Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

Bimekizumab efficacy and safety in Korean patients with moderate to severe plaque psoriasis: A phase 3, randomized, placebo-controlled, double-blinded study.

Bimekizumab treatment has demonstrated significant improvements in clinical outcomes in patients with moderate to severe plaque psoriasis; however, studies so far have focused on predominantly White patient populations from North America and Europe, with one smaller study in a Japanese population. Here, clinical responses, safety, and tolerability of bimekizumab treatment in Korean patients are reported. Korean patients with moderate to severe plaque psoriasis were randomized to bimekizumab 320 mg every 4 weeks (Q4W) or placebo Q4W to week 16. Co-primary efficacy end points were achievement of ≥90% improvement from baseline in the Psoriasis Area and Severity Index (PASI 90) and Investigator's Global Assessment score of 0/1 (clear/almost clear) at week 16. Secondary efficacy end points included achievement of PASI 75 at week 4 and Dermatology Life Quality Index 0/1 at week 16. Safety outcomes were also assessed. Statistical analysis of the co-primary efficacy end points was performed using a type I error rate, at a two-sided α level of 0.05. Overall, 47 Korean patients were randomized to treatment (bimekizumab: 32, placebo: 15). At week 16, bimekizumab-treated patients had significantly higher clinical responses versus placebo-treated patients (PASI 90: 81.3% vs. 0%; IGA 0/1: 87.5% vs. 0%, p < 0.001 for both). Bimekizumab showed a rapid onset of clinical response, with 75.0% of patients achieving PASI 75 by week 4 (0% in placebo patients [nominal p < 0.001]). A higher proportion of bimekizumab-treated patients achieved DLQI 0/1 at week 16 (46.9% vs. 6.7% in placebo patients, nominal p = 0.007), indicating greater improvements in health-related quality of life (HRQoL) following bimekizumab treatment. Bimekizumab was well-tolerated in Korean patients, with no new safety signals identified. Treatment with bimekizumab led to rapid improvements in clinical responses and HRQoL versus placebo in Korean patients, consistent with responses in global populations. These findings suggest that bimekizumab is an effective and well-tolerated treatment option in Korean patients with psoriasis.

Differences in Depressive Symptom Profile by Age Group in Koreans With Major Depressive Disorder: Results From Nationwide General Population Surveys.

OBJECTIVE: This study investigated to what extent a range of depressive symptoms was differentially present depending on age group in Korean population. METHODS: Data was pooled from five nationally representative surveys in which 29,418 respondents aged at least 18 years were interviewed face-to-face using the Korean version of the Composite International Diagnostic Interview. A total of 691 (2.1%) respondents were found to have had at least 1 episode of major depressive disorder (MDD) within the last 12 months. Logistic regression analysis was conducted to identify the association between age groups (18-39 years, 40-59 years, and 60 years or older) and 26 depressive symptoms among the respondents with MDD. RESULTS: Associations were observed between somatic symptoms-including insomnia, awakening 2 h earlier-and cognitive symptoms such as feelings of guilt, thoughts of death, and suicidal ideation with the older age group. Whereas, atypical depressive symptoms such as increased appetite, weight gain, and hypersomnia were associated with the younger age group. When adjusted for sociodemographic factors, symptoms such as depressed mood, awakening 2 h earlier, and feeling guilty in the older age group, and hypersomnia, psychomotor retardation, and worse in the morning in the younger age group still remained statistically significant. Furthermore, fatigue and decreased libido were newly associated with the younger age group. CONCLUSION: The findings of this study revealed distinct patterns of symptomatology in MDD based on age groups. These differences should be considered owing to their potential relevance to treatment response and prognosis in the clinical setting.

Definition Change and Update of Clinical Guidelines for Interstitial Cystitis and Bladder Pain Syndrome.

