Search Results (984)

Although acetaminophen (APAP) overdose represents the predominant cause of drug-induced acute liver failure (ALF) worldwide and has been extensively studied, the modes of cell death remain debatable and the treatment approach for APAP-induced acute liver failure is still limited. This study investigated the mechanisms of APAP hepatotoxicity in primary mouse hepatocytes (PMHs) by using integrated methods (MTT assay, HPLC analysis for glutathione (GSH), Calcein-AM for labile iron pool detection, confocal microscopy for lipid peroxidation and mitochondrial superoxide measurements, electron microscopy observation, and Western blot analysis for ferritin), focusing on the role of iron dysregulation under oxidative stress. Our results showed that 20 mM APAP treatment induced characteristic features of ferroptosis, including GSH depletion, mitochondrial dysfunction, and iron-dependent lipid peroxidation. Further results showed significant ferritin degradation and subsequent iron releasing. Iron chelator deferoxamine (DFO) and N-acetylcysteine (NAC) could alleviate APAP-induced hepatotoxicity, while autophagy inhibitors did not provide a protective effect. In vitro experiments confirmed that hydrogen peroxide directly damaged ferritin structure, leading to iron releasing, which may aggravate iron-dependent lipid peroxidation. These findings provide evidence that APAP hepatotoxicity involves a self-amplifying cycle of oxidative stress and iron-mediated oxidative damaging, with ferritin destruction playing a key role as a free iron source. This study offers new insights into APAP-induced liver injury beyond conventional cell death classifications, and highlights iron chelation as a potential therapeutic strategy alongside traditional antioxidative treatment with NAC. Full article

Ceftazidime–avibactam (CAZ-AVI) is a second-generation intravenous β-lactam/β-lactamase inhibitor combination. In recent years, substantial evidence has emerged regarding the efficacy and safety of CAZ-AVI. However, data on its use in critically ill patients remain limited. Background/Objectives: This multicenter, retrospective, observational cohort study was conducted across four Intensive Care Units (ICUs) in three hospitals in the Marche region of Italy. The primary objective was to evaluate the 30-day clinical outcomes and identify risk factors associated with 30-day clinical failure—defined as death, microbiological recurrence, or persistence within 30 days after discontinuation of therapy—in critically ill patients treated with CAZ-AVI. Methods: The study included all adult critically ill patients admitted to the participating ICUs between January 2020 and September 2023 who received CAZ-AVI for at least 72 h for the treatment of a confirmed or suspected Gram-negative bacterial (GNB) infection. Results: Among the 161 patients included in the study, CAZ-AVI treatment resulted in a positive clinical outcome (i.e., clinical improvement and 30-day survival) in 58% of cases (n = 93/161), while the overall mortality rate was 24% (n = 38/161). Relapse or persistent infection occurred in a substantial proportion of patients (25%, n = 41/161). Notably, acquired resistance to CAZ-AVI was observed in 26% of these cases, likely due to suboptimal use of the drug in relation to its pharmacokinetic/pharmacodynamic (PK/PD) properties in critically ill patients. Furthermore, treatment failure was more frequent among immunosuppressed individuals, particularly liver transplant recipients. Conclusions: This study demonstrates that the mortality rate among ICU patients treated with this novel antimicrobial combination is consistent with findings from other studies involving heterogeneous populations. However, the rapid emergence of resistance underscores the need for vigilant surveillance and the implementation of robust antimicrobial stewardship strategies. Full article

Cardiorenal syndrome (CRS) is a term used to describe the combined dysfunction of the heart and kidneys. This complex disorder is widely acknowledged to be challenging in both its diagnosis and management, and this is the case particularly in the elderly population, due to multi-morbidity, polypharmacy, and age-related physiological changes. Given advancements in medicine and more prolonged cumulative exposure to risk factors in the elderly population, it is likely that the prevalence of chronic kidney disease (CKD) and heart failure (HF) will continue to rise going forward. Hence, understanding the mechanisms involved in the development of CRS is paramount. There are five different CRS types—they are categorised depending on the primary organ involved the acuity of disease. The pathophysiological process behind CRS is complex, involving the interplay of many processes including hemodynamic changes, neurohormonal activation, inflammation, oxidative stress, and endothelial dysfunction and vascular stiffness. The numerous diagnostic and management challenges associated with CRS are significantly further exacerbated in an elderly population. Biomarkers used to aid the diagnosis of CRS, such as serum creatinine and brain natriuretic peptide (BNP), can be challenging to interpret in the elderly population due to age-related renal senescence and multiple comorbidities. Polypharmacy can contribute to the development of CRS and therefore, before initiating treatment, coordinating a patient-centred, multi-speciality, holistic review to assess potential risks versus benefits of prescribed treatments is crucial. The overall prognosis of CRS in the elderly remains poor. Treatments are primarily directed at addressing the sequelae of the underlying aetiology, which often involves the removal of fluid through diuretics or ultrafiltration. Careful considerations when managing elderly patients with CRS is essential due to the high prevalence of frailty and functional decline. As such, in these patients, early discussions around advance care planning should be prioritised. Full article

