Clinical Treatment Failure Research Articles

Raddeanin A Inhibits Colorectal Cancer Growth and Ameliorates Oxaliplatin Resistance Through the WNT/β-Catenin Signaling Pathway.

Background: Chemotherapy based on oxaliplatin (OXA) is the first-line treatment for advanced colorectal cancer (CRC), and acquired resistance to OXA is the main reason for clinical treatment failure in CRC. Methods: To search for compounds that can reverse OXA resistance, we screened a small molecule inhibitor drug library and identified a drug, Raddeanin A (RA), that enhanced the anticancer effect of OXA. Using human CRC cell lines, CRC organoid models, and invivo subcutaneous tumorigenic studies, we determined that RA inhibits the proliferation of CRC cells by promoting apoptosis and inducing cell cycle arrest. Results: We constructed OXA-resistant CRC cell lines and demonstrated that RA enhances the sensitivity of these cells to OXA. Further experiments showed that the mechanism by which RA enhanced the anticancer effects of OXA in CRC was by inhibiting the activation of the WNT/β-catenin signaling pathway. Conclusions: Because RA has been shown to be biocompatible in animal models, there is a possibility that RA could be developed as a sensitizer for resistant cancer cells or as a novel lead compound to enhance the therapeutic efficacy of OXA in resistant CRCs.

Clinical Relapse Versus Treatment Failure: The Case for Surveillance for Re-Appearance of Minimal Measurable Disease in Pediatric Patients with Higher Risk B-ALL.

Clinical Relapse Versus Treatment Failure: The Case for Surveillance for Re-Appearance of Minimal Measurable Disease in Pediatric Patients with Higher Risk B-ALL.

Copper-coordinated nanomedicine for the concurrent treatment of lung cancer through the induction of cuproptosis and apoptosis

The resistance of tumor cells to apoptosis often leads to chemoresistance and treatment failure in clinic. In this study, we have developed a Cu2+-coordinated lignosulfonate (CLS) /doxorubicin (DOX) biological complex (referred to as LCD) with the aim of overcoming cellular resistance to apoptosis for combined lung cancer therapy. The copper complexes modified by CLS exhibit significant water solubility and excellent in vivo biocompatibility. The proportion of copper in the composite is simultaneously increased. Due to the coordination and π-π stacking effects, the self-assembled LCD exhibits nanometer-scale particle size, a narrow and homogeneous grain distribution, as well as excellent dispersion stability. Furthermore, LCD has the potential to disassemble in the presence of high levels of glutathione (GSH) and low pH, leading to effective drug release. Cu2+-mediated cuproptosis can lead to the down-regulation of FDX1 and DLAT protein expression by reducing mitochondrial membrane potential, resulting in non-apoptotic programmed cell death (PCD) regardless of cellular resistance to apoptosis. Moreover, the released DOX not only exhibits a preference for localizing in the cell nucleus to induce apoptosis for combined chemotherapy, but also generates a substantial amount of H2O2. This H2O2 further produces ROS to induce apoptosis through Fenton reaction with Cu2+. LCD demonstrates significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity through the combined action of cuproptosis and apoptosis. This study may provide a potential avenue for the advancement of self-delivery nanomedicine to overcome resistance to apoptosis in tumor therapy.

Correlative expression of exosomal miRNAs in chemotherapy resistance of triple-negative breast cancer: An observational study.

Drug resistance in tumors is the primary contributor to clinical treatment failures, and aberrant expression of small RNA molecules, specifically microRNAs (miRNAs), in tumor tissues is intricately associated with drug resistance. The aim of this study is to investigate the targets and mechanisms through which exosomal miRNAs from triple-negative breast cancer (TNBC) regulate chemotherapy resistance in tumor cells. Utilizing high-throughput sequencing technology, we conducted exosomal miRNA sequencing on serum samples obtained from TNBC patients who were either sensitive or resistant to AC-sequential T chemotherapy. Subsequently, we identified and screened differentially expressed miRNAs. The observed differences in miRNA expression were further validated through quantitative reverse transcription-polymerase chain reaction. In comparison to TNBC patients who exhibited sensitivity to the AC-sequential T regimen chemotherapy, we identified significant differences in the expression of 85 miRNAs within serum exosomes of patients displaying chemotherapy resistance. Furthermore, we observed a substantial difference in the expression of hsa-miR-6831-5p between TNBC patients who were responsive to chemotherapy and those who were drug-resistant and underwent treatment with the AC-sequential T regimen. hsa-miR-6831-5p holds the potential to serve as a diagnostic marker for assessing the chemosensitivity of the AC-sequential T regimen in TNBC.

