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Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

Background A prospective cohort study was set up to investigate a possible association between antibiotic prescribing and antibiotic resistance of E. coli urinary tract infection in the community. Participation of patients with urinary tract infection was obtained through an opt-out methodology. This short paper reports on the acceptability of the opt-out recruitment approach. Methods Participating practices (22) were requested to send a urine sample from all patients presenting with symptoms of urinary tract infection. Upon receipt of the sample in the laboratory, a letter explaining the study, an opt-out form and a freepost envelope were sent to all adult patients. A website with additional information and including an 'opt-out' button was set up for the study. Results A total of 1362 urine samples were submitted by the 22 participating practices representing 1178 adult patients of whom 193 actively responded to the letter: 142 opted out by letter, 15 through the website, 2 by phone and 12 sent the letter back without indication, making a total of 171 patients or 14.5% opt-out; the remaining 22 patients (1.9%) explicitly opted in. The total group consisted of 80% women and the mean age was 50.9 years (sd 20.8). No significant differences were found between patients who participated and those who opted out in terms of age, gender or whether the urine sample was positive or not. Conclusions Overall the opt-out method was well received and participation in the study reached 85.5%. The low number of complaints (2) indicates that this is a generally acceptable method of patient recruitment. The 14.5% opt-out shows that it effectively empowers patients to decline participation. The similarity between patients opting out and the rest of the patients is reassuring for extrapolation of the results of the study.

Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei. We performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei. This study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally.

Background: Urinary tract infections (UTIs) are one of the most common conditions in women. Current information on the presentation, management, and natural course of the infection is based on paper diaries filled out and subsequently posted by patients. Objective: The aim of this study is to explore the feasibility of a smartphone app to assess the natural course and management of UTIs. Methods: A smartphone app was developed to collect data from study participants presenting with symptoms of UTI in general practice. After initial demographic and treatment information, symptom severity was recorded by the patient after a reminder on their smartphone, which occurred twice daily for a period of 7 days or until symptom resolution. Results: A total of 181 women aged 18-76 years downloaded the smartphone app. The duration of symptoms was determined from the results of 178 participants. All patients submitted a urine sample, most patients were prescribed an antibiotic (163/181, 90.1%), and 38.7% (70/181) of the patients had a positive culture. Moderately bad or worse symptoms lasted a mean of 3.8 (SD 3.2; median 4) days, and 70.2% (125/178) of the patients indicated that they were cured on day 4 after consultation. This compares with other research assessing symptom duration and management of UTIs using paper diaries. Patients were very positive about the usability of the smartphone app and often found the reminders supportive. On the basis of the feedback and the analysis of the data, some suggestions for improvement were made. Conclusions: Smartphone diaries for symptom scores over the course of infections are an efficient and acceptable means of collecting data in research.

Shigella sonnei increasingly dominates the international epidemiological landscape of shigellosis. Treatment options for S. sonnei are dwindling due to resistance to several key antimicrobials, including the fluoroquinolones. Here we analyse nearly 400  S. sonnei whole genome sequences from both endemic and non-endemic regions to delineate the evolutionary history of the recently emergent fluoroquinolone-resistant S. sonnei . We reaffirm that extant resistant organisms belong to a single clonal expansion event. Our results indicate that sequential accumulation of defining mutations ( gyrA -S83L, parC -S80I, and gyrA -D87G) led to the emergence of the fluoroquinolone-resistant S. sonnei population around 2007 in South Asia. This clone was then transmitted globally, resulting in establishments in Southeast Asia and Europe. Mutation analysis suggests that the clone became dominant through enhanced adaptation to oxidative stress. Experimental evolution reveals that under fluoroquinolone exposure in vitro, resistant S. sonnei develops further intolerance to the antimicrobial while the susceptible counterpart fails to attain complete resistance. Shigella sonnei is one of the main species causing shigellosis worldwide. Here the authors analyse nearly 400  S. sonnei genome sequences and carry out experimental evolution experiments to shed light into the evolutionary processes underlying the recent emergence of fluoroquinolone resistance in this pathogen.

Salmonella enterica serovar Agona has caused multiple food-borne outbreaks of gastroenteritis since it was first isolated in 1952. We analyzed the genomes of 73 isolates from global sources, comparing five distinct outbreaks with sporadic infections as well as food contamination and the environment. Agona consists of three lineages with minimal mutational diversity: only 846 single nucleotide polymorphisms (SNPs) have accumulated in the non-repetitive, core genome since Agona evolved in 1932 and subsequently underwent a major population expansion in the 1960s. Homologous recombination with other serovars of S. enterica imported 42 recombinational tracts (360 kb) in 5/143 nodes within the genealogy, which resulted in 3,164 additional SNPs. In contrast to this paucity of genetic diversity, Agona is highly diverse according to pulsed-field gel electrophoresis (PFGE), which is used to assign isolates to outbreaks. PFGE diversity reflects a highly dynamic accessory genome associated with the gain or loss (indels) of 51 bacteriophages, 10 plasmids, and 6 integrative conjugational elements (ICE/IMEs), but did not correlate uniquely with outbreaks. Unlike the core genome, indels occurred repeatedly in independent nodes (homoplasies), resulting in inaccurate PFGE genealogies. The accessory genome contained only few cargo genes relevant to infection, other than antibiotic resistance. Thus, most of the genetic diversity within this recently emerged pathogen reflects changes in the accessory genome, or is due to recombination, but these changes seemed to reflect neutral processes rather than Darwinian selection. Each outbreak was caused by an independent clade, without universal, outbreak-associated genomic features, and none of the variable genes in the pan-genome seemed to be associated with an ability to cause outbreaks.

