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For the first time since 2015, the World Health Organization’s (WHO) global Antimicrobial Resistance and Use Surveillance (GLASS) featured both global reports for antimicrobial resistance (AMR) and antimicrobial consumption (AMC) data in its annual reports. In this study we investigated the relationship of AMR with AMC within participating countries reported in the GLASS 2022 report. Our analysis found a statistically significant correlation between beta-lactam/cephalosporin and fluoroquinolones consumption and AMR to these antimicrobials associated with bloodstream E . coli and Klebsiella pneumoniae among the participating countries (P<0.05). We observed that for every 1 unit increase in defined daily dose DDD of beta-lactam/cephalosporins and quinolone consumptions among the countries, increased the recoveries of bloodstream-associated beta-lactam/cephalosporins-resistant E . coli / Klebsiella spp. by 11–22% and quinolone-resistant E . coli / Klebsiella spp. by 31–40%. When we compared the antimicrobial consumptions between the antimicrobial ATC (Alphanumeric codes developed by WHO) groups and countries, we observed a statistically significant higher daily consumption of beta-lactam-penicillins (J01C, DDD difference range: 5.23–8.13) and cephalosporins (J01D, DDD difference range: 2.57–5.13) compared to other antimicrobial groups among the countries (adjusted for multiple comparisons using Tukey’s method). Between the participating countries, we observed a statistically significant higher daily consumption of antimicrobial groups in Iran (DDD difference range: 3.63–4.84) and Uganda (DDD difference range: 3.79–5.01) compared to other participating countries (adjusted for multiple comparisons using Tukey’s method). Understanding AMC and how it relates to AMR at the global scale is critical in the global AMR policy development and implementation of global antimicrobial stewardship.

Antibiotics are antibacterial compounds that interfere with bacterial growth, without harming the infected eukaryotic host. Among the clinical agents, beta-lactams play a major role in treating infected humans and animals. However, the ever-increasing antibiotic resistance crisis is forcing the pharmaceutical industry to search for new antibacterial drugs to combat a range of current and potential multi-resistant bacterial pathogens. In this review, we provide an overview of the development, innovation, and current status of therapeutic applications for beta-lactams with a focus on semi-synthetic cephalosporins. Cephalosporin C (CPC), which is a natural secondary metabolite from the filamentous fungus Acremonium chrysogenum , plays a major and demanding role in both producing modern antibiotics and developing new ones. CPC serves as a core compound for producing semi-synthetic cephalosporins that can control infections with different resistance mechanisms. We therefore summarize our latest knowledge about the CPC biosynthetic pathway and its regulation in the fungal host. Finally, we describe how CPC serves as a key lead generation source for the in vitro and better, in vivo synthesis of 7-aminocephalosporanic acid (7-ACA), the major core compound for the pharmaceutical synthesis of current and future semi-synthetic cephalosporins. Key points • Latest literature on cephalosporin generations • Biotechnical production of cephalosporins • In vivo production of 7-ACA

