The World Health Organization (WHO) 14 June 2024 released its latest report on antibacterial agents, including antibiotics, in clinical and preclinical development worldwide. Although the number of antibacterial agents in the clinical pipeline increased from n.80 in 2021 to n.97 in 2023, there is a pressing need for new, innovative agents for serious infections and to replace those becoming ineffective due to widespread use. “Antimicrobial resistance is only getting worse yet we’re not developing new trailblazing products fast enough to combat the most dangerous and deadly bacteria” said Dr Yukiko Nakatani, WHO’s Assistant Director-General for Antimicrobial Resistance ad interim. “Innovation is badly lacking yet, even when new products are authorized, access is a serious challenge”. Encouragingly, non-traditional biological agents, such as bacteriophages, antibodies, anti-virulence agents, immune-modulating agents and microbiome-modulating agents, are increasingly being explored as complements and alternatives to antibiotics. The preclinical non-traditional antibacterial pipeline is active and innovative, with many non-traditional approaches, as part of a stable number of preclinical candidates over the last 4 years. Gram-negative bacteria have built-in abilities to find new ways to resist treatment and can pass along genetic material that allows other bacteria to become drug resistant as well. Universal access to quality and affordable tools for preventing, diagnosing and treating infections is key to mitigating AMR’s impact on public health and the economy, as per WHO’s Strategic and Operational Priorities for Addressing AMR in the Human Health Sector, the AMR resolution adopted by the 77th World Health Assembly and the People-centred approach to addressing AMR and core package of AMR interventions.
The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR.
Acknowledging the urgency of addressing antimicrobial resistance (AMR), an opportunity exists to extend AMR action-focused research beyond the confines of an isolated biomedical paradigm. An AMR learning system, AMR-X, envisions a national network of health systems creating and applying optimal use of antimicrobials on the basis of their data collected from the delivery of routine clinical care. AMR-X integrates traditional AMR discovery, experimental research, and applied research with continuous analysis of pathogens, antimicrobial uses, and clinical outcomes that are routinely disseminated to practitioners, policy makers, patients, and the public to drive changes in practice and outcomes. AMR-X uses connected data-to-action systems to underpin an evaluation framework embedded in routine care, continuously driving implementation of improvements in patient and population health, targeting investment, and incentivising innovation. All stakeholders co-create AMR-X, protecting the public from AMR by adapting to continuously evolving AMR threats and generating the information needed for precision patient and population care.
Complicated UTIs caused by resistant Enterobacterales can be treated with Trimetropim/sulphamethoxazol, ciprofloxacin, or levofloxacin. Nitrofurantoin and TMP/SMX are recommended for uncomplicated cystitis. Primary treatment of infections due to ESBL-producing Enterobacterales that occur outside the urinary tract is carbapenems. Primary treatment of infections due to CRE that occur outside the urinary tract is medication that combines beta-lactams and beta-lactamase inhibitors. Primary treatment of Pseudomonas aeruginosa infections with difficult-to-treat resistance includes ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, or cefiderocol. Antimicrobial resistance is a global crisis, and resistant pathogens cause more than 2.8 million infections and 35,000 deaths annually. Even when bacterial cultures indicate resistance, choosing the most effective antibiotic can be challenging. The Infectious Diseases Society of America published guidelines for treating infections with the most common resistant gram-negative organisms. These guidelines do not apply to empiric treatment.
Antimicrobial resistance (AMR), a huge global health threat, will be back in the spotlight when the UN will conduct a second high-level meeting on AMR in September, 2024. Ahead of this meeting, The Lancet published a series on AMR and estimated that 10% of the global AMR burden can be averted with existing interventions such as improving water, sanitation, and hygiene (WASH), controlling infection and taking preventive measures in health-care facilities, and conducting vaccination in low-income and middle-income countries (LMICs).
Although several efforts are underway in the research and development of new antibiotics and antimicrobial stewardship, the progress is threatened by blind spots, including excessive focus on high-income nations, human antibiotic overuse, antibiotic stewardship in hospitals, and antimicrobial development, with relatively little focus on antibiotic overuse in animals, primary care providers in LMICs, and the development of rapid tests for detecting AMR.
In conclusion, the current approach on managing AMR has many blind spots. We believe that explicitly recognising these blind spots is the first step towards developing a more realistic, grounded, and equitable management strategy.
The commitments are laid out in a political declaration adopted the 26th September 2024 by 193 United Nations (UN) member states at the UN High-Level Meeting on AMR in New York. The meeting was focused on scaling up global, regional, and national efforts to tackle the problem. Setting a target goal of reducing global AMR deaths by 10% by 2030, the declaration calls on countries to fully implement and fund national AMR action plans, to reduce inappropriate antibiotic use in people and animals, to ensure equitable and timely access to antibiotics in all countries, to prioritize infection prevention efforts, and to promote efforts to boost antibiotic research and development.