The clinical guidelines for interstitial cystitis (IC) and bladder pain syndrome (BPS) have been revised by updating our previous guidelines. The symptoms of IC and BPS, collectively called as hypersensitive bladder (HSB) symptoms, are virtually indistinguishable between IC and BPS; however, IC and BPS should be considered as a separate entity of disorders. We define IC as a bladder disease with Hunner lesions, usually associated with HSB symptoms and bladder inflammation, and BPS as a condition with HSB symptoms in the absence of Hunner lesions and any confusable diseases. Pathophysiology totally differs between IC and BPS. IC involves immunological inflammation probably resulting from autoimmunity, while BPS is associated with the interaction of multiple factors such as neurogenic inflammation, exogenous substances, urothelial defects, psychological stress, and neural hyperactivity. Histopathology also differs between IC and BPS. IC is associated with severe inflammation of the whole bladder accompanied by plasma cell infiltration and urothelial denudation, while BPS shows little pathological changes. Management should begin with a differential diagnosis of IC or BPS, which would require cystoscopy to determine the presence or absence of Hunner lesions. The patients should be treated differently based on the diagnosis following the algorithm, although pain management would be common to IC and BPS. Clinical studies are also to be designed and analyzed separately for IC and BPS.

The TGFß type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial.

Functional blockade of the transforming growth factor-beta (TGFß) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFß type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFß levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

Synergistic anticancer immunity in metastatic triple-negative breast cancer through an in situ amplifying Peptide-Drug Conjugate.

Despite significant progress in combining cancer immunotherapy with chemotherapy to treat triple negative breast cancer (TNBC), challenges persist due to target depletion and tumor heterogeneity, especially in metastasis. Chemotherapy lacks precise targeting abilities, and targeted therapy is inadequate in addressing the diverse heterogeneity of tumors. To address these challenges, we introduce RGDEVD-DOX as a tumor-specific immunogenic agent, namely TPD1, which targets integrin αvß3 and gets continuously activated by apoptosis. TPD1 facilitates the caspase-3-mediated in situ amplification that results in tumor-specific accumulation of doxorubicin. This local concentration of doxorubicin induces immunogenic cell death and promotes the recruitment of immune cells to the tumor site. Notably, the tumor-targeting capabilities of TPD1 help bypass the systemic immunotoxicity of doxorubicin. Consequently, this alters the tumor microenvironment, converting it into a 'hot' tumor that is more susceptible to immune checkpoint inhibition. We demonstrated the anti-metastatic and anti-cancer efficacy of this treatment using various xenograft and metastatic models. This study underscores the high potential of caspase-3 cleavable peptide-drug conjugates to be used in conjunction with anti-cancer immunotherapies.

[Postoperative Imaging Findings of Colorectal Surgery: A Pictorial Essay]. / 대장 직장 ìˆ˜ìˆ ì˜ ìˆ˜ìˆ í›„ 영상 소견들: 임상화보.

Postoperative colorectal imaging studies play an important role in the detection of surgical complications and disease recurrence. In this pictorial essay, we briefly describe methods of surgery, imaging findings of their early and late complications, and postsurgical recurrence of cancer and inflammatory bowel disease.

Nano-anticoagulant based on carrier-free low molecular weight heparin and octadecylamine with an albumin shuttling effect.

Low-molecular-weight heparin (LMWH), derived from unfractionated heparin (UFH), has enhanced anticoagulant efficacy, long duration of action, and extended half-life. Patients receiving LMWH for preventive therapies would strongly benefit from its long-term effects, however, achieving this is challenging. Here, we design and evaluate a nanoengineered LMWH and octadecylamine conjugate (LMHO) that can act for a long time while maintaining close to 97 ± 3% of LMWH activity via end-specific conjugation of the reducing end of LMWH. LMHO can self-assemble into nanoparticles with an average size of 105 ± 1.7 nm in water without any nanocarrier and can be combined with serum albumin, resulting in a lipid-based albumin shuttling effect. Such molecules can circulate in the bloodstream for 4-5 days. We corroborate the self-assembly capability of LMHO and its interaction with albumin through molecular dynamics (MD) simulations and transmission electron microscopy (TEM) analysis. This innovative approach to carrier-free polysaccharide delivery, enhanced by nanoengineered albumin shuttling, represents a promising platform to address limitations in conventional therapies.

Excluding confusable diseases in patients with presumptive diagnosis of interstitial cystitis: A large patient cohort study.

