Antimicrobial Stewardship in the Management of Multidrug-Resistant Gram-Negative Bacteria Infections

Abstract

Antimicrobial resistance constitutes a public health menace globally, affecting treatment outcomes in healthcare settings. This problem is exacerbated in Gram-negative bacteria including Klebsiella pneumonia, Pseudomonas aeruginosa, Acinetobacter baumannii, E. coli, Salmonella spp., and others belonging to the Enterobacteriaceae family. These organisms have developed resistance mechanisms that render common antibiotics ineffective, making infections caused by these pathogens difficult to treat. Particularly, unregulated antibiotic use, selective pressure, and horizontal gene transfer are some of the contributors to their resistance to the available antibiotics. Effective antimicrobial stewardship plays a crucial role in managing these infections and preventing their further escalation through Antimicrobial Stewardship programs, de-escalation therapy, combination therapy, antibiotics dose optimization, and prophylactic antibiotic are used in those at high risk of infection. Education and training are vital for healthcare providers to enhance their knowledge of antimicrobial stewardship principles and implementation.

1. Introduction

1.1 Background and significance

Antimicrobial stewardship (AMS) is defined as “an organizational or healthcare-system-wide approach for fostering and monitoring judicious use of antimicrobials to preserve their effectiveness” [1]. Multidrug-resistant Gram-negative bacterial infections have become a major global health concern due to the limited treatment options available and the high mortality rates associated with these infections [2]. Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, have developed resistance mechanisms that render common antibiotics ineffective, making infections caused by these pathogens difficult to treat [3]. Antimicrobial stewardship programs focus on improving the appropriate use of antimicrobial agents, to preserve their effectiveness and minimize the emergence and spread of resistance [4]. In the case of multidrug-resistant Gram-negative bacterial infections, effective antimicrobial stewardship plays a crucial role in managing these infections and preventing their further escalation [5].

The topic of antimicrobial stewardship in the management of multidrug-resistant Gram-negative bacterial infections holds significant importance due to several reasons:

1. Addressing the global health threat: Multidrug-resistant Gram-negative bacterial infections pose a significant global health threat, leading to increased morbidity, mortality, and healthcare costs. Antimicrobial stewardship plays a vital role in combating this threat by promoting rational antibiotic use, optimizing treatment regimens, and preventing the further emergence and spread of antimicrobial resistance [6].

2. Preserving antibiotic effectiveness: Antimicrobial stewardship programs are crucial for preserving the effectiveness of existing antibiotics. By promoting appropriate antibiotic-prescribing practices, optimizing drug dosage and duration, and reducing unnecessary antibiotic use, antimicrobial stewardship helps slow down the development of resistance and extends the lifespan of available antibiotics [7].

3. Enhancing patient outcomes: Multidrug-resistant Gram-negative bacterial infections are associated with poorer patient outcomes, including increased treatment failure rates, prolonged hospital stays, and higher mortality rates. Effective antimicrobial stewardship ensures that patients receive the most appropriate and effective antibiotics, leading to improved clinical outcomes and reduced adverse events [7, 8].

4. Reducing healthcare costs: The economic burden associated with multidrug-resistant Gram-negative bacterial infections is significant. Antimicrobial stewardship programs help optimize antibiotic use, prevent unnecessary treatments, and reduce the length of hospital stays, resulting in cost savings for healthcare systems, patients, and society as a whole [9, 10].

5. Combating antimicrobial resistance: Antimicrobial stewardship is a crucial component of the global efforts to combat antimicrobial resistance. By implementing evidence-based practices, surveillance of antibiotic use and resistance patterns, and education and training initiatives, antimicrobial stewardship programs contribute to the overall reduction of antimicrobial resistance, protecting the effectiveness of antibiotics for future generations [11, 12].

6. Improving infection control: Multidrug-resistant Gram-negative bacteria are often associated with healthcare-associated infections. Antimicrobial stewardship programs emphasize infection prevention and control measures, such as hand hygiene, environmental cleaning, and adherence to best practices, which can help reduce the transmission of these resistant pathogens and prevent outbreaks [13].

7. Interdisciplinary collaboration: Antimicrobial stewardship requires collaboration among various healthcare professionals, including physicians, pharmacists, microbiologists, infection control practitioners, and administrators. By fostering interdisciplinary teamwork and communication, antimicrobial stewardship programs promote a holistic approach to patient care, ensuring that the right antibiotics are prescribed at the right time and in the right dosage [14].

