Temporal Shifts in Etiological Agents and Antibiotic Resistance Patterns of Biliary Tract Infections in Sichuan Province, China (2017-2023).

Purpose: We analyzed the pathogenic bacteria and antibiotic resistance distributions in patients with biliary tract infections (BTI) using samples from the Antimicrobial Resistant Investigation Network of Sichuan Province (ARINSP) to promote the rational use of antibiotics to reduce multidrug resistance. Patients and Methods: Participating hospitals identified isolates between 2017 and 2023 and conducted antimicrobial susceptibility tests. Isolated bacteria were identified and tested for drug sensitivity using MOLDI-TOF mass spectrometry system, VITEK automated drug sensitivity system and paper diffusion method, and the results were interpreted with reference to CLSI M100 30th edition standards. WHONET 5.6 was used to analyze the results. Results: In total, 25,573 bacterial isolates were collected; 18,134 were Gram-negative (70.9%). The top five most frequently isolated bacteria were Escherichia coli (8,181/25,573; 32.0%), Klebsiella pneumoniae (3,247/25,573; 12.7%), Enterococcus faecium (2,331/25,573; 9.1%), Enterococcus faecalis (1,714/25,573; 6.7%), and Enterobacter cloacae (1,429/25,573; 5.6%). E. coli and E. faecalis slowly declined over time, while K. pneumoniae slowly increased; E. faecium frequency was stable; E. coli resistance to ampicillin was the highest among all antibiotics tested; resistance rates decreased with the addition of sulbactam. K. pneumoniae resistance to aztreonam, imipenem, meropenem, ertapenem, and chloramphenicol remained low. E. cloacae was highly resistant to cephalosporins, especially cefoxitin and cefazolin. E. faecalis' resistance to teicoplanin remained low, decreasing from 6.9% in 2017 to 0.0% in 2019 before stabilizing. Conclusion: The most frequently isolated bacteria from patients with BTIs were Enterobacteriaceae, including E. coli and K. pneumoniae, followed by E. faecium and E. faecalis. Isolates exhibited high resistance to routinely used antibiotics (cephalosporins) and were highly sensitive to tigecycline, carbapenem, amikacin, and vancomycin. The results guide the rational use and continual revision of antibiotic regimens for BTIs to reduce antibiotic resistance.

Modification of carbapenemase inhibition test and comparison of its performance with NG-Test CARBA 5 for detection of carbapenemase-producing Enterobacterales.

AIMS: Adequately and accurately identifying carbapenemase-producing Enterobacterales (CPE) is vital for selecting appropriate antimicrobial therapy and implementing effective infection control measures. This study aims to optimize the phenotypic detection method of carbapenemase for routine diagnostics in clinical microbiology laboratories. METHODS AND RESULTS: Carbapenemase genes in 2665 non-duplicate CRE clinical strains collected from various regions of China were confirmed through whole-genome sequencing (WGS). The carbapenemase inhibition test (CIT) was conducted and interpreted using different methods and breakpoints, then compared with the NG-Test CARBA 5 for carbapenemase detection. The diagnostic performance of the CIT method was optimal when the carbapenemase types were determined by comparing the inhibition zone diameters of the imipenem disc with 3-aminophenylboronic acid (APB) plus ethylenediaminetetraacetic acid (EDTA) to those of the imipenem disc with either APB or EDTA alone, with a breakpoint of 4 mm. The overall sensitivities of the current CIT, the modified CIT, and NG-Test CARBA 5 were 91.4%, 94.9%, and 99.9%, respectively. For detecting isolates co-producing Klebsiella pneumoniae carbapenemase (KPC) and metallo-ß-lactamases (MBLs), the modified CIT method had higher sensitivity than the current method (70.0% vs. 53.3%), though this difference was not statistically significant (P = 0.063). The NG-Test CARBA 5 showed excellent performance for multi-carbapenemases diagnosis, with sensitivity and specificity of 97.1% and 100%, respectively. CONCLUSIONS: Optimizing and standardizing the CIT method for clinical use is necessary. It has certain advantages in diagnosing multi-carbapenemase and rare carbapenemase production. However, for identifying common carbapenemase types, the NG-Test CARBA 5 demonstrated superior performance.

