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The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria.New antibacterial agents are urgently needed to address the global increase in resistance. In this Review, Theuretzbacher and colleagues critically review the current published literature and publicly available information on antibacterial agents in all phases of clinical development.

Background Infections due to Citrobacter species are increasingly observed in hospitalized patients and are often multidrug-resistant. Yet, the magnitude and burden of Citrobacter spp. resistance in the hospital setting have not been reported. We aimed to evaluate the epidemiology of  Citrobacter spp. infections among hospitalized patients, their main resistance patterns and Citrobacter spp. involvement in hospital outbreaks. Methods We conducted a systematic review and meta-analysis of published literature (PROSPERO registration Jan-2023, CRD42023390084). We searched Embase, Medline and grey literature for studies on hospitalized patients diagnosed with  Citrobacter  spp. infections, and nosocomial outbreaks due to Citrobacter spp. published during the years 2000–2022. We included observational, interventional, surveillance studies and outbreak reports. Outcomes of interest were the frequency of Citrobacter spp. infections among hospitalized patients and 3rd generation cephalosporin and/or carbapenem resistance percentages in these infections. We used random-effects models to generate pooled outcome estimates and evaluated risk of bias and quality of reporting of outbreaks. Results We screened 1609 deduplicated publications, assessed 148 full-texts, and included 41 studies (15 observational, 13 surveillance and 13 outbreak studies). Citrobacter spp. urinary tract- and bloodstream infections were most frequently reported, with Citrobacter freundii being the main causative species. Hospital-acquired infection occurred in 85% (838/990) of hospitalized patients with Citrobacter infection. After 2010, an increasing number of patients with Citrobacter spp. infections was reported in observational studies. Pooled frequency estimates for Citrobacter spp. infections could not be generated due to lack of data. The pooled prevalence of ESBL and carbapenemase producers among Citrobacter isolates were 22% (95%CI 4–50%, 7 studies) and 18% (95%CI 0–63%, 4 studies), respectively. An increased frequency of reported Citrobacter outbreaks was observed after 2016, with an infection/colonization ratio of 1:3 and a case-fatality ratio of 7% (6/89 patients). Common outbreak sources were sinks, toilets, contaminated food and injection material. Implemented preventive measures included environmental cleaning, isolation of positive patients and reinforcement of hand hygiene. Only seven out of 13 outbreaks (54%) were definitively controlled. Conclusion This review highlights the clinical importance of endemic and epidemic Citrobacter spp. in healthcare settings. As an emerging, multidrug‑resistant nosocomial pathogen it requires heightened awareness and further dedicated surveillance efforts.

Time to react\" [4] in 2009. Because the model estimates reported in the AMR Review [1] are partly based on the ECDC [4] methodology, we will discuss both reports, which estimated the burden of AMR in Europe and the world, respectively. [...]overlapping catchment areas between hospitals and uncertainty in catchment population estimates are ignored. Scientific Scrutiny Although the results from these burden reports are often cited, none of these burden estimates themselves have been published in peer-reviewed literature.

Since the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has emerged, disseminated globally and become a leading cause of bacterial infections in both health-care and community settings. However, there is marked geographical variation in MRSA burden owing to several factors, including differences in local infection control practices and pathogen-specific characteristics of the circulating clones. Different MRSA clones have resulted from the independent acquisition of staphylococcal cassette chromosome mec (SCC mec ), which contains genes encoding proteins that render the bacterium resistant to most β-lactam antibiotics (such as methicillin), by several S. aureus clones. The success of MRSA is a consequence of the extensive arsenal of virulence factors produced by S. aureus combined with β-lactam resistance and, for most clones, resistance to other antibiotic classes. Clinical manifestations of MRSA range from asymptomatic colonization of the nasal mucosa to mild skin and soft tissue infections to fulminant invasive disease with high mortality. Although treatment options for MRSA are limited, several new antimicrobials are under development. An understanding of colonization dynamics, routes of transmission, risk factors for progression to infection and conditions that promote the emergence of resistance will enable optimization of strategies to effectively control MRSA. Vaccine candidates are also under development and could become an effective prevention measure. Staphylococcus aureus is a common commensal bacterium in the nasal mucosa. Several strains have acquired resistance to methicillin (methicillin-resistant S. aureus , MRSA) and most β-lactam antibiotics; such drug resistance, in addition to the intrinsic high virulence potential of S. aureus , makes MRSA an important source of health-care-associated and community-associated infections.