1.2 Multidrug-resistant Gram-negative bacteria (MDR-GNB)

Multidrug-resistant Gram-negative bacteria (MDR-GNB) refer to the ability of these bacteria to exhibit resistance to multiple classes of antibiotics [15, 16]. Gram-negative bacteria are a group of bacteria that have a distinct cell wall structure and include common pathogens such as Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The term “multidrug” signifies resistance to multiple classes of antibiotics, which means that these bacteria are unaffected by several types of antimicrobial agents commonly used in clinical practice. This resistance can include resistance to β-lactams (such as penicillins and cephalosporins), fluoroquinolones, aminoglycosides, carbapenems, and other important antibiotic classes. Multidrug-resistant Gram-negative bacteria are of particular concern because they limit the treatment options available to healthcare professionals, leading to increased reliance on less effective or more toxic antibiotics [17]. MDR-GNB has acquired genetic mechanisms that enable them to evade the effects of different antibiotics, making them difficult to treat. These resistance mechanisms can include the production of enzymes that inactivate antibiotics, changes in the bacterial cell wall structure that prevent drug entry, and efflux pumps that actively remove antibiotics from within the bacterial cell [18, 19].

1.3 Importance of antimicrobial stewardship in managing multidrug-resistant infections

Antimicrobial stewardship plays a critical role in managing multidrug-resistant infections by addressing the challenges posed by antimicrobial resistance. The importance of antimicrobial stewardship in managing multidrug resistance infections can be summarized as follows:

1. Rational and appropriate antibiotic use: Antimicrobial stewardship programs promote the rational and appropriate use of antibiotics. Antibiotic use has been associated with the persistence of resistance genes in infants gut [20], thus stressing the importance of regulating antibiotic use. This involves ensuring that antibiotics are prescribed only when necessary, selecting the most effective drug based on local resistance patterns, optimizing dosing regimens, and considering duration of treatment. By using antibiotics judiciously, antimicrobial stewardship helps minimize the selection pressure that drives the development and spread of multidrug-resistant bacteria [11, 21].

2. Preservation of antibiotic effectiveness: Multidrug resistance threatens the effectiveness of existing antibiotics. Antimicrobial stewardship aims to preserve the efficacy of available antibiotics by preventing their overuse or misuse [21, 22]. By implementing strategies to reduce unnecessary antibiotic prescription, such as avoiding empirical treatment when it is not warranted and de-escalating therapy based on culture results, antimicrobial stewardship helps maintain the effectiveness of antibiotics for both current and future patients.

3. Preventing treatment failures and complications: Multidrug-resistant infections are associated with higher treatment failure rates and increased morbidity and mortality. Antimicrobial stewardship programs ensure that patients receive appropriate and effective antibiotic therapy, tailored to the specific infection and local resistance patterns [7, 23]. This helps minimize treatment failures, reduce the risk of complications, and improve patient outcomes.

4. Reducing adverse effects and collateral damage: Certain antibiotics used to treat multidrug-resistant infections can have significant side effects or toxicities. Antimicrobial stewardship helps minimize the exposure of patients to potentially harmful antibiotics by promoting the use of more targeted therapies and avoiding unnecessary or prolonged treatment courses [24]. This reduces the occurrence of adverse effects and associated patient harm.

5. Controlling the spread of multidrug-resistant bacteria: Antimicrobial stewardship programs emphasize infection prevention and control measures, such as hand hygiene, isolation precautions, and appropriate environmental cleaning [25]. By effectively implementing these measures, antimicrobial stewardship helps contain the spread of multidrug-resistant bacteria within healthcare settings and reduces the risk of outbreaks.

6. Optimizing healthcare resource utilization: Multidrug-resistant infections are often associated with increased healthcare costs, longer hospital stays, and additional resource utilization. Antimicrobial stewardship programs can help optimize resource utilization by reducing the length of hospital stays, minimizing the need for expensive broad-spectrum antibiotics, and preventing complications related to inappropriate antibiotic use [7, 23]. This leads to cost savings for healthcare systems and improved allocation of limited resources.

7. Combating antimicrobial resistance: Multidrug resistance is a significant contributor to the global problem of antimicrobial resistance. Antimicrobial stewardship programs play a vital role in addressing this challenge by promoting responsible antibiotic use, reducing the emergence and spread of resistant bacteria, and preserving the effectiveness of antibiotics for future generations [11].

