Antimicrobial resistance: Current challenges and future directions

Abstract

Background

The misuse of antibiotics has led to the emergence of antimicrobial resistance (AMR), particularly threatening critically ill patients reliant on these medications. This review explores the challenges of superbugs and AMR in critical care settings and highlights potential solutions.

Methods

This narrative review used keywords like “antimicrobial resistance” and “superbugs” in PubMed, Scopus, and Google Scholar databases.

Results

The overuse and misprescription of antibiotics contribute to developing superbugs, rendering traditional treatments ineffective in critical care. AMR in critical care leads to increased costs, extended hospital stays, and limited treatment options. Combating AMR requires a multifaceted approach, including antibiotic stewardship, research, and development of novel antibiotics and alternative therapies, and rigorous infection control measures. Public education and collaboration among stakeholders are crucial for effective strategies. Future success hinges on a paradigm shift toward antibiotic stewardship, innovation in antimicrobials, and infection control. Implementing legislation and antimicrobial stewardship (AMS) programs are necessary steps. Research gaps exist in understanding environmental factors influencing AMR. New classes of antibiotics, faster diagnostics, and optimized drug combinations are future directions. Global collaboration in research, surveillance, and policy development is paramount.

Conclusion

AMR poses a significant threat to critical care. This review emphasizes the need for a multifaceted approach to protect the effectiveness of critical care interventions. Addressing these challenges and exploring potential solutions can ensure effective treatment for critically ill patients.

Introduction

Antibiotic resistance refers to when bacteria change their response to the use of antibiotics and become antibiotic-resistant. These bacteria may infect humans and are more complex to treat than nonresistant bacteria. Antimicrobial resistance (AMR) is a broader term, encompassing resistance to drugs to treat infections caused by other microbes as well, such as parasites (e.g. malaria), viruses (e.g. HIV), and fungi (e.g. Candida).¹ While Salvarsan, the first antibiotic for syphilis, was found by Paul Ehrlich in 1910, the discovery of penicillin in 1928 by Alexander Fleming launched a medical revolution. A decline in antibiotic discovery and the rise of drug-resistant bacteria has created a critical situation–the current AMR.² The misuse of antibiotics has led to the development of resistant bacteria, which was recognized as early as 1945 by Alexander Fleming and later acknowledged by world leaders in a 2016 Political Declaration of the United Nations General Assembly.³ The impact of overuse and misprescription of antibiotics across health care and agricultural sectors has contributed to the development and spread of AMR.⁴

The emergence of superbugs resistant to multiple antibiotics and other antimicrobial drugs poses a significant threat to critically ill patients. These superbugs can render traditional treatments ineffective, leading to prolonged illnesses, increased mortality, and limited treatment options. In critical care settings, where patients are often immunocompromised and require intensive antibiotic therapy, the risk of AMR is exceptionally high. The rise of superbugs and AMR is a critical global health concern, with three superbugs–Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii–identified as a priority by the World Health Organization (WHO).⁵ It is estimated that superbugs could cause 10 million deaths by 2050, necessitating new classes of antimicrobial agents due to the rapid dissemination of AMR and the emergence of multidrug-resistant (MDR) pathogens.⁶ AMR is considered a significant threat to human and animal health, with resistance detected to all antibiotics, including those that form the last line of defense against MDR infections.⁷ India's ‘National One Health Mission’ aims to facilitate better management of diseases affecting humans, animals, and the environment.⁸ Promotion of intensive poultry production may also increase AMR, especially within resource-limited settings due to a lack of effective biosafety and biosecurity measures.⁹ Microplastics, heavy metals, and antibiotics are potential sources of environmental pollutants. Together, they have a positive synergetic effect on developing antibiotic-resistant bacteria.¹⁰

This review explores the alarming rise of AMR in critical care settings, fueled by the emergence of superbugs. It exposes the growing threat to the patients and unveils the gaps in our current knowledge. The review proposes potential solutions and future research directions to combat AMR. Clinicians, researchers, and policymakers will find this up-to-date analysis essential in understanding the gravity of AMR and navigating the path forward.

