The increasing trend in resistance to antimicrobial agents is a major threat to the management of infectious diseases. If nothing is done, we may return to a pre-antibiotic era where a minor infection is potentially fatal. Therefore, it is important to use antibiotics judiciously to prevent serious public health threats. To this day, many policies and guidelines have been laid out to define the ideal selection, the correct dosing, and the appropriate duration of antibiotic therapy. Unfortunately, their adaptation still leaves much to be desired. We suspect that demand for inappropriate or unnecessary use represents a major cause of emerging resistance. The consequence is that broadening the antimicrobial spectrum leads to never-decreasing antibiotic exposure, which differentiates these drugs from other substances and increases the selection pressure that leads to the emergence of antimicrobial resistance and indirectly raises the cost. In the face of these threats, the principle of "maximum therapeutic effect with minimal risk" must drive the antimicrobial strategy. It is essential that evidence-based interventions be integrated by all hospitals, physicians, and other health professionals into daily practice.
Antibiotic stewardship, Global health, Multidrug-resistant bacteria, Precision medicine, Probiotics
The excessive, unnecessary, and inappropriate use of antibiotics in human, animal, agriculture, and veterinary medicine leads to antibiotic resistance, which is considered to be a major global public health threat of the 21 st century. Antimicrobial resistance endangers the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses, and fungi. Clinical management of infected patients is challenged by an increase in morbidity and mortality, longer hospital stays, and higher costs. In several countries, antibiotic sales in the community exceed those in hospitals, which rekindle ethical and economic concerns and demonstrates that human behavior, particularly the irrational use of antibiotics, is likely to be one of the most important drivers of resistance development. The burden of antibiotic use and resistance is particularly high in low- and middle-income countries (LMICs), where poverty-infection-malnutrition vicious cycle and the recourse to informal healthcare providers foster the emergence and spread of drug resistance. Given the widespread therapeutic misuse, and sometimes the non-therapeutic use of antibiotics, all nations bear a great responsibility in developing effective and visionary policies, stimulating effective interventions, and enhancing active collaboration in international networks. In this article, author summarized the present updates on antibiotic stewardship to combat antimicrobial resistance menace, present challenges, and future directions.
Uncontrolled antimicrobial and antibiotic usage during the past century have posed a multifaceted threat to human life, namely antimicrobial resistance (AMR). To combat the seriousness of AMR and to prolong the lifespan of antibiotics and antimicrobial agents, various methods have been introduced and implemented worldwide, among which antibiotic stewardship (ABS) programs and responses are considered key strategies [1-3]. Responsible usage of antibiotics through the ABS approach prevails over provoking AMR and economic burden, with encouraging outcomes such as reduced undisposed drug effluents and decreased ecological issues [4,5]. Antibiotic stewardship (AS) practices were introduced during the early 1940s, while at the same time, penicillin became an available antibiotic for treating bacterial infections [4]. Treatment regimens suggest that if treatment is prolonged into the fourth day or if clinical improvement occurs during treatment with penicillin and if the next day there is no continuation of treatment, the approval alteration should be recorded, and on the next day, an exchange of the drug should be attempted. Nowadays, these programs, namely antibiotic stewardship (AS) or antibiotic reserve, encourage the use of antibiotics for the treatment of life-threatening infections in humans [6]. The worldwide consensus about ABS is that approved components of ABS are surveillance for the target microbial species coupled with regular, pertinent, and commensurate benchmarking; clear communications; appropriateness review of antibiotic prescriptions; obligatory approval of antibiotic purchases; integrated infection treatment plans; and standardized digital systems [7].
Antibiotic Stewardship (AS) Protocol advocates for the proficient use of chosen antibiotics intended for the exact source of contaminating microorganisms at the precise quantity, form, and timeframe to acquire the best results by reducing the occurrence of resistance, toxicity, bacterial elimination, and adverse activities [8-11]. Antibiotic stewardship is a fundamental part of the infection prevention and drug security agendas, encouraging conservative drug utilization. The foremost imperative transformation was the idea of "optimal practices" concerning antibiotic use by the participants generally and among healthcare specialists regarding these practices [11-13]. To enable a more structured survey and scrutiny of antibiotic utilization scores, foundational standards and diagnostic categories were planned. Antibiotic Stewardship encompasses designated standards and agendas suggested to develop and assess the optimal use of antibiotics through a multiplex mechanism to integrate with other components of an operational program in certified organizations [14].