2. Challenges in managing multidrug-resistant Gram-negative bacterial infections

Managing multidrug-resistant Gram-negative (MDR-GNB) bacterial infections poses several challenges, which include:

2.1 Limited treatment options

The challenge of limited treatment options in managing multidrug-resistant Gram-negative bacterial infections refers to the reduced effectiveness of available antibiotics against these infections. MDR-GNB has developed various mechanisms to evade the effects of commonly used antibiotics, making them resistant to multiple classes of drugs. MDR-GNB often exhibit resistance to multiple classes of antibiotics, limiting the available treatment options [26]. This scarcity of effective antibiotics can make it challenging to find appropriate therapies that can effectively target and eliminate the infection. Moreover, MDR-GNB are associated with higher morbidity and mortality rates compared to infections caused by susceptible strains [27]. Treatment failures, prolonged hospital stays, and increased risk of complications contribute to the poorer outcomes observed in patients with these infections.

2.2 Rapid spread of resistance mechanism

Gram-negative bacteria possess complex resistance mechanisms, including the production of enzymes that can degrade antibiotics, altered outer membrane permeability, and efflux pumps that actively remove antibiotics from within the bacterial cell [28, 29]. These complex resistance mechanisms make it difficult to combat multidrug-resistant infections and require the use of multiple strategies to overcome them. Several factors contribute to the complex and rapid spread of resistance mechanisms. These include genetic plasticity, which enables GNB to acquire resistance genes through various mechanisms [30]. These bacteria can acquire resistance genes through horizontal gene transfer, where genetic material is transferred between different bacteria, including those of the same or different species. This transfer can occur through plasmids, integrons, or transposons, facilitating the rapid spread of resistance mechanisms [31]. These elements can move between bacteria, allowing resistance genes to be transferred to new bacteria strains or species. Mobile genetic elements contribute to the horizontal transfer of resistance mechanisms and can rapidly disseminate resistance within a population or across different geographical locations. Likewise, the widespread use and misuse of antibiotics create a selective pressure that favors the survival and proliferation of multidrug-resistant bacteria [32]. Exposure to antibiotics provides a survival advantage to the bacteria carrying resistance mechanisms, allowing them to outcompete susceptible strains. The continuous exposure to suboptimal antibiotic concentrations or incomplete treatment courses can further drive the selection and expansion of resistant strains [33]. Healthcare settings and community transmission also contribute to the spread of MDR-GNB within healthcare facilities, where vulnerable patients with compromised immune systems and invasive medical procedures create opportunities for transmission. The complex network of healthcare-associated infections allows for the rapid dissemination of resistant strains. Additionally, these bacteria can also spread in community settings, where factors such as overcrowding, poor hygiene practices, and close contact contribute to their transmission [34].

2.3 The need for effective infection prevention

Effective infection prevention is crucial in managing multidrug-resistant Gram-negative bacterial infections due to high transmission rates [35]. MDR-GNB has the potential for rapid transmission within healthcare settings and the community [36]. These bacteria can survive on surfaces, medical equipment, and the hands of healthcare workers, facilitating their spread to susceptible individuals [37]. The challenge lies in preventing the transmission of these resistant bacteria to vulnerable patients and limiting the development of outbreaks. MDR-GNB can persist in the environment for extended periods, surviving on surfaces and in water sources. This persistence increases the risk of indirect transmission to patients and poses challenges for effective infection prevention. Rigorous cleaning and disinfection protocols, as well as appropriate water management strategies, are necessary to reduce the environmental reservoir of these resistant bacteria. The ability of MDR-GNB to colonize various sites in the human body, including the skin, gastrointestinal tract, and respiratory tract is another factor [38]. Colonized individuals serve as a reservoir for transmission to others. Addressing the challenge of effective infection prevention requires a comprehensive approach that includes strict adherence to infection control measures, robust environmental cleaning and disinfection practices, surveillance of multidrug-resistant organisms, and appropriate use of antimicrobials. It also involves active collaboration between healthcare facilities, public health agencies, and the communities to raise awareness, implement preventive measures, and reduce the burden of multidrug-resistant Gam-negative bacterial infections.

3. Antimicrobial stewardship strategies for managing multidrug resistance

3.1 Antimicrobial stewardship programs (ASPs)

Antimicrobial Stewardship Programs (ASPs) are comprehensive strategies designed to optimize the use of antimicrobial agents in healthcare settings. They are crucial in managing multidrug-resistant infections. They help to preserve the effectiveness of existing antibiotics, reduce treatment failures, prevent the emergence of resistance, improve patient outcomes, and optimize healthcare resource utilization. Additionally, ASPs contribute to the global effort of combating antimicrobial resistance by promoting responsible antibiotic use and reducing the spread of multidrug-resistant bacteria [7, 9, 11].

