/t StatisticP-ValueSex, Male18 (69.2%)390 (62.7%)0.4560.499Age (year)74.1±11.870.7±15.41.1220.262CURB-65 score ≥313 (50.0%)142 (22.8%)10.1240.001Weighta, kg66.9 ± 10.966.4 ± 14.90.1540.877Bedridden (%)5 (19.2%)198 (31.8%)1.8420.175Comorbidities Hepatic disease20 (76.9%)321 (51.6%)6.4150.011 Renal disease19 (73.1%)303 (48.7%)5.9260.015 Malnutrition16 (61.5%)199 (32.0%)9.8260.002 Hypoalbuminemia24 (92.3%)379 (60.9%)10.4480.001Notes: Data are presented as mean (standard deviations) or n (%). χ2, chi-square test; t, independent-samples t-test. aWeight data were available for 21 cases in the study group and 424 cases in the controls.Figure 1Study profile. Flow diagram showing patient screening, exclusion, and the final study and control groups.Flowchart sequence: Hospitalized adults, greater than or equal to 18 years, treated with tigecycline from Jan 1, 2023, to May 31, 2025; 32 patients switched to omadacycline due to tigecycline intolerance; absence of crucial data; indeterminate causality for omadacycline transition; inability to determine treatment efficacy; 26 omadacycline users; 26 omadacycline users after 1 colon 5 propensity score matching; 662 patients continued tigecycline without switching during hospitalization; absence of crucial data; inability to determine treatment efficacy; 622 controls; 492 not matched; 130 controls after 1 colon 5 propensity score matching.Flowchart sequence: hospitalized adults, switch to omadacycline, continue tigecycline, matching outcomes.
All patients received tigecycline according to the manufacturer’s recommended dosing regimen, consisting of a 100 mg loading dose followed by 50 mg every 12 hours. Within three days after tigecycline discontinuation, all patients were switched to omadacycline therapy, administered as a 200 mg loading dose on Day 1, followed by 100 mg once daily. Most patients received tigecycline or omadacycline in combination with other antimicrobial agents.
The average duration of omadacycline treatment was longer than that of tigecycline (10.8±6.2 days vs 7.6±5.2 days, P=0.048).
Table 2 summarizes the infection characteristics of the 26-patient cohort. Carbapenem-resistant Enterobacteriaceae (CR-KP) and Acinetobacter baumannii (CR-AB) were the predominant isolated bacteria. Tigecycline susceptibility was 70.6% (12/17), with 29.4% (5/17) exhibiting intermediate resistance.Table 2Infection Profiles and Pathogen DistributionCharacteristicsNumberSpecimen typea Sputum (culture)6 Sputum (mNGS)1 BALF (culture)9 BALF (mNGS)3 Lung aspirate (culture)1 Blood (culture)3 Blood (mNGS)2Identified bacteria CR-KP12 CR-AB12 Others4Tigecycline susceptibilityb Susceptible12 Intermediate5 Resistant0Notes: aThree patients received empirical anti‑MDR therapy without microbiological pathogen confirmation. bTigecycline susceptibility was tested in 17 cases, while omadacycline was not routinely tested due to undefined CLSI breakpoints for most Gram-negative bacilli.Abbreviations: BALF, bronchoalveolar lavage fluid; mNGS, metagenomic next-generation sequencing; CR-KP, carbapenem-resistant Klebsiella pneumoniae; CR-AB, carbapenem-resistant Acinetobacter baumannii; MRSA, Methicillin-resistant Staphylococcus aureus.
Safety
Tigecycline-induced ADRs were systematically monitored and analyzed (Table 3). Moderate to severe ADRs (Grade ≥3) occurred in 46.2% (12/26) of patients. The predominant ADR was hypofibrinogenemia, occurring in 61.5% (16/26) of patients, followed by thrombocytopenia (42.3%, 11/26) and prolonged PT/APTT (26.9%, 7/26).