Background/Objectives: Anti-tumour necrosis factor (anti-TNF) medications were historically commonly prescribed as the first-line biologic treatment for chronic inflammatory pouch conditions. However, their use in these conditions is mainly based on retrospective studies of relatively small numbers of patients with short follow up periods. We aimed to describe the long-term outcomes of first-line anti-TNF therapy in a large, multi-centre, multi-national patient cohort with chronic inflammatory pouch conditions. Methods: This was an observational, retrospective, multi-centre, multi-national study. We included patients with chronic inflammatory pouch conditions initially treated with anti-TNF drugs infliximab (IFX) or adalimumab (ADA), who had a follow up of at least 1 year. The primary outcome was anti-TNF treatment persistence, defined as continuation of anti-TNF throughout the study period. The secondary outcome was pouch failure, defined by the need for a defunctioning ileostomy or pouch excision. Results: We recruited 98 patients with chronic inflammatory pouch conditions initially treated with anti-TNF medications—63 (64.3%) treated with IFX and 35 (35.7%) treated with ADA. Average follow up length was 94.2 months (±54.5). At the end of the study period only 22/98 (22.4%) patients were still on anti-TNF treatment. In those in whom the first-line anti-TNF was discontinued, the median time to discontinuation was 12.2 months (range 5.1–26.9 months). The most common cause for anti-TNF discontinuation was lack of efficacy despite adequate serum drug levels and absence of anti-drug antibody formation (30 patients, 30.6%). Loss of response due to anti-drug antibody formation was the cause for discontinuation in 18 patients (18.4%), while 12 patients (12.2%) stopped treatment because of adverse events or safety concerns. Out of the 76 patients discontinuing anti-TNF treatment, 34 (34.7% of the cohort) developed pouch failure, and 42 (42.8% of the cohort) are currently treated with a different medical therapy. Conclusions: First-line anti-TNF therapy for chronic pouch inflammatory conditions is associated with low long-term persistence rates. This is due to a combination of lack of efficacy and adverse events. A significant percentage of patients initially treated with anti-TNF therapy develop pouch failure. Full article

Background: The development of brain metastases (BM) is a relatively uncommon but significantly adverse event in the spread of colorectal cancer (CRC). Although management of CRC BM has improved with advances in imaging and systemic therapies, clinical outcomes remain poor. Methods: This retrospective cohort study used the U.S. National Cancer Database to evaluate survival outcomes, treatment patterns, and prognostic factors in CRC patients diagnosed with BM between 2010 and 2020. Patients with isolated brain-only metastases formed the primary analytic cohort, while those with additional extracranial metastases were included for descriptive comparison. Multivariable Cox proportional hazards and logistic regression models were used to assess factors associated with of survival. Proportional hazards assumptions were tested using Schoenfeld residuals. Accelerated failure time models were also employed. Results: From a cohort of 1,040,877 individuals with CRC, 795 had metastatic disease present along with relevant data, of which 296 had isolated BM. Median overall survival (mOS) in BM-only metastatic disease group was 7.82 months (95% CI: 5.82–9.66). The longest survival was observed among patients treated with stereotactic radiosurgery combined with systemic therapy (SRS+Sys), with a median OS of 23.26 months (95% CI: 17.51–41.95) and a 3-year survival rate of 35.8%. In adjusted Cox models, SRS, systemic therapy, and definitive surgery of the primary site were each independently associated with reduced hazard of death. Rectal cancer patients had longer survival than those with colon primaries (mOS: 10.35 vs. 6.08 months). Age, comorbidity burden, and insurance status were not associated with survival in adjusted analyses. Conclusions: SRS+Sys was associated with longer survival compared to other treatment strategies. However, treatment selection is highly dependent on individual clinical factors such as performance status, comorbidities, and disease extent; therefore, these findings must be interpreted with caution Future prospective studies incorporating molecular and biomarker data are warranted to better guide care in this rare and high-risk group. Full article

