Combating antimicrobial resistance in osteoarticular infections: Current strategies and future directions

Abstract

The emergence of antimicrobial resistance (AMR) has profoundly impacted the management of osteoarticular infections (OAIs), presenting significant challenges for healthcare systems worldwide. This review provides a comprehensive overview of the current landscape of AMR in OAIs, emphasizing the necessity for assertive and innovative strategies to combat this escalating health threat. It discusses the evolution of resistance among key pathogens, including ESKAPEE organisms, and the implications for treatment protocols and healthcare outcomes. The importance of antibiotic stewardship programs (ASPs) is highlighted as a core strategy to optimize antibiotic use and mitigate the development of resistance. Additionally, the review explores the potential of pharmacological approaches, including novel antibiotic regimens and combination therapies, alongside surgical interventions and alternative therapies such as bacteriophage-based treatments and probiotics, in managing these complex infections. The role of rapid diagnostic methods in improving treatment accuracy and the critical need for global surveillance to track AMR trends are also examined. By integrating insights from recent literature and expert recommendations, this review underscores the multifaceted approach required to address the challenge of AMR in OAIs effectively. It calls for a concerted effort among clinicians, researchers, and policymakers to foster innovation in treatment strategies, enhance diagnostic capabilities, and implement robust stewardship and surveillance programs. The goal is to adapt to the evolving landscape of OAIs and ensure optimal patient care in the face of rising AMR.

2. Introduction

The landscape of osteoarticular infections (OAIs) has been drastically altered by the emergence and escalation of antimicrobial resistance (AMR), which has become a significant hurdle in their management.^1,2 The complexity of these infections, coupled with the burgeoning issue of resistant pathogens, requires assertive and proactive measures to combat the problem. The rise of AMR in OAIs not only complicates therapeutic decisions but also poses a significant risk of prolonged illness, recurrent infections, and heightened healthcare costs. It is imperative that healthcare providers adopt assertive strategies to curb the spread of AMR and mitigate the associated risks.^{3, 4, 5, 6}

Recent literature highlights the evolving nature of OAIs, especially in the context of pediatric populations. The proposals from the Pediatric Infectious Pathology Group in 2023 emphasize the need for updated treatment strategies in light of the changing landscape of these infections.⁷ Moreover, the global challenge of AMR requires ongoing surveillance to ensure timely and appropriate treatment, outbreak detection, and monitoring of intervention effectiveness.^6,8 However, the capacity for high-quality and high-coverage surveillance varies greatly between countries, often being scarce in resource-limited settings.

The bacterial aspects of chronic OAIs, particularly in adults, have also been a focus of recent studies. The presence of osteosynthesis material, often used in orthopaedic surgeries, has been linked to a higher rate of resistance to antibiotics.^9,10 Pathogens such as Methicillin-resistant Staphylococcus aureus (MRSA) and Enterobacteriaceae producing extended spectrum beta-lactamases (ESBLs) are particularly notable in the emergence of AMR. The deep localization of the infection and the presence of biofilm on osteosynthesis materials pose additional challenges in treatment, limiting the efficacy of antibiotics and enabling bacteria to evade immune defenses.¹⁰

There is a growing concern about the burden of OAIs within the context of AMR. As pathogens evolve and become resistant to existing treatments, it is crucial to evaluate the effectiveness of current therapeutic strategies. This review aims to provide a detailed examination of the relationship between OAIs and AMR. It highlights the importance of revisiting and revising treatment protocols and practices to adapt to the evolving nature of these infections.

The objective of this review is to recognize the significant implications of AMR in the realm of OAIs and discuss the ongoing management strategies and future directions in effective prevention of the same. The emergence of resistance not only poses a direct threat to patient health but also has broader implications for public health policy and healthcare resource allocation. By providing a comprehensive analysis of the current state of AMR in OAIs and evaluating the efficacy of existing management strategies, this review seeks to contribute to the ongoing efforts to combat this pressing healthcare challenge.

