The present study was conducted among hospitalized patients (>18-years-old) receipt of ≥72 consecutive hours of ERV therapy for infection in participating hospitals from 21 provinces of China during September 2023 to September 2024. The data for this multicenter study were systematically obtained using a standardized “Eravacycline Clinical Application Evaluation Data Collection Form”, which was uniformly used by reporting physicians across all participating centers. This form was specifically designed for this study to ensure consistent and comprehensive data capture across all sites, encompassing key elements such as patient demographics, infection details, microbiological results, treatment regimens, and clinical outcomes.

Patients with multiple pathogens were excluded to avoid confounding variables, ensuring that the observed clinical and microbiological outcomes could be attributed specifically to the treatment of A. baumannii or K. pneumoniae. A total of 1,796 adult patients with A. baumannii (n=1,214) or K. pneumoniae (n=582) infections were included. Infection was defined by physicians according to positive culture, clinical signs, laboratory test results and imaging evidence. To differentiate infection from colonization, we required not only a positive culture but also corresponding clinical symptoms (e.g., fever, purulent sputum), elevated inflammatory markers, and/or radiological evidence of new infiltrates. The following patient characteristics were collected: demographics, underlying conditions, immunosuppressive regimen, recent surgery, medical ventilation, laboratory test results (WBC count, neutrophil count, CRP and PCT) before, at the 3^rd day and the end of treatment, clinical outcomes at the end of treatment, clinical outcomes at day 30. Clinical data were systematically collected by thoroughly reviewing the medical charts that were implemented in the centralized medical software of each hospital. The following microbiological characteristics were recorded: causal pathogen(s), antimicrobial susceptibility testing (AST) by broth microdilution and/or disk diffusion, and microbiological outcomes at the end of treatment (eradication, persistence, relapse with another pathogen). Finally, ERV treatment characteristics were recorded: dose, duration of intravenous infusion and side effects. ChinaCAST recommends that MIC ≤ 1mg/L by broth microdilution or disk diffusion zone diameters ≥15 mm to be considered as susceptible. The MIC values reported in this study were determined quantitatively using the broth microdilution method. 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.

This study was conducted in accordance with the Declaration of Helsinki. Given the retrospective observational nature of the study and the absence of any modification to patient management, the need for informed consent was waived by the ethics committee. All data were anonymized and kept confidential. The study protocol was approved by the Ethics Committee of Peking Union Medical College Hospital (Protocol code I-23ZM0067).

The primary objective consisted of determining the microbiological and clinical outcome at the end of treatment. Microbiological outcomes including eradication, persistence and relapse with another pathogen. For cases who were unable to collect specimen for bacteria culture, clinical outcomes at the end of treatment were analyzed which included clinical resolution (clinical success): defined as complete resolution or significant improvement of clinical signs and symptoms of the index infection; clinical failure: defined as persistence or worsening of signs and symptoms, or the requirement of additional rescue therapy.

Secondary objectives were to determine the clinical outcome at day 30, including infection cure (resolution of all signs and symptoms, normalization of laboratory findings, and confirmed/presumed pathogen eradication), relapse (recurrence of clinical manifestations with abnormal laboratory findings), attributable mortality (death directly related to the index infection) and unattributable mortality (death from unrelated causes during follow-up).

Medians and IQRs are presented for continuous variables. Categorical variables were expressed as % (m/n) and examined using χ²/Fisher’s exact test. P value < 0.05 was considered statistically significant. Multivariable logistic regression models were constructed to identify independent factors associated with the primary composite outcome of treatment failure and with 30-day overall mortality. Variables with a P-value < 0.1 in univariate analysis were included in the initial models. A stepwise selection method was used to retain significant predictors in the final models. Results are presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Statistical analyses were performed and graphs were plotted using R (4.2.1) (https://cran.r-project.org).

A total of 1,796 adult patients (aged over 18 years) from 21 Chinese provinces received ≥72 hours of eravacycline for A. baumannii (n=1,214) or K. pneumoniae (n=582) infections (Table 1). The cohort exhibited male predominance (sex ratio 1.98:1) with a median age of 62 years (IQR 50–74). No intergroup difference was observed in median treatment duration (8 days). Patients with A. baumannii infections had higher rates of ICU admission (63.8% vs 44.2%; P < 0.001) and mechanical ventilation (60.0% vs 46.4%; P < 0.001), whereas K. pneumoniae infections were associated with greater hematological comorbidities (25.8% vs 11.0%; P < 0.001) and neutropenia (20.6% vs 10.7%; P < 0.001).