Exposure-response modelling of osimertinib in patients with non-small cell lung cancer.

AIMS: Osimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events. METHODS: Comprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUCss) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis. RESULTS: E-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUCss; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control. CONCLUSIONS: E-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

Adjuvant Osimertinib in Patients With Stage IB to IIIA EGFR Mutation-Positive NSCLC After Complete Tumor Resection: ADAURA China Subgroup Analysis.

Introduction: In Chinese patients with NSCLC, prevalence of EGFR-mutated (EGFRm) disease is high. In the global phase 3 ADAURA study (NCT02511106), adjuvant osimertinib was found to have a statistically significant and clinically meaningful improvement in disease-free survival (DFS) versus placebo in resected stage IB to IIIA EGFRm NSCLC. We present efficacy and safety data from a subgroup analysis of 159 Chinese patients enrolled in the People's Republic of China from ADAURA. Methods: In ADAURA, patients with completely resected stage IB to IIIA EGFRm (exon 19 deletion/exon 21 L858R) NSCLC were randomized 1:1 to receive osimertinib (80 mg once daily) or placebo for 3 years or until disease recurrence/discontinuation. Adjuvant chemotherapy was permitted before randomization, per physician/patient choice. Primary end point was investigator-assessed DFS in stage II to IIIA disease; secondary end points included DFS in stage IB to IIIA (overall population), overall survival, health-related quality of life (HRQoL), and safety. Results: Of 682 patients enrolled globally, 159 patients in the People's Republic of China were included in this subgroup analysis (osimertinib n = 77; placebo n = 82). Baseline characteristics were balanced across the treatment arms. At data cutoff, stage II to IIIA DFS hazard ratio (HR) was 0.23 (95% confidence interval [CI]: 0.13-0.42; maturity 59%); stage IB to IIIA DFS HR was 0.29 (95% CI: 0.17-0.48; maturity 42%). At 13% maturity (21 deaths), HR for overall survival in the stage IB to IIIA population was 0.51 (95% CI: 0.21-1.20). HRQoL was maintained from baseline, and safety was consistent with the global population. Conclusions: In this population of Chinese patients from ADAURA, adjuvant osimertinib was found to have a clinically meaningful improvement in DFS versus placebo, with maintained HRQoL and a safety profile consistent with the global study population.

Pan-Tumor Analytical Validation and Osimertinib Clinical Validation in EGFR Mutant Non-Small-Cell Lung Cancer, Supporting the First Next-Generation Sequencing Liquid Biopsy in Vitro Diagnostic.

Comprehensive genotyping is necessary to identify therapy options for patients with advanced cancer; however, many cancers are not tested, partly because of tissue limitations. Next-generation sequencing (NGS) liquid biopsies overcome some limitations, but clinical validity is not established and adoption is limited. Herein, clinical bridging studies used pretreatment plasma samples and data from FLAURA (NCT02296125; n = 441) and AURA3 (NCT02151981; n = 450) pivotal studies to demonstrate clinical validity of Guardant360 CDx (NGS LBx) to identify patients with advanced EGFR mutant non-small-cell lung cancer who may benefit from osimertinib. The primary end point was progression-free survival (PFS). Patients with EGFR mutation as identified by NGS LBx had significant PFS benefit with first-line osimertinib over standard of care (15.2 versus 9.6 months; hazard ratio, 0.41; P < 0.0001) and with later-line osimertinib over chemotherapy (8.3 versus 4.2 months; hazard ratio, 0.34; P < 0.0001). PFS benefits were similar to the original trial cohorts selected by tissue-based EGFR testing. Analytical validation included accuracy, precision, limit of detection, and specificity. Analytical validity was established for EGFR mutation detection and pan-tumor profiling. Panel-wide limit of detection was 0.1% to 0.5%, with 98% to 100% per-sample specificity. Patients with EGFR mutant non-small-cell lung cancer by NGS LBx had improved PFS with osimertinib, confirming clinical validity. Analytical validity was established for guideline-recommended therapeutic targets across solid tumors. The resulting US Food and Drug Administration approval of NGS LBx demonstrated safety and effectiveness for its intended use and is expected to improve adherence to guideline-recommended targeted therapy use.