Methods

This narrative review aimed to synthesize current knowledge on AMR. The literature search was conducted between June 01 and July 08, 2024, utilizing three significant databases: PubMed, Scopus, and Google Scholar. We employed a combination of keywords, including “antimicrobial resistance,” “superbugs,” “infection,” and “multidrug-resistant pathogens” to identify relevant articles. A comprehensive and focused search was restricted to English-language publications with available full text. Articles deemed nonrelevant to AMR or lacking a clear focus on critical care were excluded. All retrieved articles were manually screened, and relevant studies were selected for inclusion in this review. This approach ensured a focused and up-to-date analysis of the current state of AMR.

Results and discussion

The main findings of the review are discussed ahead under several subheadings.

The rise of superbugs and antimicrobial resistance and its significance

The emergence and spread of AMR from the One Health perspective are highlighted as a constantly growing global health threat, emphasizing the need for novel technological innovations to complement existing strategies in the fight against AMR.¹¹ The fear of postantibiotic era has prompted the recognition of AMR as one of the top 10 global public health threats by the WHO.⁴ The proposed strategies to overcome resistance include rationalizing the use of existing antibiotics and developing alternative antibiotics, both of which are challenging to implement and likely to provide only temporary solutions. The emergence of superbugs and the rapid dissemination of AMR necessitates a coordinated, dedicated international multidisciplinary effort, as no isolated country can tackle this global health threat. Developing new antimicrobials, surveillance and analysis of AMR trends, and optimizing antibiotic use are crucial in combating AMR.¹²

AMR is a critical global issue, jeopardizing public health and development efforts; its significance is highlighted in Table 1. It is estimated that drug-resistant bacterial infections were responsible for 1.27 million deaths worldwide in 2019, contributing to nearly 5 million fatalities overall.¹³ The overuse and misuse of antimicrobials in humans, animals, and plants are the primary reasons behind the rise of these so-called “superbugs.” This global problem has its harshest impact in low- and middle-income countries, where poverty and inequality exacerbates the situation.

Table 1.

Significance of antimicrobial resistance (AMR).

Aspect	Description
Public health threat	AMR makes infections harder to treat, increasing risk of: ∗Disease spread ∗Severe illness ∗Death
Global problem	Affects all regions and income levels, with low- and middle-income countries most impacted.
Economic burden	AMR increases healthcare costs and reduces productivity.
Endangers medical advancements	Puts the effectiveness of modern medicine at risk, including surgeries and lifesaving treatments.

AMR not only complicates treating infections but also significantly increases the risks associated with surgeries, caesarean sections, and cancer chemotherapy. Furthermore, the world faces a critical shortage of new antibiotics and unequal access to existing ones. The research and development (R and D) pipeline is failing to keep pace with the growing resistance, highlighting the urgent need for innovative solutions and ensuring everyone gets the necessary vaccines, diagnostics, and medications. The economic consequences of AMR are equally concerning. The World Bank estimates that by 2050, it could incur an additional $1 trillion in healthcare costs and economic losses ranging from $1 trillion to $3.4 trillion annually by 2030.¹⁴

Preventing infections is crucial to reducing unnecessary antimicrobial use to combat this threat. Additionally, ensuring access to accurate diagnoses and appropriate infection treatments are vital. Robust surveillance of AMR trends, antimicrobial use, and investment in research and development for new vaccines, diagnostics, and medicines are also essential for strategic information and innovation.¹⁵

Development and spread of drug resistance

Microbes like bacteria, viruses, and fungi constantly evolve to survive, and their goal is to reproduce and spread. When they encounter something that hinders their growth, like an antibiotic, they adapt through genetic changes, which is how the AMR develops. Understanding the various causes is crucial for developing strategies to combat AMR and ensure the continued effectiveness of these life-saving drugs (Fig. 1).

Fig. 1.

Reasons for the development and spread of antimicrobial (drug) resistance (AMR).