Notably, 65.4% (17/26) of patients experienced two or more concurrent ADRs. A total of 49 ADR events were recorded, with coagulation disorders representing the majority (55.1%, 27/49), including decreased fibrinogen levels (16 cases), elevated INR (4 cases), and prolonged PT/APTT (7 cases).Table 3Adverse Drug Reactions Before and After Switching from Tigecycline to OmadacyclineVariablesTigecyclineOmadacyclineNumber of ADRs per patient 192 212 ≥35ADR Severity Grade 171 Grade 27 Grade 3–5121Therapeutic intervention for ADR191ADR Manifestations Nausea/vomit61 Blood fibrinogen decreased16 Elevated INR4 Prolonged PT/APTT7 Platelet count decreased11 Hepatic aminotransferase increase11 Blood bilirubin increased3 Kidney function abnormalities1 Total492Abbreviations: ADR, adverse drug reaction; INR, international normalized ratio; PT, prothrombin time; APTT, activated partial thromboplastin time.
The primary reason for tigecycline discontinuation was hypofibrinogenemia (61.5%, 16/26), followed by thrombocytopenia (19.2%, 5/26), gastrointestinal disturbances (11.5%, 3/26), and other adverse events (7.7%, 2/26). Following the transition to omadacycline therapy, complete resolution of ADRs was achieved in 61.5% (16/26) of cases. The remaining patients demonstrated partial improvement (15.4%), no significant change (19.2%), or symptom exacerbation (3.8%).
2 patients (7.7%) experienced new-onset adverse effects during omadacycline treatment: one case of mild nausea and one instance of elevated hepatic transaminases. Both cases were managed without treatment discontinuation.
Efficacy
To compare therapeutic efficacy, a 1:5 propensity score matching was performed between the study and control groups based on age, sex, and CURB-65 score. After matching, the analysis included 26 patients in the study group and 130 matched controls, with all standardized mean differences (SMDs) below 0.1, indicating well-balanced covariates (Table 4). Notably, before matching, the study group had a significantly higher proportion of patients with CURB-65 ≥3 than the control group (50.0% vs 22.8%, P=0.001).
Following matching, clinical effectiveness rates were 53.8% (14/26) in the study group and 61.5% (80/130) in the matched controls (OR, 0.729; 95% CI, 0.312–1.703; P=0.514), with no statistically significant difference between groups.Table 4Baseline Characteristics Before and After Propensity Score MatchingCharacteristicsStudy Group (n=26)Before MatchingAfter MatchingControls (n=622)SMDP-ValueControls (n=130)SMDP-ValueSex, Male18 (69.2%)390 (62.7%)0.1380.49992 (70.8%)0.0340.875Age (year)74.1±11.870.7±15.40.2500.26273.6±13.30.0440.839CURB-65 score≥313 (50.0%)142 (22.8%)0.5890.00160 (46.2%)0.0770.720<313 (50.0%)480 (77.2%)70 (53.8%)Notes: Categorical data are presented as n (%); Continuous data are presented as mean ± standard deviation.Abbreviation: SMD, Standardized mean difference.
Discussion
Tigecycline and omadacycline share structural similarities and exhibit comparable antibacterial spectra and clinical indications. Tigecycline is characterized by a glycylamide moiety at the 9-position of the tetracycline ring, a unique structural feature not found in any naturally occurring or semi-synthetic tetracycline. In contrast, omadacycline incorporates an alkylaminomethyl group at the C-9 position of the D-ring.11 Tigecycline received FDA approval in 2005, followed by omadacycline in October 2018.6 Both antibiotics are indicated for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP), with tigecycline additionally approved for complicated intra-abdominal infections (CIAI).
These agents are active against a broad range of Gram-positive and Gram-negative, aerobic, anaerobic, and atypical pathogens.11,12 The main contribution of this study is a real-world description of the clinical course after switching to omadacycline in tigecycline-intolerant patients.