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

In vitro activity of ceftazidime-avibactam, imipenem-relebactam, aztreonam-avibactam, and comparators toward carbapenem-resistant and hypervirulent Klebsiella pneumoniae isolates.

IMPORTANCE: To our knowledge, this is the first study to report the in vitro activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA), toward carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) strains. Our in vitro activity study revealed that only few antibacterial agents (including several novel agents) exhibit high antimicrobial activity toward carbapenem-resistant Klebsiella pneumoniae (CRKP) and CR-hvKP isolates. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates.

Preliminary study of low-dose photodynamic therapy on the oxidative stress response of Cutibacterium acnes.

PURPOSE: The objective of this study was to investigate the influence of photodynamic therapy (PDT) employing different, lower 5-aminolevulinic acid (ALA) dosages on the proliferative activity of Cutibacterium acnes (C. acnes). METHODS: In this in vitro bacterial experiment, we examined the effects of PDT using different doses of ALA (0.05 mmol/L; 0.1 mmol/L; 0.5 mmol/L; 1.0 mmol/L; 2.5 mmol/L). To elucidate the underlying mechanisms, we assessed colony-forming units (CFUs), bacterial staining for live/dead, antioxidant enzyme activity, and gene expression of oxidative stress markers following treatment with different doses of ALA-PDT. RESULTS: Our findings demonstrate that CFU, bacterial staining for live/dead, as well as the activity and gene expression of superoxide dismutase (SOD) and catalase (CAT), all exhibited significant increases when the ALA concentration was 0.1/0.5 mmol/L. However, both CFU and cell growth of C. acnes decreased when the ALA concentration reached 1.0 mmol/L. CONCLUSION: Lower concentration of ALA-PDT (0.1/0.5 mmol/L) appears to promote the growth of C.acnes while higher doses (1.0 /2.5 mmol/L) are associated with eradication. The procedure is possibly mediated by the activation of antioxidant-related genes and enzyme expression in cells.

Emergence of KPC-134, a KPC-2 variant associated with ceftazidime-avibactam resistance in a ST11 Klebsiella pneumoniae clinical strain.

The emergence of various new Klebsiella pneumoniae carbapenemase (KPC) variants leading to ceftazidime-avibactam treatment failure is a new challenge in current clinical anti-infection treatment. Here, we report a ceftazidime-avibactam-resistant K. pneumoniae 1072-2 clinical strain carrying a novel KPC variant, KPC-134, which differs from KPC-2 by both single mutation (D178A) and 8-amino acid insertions (asp-asp-asn-arg-ala-pro-asn-lys). The results of antimicrobial susceptibility testing showed that the isolate was resistant to meropenem (MIC = 4 mg/L), ceftazidime (MIC ≥ 32 mg/L), cefepime (MIC ≥128 mg/L), aztreonam (MIC ≥128 mg/L), and ceftazidime-avibactam (MIC ≥128 mg/L) but sensitive to imipenem (MIC = 0.5 mg/L), imepenem-relebactam (MIC = 0.5 mg/L), meropenem-vaborbactam (MIC = 2 mg/L), and aztreonam-avibactam (MIC = 4 mg/L). The plasmid containing blaKPC-134 was isolated from K. pneumoniae, and the blaKPC-134 gene was cloned into plasmid pHSG398 and transformed into an Escherichia coli DH5α to observe changes in antimicrobial resistance. The results indicated that the transformant was positive for blaKPC-134 and increased MICs of ceftazidime-avibactam, ceftazidime, cefepime, and aztreonam by 512-fold, 256-fold, 16-fold, and 4-fold, respectively, compared with the recipient. The results of third-generation sequencing showed that the blaKPC-134 gene was carried by a 133,789 bp IncFII-IncR plasmid, and many common resistance genes (including blaCTX-M-65, blaTEM-1B, blaSHV-12, rmtB, and catB4) along with the IS26, tnpR, ISkpn8, ISkpn6-like, and Tn1721 elements were identified. IMPORTANCE The emergence of various new KPC variants leading to ceftazidime-avibactam treatment failure is a new challenge for clinical anti-infection treatment. Here, we describe the characterization of a ceftazidime-avibactam-resistant blaKPC-134-positive Klebsiella pneumoniae clinical strain for the first time. K. pneumoniae bearing with KPC variant often mislead clinical anti-infection treatment because of their unique antimicrobial susceptibility profile and the tendency of conventional carbapenemase assays to give false negative results. Therefore, timely identification of KPC variants and effective anti-infective therapy are key to saving infected patients.