There is ongoing controversy about the role of health-care workers in transmission of meticillin-resistant Staphylococcus aureus (MRSA). We did a search of the literature from January, 1980, to March, 2006, to determine the likelihood of MRSA colonisation and infection in health-care workers and to assess their role in MRSA transmission. In 127 investigations, the average MRSA carriage rate among 33 318 screened health-care workers was 4·6%; 5·1% had clinical infections. Risk factors included chronic skin diseases, poor hygiene practices, and having worked in countries with endemic MRSA. Both transiently and persistently colonised health-care workers were responsible for several MRSA clusters. Transmission from personnel to patients was likely in 63 (93%) of 68 studies that undertook genotyping. MRSA eradication was achieved in 449 (88%) of 510 health-care workers. Subclinical infections and colonisation of extranasal sites were associated with persistent carriage. We discuss advantages and disadvantages of screening and eradication policies for MRSA control and give recommendations for the management of colonised health-care workers in different settings.

The worldwide increase in resistance to antimicrobial drugs has made reducing the unnecessary use of antibiotics a public health priority. There have been campaigns in many countries to educate the public about appropriate use of antibiotics in outpatients. By use of a comprehensive search strategy and structured interviews, we were able to identify and review the characteristics and outcomes of 22 campaigns done at a national or regional level in high-income countries between 1990 and 2007. The intensity of the campaigns varied widely, from simple internet to expensive mass-media campaigns. All but one campaign targeted the public and physicians simultaneously. Most campaigns that were formally evaluated seemed to reduce antibiotic use. The effect on resistance to antimicrobial drugs cannot be assessed accurately at present. Although the most effective interventions and potential adverse outcomes remain unclear, public campaigns can probably contribute to more careful use of antibiotics in outpatients, at least in high-prescribing countries.

Objectives To compile current published reports on nosocomial outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), evaluate the role of healthcare workers (HCWs) in transmission, and evaluate outbreak management practices. Methods Narrative literature review. Short conclusion The coronavirus disease 2019 (COVID-19) pandemic has placed a large burden on hospitals and healthcare providers worldwide, which increases the risk of nosocomial transmission and outbreaks to “non-COVID” patients or residents, who represent the highest-risk population in terms of mortality, as well as HCWs. To date, there are several reports on nosocomial outbreaks of SARS-CoV-2, and although the attack rate is variable, it can be as high as 60%, with high mortality. There is currently little evidence on transmission dynamics, particularly using genomic sequencing, and the role of HCWs in initiating or amplifying nosocomial outbreaks is not elucidated. There has been a paradigm shift in management practices of viral respiratory outbreaks, that includes widespread testing of patients (or residents) and HCWs, including asymptomatic individuals. These expanded testing criteria appear to be crucial in identifying and controlling outbreaks.

The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori. World Health Organization.

The scarcity of novel antibiotic compounds in a time of increasing resistance rates has begun to ring alarm bells at the highest echelons of government. Large new financial incentives to accelerate antibiotic research and development, such as market entry rewards (MERs), are being considered. However, there is little focus on how to sustain the efficacy of new, promising antibiotics reaching the market. Currently, inappropriate use of antibiotics is commonplace, which has accelerated resistance development. In an attempt to halt this trend, antibiotic stewardship policies are being implemented in many resource-rich settings. Unfortunately, this has not yet had an impact on the amount of antibiotics being prescribed globally. One important hurdle is misalignment of incentives. While governments and health services are incentivized to promote prudent use of this common good, pharmaceutical companies are incentivized to increase volume of sales to maximize profits. This problem must be addressed or else the major efforts going into developing new antibiotics will be in vain. In this paper we outline an approach to realign the incentives of pharmaceutical companies with wider antibiotic conservation efforts by making a staged bonus a component of an MER for antibiotic developers when resistance to their drug remains low over time. This bonus could address the lack of stewardship focus in any innovation-geared incentive.

10 years ago, the quality of research into the control of MRSA left much to be desired. Since then, progress has been made, but results from high-quality studies show discrepancies and contradict some common beliefs and practices. Uncertainty remains over the most effective strategies to control endemic MRSA and, in particular, the effectiveness of individual measures combined in prevention bundles.