3.2 De-escalation therapy

De-escalation therapy is a strategy employed in the management of multidrug resistance that involves starting empiric broad-spectrum antibiotic treatment and subsequently narrowing down the antibiotic regimen based on clinical response and susceptibility testing. The goal of de-escalation is to optimize antimicrobial therapy by reducing the use of broad-spectrum antibiotics and minimizing the selection pressure for antibiotic resistance [39, 40]. De-escalation therapy begins with the administration of empiric broad-spectrum antibiotics that cover a wide range of potential pathogens, including multidrug-resistant bacteria. This initial approach ensures that appropriate antimicrobial therapy is promptly initiated, particularly in cases of severe infections where the causative organism may not be immediately identifiable. During de-escalation therapy, close monitoring of the patient’s clinical response is essential. If the patient shows signs of improvement, such as decreased fever, resolution of symptoms, and improvement in laboratory markers, it indicates that the initial empiric therapy is effective [41]. Additionally, microbiological assessment, including culture and susceptibility testing, is crucial in identifying the causative pathogen and determining its susceptibility to antibiotics. Once the microbiological results become available, the antibiotic regimen is tailored to the specific pathogen and its susceptibility profile. De-escalation involves narrowing down the antibiotic coverage by selecting a more targeted and narrow-spectrum antibiotic or combination of antibiotics [42]. This approach helps minimize the unnecessary use of broad-spectrum antibiotics, which are associated with a higher risk of promoting antimicrobial resistance. De-escalation therapy takes into account the local resistance patterns and susceptibility data of pathogens commonly encountered in the healthcare facility or community. By considering local epidemiology, clinicians can choose antibiotics that are effective against the prevalent multidrug-resistant bacteria while avoiding unnecessary use of broad-spectrum agents [43].

3.3 Combination therapy

Combination therapy, as a strategy for managing multidrug resistance, involves the simultaneous use of two or more antibiotics with different mechanisms of action to enhance treatment efficacy and overcome resistance mechanisms. Combination therapy aims to achieve synergistic effects, where the combined action of multiple antibiotics is greater than the sum of their individual effects [44]. By targeting different bacterial pathways or mechanisms, combination therapy can enhance bacterial killing, inhibit resistance mechanisms, and improve treatment outcomes. Combination therapy allows for broader coverage of potential pathogens, including those that may exhibit resistance to individual antibiotics. By combining antibiotics with different spectra of activity, the regimen can effectively target a wider range of bacteria, including multidrug-resistant strains. This broader coverage increases the likelihood of successful treatment, especially in infections where the causative organisms are unknown or resistant pathogens are prevalent. The use of combination therapy can help prevent the emergence of resistance [45]. Resistance mechanisms can be complex and multifaceted, requiring the coordinated action of multiple genetic changes in bacteria. By utilizing multiple antibiotics that target different pathways, the likelihood of bacteria developing simultaneous resistance to all components of the combination is reduced. This reduces the risk of treatment failure due to the emergence of resistance during therapy. Combination therapy can overcome existing resistance in multidrug-resistant bacteria. By utilizing antibiotics with different mechanisms of action, combination therapy can circumvent specific resistance mechanisms employed by bacteria. For example, if a bacterium possesses efflux pumps that can actively pump out a particular antibiotic, combining it with another antibiotic that is not a substrate for the efflux pump can help overcome this resistance mechanism and improve treatment efficacy [46].

3.4 Dose optimization

Dose optimization is a strategy employed in the management of multidrug resistance that focuses on achieving optimal drug concentrations at the site of infection to maximize treatment efficacy against resistant pathogens [47]. By adjusting the dosage of antibiotics, dose optimization aims to overcome resistance mechanisms, improve bacterial killing, and enhance treatment outcomes. Dose optimization takes into account the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics [48]. PK refers to how the body processes a drug, including absorption, distribution, metabolism, and elimination. PD refers to the relationship between drug exposure and its effect on bacteria. Understanding the PK/PD properties of antibiotics is crucial in determining the optimal dosage regimen to achieve effective drug concentrations at the site of infection. The effectiveness of antibiotics against resistant pathogens is often related to achieving adequate drug exposure. By optimizing the dosage, the goal is to ensure that the antibiotic concentration at the site of infection exceeds the minimum inhibitory concentration (MIC) for the target pathogen. This exposure-response relationship is critical in achieving optimal bacterial killing and minimizing the risk of treatment failure [49]. Dose optimization should be employed alongside other comprehensive strategies and guided by PK/PD principles and individual patient factors to ensure the effective management of multidrug resistance.