Antimicrobial resistant Salmonella enterica serovar Concord ( S . Concord) is known to cause severe gastrointestinal and bloodstream infections in patients from Ethiopia and Ethiopian adoptees, and occasional records exist of S . Concord linked to other countries. The evolution and geographical distribution of S . Concord remained unclear. Here, we provide a genomic overview of the population structure and antimicrobial resistance (AMR) of S . Concord by analysing genomes from 284 historical and contemporary isolates obtained between 1944 and 2022 across the globe. We demonstrate that S . Concord is a polyphyletic serovar distributed among three Salmonella super-lineages. Super-lineage A is composed of eight S . Concord lineages, of which four are associated with multiple countries and low levels of AMR. Other lineages are restricted to Ethiopia and horizontally acquired resistance to most antimicrobials used for treating invasive Salmonella infections in low- and middle-income countries. By reconstructing complete genomes for 10 representative strains, we demonstrate the presence of AMR markers integrated in structurally diverse IncHI2 and IncA/C2 plasmids, and/or the chromosome. Molecular surveillance of pathogens such as S . Concord supports the understanding of AMR and the multi-sector response to the global AMR threat. This study provides a comprehensive baseline data set essential for future molecular surveillance. Authors carry out a longitudinal genomic analysis of Salmonella enterica serovar Concord isolates from various geographical locations, to reconstruct population diversity, evolution and antimicrobial resistance distribution.

Paratyphoid B fever (PTB) is caused by an invasive lineage (phylogroup 1, PG1) of Salmonella enterica serotype Paratyphi B (SPB). However, little was known about the global population structure, geographic distribution, and evolution of this pathogen. Here, we report a whole-genome analysis of 568 historical and contemporary SPB PG1 isolates, obtained globally, between 1898 and 2021. We show that this pathogen existed in the 13th century, subsequently diversifying into 11 lineages and 38 genotypes with strong phylogeographic patterns. Following its discovery in 1896, it circulated across Europe until the 1970s, after which it was mostly reimported into Europe from South America, the Middle East, South Asia, and North Africa. Antimicrobial resistance recently emerged in various genotypes of SPB PG1, mostly through mutations of the quinolone-resistance-determining regions of gyrA and gyrB . This study provides an unprecedented insight into SPB PG1 and essential genomic tools for identifying and tracking this pathogen, thereby facilitating the global genomic surveillance of PTB. Hawkey et al. provide insights into the spatio-temporal distribution and genetic diversity of Salmonella Paratyphi B — the agent of paratyphoid B fever — and report a genotyping scheme facilitating the international surveillance of this pathogen.

Paratyphoid B fever (PTB) is caused by an invasive lineage (phylogroup 1, PG1) of Salmonella enterica serotype Paratyphi B (SPB). However, little was known about the global population structure, geographic distribution, and evolution of this pathogen. Here, we report a whole-genome analysis of 568 historical and contemporary SPB PG1 isolates, obtained globally, between 1898 and 2021. We show that this pathogen existed in the 13th century, subsequently diversifying into 11 lineages and 38 genotypes with strong phylogeographic patterns. Following its discovery in 1896, it circulated across Europe until the 1970s, after which it was mostly reimported into Europe from South America, the Middle East, South Asia, and North Africa. Antimicrobial resistance recently emerged in various genotypes of SPB PG1, mostly through mutations of the quinolone-resistance-determining regions of gyrA and gyrB. This study provides an unprecedented insight into SPB PG1 and essential genomic tools for identifying and tracking this pathogen, thereby facilitating the global genomic surveillance of PTB.

Background Streptococcus pneumoniae is an important cause of microbial disease in humans. The introduction of multivalent vaccines has coincided with a dramatic decrease in the number of pneumococcal-related deaths. In spite of this, at a global level, pneumococcal infection remains an important cause of death among children under 5 years of age and in adults 65 years of age or older. In order to properly manage patients and control the spread of infection, a rapid and highly sensitive diagnostic method is needed for routine implementation, especially in resource-limited regions where pneumococcal disease is most prevalent. Methods Using the gene encoding leader peptidase A as a molecular diagnostics target, a real-time RPA assay was designed and optimised for the detection of S. pneumoniae in whole blood. The performance of the assay was compared to real-time PCR in terms of its analytical limit of detection and specificity. The inhibitory effect of human genomic DNA on amplification was investigated. The potential clinical utility of the assay was investigated using a small number of clinical samples. Results The RPA assay has a limit of detection equivalent to PCR (4.0 and 5.1 genome equivalents per reaction, respectively) and was capable of detecting the equivalent of <1 colony forming unit of S. pneumoniae when spiked into human whole blood. The RPA assay was 100 % inclusive (38/38 laboratory reference strains and 19/19 invasive clinical isolates) and 100 % exclusive; differentiating strains of S. pneumoniae species from other viridans group streptococci, including S. pseudopneumoniae . When applied to the analysis of a small number ( n  = 11) of clinical samples (blood culture positive for S. pneumoniae ), the RPA assay was demonstrated to be both rapid and sensitive. Conclusions The RPA assay developed in this work is shown to be as sensitive and as specific as PCR. In terms of reaction kinetics, the RPA assay is shown to exceed those of the PCR, with the RPA running to completion in 20 minutes and capable generating a positive signal in as little as 6 minutes. This work represents a potentially suitable assay for application in point-of-care settings.