AB042. Combined anti-PD-L1 and anti-VEGFR2 therapy promotes the antitumor immune response in glioblastoma multiforme by reprogramming tumor microenvironment.

Inhibitors of programmed cell death ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) are commonly used in the clinic, but they are beneficial for only a minority of glioblastoma multiforme (GBM) patients. GBM has significant immunosuppressive properties, and there are many immunosuppressive cells and dysfunctional effector T-cell in the tumor microenvironment (TME), which is one of the important reasons for the failure of clinical treatment of GBM. P21-activated kinase 4 (PAK4) is a threonine protein kinase, and as a pivotal immune suppressor in the TME. PAK4 knockdown attenuates vascular abnormalities and promotes T-cell infiltration. Using RNA sequencing (RNA-seq) technology, western blotting, and immunofluorescence, we identified changes in genes expression following VEGFR2 knockdown. The impact of anti-PD-L1 and anti-VEGFR2 on GBM cells apoptosis was assessed using coculture assays, western blotting, and flow cytometry. Additionally, the therapeutic efficacy of anti-PD-L1 and anti-VEGFR2 therapy was evaluated through in vivo experiments, immunohistochemistry, and immunofluorescence. Our studies revealed that VEGFR2 binds and phosphorylates signal transducer and activator of transcription 3 (p-STAT3), thereby regulating the expression of PAK4. Anti-PD-L1 and anti-VEGFR2 therapy can increase the secretion of interferon-gamma (IFN-γ), granzyme B, and perforin by immune cells and promoting the cytotoxic effects of cytotoxic cluster of differentiation 8 (CD8)+ T cells, and overexpression of PAK4 could reverse this effect. We also demonstrated that combination therapy with anti-PD-L1 and anti-VEGFR2 agents prevents tumor growth in an intracranial tumor model. Our results support that anti-VEGFR2 therapy can downregulate PAK4, reprogram the TME by increasing CD8+ T cells infiltration and activation, and enhance the therapeutic effect of anti-PD-L1 therapy on GBM cells.

A prediction method for the individual serum concentration and therapeutic effect for optimizing adalimumab therapy in inflammatory bowel disease.

Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM's effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase. We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect. Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient's final time point matched the observed effects in 9 of the 11 patients. This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.

Artificial intelligence–based skeletal muscle estimates and outcomes of EUS-guided treatment of pancreatic fluid collections

Background and AimsSkeletal muscle status may impact clinical outcomes of a variety of pancreatic diseases. Skeletal muscle quality and quantity have not been fully examined in relation to the outcomes of endoscopic ultrasound (EUS)-guided treatment of pancreatic fluid collections (PFCs). MethodsUsing a multi-institutional cohort of 372 patients receiving EUS-guided treatment of PFCs in 2010-2020, we examined the association of skeletal muscle status with adverse outcomes including clinical treatment failure and in-hospital mortality. Utilizing an in-house deep learning-based platform for pre-procedural computed tomography images, we calculated skeletal muscle density (SMD) and skeletal muscle index (SMI, height-adjusted muscle area) as surrogates for muscular quality and quantity, respectively. Multivariable logistic regression analysis was conducted to calculate odds ratios (ORs) for adverse outcomes. ResultsLower-level SMD was associated with higher risks of clinical failure and in-hospital mortality (Ptrend < 0.001). The adjusted OR for clinical failure comparing the extreme quartiles was 3.64 (95% confidence interval, 1.52-8.72). Compared with patients in the top two quartiles, patients in the lowest quartile had an adjusted OR for in-hospital mortality of 12.4 (95% confidence interval, 3.43-44.8). We observed no effect modification by the PFC types on the SMD-outcome relationship (Pinteraction > 0.16). SMD was not associated with the risk of procedure-related adverse events or PFC recurrence. SMI was not associated with adverse outcomes (Ptrend > 0.39). ConclusionsIn patients with endoscopically managed PFCs, SMD, but not SMI, was associated with the risks of clinical failure and in-hospital mortality, supporting the prognostic role of skeletal muscle quality.