3.5 Prophylactic antibiotic use

Prophylactic antibiotic use, as a strategy for managing multidrug resistance, involves the administration of antibiotics to prevent infections in individuals at high risk of developing infections [50]. While the primary aim of prophylaxis is to prevent infections, it can also play a role in managing multidrug resistance. Prophylactic antibiotics are typically administered to individuals who are at increased risk of developing infections, such as surgical patients, immunocompromised individuals, or patients with specific medical conditions [51]. By targeting those at high risk, prophylaxis aims to prevent infections that could potentially lead to multidrug-resistant bacteria colonization or subsequent spread. The choice of antibiotics for prophylaxis is important to consider. Narrow-spectrum antibiotics with activity against the expected pathogens in the specific procedure or patient population are preferred. This approach helps minimize the disruption of the normal flora and reduces the selective pressure for multidrug resistance. Additionally, the selection of antibiotics should consider local resistance patterns and susceptibility data to ensure their effectiveness. The duration of prophylactic antibiotic use should be limited to the perioperative or high-risk period to avoid unnecessary prolonged exposure. Prolonged prophylactic use can lead to increased antibiotic consumption, potential adverse effects, and the development of resistance [52]. It is essential to adhere to recommended guidelines regarding the appropriate duration of prophylaxis for each indication. Prophylactic antibiotic use should be part of a comprehensive approach to infection prevention that includes other measures such as strict aseptic techniques, proper hand hygiene, adherence to infection control protocols, and vaccination. Combining prophylactic antibiotics with these multimodal strategies can further reduce the risk of infections and multidrug resistance. However, the risk of promoting antibiotic resistance should always be considered, and prophylactic antibiotic use should be tailored to individual patient needs while emphasizing the importance of antimicrobial stewardship.

3.6 Guidelines on antibiotic prescription

Guidelines on antibiotic prescription are an essential strategy for managing multidrug-resistant bacteria by promoting appropriate and judicious use of antibiotics. These guidelines provide evidence-based recommendations to healthcare providers regarding the selection, dosage, and duration of antibiotic therapy for specific infections [53]. Guidelines on antibiotic prescribing promote rational antibiotic use by guiding healthcare providers in choosing the most effective antibiotic therapy while minimizing the risk of resistance [11, 54]. They provide recommendations based on the local epidemiology of bacterial pathogens and their susceptibility patterns, considering factors such as resistance rates, healthcare-associated infections, and community-acquired infections. Guidelines take into account the specific characteristics of different infections and provide recommendations for tailored treatment [55]. By providing guidance on appropriate antibiotic selection, dosage, and duration, guidelines help ensure that patients receive optimal therapy, increasing the likelihood of successful treatment outcomes and minimizing the development of multidrug resistance. It also empowers healthcare providers with up-to-date information on the latest advancements in antimicrobial therapy and resistance patterns [56, 57].

4. The roles of healthcare providers in antimicrobial stewardship

4.1 Multidisciplinary team approach

The multidisciplinary team approach is a crucial aspect of antimicrobial stewardship, involving collaboration among various healthcare providers with different areas of expertise [58]. This team typically includes physicians, pharmacists, microbiologists, infection control practitioners, and other relevant healthcare professionals. The multidisciplinary team brings together professionals from different backgrounds, each with their unique knowledge and perspectives on antimicrobial use. Physicians provide clinical expertise; pharmacists contribute their knowledge of drug interactions and dosing; microbiologists offer insights into microbial identification and susceptibility, and infection control practitioners focus on preventing healthcare-associated infections. By working collaboratively, the team can develop comprehensive strategies to optimize antimicrobial use. Multidisciplinary teams play a crucial role in developing and implementing evidence-based guidelines and protocols for antimicrobial use. These guidelines provide standardized approaches to the diagnosis, treatment, and monitoring of infections, considering local epidemiology and antimicrobial resistance patterns. The team members contribute their expertise to ensure that guidelines are practical, feasible, and align with the best available evidence. The multidisciplinary team approach allows for continuous quality improvement in antimicrobial stewardship [59].

