Open access peer-reviewed chapter
Abstract
Antimicrobial resistance (AMR) is a major concern for global health security because of its impact on human, environment, and animal health. This tendency of AMR was corroborated by Alexander Fleming who discovered the first antibiotic. This chapter focuses on the global concern of AMR, its causes, and solutions. Antimicrobial stewardship (AMS) is one of the solutions employed globally to tackle the challenge of AMR. The objective of the AMS includes: reducing antibiotic abuse, lowering healthcare costs, and tackling AMR. Therefore, it is pertinent to decrease AMR and protect global health. Many countries are implementing antimicrobial stewardship programs (ASPs) in order to reduce AMR. The misuse of antibiotics is one of the major factors that cause AMR. To reduce antibiotic abuse pharmacists have a key role to play. Finding new drugs to treat resistant pathogens is another solution to AMR. Plants have contributed immensely to traditional medicine and drug discovery due to the presence of bioactive secondary metabolites. They have the potential to contribute immensely to tackling AMR.
Keywords
- antimicrobial resistance
- antimicrobial stewardship
- global health
- plants
- secondary metabolites
1. Introduction
Antibiotics are considered as a substance of biological origin or produced by a microorganism that can be lethal to other organisms or inhibit their growth [1]. In 1928 Alexander Fleming discovered the first antibiotic from fungi and by 1940 other useful antibiotics were discovered from bacteria [2]. The period of 1930–1960 is regarded as the antibiotics golden era due to the discovery of many antibiotics [3].
The drugs that are most prescribed across the globe are antibiotics [4]. It is estimated that by 2030 the use of antibiotics will increase up to 67% in highly populated countries around the world [5]. Antibiotics have contributed immensely by reducing mortality and morbidity rates, especially in developing countries [6]. However, there is a need for new antibiotics due to the existence of resistant bacteria and the advent of new diseases [2].
Antibiotics mechanism of action includes:
Inhibiting the synthesis of cell wall
Breaking down of cell membrane function or structure
Inhibiting the structure and function of nucleic acids
Inhibiting protein synthesis
Blocking of important metabolic pathways [1].
Antibiotics have played an unparalleled role in the advancement of society and medicine, and they are now a requirement in all healthcare systems. Antibiotic treatment has contributed to controlling bacterial infections; enhancing major surgeries; cancer therapy; and other successful aspects of modern medicine [5].
It is pertinent to sustain the effectiveness of present antibiotics in order to prevent any retrogression recorded in dialysis, surgery, and chemotherapy among others [7]. If the challenge of antimicrobial resistance (AMR) is not tackled then gains recorded in controlling/treating illnesses like HIV, TB, and malaria would be in dire situation [4].
1.1 Antimicrobial resistance
The case of methicillin-resistant S
AMR is the main issue when treating a certain disease for a long time. AMR occurs when microorganisms stop responding to medications that once killed them. The rise in AMR is caused by both microbial behavior and how people take antimicrobial medications. This resistance could be extremely harmful since it might make some illnesses impossible to cure, which could result in serious consequences or even death. To combat AMR, researchers are striving to create novel therapeutics [9].
Bacteria can develop antibiotic resistance in addition to the intrinsic mechanism of resistance. Other mechanisms may also contribute to the development of antibiotic resistance in bacteria. These include antibiotic efflux or poor drug penetration that lowers the antibiotic’s intracellular concentration, modification of the antibiotic’s target site caused by posttranslational target modification or genetic target mutation, and inactivation of the antibiotic through modification or hydrolysis [5].
1.1.1 Virulence
Human skin, mucous membranes, and internal organs all contain bacteria. The ability of bacteria to cause disease is known as pathogenicity, and a pathogen carries a number of elements known as virulence that enable the bacterium to enhance its level of pathogenicity. Toxicity and invasiveness are two of a pathogen’s most crucial characteristics that aid in the development of a disease. Both virulence and the state of the host’s immune system have the potential to affect the final balance of a bacterial illness course. The coevolution of the host and bacterium may have occurred over a period of millions of years. During this time, pathogens have altered their virulence to adapt to the host’s immune system [10].