The distribution of infection types reflected the distinct epidemiological profiles of each pathogen. Pneumonia was the predominant manifestation for A. baumannii, occurring in 91.7% (1,113/1,214) of cases. The high acuity of these respiratory infections was underscored by the frequent requirement for ventilatory support including mechanical ventilation, endotracheal intubation, and tracheostomy, which was documented in 82.3% (916/1,113) of A. baumannii pneumonia patients. Conversely, K. pneumoniae infections presented with a broader anatomical distribution. While pneumonia was also common (86.8%, 505/582), a substantial proportion of cases were bloodstream infections (16.7%, 97/582). Among patients with K. pneumoniae pneumonia, 67.9% (343/505) required ventilatory support.

Differences were also observed in treatment patterns. Prior to eravacycline initiation, 48.6% of patients with K. pneumoniae infections had received pretreatment antimicrobial therapy, with carbapenems (29.6%) and ceftazidime-avibactam (8.1%) being notable exposures. In comparison, the pretreatment exposure rate was 40.2% in the A. baumannii group, where carbapenem use was documented in 23.9% of cases and ceftazidime-avibactam in 3.0%. During eravacycline treatment, concomitant antibiotic therapy was employed in 27.8% of A. baumannii infections, predominantly with polymyxins (19.4%). This practice was less frequent in K. pneumoniae infections, where 19.2% of patients received concomitant therapy, most commonly involving polymyxins (12.4%).

According to the information uploaded by participating hospitals, the antimicrobial susceptibility profiles of ERV (N = 1,070), tigecycline (N = 1,398), imipenem (N = 1,023), meropenem (N = 1,014) and colistin (N = 1,143) were summarized in Table 2. Eravacycline demonstrated high activity against both pathogens (overall susceptibility 96.0%, 1,027/1,070), with significantly higher susceptibility for A. baumannii versus K. pneumoniae (96.9% vs 93.8%; P = 0.023). In contrast, tigecycline susceptibility was substantially lower (75.8%, 1,060/1,398).

Comparative MIC analysis of 551 isolates with MIC for both ERV and tigecycline revealed 4-fold lower geometric mean MICs for eravacycline versus tigecycline against both A. baumannii (0.588 vs 1.993 μg/mL; P < 0.001) and K. pneumoniae (0.675 vs 1.892 μg/mL; P < 0.001) (Figure 1). Notably, 66.7% (16/24) of tigecycline-resistant A. baumannii and 82.4% (14/17) of K. pneumoniae isolates remained eravacycline-susceptible (Table 2).

Carbapenem non-susceptibility was prevalent: Only 5.1% (35/687) of A. baumannii and 16.1% (54/336) of K. pneumoniae isolates were imipenem-susceptible. Eravacycline maintained ≥96.9% susceptibility against carbapenem-resistant strains (Table 2). Colistin susceptibility was 90.6% (1,036/1,143), with eravacycline retaining activity against 86.7% (26/30) of colistin-resistant A. baumannii and 88.0% (22/25) of K. pneumoniae.

At end of treatment (EOT), microbiological outcomes were assessed in 1,037 patients. Overall microbiological eradication was 76.1% (789/1,037). Microbiological persistence occurred in 9.4% (97/1,037) and relapse in 14.6% (151/1,037) (Supplementary Table 1). Among 759 patients without EOT microbiological cultures, clinical cure was achieved in 91.4% (694/759). Composite treatment failure (microbiological persistence/relapse or clinical failure) occurred in 17.4% (313/1,796) of the cohort. Treatment failure was associated with elevated inflammatory markers: Failure cases exhibited significantly higher WBC, neutrophil counts, CRP, and PCT levels at day 3 and EOT versus success cases (P < 0.05; Figure 2). Monotherapy (75.0%, 1,347/1,796) and concomitant therapy (25.0%, 449/1,796) yielded comparable outcomes (Supplementary Table 2).