The AMR arises from a complex interplay between the natural defenses of microbes and how antibiotics are used (Fig. 1). At the microbial level, some possess genes for antibiotic resistance. When exposed to antibiotics, these microbes survive and reproduce, their resistant genes multiplying each generation. Over time, these resistant microbes become the dominant population, leaving us with fewer and fewer susceptible ones. The constant process of microbial replication can also lead to mutations in their genetic code. Some of these mutations can grant resistance to antibiotics. Only these resistant microbes survive and thrive in the presence of the drug, perpetuating the resistant strain and making it harder to treat infections.¹⁶

Microbes can also be ‘social’, sharing genes through horizontal gene transfer. It includes genes for antibiotic resistance. A previously non-resistant microbe can acquire resistance genes from its neighbor, further complicating treatment options. However, human behavior also plays a significant role in fueling AMR. Sometimes antibiotics are prescribed for viral infections where they are ineffective, or for conditions that do not require them at all. This inappropriate use creates selective pressure, promoting the growth of resistant bacteria. Without a definitive diagnosis, prescription of broad-spectrum antibiotics can inadvertently allow resistant strains to flourish. Hospitals are hotspots for antibiotic use, especially for critically ill patients; however, this heavy use is selected for resistant microbes that thrive in this environment. The proximity of sick patients further accelerates the spread of these resistant strains. The use of antibiotics in animal feed is suspected to contribute to resistance to human pathogens. While the exact impact on human health is debated, it is a concern that requires further investigation.¹⁶ Table 2 provides a snapshot of how different bacteria can exhibit varying resistance levels against different classes of antimicrobials. It highlights the growing concern with some bacteria like methicillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase -producing Klebsiella.¹⁷

Table 2.

Comparison of antimicrobial resistance (AMR) in common bacteria.

Bacteria	Antimicrobial class	Common infection	% Resistance
Escherichia coli (E. coli)	Penicillin (Amoxicillin)	Urinary tract infections (UTIs)	Up to 80%
Staphylococcus aureus (S. aureus)	Methicillin-resistant Staphylococcus aureus (MRSA)	Skin infections, pneumonia	Varies by region, can be >50% in hospitals
Klebsiella pneumoniae	Extended-spectrum β-lactamase (ESBL)-producing	Pneumonia, bloodstream infections	Increasing globally, can be >30%
Pseudomonas aeruginosa	Fluoroquinolones (Ciprofloxacin)	Hospital-acquired infections	Resistance rising, can be >20%
Enterococcus faecium	Vancomycin-resistant enterococcus (VRE)	Hospital-acquired infections	Lower prevalence but concerning due to limited treatment options

Reasons for the emergence of antimicrobial resistance

Several key factors are responsible forthe emergence of AMR like overuse and misuse of antimicrobials (in humans, animals, and plants), insufficient sanitation and hygiene in the community, hospitals, and slaughterhouses, and lack of adequate investment in R and D, in the development of new antimicrobials, and AMR surveillance and prevention (Table 3).

Table 3.

Reasons and impact of antimicrobial resistance (AMR).

Factors	Impact
Overuse and misuse of antimicrobials: ∗In humans: unnecessary antibiotics for colds, over prescription practices. ∗In animals: routine use of antibiotics in livestock for growth promotion. ∗In plants: use of antimicrobials in agriculture.	Creates selective pressure for microbes to develop resistance.
Inadequate sanitation and hygiene: ∗Poor hygiene practices in hospitals and communities. ∗Limited access to clean water and sanitation facilities.	Allows for easier spread of resistant microbes.
Lack of investment in research & development: ∗Insufficient funding for development of new antimicrobials and alternative therapies. ∗Limited research into AMR surveillance and prevention.	Hinders progress in combating AMR.

The critical care conundrum

Critically ill patients often rely on broad-spectrum antibiotics to fight infections. However, this very reliance can contribute to the emergence of resistant strains. The challenge is in finding the right balance–providing effective treatment while minimizing the selection pressure for resistant bacteria. The critical care conundrum in AMR significantly impacts healthcare systems, increasing costs and resource utilization (Table 4). The rise of resistant clinical pathogens necessitates more extended hospital stays, costly second-line drugs, and more sophisticated healthcare systems, resulting in additional healthcare expenditure.⁴

Table 4.

Consequences and impact of antimicrobial resistance (AMR) in critical care.