Introduction: The World Health Organization has declared carbapenem-resistant organisms a research and development priority. Although ceftazidime–avibactam was approved around a decade ago, there is still a lack of prospective data on the treatment of resistant pathogens with this agent. Methods: We conducted a prospective, observational, single-center, investigator-initiated study of patients treated with ceftazidime–avibactam for infections caused by carbapenem-resistant organisms. The primary outcome was clinical cure 14 days after the initiation of ceftazidime-avibactam treatment. Secondary outcomes, which were assessed on day 30, included microbiological failure, development of resistance, all-cause mortality, and length of stay in the intensive care unit. Results: A total of 50 patients were included in the study. At baseline, the median Charlson Comorbidity Index and Sequential Organ Failure Assessment Score were 5.5 and 7. Approximately three-quarters of the patients were treated in an intensive care unit and had undergone mechanical ventilation within the previous 7 days prior to the commencement of ceftazidime–avibactam treatment. Half of the patients were diagnosed with nosocomial pneumonia. Most infections were caused by Pseudomonas aeruginosa (48%) and Klebsiella pneumonia (28%). Clinical cure at day 14 was achieved in 59% of patients. Four deaths (9%) and two cases of microbiological failure (4%) were observed. The median length of stay in the intensive care unit was 14 days. There was no emergence of resistance to ceftazidime–avibactam. Discussion: Our study contributes to the growing body of evidence supporting the effectiveness of ceftazidime–avibactam in treating infections caused by carbapenem-resistant organisms. In this cohort of critically ill patients, our results in terms of both clinical success and survival are in the upper range compared to those from mainly retrospective and some prospective studies. Although the benefits of ceftazidime–avibactam have been demonstrated in this and other studies, it must be prescribed cautiously to ensure it remains effective. Full article

The study investigates the influence of microstructures on fatigue behavior and failure mechanisms of the α-β titanium alloy Ti6246, fabricated via Powder Bed Fusion-Laser Beam (PBF-LB). In particular, the investigation assesses the effect of two post-processing heat treatments, namely α-β annealing at 875 °C (AN875) and solution treatment at 825 °C followed by aging at 500 °C (STA825), on the alloy’s rotating and bending fatigue behavior. The results indicate that the STA825 condition provides superior fatigue resistance (+25%) compared to AN875, due to the presence of a finer bilamellar microstructure, characterized by thinner primary α lamellae (α_p) and a more homogeneous distribution of secondary α lamellae (α_s) within the β matrix. Additionally, an investigation conducted using the Kitagawa–Takahashi (KT) approach and the El-Haddad model, based on the relationship between the fatigue limit and defect sensitivity, revealed improved crack propagation resistance from pre-existing defects (ΔK_th) for the STA825 condition compared to AN875. Notably, the presence of fine α_s after aging for STA825 is effective in delaying crack nucleation and propagation at early stages, while refined α_p contributes to hindering macrocrack growth. The fatigue behavior of the STA825-treated Ti6246 alloy was even superior to that of the PBF-LB-processed Ti64, representing a viable alternative for the production of high-performance components in the automotive and aerospace sectors. Full article

The electrical ventricular storm (VES) is defined as multiple sustained ventricular arrhythmias arising in a short time, often refractory to standard antiarrhythmic treatment. The three pillars of the physiopathogenesis of the VES are autonomic dysfunction, triggers, and an altered ventricular substrate. Incessant or highly recurrent ventricular arrhythmia impacts the hemodynamic status by worsening heart failure and increasing mortality. A stepwise, team-based, and tailored therapeutic approach is required to stop ventricular arrhythmia and regain the hemodynamic and electric stability of the patient. The authors focused on describing all currently available therapeutic approaches for VES, intending to establish the best VES therapeutic approaches. This process involves considering the patient’s specific condition, responses to previous treatments, and the potential risks and benefits of each approach. The options range from adjusting antiarrhythmic therapy to reprogramming of the ICD, sedation, epidural anaesthesia, stellate ganglia anaesthetic block, and the use of ECMO or left ventricular assist devices and radiofrequency catheter ablation. Particular attention is paid to the detailed management of genetic primary arrhythmia syndromes like long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome and Wolff–Parkinson–White syndrome, early repolarisation syndrome, right ventricular arrhythmogenic dysplasia, and idiopathic ventricular fibrillation. After overcoming the acute events of VES and obtaining hemodynamic stability, the treatment should shift toward an optimal balance of heart failure therapy, controlling the substrate by revascularisation procedures and resolving other pathology-generating ventricular arrhythmias. This article provides a comprehensive overview of ESV’s current management options using the most efficient strategies known to date. Full article

