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Objectives: The COVID-19 pandemic has posed a significant threat to the global healthcare system, presenting a major challenge to antimicrobial stewardship worldwide. This study aimed to provide a comprehensive and up-to-date picture of global antimicrobial resistance (AMR) and antibiotic use in COVID-19 patients., Methods: We conducted a systematic review to determine the prevalence of AMR and antibiotic usage among COVID-19 patients receiving treatment in healthcare facilities. Our search encompassed the PubMed, Web of Science, Embase, and Scopus databases, spanning studies published from December 2019 to May 2023. We utilized random-effects meta-analysis to assess the prevalence of multidrug-resistant organisms (MDROs) and antibiotic use in COVID-19 patients, aligning with both the WHO's priority list of MDROs and the AWaRe list of antibiotic products. Estimates were stratified by region, country, and country income. Meta-regression models were established to identify predictors of MDRO prevalence and antibiotic use in COVID-19 patients. The study protocol was registered with PROSPERO (CRD 42023449396)., Results: Among the 11,050 studies screened, 173 were included in the review, encompassing a total of 892,312 COVID-19 patients. MDROs were observed in 42.9% (95% CI 31.1-54.5%, I 2 = 99.90%) of COVID-19 patients: 41.0% (95% CI 35.5-46.6%) for carbapenem-resistant organisms (CRO), 19.9% (95% CI 13.4-27.2%) for methicillin-resistant Staphylococcus aureus (MRSA), 24.9% (95% CI 16.7-34.1%) for extended-spectrum beta-lactamase-producing organisms (ESBL), and 22.9% (95% CI 13.0-34.5%) for vancomycin-resistant Enterococcus species (VRE), respectively. Overall, 76.2% (95% CI 69.5-82.9%, I 2 = 99.99%) of COVID-19 patients were treated with antibiotics: 29.6% (95% CI 26.0-33.4%) with "Watch" antibiotics, 22.4% (95% CI 18.0-26.7%) with "Reserve" antibiotics, and 16.5% (95% CI 13.3-19.7%) with "Access" antibiotics. The MDRO prevalence and antibiotic use were significantly higher in low- and middle-income countries than in high-income countries, with the lowest proportion of antibiotic use (60.1% (95% CI 52.1-68.0%)) and MDRO prevalence (29.1% (95% CI 21.8-36.4%)) in North America, the highest MDRO prevalence in the Middle East and North Africa (63.9% (95% CI 46.6-81.2%)), and the highest proportion of antibiotic use in South Asia (92.7% (95% CI 90.4-95.0%)). The meta-regression identified antibiotic use and ICU admission as a significant predictor of higher prevalence of MDROs in COVID-19 patients., Conclusions: This systematic review offers a comprehensive and current assessment of MDRO prevalence and antibiotic use among COVID-19 patients in healthcare facilities. It underscores the formidable challenge facing global efforts to prevent and control AMR amidst the backdrop of the COVID-19 pandemic. These findings serve as a crucial warning to policymakers, highlighting the urgent need to enhance antimicrobial stewardship strategies to mitigate the risks associated with future pandemics., Competing Interests: Declaration of Competing Interest All authors declare no competing interests. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antibiotic resistance in Gram-negative bacteria remains one of the most pressing challenges to global public health. Blocking the transportation of lipopolysaccharides (LPS), a crucial component of the outer membrane of Gram-negative bacteria, is considered a promising strategy for drug discovery. In the transportation process of LPS, two components of the LPS transport (Lpt) complex, LptA and LptC, are responsible for shuttling LPS across the periplasm to the outer membrane, highlighting their potential as targets for antibacterial drug development. In the current study, a protein-protein interaction (PPI) model of LptA and LptC was constructed, and a molecular screening strategy was employed to search a protein-protein interaction compound library. The screening results indicated that compound 18593 exhibits favorable binding free energy with LptA and LptC. In comparison with the molecular dynamics (MD) simulations on currently known inhibitors, compound 18593 shows more stable target binding ability at the same level. The current study suggests that compound 18593 may exhibit an inhibitory effect on the LPS transport process, making it a promising hit compound for further research.

FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105)., Competing Interests: S.Z., Y.J., and Z.W. are employees of Qilu Pharmaceutical Co. Ltd. Other authors declared no conflicts of interest regarding this article.