The complete Political Declaration is here available:
https://www.un.org/pga/wp-content/uploads/sites/108/2024/09/FINAL-Text-AMR-to-PGA.pdf
UN General Assembly President Philemon Yang called the declaration a “strong blueprint,” but said countries now must act. “We must build on this political will with resources and accountability to ensure effective implementation,” Yang said at the opening of the meeting. “Let us together rise to meet this challenge and secure a safer, healthier future for all.” The declaration calls for all countries to have national AMR action plans implemented, with national targets, by 2030. Furthermore, it calls for governments to commit to sustainable financing of those plans and sets a target of $100 million in international financing to help at least 60% of countries implement their national action plans.
The document also addresses the weak antibiotic pipeline, which the WHO and other groups have deemed insufficient to address the growing challenge of multidrug-resistant bacteria. To address the challenging financial market for new antibiotics, the declaration highlights the need for governments to develop new incentives and funding mechanisms to promote research and development into new antibiotics, along with diagnostics and vaccines.
While National Guidelines serve as the gold standard on which to base SSTI treatment decisions, an Advisory Panel of experts convened by the ASHP Foundation, as a part of Medication-Use Evaluation Resources initiative, (for an approach to antibiotic stewardship in the treatment of SSTIs, with a focus on oral AB in the emergency department setting for patients who will be treated as outpatients), stressed that institutional guidelines must be regularly updated and grounded in local antimicrobial resistance patterns, patient-specific factors, and logistical considerations. SSTI treatment considerations for antibiotic selection in the ED supported by current, evidence-based guidelines, including guidance on optimal oral antibiotic selection for patients discharged for outpatient treatment, are a useful tool to improve the quality and efficiency of care, enhance patient-centric outcomes and satisfaction, decrease healthcare costs, and reduce overuse of antibiotics.
Newborns are particularly exposed to infections due to the poor effectiveness and the immaturity of their immune systems. For this reason, in Neonatal Intensive Care Units (NICUs), the use of antimicrobial drugs is often decisive and life-saving, and it must be started promptly to ensure its effectiveness in consideration of the possible rapid evolution of the infection towards sepsis. Nevertheless, the misuse of antibiotics in the neonatal period leads not only to an increase in the development and wide spreading of antimicrobial resistance (AMR) but it is also associated with various short-term (e.g., alterations of the microbiota) and long-term (e.g., increased risk of allergic disease and obesity) effects. It appears fundamental to use antibiotics only when strictly necessary; specific decision-making algorithms and electronic calculators can help limit the use of unnecessary antibiotic drugs. The aim of this narrative review is to summarize the right balance between the risks and benefits of antimicrobial therapy in NICUs; for this purpose, specific Antimicrobial Stewardship Programs (ASPs) in neonatal care and the creation of a specific antimicrobial stewardship team are requested.
ESKAPE pathogens – Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. — were initially identified as critical multidrug-resistant bacteria for which effective therapies quickly became necessary. Even now, despite the introduction of numerous new antibiotics and antibiotic adjuvants, such as new β-lactamase inhibitors, these organisms continue to represent important therapeutic challenges. These bacteria share several key biological characteristics, including adaptations for survival in the modern healthcare context, different methods for acquiring resistance determinants, and the spread of clones at high risk of success throughout the world. With the advent of next-generation sequencing, new tools to track and combat the spread of these organisms have rapidly evolved, as has a renewed interest in non-traditional antibiotic approaches. In this review, authors explore the current epidemiology and clinical impact of this important group of bacterial pathogens and discuss relevant mechanisms of resistance to recently introduced antibiotics that influence their use in clinical settings. Additionally, they discuss emerging therapeutic strategies necessary for effective patient care in the era of widespread antimicrobial resistance.
Time-dependent antibiotics require drug concentrations greater than the minimum inhibitory concentration (MIC) for a certain time period between doses, which usually ranges from 40 to 50% of inter-dose interval for their best action. Continuous infusions are preferred over extended infusions for beta-lactam antibiotics and are associated with clinical benefits like decrease in hospital stay, cost of therapy and mortality. For vancomycin, continuous infusion is associated with reduced toxicity and cost of therapy but no mortality benefit. Recent times have seen a surge in rapid culture-independent novel assays and molecular diagnostics for common respiratory pathogens, as well as the availability of updated tests for newer strains of pathogens. These include antigen detection assays, reverse transcription–quantitative polymerase chain reaction (RT qPCR) testing, multiplex PCR panels targeting multiple organisms, plasma cell-free DNA, next-generation sequencing (NGS), etc. on blood, and upper and lower respiratory tract specimens to detect viral, bacterial, fungal, and mycobacterial infections. Appropriate use of these newer methods leads to reduced antibiotic usage.