The Antibiotic Stewardship principles recommend, among other things, the adoption cycles, diagnostic trials, contamination, treatments, and achievements. The strategic goal of AS is to align healthcare facility workflows concerning antibiotic usage with the best evidence and consensus assessments, which are themselves of importance to the ethical tenets of AS [15]. The centers chosen were through mutual consideration by the editors concerning the AS journal, supplemented by a general opinion among the installed members of AS Research and Progress. Antibiotic stewardship programs (ASPs) are intended to capitalize on outcomes where such intervention can offer benefits. The principal objective of ASP is the usage of measured doses of antibiotics to attain the best medicinal effect, comprising minimal adverse fallout and allergic reactions, and no antibiotic resistance [1-2,16]. The broad aim is to focus on increasing the illness and condition to adopt adaptations that protect and optimize medication interventions. The prime objective is to secure the key goals with a direct consequence through antibiotic usage [1-2, 16].
Antimicrobial resistance is not only a threat to global health but also a threat to development, food safety, and global security. The data reveals a very alarming picture of antimicrobial resistance in 114 countries [16-18]. An increasing number of infections, such as pneumonia, tuberculosis, blood poisoning, gonorrhea, and foodborne diseases, are becoming harder and sometimes impossible to treat as antibiotics become less effective [1-3,19]. As antibiotics are used to treat many infections in different pharmacy settings, antimicrobial resistance can be connected to many causes [19]. Overuse and misuse of antibiotics seem to be widespread in different healthcare settings. They include prescribing by anyone without clinical guidance from professionals, new patients starting on antibiotics without any proper diagnosis, buying antibiotics without a proper prescription, not following an antibiotic regimen and dosages, continuing the medication even after symptoms are relieved, and using remaining antibiotic prescriptions for later infections [20,21]. Scientific evidence supports that most of these issues are not urgent or severe enough to require antibiotics and are indicated for self-limiting viral infections, where long-term resistance development may occur [22].
Poor quality of antibiotics is a potential barrier to managing antibiotic resistance. It includes a lack of active ingredients and/or the presence of incorrect ingredients, inadequate quantities of active ingredients, larger than normal dosages administered intentionally or accidentally, unclear formulation and/or dosages, inadequate product packaging, and expired or changed lot maturation [22,23]. In many countries, antibiotics are available without a healthcare professional’s suitable prescription. Although both prescription and non-prescription antibiotics include broad-spectrum antibiotics, the availability of antibiotics without medical advice also means that others may not regard general hygiene, infection prevention, and control measures, which can lead to the spread of antibiotic resistance. Antibiotics are also dispensed in unrecognized pharmacies or community shops, in both high- and low-income countries, with an indication that close regulation of medical advertising and counterfeiting needs to eradicate management activities [22,23].
Antibiotic overuse in the community and hospitals worldwide has reached alarming levels, leading to the accelerated emergence of antimicrobial resistance [22]. To combat this issue, the implementation of Antibiotic Stewardship Programs (ASP) has been encouraged, especially in healthcare facilities where they need to be tailored to each institution based on their specific boundary conditions [24]. ASP is mainly a hospital-based set of measures that induce appropriate antibiotic use to reduce resistance, cure infections, and minimize costs. The core of these activities relies on the implementation of correct guidelines, such as restriction protocols, tracking infection rates, repartitioning of resistant bacteria that are prevalent in the area, and developing efficient prescriptive tools without avoiding undertreatments and/or bacterial relapses in patients who will be treated [25]. In other words, to have more effectiveness in clinical practice, treatments should be adapted to real-life conditions, taking into account the existence of comorbidities and the pharmacological properties of the drugs in special populations such as obese patients, children, the elderly, and hospitalized patients [26]. At the same time, even strong guidelines are useless if they are not known or not applied by health practitioners. Only a low proportion of patients with respiratory infections received doctor recommendations to curb unnecessary antibiotic use, highlighting the fact that not enough people are aware of these guidelines. Furthermore, we do not have any compelling proof that tells us that implementing these two proposed actions really 'cure' the problem or, in other words, reduce antimicrobial resistance and plasmid treatment dynamics in a globalized world [27].
