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We have failed to keep pace with the ability of many pathogens to develop resistance to antibiotics. Progress has recently been made on 4 of 10 key challenges to ensuring that antibiotics retain an effective role in medicine, but more daunting challenges remain. Two major ways that modern medicine saves lives are through antibiotic treatment of severe infections and the performance of medical and surgical procedures under the protection of antibiotics. Yet we have not kept pace with the ability of many pathogens to develop resistance to antibiotics that are legacies of the golden era of antibiotic discovery, the 1930s to 1960s. We call that period “golden” because success seemed routine then; we call it an “era” because it ended. When industry scientists shifted from making variants of old drugs to pursuing fundamentally new drugs with activity against resistant pathogens, they generally failed. . . .

This commentary examines how specific sustainable development goals (SDGs) are affected by antimicrobial resistance and suggests how the issue can be better integrated into international policy processes. Moving beyond the importance of effective antibiotics for the treatment of acute infections and health care generally, we discuss how antimicrobial resistance also impacts on environmental, social, and economic targets in the SDG framework. The paper stresses the need for greater international collaboration and accountability distribution, and suggests steps towards a broader engagement of countries and United Nations agencies to foster global intersectoral action on antimicrobial resistance.

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

The worldwide increase in antibiotic resistance is a concern for public health. The fact that the choice of dose and treatment duration can affect the selection of antibiotic-resistant mutants is becoming more evident, and an increased number of studies have used pharmacodynamic models to describe the drug exposure and pharmacodynamic breakpoints needed to minimize and predict the development of resistance. However, there remains a lack of sufficient data, and future work is needed to fully characterize these target drug concentrations. More knowledge is also needed of drug pharmacodynamics versus bacteria with different resistance mutations and susceptibility levels. The dosing regimens should exhibit high efficacy not only against susceptible wild-type bacteria but, preferably, also against mutated bacteria that may exist in low numbers in “susceptible” populations. Thus, to prolong the life span of existing and new antibiotics, it is important that dosing regimens be carefully selected on the basis of pharmacokinetic and pharmacodynamic properties that prevent emergence of preexisting and newly formed mutants.

Appropriate antibiotic therapy is critical in the management of severe sepsis and septic shock to reduce mortality, morbidity and health costs. New methods for rapid antibiotic susceptibility testing are needed because of increasing resistance rates to standard treatment. The purpose of this study was to evaluate the performance of a novel microfluidic method and the potential to directly apply this method on positive blood cultures. Minimum inhibitory concentrations (MICs) of ciprofloxacin, ceftazidime, tigecycline and/or vancomycin for Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus were determined using a linear antibiotic concentration gradient in a microfluidic assay. Bacterial growth along the antibiotic gradient was monitored using automated time-lapse photomicrography and growth inhibition was quantified by measuring greyscale intensity changes in the images. In addition to pure culture MICs, vancomycin MICs were determined for S. aureus from spiked and clinical blood cultures following a short centrifugation step. The MICs were compared with those obtained with the Etest and for S. aureus and vancomycin also with macrodilution. The MICs obtained with the microfluidic assay showed good agreement internally as well as with the Etest and macrodilution assays, although some minor differences were noted between the methods. The time to possible readout was within the range of 2 to 5 h. The examined microfluidic assay has the potential to provide rapid and accurate MICs using samples from positive clinical blood cultures and will now be tested using other bacterial species and antibiotics.

The World Health Organization (WHO) has prepared a draft Global action plan on antimicrobial resistance that will be discussed at this year's World Health Assembly. However, more is required if the world is to grapple effectively with this huge and complex problem. Global collective action is required in three areas: 1. access, 2. conservation, and 3. innovation. The problem of antimicrobial resistance requires that all three areas be tackled simultaneously. Without conservation and innovation, universal access will simply drive resistance and deplete existing stocks of effective antimicrobials. Given these global coordination issues, there is a clear role for a binding international legal framework to encompass the issues of access, conservation and innovation.

Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli , offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-kill experiments (using strains with minimum inhibitory concentrations, MIC CIP 0.023–1 mg/L and MIC CST 0.5–0.75 mg/L). It was also sought to demonstrate an approach of simulating concentrations at the site of infection with population pharmacokinetic and whole-body physiologically based pharmacokinetic models to explore the clinical value of the combination when facing more resistant strains (using extrapolated strains with lower susceptibility). The combined effect in the final model was described as the sum of individual drug effects with a change in drug potency: for ciprofloxacin, concentration at half maximum killing rate (EC 50 ) in combination was 160% of the EC 50 in monodrug experiments, while for colistin, the change in EC 50 was strain-dependent from 54.1% to 119%. The benefit of co-administrating a lower-than-commonly-administrated colistin dose with ciprofloxacin in terms of drug effect in comparison to either monotherapy was predicted in simulated bloodstream infections and pyelonephritis. The study illustrates the value of pharmacokinetic-pharmacodynamic modelling and simulation in streamlining rational development of antibiotic combinations.

Data on antibiotic use are not publicly available in most European Union countries. We obtained data for non-hospital antibiotic sales for 1997 from the 15 member states and analysed these according to the Anatomic Therapeutic Chemical classification system, and expressed them as defined daily doses per 1000 people per day. Sales of antibiotics varied more than four-fold: France (36·5), Spain (32·4), Portugal (28·8), and Belgium (26·7) had the highest sales, whereas the Netherlands (8·9), Denmark (11·3), Sweden (13·5), and Germany (13·6) had the lowest. There was also profound variation in use of different classes of antibiotics. Detailed knowledge of antibiotic use is necessary to implement national strategies for optimum antibiotic use, and to address the threat posed by resistant microorganisms.

The United Nations 2024 Political Declaration of the High-level Meeting on Antimicrobial Resistance needs bold targets, clear indicators, and strengthened country capacities to make progress, write Viroj Tangcharoensathien, Otto Cars, and Angkana Lekagul

Otto Cars talks to Gary Humphreys about the lack of progress on antimicrobial resistance (AMR) and the urgent need for comprehensive, cross-sectoral action.Otto Cars talks to Gary Humphreys about the lack of progress on antimicrobial resistance (AMR) and the urgent need for comprehensive, cross-sectoral action.