Consequence	Impact
Limited treatment options	Increased mortality and morbidity
Prolonged hospital stays	Increased healthcare costs and resource utilization
Diagnostic challenges	Delays in appropriate treatment
Increased mortality and morbidity	Higher burden on healthcare systems
Rise of multidrug-resistant (MDR) pathogens	Dependence on costly drugs and complex treatment regimens

Addressing AMR requires multifaceted interventions involving stakeholders from various levels, including policymakers, researchers, healthcare providers, and the public (Table 5). In the context of critical care, it is crucial to triage patients to ensure optimal utilization of limited intensive care unit (ICU) resources, especially in intensive care.¹⁸ Furthermore, the disparity in critical care services between high-income countries (HICs), low-income countries (LICs), and low and middle-income countries (LMICs) highlight the challenges faced by resource-limited settings in providing specialized intensive care.¹⁹

Table 5.

Role of stakeholders involved in addressing antimicrobial resistance (AMR).

Stakeholder	Role
Policymakers	Develop and implement national AMR action plans
Researchers	Discover new antibiotics and diagnostics
Healthcare providers	Implement antibiotic stewardship programs and ensure appropriate antibiotic use
Public	Practice responsible antibiotic use and maintain good hygiene
Pharmaceutical industry	Invest in research and development of new antimicrobials
Animal health industry	Promote responsible use of antibiotics in animals

Public education and policy engagement are crucial weapons in the fight against AMR. Public awareness campaigns can empower individuals to make informed choices, such as seeking medical advice before taking antibiotics and completing the entire prescribed course. Successful campaigns, like those in the Netherlands and the UK, have used targeted messaging and community outreach to improve antibiotic use in humans and animals. On the policy front, legislation restricting unnecessary antibiotic use in agriculture and promoting the development of new antibiotics can create a more sustainable environment. For example, Denmark's successful reduction in antibiotic use in livestock demonstrates the effectiveness of policy interventions. By fostering public understanding and implementing effective policies, we can create a more responsible approach to antibiotic use, ultimately slowing the emergence and spread of AMR.²⁰

To combat the growing threat of AMR, policymakers can take concrete steps (Fig. 2). Investing in robust national surveillance systems for both human and animal populations is essential for tracking resistance trends. Promoting antibiotic stewardship programs in healthcare facilities, through financial incentives and evidence-based prescribing guidelines, can minimize unnecessary use. Addressing antibiotic use in agriculture requires phased bans on non-therapeutic use, encouraging alternatives like vaccines, and supporting farmers in adopting responsible practices. Finally, fostering research and development of new antibiotics through incentives and streamlined regulations, alongside public awareness campaigns and education for healthcare professionals and communities, are crucial for a multipronged approach to tackling AMR. By implementing these specific and actionable recommendations, policymakers can play a critical role in mitigating AMR and safeguarding public health for future generations.

Fig. 2.

Actionable steps for policymakers in dealing with antimicrobial resistance (AMR).

Infections caused by superbugs/AMR are more difficult to treat, resulting in more extended hospital stays, higher healthcare costs, and an increased risk of death.⁴ With fewer effective antibiotics available, clinicians may resort to less effective drugs with potentially severe side effects. Furthermore, diagnosing infections caused by resistant pathogens can be more complex, delaying appropriate treatment and compromising patient outcomes.²¹

AMR not only leads to increased mortality and morbidity but also adds a financial burden on the healthcare system and significant economic losses, with predictions that it could become the leading cause of death by 2050.²² The impact of AMR on critical care includes increased dependency on costly drugs and diagnostic procedures, leading to extra expenditure on healthcare systems. Effective interventions to address AMR require collaboration among stakeholders at both hospital and community levels, including policymakers, researchers, healthcare providers, and the public.²³

Combating the threat

A multipronged approach is needed to address the growing threat of AMR (Fig. 3). Strict adherence to antibiotic prescribing guidelines, ensuring appropriate use and dosage, are crucial in curbing the emergence of resistant strains. Increased investment in R and D of novel antibiotics, antivirals, and antifungals is essential to stay ahead of resistance. Implementing infection control measures in hospitals and other healthcare settings is vital to prevent the spread of resistant pathogens.²⁴ Exploring alternative therapies, such as bacteriophages (viruses that infect bacteria), and phage therapy holds promise for tackling resistant infections.²⁵

Fig. 3.

Multipronged approach to combat antimicrobial resistance (AMR).