National governments, international organizations, and educational groups have made efforts to promote the design and implementation of Antimicrobial Stewardship Program administrative directives in institutions to combat the expanding danger of antibiotic resistance [28,29]. Numerous initiatives have pledged to decrease the amount or divert the intensity of antibiotic resistance. In addition, a country-wide strategy is planned to serve as the critical institutions or hospitals that operate in the clinical pipeline of the most severely sick patients and/or high concentrations of antibiotic resistance [19]. The global health promotion aiming to execute National Action Plans and Joint Programming Initiative are among the numerous other worldwide programs supporting this important action [28,29].
At the same time, NGOs are important in varying degrees locally. Regardless of the means through which compensatory programs have been implemented, there is a sizable consensus between documents about the basic components of an antimicrobial stewardship initiative [28]. The coordinating entities at the institutional level should consider the guidelines of the professional organizations. In brief, the goals of such a general guide are to improve the quality of patient recovery, diminish the frequency of antibiotic resistance, defend antibiotic expenditure by optimal use, and enhance public health in general [4,30].
Antibiotics are commonly prescribed drugs in hospitals; however, a significant portion of the course of antibiotics is either incorrect or inappropriate, which ultimately leads to the inadequacy of antibiotics. This antibiotic use also adversely promotes the fabrication of multidrug-resistant bacteria (MDRO) pathogens, consequently reducing the effective therapeutic options for the treatment of bacterial infections [12,31]. The consequences of MDRO are a prolonged length of hospital stay, an augmented economic burden, an increased death rate, and excessive reservoirs of future infections. Hospitals are important stewardship sites [32,33]. Below, we have summarized and discussed hospital-based antibiotic stewardship practices.
The initiation of antibiotic stewardship programs (ASPs) introduced fundamental changes to uncover many factors that primarily increased the use of broad-spectrum antibiotics in hospitals, and, as a result, the unnecessary adverse effects associated with antibiotic treatments were reduced [34-36]. In this regard, a list of core and complementary ASP interventions that hospital facilities should adopt to improve the responsible use of antibiotics in hospitals has been assembled. The core elements include leadership commitment, accountability, drug expertise, action, tracking, reporting, evaluation, feedback, and education [36]. Currently, these elements are updated as Core Elements of Hospital Antibiotic Stewardship Programs. In addition to these elements, additional components were also added for each healthcare setting (acute-care hospitals, long-term care, and post-acute care settings). Subsequently, the adherence to the core elements in these healthcare facilities was monitored using widely used surveys [35,37].
Community-based interventions can play a crucial role in reducing the widespread problem of overuse of antibiotics. During the past two decades, there have been multiple strategies implemented in a community-based setting, such as public awareness campaigns, educational programs targeting parents and doctors. Such campaigns are intended to promote appropriate use of antibiotics for RTIs, to recognize as well as to reduce the risk of AMR, and to treat infections without antibiotics [38-40]. Patients are instructed to wait for at least two to three days for viral illness before contacting a health provider, and the use of antibiotics should be restrained for all cough illnesses without considerable airflow obstruction, for nasal discharge without other signs of sinusitis, and for pharyngitis without suspected streptococcal infection, so that the intrinsic healing process is not interrupted and unnecessary complications like resistance are prevented in the interest of public health [39-41]. Moreover, symptom recovery has been widely reported for 5-15 days, consistent with the illness course caused by most viral infections [41]. Reducing antibiotic prescriptions can be achieved by sharing clinical decision-making and bringing patients to the front of the battle line to achieve rapid recovery and cope with the sustained consequences. Over-the-counter distribution of antibiotics is ubiquitous in multiple areas. The approach to over-the-counter distribution could include implementing the same guidelines that govern prescription use of these medications for humans as well as for animals. Requirements need to be put in place on telemedicine services [40,41].