4.2 Education and training

Education and training are essential roles of healthcare providers in antimicrobial stewardship. Education plays a vital role in raising awareness about antimicrobial resistance and the importance of antimicrobial stewardship [60]. Healthcare providers need to understand the consequences of inappropriate antimicrobial use, including the development of resistance, increased healthcare costs, and adverse patient outcomes. Training programs provide healthcare professionals with updated information on antimicrobial resistance patterns, new treatment guidelines, and emerging resistance mechanisms. By staying informed, healthcare providers can make informed decisions and contribute to effective stewardship practices. Education and training initiatives emphasize the importance of patient education regarding antimicrobial use. Healthcare providers learn how to effectively communicate with patients, explaining when antibiotics are necessary and educating them about the risks of inappropriate antibiotic use. Patients are educated about the importance of completing the full course of antibiotics as prescribed, avoiding the sharing or saving of antibiotics, and understanding that antibiotics are not effective against viral infections. By engaging patients in these discussions, healthcare providers help reinforce responsible antibiotic use and promote patient adherence [61].

4.3 Prescription and dispensing practices

Prescription and dispensing practices are vital roles of healthcare providers in antimicrobial stewardship. By following appropriate prescribing and dispensing practices, healthcare providers contribute to the responsible use of antimicrobial agents [62]. Healthcare providers have a responsibility to prescribe antimicrobial agents judiciously. By following evidence-based guidelines and considering factors such as the type and severity of the infection, local resistance patterns, and patient-specific factors (e.g., allergies and renal function), healthcare providers can select the most appropriate antibiotic therapy. This ensures that antibiotics are used only when necessary and minimizes the risk of antibiotic resistance. When prescribing antibiotics, healthcare providers should consider using narrow-spectrum antibiotics whenever possible. Narrow-spectrum antibiotics target specific bacteria, reducing the disruption of the body’s normal flora and minimizing the selection pressure for resistance. Targeted therapy, based on culture and susceptibility results, helps ensure that the chosen antibiotic is effective against the identified pathogen [63]. This approach minimizes the unnecessary use of broad-spectrum antibiotics, which can contribute to the emergence of multidrug-resistant organisms.

4.4 Use of clinical decision support systems

The use of Clinical Decision Support Systems (CDSS) is an important role of healthcare providers in antimicrobial stewardship. CDSS refers to computer-based tools that provide healthcare professionals with clinical knowledge and patient-specific information to assist in decision-making [64]. CDSS can integrate evidence-based guidelines for antimicrobial use directly into the clinical workflow. This allows healthcare providers to access up-to-date recommendations at the point of care. The CDSS can provide guidance on appropriate antibiotic selection, dosing, and duration of therapy based on the specific infection and patient characteristics. By incorporating guidelines, CDSS helps ensure that healthcare providers have easy access to the most current and relevant information to support their prescribing decisions. CDSS can provide real-time alerts and reminders to healthcare providers when prescribing antimicrobials. These alerts can notify providers about potential drug interactions, allergies, duplicate therapies, or inappropriate antibiotic choices. By receiving these alerts, healthcare providers can review and reconsider their prescribing decisions, potentially leading to more appropriate antibiotic selection and improved patient outcomes [65]. CDSS can integrate with microbiology laboratory systems to provide real-time access to microbial identification and susceptibility results. This allows healthcare providers to make informed decisions regarding appropriate antibiotic therapy. CDSS can also incorporate local antimicrobial resistance data, providing information on prevalent resistance patterns and suggesting alternative antibiotics when necessary. By utilizing these integrated data sources, healthcare providers can make more targeted antibiotic choices and avoid unnecessary broad-spectrum use.

5. Best practices in antimicrobial stewardship in multidrug-resistant Gram-negative bacterial infections

5.1 Surveillance and monitoring

Surveillance and monitoring are crucial best practices in antimicrobial stewardship, particularly when addressing multidrug-resistant Gram-negative bacterial infections [66]. Surveillance and monitoring systems allow healthcare facilities to identify and track the emergence and spread of MDR-GNB. By routinely collecting and analyzing data on bacterial isolates and their antibiotic susceptibility patterns, healthcare providers can detect changes in resistance profiles and identify emerging resistance mechanisms [67]. This early detection helps guide appropriate empiric antibiotic therapy and infection control measures. Surveillance data on MDR-GNB infections enable healthcare providers to make informed decisions regarding empiric antibiotic therapy. Knowing the local resistance patterns helps in selecting antibiotics that are likely to be effective against the prevalent pathogens. This targeted approach improves patient outcomes by reducing the risk of inadequate initial therapy and minimizing the unnecessary use of broad-spectrum antibiotics. Surveillance systems enable the monitoring of trends and changes in antimicrobial resistance patterns over time [68]. By tracking resistance data, healthcare providers can identify shifts in susceptibility profiles, new mechanisms of resistance, or the emergence of novel resistant strains. This information is crucial for guiding treatment decisions, developing local antimicrobial guidelines, and informing public health efforts to address antimicrobial resistance at a regional or national level [69].