The primary use of antimicrobials in dairy cattle is associated with the occurrence of mastitis and conventional dry cow therapy (CDCT). However, in many cases, antimicrobial therapy is unnecessary due to the high likelihood of spontaneous recovery or because the infection is caused by pathogens that are refractory to treatment. Our review addresses a fundamental question: how to optimize the treatment and control of mastitis in dairy cattle. We explored the combined use of microbiological culture and clinical history to enable a more targeted and effective use of antimicrobials. Customizing treatments based on specific pathogens minimizes public health risks. Additionally, we emphasized the effectiveness and safety of penicillins and cephalosporins administered intramammarily. Furthermore, we recommended the adoption of selective dry cow therapy (SDCT) as a priority in herds with rigorous mastitis control measures. This approach is essential for maintaining sustainable dairy production while ensuring public health safety, particularly in Brazil. We highlighted two key conclusions: i. microbiological culture should form the foundation of mastitis diagnosis and treatment and ii. it is necessary to demystify the belief that the success of mastitis treatment is conditioned solely on the direct action of drugs, particularly those critically important to public health. By embracing these principles, veterinarians and farmers can contribute jointly to sustainable dairy production and the protection of public health. Key words: antibiotic stewardship, dairy cattle health, microbiological culture, selective therapy, mastitis control. O uso prim rio de antimicrobianos em bovinos de leite est associado ocorr ncia de mastite e terapia convencional de vaca seca (TCVS). No entanto, em muitos casos, a terapia antimicrobiana desnecess ria devido alta probabilidade de recupera o espont nea ou porque a infec o causada por pat genos refrat rios ao tratamento. Essa revis o aborda uma quest o fundamental: como otimizar o tratamento e o controle da mastite em bovinos de leite. Exploramos o uso combinado da cultura microbiol gica e do hist rico cl nico para permitir um uso mais direcionado e eficaz de antimicrobianos. Personalizar os tratamentos com base em pat genos espec ficos minimiza os riscos sa de p blica. Al m disso, enfatiza-se a efic cia e a seguran a das penicilinas e cefalosporinas administradas por via intramam ria. Recomendamos tamb m a ado o da terapia seletiva de vaca seca (TSVS) como prioridade em rebanhos com medidas rigorosas de controle de mastite. Essa abordagem essencial para manter a produ o de leite sustent vel, garantindo ao mesmo tempo a seguran a da sa de p blica, particularmente no Brasil. Destaca-se duas conclus es principais: i. a cultura microbiol gica deve ser a base do diagn stico e tratamento da mastite e ii. necess rio desmistificar a cren a de que o sucesso do tratamento da mastite est condicionado exclusivamente a o direta dos medicamentos, especialmente aqueles de import ncia cr tica para a sa de p blica. Ao adotar esses princ pios, veterin rios e produtores podem contribuir conjuntamente para a sustentabilidade da produ o de leite e a prote o da sa de p blica. Palavras-chave: uso racional de antimicrobianos, sa de de bovinos de leite, cultura microbiol gica, terapia seletiva, controle de mastite.

[This corrects the article DOI: 10.1371/journal.pone.0244673.].

The animal reservoir of Enterobacterales producing Extended-Spectrum-β-Lactamases (ESBL) and plasmid-borne cephalosporinases (pAmpC) is a global concern. Using genome data, we analyzed a population of Escherichia coli and Salmonella species resistant to third-generation cephalosporins (3GC-R) recovered from healthy food animals (HA) and diseased food animals (DA) across Europe. Among the isolates collected from HA (n = 4,498) and DA (n = 833) in up to twelve European countries, 62 (1.4%) and 45 (5.4%) were 3GC-R, respectively. The genomes of these 3GC-R 107 isolates were sequenced to identify bla ESBL and bla AmpC , sequence types (STs), virulence-associated genes, and Salmonella serovars. We also assessed their population structure using core genome multilocus sequence typing. The 78 3GC-R Escherichia coli originated from poultry (n = 27), swine (n = 26), and cattle (n = 25). Almost all (n = 77; 98.7%) harbored at least one bla ESBL or bla AmpC , with bla CTX-M-1 predominating. We identified 51 STs, with ST10 and ST101 being the most frequent. The population of 3GC-R E . coli was polyclonal. The 29 3GC-R Salmonella spp. were mostly retrieved from healthy broiler (96.5%). bla CMY-2 dominated in this population. We found two clusters of CMY-2-producing Salmonella spp. in Germany: one with 15 isolates of S . Heidelberg isolates and another with six S . Minnesota, all of them with bla CMY-2 . Our results confirm the low prevalence of 3GC-R E . coli and Salmonella spp. in HA and DA. bla CTX-M-1 was dominating in a highly diverse population of E . coli . 3GC-R E . coli isolated from HA and DA were genetically unrelated, with high clonal diversity suggesting multiple origins of contamination. This contrasted with the clonal population of 3GC-R Salmonella spp. in which bla CMY-2 dominated through two dominant serovars in this collection.