Understanding these challenges and resolving the obstacles will help in effective antibiotic stewardship implementation. Lack of infection control practices and the capacity of providers, especially in resource-constrained setups, are crucial challenges for effective ASP [42,43]. Diagnostic issues, particularly for the initiation of appropriate treatment, are a demanding process. All these will be compounded by human behavioral issues such as habits, lack of supervision, knowledge, and feeling a lack of need for stewardship [44,45]. Rational use of antibiotics requires changes in organizational and individual behaviors, as well as policies. Behavioral change theories could be applied to understand the ground reality and to plan and execute interventions [46,47]. Soon, the present antibiotics will be ineffective against several microbial agents as the majority acquire resistance capability [3]. Different levels of stakeholders, including consumer groups, should consider implementing effective stewardship. This discussion addresses the challenges faced by antibiotic stewardship programs at the healthcare level and describes the research areas that need attention in facilitating the success of antibiotic stewardship [48,49]. Strengthening infection prevention and control would support ASPs. Integrating point-of-care diagnostics may also improve the initiation of appropriate antibiotics. Qualitative and quantitative research at multidisciplinary levels, considering the local constraints and the cultural and diverse nature of stewardship success, will support future initiatives. Associations at different levels should play a vital role in policy direction and guidelines [50,51].
The level of knowledge of health professionals about the prudent use of antibiotics is not within the desired parameters [52,53]. The attitudes and adequate knowledge of using antibiotics together have a greater positive impact in the process of controlling the resistance of microorganisms to antibiotics, also aiming at ensuring the optimal efficacy of the treatment of diseases. It was concluded that preservice teachers had a good knowledge of antibiotic resistance, but they lacked knowledge of the effective use of antibiotics and of infection risk factors and prevention [54,55].
Misinformation is also disseminated through the media. A considerable number of people know that antibiotics cannot kill viruses, but do not refrain from asking for them when they have viral infections such as the flu [54,55]. The role of pharmacists is crucial for changing the medicines prescribed generically and for carrying out information campaigns. The use of existing healthcare facilities more effectively is essential, either in building capacity or in caring for patients. Such measures include surgical procedures that are less vulnerable to infections, including cancer therapy, counseling patients to take appropriate and timely action, and providing tailored advice to patients [56-58].
Achieving effective and long-lasting reduction in AMR through ASI and policy interventions could be costly, difficult to maintain, and costly. Finally, the economic constraints consume or restrict the allocation of financial and human capital to battle infections, even though the dire need for such investments is increasingly recognized [59-61]. Consequently, isolating investment in the right sets of interventions and approaches for the optimum impact is of the utmost importance. Policymakers, nevertheless, have financial budget constraints and institutional capacity problems that limit the allocation of resources for repetitive, incremental, and one-size-fits-all forms of awareness efforts [59-62]. The available data are insufficient to recognize optimal expenditure at operational stages. It is clear that the current data are not organized in ways that may be effectively employed for cutting operational allocation decisions other than to achieve 'awareness', 'education', and 'research' that are predetermined primary goals. Furthermore, estimated position-taking and anything that encourages such a process will be difficult to attain without clearly articulated, stable plans. All useful information on AMR increments funding investments, the appropriateness of measures, the incorporation of responsibilities for stakeholders, and the obstruction of those who work in the public sector to achieve multiple objectives while managing the taxation funds [61-63].
Although antibiotic resistance is considered by a multitude of interwoven factors, it must be acknowledged that relentless and rampant misuse of antibiotics all over the world, particularly in low- and middle-income countries, can lead to the emergence of new and widespread resistance [64]. People in several developing countries, without any medical prescription, can purchase antibiotics over the counter at their own discretion and excessively use them. Consequently, people can be self-medicating with antibiotics. They can utilize antibiotics as putative broad-spectrum medications and rather discontinue them once their symptoms have been alleviated and they feel improved [65,66]. Additionally, the substitution of diarrheal, infectious, or mucopurulent genital discharge with antibiotics, without any supporting evidence, may contribute to the spread of antimicrobial resistance in developing countries [67,68].