Antimicrobial resistance (AMR) and the possible consequences of rising ambient temperatures brought on by global warming have been extensively discussed. However, the epidemiological evidence on the effects of temperature on AMR is rare and little is known about the role of socioeconomic inequities. This ecological study obtained 31 provinces AMR data of Escherichia Coli (E. coli) from the China Antimicrobial Resistance Surveillance System (CARSS) over the period from 2014 to 2020, which were linked to the meteorological and socioeconomic data published in the China Statistical Yearbook. Modified difference-in-differences (DID) analyses were performed to estimate the effect of ambient temperature on AMR of E. coli to third-generation cephalosporins (ceftriaxone and cefotaxime), carbapenems, and quinolones, adjusting for variations in meteorological and socioeconomic factors. We estimated that every 1 °C increase in average ambient temperature was associated with 2.71 % (95 % confidence interval [CI]: 1.20-4.24), 32.92 % (95 % CI: 15.62-52.81), and 1.81 % (95 % CI: 0.47-3.16) increase in the prevalence of E. coli resistance to third-generation cephalosporins (ceftriaxone and cefotaxime), carbapenems and quinolones, respectively. The link was more profound in the regions with lower temperature and a median level of average humidity, and the regions with lower income, lower expenditure (in economics), lower health resources, and lower hospital admissions. Neither the replacement of the temperature variable nor the alternative approaches for confounding adjustment changed the positive association between ambient temperature and AMR. In general, there exists a positive association between ambient temperature and AMR, although the strength of such an association varies by socioeconomic and health services factors. The association is possibly nonlinear, especially for E. coli resistance to third-generation cephalosporins. The findings suggest that AMR control programs should explicitly incorporate weather patterns to increase their effectiveness., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Antimicrobial resistance (AMR) of Klebsiella pneumoniae ( K. pneumoniae ) poses a significant global public health threat and is responsible for a high prevalence of infections and mortality. However, knowledge about how ambient temperature influences the AMR of K. pneumoniae is limited in the context of global warming., Methods: AMR data of 31 Chinese provinces was collected from the China Antimicrobial Resistance Surveillance System (CARSS) between 2014 and 2020. Socioeconomic and meteorological data were collected from the China Statistical Yearbook during the same period. A modified difference-in-differences (DID) approach was applied to estimate the association between ambient temperature and third-generation cephalosporin-resistant K. pneumoniae (3GCRKP) and carbapenem-resistant K. pneumoniae (CRKP). Furthermore, moderating effects of socioeconomic factors were also evaluated., Results: Every 1°C increase in annual average temperature was associated with a 4.7% (relative risk (RR):1.047, 95% confidence intervals (CI): 1.031-1.082) increase in the detection rate of 3GCRKP, and a 10.7% (RR:1.107, 95% CI: 1.011-1.211) increase in the detection rate of CRKP. The relationships between ambient temperature and 3GCRKP and CRKP were found to be moderated by socioeconomic status (GDP per capita , income per capita , and consumption per capita ; the interaction p -values <0.05), where higher economic status was found to strengthen the effects of temperature on the detection rate of 3GCRKP and weaken the effects on the detection rate of CRKP., Discussion: Ambient temperature was found to be positively associated with AMR of K. pneumoniae , and this association was moderated by socioeconomic status. Policymakers should consider the impact of global warming and high temperatures on the spread of 3GCRKP and CRKP when developing strategies for the containment of AMR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zeng, Li, Zhao, Li, Liu, Shi, Yang, Xia, Yang and Yang.)

Low-cost and low-barrier antibiotic stewardship strategies are urgently needed to deal with the widespread problem of antibiotic resistance. Social norm feedback could be a promising strategy. In this mixed-methods systematic review (PROSPERO: CRD42022361039), we aimed to identify the key behaviour change techniques used in social norm feedback for antibiotic stewardship and assess their effectiveness in reducing antibiotic prescribing. We searched PubMed, Embase, Web of Science, and Scopus for peer-reviewed studies published between Jan 1, 2000, and Jan 20, 2022. 3547 studies were screened, of which 23 studies reporting the effects of social norm feedback interventions on antibiotic prescribing met the inclusion criteria. 19 behaviour change techniques were tested in the included studies. The meta-analyses showed that social norm feedback is an effective strategy for reducing antibiotic prescribing, with an overall rate difference of 4% (p<0·0001). The behaviour change technique with the highest effective ratio (ER=13) was information about health consequences, followed by instruction on how to perform the behaviour (ER=9) and adding objects to the environment (ER=9). Social norm feedback is a promising strategy to reduce antibiotic prescribing, and can be incorporated into the clinical decision-making support system., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Antibiotic resistance genes (ARGs) as emerging environmental contaminants pose severe global risks to public health and ecosystems. Municipal wastewater treatment plants (WWTPs) are crucial transmitters for the dissemination and propagation of ARGs into receiving water bodies via mobile genetic elements (MGEs). However, the comprehensive and deep deciphering of the diversity, abundance, and potential hosts of ARGs in two distinct altitudinal WWTPs is scarce. In this work, we revealed the elevational distribution characteristics of the resistance genes and microbial community of six WWTPs from two distinct geographical zones: a low-elevation (LE) region (Shandong, 10-22 m above sea level) and a high-elevation (HE) region (Gansu, 1,520-1,708 m above sea level). Significant elevational variations in the diversity and relative abundance of resistance genes were observed. Wastewater treatment could significantly reduce the concentrations of ARGs and MGEs by about 1-2 and 2-3 orders of magnitude, respectively. However, above 69.95% of resistance