1.2 Global concern of AMR
AMR is an increasing challenge to the global economy, human health, and sustainable development due to the indisposition, death, and economic cost it causes [7, 11]. AMR is a global challenge; however, antibiotics have contributed immensely to medicine by treating bacterial infections in animals [5]. Inappropriate use of antibiotics is widely regarded to contribute to the growing challenge of resistant bacteria [12]. Sir Alexander Fleming, who discovered antibiotics, had cautioned that the public would demand antibiotics and this would begin an era of abuses. Therefore, the primary driver of resistance development is the overuse of antibiotics [9].
The infections that are caused by multidrug-resistant pathogens are linked with a high rate of mortality [13, 14]. The coronavirus pandemic has led to an increase in multidrug-resistant pathogens and this heightens the challenge of AMR [15]. The resistance of antibiotics is associated with: pumping antibiotics out of cell, decreasing uptake of antibiotics, distorting the target to reduce the binding of antibiotics with the target, and enzyme inactivation [16].
By 2050, AMR-related mortality is estimated to outpace diseases like cancer and diabetes, killing 10 million people annually [17, 18]. Major concerns about the security of the global health system include the escalation of AMR and the dearth of novel medications to treat drug-resistant bacterial illnesses [7]. The World Economic Forum, the World Health Organization (WHO), the Centre for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America have all identified antibiotic resistance as a global public health concern [19, 20]. The World Health Assembly asked WHO to submit a worldwide action plan to address the issue of antibiotic resistance [21].
People in the UK have voted for a government-sponsored $10 million award (longitude award challenge) to find new ways to prevent antibiotic resistance [22, 23]. According to the US President’s Council of Advisors on Science and Technology’s recommendations, President Barack Obama in the United States instructed the National Security Council to create a comprehensive national action plan (NAP) to combat antibiotic resistance by 2015 [24, 25]. Multidrug-resistant (MDR) bacterial infections have been linked to over 8 million hospital stays and are currently costing healthcare systems over $20 billion, according to research by the WHO [26].
AMR is a critical issue that needs to be addressed on a global scale since it has a detrimental influence on patient safety, public health, and clinical outcomes. It also poses a threat to the advancements made in contemporary medicine, as it makes it difficult to treat severe infectious diseases effectively given how infrequently new antibiotics are being developed [27]. This places a significant load on healthcare systems all across the world [28]. Many nations have created and are putting into practice their NAPs for AMR [29].
1.3 Causes of AMR
Microbial resistance results because of improper antibiotic usage [30]. The overuse of antibiotics is discouraged nevertheless overprescription is still practiced around the world [31]. The misuse of antibiotics is facilitated by self-medication behaviors and the unrestricted procurement of antibiotics without prescriptions, particularly in low-income nations [31, 32]. It is pertinent to control AMR because of its potential to incur US $1 trillion in healthcare costs by 2050 if left unchecked [33, 34]. The improper use of antibiotics is present in hospitalized patients and community [35, 36]. About 62% of antibiotics sold in community pharmacies around the world are given out with no prescription [37]. Community pharmacists frequently give antibiotics without a prescription due to a variety of factors including complacency, patient pressure, and fear of losing customers [38, 39]. There are various studies that have confirmed inappropriate prescription of antibiotics [40, 41]. A meta-analysis revealed that in a particular community pharmacy setting, 62% of antibiotics were dispensed without a prescription to treat illnesses that do not even require antibiotic therapy [42].
Furthermore, infection control guidelines, sanitation settings, water hygienic practices, diagnostic and treatment procedures, drug quality, and travel or migration quarantine are additional significant factors that have the potential to cause antibiotic resistance. The exchange of genetic material between organisms enhances the spread of antibiotic resistance, in addition to the mutation of numerous genes located on the chromosome of the microbe [5]. Resistance results from diverse genetic mutations and alterations that make microorganisms less sensitive to certain types of antibiotics. As a result, infections become more difficult to treat and rates of transmission, sickness severity, and mortality considerably rise [43, 44]. Antibiotic resistance has resulted because bacterial infections are becoming more challenging to treat because of pharmaceutical industry’s failure to produce new medications [40].