OBJECTIVE: To analyze the results of excluding confusable diseases in patients with a presumptive diagnosis of interstitial cystitis (IC). METHODS: We retrospectively reviewed the electronic medical records of consecutive patients with IC between October 2005 and December 2019. RESULTS: Patients with pelvic pain underwent an initial workup. Of these, 646 patients (164 men, 25.4%; 482 women, 74.6%) underwent observational cystoscopy under the suspicion of IC. Fourteen patients had genitourinary tract malignancies (2.2%) (bladder cancer, n = 13; prostate cancer, n = 1). Of the 13 patients with bladder cancer, three were diagnosed during initial observation cystoscopy. The remaining 10 patients were diagnosed during subsequent follow-up cystoscopic surgery. Urinary tuberculosis was identified in seven (1.1%) of 646 patients during the examination. Five (0.8%) of the six patients with suspected urinary tuberculosis at baseline imaging were positive for tuberculosis in the acid-fast bacillus test. One patient developed tuberculous granulomas in the bladder tissue after a cystectomy for intractable pelvic pain. CONCLUSION: Our results show that continuous efforts to rule out bladder tumors or tuberculosis are still essential in the follow up of patients with suspected IC, even if these diseases are not excluded at the initial examination. Imaging studies are necessary to rule out tuberculosis.

Psychotropic Medications Promote Time-Dependent Reduction of Suicidal Ideation in Mood Disorder: A Prospective Cohort Study.

BACKGROUND: Despite a plethora of research on the topic, there is still no solid evidence that pharmacological treatment actually reduces the risk of suicide in patients with mental illness. In this study, we aimed to assess the effect of psychotropic medications on suicidal ideation in patients with major depressive disorder (MDD) and bipolar disorder (BPD) in two age groups: less than 25 years and 25 years and older. METHODS: We analyzed 312 patients with mood disorders with current suicidal thoughts or recent suicide attempts. We followed the participants from baseline for 6 months and assessed changes in suicidal ideation with Columbia-Suicide Severity Rating Scale (C-SSRS). The effect of psychotropic drug administration on suicidal ideation over time was analyzed using a linear mixed model. RESULTS: In patients aged 25 years and older with mood disorders, suicidal ideation was more severe when using psychotropic drugs than when not using them. However, suicidal ideation decreased rapidly over time. The time-dependent reduction in suicidal ideation was accelerated when using antidepressants and sedatives/hypnotics in adult MDD, and when using mood stabilizers in adult BPD. However, this effect was not observed in participants aged less than 25 years. CONCLUSION: Adequate psychotropic medication may reduce suicidal ideation in patients with mood disorders aged 25 years and older. Additional research on psychotropic drugs is needed to effectively reduce the risk of suicide among children and adolescents with mood disorders.

Smoking Cessation and Risk of Hidradenitis Suppurativa Development.

Importance: Although tobacco smoking is established as a risk factor for hidradenitis suppurativa (HS), studies on the effects of smoking cessation on HS are limited, and evidence is lacking. Objective: To examine the association between changes in smoking status and the development of HS. Design, Setting, and Participants: This population-based cohort study enrolled participants from the Korean National Health Insurance Service database who had undergone 2 consecutive biennial health examinations (2004-2005 and 2006-2007) as the primary cohort. Within the primary cohort, the secondary cohort comprised individuals who underwent all biennial health examinations throughout the follow-up period and maintained the same smoking status from 2006 to 2007 to the end of the follow-up period. Data were analyzed from July to December 2023. Exposures: Changes in smoking habit status. Main Outcomes and Measures: Risk of HS development. The HS risk according to change in smoking status between the 2 consecutive health examinations was estimated using a Cox proportional hazards model. Results: Of the 6 230 189 participants enrolled, the mean (SD) age was 47.2 (13.5) years, and 55.6% were male. During 84 457 025 person-years of follow-up, 3761 HS events occurred. In the primary cohort, compared to those who consistently reported active smoking at both checkups (ie, sustained smokers), lower HS risk was seen among those who were confirmed to smoke initially but quit by the second checkup (ie, smoking quitters) (adjusted hazard ratio [AHR], 0.68; 95% CI, 0.56-0.83), those who maintained cessation status throughout (AHR, 0.67; 95% CI, 0.57-0.77), and those who reported never smoking at either checkup (ie, never smokers) (AHR, 0.57; 95% CI, 0.52-0.63). Those who initially quit smoking but resumed by the second checkup and those who had no previous smoking history but started at the second checkup (ie, new smokers) exhibited similar HS risk as sustained smokers. The secondary cohort results aligned with those of the primary cohort, showing a more pronounced risk reduction with smoking cessation (AHR, 0.57; 95% CI, 0.39-0.83). Considering time-smoking interaction, the cumulative incidence and the risk of HS in smoking quitters were similar to those in sustained smokers in the early stages of observation. However, 3 to 4 years after smoking cessation, the rate decelerated, resembling that of never smokers, and there was a statistically significant decrease in the risk that persisted (between 3 and 6 years from the index date: AHR, 0.58; 95% CI, 0.36-0.92; and ≥12 years from the index date: AHR, 0.70; 95% CI, 0.50-0.97). New smokers initially paralleled never smokers but accelerated after 2 to 3 years, reaching sustained smokers' levels. Conclusions and Relevance: In this cohort study, quitting smoking and sustaining a smoke-free status were associated with a reduced risk of HS development compared to continuous smoking. In contrast, resuming or initiating smoking may have as detrimental an effect on HS development as continual smoking.

