Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors.

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRKWT, TRKG595R and TRKG667C with IC50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC50 = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

Risk factors of different mortality periods in older patients with end-stage renal disease undergoing urgent-start peritoneal dialysis: a retrospective observational study.

BACKGROUND: The first six months of therapy represents a high-risk period for peritoneal dialysis (PD) failure. The risk of death in the first six months is higher for older patients treated with urgent-start PD (USPD). However, there are still gaps in research on mortality and risk factors for death in this particular group of patients. We aimed to investigate mortality rates and risk factors for death in older patients with end-stage renal disease (ESRD) receiving USPD within and after six months of therapy. METHODS: We retrospectively studied the clinical information of older adults aged ≥ 65 years with ESRD who received USPD between 2013 and 2019 in five Chinese hospitals. Patients were followed up to June 30, 2020. The mortality and risk factors for death in the first six months of USPD treatment and beyond were analyzed. RESULTS: Of the 379 elderly patients in the study, 130 died over the study period. During the follow-up period, the highest number (45, 34.6%) of deaths occurred within the first six months. Cardiovascular disease was the most common cause of death. The baseline New York Heart Association (NYHA) class III-IV cardiac function [hazard ratio (HR) = 2.457, 95% confidence interval (CI): 1.200-5.030, p = 0.014] and higher white blood cell (WBC) count (HR = 1.082, 95% CI: 1.021-1.147, p = 0.008) increased the mortality risk within six months of USPD. The baseline NYHA class III-IV cardiac function (HR = 1.945, 95% CI: 1.149-3.294, p = 0.013), lower WBC count (HR = 0.917, 95% CI: 0.845-0.996, p = 0.040), lower potassium levels (HR = 0.584, 95% CI: 0.429-0.796, p = 0.001), and higher calcium levels (HR = 2.160, 95% CI: 1.025-4.554, p = 0.043) increased the mortality risk after six months of USPD. CONCLUSION: Different risk factors correlated with mortality in older adults with ESRD within and after six months of undergoing USPD, including baseline NYHA class III-IV cardiac function, WBC count, potassium, and calcium levels.

Discovery of imidazo[1,2-b]pyridazine macrocyclic derivatives as novel ALK inhibitors capable of combating multiple resistant mutants.

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) often loses effectiveness against non-small cell lung malignancies (NSCLCs) with ALK gene rearrangements (ALK+). 19 novel imidazo[1,2-b]pyridazine macrocyclic derivatives were designed, synthesized, and tested for their biological activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly the G1202R mutation and the lorlatinib-resistant L1196M/G1202R double mutations. Of all the target substances, O-10 had the most effective enzymatic inhibitory activity, with IC50 values for ALKWT, ALKG1202R, and ALKL1196M/G1202R of 2.6, 6.4, and 23 nM, respectively. O-10, on the other hand, reduced the growth of ALK-positive Karpas299, BaF3-EML4-ALKG1202R, and BaF3-EML4-ALKL1196M/G1202R cells with IC50 values of 38, 52, and 64 nM, respectively. This was equally effective to the reference drug Repotrectinib (IC50 = 40, 164, and 208 nM). The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound O-10 were further evaluated. O-10 was regarded as an effective ALK inhibitor for the treatment of mutations overall.

Formononetin Inhibits Mast Cell Degranulation to Ameliorate Compound 48/80-Induced Pseudoallergic Reactions.

Formononetin (FNT) is a plant-derived isoflavone natural product with anti-inflammatory, antioxidant, and anti-allergic properties. We showed previously that FNT inhibits immunoglobulin E (IgE)-dependent mast cell (MC) activation, but the effect of FNT on IgE-independent MC activation is yet unknown. Our aim was to investigate the effects and possible mechanisms of action of FNT on IgE-independent MC activation and pseudoallergic inflammation. We studied the effects of FNT on MC degranulation in vitro with a cell culture model using compound C48/80 to stimulate either mouse bone marrow-derived mast cells (BMMCs) or RBL-2H3 cells. We subsequently measured ß-hexosaminase and histamine release, the expression of inflammatory factors, cell morphological changes, and changes in NF-κB signaling. We also studied the effects of FNT in several in vivo murine models of allergic reaction: C48/80-mediated passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA), and 2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD). The results showed that FNT inhibited IgE-independent degranulation of MCs, evaluated by a decrease in the release of ß-hexosaminase and histamine and a decreased expression of inflammatory factors. Additionally, FNT reduced cytomorphological elongation and F-actin reorganization and attenuated NF-κB p65 phosphorylation and NF-κB-dependent promoter activity. Moreover, the administration of FNT alleviated pseudoallergic responses in vivo in mouse models of C48/80-stimulated PCA and ASA, and DNCB-induced AD. In conclusion, we suggest that FNT may be a novel anti-allergic drug with great potential to alleviate pseudoallergic responses via the inhibition of IgE-independent MC degranulation and NF-κB signaling.