The threat of AMR is a global concern, and combating it requires a multifaceted approach. One key aspect is the involvement of regional and local groups in policy development, as they possess practical experience crucial for effective initiatives. However, knowledge gaps, including inadequate surveillance and monitoring, hinder AMR policy development. The WHO has recognized AMR as a significant global health threat and enacted a Global Action Plan. However, large-scale antimicrobial stewardship programs still need to be improved in many parts of the world.³ Improved surveillance, such as through the Fleming Fund, is vital to detect emerging resistance trends.²⁶ Weaknesses in combating AMR include insufficient public awareness, limited community engagement, weak cooperation, and inadequate human resources.

Additionally, practices like irrational prescription and overuse of antimicrobials contribute to the threat of AMR. To address these challenges, a broadened perspective considering stakeholder groups and using the “theory of change” can help explore opportunities for adaptation and reduction of antimicrobial use.²⁷ Efforts to raise awareness and understanding of AMR risks and responses have been implemented in several countries, emphasizing the importance of targeted, nationwide campaigns.²⁸

The future of critical care

The fight against superbugs and AMR demands a global collaborative effort and communication and knowledge sharing between healthcare professionals, researchers, and policymakers is crucial. Public education about the responsible use of antibiotics is essential to promote better stewardship practices. It is crucial to invest in training on AMR issues and the rapid implementation of antimicrobial stewardship (AMS) programs to prepare for the future,²⁸ as the lack of formal education on AMR during training could hinder healthcare professionals' ability to address AMR-related tasks.

Global perspective of antimicrobial resistance

The impact of AMR is not equally felt across the globe. Fig. 4 depicts high rates of specific resistant bacteria. Factors like antibiotic use patterns (both human and animal) and healthcare infrastructure play a role in these variations. LMICs might face challenges implementing strong antibiotic stewardship programs due to limited resources, while HICs might overuse broad-spectrum antibiotics. While the WHO has provided technical assistance and all 11 countries in the Southeast Asia Region (SEAR) have national action plans; however, here the fight against AMR faces challenges. Despite increased awareness and actions, data shows a worrying rise in drug resistance. This fragmented progress can be attributed to limited resources, slow behavioral change, and the effect of COVID-19. Countries like Bangladesh, India, Indonesia, Nepal, Sri Lanka, and Thailand exemplify this struggle.²⁹

Fig. 4.

Global distribution of antimicrobial resistance (AMR) emergence events. Points represent locations. Countries are shaded by event count. (Adapted from: Mendelsohn E et al.).³⁰

Challenges and differences in care in high-income countries and low-middle-income countries

It is essential to recognize the differences in care provision between HICs, LICs, and LMICs. While HICs have specialized intensive care units, LICs, and LMICs often lack specialized critical care services due to resource limitations and specialized training for managing critically ill patients.³¹ Furthermore, there is a need for future policies to enhance public awareness of AMR, deploy adequate human resources, upgrade laboratory capacity, and ensure resource mobilization to combat AMR effectively. The growing challenge of superbugs and AMR necessitates a paradigm shift in critical care. By implementing a comprehensive strategy that prioritizes antibiotic stewardship, fosters innovation in antimicrobials, and emphasizes infection control, the effectiveness of critical care interventions can be safeguarded to ensure better outcomes for critically ill patients.

LMICs are disproportionately affected by AMR despite using fewer antibiotics overall (Table 6). This is due to limited access to clean water and sanitation, overcrowded healthcare facilities, and lack of advanced diagnostics, all of which contribute to the spread of infections and unnecessary antibiotic use. Further hindering their response, LMICs face resource constraints, including a shortage of healthcare personnel and diagnostics. To address AMR, LMICs can implement resource-light strategies like strengthening infection control, developing national action plans with achievable goals, collaborating regionally for data sharing, and advocating for international funding to support these efforts.

Table 6.

Impact of antimicrobial resistance (AMR) in low-middle-income countries (LMICs).