Deciphering the impact of human behavior on the use and abuse of antibiotics should result in antibiotic stewardship. Therefore, some alternative strategies from a public health standpoint may be necessary [69,70]. An intriguing question at this juncture consists of illustrating the strength of behavioral interventions on the rational use of antibiotics by people. Nonetheless, protecting the very few antibiotics that are effective against multi-cumulative resistant strains is no longer sufficient; we have no alternative but to act rationally and realistically [71]. The strategies of communication and sensible advice have, at present, been somewhat more examined among antibiotics. These strategies still currently endure the techniques of medical education and the rules of clinical practice worldwide. Therefore, behavioral interventions, supplemented alone or in hybrid with restrictive and environmental strategies, might be advantageous not only for health but for the pharmaceutical economic systems of lower- and middle-income countries [69,71].
The probable obstacles to the implementation of high-quality antibiotic stewardship with their coping strategies regarding the non-availability of diagnostic tests based on ASP have been illustrated. Specific manipulable barriers related to diagnosing urinary tract infections, community-acquired pneumonia, and optimizing intravenous to oral conversion have been addressed [72,73]. The potential role of rapid diagnostic tests at the point of care is highlighted. There are newer high-end molecular diagnostic approaches that not only identify the pathogens but also aid in determining the resistance genetic elements [63]. Techniques like generalizable technology for base calling and direct-from-sample specimen processing, biosensors powered by smartphones, and different digital/machine learning technologies to interpret the data generated by the diagnostic test methods are also discussed [74,75].
The recent technological development focuses on developing nano-device based platforms or the intersection of chemistry, physics, and molecular biology to generate bio-electronic systems for rapid and sensitive antibiotic resistance panels to recognize a wide range of antibiotic groups [76,77]. There are a variety of biosensors based on ion-sensitive field-effect transistors, such as photonic sensors, quartz crystal microbalance, surface acoustic wave sensors, and electrochemical sensors for label-free detection. Antibiotic derivative detection by molecular imprinting smartphone sensors makes use of the mobile phone and its components [78-80]. Surface acoustic wave consists of a few functionalizing layers, which include a potassium chloride solution acting as an electrolyte, a cellulose-based polymer selective to the studied compound, an Ag film, and a polyimide substrate [81].
A comprehensive digital strategy and well-organized digital health infrastructure could be the answer to the complexity and multiplicity of challenges encountered in antibiotic stewardship implementation, including antimicrobial resistance control and containment. Digital health solutions are key to making these applications simple to use, economical, interconnected, groundbreaking, individualized, and time-conscious. The significance of digital health in helping poorer countries to accomplish their digital development over the next decade in order to work more efficiently to attain universal health coverage allows them to benefit democratically from digital health knowledge [82-85]. The ingenious use of digital health can help revive the aspiration of health for all, including realizing the value of antibiotics by replenishing the diminishing antibiotic pipeline [82-85]. The whirlwind of immunological science about the long COVID impact on the immune system reserves somewhat painful echoes for individual health, with probable secular alterations in trajectory [86,87].
Internet applications and digital resources are assuming a growing and critical role in offering tailored evidence-based antimicrobial choices and providing pertinent information on the accurate delivery of antibiotics amid pandemics, particularly to patients who may never interact with healthcare professionals physically, and those who have no access to healthcare systems at all, such as refugees and internally displaced persons leading isolated lives in rural or weather-sensitive areas, or dwelling in an outer space base [88-90]. Digital health offers potential to enhance numerous stages of antibiotic stewardship, particularly demand generation and individual commitment, and to offer tailored and targeted solutions, improving decision-making and end-user support. This can be addressed in an implementation strategy that integrates these enhanced antibiotic-present techniques for improved responsiveness by healthcare providers and increased patient knowledge regarding their roles in achieving a worldwide sustainable antimicrobial response. The aim is to ensure that all taking antibiotics are motivated and kept informed about the worldwide difficulties of antimicrobial resistance and antibiotic scarcity [88-90].