Optic nerve sheath diameter correlates with both success and failure of hydrocephalus treatment in pediatric patients with pineal region lesions.

Pineal region lesions in children are heterogenous pathologies often symptomatic due to occlusive hydrocephalus and thus elevated intracranial pressure (ICP). MRI-derived parameters to assess hydrocephalus are the optic nerve sheath diameter (ONSD) as a surrogate for ICP and the frontal occipital horn ratio (FOHR), representing ventricle volume. As elevated ICP may not always be associated with clinical signs, the adjunct of ONSD could help decision making in patients undergoing treatment. The goal of this study is to assess the available magnetic resonance imaging (MRI) of patients with pineal region lesions undergoing surgical treatment with respect to pre- and postoperative ONSD and FOHR as an indicator for hydrocephalus. Retrospective data analysis was performed in all patients operated for pineal region lesions at a tertiary care center between 2010 and 2023. Only patients with pre- and postoperative MRI were selected for inclusion. Clinical data and ONSD at multiple time points, as well as FOHR were analyzed. Imaging parameter changes were correlated with clinical signs of hydrocephalus before and after surgical treatment. Thirty-three patients with forty operative cases met the inclusion criteria. Age at diagnosis was 10.9 ± 4.6years (1-17years). Hydrocephalus was seen in 80% of operative cases preoperatively (n = 32/40). Presence of hydrocephalus was associated with significantly elevated preoperative ONSD (p = 0.006). There was a significant decrease in ONSD immediately (p < 0.001) and at 3months (p < 0.001) postoperatively. FOHR showed a slightly less pronounced decrease (immediately p = 0.006, 3months p = 0.003). In patients without hydrocephalus, no significant changes in ONSD were observed (p = 0.369). In 6/6 patients with clinical hydrocephalus treatment failure, ONSD increased, but in 3/6 ONSD was the only discernible MRI change with unchanged FOHR. ONSD measurements may have utility in evaluating intracranial hypertension due to hydrocephalus in patients with pineal region tumors. ONSD changes appear to have value in assessing hydrocephalus treatment failure.

Design, synthesis, and ex vivo anti-drug resistant cervical cancer activity of novel molecularly targeted chalcone derivatives

Chemotherapy toxicity and tumor multidrug resistance remain the main reasons for clinical treatment failure in cervical cancer. In this study, 79 novel chalcone derivatives were designed and synthesized using the principle of active substructure splicing with the parent nucleus of licorice chalcone as the lead compound and VEGFR-2 and P-gp as the target of action and their potentials for anticervical cancer activity were preliminarily evaluated. The results showed that the IC50 values of candidate compound B20 against HeLa and HeLa/DDP cells were 3.66 ± 0.10 and 4.35 ± 0.21 μΜ, respectively, with a resistance index (RI) of 1.18, which was significantly higher than that of the positive drug cisplatin (IC50:13.60 ± 1.63, 100.03 ± 7.94 μΜ, RI:7.36). In addition, B20 showed significant inhibitory activity against VEGFR-2 kinase and P-gp-mediated rhodamine 123 efflux, as well as the ability to inhibit the phosphorylation of VEGFR-2 and downstream PI3K/AKT signaling pathway proteins, inducing apoptosis, blocking cells in the S-phase, and inhibiting invasive migration and tubule generation by HUVEC cells. Acceptable safety was demonstrated in acute toxicity tests when B20 was at 200 mg/kg. In the nude mouse HeLa/DDP cell xenograft tumor model, the inhibition rate of transplanted tumors was 39.2 % and 79.2 % when B20 was at 10 and 20 mg/kg, respectively. These results suggest that B20 is a potent VEGFR-2 and P-gp inhibitor with active potential for treating cisplatin-resistant cervical cancer.