Region	Challenge	Intervention (LMIC-tailored)	Impact
Developing countries (Example: South East Asia and Africa)	Limited resources for antibiotic stewardship	∗ Community education program promoting proper antibiotic use. ∗∗ Strengthen infection control practices in hospitals.	Increased awareness, more targeted antibiotic use, reduced transmission rates.
Developed countries (Example: Northern America and Europe)	Over-reliance on broad-spectrum antibiotics	Regional surveillance system tracking AMR trends	Early detection of emerging resistance, targeted interventions

Over-the-counter prescription legislation

The improper use of antimicrobials, including over-the-counter (OTC) use by consumers, contributes to AMR. This resistance has led to challenges in treating infectious diseases, burdening healthcare systems and global economies. The AMS has been introduced to reduce inappropriate use of antimicrobials and optimize prescribing, aiming to improve patient care and reduce hospital costs.³² In nations without it, legislation regarding OTC prescription of antimicrobial drugs is crucial to address this issue. Additionally, introducing new classes of antimicrobials to combat multidrug-resistant pathogens is essential. Furthermore, AMS significantly reduces AMR, optimizing prescribing and reducing inappropriate use.³³

Bundle approach and hospital antibiotic policy

In health care, “bundle delivery” usually refers to interventions or practices implemented together to improve patient outcomes. It is most commonly used in hospitals for specific procedures or conditions. A bundled approach and hospital antibiotic policy are crucial in addressing AMR in ICUs (Table 7). It is known that 30%–60% of antibiotics prescribed in ICUs are inappropriate, highlighting the need for a multimodal and multiprofessional strategy to combat AMR. However, there are challenges, such as poor involvement of nurses and inadequate training of healthcare professionals in dealing with AMR. The AMS plays a significant role in providing regular updates to healthcare professionals on measures addressing AMR, but some facilities have limitations in communication and reporting of outcomes.³⁴ Understanding appropriate antimicrobial use and implementing improvement strategies based on social and behavioral change theories are essential for tackling AMR in ICUs. The work on AMR reduction mainly focuses on hospital settings, but there is a need for more AMS in primary care settings. Furthermore, implementing personal protective equipment (PPE) in AMS is crucial, but there needs to be more clarity and an established framework for its incorporation into stewardship programs.³⁵

Table 7.

Bundle approach for addressing antimicrobial resistance (AMR) in intensive care units (ICUs).

Element	Description
Performance monitoring	Regularly monitor and audit antibiotic use to identify areas for improvement
Protocol-based selection	Use pre-defined protocols for antibiotic selection based on infection type and local resistance patterns
Dose optimization	Individualize antibiotic dosing based on patient factors like kidney function
De-escalation therapy	Narrow the antibiotic spectrum once culture and sensitivity results are available
Prophylaxis duration	Limit the duration of antibiotic prophylaxis to prevent unnecessary use

Optimization of drugs and doses based on metabolic functions

The optimization of drugs and doses based on metabolic functions of the liver and kidney involves understanding the metabolic stability and clearance of drugs.³⁶ Km and Vmax are two critical parameters used in biochemistry to describe the behavior of enzymes. Enzymes are biological catalysts crucial in facilitating chemical reactions in living organisms. Vmax and Km are used to calculate intrinsic clearance (CLint), representing the maximal rate of drug metabolism and the concentration at which the metabolism rate is 50% of Vmax, respectively.³⁷ The relative contribution of the liver and kidneys in drug elimination is crucial for appropriate drug use in impaired organ states. Furthermore, drug dosing adjustments, including dose reductions and lengthening the dosing interval, are considered for individuals with underperforming organs, such as those with liver dysfunction or compromised renal function.³⁸

Pharmacogenomics as a precision medicine

Pharmacogenomics plays a crucial role in addressing AMR by enabling the development of personalized drug prescriptions and dosages. The emergence and spread of resistance mechanisms among bacterial populations have rendered classic antimicrobial drugs obsolete, leading to an urgent need for innovative solutions.³⁹ Genomics has facilitated the identification of new drug targets and the understanding of antibiotic action mechanisms, which is essential for developing novel antimicrobial agents.⁴⁰ Metagenomics and functional metagenomics have also been employed to study antibiotic resistance genes in microbial communities, providing insights into the potential for antibiotic resistance and uncovering novel antibiotic resistance determinants.⁴¹ Furthermore, whole-microbial-genome sequencing has emerged as a cost-efficient and convenient approach for routine clinical antibiotic-resistance detection, offering valuable data for epidemiological studies, and research on new drug-resistance mechanisms.⁴²

Monitoring drug levels in high-performance liquid chromatography to ensure optimized drug delivery