Efficacy and Safety of Lurasidone vs. Quetiapine XR in Acutely Psychotic Patients With Schizophrenia in Korea: A Randomized, Double-Blind, Active-Controlled Trial.

OBJECTIVE: This study was performed to evaluate the efficacy and safety of lurasidone (160 mg/day) compared to quetiapine XR (QXR; 600 mg/day) in the treatment of acutely psychotic patients with schizophrenia. METHODS: Patients were randomly assigned to 6 weeks of double-blind treatment with lurasidone 160 mg/day (n=105) or QXR 600 mg/day (n=105). Primary efficacy measure was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions severity (CGI-S) score. Adverse events, body measurements, and laboratory parameters were assessed. RESULTS: Lurasidone demonstrated non-inferiority to QXR on the PANSS total score. Adjusted mean±standard error change at week 6 on the PANSS total score was -26.42±2.02 and -27.33±2.01 in the lurasidone and QXR group, respectively. The mean difference score was -0.91 (95% confidence interval -6.35-4.53). The lurasidone group showed a greater reduction in PANSS total and negative subscale on week 1 and a greater reduction in end-point CGI-S score compared to the QXR group. Body weight, body mass index, and waist circumference in the lurasidone group were reduced, with significantly lower mean change compared to QXR. Endpoint changes in glucose, cholesterol, triglycerides, and low-density lipoprotein levels were also significantly lower. The most common adverse drug reactions with lurasidone were akathisia and nausea. CONCLUSION: Lurasidone 160 mg/day was found to be non-inferior to QXR 600 mg/day in the treatment of schizophrenia with comparable efficacy and tolerability. Adverse effects of lurasidone were generally tolerable, and beneficial effects on metabolic parameters can be expected.

Investigating the Immune-Stimulating Potential of ß-Glucan from Aureobasidium pullulans in Cancer Immunotherapy.

ß-glucan, a polysaccharide found in various sources, exhibits unique physicochemical properties, yet its high polymerization limits clinical applications because of its solubility. Addressing this limitation, we introduce PPTEE-glycan, a highly purified soluble ß-1,3/1,6-glucan derived from Aureobasidium pullulans. The refined PPTEE-glycan demonstrated robust immune stimulation in vitro, activated dendritic cells, and enhanced co-stimulatory markers, cytokines, and cross-presentation. Formulated as a PPTEE + microemulsion (ME), it elevated immune responses in vivo, promoting antigen-specific antibodies and CD8+ T cell proliferation. Intratumoral administration of PPTEE + ME in tumor-bearing mice induced notable tumor regression, which was linked to the activation of immunosuppressive cells. This study highlights the potential of high-purity Aureobasidium pullulans-derived ß-glucan, particularly PPTEE, as promising immune adjuvants, offering novel avenues for advancing cancer immunotherapy.

Metabolic profiling of psoriasis vulgaris and palmoplantar pustulosis.