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis and obstetric complications, driven by antiphospholipid antibodies (APLAs). This review synthesizes the latest advancements and current understanding, diagnosis, and treatment of APS. APLAs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2-GPI), interfere with coagulation and endothelial function, as well as with placental health. APS can be primary or secondary; it is often associated with systemic autoimmune diseases like lupus. The pathogenesis of APS remains only partially understood. APLAs promote thrombosis through endothelial damage, platelet activation, and inflammatory signaling pathways. Laboratory diagnosis relies on persistent positivity for APLAs and LAC through tests like ELISA and clotting assays, following a three-step confirmation process. New integrated test systems have been introduced to improve standardization. Classification criteria have evolved, with the 2023 EULAR-ACR criteria providing a weighted, domain-based scoring system, enhancing diagnostic precision. Catastrophic APS (CAPS) is a severe, rare manifestation of APS, characterized by multi-organ failure due to rapid, widespread microthrombosis and systemic inflammation, which requires urgent anticoagulation. Seronegative APS is proposed for patients with clinical features of APS but negative standard antibody tests, possibly due to non-criteria antibodies or transient immunosuppression. Treatment primarily involves long-term anticoagulation with vitamin K antagonists; direct oral anticoagulants are generally not recommended. APS diagnosis and management remain complex due to clinical heterogeneity and laboratory challenges. Continued refinement of diagnostic tools and criteria is essential for improving outcomes in this life-threatening condition. Full article

Background/Objectives: Radicular pain is a frequent pathology, and disc herniation is the commonest aetiology. A meta-analysis summarising international guidelines for radicular pain, published in 2021, showed that lumbar traction’s place is still a topic of debate. In this study, our aim was to evaluate the effectiveness of lumbar tractions in treating radicular pain of discal origin in association with medical treatment versus medical treatment alone. We performed a randomised, controlled, interventional, prospective, superiority trial in Reims Hospital Rheumatology Unit. Methods: We included participants with radicular pain and concordant disc herniation with ambulatory treatment failure. Participants were randomised into two groups: medical group (analgesics, anti-inflammatories treatments, at least two epidural injections); tractions group with this medical treatment associated with lumbar tractions. The primary outcome was the difference in the proportion of participants experiencing a minimum of 25% improvement in radicular pain at one month follow-up between the two groups. Results: We included 424 participants: 211 in the tractions group and 213 in the medical group. We analysed 388 participants (194 in each group). We collected demographic and clinical data, lumbar and radicular Numeric Pain Scale at baseline, one and three months. A statistical difference was found for the primary outcome: 120/194 participants (62%) in tractions group and 98/194 participants (51%) in medical group (p = 0.024). Conclusions: To our knowledge, this is the first randomised and controlled study on this topic with these results. We can assert the superiority of lumbar tractions in association with medical treatment over medical treatment alone for radicular pain with concordant disc herniation. Full article