With the enhanced understanding of the human microbiome and the complex interactions between the different commensal microbial populations, the precision medicine approach has been proposed as a method for preventing antimicrobial resistance while retaining the ability to effectively treat infections. This approach could also reduce the pressure of antimicrobial selective pressure [91]. The use of a precision medicine approach, along with the availability of microbiomes that are disrupted by treatment with a specific antimicrobial, could help determine what required supplements or alterations might be beneficial in maintaining health and aid patient outcomes while minimizing the impact on the antimicrobial resistance of individual courses [91]. This approach postulates that the variations between individuals and organisms across geographical locations would probably underline their unique microbiome compositions and therefore the microbes supplemented into their diets. Moreover, these differences might also play a role in the diverse resistomes observed among various intermingling commensals [92].
In addition to using this approach for key preservation, investigations to decipher the activities of the specific microbes involved in the fundamental tasks in the overall functionality of the microbiome communities might reveal novel drug targets for the inhibition of infective microbes or for modifying host physiology [93]. Putting precision medicine into practice, however, requires investigating the potential displacement of the pathological threat of antibiotic resistance by alternative risks. Safety and efficacy studies should evaluate the selection of predominant commensals and the resultant health outcomes, as well as the selection for age-based hints indicating the presence of preliminary resistances, with the participant’s microbiome health status in mind [94]. Furthermore, post-experimental monitoring studies are required to ensure that all players have returned to or supported the original microbiome state. While only a few of these issues are directly associated with antimicrobial resistance, new questions keep emerging, and top research priorities may alternate in relevance in the context of such a multidisciplinary large-scale project. In the real-world delivery of this precision medicine-based potential concept, role-based awareness is required to understand and exploit the potential of the situation [95,96].
The downslide of antimicrobial discovery among pharmaceuticals is largely related to the complexities posed by the very nature of antimicrobials themselves. Antimicrobials usually consist of diverse chemical species, which adds to the already present regulatory complexities. Over the last two to four decades, there has been a noticeable acknowledgment of the fact that a "one-size-fits-all" drug does not exist. The era of precision medicine is confidently displaying itself, where tailoring treatment to the individual patient is becoming the new norm. With this new realization comes the concept of precision antimicrobials as well. For example, antimicrobials that are active against susceptible bacteria elsewhere in the human system may not be effective against those in the central nervous system. This also means that, through precision tools, bacterial diseases can be screened and treated individually, vastly limiting the need for classical therapeutic antimicrobials. The use of genome editing tools to reshape bacterial growth patterns or modify bacteria so that they are no longer lethal but instead acquire new properties that promote beneficial aspects is in clinical exploratory stages [97,98]. The use of bacteriophage as a specific antimicrobial is still largely unexploited, at least in the West. The utility of gut commensals to replace pathogenic resistant isolates from the gut lumen also seems feasible [99]. Alongside the classical candidates comprising pharmacokinetic/pharmacodynamic modifying agents, bacterial virulence inventory modification tools, and immunological mediators, there are possible combinations to achieve supportive and definitive targets for combating ignoble bacterial infections [100]. The fact that all these newer influences do have a role to play only goes to show the inherent resistance that nature has toward what we know today as "resistant infections."
In conclusion, we assert that the hosts of community and government must take up every possible responsibility to prevent antibiotic resistance. The absence of the orchestration of efforts from every party will see us struggle mightily from the present day, where we are just receiving overtures of the catastrophes. The Antibiotic Stewardship Program is clearly just a foundational block that still requires other measures to fortify it. However, even a journey of a thousand miles must begin with the first steps. Little by little, we can and will evolve it into a more effective program, successfully able to combat the menace. Until we achieve our collective goal, we should at least feel satisfied that every patient we successfully treated with the infection and hence prevented prolonged antibiotic administration or double coverage with broad-spectrum antibiotics is singing our praises together with us.
Authors have no conflict of interest.