[Clinical Outcome and Risk Factors of Treatment Failure of Peritoneal Dialysis Associated Peritonitis Caused by Klebsiella Pneumoniae:A Multicenter Study].

Objective To investigate the treatment outcomes,prognosis,and risk factors of treatment failure of peritoneal dialysis associated peritonitis (PDAP) caused by Klebsiella pneumoniae,and thus provide clinical evidence for the prevention and treatment of this disease. Methods The clinical data of PDAP patients at four peritoneal dialysis centers from January 1,2014 to December 31,2019 were collected retrospectively.The treatment outcomes and prognosis were compared between the patients with PDAP caused by Klebsiella.pneumoniae and that caused by Escherichia coli.Kaplan-Meier method was employed to establish the survival curve of technical failure,and multivariate Logistic regression to analyze the risk factors of the treatment failure of PADP caused by Klebsiella pneumoniae. Results In the 4 peritoneal dialysis centers,1034 cases of PDAP occurred in 586 patients from 2014 to 2019,including 21 cases caused by Klebsiella pneumoniae and 98 cases caused by Escherichia coli.The incidence of Klebsiella pneumoniae caused PDAP was 0.0048 times per patient per year on average,ranging from 0.0024 to 0.0124 times per patient per year during 2014-2019.According to the Kaplan-Meier survival curve,the technical failure rate of Klebsiella pneumoniae caused PDAP was higher than that of Escherichia coli caused PDAP (P=0.022).The multivariate Logistic regression model showed that long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP (OR=1.082,95%CI=1.011-1.158,P=0.023).Klebsiella pneumoniae was highly sensitive to amikacin,meropenem,imipenem,piperacillin,and cefotetan,and it was highly resistant to ampicillin (81.82%),cefazolin (53.33%),tetracycline (50.00%),cefotaxime (43.75%),and chloramphenicol (42.86%). Conclusion The PDAP caused by Klebsiella pneumoniae had worse prognosis than that caused by Escherichia coli,and long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP.

Design, synthesis and biological evaluation of novel macrocyclic derivatives bearing aniline pyrimidine scaffolds as EGFR-TKIs.

Based on EGFR-TKI Osimertinib as lead compound, a series of novel macrocyclic derivatives bearing aniline pyrimidine scaffolds were designed and synthesized by macrocyclization. Their structures were identified by 1H NMR, 13C NMR, 19F NMR and HRMS. The pharmacological activities of the target compounds were tested and the preliminary structure-activity relationship was discussed. Among them, 17-membered ring compound H1 displayed the best inhibitory activities against EGFRL858R/T790M and EGFRd746-750/T790M with IC50 value of 2.92 nM and 0.34 nM, respectively. Exhilaratingly, 17-membered ring compound H7 possessed the most potent antiproliferative activity against BaF3-EGFRdel19/T790M cell lines (IC50 = 0.035 µm), which rivaled that of Osimertinib (IC50 = 0.033 µm).

Influence of Early-Onset Peritonitis on Mortality and Clinical Outcomes in ESRD Patients with Diabetes Mellitus on Peritoneal Dialysis: A Retrospective Multicenter Study.