Increased epithelial and endothelial permeability, along with dysregulated inflammatory responses, are key aspects of acute respiratory distress syndrome (ARDS) pathophysiology, which not only impact the lungs but also contribute to detrimental organ crosstalk with distant organs, ultimately leading to multiple organ dysfunction syndrome (MODS)—the primary cause of morbidity and mortality in patients with lung injury (LI) and ARDS. It is predominantly manifested by hypoxemic respiratory failure and bilateral pulmonary infiltrates, which cannot be fully attributed to cardiac failure or hypervolemia, but rather to alveolo-capillary barrier dysfunction, dysregulated systemic and pulmonary inflammation, immune system abnormalities, and mechanical stimuli-related responses. However, these pathological features are not uniform among patients with ARDS, as distinct subphenotypes with unique biological, clinical, physiological, and radiographic characteristics have been increasingly recognized in recent decades. The severity of ARDS, clinical outcomes, mortality, and efficacy of applied therapeutic measures appear significant depending on the respective phenotype. Acknowledging the heterogeneity of ARDS and defining distinct subphenotypes could significantly modify therapeutic strategies, enabling more precise and targeted treatments. To address these issues, a comprehensive literature search was conducted in PubMed using predefined keywords related to ARDS pathophysiology, subphenotypes, and personalized therapeutic approaches. Optimizing the identification and characterization of discrete ARDS subphenotypes—based on clinical, biological, physiological, and radiographic criteria—will deepen our understanding of ARDS pathophysiology, promote targeted recruitment in prospective clinical studies to define patient clusters with heterogeneous therapeutic responses, and support the shift toward individualized treatment strategies. Full article

Objective: Gut dysbiosis has been implicated in the pathology of inflammatory bowel disease (IBD). There is some evidence to suggest that the use of antibiotic treatment can incite an early clinical response or remission when used in conjunction with standard-of-care (SOC) therapy to treat IBD-related flares. Furthermore, antibiotics have been historically investigated for use as a bridge when initiating biologic therapy while waiting for peak biologic treatment effect to occur. This study investigated and compared the time to clinical response when treated with combination antibiotics, metronidazole monotherapy, or SOC therapy in pediatric patients with an active IBD flare. Methods: This study was a retrospective, Institution Review Board-approved, single-centered cohort study which included patients who were less than 18 years of age with a confirmed diagnosis of IBD who received conventional treatment alone or with either combination antibiotic therapy or metronidazole monotherapy to treat an active IBD flare between March 2013 and January 2024. Patients were excluded if they received antibiotic therapy to treat an active infection, had positive stool cultures or enteric pathogen polymerase chain reaction panel, or had colonic disease limited to the rectum. Results: Fifty-nine patients were included and divided into metronidazole monotherapy (n = 18), SOC therapy (n = 20), and combination antibiotics (n = 21). The primary outcome of days to clinical response was not significantly different across all groups; however, patients who received combination antibiotics achieved the fastest time to clinical response (median (IRQ))—4 days (1, 65), compared to 7.5 days (1, 119) for the SOC group and 9 days (2, 217) for the metronidazole group. Secondary outcomes of achievement of clinical response, remission, or failure were determined to be non-significant between all groups. Conclusions: There is no significant difference in time to clinical response, attaining clinical response or remission, or treatment failure rate for patients treated with combination antibiotics, metronidazole monotherapy, or SOC. However, results of this study suggest that the use of combination antibiotics plus SOC may lead to a faster time to clinical response and remission compared to SOC therapy alone. Further studies are warranted to elucidate the role of antimicrobial therapy in management of pediatric IBD. Full article

Pulmonary hypertension (PH) is broadly defined as a mean pulmonary arterial pressure (mPAP) exceeding 20 mm Hg at rest. Pulmonary arterial hypertension (PAH) is a specific subset of PH characterized by a normal pulmonary arterial wedge pressure (PAWP), combined with elevated mPAP and increased pulmonary vascular resistance (PVR), without other causes of pre-capillary hypertension such as lung diseases or chronic thromboembolic pulmonary hypertension. The majority of PAH cases are idiopathic; other common etiologies include connective tissue disease-associated PAH, congenital heart disease, and portopulmonary hypertension. To a lesser extent, genetic and familial forms of PAH can also occur. The pathophysiology of PAH involves the following four primary pathways: nitric oxide, endothelin-1, prostacyclin, and activin/bone morphogenetic protein (BMP). Dysregulation of these pathways leads to a progressive vasculopathy marked by vasoconstriction, vascular proliferation, elevated right heart afterload, and ultimately right-sided heart failure. Diagnosing PAH is challenging and often occurs at advanced stages. The gold standard for diagnosis remains invasive right heart catheterization. Along with invasive hemodynamic measurements, several noninvasive imaging modalities such as echocardiography and ventilation-perfusion scanning are key adjunct techniques. Also, recent advancements in cardiac magnetic resonance (CMR) have opened a new era for PAH management. Additionally, CMR and echocardiography not only enable diagnosis but also aid in evaluating disease severity and monitoring treatment responses. Current PAH treatments focus on targeting molecular pathways, reducing inflammation, and inhibiting right-sided heart failure. Integrating imaging with basic science techniques is crucial for enhanced patient diagnosis, and precision medicine is emerging as a key strategy in PAH management. Additionally, the incorporation of artificial intelligence into both molecular and imaging approaches holds significant potential. There is a growing need to integrate new imaging modalities with high resolution and reduced radiation exposure into clinical practice. In this review, we discuss the molecular pathways involved in PAH, the imaging modalities utilized for diagnosis and monitoring, and current targeted therapies. Advances in molecular understanding and imaging technologies, coupled with precision medicine, could hold promise in improving patient outcomes and revolutionizing the management of PAH patients. Full article