Surveillance and monitoring systems enhance the ability to anticipate and respond to new threats posed by MDR-GNB by continuously monitoring resistance patterns, healthcare providers can detect the emergence of resistance to specific antibiotics or classes of antibiotics [70]. This information helps guide the development of alternative treatment strategies, such as novel antimicrobial agents or combination therapies, before resistance becomes widespread. Surveillance and monitoring efforts promote collaboration and data sharing among healthcare facilities, public health agencies, and research institutions. By sharing data on resistance patterns, outbreaks, and best practices, healthcare providers can learn from each other’s experiences and adopt successful strategies in their own settings. Collaboration and data sharing also facilitate regional or national surveillance networks, enabling a broader understanding of the epidemiology of multidrug-resistant Gram-negative bacterial infections and supporting coordinated efforts to combat antimicrobial resistance [71].

5.2 Guidelines for antibiotic use

Guidelines for antibiotic use are essential best practices in antimicrobial stewardship, particularly in addressing multidrug-resistant Gram-negative bacterial infections. These guidelines provide evidence-based recommendations for healthcare providers to optimize antimicrobial therapy and combat the challenges posed by resistant bacteria [72]. Guidelines for antibiotic use provide evidence-based recommendations for the selection, dosing, and duration of antimicrobial therapy for multidrug-resistant Gram-negative bacterial infections. These guidelines are developed based on extensive research, clinical trials, and expert consensus. By following these recommendations, healthcare providers can make informed decisions about appropriate antibiotic therapy, considering factors such as the type of infection, local resistance patterns, and individual patient characteristics. Guidelines for antibiotic use emphasize the importance of targeted therapy for multidrug-resistant Gram-negative bacterial infections. Targeted therapy involves selecting antibiotics that are specifically effective against the identified pathogens, taking into account their susceptibility patterns. This approach helps minimize the unnecessary use of broad-spectrum antibiotics, reducing the selective pressure for resistance and preserving the effectiveness of antibiotics. Guidelines may address the use of combination therapy for multidrug-resistant Gram-negative bacterial infections and provide recommendations on when combination therapy may be warranted and which specific combinations are supported by evidence. Guidelines for antibiotic use often include recommendations for implementing infection control measures to prevent the spread of MDR-GNB [66]. These measures may include strategies such as contact precautions, hand hygiene, environmental cleaning, and patient cohort. By incorporating infection control guidelines into antibiotic use recommendations, healthcare providers can contribute to reducing the transmission of resistant bacteria and protecting vulnerable patients.

5.3 Close collaboration between clinicians and microbiologists

Close collaboration between clinicians and microbiologists is considered a best practice in antimicrobial stewardship, particularly in the management of multidrug-resistant Gram-negative bacterial infections [73]. This collaboration facilitates effective communication, decision-making, and patient care. Microbiologists play a critical role in identifying the causative pathogens and their antimicrobial susceptibility patterns. Close collaboration between clinicians and microbiologists ensures that accurate and timely microbiological results are provided to guide appropriate antibiotic therapy. Rapid identification of MDR-GNB allows clinicians to initiate targeted therapy promptly, leading to better patient outcomes and reduced spread of resistant strains. In cases where microbiological results are not immediately available, clinicians rely on empirical antibiotic therapy. Collaboration between clinicians and microbiologists helps in selecting appropriate empiric therapy based on local resistance patterns and the knowledge of circulating MDR-GNB [65]. Microbiologists can provide valuable input regarding the likelihood of resistance to specific antibiotics, helping clinicians make informed decisions and avoid the unnecessary use of broad-spectrum agents. Close collaboration allows for effective feedback and quality improvement initiatives. Microbiologists can provide feedback to clinicians regarding the appropriateness of antibiotic prescribing based on microbiological data. This feedback helps clinicians understand the impact of their prescribing decisions on resistance patterns and guides them in optimizing antibiotic use. Regular meetings and discussions between clinicians and microbiologists enable the exchange of information and the identification of areas for improvement in antimicrobial stewardship practices.