The goal of this study is to investigate the origin, prevalence, and evolution of the pESI megaplasmid in Salmonella isolated from animals, foods, and humans. We queried 510,097 Salmonella genomes under the National Center for Biotechnology Information (NCBI) Pathogen Detection (PD) database for the presence of potential sequences containing the pESI plasmid in animal, food, and environmental sources. The presence of the pESI megaplasmid was confirmed by using seven plasmid-specific markers ( rd A, pil L, Sog S, Trb A, ipf , ipr 2 and Inc FIB(pN55391)). The plasmid and chromosome phylogeny of these isolates was inferred from single nucleotide polymorphisms (SNPs). Our search resolved six Salmonella clusters carrying the pESI plasmid. Four were emergent Salmonella Infantis clusters, and one each belonged to serovar Senftenberg and Alachua. The Infantis cluster with a pESI plasmid carrying bla CTX-M-65 gene was the biggest of the four emergent Infantis clusters, with over 10,000 isolates. This cluster was first detected in South America and has since spread widely in United States. Over time the composition of pESI in United States has changed with the average number of resistance genes showing a decrease from 9 in 2014 to 5 in 2022, resulting from changes in gene content in two integrons present in the plasmid. A recent and emerging cluster of Senftenberg, which carries the bla CTX-M-65 gene and is primarily associated with turkey sources, was the second largest in the United States. SNP analysis showed that this cluster likely originated in North Carolina with the recent acquisition of the pESI plasmid. A single Alachua isolate from turkey was also found to carry the pESI plasmid containing bla CTX-M-65 gene. The study of the pESI plasmid, its evolution and mechanism of spread can help us in developing appropriate strategies for the prevention and further spread of this multi-drug resistant plasmid in Salmonella in poultry and humans.

Data about the prevalence of plasmid-mediated quinolone resistance (PMQR) and extended-spectrum beta-lactamase (ESBL) production in P. aeruginosa compared to the Enterobacteriaceae family is limited. The availability of limited therapeutic options raises alarming concerns about the treatment of multidrug-resistant P. aeruginosa. This study aimed to assess the presence of PMQR and ESBL genes among P. aeruginosa strains. Fifty-six P. aeruginosa strains were isolated from 330 patients with different clinical infections. Phenotypically fluoroquinolone-resistant isolates were tested by PCR for the presence of six PMQR genes. Then, blaTEM, blaSHV, and blaCTX-M type ESBL genes were screened to study the co-existence of different resistance determinants. Overall, 22/56 (39.3%) of the studied P. aeruginosa isolates were phenotypically resistant to fluoroquinolones. PMQR-producing P. aeruginosa isolates were identified in 20 isolates (90.9%). The acc(6')-Ib-cr was the most prevalent PMQR gene (77.3%). The qnr genes occurred in 72.7%, with the predominance of the qnrA gene at 54.5%, followed by the qnrS gene at 27.3%, then qnrB and qnrC at 22.7%. The qepA was not detected in any isolate. The acc(6')-Ib-cr was associated with qnr genes in 65% of positive PMQR isolates. Significant differences between the fluoroquinolone-resistant and fluoroquinolone-susceptible isolates in terms of the antibiotic resistance rates of amikacin, imipenem, and cefepime (P value < 0.0001) were found. The ESBL genes were detected in 52% of cephalosporin-resistant P. aeruginosa isolates. The most frequent ESBL gene was blaCTX-M (76.9%), followed by blaTEM (46.2%). No isolates carried the blaSHV gene. The acc(6')-Ib-cr gene showed the highest association with ESBL genes, followed by the qnrA gene. The correlation matrix of the detected PMQR and ESBL genes indicated overall positive correlations. The strongest and most highly significant correlation was between qnrA and acc(6')-Ib-cr (r = 0.602) and between qnrA and blaCTX-M (r = 0.519). A high prevalence of PMQR genes among the phenotypic fluoroquinolone-resistant P. aeruginosa isolates was detected, with the co-carriage of different PMQR genes. The most frequent PMQR was the acc(6')-Ib-cr gene. Co-existence between PMQR and ESBL genes was found, with 75% of PMQR-positive isolates carrying at least one ESBL gene. A high and significant correlation between the ESBL and PMQR genes was detected.