genes were enriched in effluent. In particular, 24 ARG subtype, 3 MGE subtypes, and 59 bacterial genera were persistent in all samples. More potential hosts for ARGs in LE region and more abundant human gut microbiota in HE region were identified. This work provides helpful information for controlling the spread of ARGs for their management and assessment, thereby mitigating the risks of ARGs in WWTPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The shortage of new antibiotics makes infections caused by gram-negative (G - ) bacteria a significant clinical problem. The key enzymes involved in folate biosynthesis represent important targets for drug discovery, and new antifolates with novel mechanisms are urgently needed. By targeting to dihydrofolate reductase (DHFR), a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (PQZ) compounds were designed, and exhibited potent antibacterial activities in vitro, especially against multi-drug resistant G - strains. Multiple experiments indicated that PQZ compounds contain a different molecular mechanism against the typical DHFR inhibitor, trimethoprim (TMP), and the thymidylate synthase (TS) was identified as another potential but a relatively weak target. A significant synergism between the representative compound, OYYF-175, and sulfamethoxazole (SMZ) was observed with a strong cumulative and significantly bactericidal effect at extremely low concentrations (2 μg/mL for SMZ and 0.03 pg/mL for OYYF-175), which could be resulted from the simultaneous inhibition of dihydropteroate synthase (DHPS), DHFR and TS. PQZ compounds exhibited therapeutic effects in a mouse model of intraperitoneal infections caused by Escherichia coli (E. coli). The co-crystal structure of OYYF-175-DHFR was solved and the detailed interactions were provided. The inhibitors reported represent innovative chemical structures with novel molecular mechanism of action, which will benefit the generation of new, efficacious bactericidal compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Antimicrobial resistance has been an increasingly serious threat to global public health. Anti-virulence strategies are being developed to manage antibiotic resistance because they apply a lower selective pressure for antimicrobial-resistant pathogens than that created using traditional bactericides. We aimed to discover novel small molecules that can reduce the production of virulence factors in Pseudomonas aeruginosa and determine the mechanism of action underlying these effects. A clinical compound library was screened, and ostarine was identified as a potential anti-virulence agent. The effects of ostarine were studied via antimicrobial susceptibility testing, bacterial growth assays, pyocyanin quantitation assays, transcriptomic analysis, quorum sensing signal molecule quantification, and real-time PCR assays. Ostarine treatment significantly decreased the synthesis of pyocyanin without any bactericidal action. Besides, ostarine treatment did not affect the relative growth rate and cell morphology of bacteria. Treatment with ostarine interfered with quorum sensing by decreasing the transcription of genes associated with quorum sensing systems and the production of signalling molecules. The inhibition of ostarine on pyocyanin production and gene expression can be alleviated when signalling molecules were supplemented externally. Overall, ostarine may act as a novel anti-virulence agent that can attenuate P. aeruginosa pyocyanin by interfering with quorum sensing systems., (© 2021. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Background: Infections caused by drug-resistant Staphylococcus aureus, especially vancomycin-intermediate Staphylococcus aureus (VISA), leave clinicians with limited therapeutic options for treatment. Persister cells is a leading cause of recalcitrant infection and antibiotic treatment failure, and there is no drug in clinical use that specifically targets persister cells currently. Here, we report a promising combination therapy of sodium new houttuyfonate (SNH) and berberine chloride (BBR) which is able to eradicate both growing and persistent drug-resistant Staphylococcus aureus., Results: The susceptibility test showed SNH exhibited anti-MRSA activity with MIC 90 at 64 μg/mL, while BBR showed weak anti-MRSA activity with MIC 90 at 512 μg/mL. MICs of BBR in combination with 1/2 MIC SNH decreased by 4 to 64 folds compared with MICs of BBR alone. The results of time-killing assays revealed that the combined use of sub-MIC SNH and BBR offered an in vitro synergistic action against growing MRSA (including pathogenic MRSA) and VISA strains. More importantly, the combination of SNH and BBR was able to eradicate VISA Mu50 and pathogenic MRSA persister cells. The synergistic effect is likely related to the interruption of the cell membrane caused by SNH, which is confirmed by scanning electron microscope and membrane potential and permeability analysis., Conclusions: Our study provide a promising clinical curative strategy for combating drug-resistant S. aureus infections, especially for recalcitrant infections caused by persister cells.

Background: Antibiotic-resistant H. pylori was increasingly found in infected individuals, which resulted in treatment failure and required alternative therapeutic strategies. Daphnetin, a coumarin-derivative compound, has multiple pharmacological activities., Methods: The mechanism of daphnetin on H. pylori was investigated focusing on its effect on cell morphologies, transcription of genes related to virulence, adhesion, and cytotoxicity to human gastric epithelial (GES-1) cell line., Results: Daphnetin showed good activities against multidrug resistant (MDR) H. pylori clinical isolates, with minimal inhibitory concentration (MIC) values ranging from 25 to 100 μg/mL. In addition, daphnetin exposure resulted in H. pylori morphological changes. Moreover, daphnetin caused increased translocation of phosphatidylserine (PS), DNA damage, and recA expression, and RecA protein production vs. control group. Of great importance, daphnetin significantly decreased H. pylori adhesion to GES-1 cell line vs. control group, which may be related to the reduced expression of colonization related genes (e.g., babA and ureI )., Conclusions: These results suggested that daphnetin has good activity against MDR H. pylori. The mechanism(s) of daphnetin against H. pylori were related to change of membrane structure, increase of DNA damage and PS translocation, and decrease of H. pylori attachment to GES-1 cells.