INTRODUCTION: The impact of early-onset peritonitis (EOP) on patients with diabetes undergoing peritoneal dialysis (PD) has not been adequately addressed. We therefore sought to investigate the effects of EOP on the therapeutic response to management and long-term prognostic outcomes in patients with diabetes undergoing PD. METHODS: For this retrospective cohort study, we analyzed the data for patients with end-stage renal disease, who were also suffering from diabetes mellitus and had undergone PD between January 1, 2013, and December 31, 2018. EOP was defined as the first episode of peritoneal dialysis-related peritonitis (PDAP) occurring within 12 months of PD initiation. All patients were divided into an EOP group and a later-onset peritonitis (LOP) group. Clinical data, treatment results, and outcomes were compared between groups. RESULTS: Ultimately, 202 patients were enrolled for the analysis. Compared to the EOP group, the LOP group had more Streptococcus (p = 0.033) and Pseudomonas (p = 0.048). Patients with diabetes in the EOP group were less likely to have PDAP-related death (OR 0.13, CI: 0.02-0.82, p = 0.030). Patients with diabetes in the EOP group were more likely to have multiple episodes of PDAP and had higher rates of technical failure and poorer patient survival than those in the LOP group, as indicated by Kaplan-Meier analysis (p = 0.019, p = 0.004, and p < 0.001). In the multivariate Cox proportional hazards model, EOP was a significant predictor for multiple PDAP (HR 4.20, CI: 1.48-11.96, p = 0.007), technical failure (HR 6.37, CI: 2.21-18.38, p = 0.001), and poorer patient survival (HR 3.09, CI: 1.45-6.58, p = 0.003). CONCLUSIONS: The occurrence of EOP is significantly associated with lower rates of PDAP-related death and poorer clinical outcomes in patients with diabetes undergoing PD.

Feasibility of a break-in period of less than 24 hours for urgent start peritoneal dialysis: a multicenter study.

PURPOSE: Urgent start peritoneal dialysis (USPD) is an effective therapeutic method for end-stage renal disease (ESRD). However, whether it is safe to initiate peritoneal dialysis (PD) within 24 h unclear. We examined the short-term outcomes of a break-in period (BI) of 24 h for patients undergoing USPD. METHODS: This real-world, multicenter, retrospective cohort study evaluated USPD patients from five centers from January 2013 to August 2020. Patients were divided into BI ≤ 24 h or BI > 24 h groups. The Primary outcomes included incidence of mechanical and infectious complications. The secondary outcome was technique failure. Moreover, we presented a subgroup analysis for patients who did not receive temporary hemodialysis (HD). RESULTS: A total of 871 USPD patients were included: 470 in the BI ≤ 24 h and 401 in the BI > 24 h groups. Mechanical and infectious complications did not differ between the two groups across the follow-up timepoints (2 weeks, 1 month, 3 months, and 6 months) (p > 0.05). Multiple logistic regression analysis revealed that BI ≤ 24 h was not an independent risk factor for mechanical complications, catheter migration, or infectious complications (p > 0.05). A BI ≤ 24 h was not an independent significant risk factor for technique failure by multivariate Cox regression analysis (p > 0.05). The subgroup analysis of patients who did not receive temporary HD returned the same results. CONCLUSION: Initiating PD within 24 h of catheter insertion was not associated with increased mechanical complications, infectious complications, or technique failures.

[Clinical Characteristics and Treatment Outcome of Pseudomonas Peritoneal Dialysis-associated Peritonitis].

Objective To explore the clinical characteristics and treatment of Pseudomonas peritoneal dialysis-associated peritonitis(PsP). Methods The data of patients receiving peritoneal dialysis in four tertiary hospitals in Jilin province from 2015 to 2019 were retrospectively analyzed.According to the etiological classification,the patients with peritoneal dialysis-associated peritonitis(PDAP)were classified into PsP group and non-PsP group.The incidence of PsP was calculated,and the clinical characteristics and treatment outcomes of the two groups were compared.Kaplan-Meier method was used to draw the survival curve,and Cox regression was performed to analyze the risk factors affecting the technical failure of PsP.The treatment options of Pseudomonas aeruginosa-caused PDAP and the drug sensitivity of PsP were summarized. Results A total of 1530 peritoneal dialysis patients with complete data were included in this study,among which 439 patients had 664 times of PDAP.The incidence of PsP was 0.007 episodes/patient-year.PsP group had higher proportion of refractory peritonitis(41.38% vs.19.69%,P=0.005),lower cure rate(55.17% vs.80.79%, P=0.001),and higher extubation rate(24.14% vs.7.09%,P=0.003)than non-PsP group.The technical survival rate of PsP group was lower than that of non-PsP group(P<0.001).Multivariate Cox regression analysis showed that Pseudomonas aeruginosa was an independent risk factor for technical failure in patients with PsP(HR=9.020,95%CI=1.141-71.279,P=0.037).Pseudomonas was highly sensitive to amikacin,meropenem,and piperacillin-tazobactam while highly resistant to compound sulfamethoxazole,cefazolin,and ampicillin. Conclusion The treatment outcome of PsP is worse than that of non-PsP,and Pseudomonas aeruginosa is an independent risk factor for technical failure of PsP.

A simplified percutaneous technique for inserting Tenckhoff catheters for peritoneal dialysis.