DeepARV: ensemble deep learning to predict drug-drug interaction of clinical relevance with antiretroviral therapy

Drug-drug interaction (DDI) may result in clinical toxicity or treatment failure of antiretroviral therapy (ARV) or comedications. Despite the high number of possible drug combinations, only a limited number of clinical DDI studies are conducted. Computational prediction of DDIs could provide key evidence for the rational management of complex therapies. Our study aimed to assess the potential of deep learning approaches to predict DDIs of clinical relevance between ARVs and comedications. DDI severity grading between 30,142 drug pairs was extracted from the Liverpool HIV Drug Interaction database. Two feature construction techniques were employed: 1) drug similarity profiles by comparing Morgan fingerprints, and 2) embeddings from SMILES of each drug via ChemBERTa, a transformer-based model. We developed DeepARV-Sim and DeepARV-ChemBERTa to predict four categories of DDI: i) Red: drugs should not be co-administered, ii) Amber: interaction of potential clinical relevance manageable by monitoring/dose adjustment, iii) Yellow: interaction of weak relevance and iv) Green: no expected interaction. The imbalance in the distribution of DDI severity grades was addressed by undersampling and applying ensemble learning. DeepARV-Sim and DeepARV-ChemBERTa predicted clinically relevant DDI between ARVs and comedications with a weighted mean balanced accuracy of 0.729 ± 0.012 and 0.776 ± 0.011, respectively. DeepARV-Sim and DeepARV-ChemBERTa have the potential to leverage molecular structures associated with DDI risks and reduce DDI class imbalance, effectively increasing the predictive ability on clinically relevant DDIs. This approach could be developed for identifying high-risk pairing of drugs, enhancing the screening process, and targeting DDIs to study in clinical drug development.

Impact of early follow-up CT in the conservative management of traumatic brain injury on surgical decision making: A retrospective, single-center analysis with special respect to coagulopathy.

Initial management of traumatic brain injury (TBI) without immediate need for surgical therapy varies across centers. The additional value of routine repeat cranial computerized tomography (CT) to neurological monitoring is controversial. This retrospective study investigates the impact of routine follow-up CT after 6h (CT6h) in initially conservatively managed TBI on surgical decision making. Furthermore, the impact of coagulopathy on lesion size and progression was examined. We reviewed charts of patients admitted to our clinic in the time between 1st January 2020 and 30th June 2022 for the ICD10 diagnosis S06.3 (traumatic brain contusion), S06.4 (epidural hematoma), S06.5 (subdural hematoma), and S06.6 (traumatic subarachnoid hemorrhage). Baseline characteristics as well as timing, reason, and consequences of first and second cranial CT, clinical course, lesion size at first and second CT as well as presence and type of coagulopathy (standard laboratory testing and prior medical history) were noted among others. Significance testing was carried out using Student's t-test. The significance level was set to p < 0.005. A total of 213 patients were included, 78 were operated after first CT, 123 underwent clinical and imaging surveillance, and 12 patients were not treated. CT6h did not anticipate imminent neurological deterioration. Early secondary deteriorating patients (9/123, 7.3%) did so before 6h after admission clustering between 3 and 4h (6/9, 66.7%). CT6h changed surgical decision making in one case (1/114, < 1%). Nine out of 106 (8.5%) patients managed conservatively after CT6h showed a late secondary clinical deterioration or failure of conservative treatment, eight out of which had stable size of hemorrhage in CT6h. There was no significant difference in lesion size at first CT related to the presence of coagulopathy, antiplatelet agents, or anticoagulant drugs for SDH or contusions. In patients with radiological progression of SDH in combined brain injury (CBI), coagulopathy was associated with a higher increase of lesion size (diameter increase > 6mm: 11.1% with vs. 2.8% without coagulopathy). This effect was not observed for contusions in CBI (volume increase > 6ml: 17.4% with vs. 22.7% without coagulopathy). Early routine follow-up CT does neither anticipate imminent neurological deterioration nor impact surgical decision making. A substantial number of patients with initially stable follow-up imaging need delayed surgery due to conservative treatment failure. If patients can be monitored clinically, surgical decision making depends on clinical status. Patients with coagulopathy do not present with larger lesions, but show a higher ratio of drastic increase in SDH in contrast to contusions.