3. Methodology

We searched PubMed/Medline, Embase and Scopus databases for studies relevant to OAI and AMR. We obtained a total of 1124 articles which after deduplication resulted in 785 articles. It is then subjected to screening for relevance by two authors independantly and 64 articles have been selected for inclusion in this narrative review. The process of inclusion of articles in this review is given by PRISMA flow diagram Fig. 1.

Fig. 1.

PRISMA flow diagram of inclusion of articles in the review.

4. AMR in osteoarticular infections

The escalation in the prevalence of AMR, particularly in relation to the clinically significant ESKAPEE pathogens (comprising Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli), has exerted substantial pressure on the healthcare, veterinary, and agricultural sectors. The common modes of antimicrobial resistance exerted by these organisms are as illustrated in Fig. 2. This has elevated AMR to the status of one of the most pressing public health issues worldwide.^11,12 Additionally, within the framework of the ‘One Health’ approach, the dissemination of AMR bacteria from food animals is recognized as having considerable implications for both animal and public health.¹³ In light of the extensive health ramifications posed by AMR bacteria and the urgent necessity for new antibiotics, various novel strategies are currently being pursued and implemented.

Fig. 2.

Modes of antimicrobial resistance exerted by the organism in the human body. [Created with biorender. com].

Recent literature further emphasizes the challenges and strategies in combating AMR in OAIs. Lorrot et al. from the Pediatric Infectious Pathology Group (GPIP) emphasizes the critical need for early diagnosis and appropriate treatment to prevent complications in OAIs. It stresses the predominance of Staphylococcus aureus, including methicillin-resistant strains, as a major causative agent and recommends empirical therapy targeting methicillin-sensitive S. aureus with high doses in children, illustrating the evolving landscape of antibiotic therapy in pediatric OAIs.¹⁴

Antibiotic stewardship, informed by local epidemiology and bacterial growth times, has been highlighted as a pivotal approach to optimizing antibiotic use and mitigating AMR development in OAIs. This strategy supports the judicious selection and administration of antibiotics, aligning with the principles of precision medicine.¹⁵ Furthermore, the application of model-informed precision dosing (MIPD) has been advocated to enhance the efficacy and safety of antibiotic treatments in OAIs. By incorporating patient variability, pathogen susceptibility, and drug properties, such as bone permeability, MIPD aims to tailor antibiotic dosing to individual patient needs, thereby improving treatment outcomes.¹⁶ An update on managing skin, soft-tissue, and OAIs in children highlights the importance of recognizing the distinct epidemiology of these infections, especially the increasing incidence of community-associated MRSA. This necessitates tailored diagnostic and management strategies to effectively address the unique challenges posed by pediatric OAIs.¹⁷ Pediatric MRSA OAIs present specific challenges due to the bacterium's resistance mechanisms. Understanding the molecular characteristics and epidemiology of MRSA in OAIs is crucial for developing effective treatment strategies and highlights the necessity for ongoing research and adaptation of clinical practices.¹⁸ These insights from recent studies underline the complexity of managing AMR in OAIs and the importance of a multifaceted approach that includes accurate diagnosis, informed antibiotic selection, and stewardship, as well as the consideration of patient-specific factors and epidemiological trends.

5. Current management strategies

5.1. Antibiotic stewardship

Antibiotic stewardship programs (ASPs) are vital in healthcare settings as they aim to optimize the use of antibiotics, thereby improving patient outcomes, reducing microbial resistance, and decreasing the spread of infections caused by multidrug-resistant organisms.^19,20 The main goal of these programs is to ensure that patients receive the appropriate antibiotic, at the correct dose, for the right duration, and through the proper route of administration.²⁰ ASPs, which have been proven highly effective, lead to better patient outcomes by reducing the incidence of adverse effects associated with antibiotic use, such as Clostridium difficile infection, and the emergence of antibiotic-resistant bacteria.²¹ By promoting the judicious use of antibiotics, ASPs help preserve the efficacy of current antibiotics, thereby playing a crucial role in combating the growing global challenge of antibiotic resistance (Table 1).