The lack of antimicrobials has made AMR a serious global problem. The cost of medications, the length of hospital stays, and the overall cost of healthcare services all rise as a result of AMR [45]. AMR is associated with poverty and the WHO has posited that by 2050 about 28 million could be pushed into extreme poverty [46]. Inappropriate management of antimicrobial agents has been shown to have a substantial impact both in developed and developing nations worldwide. The population’s general lack of awareness and perhaps the prescribers’ lack of knowledge are the main factors in the misuse of antibiotics. This may cause them to select the wrong treatment course or therapeutic agent, increasing the likelihood of the emergence of microbial resistance [47, 48].
1.4 Solution to AMR
Despite the WHO’s repeated warnings new antibiotics are needed to address the growing threat of antibiotic resistance [49]. The rise of AMR rates has prompted calls from the WHO and UN urging nations to create NAPs [50]. Otherwise, AMR rates will increase significantly, having a negative influence on death, morbidity, and expenditures [51, 52].
Five strategic goals are outlined in the Global Action Plan on AMR as a guide for nations creating their NAPs on AMR:
Objective 1: Improve public knowledge and comprehension of AMR through effective outreach, instruction, and training.
Objective 2: Through observation and research, strengthen the body of information and evidence.
Objective 3: Reduce the likelihood of infection by implementing efficient sanitation, hygiene, and infection prevention practices.
Objective 4: Optimize the use of antimicrobial drugs for both human and animal health.
Objective 5: Develop the financial justification for long-term investments that consider the requirements of all nations and boost spending on innovative drugs, diagnostic equipment, vaccinations, and other interventions [53].
Utilizing antimicrobial drugs sparingly and for the shortest possible time is a crucial step in preventing and reducing resistance [54]. To promote appropriate antibiotic use in community settings, approaches like encouraging prescribers to include the diagnosis on the prescription, implementing delayed prescribing, point-of-care testing, and creating collaborative practice agreements can be effective options [55, 56]. A global action plan on antibiotic resistance is necessary in order to enrich public perceptions of antibiotic resistance, lowering the frequency of infections, stepping up monitoring and research efforts, and maximizing the use of antibiotics [57]. To ensure the best possible use of antibiotics in the public, proper dispensing procedures at community pharmacies are crucial in this situation [58]. To clarify, analyze, and examine pharmacists’ and patients’ perspectives, beliefs, and feelings, qualitative research methods are useful in pharmacy studies [59].
A distinct and fruitful strategy to combat AMR could be the use of alternative medicines for the treatment and control of infectious diseases. These treatments include vaccinations (against MRSA and MDR
2. Antimicrobial stewardship
One of the methods for reducing antibiotic resistance is known as antimicrobial stewardship (AMS) [62]. It ensures that the best antimicrobial therapies are chosen, administered, and continued for the shortest possible time to produce the best therapeutic results with the least amount of chance that the patient may experience adverse effects or the emergence of AMR [63]. Succinctly, AMS programs work to raise the success rates of treating infections, decrease treatment failures, and correctly prescribe therapy and prophylaxis [64]. The WHO has pushed for and taken the lead in developing frameworks for antimicrobial stewardship programs (ASPs) by working with other professional, national, and international organizations [53, 65]. AMS is accomplished by preventing the unnecessary use of medications and by offering focused, targeted care when it is appropriate in order to raise the standard of patient care [66].
Antibiotic stewardship is a method that makes sure antibiotics are used correctly and in sufficient amounts when necessary. Additionally, this assures that antibiotic use yields the most advantages, stops the spread of infections, and improves both health and economic benefits [67]. Evidence demonstrates that antibiotic stewardship initiatives are successful in encouraging judicious antibiotic usage and enhancing clinical results in the hospital context [68]. Reviews have demonstrated the effectiveness of ASPs in boosting antibiotic policy adherence; reducing the length of antibiotic therapy; decreasing antibiotic resistance, morbidities, mortalities, healthcare-associated infections, costs, and extended hospital stays [69]. ASPs help to promote achieving the sustainable development goals (SDGs) [70]. A thorough stewardship program should include constant monitoring and audit of antibiotic consumption patterns with clinician feedback; the development of an antibiotic formulary; nonstop educational initiatives; antibiotic de-escalation to ease the switch from broad spectrum to narrow spectrum antibiotics; the development of infection treatment guidelines; antibiotic restriction programs; and the enforcement of proper medication regimens [71].