Psoriasis is a chronic inflammatory skin disorder with various subtypes, including psoriasis vulgaris (PV) and palmoplantar pustulosis (PPP). Metabolomics studies have provided insights into psoriasis pathogenesis. However, research on metabolomic alterations in PV and PPP patients is limited. We aimed to explore and compare the metabolic profiles of patients with PV and PPP to those of healthy volunteers (HVs). A single-centre retrospective cohort was constructed, comprising Korean patients with psoriasis and HVs matched by age and sex. Clinical information including demographics, disease severity, and comorbidities were collected. Plasma samples were subjected to targeted metabolic analysis using an Absolute IDQ®p180 kit, which quantified 188 metabolites, including amino acids and carnitines. Statistical significance was assessed using an independent t-test and chi-square test, with p-values adjusted by the Benjamini-Hochberg procedure. Pathway analyses were employed to gain a comprehensive understanding of the metabolite profile. This study included 93 patients (73 PV and 20 PPP) and an equal number of HVs. PV patients showed increased levels of sarcosine, serotonin, propionylcarnitine, proline, aspartic acid, tyrosine, taurine, spermine and ornithine, but exhibited a decreased level of acetylcarnitine than matched HVs. Notably, sarcosine levels were significantly elevated in PPP patients. Furthermore, the sarcosine/glycine ratio was significantly higher in both PV and PPP patients than in HVs. Pathway analysis showed significant increases in metabolites involved in amino acid metabolism and the urea cycle in PV patients. In conclusion, this study demonstrated distinct metabolic profiles in PV and PPP patients compared to HVs, suggesting sarcosine as a potential biomarker for psoriasis.

Coccygodynia in a Long-Term Cancer Survivor Diagnosed with Metastatic Cancer: A Case Report.

Background and Objectives: Rectal cancer is considered cured if no recurrence is found during the 5-year follow-up period after treatment. After this period, patients often believe that the cancer is completely eradicated. However, in modern society, where lifespans have become longer, it is important to recognize that metastatic cancer may occur long after the initial treatment has concluded. This highlights the necessity of continued vigilance and the long-term follow-up of cancer survivors. Case report: We present a case of metastatic cancer of the coccyx in an 87-year-old female patient. This patient had undergone successful surgery and treatment for rectal cancer 10 years prior. She was considered cured after the standard 5-year follow-up period as she showed no signs of recurrence. The patient presented with simple coccygeal pain as the main complaint, without any other accompanying symptoms such as weight loss, fever, or changes in bowel habits, typically associated with cancer recurrence. During the clinical evaluation, irregularities in the bone cortex were detected while performing a nerve block using ultrasound. Given these findings, further diagnostic evaluations were performed. Advanced imaging techniques including MRI and CT scans led to a diagnosis of coccygeal metastasis. Conclusions: While the 5-year mark post-treatment is a significant milestone for rectal cancer patients, it does not guarantee the absolute eradication of the disease. Long-term monitoring and a thorough evaluation of new symptoms are essential for the early detection and management of late metastatic recurrences. This approach ensures that patients receive timely and appropriate care, potentially improving outcomes and quality of life.

Adaptive immunity of materials: Implications for tissue healing and regeneration.

Recent cumulative findings signify the adaptive immunity of materials as a key agenda in tissue healing that can improve regenerative events and outcomes. Modulating immune responses, mainly the recruitment and functions of T and B cells and their further interplay with innate immune cells (e.g., dendritic cells, macrophages) can be orchestrated by materials. For instance, decellularized matrices have been shown to promote muscle healing by inducing T helper 2 (Th2) cell immunity, while synthetic biopolymers exhibit differential effects on B cell responses and fibrosis compared decellularized matrices. We discuss the recent findings on how implantable materials instruct the adaptive immune events and the subsequent tissue healing process. In particular, we dissect the materials' physicochemical properties (shape, size, topology, degradation, rigidity, and matrix dynamic mechanics) to demonstrate the relations of these parameters with the adaptive immune responses in vitro and the underlying biological mechanisms. Furthermore, we present evidence of recent in vivo phenomena, including tissue healing, cancer progression, and fibrosis, wherein biomaterials potentially shape adaptive immune cell functions and in vivo outcomes. Our discussion will help understand the materials-regulated immunology events more deeply, and offer the design rationale of materials with tunable matrix properties for accelerated tissue repair and regeneration.

Skin Toxicities Induced by Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and their Influence on Treatment Adjustments in Lung Cancer Patients.