Analysis on Bacterial Distribution and Change of Drug Resistance Rate in ICUs Across Southwest China from 2018 to 2022.

Purpose: To analyze the distribution of bacteria and their drug resistance changes in Intensive Care Units (ICUs) across Southwest China from 2018 to 2022 and establish the antibiogram in this region to provide a basis for early empirical antimicrobial use. Methods: Non-repetitive pathogens isolated from 109 member units with qualified data were obtained from the Antimicrobial Resistance Surveillance System in Sichuan Province, southwest China. The results obtained were interpreted with reference to CLSI M100-31th, and analyzed with WHONET 5.6 software. Results: A total of 46,728 clinical isolates in ICUs were collected from 2018 to 2022, of which gram-negative organisms accounted for 76.1%, and gram-positive were 23.9%. The top 5 were Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, respectively. From 2018 to 2022, the resistance rates of Klebsiella pneumoniae to imipenem and meropenem changed from 14.5% and 17.8% to 14.0% and 14.4%, showing a steady downward trend. Escherichia coli was always highly sensitive to carbapenems, with a total resistance rate of 3.8%. Among non-fermented gram-negative bacteria, the resistance rates of Pseudomonas aeruginosa to imipenem and meropenem decreased significantly, changed from 25.3% and 22.9% in 2018 to 20.0% and 15.1% in 2022. However, Acinetobacter baumannii showed high resistance rates of 76.2% and 76.9% to imipenem and meropenem, respectively. MRSA and MRCNS accounted for 31.7% and 82.7%, respectively. No vancomycin and linezolid-resistant Staphylococcus aureus was isolated. Enterococcus faecalis maintained high activity to vancomycin, teicoplanin, and linezolid; no vancomycin or teicoplanin-resistant Enterococcus faecium strains were detected. Conclusion: From 2018 to 2022, the isolated bacteria in ICU were mainly gram-negative bacteria, and the growth of some multidrug-resistant bacteria was effectively controlled. All levels of medical institutions should continue to strengthen bacterial resistance surveillance, promote the establishment of antimicrobial stewardship program, and enhance restrictions on outpatient antimicrobial use.

Klebsiella pneumoniae bacteremia mortality: a systematic review and meta-analysis.

Objective: To analyze the mortality rate of patients with Klebsiella pneumoniae bacteremia (KPB) and the impact of extended spectrum beta-lactamase (ESBL) producing or carbapenem-resistance (CR) KP on the mortality rate among patients with bacteremia. Methods: EMbase, Web of Science, PubMed, and The Cochrane Library were searched up to September 18th, 2022. Two reviewers independently extracted data and evaluated risk of bias of included studies by ROBINS-I tool. A meta-regression analysis was conducted using a mixed-effects model to explore possible sources of heterogeneity. A random-effects model was used for pooled analysis in case of significant heterogeneity (I2>50%). Otherwise, the fixed-effects model was performed. Results: A total of 157 studies (37,915 enrolled patients) were included in the meta-analysis. The pooled death proportions of KPB were 17% (95% CI=0.14-0.20) at 7-day, 24% (95% CI=0.21-0.28) at 14-day, 29% (95% CI=0.26-0.31) at 30-day, 34% (95% CI=0.26-0.42) at 90-day, and 29% (95% CI=0.26-0.33) in hospital, respectively. Heterogeneity was found from the intensive care unit (ICU), hospital-acquired (HA), CRKP, and ESBL-KP in the meta-regression analysis. More than 50% of ICU, HA, CRKP, and ESBL-KP were associated with a significant higher 30-day mortality rates. The pooled mortality odds ratios (ORs) of CRKP vs. non-CRKP were 3.22 (95% CI 1.18-8.76) at 7-day, 5.66 (95% CI 4.31-7.42) at 14-day, 3.87 (95% CI 3.01-3.49) at 28- or 30-day, and 4.05 (95% CI 3.38-4.85) in hospital, respectively. Conclusions: This meta-analysis indicated that patients with KPB in ICU, HA-KPB, CRKP, and ESBL-KP bacteremia were associated with a higher mortality rate. The high mortality rate caused by CRKP bacteremia has increased over time, challenging the public health.

Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2-IA3 EGFR-Mutated NSCLC: ADAURA2.

INTRODUCTION: Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2-IA3 EGFRm NSCLC, following complete tumor resection. PATIENTS AND METHODS: ADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated. RESULTS: Study enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027.

Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial.

PURPOSE: The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106) primary analysis demonstrated a clinically significant disease-free survival (DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage IB-IIIA non-small-cell lung cancer (NSCLC) after complete tumor resection (DFS hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an updated exploratory analysis of final DFS data. METHODS: Overall, 682 patients with stage IB-IIIA (American Joint Committee on Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated (exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage, mutational status, and race) to receive osimertinib 80 mg once-daily or placebo for 3 years. The primary end point was DFS by investigator assessment in stage II-IIIA disease analyzed by stratified log-rank test; following early reporting of statistical significance in DFS, no further formal statistical testing was planned. Secondary end points included DFS in stage IB-IIIA, overall survival, and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end points. RESULTS: At data cutoff (April 11, 2022), in stage II-IIIA disease, median follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29% (placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34); 4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated with osimertinib had local/regional and distant recurrence versus placebo. CNS DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety profile of osimertinib was consistent with the primary analysis. CONCLUSION: These updated data demonstrate prolonged DFS benefit over placebo, reduced risk of local and distant recurrence, improved CNS DFS, and a consistent safety profile, supporting the efficacy of adjuvant osimertinib in resected EGFR-mutated NSCLC.

The Distribution of K. pneumoniae in Different Specimen Sources and Its Antibiotic Resistance Trends in Sichuan, China From 2017 to 2020.

OBJECTIVE: We aim to analyze the distribution of Klebsiella pneumoniae in different specimen sources and its antibiotic resistance trends from the Antimicrobial Resistant Investigation Network of Sichuan Province (ARINSP) between 2017 and 2020. METHODS: According to the monitoring scheme, each participating hospital identified the bacteria and performed antimicrobial susceptibility tests using approved procedures. The data of non-repetitive isolates collected from outpatients and inpatients were submitted to ARINSP. The WHONET 5.6 software was used to analyze the results according to the Clinical and Laboratory Standards Institute (CLSI). RESULTS: Between 2017 and 2020, 833,408 non-repetitive clinical isolates of bacteria were isolated in total. The bacterial strains isolated from sputum and broncho-alveolar lavage accounted for 48.7, 56.4, 49.2, and 43.7% from 2017 to 2020 respectively, among all sources. The number of Klebsiella pneumoniae isolates from sputum and broncho-alveolar lavage increased from 18,809 in 2018, 19,742 in 2019, to 19,376 in 2020, playing a predominant role among all specimens. Meropenem-resistant K. pneumoniae occurrences (5.7% in 2017, 7.3% in 2018, 8.0% in 2019, and 7.5% in 2020) remained highest among carbapenems, and increased slightly over time. The resistance rate to tigecycline remained lowest, and declined from 2.4% in 2017, to 0.4% in 2018, and from 0.7% in 2019, to 0.6% in 2020. CONCLUSION: The overall resistance rates of Klebsiella pneumoniae to carbapenems increased in Sichuan Province, giving a significant challenge to control K. pneumoniae related infections. Tigecycline has retained activity to against K. pneumoniae. Ongoing surveillance is essential. It can help for implementing intervention programs to reduce the occurrence of antimicrobial resistance and to provide with a rational use of antimicrobials.

Metabolomic Response of Early-Stage Wheat (Triticum aestivum) to Surfactant-Aided Foliar Application of Copper Hydroxide and Molybdenum Trioxide Nanoparticles.