Medical professionals, clinical microbiologists, pharmacists, nurses, and/or administrative staff typically make up multidisciplinary teams for ASPs and the interventions they use can vary greatly depending on the healthcare system and cultural context [72]. ASPs must be implemented in order to improve the prudent use of antibiotics in healthcare facilities and the general public [73, 74].
2.1 Objectives of AMS
Reduced antibiotic abuse, lower healthcare costs, improved clinical outcomes, and a decrease in AMR are the objectives of AMS [62]. The ASPs are targeted to ensure the responsible use and continuous efficacy of available antimicrobials through a wide range of treatments incorporating quality improvement efforts [4].
2.2 Role of pharmacists in AMS
According to the CDC and the American Society of Health-System Pharmacists (ASHP), pharmacists have a significant role to play in infection prevention and control programs which are important to AMS [75, 76]. Pharmacists contribute to AMS programs in the following ways: leading of AMS programs in healthcare facilities, formulary development; automatic change and stop orders; dose optimization therapeutic drug monitoring; and providing empirical antimicrobial guidance [62]. Additionally, AMS activities led by pharmacists maximize patient clinical outcomes, enhance the proper administration of antibiotics, and lower the cost of antibiotics [68, 77, 78].
Lack of training and information are among the major obstacles that affect the participation of pharmacists in AMS [62, 79]. Patient education relies heavily on pharmacists and numerous studies have demonstrated the benefits of instructing patients on proper antibiotic usage [70]. Therefore, it is advised that undergraduate pharmacy students should be trained in the areas of antimicrobial therapy, AMR, and AMS [62]. Pharmacists play critical roles in ASPs like: taking part in antimicrobial ward rounds; editing and writing antimicrobial guidelines; keeping track of antimicrobial consumption and spending; and educating healthcare professionals about antimicrobials [79]. Community pharmacies are the best place to introduce ASPs because of the effect antibiotic resistance has on the patient’s condition and the cost to society [80]. Community pharmacists play a crucial role in patient management since they are frequently the first healthcare providers that people see about their condition [81]. They are crucial stewards of antibiotics and play a significant role in informing, educating, and counseling patients and healthcare professionals on how to use antibiotics properly [82].
In Sub-Saharan Africa (SSA), there is a shortage of infectious disease pharmacists. However recent studies have demonstrated that with the right training, pharmacists in SSA can create and oversee AMS programs that are comparable to those in the UK or the USA [4]. Existing research indicates that pharmacists are crucial in developing and managing antimicrobial guidelines and policies; evaluating individual patient regimens to optimize therapy; auditing antimicrobial consumption outcomes both prospectively and retrospectively; and training clinical teams and patients [83]. Additionally, it has been noted that doctors frequently rely on the advice and knowledge of pharmacists about antibiotic stewardship [84]. Studies have shown that AMS with a pharmacist reduced antibiotic consumption compared [85].
2.3 Implementation of AMS across the globe
Due to the growing concern about AMR and the drying up of the supply of new antibiotics, there has been a global push for the implementation of ASPs [72]. More detailed instructions on how to set up, carry out, and assess efficient AMS programs at the national and healthcare facility level are increasingly needed, particularly in developing countries [53]. The adoption of AMS principles in the real world is thought to depend heavily on education [86]. Healthcare systems around the world have embraced AMS as a crucial strategy for combating AMR [87].
The implementation of AMS in Nigerian hospitals is insufficient even though AMS is a part of the Nigerian National Antimicrobial Resistance Action Plan 2017–2022 [79]. The enforcement of a law banning the distribution of antibiotics without a prescription among community pharmacists in Saudi Arabia dramatically reduced such malfeasance [88]. In 2007, the Thailand Ministry of Public Health started a campaign “Antibiotic Smart Use” to encourage prudent antibiotic use in Thailand hospitals. In 2016, the Royal Thai Government released a National Strategic Plan on AMR [64].