Mechanisms of angiogenesis in tumour.

Angiogenesis is essential for tumour growth and metastasis. Antiangiogenic factor-targeting drugs have been approved as first line agents in a variety of oncology treatments. Clinical drugs frequently target the VEGF signalling pathway during sprouting angiogenesis. Accumulating evidence suggests that tumours can evade antiangiogenic therapy through other angiogenesis mechanisms in addition to the vascular sprouting mechanism involving endothelial cells. These mechanisms include (1) sprouting angiogenesis, (2) vasculogenic mimicry, (3) vessel intussusception, (4) vascular co-option, (5) cancer stem cell-derived angiogenesis, and (6) bone marrow-derived angiogenesis. Other non-sprouting angiogenic mechanisms are not entirely dependent on the VEGF signalling pathway. In clinical practice, the conversion of vascular mechanisms is closely related to the enhancement of tumour drug resistance, which often leads to clinical treatment failure. This article summarizes recent studies on six processes of tumour angiogenesis and provides suggestions for developing more effective techniques to improve the efficacy of antiangiogenic treatment.

The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma.

The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/β-catenin pathway, PTEN/PI3K/AKT pathway, TGF-β pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.

Vancomycin heteroresistance caused by unstable tandem amplifications of the vanM gene cluster on linear conjugative plasmids in a clinical Enterococcus faecium.

Vancomycin heteroresistance is prone to missed detection and poses a risk of clinical treatment failure. We encountered one clinical Enterococcus faecium strain, SRR12, that carried a complete vanM gene cluster but was determined as susceptible to vancomycin using the broth microdilution method. However, distinct subcolonies appeared within the clear zone of inhibition in the E-test assay, one of which, named SRR12-v1, showed high-level resistance to vancomycin. SRR12 was confirmed as heteroresistant to vancomycin using population analysis profiling and displayed "revive" growth curves with a lengthy lag phase of over 13 hours when exposed to 2-32 mg/L vancomycin. The resistant subcolony SRR12-v1 was found to carry an identical vanM gene cluster to that of SRR12 but a significantly increased vanM copy number in the genome. Long-read whole genome sequencing revealed that a one-copy vanM gene cluster was located on a pELF1-like linear plasmid in SRR12. In comparison, tandem amplification of the vanM gene cluster jointed with IS1216E was seated on a linear plasmid in the genome of SRR12-v1. These amplifications of the vanM gene cluster were demonstrated as unstable and would decrease accompanied by fitness reversion after serial passaging for 50 generations under increasing vancomycin pressure or without antibiotic pressure but were relatively stable under constant vancomycin pressure. Further, vanM resistance in resistant variants was verified to be carried by conjugative plasmids with variable sizes using conjugation assays and S1-pulsed field gel electrophoresis blotting, suggesting the instability/flexibility of vanM cluster amplification in the genome and an increased risk of vanM resistance dissemination.

Extracellular matrix stiffness modulates the mechanophenotypes and focal adhesions of colon cancer cells leading to their invasions via YAP1

Distal metastasis is the main cause of clinical treatment failure in patients with colon cancer. It is now known that the invasion and metastasis of cancer cells is precisely regulated by chemical and physical factors in vivo. However, the role of extracellular matrix (ECM) stiffness in colon cancer cell (CCCs) invasion and metastasis remains unclear. Here, bioinformatical analysis suggested that a high expression level of yes associated protein 1 (YAP1) was significantly associated with metastasis and poor prognosis in colon cancer patients. We further investigated the effects of polyacrylamide hydrogels with different stiffnesses (3, 20, and 38 ​kPa), which were simulated as ECM, on the mechanophenotype (F-actin cytoskeleton organization, electrophoretic rate, membrane fluidity, and Young's modulus) of CCCs. The results showed that a stiffer ECM could induce the maturation of focal adhesions and formation of stress fibers in CCCs, regulate their mechanophenotypes, and promote cell motility. We also demonstrated that the expression levels of YAP1 and paxillin were positively correlated in patients with colon cancer. YAP1 knockdown reduces paxillin clustering and cell motility and alters the cellular mechanophenotypes of CCCs. This is of great significance for an in-depth understanding of the invasion and metastatic mechanisms of colon cancer and for the optimization of clinical therapy from the perspective of mechanobiology.