Adrenomedullin (AM) is a bioactive peptide that is strongly induced during severe inflammation, including pneumonia and sepsis, and serves as an organ-protective factor. The plasma concentration of AM is markedly increased in the novel coronavirus disease COVID-19 and is closely related to the severity of the disease and prognosis of patients. We performed two investigator-initiated trials to evaluate the efficacy and safety of AM in patients with moderate-to-severe COVID-19. This multicenter, double-blind, placebo-controlled phase-2a trial evaluated COVID-19 patients with severe (n = 33) and moderate (n = 31) pneumonia in Japan. Patients were randomly assigned to receive either 15 ng/kg/min AM or placebo. The primary endpoint was the duration of mechanical ventilation (MV) for severe pneumonia and oxygen support for moderate pneumonia. The main secondary endpoint was clinical status up to 30 days after the intervention. No differences in primary or secondary endpoints were observed between the AM and placebo groups in patients with severe or moderate pneumonia. In the severe pneumonia group, three patients in the placebo group died due to respiratory failure, and one patient in the AM group died due to respiratory failure. The respiratory function test at 30 days in the moderate pneumonia group tended to be better than that in the AM group and approached significance (p = 0.073). Although mild adverse events caused by the vasodilatory effects of AM were noted, the safety of AM for treating pneumonia was confirmed. In these trials, we did not observe a definitive efficacy of AM in moderate to severe pneumonia. Alternative strategies for the treatment of AM in pneumonia require further research. Full article

Background: Multidrug-resistant (MDR) Gram-negative infections, particularly those caused by carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat Pseudomonas aeruginosa (DTR-Pa), present a growing global healthcare challenge, especially in critically ill populations. Imipenem–relebactam (I/R), a novel β-lactam/β-lactamase inhibitor combination, has shown efficacy in clinical trials, but real-world data remain limited. Methods: We conducted a multicenter, retrospective–prospective observational study across tertiary-care hospitals in Italy between January 2020 and May 2025. Adult patients (≥18 years) treated with I/R for ≥48 h for suspected or confirmed MDR Gram-negative infections were included. Primary endpoints were clinical success at the end of therapy and 30-day all-cause mortality. Secondary endpoints included microbiological eradication, recurrence, safety, and predictors of treatment failure. Statistical analysis involved descriptive methods and correlation analysis for mortality predictors. Results: Twenty-nine patients were included (median age 66 years; 58.6% ICU admission; 71.4% mechanical ventilation). Clinical success was achieved in 22/29 patients (75.9%), while 30-day mortality was 24.1% (7/29). The most common pathogen was Klebsiella pneumoniae (62.1%), with 41.4% of infections being polymicrobial. Microbiological eradication was confirmed in all the BSIs. Parenteral nutrition (p = 0.016), sepsis at presentation (p = 0.04), candidemia (p = 0.036), and arterial catheter use (p = 0.029) were significantly more frequent in non-survivors. Survivors showed significant reductions in CRP, PCT, and bilirubin at 48 h, while non-survivors did not. Parenteral nutrition (rho = 0.427, p = 0.023), sepsis (rho = 0.378, p = 0.043), and arterial catheter use (rho = 0.384, p = 0.04) were significantly correlated with mortality. Conclusions: In this Italian multicenter cohort of critically ill patients, imipenem–relebactam demonstrated high clinical success and acceptable mortality rates in the treatment of severe MDR Gram-negative infections, particularly those caused by KPC-producing K. pneumoniae. Early biomarker dynamics may aid in monitoring treatment response. Larger prospective studies are needed to confirm these findings and define optimal treatment strategies. Full article