Monitoring drug levels in high-performance liquid chromatography (HPLC) to ensure optimized drug delivery in AMR involves various aspects, such as method development, validation, and drug concentration analysis. The HPLC analysis method typically includes parameters such as the mobile phase composition, gradient mode, temperature, detection wavelength, flow rate, and injection volume. The robustness of the HPLC method is crucial, as deliberate small changes in analytical parameters should not significantly affect the results. Additionally, the application of HPLC methods in the quality control analysis of drugs has been supported by satisfactory results, including the successful assessment of drugs in their tablet dosage form and using the standard addition technique. Furthermore, developing and validating a sensitive, efficient, and economical HPLC method has been crucial for quantifying drug concentration in ultrafiltrate, contributing to the overall monitoring of drug levels in HPLC for optimized drug delivery.^43,44

Sterilization norms in the hospitals

Strict adherence to sterilization norms in central sterile services departments (CSSD) and operating rooms is crucial in preventing AMR. Compliance with national guidelines and directives, such as the European Union Medical Devices Directive, is essential to ensure the sterility of medical devices.⁴⁵ It is emphasized that only staff trained explicitly in sterilization should carry out this function. Additionally, the guidelines play a significant role in providing a framework for clinical practice, defining parameters for device operation, and ensuring occupational safety. Furthermore, hospital environmental hygiene, hand hygiene, and the safe use and disposal of medical devices are also essential in preventing infections associated with medical devices. The Medical Devices Directive 93/42/EEC and other related directives are crucial in setting standards for decontamination and sterilization in the healthcare sector. These directives outline expectations regarding design and testing, quality system expectations, and documentation requirements to gain and keep a Conformité Européenne mark. Harmonized Europan standards provide prescriptive detail for compliance with essential requirements, emphasizing the importance of interpreting and implementing these standards.

Areas of agreement and controversies in antimicrobial resistance

Fig. 5 summarizes the critical analysis of the published studies on AMR, highlighting areas of agreement and controversy. The scientific community agrees that antibiotic resistance is a severe global threat driven by overuse in humans and animals, leading to increased healthcare costs and the emergence of multidrug-resistant bacteria. However, there is an ongoing debate on the exact link between agricultural antibiotics and human resistance, the best implementation of rapid diagnostics in resource-limited areas, and the cost-effectiveness of solutions like new drugs or stewardship programs. Additionally, regional variations in resistance patterns and the environmental impact of antibiotics require further investigation.

Fig. 5.

Critical analysis of antimicrobial resistance (AMR) studies, highlighting the areas of agreements and controversies.

Ongoing clinical trials and their potential impact on antimicrobial resistance

The fight against AMR gets a boost from ongoing clinical trials with promising early-stage candidates, particularly targeting troublesome Gram-negative bacteria. Challenges like high costs and potential for resistance emergence during development still exist. Examples include a Phase II trial for a new drug combo against multidrug-resistant E. coli and a Phase 1B trial for a broader-spectrum carbapenem antibiotic.

Successful trials could offer new treatment options, reduce reliance on broad-spectrum antibiotics, and improve patient outcomes, especially in critical care. However, continued research and responsible use of new antibiotics through stewardship programs are crucial to maintain a steady stream of new drugs and minimize the emergence of further resistance.

Research gaps

There are several research gaps in understanding AMR (Table 8). More effective strategies to combat this growing threat can be developed by addressing these knowledge gaps. These strategies include environmental aspects where the contribution of antibiotic residues and other environmental pollutants, like heavy metals, to the development and spread of AMR is not well-known. The impact of these elements on the spread of resistance genes among bacteria is to be assessed by more research. More systematic monitoring of antibiotic levels in the environment is needed, and better methods are needed to track their pathways. Additionally, there are gaps in surveillance for resistant pathogens in different environments, including human and animal health sectors. A better understanding of the mechanism of the spread of resistant bacteria between different reservoirs, such as humans, animals, and the environment, is needed. It includes pinpointing the sources and behaviors of resistant pathogens in the environment. New classes of antimicrobials are urgently needed to be discovered and developed to combat resistant pathogens.

Table 8.

Research gaps and future directions in antimicrobial resistance (AMR).