Hyperbaric Oxygen‐Facilitated Cancer Treatment: A Minireview

Hypoxia in malignant tumors is a major factor in inducing the failure of clinical cancer treatment. Although several strategies have been developed to relieve hypoxia, most are still in the preclinical research phase. Therefore, hyperbaric oxygen (HBO), an approved adjuvant therapy for alleviating hypoxia clinically, is an excellent choice for enhancing the efficacy of cancer treatment that is impeded by tumor hypoxia. In this minireview, recent advances in HBO‐facilitated cancer treatment, including clinical applications and nanomedicine‐mediated cancer therapy are introduced. At the end of this minireview, the potential challenges faced by HBO therapy before clinical use are discussed. It is hoped that this review will provide a reference for future clinical research on the application of HBO in cancer treatment.

Chinese Expert Consensus on Second-line Treatment for Non-small Cell Lung Cancer with Negative Driver Gene Mutations

For advanced non-small cell lung cancer (NSCLC) patients with negative driver gene mutations, chemotherapy has always been the standard treatment option, and immune checkpoint inhibitors (ICIs) provide other treatment option for these patients. At present, the first-line treatment can choose chemotherapy, anti-angiogenic drugs or immunotherapy. Although the initial treatment can achieve a certain clinical curative effect, disease progression or treatment failure is eventually unavoidable. The second-line and subsequent treatments have poor efficacy and more effective drugs are needed clinically. An expert panel of respiratory medicine, pathology and medical oncology organized by Expert Committee on Non-small Cell Lung Cancer of the Chinese Society of Clinical Oncology conducted an in-depth discussion on evidences of clinical studies for second-line treatment of NSCLC patients with negative driver gene mutations, aiming to provide guidances for Chinese clinicians in choosing second-line treatment for NSCLC patients with negative driver gene mutations. .

Antibody-antibiotic conjugate targeted therapy for orthopedic implant-associated intracellular S. aureus infections

IntroductionTreating orthopedic implant-associated infections, especially those caused by Staphylococcus aureus (S. aureus), remains a significant challenge. S. aureus has the ability to invade host cells, enabling it to evade both antibiotics and immune responses during infection, which may result in clinical treatment failures. Therefore, it is critical to identify the host cell type of implant-associated intracellular S. aureus infections and to develop a strategy for highly targeted delivery of antibiotics to the host cells. ObjectivesIntroduced an antibody-antibiotic conjugate (AAC) for the targeted elimination of intracellular S. aureus. MethodsThe AAC comprises of a human monoclonal antibody (M0662) directly recognizes the surface antigen of S. aureus, Staphylococcus protein A, which is conjugated with vancomycin through cathepsin-sensitive linkers that are cleavable in the proteolytic environment of the intracellular phagolysosome. AAC, vancomycin and vancomycin combined with AAC were used in vitro intracellular infection and mice implant infection models. We then tested the effect of AAC in vivo and in vivo by fluorescence imaging, in vivo imaging, bacterial quantitative analysis and bacterial biofilm imaging. ResultsIn vitro, it was observed that AAC captured extracellular S. aureus and co-entered the cells, and subsequently released vancomycin to induce rapid elimination of intracellular S. aureus. In the implant infection model, AAC significantly improved the bactericidal effect of vancomycin. Scanning electron microscopy showed that the application of AAC effectively blocked the formation of bacterial biofilm. Further histochemical and micro-CT analysis showed AAC significantly reduced the level of bone marrow density (BMD) and bone volume fraction (BV/TV) reduction caused by bacterial infection in the distal femur of mice compared to vancomycin treatment alone. ConclusionsThe application of AAC in an implant infection model showed that it significantly improved the bactericidal effects of vancomycin and effectively blocked the formation of bacterial biofilms, without apparent toxicity to the host.