Omadacycline demonstrates comparable in vitro activity to tigecycline against resistant Gram-positive pathogens.1,7,13,14 Omadacycline exhibits comparable antimicrobial activity to tigecycline against Gram-positive pathogens, including MRSA, VRE, and PRSP, with both agents showing MIC90 values ≤0.5 mg/L. While tigecycline shows lower MIC90 values against Gram-negative organisms including Escherichia coli, Enterobacter species, Klebsiella pneumoniae, and Acinetobacter baumannii, susceptibility interpretation remains challenging due to the absence of Clinical and Laboratory Standards Institute (CLSI) breakpoints for omadacycline against these strains.1 Employing Food and Drug Administration (FDA)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria, a study reported that omadacycline indicated susceptibility rates of 70%–96% against major resistant Gram-negative strains.15 Chinese surveillance data confirm these findings, showing similar susceptibility patterns among clinical isolates. Importantly, omadacycline retains partial activity against some tigecycline-nonsusceptible Gram-positive strains.16
Phase III clinical trials have shown that tigecycline is non-inferior to levofloxacin in community-acquired bacterial pneumonia and to vancomycin/aztreonam in acute bacterial skin and skin structure infections, while omadacycline is non-inferior to moxifloxacin in community-acquired bacterial pneumonia and to linezolid in acute bacterial skin and skin structure infections.17–20 These trials compared each agent with its own comparator and did not compare omadacycline directly with tigecycline. In our study, after 1:5 propensity score matching based on age, sex, and CURB-65 score, clinical effectiveness was 53.8% in the omadacycline-switch group and 61.5% in the tigecycline-only group (OR 0.729, 95% CI 0.312–1.703; P = 0.514). Matching on additional clinical parameters was not feasible due to sample size constraints, and residual confounding cannot be excluded.
In phase III clinical trials, both drugs most commonly caused gastrointestinal adverse effects: tigecycline was associated with nausea (26%), vomiting (18%), and diarrhea (12%), while omadacycline showed lower rates of nausea (15%), vomiting (8%), and diarrhea (2%).21,22 Furthermore, omadacycline’s gastrointestinal effects were primarily observed during the high-dose oral loading period (450 mg) in the first two days of the OASIS-2 study, with rates similar to comparators in the IV-to-oral OPTIC trial at standard doses.18,20 Both drugs share other adverse effects including central nervous system impairment, metabolic and nutritional disorders, hepatotoxicity, urinary system damage, and respiratory system injury.7,23,24 Regarding treatment discontinuation due to adverse events, tigecycline showed a 7% discontinuation rate (versus 6% for comparators), while omadacycline demonstrated discontinuation rates of 5.5% in CABP (versus 7.0% for comparators) and 1.7% in ABSSSI (versus 1.5%).21,25 These trial data are not from a direct comparison between omadacycline and tigecycline. In our cohort, patients in the omadacycline group had pre-existing tigecycline intolerance, so the two groups are not directly comparable for safety. Hematologic adverse event improvement after switching therefore reflects the clinical course after tigecycline discontinuation.
This study identified hypofibrinogenemia as the predominant adverse event leading to tigecycline discontinuation, occurring in 61.5% of cases. Although hematotoxicity showed a relatively low incidence in pre-marketing clinical trials, post-marketing pharmacovigilance data have established tigecycline-associated coagulation disorders as a significant clinical concern. Accumulating evidence indicates that tigecycline administration frequently induces reversible coagulopathies, characterized primarily by marked reductions in fibrinogen levels and secondary prolongation of APTT and PT.26 A comprehensive pharmacovigilance analysis of tetracycline-class antibiotics utilizing the FAERS database (n=15,020 reports) revealed the following reporting distribution: doxycycline (64.19%), minocycline (24.37%), tigecycline (9.60%), omadacycline (1.19%), sarecycline (0.48%), and eravacycline (0.17%).8 For tigecycline, the most frequently reported adverse events were decreased blood fibrinogen (including hypofibrinogenemia) and elevated bilirubin, followed by thrombocytopenia, elevated liver enzymes, and septic shock.
In contrast, omadacycline adverse event reports primarily involved medication administration errors (improper indications, dosing, or duration) and gastrointestinal disturbances (nausea/vomiting).