AIM: Successful catheter implantation is highly essential for delivering effective peritoneal dialysis (PD). The aim of the present study was to describe a newly developed, minimally invasive percutaneous technique for providing safe, timely, and effective peritoneal catheter insertion and assess the long-term outcome. MATERIALS AND METHODS: 100 PD catheters were placed in 100 consecutive patients by a nephrologist using the modified percutaneous technique with a special trocar, from August 1, 2010 to December 31, 2011. The patients were followed up until October 31, 2015. Demographic and clinical features of study subjects, duration of hospital stay, follow-up time, complications, and catheter survival were assessed in all patients. RESULTS: The patient study group included 47 men and 53 women, with a mean age of 55.3 ± 13.7 years. The mean hospitalization time was 17.1 ± 8.6 days, and the mean duration of follow-up was 44.7 ± 15.1 months. 71 patients were still on continuous ambulatory peritoneal dialysis at the time of study completion. Peritonitis was the most common complication observed, with an incidence of 28%. None of the patients experienced surgical complications such as bleeding or incisional hernia. The mean catheter survival time was 57.0 ± 1.5 months. CONCLUSION: Peritoneal catheter placement using our modified percutaneous technique is simple, safe, minimally invasive, and efficient. It carried less morbidity with respect to bowel perforation, catheter-related infection, and exit-site leak.
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Enantiomeric separation of vilanterol trifenatate by chiral liquid chromatography.

Vilanterol trifenatate is a novel chiral long-acting ß2-agonist developed. Vilanterol combined with inhaled corticosteroids can treat COPD and asthma. A simple liquid chromatographic method is developed for the quantitative determination of R-vilanterol and S-vilanterol (impurity S). HPLC separation was achieved on Chiralpak ID (250 × 4.6 mm; particle size 5 µm) column using hexane-ethanol-ethanolamine (75:25:0.1, v/v/v) as mobile phase at a flow rate of 1.0 mL/min. The resolution is greater than 3.3. Ethanolamine in the mobile phase is vital to enhance chromatographic efficiency and resolution between the isomers. The method was validated with respect to accuracy, specificity, precision, LOD, LOQ, linearity, and robustness as ICH guidelines.

Amperometric sensor for dopamine based on surface-graphenization pencil graphite electrode prepared by in-situ electrochemical delamination.

A surface-graphenized pencil graphite electrode (SGPGE) served as an amperometric sensor for dopamine (DA). It was prepared through a one-step in-situ electrochemical graphene delamination. The graphite particles on the outer surface of the pencil graphite electrode (PGE) were delaminated by controlling the electrochemical delaminating conditions such as the applied anodic voltage and polarization duration, as well as the kind of electrolytes. The best conditions were identified by scanning electron microscopy, Raman spectra, cyclic voltammetry and differential pulse voltammetry (DPV). As a result, the electrode was endowed with an optimum combination of graphene delamination efficiency and electrochemical activity. The electrochemical treatment activates the surface sensing sites and improves the sensing performance. The NaOH-teated anodically graphenized electrode was used to sense dopamine by DPV. The best oxidation voltage of dopamine is at around 0.17 V (vs. SCE). The electrode respondsy to dopamine in the ranges of 0.15 to 45 µM, the detection limit is 8.2 nM (S/N = 3), and the sensitivity is 20.81 µA µM-1 cm-2. In real human urine samples, the sensor exhibited detection recoveries of 97.4-98.8% and low relative standard deviations of 3.49-3.92%. Graphical abstract Schematic presentation of a surface-graphenized pencil graphite electrode (SGPGE) for detecting dopamine. It was prepared by a one-step in situ electrochemical graphene delamination.

Immobilization of Enzymes on a Phospholipid Bionically Modified Polysulfone Gradient-Pore Membrane for the Enhanced Performance of Enzymatic Membrane Bioreactors.