Table 1.

Key components and outcomes of antibiotic stewardship programs (ASPs).

Component	Description	Outcome
Guideline Implementation	Adoption of evidence-based antibiotic use guidelines	Reduced inappropriate antibiotic use
Dose Optimization	Adjusting doses based on patient-specific factors	Lowered toxicity, improved efficacy
Duration Control	Limiting the length of antibiotic courses	Decreased resistance development
Antibiotic Review and Feedback	Regular review of antibiotic prescriptions with feedback	Enhanced prescribing practices

ASPs usually involve a team of experts from various fields, such as infectious disease physicians, pharmacists, microbiologists, and infection control professionals. Together, they collaborate to implement policies and guidelines, monitor antibiotic prescribing practices, provide education and feedback to healthcare providers, and evaluate treatment outcomes. This comprehensive approach ensures that antibiotic therapy follows the latest evidence and best practices.

ASPs prioritize the reduction of broad-spectrum antibiotics and instead promote more targeted therapy based on culture results and patient clinical status. This approach helps lower the selection pressure for resistant organisms and reduces unnecessary drug exposure and associated toxicities.^22,23 Additionally, ASPs advocate for the careful use of diagnostic testing to guide antibiotic prescribing decisions, commonly referred to as diagnostic stewardship.^24,25

ASPs also play a significant role in resource optimization within healthcare settings. By reducing inappropriate antibiotic use, these programs can lead to cost savings through decreased drug expenditures and shorter hospital stays.²⁵ Furthermore, they contribute to the overall quality of patient care by reducing the incidence of hospital-acquired infections and improving treatment success rates.

The emergence of AMR in OAIs presents a formidable challenge that necessitates the integration of specialized strategies within the framework of ASPs. Avershina et al. emphasizes the global threat posed by rising antibiotic resistance, projected to cause more deaths than all cancers combined by 2050.²⁶ It highlights the role of nosocomial infections in spreading multidrug-resistant bacteria and discusses strategies for faster diagnostics and novel therapeutic approaches, including hospital disinfection methods to prevent the spread of MDR bacteria. This underscores the necessity of early and accurate diagnostics, alongside comprehensive infection control measures in managing OAIs. The core components of ASP is reflected in Fig. 3.

Fig. 3.

Core components of antibiotic stewardship program [Created with biorender. com].

Moreover, the review on alternative strategies to combat AMR illustrates the stagnation in the development of new antibiotic classes and proposes novel approaches such as combination therapy, targeting enzymes or proteins responsible for AMR, drug delivery systems, physicochemical methods, and the CRISPR-Cas system.²⁷ These innovative strategies offer promising avenues for the treatment of drug-resistant OAIs, potentially altering the clinical management landscape of such infections.

Integrating these advanced diagnostic and therapeutic strategies into ASPs can significantly enhance the management of OAIs. By ensuring antibiotic use is both judicious and targeted, and by incorporating novel approaches to address AMR, healthcare settings can not only achieve the core objectives of ASPs but also contribute to the global effort against the escalating issue of antibiotic resistance. This comprehensive strategy aligns with optimizing antibiotic use, improving patient outcomes, and addressing the specific challenges posed by AMR in OAIs.

5.2. Pharmacological approaches

Pharmacological strategies against AMR leverage various antibiotic regimens, combination therapies, and novel agents. Antibiotic combination therapy, utilizing two or more antibiotics, aims to achieve synergistic activity, enhancing the treatment's effectiveness against MDR infections.^28,29 For instance, combining beta-lactam antibiotics with aminoglycosides has been widely used to treat Gram-negative bacterial infections due to their synergistic effects. Furthermore, the combination of antibiotics with biocides—despite receiving little attention—shows potential in countering AMR. Studies have indicated varying effects, from synergism to antagonism, when antibiotics were combined with different biocides against P. aeruginosa, suggesting the need for further research to explore the evolutionary consequences of these combinations.²⁷