The microbiological and clinical outcomes of eravacycline therapy, stratified by the primary infection site, are comprehensively detailed in Table 3 and Figure 3A. The analysis across different infection types revealed distinct patterns of treatment efficacy. Pneumonia, being the most common infection in the cohort, demonstrated favorable outcomes with an overall microbiological eradication rate of 76.0% (723/951) at the end of treatment (EOT). Clinical resolution at EOT was achieved in 90.8% (605/666) of assessable pneumonia patients. By day 30, the infection cure rate for pneumonia was 83.6% (1353/1618), with an attributable mortality of 5.6% (91/1618).

For other infection types, the overall EOT microbiological eradication rates were 64.0% (16/25) for lung abscess, 74.5% (114/153) for intra-abdominal infection, 66.0% (103/156) for bloodstream infection, 62.5% (15/24) for urinary tract infection, and 50.0% (2/4) for central nervous system infection. The corresponding day 30 infection cure rates for these infection types were 92.0% (46/50), 77.9% (204/262), 70.1% (176/251), 70.5% (31/44), and 62.5% (5/8), respectively. Across all infection types, clinical resolution rates at the end of treatment were consistently high, ranging from 75.0% to 96.0%. The 30-day attributable mortality was lowest in pneumonia (5.6%) and lung abscess (2.0%), and highest in bloodstream infections (11.6%) and central nervous system infections (12.5%).

Among 1,070 cases with available ERV susceptibility data, infections caused by non-susceptible strains (MIC >1 μg/mL) showed a higher rate of treatment failure at the end of treatment (23.26%, 10/43) compared to susceptible strains (12.95%, 133/1027), though this difference did not reach statistical significance (p=0.086) (Table 4 and Figure 3B). Multivariable logistic regression analysis (Supplementary Table 3) identified several independent predictors of early treatment failure. Higher baseline white blood cell (WBC) count was associated with reduced risk (OR 0.95, 95% CI: 0.92–0.98, p<0.001), whereas elevated inflammatory markers, including baseline CRP (OR 1.00, 95% CI: 0.99–1.00, p=0.048) and CRP after 3 days of treatment (OR 1.01, 95% CI: 1.01–1.01, p<0.001), significantly increased the risk of failure. Increased neutrophil counts at day 3 also predicted poorer outcomes (OR 1.04, 95% CI: 1.01–1.07, p=0.018). Clinical interventions influenced outcomes substantially: central venous catheterization (OR 2.15, 95% CI: 1.18–3.90, p=0.012), tracheostomy (OR 2.86, 95% CI: 1.75–4.66, p<0.001), and other indwelling catheters (OR 2.49, 95% CI: 1.27–4.86, p=0.008) were associated with higher failure rates. In contrast, mechanical ventilation (OR 0.52, 95% CI: 0.29–0.93, p=0.029) and arterial catheterization (OR 0.58, 95% CI: 0.34–0.99, p=0.048) appeared protective.

At day 30, the overall cure rate was 83.57% (1501/1,796). Relapse occurred in 4.34% (78/1,796) of cases, and overall mortality was 12.08% (217/1,796), with 5.4% (97/1,796) attributed directly to infection. Infections caused by non-susceptible isolates were associated with significantly lower cure rates (74.4% vs. 87.7%, p=0.04) (Table 4). This association was attenuated and lost statistical independence in the adjusted model (OR 2.73, 95%CI: 0.88-8.45, p=0.082). Multivariable analysis (Supplementary Table 4) indicated that elevated CRP levels at the end of treatment, was the strongest predictor of 30-day failure (OR 1.03, 95% CI: 1.02–1.04, p<0.001). Bloodstream infection (OR 2.41, 95% CI: 1.18–4.93, p=0.016) and sepsis (OR 1.94, 95% CI: 1.01–3.69, p=0.045) were also independent risk factors, nearly doubling the odds of failure. Invasive procedures further modulated outcomes: endotracheal intubation increased risk (OR 2.65, 95% CI: 1.21–5.81, p=0.015), whereas mechanical ventilation was strongly protective (OR 0.27, 95% CI: 0.13–0.58, p<0.001).

Adverse events (AEs) occurred in 41 patients (2.28%, 41/1,796). The most frequent AEs were gastrointestinal disorders (1.11%, 20/1,796) and hepatotoxicity (0.56%, 10/1,796). One patient experienced a severe AE resulting in acute liver injury.