Surfactants are commonly used in foliar applications to enhance interactions of active ingredients with plant leaves. We employed metabolomics to understand the effects of TritonTM X-100 surfactant (SA) and nanomaterials (NMs) on wheat (Triticum aestivum) at the molecular level. Leaves of three-week-old wheat seedlings were exposed to deionized water (DI), surfactant solution (SA), NMs-surfactant suspensions (Cu(OH)2 NMs and MoO3 NMs), and ionic-surfactant solutions (Cu IONs and Mo IONs). Wheat leaves and roots were evaluated via physiological, nutrient distribution, and targeted metabolomics analyses. SA had no impact on plant physiological parameters, however, 30+ dysregulated metabolites and 15+ perturbed metabolomic pathways were identified in wheat leaves and roots. Cu(OH)2 NMs resulted in an accumulation of 649.8 µg/g Cu in leaves; even with minimal Cu translocation, levels of 27 metabolites were significantly changed in roots. Due to the low dissolution of Cu(OH)2 NMs in SA, the low concentration of Cu IONs induced minimal plant response. In contrast, given the substantial dissolution of MoO3 NMs (35.8%), the corresponding high levels of Mo IONs resulted in significant metabolite reprogramming (30+ metabolites dysregulated). Aspartic acid, proline, chlorogenic acid, adenosine, ascorbic acid, phenylalanine, and lysine were significantly upregulated for MoO3 NMs, yet downregulated under Mo IONs condition. Surprisingly, Cu(OH)2 NMs stimulated wheat plant tissues more than MoO3 NMs. The glyoxylate/dicarboxylate metabolism (in leaves) and valine/leucine/isoleucine biosynthesis (in roots) uniquely responded to Cu(OH)2 NMs. Findings from this study provide novel insights on the use of surfactants to enhance the foliar application of nanoagrochemicals.

First Report of bla IMP-4 and bla SRT-2 Coproducing Serratia marcescens Clinical Isolate in China.

Carbapenem-resistant Enterobacterales (CRE) has become a major therapeutic concern in clinical settings, and carbapenemase genes have been widely reported in various bacteria. In Serratia marcescens, class A group carbapenemases including SME and KPC were mostly identified. However, there are few reports of metallo-ß-lactamase-producing S. marcescens. Here, we isolated a carbapenem-resistant S. marcescens (S378) from a patient with asymptomatic urinary tract infection which was then identified as an IMP-4-producing S. marcescens at a tertiary hospital in Sichuan Province in southwest of China. The species were identified using MALDI-TOF MS, and carbapenemase-encoding genes were detected using PCR and DNA sequencing. The results of antimicrobial susceptibility testing by broth microdilution method indicated that the isolate S. marcescens S378 was resistant to meropenem (MIC = 32 µg/ml) and imipenem (MIC = 64 µg/ml) and intermediate to aztreonam (MIC = 8 µg/ml). The complete genomic sequence of S. marcescens was identified using Illumina (Illumina, San Diego, CA, United States) short-read sequencing (150 bp paired-end reads); five resistance genes had been identified, including bla IMP-4, bla SRT-2, aac(6')-Ic, qnrS1, and tet(41). Conjugation experiments indicated that the bla IMP-4-carrying plasmid pS378P was conjugative. Complete sequence analysis of the plasmid pS378P bearing bla IMP-4 revealed that it was a 48,780-bp IncN-type plasmid with an average GC content of 50% and was nearly identical to pP378-IMP (99% nucleotide identity and query coverage).

Ceftazidime-Avibactam Therapy Versus Ceftazidime-Avibactam-Based Combination Therapy in Patients With Carbapenem-Resistant Gram-Negative Pathogens: A Meta-Analysis.