Enzyme inhibitors: Represent another vital strategy, targeting key bacterial enzymes like penicillin-binding proteins (PBPs) and type II topoisomerases. These inhibitors disrupt critical bacterial processes such as cell wall synthesis and DNA replication,³⁰ offering a potent means of combating bacterial infections. In the context of osteoarticular infections, a systematic approach to antibiotic selection is fundamental in preventing surgical site infections (SSIs), especially after procedures like colorectal surgery. An observational study explored the impact of various prophylactic antibiotic regimens on the prevention and bacterial flora of SSIs. It was found that the choice of prophylactic antibiotics, especially those leading to the emergence of cephalosporin-resistant Enterobacterales and Bacteroides spp., could influence the bacterial flora involved in SSIs, suggesting a need to re-evaluate cefoxitin as a prophylactic agent due to the downstream effects of more resistant and anaerobic flora should an infection develop.³¹

CRISPR-Cas system and RNA silencing techniques: Exemplify genetic approaches that directly target and modify bacterial DNA or RNA to combat resistance.^{32, 33, 34} Small molecules, including improved chemical entities and antimicrobial peptides (AMPs), provide new avenues for drug development, targeting novel bacterial mechanisms or improving the properties of existing antibiotics (Fig. 4).^{35, 36, 37}

Fig. 4.

Pharmacological strategies to combat antimicrobial resistance [Created with biorender. com].

5.3. Surgical interventions

Surgical interventions play a critical role in managing OAIs, especially when dealing with resistant organisms. Procedures range from debridement and removal of infected tissue to the management of infected orthopaedic implants. Debridement is essential for reducing bacterial load and necrotic tissue, thereby facilitating effective antibiotic penetration and healing.^38,39 In cases involving prosthetic joint infections, removing or replacing the infected implant is often necessary. Biofilms on implants, which are highly resistant to antibiotics, necessitate surgical removal to effectively manage the infection.⁴⁰ Biofilms can be managed effectively by following strategies such as active surface modification of the implants [inorganic and organic molecules], passive surface modification of the implants [metals, ceramics, nanopatterning, UV irradiation of titanium dioxide, biosurfactants, bioactive glass, and bioactive molecules], local carriers and coatings [drug carrier, hydrogel carrier, and biphasic ceramic carrier], and biofilm eradication techniques [phage therapy, sphingosine, radioimmunotherapy, engineered cationic amphipathic peptide, and photodynamic therapy].⁴¹ Revision surgeries, including the use of new implants or bone grafts, are crucial for restoring function to the affected area. In extreme situations, amputation may be considered the last resort to control extensive infections that are unmanageable through other means. Postoperative antibiotic therapy, guided by cultures obtained during surgery, is essential for treating residual infection and preventing recurrence (Fig. 5).^42,43

Fig. 5.

Surgical strategies to combat antimicrobial resistance [Created with biorender. com].

5.4. Alternative therapies

Non-antibiotic therapies offer promising alternatives to conventional antibiotics, particularly in the context of rising AMR. These include physicochemical methods such as photoinactivation, atmospheric pressure non-thermal plasma (APNTP), sonodynamic antimicrobial chemotherapy, and the use of metals, metal oxides, and essential oils (EOs) (Fig. 6).⁴⁴ EOs have shown significant antimicrobial activity against MDR bacteria, primarily through mechanisms like disrupting bacterial cell membranes and inhibiting efflux pumps.^45,46 The potential of EOs is further enhanced when combined with nanoparticle technology, which could improve the chemical stability, solubility, and delivery of EOs, making them more effective against bacterial pathogens.^47,48

Fig. 6.

Physico-chemical methods of curbing antimicrobial resistance [Created with biorender. com].

Combating AMR in OAIs necessitates a multifaceted approach that integrates conventional and novel pharmacological treatments, surgical interventions, and alternative therapies. This integrated strategy is vital for managing infections effectively, especially in the face of rising AMR challenges. While pharmacological approaches remain the cornerstone of treatment, the potential of surgical and non-antibiotic therapies cannot be overlooked. Continued research and innovation in these areas are essential to develop more effective, sustainable strategies against AMR, ensuring better outcomes for patients with OAIs.