Dalbavancin utilization registry investigating value and effectiveness (DRIVE): Outcomes report on real-world use

ObjectivesDalbavancin has potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, and is approved for treatment of acute bacterial skin and skin structure infections (ABSSSI). We describe real-world use of dalbavancin in patients with ABSSSI, bloodstream infection (BSI), bone and joint infection (BJI), or other infection (OI). MethodsDalbavancin Utilization Registry Investigating Value and Effectiveness (DRIVE) was a phase 4 observational, multicenter, retrospective study of the real-world use of dalbavancin in adults across the United States. Data collected March 2017 – November 2018, at hospitals, intensive care units, and outpatient parenteral antibiotic therapy units, included patient demographics, diagnosis, microbiology, antibiotic use, clinical outcome, and adverse events up to 60 days after the last dose of dalbavancin. Patients were treated entirely at the physicians’ discretion. All patients who received ≥ 1 dose of dalbavancin between February 2016 and the end of the data collection period were included in the safety population. Patients with clear clinical success or failure of dalbavancin treatment, according to definitions similar to those used in the dalbavancin phase 3 trials, were included in the evaluable population and the post-hoc analysis. ResultsThe safety population comprised 1168 patients treated at 31 healthcare sites. Median cumulative dalbavancin dose was 1500 mg for all infection categories, most commonly as 1 infusion; 36.9 % of BSI patients and 58.6 % of BJI patients received ≥ 2 infusions; most were treated as outpatients. Serious adverse drug reactions were reported in 0.7 % of patients overall. Clinical success was achieved in 747/815 (91.7 %) evaluable patients with ABSSSI (BSI, 43/48 [89.6 %]; BJI, 75/87 [86.2 %]; OI, 7/7 [100 %]). ConclusionsDalbavancin demonstrated high rates of real-world clinical success and safety when treating patients for suspected or confirmed Gram-positive infections.

Risk factors for clinical treatment failure and death in patients with ceftazidime-avibactam-resistant Gram-negative bacteria: A single-centre retrospective analysis

ObjectiveIn recent years, the number of Gram-negative bacteria (GNB) resistant to ceftazidime-avibactam (CZA) isolated from clinic has been increasing. We aimed to evaluate the clinical efficacy in patients with CZA-resistant GNB infections, and analyze the risk factors for clinical treatment failure and death. MethodsClinical data of patients with CZA-resistant GNB infections were collected retrospectively, and the influencing factors were analyzed by binary logistic regression. ResultsA total of 75 patients with CZA-resistant GNB infections were enrolled in the study, and the clinical effective rate was 56% (42/75). Multivariate analysis showed that continuous renal replacement therapy (CRRT) during anti-infection treatment was an independent risk factor for clinical treatment failure (OR 0.177, 95% CI 0.05–0.63, p ​= ​0.008). The 28-day mortality rate in 75 patients was 18.7% (14/75). Multivariate analysis showed that the regimen of colistin E 750,000 U q12h (OR 0.020, 95% CI 0.00–0.56, ​p ​= ​0.021), co-administration of tigecycline (OR 8.851, 95% CI 2.38–1316.87, ​p ​= ​0.012) and CRRT during anti-infection treatment (OR 79.610, 95% CI 4.87–1300.26, p ​= ​0.002) were independent affecting factors for 28-day mortality in patients with CZA-resistant GNB infections. ConclusionsPatients with CZA-resistant GNB infections had a higher possibility of clinical treatment failure and death. The results of the study based on small sample size from a single center showed that clinical treatment failure and death were more likely to happen in patients on CRRT, and the regimen of colistin E 750,000 U q12h or co-administration of tigecycline may reduce or increase mortality, respectively. Further validation in rigorously designed multicenter clinical studies with larger sample sizes is needed.