Skin toxicities caused by epidermal growth factor receptor tyrosine kinase inhibitors can affect patient quality of life and lead to treatment adjustments, including dose reduction or discontinuation. This retrospective study aimed to profile skin toxicities and their impact on treatment adjustments. A total of 288 non-small cell lung cancer patients treated with first-, second-, or third-generation epidermal growth factor receptor tyrosine kinase inhibitors were included. Skin toxicities, including papulopustular rash, xerosis, paronychia, and pruritus, were assessed based on medical records, and their severity was evaluated based on the required dermatological intervention. Papulopustular rash was the most common toxicity (74.3%), followed by pruritus (61.1%), xerosis (52.4%), and paronychia (39.6%). Papulopustular rash was more common in males and more severe in younger patients. Papulopustular rash was more prevalent in patients treated with first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors, while paronychia was notably frequent for the second-generation epidermal growth factor receptor tyrosine kinase inhibitors. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors frequently caused multiple skin toxicities. Importantly, skin toxicities led to epidermal growth factor receptor tyrosine kinase inhibitor treatment adjustments in 26.7% of cases, with second-generation epidermal growth factor receptor tyrosine kinase inhibitors demonstrating higher adjustment rates. Papulopustular rash and paronychia were the main causes of treatment adjustments, with even mild paronychia being linked to treatment adjustments. Effective management of skin toxicities is essential for optimizing treatment outcomes in patients receiving epidermal growth factor receptor tyrosine kinase inhibitors.

Optimizing Treatment for Carbapenem-Resistant Acinetobacter baumannii Complex Infections: A Review of Current Evidence.

Carbapenem-resistant Acinetobacter baumannii complex (CRAB) poses a significant global health challenge owing to its resistance to multiple antibiotics and limited treatment options. Polymyxin-based therapies have been widely used to treat CRAB infections; however, they are associated with high mortality rates and common adverse events such as nephrotoxicity. Recent developments include numerous observational studies and randomized clinical trials investigating antibiotic combinations, repurposing existing antibiotics, and the development of novel agents. Consequently, recommendations for treating CRAB are undergoing significant changes. The importance of colistin is decreasing, and the role of sulbactam, which exhibits direct antibacterial activity against A. baumannii complex, is being reassessed. High-dose ampicillin-sulbactam-based combination therapies, as well as combinations of sulbactam and durlobactam, which prevent the hydrolysis of sulbactam and binds to penicillin-binding protein 2, have shown promising results. This review introduces recent advancements in CRAB infection treatment based on clinical trial data, highlighting the need for optimized treatment protocols and comprehensive clinical trials to combat the evolving threat of CRAB effectively.

The Microbiological Characteristics of Acinetobacter Baumannii Associated With Early Mortality in Patients With Bloodstream Infection.

Background: Despite rapid deaths resulting from Acinetobacter baumannii bacteremia, the clinical impact of the microbiological characteristics of A baumannii strains on early mortality (EM) is unclear. We aimed to identify the microbiological characteristics of A baumannii strains associated with EM. Methods: Clinical information and isolates from patients with A baumannii bacteremia from January 2015 to December 2021 were collected. EM was defined as death within 3 days of the initial positive blood culture, whereas late mortality meant death within 5-30 days. The microbiological characteristics of A baumannii were analyzed using multilocus sequence typing, polymerase chain reactions, and a Galleria mellonella in vivo infection model. Results: Among 130 patients, 69 (53.1%) died within 30 days and EM occurred in 38 (55.1% of 30-day deaths). Sequence type 191 (ST191) strain was more prevalent in patients with EM than in 30-day survivors (31.6% vs 6.6%). Regarding virulence genes, bfmS was more frequent (92.1% vs 47.5%), whereas bauA was less frequent (13.2% vs 52.5%) in patients with EM than in 30-day survivors. Higher clinical severity, pneumonia, and ST191 infection were identified as independent risk factors for EM. In the G mellonella infection model, ST191, bfmS+, and bauA- isolates showed higher virulence than non-ST191, bfmS-, and bauA+ isolates, respectively. Conclusions: ST191 and bfmS were more frequently found in the EM group. ST191 infection was also an independent risk factor for EM and highly virulent in the in vivo model. Tailored infection control measures based on these characteristics are necessary for A baumannii bacteremia management.