6. Challenges and limitations

Understanding and managing AMR in OAIs encapsulates a complex interplay of diagnostic, treatment, and healthcare system challenges that significantly impede effective combat against AMR. The management of these infections, including osteomyelitis, spondylodiscitis, septic arthritis, and periprosthetic joint infections, requires a nuanced approach that considers the unique hurdles posed by the resistance phenomenon.

Early detection stands as a critical barrier in managing AMR within OAIs. Traditional methods, while reliable, are slow, often delaying the initiation of targeted therapy. The advent of rapid diagnostic tools like PCR and next-generation sequencing heralds promise, yet their high costs and limited availability, especially in resource-constrained environments, pose significant challenges. Moreover, the precise identification of resistance mechanisms in pathogens, crucial for tailoring effective treatment regimens, remains a technical and logistical challenge.⁴⁹ These diagnostic limitations are compounded by the global insufficiency in surveillance systems, which is particularly acute in low- and middle-income countries, hindering the effective tracking and management of emerging resistant strains.⁵⁰

On the treatment front, the dwindling arsenal of effective antibiotics against resistant pathogens underscores the urgent need for novel therapeutic agents. The development pipeline for new antibiotics, especially those targeting novel mechanisms of action, has not kept pace with the rapid emergence of resistance, leaving clinicians with limited options. Ensuring the appropriate use of existing antibiotics to forestall resistance development is another critical challenge, exacerbated by practices such as overprescription, incomplete treatment courses, and unnecessary reliance on broad-spectrum antibiotics. The exploration of alternative therapies, such as bacteriophages and immunotherapy, offers potential avenues for treatment but remains in nascent stages of development and clinical application.

Healthcare system challenges further complicate the management of OAIs.⁵¹ Access to care is uneven globally, with significant disparities in resource-limited settings. Such limitations in access, coupled with infrastructural deficiencies, including inadequate laboratory capacities, impair the effective management of AMR. Poor infection control practices in healthcare settings fuel the transmission of resistant organisms, while a lack of education and awareness among healthcare providers and the public about AMR exacerbates misuse and overuse of antibiotics. The economic implications of AMR, encompassing both direct treatment costs and broader impacts on productivity and healthcare resources, underscore the need for comprehensive strategies to address this global health threat.^51,52

Addressing the multifaceted challenges of AMR in OAIs requires a coordinated, multidisciplinary approach. This includes leveraging advances in diagnostic technologies to enable timely and accurate pathogen identification, fostering the development of new antibiotics and alternative therapies, and implementing robust stewardship programs to optimize antibiotic use. Enhancing global surveillance systems and ensuring equitable access to healthcare resources are essential for effective AMR management.^53,54 Moreover, targeted education and awareness initiatives can empower healthcare providers and the public to contribute to the containment of AMR. The complexity of these challenges necessitates sustained collaboration across the clinical, research, and policy domains to mitigate the impact of AMR on OAIs management and public health at large.

7. Advanced anti-infective and antibacterial strategies to combat AMR

7.1. Bacteriophages based-therapy

Bacteriophage-based therapy is emerging as a promising alternative to conventional antibiotics, especially in the context of OAIs, where AMR is a significant challenge.^55,56 The use of bacteriophages, viruses that selectively infect and kill bacteria, offers a potential strategy to tackle difficult-to-treat and multidrug-resistant pathogens commonly associated with bone and joint infections.⁵⁶ This approach has gained attention due to the limited pipeline of new antibiotics and the urgent need for innovative antimicrobial strategies.