According to a study conducted in Australia, clinical leaders’ involvement and executive-level support were essential for the successful implementation of AMS programs [89]. In order to implement a comprehensive and sustainable ASP it is pertinent to take into consideration the following: the need for developing formal AMS policies and incorporating them into the clinical governance structure; establishing a multidisciplinary approach to AMS with clear roles and responsibilities for each team member and importance of organizational investment in staffing, information management systems, and staff education [64].
3. Plants contribution to medicine
Traditional medicine is acknowledged by the WHO as an essential alternative healthcare delivery system for the majority of the global population [90]. According to WHO, more than 80% of people in developing nations still rely on herbal medicine to treat diseases [91]. Globally, herbal medicine either forms the backbone of healthcare delivery or works in tandem with it [92]. Numerous plants have secondary metabolites also referred to as bioactive metabolites because of their antimicrobial properties [93].
The large and diverse groups of organic compounds that make up the secondary metabolites in plants are produced in small amounts, and they play no direct role in vital processes like photosynthesis and respiration [94]. The primary function of a plant’s secondary metabolites is to defend itself against pathogens and predators. These secondary metabolites have significant applications in modern medicine as they are useful for treating or preventing some human ailments [95]. Examples of secondary metabolites include: tannins, flavonoids, terpenoids, and saponins and they possess antibacterial properties [90].
The combination of compounds known as secondary metabolites found in plants is primarily responsible for the good therapeutic effects of plant materials [96]. Secondary metabolites are efficient and more affordable than conventional drugs. They have been seen to be the preferred first-line therapy option for people, particularly traditional healers, in treating infections and other disorders [97]. About 25% of drugs produced are derived from plants and even synthetic drugs derive their structures from natural products. This is because plant secondary metabolites provide protection against microbial infection and insects [2].
Plant defense mechanisms vary depending on their unique needs and are influenced by physiological conditions, climatic changes, and environmental factors [98, 99]. Secondary metabolites can treat diseases by themselves or in conjunction with other substances or metabolites. Numerous studies have shown that such combinations can improve the effectiveness of a disease’s treatment [100]. Due to their bioactivity, secondary metabolites have historically been employed in medical systems across the globe [101].
Natural products derived from medicinal plants give room for the discovery of new drugs [102]. There are many medications made of various secondary metabolites that have the potential to address the issue of drug resistance and open up a new avenue for researchers to find new medications [101]. Concern over antibiotic resistance is now widespread. The rise of MDR bacteria poses a danger to the therapeutic efficacy of several currently available medications. Treatment relies heavily on the use of plant extracts and phytochemicals, both of which have well-known antibacterial effects [103]. In order to survive and thrive in the natural environment, plants produce a variety of biologically active substances that shield them from pests, abiotic stress and disease infections [104]. In developed and developing nations, there is increased interest in medicinal plants due to their potential to cure infectious diseases [105].
3.1 Pharmacological activities of secondary metabolites
Secondary metabolites perform biological activity that neutralizes bacteria or animal cells by interacting with specific targets within those structures. However, the variety of metabolic routes that plants take to produce these metabolites ensures the presence of unique structures in these defense molecules that can be used to create new medications and pharmaceuticals. Because of this, plants are a significant source of compounds that can be utilized to enhance health and/or treat ailments [94]. Secondary metabolite chemicals found in many plants such as phenolics, alkaloids, carotenoids, and anthocyanins that accumulate in vegetables and fruit, may act as antioxidants. Antioxidants have the potential to lessen the oxidative and structural harm brought on by free radical molecules, and they are crucial in the prevention of cancer, the slowing of aging, UV protection, and the reduction of tissue inflammation in maintaining human health [105].