The reported incidence of tigecycline-induced hypofibrinogenemia ranges from 42.6% to 60.8% in contemporary literature.27 Our study cohort demonstrated a significantly higher prevalence of predisposing comorbidities, including hepatic/renal impairment, malnutrition, and hypoalbuminemia, all established risk factors for coagulation disorder.4,28 From a clinical perspective, coagulation disorders present a more severe adverse effect profile than gastrointestinal disturbances due to their potential for life-threatening hemorrhagic complications. Therapeutic evaluation of conventional coagulation support strategies, including vitamin K1 administration, fresh frozen plasma/cryoprecipitate transfusion, and fibrinogen concentrate supplementation, revealed no significant impact on fibrinogen level.4 These findings strongly support current clinical consensus that prompt discontinuation of tigecycline represents the optimal therapeutic approach upon detection of hypofibrinogenemia. Consequently, for cases of moderate-to-severe hypofibrinogenemia, switching to alternative antimicrobial agents with a lower potential for coagulopathy is strongly recommended as a management strategy.
In this study, thrombocytopenia emerged as the second most frequent indication for transition, accounting for 19.2% of cases. Our previous investigations into tigecycline-induced thrombocytopenia revealed a pattern similar to that observed with hypofibrinogenemia, while conventional interventions (including platelet transfusions, corticosteroids, intravenous immunoglobulin, plasma exchange, and anti-Rh immune globulin) have demonstrated variable efficacy, the cessation of tigecycline therapy consistently emerges as the most reliable strategy.5,29
During the observation period, complete or partial recovery of adverse drug reactions occurred in 77% of patients following tigecycline discontinuation, while the remaining 23% demonstrated either static or progressive symptoms. Although the subsequent initiation of omadacycline therapy introduces potential confounding in attributing ADR resolution causally, multiple lines of evidence implicate tigecycline as the primary causative agent for persistent adverse effects. Ma et al documented that 24.3% of patients with tigecycline-induced hypofibrinogenemia failed to achieve recovery of fibrinogen levels after drug discontinuation.27 Our prior study on tigecycline-associated thrombocytopenia yielded similar results, with only 54.3% of patients achieving complete platelet count recovery at discharge.5 Comprehensive pharmacovigilance data have consistently shown minimal hematologic toxicity associated with omadacycline.
These findings strongly suggest that the observed irreversible ADRs are more likely attributable to tigecycline’s persistent hematotoxicity rather than subsequent omadacycline therapy. One hypothesis is that the delayed recovery patterns may reflect sustained bone marrow suppression related to tigecycline; this remains speculative and requires further mechanistic investigation.
This study had several limitations. First, the retrospective design carries risks of selection bias and incomplete data collection. Second, the omadacycline group was small (n=26), representing only 4.6% of tigecycline-treated patients, which limited statistical power and resulted in wide confidence intervals.
Third, several baseline comorbidities (hepatic disease, renal disease, malnutrition, and hypoalbuminemia) remained imbalanced after PSM, and residual confounding from pathogen distribution, infection severity, ICU/mechanical ventilation status, and concomitant antimicrobial therapy cannot be excluded. Clinical effectiveness was also assessed by non-blinded clinicians, which may have introduced assessment bias. Fourth, immortal-time bias cannot be fully excluded, although time zero was aligned to tigecycline initiation in both groups.
Fifth, we lacked bacterial susceptibility data for omadacycline, and current CLSI guidelines have not established definitive breakpoints for this agent against certain Gram-negative pathogens. Finally, this was a single-institution study, which may limit generalizability. These limitations highlight the need for prospective, multicenter studies to better characterize the course of tigecycline-associated coagulopathies after switching to omadacycline.
Conclusions
In conclusion, among tigecycline-intolerant patients with pneumonia, switching to omadacycline was associated with improvement or resolution of most pre-existing tigecycline-related hematologic adverse events, and there was no statistically significant difference in clinical effectiveness compared with tigecycline-treated controls. These findings are observational and hypothesis-generating, and prospective, multicenter studies are needed to confirm them.