Clinical applications of bacteriophage therapy in the treatment of bone and joint infections have shown promising results. Studies have included case reports and series where bacteriophages were used to treat periprosthetic joint infections, fracture-related infections, osteomyelitis, and sacroiliac joint infections.^{57, 58, 59} These interventions varied in their administration methods, including intravenous delivery, intraoperative injection into the joint, local intraoperative application, and administration via drains. In combination with antibiotic therapy, bacteriophage treatment achieved complete infection eradication in a significant number of patients, with very few reporting side effects. This evidence underscores bacteriophages' potential as a viable treatment option for bone and prosthesis infections alongside antibiotic therapy.⁵⁷

7.2. Probiotics

Probiotics, recognized for their health-promoting effects, are live microorganisms, mainly from the genera Lactobacillus and Bifidobacterium. They offer a novel approach to counteract antibiotic resistance, particularly in the context of OAIs.^60,61 Probiotics have been observed to reduce the incidence, duration, and severity of antibiotic-associated diarrhea, indirectly supporting better adherence to antibiotic regimens and potentially mitigating the evolution of antibiotic resistance.^62,63 By maintaining a balanced microbiota during antibiotic use, probiotics may help in reducing the spread of antibiotic resistance, although direct evidence supporting this effect requires further investigation.⁶⁰

Moreover, probiotics play a significant role against infectious pathogens through their effects on the epithelium, production of antimicrobial compounds, and competitive exclusion. The use of probiotic supplements could decrease the risk of infectious diseases and the subsequent need for antibiotics, contributing to the reduction or delay in the development of multidrug-resistant bacteria. This aspect is crucial in managing OAIs, where antibiotic resistance poses significant treatment challenges.⁶⁴

However, it is essential to consider the complexity of the interaction between probiotics, antibiotic resistance, and the host microbiota. Some concerns have been raised about the potential for probiotics to contribute to the spread of antibiotic resistance genes through horizontal gene transfer among pathogens, probiotics, and gut microbiota. Such transference could potentially exacerbate the antibiotic resistance crisis.⁶⁵

7.3. Fecal microbiota transplantation

The intestinal tract is a well-known reservoir for antibiotic-resistant organisms (AROs) and presents a unique opportunity for intervention. Strategies such as FMT, which was initially effective against recurrent infections caused by the bacteria Clostridium difficile, are now being explored for broader applications in ARO decolonization.⁶⁶ FMT leverages the principle of restoring intestinal microbiome diversity, which is disrupted by antibiotic exposure, thereby enhancing resistance to ARO colonization.^67,68 This therapy aims to rebalance the gut microbiota, providing a barrier against ARO dominance. The potential of FMT in this context is underpinned by the complex interplay between the microbiome, AROs, and the host.

Clinical evidence supports the effectiveness of fecal microbiota transplantation (FMT) in reducing colonization by antibiotic-resistant organisms (AROs).^{69, 70, 71, 72} This treatment has shown promising outcomes, such as reduced need for hospital isolation and lower rates of recurrent infections post-FMT. However, many studies lack control groups and standardized protocols, which limits the generalizability of findings. Despite encouraging results, we still have significant gaps in our understanding of the safety and efficacy of FMT for ARO decolonization. It is important to conduct mechanistic studies, include control groups in clinical trials, and gather long-term follow-up data. Future research should focus on these areas to better determine the role of FMT in combating antibiotic resistance.

8. Future directions

To effectively address and mitigate AMR in OAIs, a comprehensive and forward-looking research agenda coupled with policy enhancements is indispensable. The multifaceted nature of AMR demands a concerted effort across several key areas, spanning the development of novel antimicrobial agents and alternative treatments, to understanding the underpinnings of resistance mechanisms and advancing rapid diagnostic capabilities.

• A) Novel Antibiotics and Alternative Therapies: The discovery and development of new antibiotics, especially those capable of combating multi-drug resistant organisms, remain a top priority. This effort must be paralleled by research into alternative therapies, such as bacteriophages,⁵⁶ antimicrobial peptides,³⁵ and immunotherapies,⁷³ which hold promise for offering new treatment avenues that could circumvent traditional resistance mechanisms.

• B) Mechanisms of Resistance: A deeper understanding of the molecular mechanisms and genetic factors that facilitate the emergence and dissemination of AMR is crucial. This includes investigating the role of biofilms in sustaining chronic infections and elucidating the processes behind horizontal gene transfer among bacterial populations, which are pivotal in the spread of resistance traits.