The antibacterial action of polyphenols is based on their capacity to prevent the development, reproduction, respiration, and any other essential function of microbes. This effect is caused by the oxidation of particular enzymes, which also inhibit several vital processes like respiration. Additionally, it has been claimed that polyphenols inhibit the creation of proteins in bacteria by binding to DNA chains. According to some scientists, certain polyphenols may be able to rupture the cell walls of microorganisms, leading to cell apoptosis. Due to their lipophilic character, monoterpenes are also known to interact with the phospholipids found in the cell membranes of numerous bacteria [94].
The most common characteristic for bacteria to live in an unfavorable environment are bacterial biofilms. Due to their high antibiotic tolerance, biofilms are one of the causes of chronic, nosocomial, and medical device-related infections, which present a significant challenge to the healthcare system. Several plant-derived substances, including phenylpropanoids, terpenoids, betulinic and ursolic acids, and alkaloids, such as berberine, indole, and chelerythrine, exhibited anti-biofilm activity toward
3.2 Mechanism of action of secondary metabolites
Secondary metabolites can affect the microbial cell in a variety of ways, including disruption of the cytoplasmic membrane’s efflux system, interaction with membrane proteins, impacting DNA/RNA synthesis and function, impairing enzyme synthesis, causing cytoplasmic constituents to coagulate, and interfering with normal cell communication (quorum sensing) [106]. Terpenoids, alkaloids, and flavonoids are some of the substances that are currently utilized as medications or dietary supplements to treat or prevent a variety of illnesses like cancer. According to estimates, 14–28% of higher plant species are used medicinally, and research into ethno-medical plant use led to the discovery of 74% of pharmacologically active plant-derived components [108].
As a result, we are aware that the alkaloids have the capacity to intercalate with DNA, interrupting transcription and replication, and that they can also suppress cell division, leading to cell death. For instance, when
3.3 Potential of natural products for combating AMR
The chemistry of natural drug products versus synthetic pharmaceuticals differs greatly, with natural products having a wider diversity of chemicals. The nitrogen, phosphorus, sulfur, and halogen content of natural products is lower, while their structural complexity, scaffold variation, stereochemistry, ring system diversity, and carbohydrate content are increased [106]. Compared to current antibiotics, crude extracts from medicinal plants have proven to be more therapeutically efficacious and less harmful. The defense against free radicals and pathogenic bacteria is greatly aided by phytochemical substances, particularly flavonoids and other natural compounds. In order to tackle infectious disorders linked to drug-resistant microbes and oxidative stress, there is a compelling need to investigate new and more effective antimicrobial/antioxidant substances of natural origin [107].
Natural plant extracts have a lower likelihood of developing resistance since they include numerous and complex phytochemicals [109]. A single plant contains a variety of phytochemicals so plant extracts can fight infections in a variety of ways.
4. Future perspectives
Some antimicrobial metals kill MDR bacteria and selectively disrupt metabolic pathways [112]. Metal nanoparticles have the potential to threaten bacterial survival and antimicrobials containing silver can impact physical stress on cells of bacteria [113]. Also, gallium can interfere with the metabolic pathways of bacteria [114]. Genetically engineered bacteria can be used to target pathogens. A good example is the use of
5. Conclusion
Antibiotics have played a crucial role in medicine by reducing morbidity and mortality rates. Without antibiotics, some successful aspects of modern medicine may not have been achieved. However, the inappropriate use of antibiotics has resulted in to the development of AMR. This poses a threat to human health, global economy, and sustainable development. World Economic Forum and WHO have labeled AMR as a matter of global public concern and many nations have taken stance on tackling this menace. This has led to increased efforts to tackle the challenge of AMR. AMS has been identified as one of the methods of reducing AMR. The method is focused on preventing unnecessary use of antibiotics in order to prevent the occurrence of AMR. Some of the objectives of the ASPs are: reducing antibiotic use and lowering healthcare costs. Multidisciplinary teams are used to champion the ASPs and pharmacists play crucial roles in these teams. Another way to tackle AMR is the development of new antibiotics. Plants have contributed immensely to healthcare delivery across the globe since prehistoric times. Bioactive secondary metabolites have pharmacological functions for treating diseases and they possess the potential to contribute to tackling AMR. The study also highlights future perspectives that should be considered in combating AMR.
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