Enzymatic membrane bioreactors (EMBRs), with synergistic catalysis-separation performance, have increasingly been used for practical applications. Generally, the membrane properties, particularly the pore structures and interface interactions, have a significant impact on the catalytic efficiency of the EMBR. Therefore, a biomimetic interface based on a phospholipid assembled onto a polysulfone hollow-fiber membrane with perfect radial gradient pores (RGM-PSF) has been prepared in this work to construct a highly efficient and stable EMBR. On account of the special pore structure of the RGM-PSF with the apertures decreasing gradually from the inner side to the outer side, the enzyme molecules could be evenly distributed on the three-dimensional skeleton of the membrane. In addition, the supported phospholipid layer in the membrane, prepared by physical adsorption, was used for the immobilization of the enzymes, which provides sufficient linkage to prevent the enzymes from leaching but also accommodates as many enzyme molecules as possible to retain high bioactivity. The properties of the EMBR were studied by using lipase from Candida rugosa for the hydrolysis of glycerol triacetate as a model. Energy-dispersive X-ray and circular dichroism spectroscopy were employed to observe the effect of lecithin on the membrane and structure changes in the enzyme, respectively. The operational conditions were investigated to optimize the performance of the EMBR by testing substrate concentrations from 0.05 to 0.25 M, membrane fluxes from 25.5 to 350.0 L·m-2·h-1, and temperatures from 15 to 55 °C. As a result, the obtained EMBR showed a desirable performance with 42% improved enzymatic activity and 78% improved catalytic efficiency relative to the unmodified membrane.

Chemical Synthesis of the ODM-201's Diastereomers through an Efficient Intramolecular 1,3-Dipolar Cycloaddition.

An efficient synthesis of ODM-201's diastereomers has been developed from (R)-methyl 3-hydroxybutanoate or (S)-methyl 3-hydroxybutanoate, respectively, with high overall yield and excellent diastereomeric purity. The key step in this synthesis is the preparation of the key intermediate (R)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid or (S)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid through intramolecular 1,3-dipolar cycloaddition of the vinyl diazo carbonyl compounds.

Molecular dynamics simulations of the enhanced recovery of confined methane with carbon dioxide.

For the first time, the enhanced recovery of confined methane (CH4) with carbon dioxide (CO2) is investigated through molecular dynamics simulations. The adsorption energy and configuration of CH4 and CO2 on the carbon surface were compared, which shows that CO2 is a good candidate in displacing confined CH4. The energy barrier required for displacing CH4 by CO2 injection was found to depend on the displacement angle. When CO2 approached vertically to the carbon surface, the displacement of CH4 occurred most easily. The curvature and size effects of the carbon nanopores on CH4 recovery were revealed and indicated that there exists an optimum pore size making the displacement occur most efficiently. The underlying mechanisms of these phenomena were uncovered. Our findings and related analyses may help to understand CO2 enhanced gas recovery from the atomic level and assist the future design in engineering.

Optimizing 3d electronic structure of LaCoO3 based on spin state tuning for enhancing photo-Fenton activity on tetracycline degradation.

The water pollution caused by the abuse of antibiotics has significant harmful effects on the environment and human health. The photo-Fenton process is currently the most effective method for removing antibiotics from water, but it encounters challenges such as inadequate response to visible light, low yield and utilization of photogenerated electrons, and slow electron transport. In this study, spin state regulation was introduced into the photo-Fenton process, and the spin state of Co3+ was regulated through Ce displacement doping. The intermediate-spin state Ce-LaCoO3 could degrade 91.6 % of tetracycline within 120 min in the photo-Fenton system, which is 15.2 % higher than that of low-spin state LaCoO3. The improved degradation effect is attributed to the reasons that Ce-LaCoO3 in the intermediate-spin state have lower band gap, better charge transfer ability, and stronger adsorption capacity of H2O2, which can accelerate the redox cycle of Co2+/Co3+ and promote the generation of ·OH. This study presents a unique strategy for synthesizing efficient photo-Fenton materials to treat antibiotic wastewater effectively.

Tuning structural and mechanical properties of two-dimensional molecular crystals: the roles of carbon side chains.

A key requirement for the future applicability of molecular electronics devices is a resilience of their properties to mechanical deformation. At present, however, there is no fundamental understanding of the origins of mechanical properties of molecular films. Here we use quinacridone, which possesses flexible carbon side chains, as a model molecular system to address this issue. Eight molecular configurations with different molecular coverage are identified by scanning tunneling microscopy. Theoretical calculations reveal quantitatively the roles of different molecule-molecule and molecule-substrate interactions and predict the observed sequence of configurations. Remarkably, we find that a single Young's modulus applies for all configurations, the magnitude of which is controlled by side chain length, suggesting a versatile avenue for tuning not only the physical and chemical properties of molecular films but also their elastic properties.

Safety of a 24-h-or-less break-in period in elderly patients undergoing urgent-start peritoneal dialysis: A multicenter retrospective cohort study.