• C) Rapid Diagnostic Methods: The development of rapid, accurate, and cost-effective diagnostic tools is essential for the early detection of resistant pathogens. Enhancing diagnostic capacities can significantly improve the management of infections by enabling timely and appropriate therapeutic interventions, thereby reducing the selective pressure for the development of resistance.

• D) Surveillance and Epidemiology: Strengthening global surveillance systems to monitor AMR trends is vital for understanding the evolution and spread of resistance. This encompasses tracking resistance in various settings, from hospitals to communities and across environmental reservoirs, to inform public health strategies and interventions.

• E) One Health Approach: Embracing a One Health approach is imperative for tackling AMR comprehensively.^4,74 This approach recognizes the interconnectedness of human, animal, and environmental health and advocates for collaborative efforts to address antibiotic use and resistance across these domains. Research under this framework should explore how practices in agriculture and veterinary medicine contribute to the AMR burden in humans and examine transmission dynamics across ecosystems.

• F) Socioeconomic and Behavioral Factors: Investigating the impact of socioeconomic factors and the behaviors of healthcare providers and patients towards antibiotic use can yield insights into more effective intervention strategies. This includes evaluating the effects of health policies, international collaborations, and regulations on AMR, as well as assessing the economic ramifications of resistance and identifying cost-effective management approaches.

• G) Vaccination Strategies: Vaccines represent a promising strategy to reduce the reliance on antibiotics and, by extension, the pressure that drives resistance development.^{75, 76, 77} Research into vaccines that can prevent infections prone to antibiotic resistance, including those affecting the osteoarticular system, is a promising area that demands further exploration.

• H) Environmental Factors: Understanding the role of environmental factors, such as pollution and climate change, in the propagation of AMR is an emerging but critical area of research.^{78, 79, 80} This includes studying how these factors influence the spread of resistance genes and the potential for environmental reservoirs to act as conduits for resistance transmission to humans.

• I) Policy Implications: Addressing AMR requires not only scientific and technological advances but also policy interventions that promote sustainable antibiotic use, enhance infection prevention and control measures, and foster global collaboration.^53,81,82 Policies should support research and development efforts, incentivize the creation of new antibiotics and alternative therapies, and implement robust stewardship programs. Additionally, international cooperation is crucial for standardizing surveillance, sharing data on AMR trends, and coordinating responses to emerging resistance threats.⁸³

The fight against AMR in OAIs necessitates a holistic and interdisciplinary approach, integrating advancements in science, technology, and policy. By focusing on these future directions, it is possible to forge a path towards more effective management and mitigation of AMR, safeguarding global health against this growing threat.

9. Conclusion

The escalating challenge of AMR in OAIs underscores the need for a comprehensive and multidisciplinary approach to mitigate its impact. The review highlights the importance of antibiotic stewardship, novel pharmacological strategies, surgical interventions, and alternative therapies as integral components of an effective management strategy. Moreover, it emphasizes the necessity of advancing diagnostic methods, understanding resistance mechanisms, and enhancing global surveillance to inform and refine treatment protocols. Addressing AMR in OAIs demands collaboration across the clinical, research, and policy-making spheres to develop innovative solutions and implement effective interventions. By prioritizing research on novel antibiotics, alternative treatments, and rapid diagnostics, alongside adopting a One Health approach and strengthening healthcare systems, we can combat the AMR crisis and ensure better outcomes for patients with OAIs. The urgency of this issue calls for immediate action to safeguard public health and combat the growing threat posed by antibiotic-resistant pathogens.

Author contribution statement

a) Conceptualization – MJ and TJ; b) Manuscript writing – TJ, SR, and NJ; c) Manuscript revision – MJ and SM; d) Data acquisition – NJ, AN, TJ, and SR; e) Images – AN and SM; and f) Supervision – VKJ. All authors have agreed to the final version to be published and agree to be accountable for all aspects of the work.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.