Research Gap	Future direction
Environmental contribution to AMR (antibiotic residues, heavy metals)	Investigate the role of environmental factors in AMR development and spread
Monitoring antibiotic levels in the environment	Develop methods to track antibiotic pathways in the environment
Surveillance for resistant pathogens	Improve surveillance across human and animal health sectors
Spread of resistant bacteria between reservoirs	Understand how resistant bacteria spread among humans, animals, and the environment
New classes of antimicrobials	Discover and develop novel antimicrobials to combat resistant pathogens

Future directions

The fight against AMR necessitates continuous exploration of novel strategies beyond traditional antibiotics. The researchers are actively exploring several promising avenues for the future (Table 8). Developing entirely new classes of antibiotics remains a top priority. Additionally, they are exploring alternative therapies like phage therapy, which utilizes viruses to target and kill specific bacteria and holds immense potential. Antibiotic resistance breakers (ARBs) offer a unique strategy by restoring the effectiveness of existing antibiotics against previously resistant bacteria. Ongoing research on ARBs could revitalize our current arsenal of antibiotics.

Faster and more accurate diagnostic tools are crucial to enabling physicians to prescribe the right antibiotics at the outset and avoid unnecessary antibiotic use. The subsequent development of resistance can be significantly reduced. Recognizing the interconnectedness of AMR across humans, animals, and the environment, the One Health approach fosters research that develops strategies to address AMR in all these sectors simultaneously. The potential use of CRISPR-Cas systems is being explored for developing a new generation of antimicrobial agents and offers a precise and versatile approach. It can be programmed to inactivate specific bacterial genes to combat antibiotic resistance, by preventing a biofilm formation or reducing bacterial virulence, thus rendering pathogens harmless. Bacteriophage or phage therapy (PT) consists of specific virulent bacteriophages that can be used for targeting MDR bacteria and can mimic the action of an antibacterial agent. Bacteriophages, viruses that target specific bacteria, hold promise as a more targeted and potentially less resistance-prone alternative. Artificial intelligence (AI) is emerging as a powerful tool for tasks like drug discovery, analyzing resistance patterns, and developing personalized treatment plans. This technology offers significant potential to combat AMR more effectively. New emerging AI based technologies are showing promise in antibiotic and drug development, by offering cheaper and faster research through algorithms that can identify hit compounds. However, alongside these advancements, developing rapid diagnostics, promoting better sanitation and hygiene, and implementing a “One Health” approach that tackles AMR across human, animal, and environmental sectors are all crucial for a comprehensive solution.

Global collaboration is paramount in coordinating research, surveillance, and policy development to tackle AMR effectively. By combining these strategies, we can slow the emergence of resistant pathogens and buy time to develop new antimicrobials.

We acknowledge the limitations of this study being a narrative review based on the published literature rather than an original research based on patient data. Moreover, a systematic search strategy for the literature search was not used, like in a systematic review and a quality assessment of the papers still needs to be done. However, this review provides up-to-date knowledge about the menace of AMR and suggests focus areas for future research and therapies.

Conclusion

The relentless rise of superbugs and AMR threatens the foundation of critical care. Overreliance on antibiotics has created a critical care conundrum – effective treatment often fuels the emergence of resistant strains, leaving limited options for critically ill patients. This review exposes the devastating consequences of AMR in critical care, including prolonged stays, increased mortality, and exorbitant healthcare costs. The future of critical care hinges on a paradigm shift, combating AMR with a multipronged approach. Strict adherence to antibiotic stewardship guidelines and unwavering commitment to infection control measures are essential. Investment in research and development of novel antibiotics, alternative therapies, and rapid diagnostics is paramount. Global collaboration among stakeholders, from policymakers to the public, is crucial to developing effective strategies and raising awareness.

Use of AI tool

We have used Grammarly and Gemini to improve the language and readability of the article. However, the final version was checked for the correctness by the authors and take full responsibility of its content.

Patients/ Guardians/ Participants consent

Not applicable.

Ethical clearance

Ethical approval and patient consent was not required for this manuscript, being a narrative review of the published literature and not involving any human intervention.

Source of support

None.

Disclosure of competing interest

The authors have none to declare.

Appendix A. Supplementary data

References 46-61 related to this article can be found online at