For the first time since 2015, the World Health Organization's (WHO) global Antimicrobial Resistance and Use Surveillance (GLASS) featured both global reports for antimicrobial resistance (AMR) and antimicrobial consumption (AMC) data in its annual reports. In this study we investigated the relationship of AMR with AMC within participating countries reported in the GLASS 2022 report. Our analysis found a statistically significant correlation between beta-lactam/cephalosporin and fluoroquinolones consumption and AMR to these antimicrobials associated with bloodstream E. coli and Klebsiella pneumoniae among the participating countries (P<0.05). We observed that for every 1 unit increase in defined daily dose DDD of beta-lactam/cephalosporins and quinolone consumptions among the countries, increased the recoveries of bloodstream-associated beta-lactam/cephalosporins-resistant E. coli/Klebsiella spp. by 11-22% and quinolone-resistant E. coli/Klebsiella spp. by 31-40%. When we compared the antimicrobial consumptions between the antimicrobial ATC (Alphanumeric codes developed by WHO) groups and countries, we observed a statistically significant higher daily consumption of beta-lactam-penicillins (J01C, DDD difference range: 5.23-8.13) and cephalosporins (J01D, DDD difference range: 2.57-5.13) compared to other antimicrobial groups among the countries (adjusted for multiple comparisons using Tukey's method). Between the participating countries, we observed a statistically significant higher daily consumption of antimicrobial groups in Iran (DDD difference range: 3.63-4.84) and Uganda (DDD difference range: 3.79-5.01) compared to other participating countries (adjusted for multiple comparisons using Tukey's method). Understanding AMC and how it relates to AMR at the global scale is critical in the global AMR policy development and implementation of global antimicrobial stewardship.

Cephalosporins are currently the most widely used antibiotics in clinical practice. The main strain used for the industrial production cephalosporin C (CPC) is Acremonium chrysogenum . CPC has the advantages of possessing a broad antibacterial spectrum and strong antibacterial activity. However, the yield and titer of cephalosporins obtained from A. chrysogenum are much lower than penicillin, which is also a β-lactam antibiotic produced by Penicillium chrysogenum . Molecular biology research into A. chrysogenum has focused on gene editing technologies, multi-omics research which has provided information on the differences between high- and low-yield strains, and metabolic engineering involving different functional genetic modifications and hierarchical network regulation to understand strain characteristics. Furthermore, optimization of the fermentation process is also reviewed as it provides the optimal environment to realize the full potential of strains. Combining rational design to control the metabolic network, high-throughput screening to improve the efficiency of obtaining high-performance strains, and real-time detection and controlling in the fermentation process will become the focus of future research in A. chrysogenum . This minireview provides a holistic and in-depth analysis of high-yield mechanisms and improves our understanding of the industrial value of A. chrysogenum . Key points • Review of the advances in A. chrysogenum characteristics improvement and process optimization • Elucidate the molecular bases of the mechanisms that control cephalosporin C biosynthesis and gene expression in A. chrysogenum • The future development trend of A. chrysogenum to meet industrial needs

Increased antimicrobial resistance (AMR) among bacteria underscores the need to strengthen AMR surveillance and promote data-based prescribing. To evaluate trends and associations between antimicrobial usage (AMU) and AMR, we explored a dataset of 34,672 bacterial isolates collected between 2015 and 2020 from clinical samples at the University Teaching Hospital (UTH) in Lusaka, Zambia. The most frequently isolated species were Escherichia coli (4,986/34,672; 14.4%), Staphylococcus aureus (3,941/34,672; 11.4%), and Klebsiella pneumoniae (3,796/34,672; 10.9%). Of the 16 drugs (eight classes) tested, only amikacin and imipenem showed good (> 50%) antimicrobial activity against both E . coli and K . pneumoniae , while nitrofurantoin was effective only in E . coli . Furthermore, 38.8% (1,934/4,980) of E . coli and 52.4% (2,079/3,791) of K . pneumoniae isolates displayed multidrug resistance (MDR) patterns on antimicrobial susceptibility tests. Among S . aureus isolates, 44.6% (973/2,181) were classified as methicillin-resistant (MRSA). Notably, all the MRSA exhibited MDR patterns. The annual hospital AMR rates varied over time, while there was a weak positive relationship (r = 0.38, 95% CI = 0.11–0.60) between the monthly use of third-generation cephalosporins (3GCs) and 3GC resistance among Enterobacterales . Overall, the results revealed high AMR rates that fluctuated over time, with a weak positive relationship between 3GC use and resistance. To our knowledge, this is the first report to evaluate the association between AMU and AMR in Zambia. Our results highlight the need to strengthen antimicrobial stewardship programs and optimize AMU in hospital settings.