5.4 Benchmarking and quality improvement

Benchmarking and quality improvement are crucial best practices in antimicrobial stewardship, particularly in the management of multidrug-resistant Gram-negative bacterial infections [74]. These practices involve measuring performance, comparing it against established benchmarks or standards, and implementing strategies to improve patient care and outcomes. Benchmarking in antimicrobial stewardship involves defining performance metrics to assess the appropriateness of antibiotic-prescribing practices. These metrics may include indicators such as antibiotic utilization rates, adherence to guidelines, rates of inappropriate prescribing, and outcomes of antimicrobial therapy. By establishing these metrics, healthcare facilities can measure their performance and identify areas that require improvement. Benchmarking allows healthcare facilities to compare their performance against established benchmarks or standards. These benchmarks may be developed based on national guidelines, expert consensus, or data from peer institutions. By comparing their performance, healthcare facilities can identify variations, gaps, or opportunities for improvement in antimicrobial-prescribing practices. Benchmarking facilitates the identification of variations in antimicrobial-prescribing practices among different healthcare providers, departments, or units within a facility [75]. By analyzing these variations, healthcare facilities can identify the best practices and areas where improvement is needed. Understanding the factors contributing to variations in prescribing practices helps develop targeted interventions and share successful strategies across the organization. Benchmarking results guide the implementation of targeted interventions to improve antimicrobial prescribing practices. These interventions may include educational initiatives, clinical decision support systems, antibiotic stewardship rounds, audit and feedback, and guideline development or revision. By tailoring interventions to address specific areas of improvement identified through benchmarking, healthcare facilities can optimize antibiotic use, reduce inappropriate prescribing, and mitigate the development of resistance.

6. Implications for practice

Antimicrobial stewardship has significant implications for practice across healthcare settings. Implementing effective antimicrobial stewardship practices can improve patient outcomes, reduce healthcare costs, and contribute to the global efforts to combat antimicrobial resistance. Antimicrobial stewardship requires strong leadership and support from healthcare administrators and management. Establishing dedicated antimicrobial stewardship teams, providing necessary resources, and fostering a culture that prioritizes responsible antibiotic use are critical for successful implementation and sustainability of antimicrobial stewardship practices.

7. Future directions for research

The field of antimicrobial stewardship continues to evolve, and there are several directions for future research that can further enhance our understanding and implementation of effective stewardship practices. Here are some potential areas for future research:

7.1 Outcome measures and impact assessment

There is a need for standardized and validated outcome measures to assess the impact of antimicrobial stewardship interventions. Future research should focus on developing robust methods to evaluate the clinical, economic, and patient-centered outcomes associated with various stewardship strategies. This will help determine the most effective interventions and their impact on patient outcomes and antimicrobial resistance rates.

7.2 Novel approaches and technologies

Research can explore the development and implementation of innovative approaches and technologies in antimicrobial stewardship. This may include the use of artificial intelligence and machine learning algorithms to guide antibiotic prescription, the application of rapid diagnostic tests to facilitate targeted therapy, or the integration of electronic health records and clinical decision support systems to improve decision-making and optimize antimicrobial use.

7.3 Antimicrobial stewardship in special populations

Future research should focus on understanding the unique challenges and considerations for antimicrobial stewardship in special populations such as pediatrics, elderly patients, immunocompromised individuals, and those with specific comorbidities. Tailored stewardship strategies that address the specific needs and risks in these populations can optimize antibiotic use and improve patient outcomes.

7.4 Antimicrobial stewardship in community settings

While much of the existing research has focused on antimicrobial stewardship in hospitals and healthcare facilities, there is a need for more research on stewardship in community settings. Investigating the effectiveness of interventions, such as education campaigns, public awareness programs, and implementation of guidelines in primary care and outpatient settings, can help promote responsible antibiotic use and reduce the development of resistance.

7.5 One Health approach

Antimicrobial resistance is a complex issue that requires a One Health approach, considering the interplay between human, animal, and environmental factors. Future research can explore the impact of antimicrobial stewardship interventions in veterinary medicine, agricultural practices, and environmental reservoirs of resistance. Understanding the interconnected nature of antimicrobial resistance across different sectors can guide comprehensive and collaborative approaches to stewardship.

7.6 Implementation science and strategies

Research should focus on implementation science and strategies to enhance the adoption and sustainability of antimicrobial stewardship programs. Identifying barriers and facilitators to implementation, understanding the organizational and cultural factors that influence uptake, and developing effective implementation strategies tailored to different healthcare settings can optimize the success and impact of stewardship interventions.

8. Conclusion

Antimicrobial stewardship plays a crucial role in managing multidrug-resistant bacterial infections. De-escalation therapy, combination therapy, dose optimization, and prophylactic antibiotic use are key strategies. Guidelines on antibiotic prescribing, a multidisciplinary team approach, education and training, surveillance and monitoring, close collaboration between clinicians and microbiologists, and benchmarking and quality improvement all contribute to the uptake and performance evaluation of antimicrobial stewardship.

Conflict of interest

The authors declare that there is no conflict of interest.