BACKGROUND: Several elderly patients with end-stage renal disease (ESRD) had to undergo urgent-start peritoneal dialysis (USPD). This study aimed to determine whether break-in period (BI) within 24 h was feasible in elderly patients undergoing USPD. METHODS: Patients with ESRD who underwent PD at five hospitals were screened. Patients were divided into the BI ≤24 h and >24 h groups. Complications were compared between the two groups. Multivariate logistic regression model was used to determine whether BI ≤24 h was associated with complications. RESULTS: A total of 175 elderly patients were included: BI ≤24 h group, 78; and BI >24 h group, 97. There was no significant difference in the rate of complications between the two groups (all p > 0.05). Furthermore, BI ≤24 h was not an independent risk factor for complications (all p > 0.05). CONCLUSIONS: Starting PD within 24 h after PD catheter insertion was feasible in elderly ESRD patients.

Clinical features and risk factors of catheter removal among 1062 episodes of peritoneal dialysis-associated peritonitis: A multicenter 7-year study.

INTRODUCTION: Studies focusing on catheter removal and the pathogenic spectrum of peritoneal dialysis-associated peritonitis (PDAP) need to be updated. METHODS: Data were collected from four peritoneal dialysis (PD) centers. Peritonitis rates were compared using Poisson regression and Logistic regression was used to examine the risk factors for catheter removal. RESULTS: The PD duration (odds ratio [OR], 1.021; 95% confidence interval [CI], 1.010-1.032), number of previous PDAP episodes (OR, 1.267; 95% CI, 1.039-1.545), dialysate white cell count >100 × 106 /L on Day 5 of PDAP (OR, 6.088; 95% CI, 3.277-11.312), Pseudomonas aeruginosa (OR, 4.122; 95% CI, 1.071-15.874) and polymicrobial infections (OR, 3.257; 95% CI, 1.519-6.982) were independent predictors of catheter removal (p < 0.05). The prevalence of polymicrobial peritonitis and fungal peritonitis has increased (p < 0.05). CONCLUSION: Attention should be paid to patients with long PD duration or a history of previous episodes of PDAP characteristics.

Multidrug-resistant organism-peritoneal dialysis associated peritonitis: clinical and microbiological features and risk factors of treatment failure.

Background: Multidrug-resistant (MDR) bacterial infection causes difficulty in the therapy of peritoneal dialysis-associated peritonitis (PDAP); however, there are few studies on multidrug-resistant organism (MDRO)-PDAP. In view of growing concerns about MDRO-PDAP, the aim of this study was to investigate the clinical features, risk factors of treatment failure, and causative pathogens of MDRO-PDAP. Methods: In total, 318 patients who underwent PD between 2013 and 2019 were included in this multicenter retrospective study. Clinical features, patient outcomes, factors related to treatment failure, and microbiological profiles associated with MDRO-PDAP were analyzed and risk factors for treatment failure associated with MDR-Escherichia coli (E. coli) were further discussed. Results: Of 1,155 peritonitis episodes, 146 eligible episodes of MDRO-PDAP, which occurred in 87 patients, were screened. There was no significant difference in the composition ratio of MDRO-PDAP between 2013-2016 and 2017-2019 (p > 0.05). E. coli was the most prevalent MDRO-PDAP isolate, with high sensitivity to meropenem (96.0%) and piperacillin/tazobactam (89.1%). Staphylococcus aureus was the second most common isolate and was susceptible to vancomycin (100%) and linezolid (100%). Compared to non-multidrug-resistant organism-PDAP, MDRO-PDAP was associated with a lower cure rate (66.4% vs. 85.5%), higher relapse rate (16.4% vs. 8.0%), and higher treatment failure rate (17.1% vs.6.5%). Dialysis age [odds ratio (OR): 1.034, 95% confidence interval (CI): 1.016-1.052, p < 0.001] and >2 previous peritonitis episodes (OR: 3.400, 95% CI: 1.014-11.400, p = 0.047) were independently associated with treatment failure. Furthermore, longer dialysis age (OR: 1.033, 95% CI: 1.003-1.064, p = 0.031) and lower blood albumin level (OR: 0.834, 95% CI: 0.700-0.993, p = 0.041) increased the risk of therapeutic failure for MDR-E. coli infection. Conclusion: The proportion of MDRO-PDAP has remained high in recent years. MDRO infection is more likely to result in worse outcomes. Dialysis age and previous multiple peritonitis infections were significantly associated with treatment failure. Treatment should be promptly individualized based on local empirical antibiotic and drug sensitivity analyses.