Objective: To systematically review and compare the efficacy and posttreatment resistance of ceftazidime-avibactam therapy and ceftazidime-avibactam-based combination therapy in patients with Gram-negative pathogens. Methods: PubMed, Embase, Web of Science, CNKI, and Wanfang Data databases were searched from their inception up to March 31, 2021, to obtain studies on ceftazidime-avibactam therapy versus ceftazidime-avibactam-based combination therapy in patients with carbapenem-resistant Gram-negative pathogens. The primary outcome was mortality rate, and the second outcomes were microbiologically negative, clinical success, and the development of resistance after ceftazidime-avibactam treatment. Results: Seventeen studies representing 1,435 patients (837 received ceftazidime-avibactam-based combination therapy and 598 received ceftazidime-avibactam therapy) were included in the meta-analysis. The results of the meta-analysis showed that no statistically significant difference was found on mortality rate (Petos odds ratio (OR) = 1.03, 95% confidence interval (CI) 0.79-1.34), microbiologically negative (OR = 0.99, 95% CI 0.54-1.81), and clinical success (OR =0.95, 95% CI 0.64-1.39) between ceftazidime-avibactam-based combination therapy and ceftazidime-avibactam therapy. Although there was no difference in posttreatment resistance of ceftazidime-avibactam (OR = 0.65, 95% CI 0.34-1.26) in all included studies, a trend favoring the combination therapy was found (according to the pooled three studies, OR = 0.18, 95% CI 0.04-0.78). Conclusions: The current evidence suggests that ceftazidime-avibactam-based combination therapy may not have beneficial effects on mortality, microbiologically negative, and clinical success to patients with carbapenem-resistant Gram-negative pathogens. A trend of posttreatment resistance occurred more likely in ceftazidime-avibactam therapy than the combination therapy. Due to the limited number of studies that can be included, additional high-quality studies are needed to verify the above conclusions.

Drilling into the Metabolomics to Enhance Insight on Corn and Wheat Responses to Molybdenum Trioxide Nanoparticles.

Metabolomics is an emerging tool to understand the potential implications of nanotechnology, particularly for agriculture. Although molybdenum (Mo) is a known plant micronutrient, little is known of its metabolic perturbations. Here, corn and wheat seedlings were exposed to MoO3 nanoparticles (NPs) and the corresponding bioavailable Mo6+ ion at moderate and excessive levels through root exposures. Physiologically, corn was more sensitive to Mo, which accumulated up to 3.63 times more Mo than wheat. In contrast, metabolomics indicated 21 dysregulated metabolites in corn leaves and 53 in wheat leaves. Five more metabolomic pathways were perturbed in wheat leaves compared to corn leaves. In addition to the overall metabolomics analysis, we also analyzed individual metabolite classes (e.g., amino acids, organic acids, etc.), yielding additional dysregulated metabolites in plant tissues: 7 for corn and 7 for wheat. Most of these were amino acids as well as some sugars. Additional significantly dysregulated metabolites (e.g., asparagine, fructose, reduced glutathione, mannose) were identified in both corn and wheat, due to Mo NP exposure, by employing individual metabolite group analysis. Targeted metabolite analysis of individual groups is thus important for finding additional significant metabolites. We demonstrate the value of metabolomics to study early stage plant responses to NP exposure.

Dissolution and Aggregation of Metal Oxide Nanoparticles in Root Exudates and Soil Leachate: Implications for Nanoagrochemical Application.

Knowledge of dissolution, aggregation, and stability of nanoagrochemicals in root exudates (RE) and soil leachate will contribute to improving delivery mechanisms, transport in plants, and bioavailability. We characterized aggregation, stability, and dissolution of four nanoparticles (NPs) in soybean RE and soil leachate: nano-CeO2, nano-Mn3O4, nano-Cu(OH)2, and nano-MoO3. Aggregation differed considerably in different media. In RE, nano-Cu(OH)2, and nano-MoO3 increased their aggregate size for 5 days; their mean sizes increased from 518 ± 43 nm to 938 ± 32 nm, and from 372 ± 14 nm to 690 ± 65 nm, respectively. Conversely, nano-CeO2 and nano-Mn3O4 disaggregated in RE with time, decreasing from 289 ± 5 nm to 129 ± 10 nm, and from 761 ± 58 nm to 143 ± 18 nm, respectively. Organic acids in RE and soil leachate can be adsorbed onto particle surfaces, influencing aggregation. Charge of the four NPs was negative in contact with RE and soil leachate, due to organic matter present in RE and soil leachate. Dissolution in RE after 6 days was 38%, 1.2%, 0.5%, and <0.1% of the elemental content of MoO3, Cu(OH)2, Mn3O4, and CeO2 NPs. Thus, the bioavailability and efficiency of delivery of the NPs or their active ingredients will be substantially modified soon after they are in contact with RE or soil leachate.