Antimicrobial Stewardship Optimization: Comparison
Please note this is a comparison between versions V1 by Md. Habibur Rahman and V2 by Jason Zhu.

Antimicrobials are a type of agent widely used to prevent various microbial infections in humans and animals. Antimicrobial resistance is a major cause of clinical antimicrobial therapy failure, and it has become a major public health concern around the world. Increasing the development of multiple antimicrobials has become available for humans and animals with no appropriate guidance. As a result, inappropriate use of antimicrobials has significantly produced antimicrobial resistance. However, an increasing number of infections such as sepsis are untreatable due to this antimicrobial resistance. In either case, life-saving drugs are rendered ineffective in most cases. The actual causes of antimicrobial resistance are complex and versatile. A lack of adequate health services, unoptimized use of antimicrobials in humans and animals, poor water and sanitation systems, wide gaps in access and research and development in healthcare technologies, and environmental pollution have vital impacts on antimicrobial resistance.

  • antimicrobial resistance
  • human
  • infection
  • sanitation

1. The Natural History of Antibiotics

In 1947, S.A. Waksman characterized the expression “antibiotic” as follows: “A chemical material, which is produced by microorganisms, is an antibiotic that keeps back bacteria and other microorganisms, and even kills them” [1][21]. In a real sense, antibiotics signify “against life”; for this situation, against organisms. There are numerous anti-infection agents: anti-bacterial, anti-viral, anti-fungal, and anti-parasitic [2][22]. Nowadays, “antibiotic” has innumerable implications: (I) an organic compound of synthetic or natural source that restrains or kills pathogenic microscopic organisms; (II) any antimicrobial compound, or (III) restricted to microbial substances of microbial origin in the Waksman convention [3][23].
1928: Alexander Fleming found the main anti-microbial, penicillin. In any regard, penicillin was controlled for more than 10 years before it was introduced as a microbial illness therapy [4][24]. The 1930s: The first widely used antimicrobial was Prontosil, a sulfonamide synthesized by German organic biochemist Gerhard Domagk [5][25]. 1945: Penicillin was initially used to treat bacterial infections on a large scale. Florey and Chain’s attempts to refine the antibiotic and scale-up manufacturing made this feasible. 1940–1962: The golden era of antibiotics. The largest number of antibiotic classes that we are using today as antimicrobials were established and familiarized with the market. Each class usually comprises a few antimicrobials that have been discovered over time or are modified adaptations of previous types. There are, for instance, various β-lactams (articulated beta-lactams), for example, multiple penicillin and cephalosporin [24].

2. Resistance to Antibiotics

Antibiotic resistance is now becoming a more serious concern around the world. In addition to phenotypically resistant bacteria, isolates with silent but intact antibiotic resistance genes may constitute a great concern. Antimicrobial resistance (AR) can be transferred across bacteria via genetic elements, resulting in the rapid creation of multidrug resistance (MDR) in germs from animals, posing a risk to human health [6][40]. Antibiotic resistance occurs as germs such as bacteria and fungi can destroy antibiotic ingredients. This means that the germs are not killed and are still rising. Contaminations caused by antibiotic-resistant bacteria are difficult to handle and, at times, nonsensical. Antibiotic-resistant infections often necessitate more extended hospital stays, more doctor appointments, and expensive and risky alternative treatments. Resistance to antibiotics does not indicate a body’s resistance to antibiotics because bacteria are immune to the antibiotics meant to kill them [7][41]. Anti-microbials are medications used to prevent and treat bacterial contaminations. Antimicrobial tolerance occurs as microscopic species become resistant to antibiotics because of their application. Antibiotic resistance develops in microbes, not humans or animals. These microbes can infect people or livestock, and the infections they cause are more difficult to cure than those caused by bacteria that are not immune [8][42].

3. Mechanisms of Antimicrobial Resistance

Antimicrobials are specialists who execute or hinder microorganisms’ development and envelop anti-infection agents, antifungals, and antivirals [9][2]. Antimicrobial resistance (AMR) is created when microorganisms adjust and fill within sight of antimicrobials, when delivering therapy with an antimicrobial medication [9][10][2,59]. The elements prompting AMR are complex and multifactorial. Resistance happens because of a characteristic developmental cycle that outfits the microorganisms with mechanisms to balance the antimicrobials’ impacts. Antimicrobial resistance can occur, for instance, when an organism develops an enzyme that wrecks the medication in a straightforward manner (for example, β-lactamases, which corrupt β-lactam antimicrobials) [11][60]. Antibiotics that follow up on the cell wall by restraining peptidoglycan synthesis incorporate β-lactams and glycopeptides. β-Lactams include penicillin, cephalosporin, monobactams, and carbapenems [12][61]. Antimicrobial resistance mechanisms are classed into four main categories: (1) limiting uptake of a drug; (2) altering a drug target; (3) inactivating a drug; (4) active drug efflux [13][26].

4. Relationship between Antibiotic Use in Animals and Antibiotic Use in Humans

Antibiotics are primarily used in animals for three purposes: surgical treatment of sick animals, prophylactic infection prevention, and growth promoters to increase feed use and development. However, preventive therapy entails treating human animals with antibiotic doses that surpass the pathogen’s minimum inhibitory concentration for a limited period. In addition, therapeutic medication is often given to intensively farmed livestock in the form of feed or drinking water; however, because sick animals may not drink or eat, this procedure can be unsuccessful in some situations. Furthermore, prophylactic therapy includes giving a group of animals low to heavy doses of antibiotics in their feed or drink for a set amount of time. Antibiotics used as growth promoters are often fed to whole herds and flocks at sub-therapeutic doses for long periods and are available over the counter from feed producers and growers [14][15][64,65].

5. Development of Antimicrobial Resistance in Human and Animal Healthcare

Antimicrobial resistance poses severe threats to human and animal healthcare. The speedy elevation and expansion of resistant microbes and ARGs in populations, animals, and the climate is regarded as a severe global issue [16][66]. Fundamentally, resistance emerges from a natural evolving phase that assists microorganisms with pathways to combat the antimicrobials impact [11][60]. Antimicrobial resistance tries to intimidate to overturn the progress of antimicrobials with modern medications [17][67]. Antibiotic resistance is caused by excessive usage and improper usage (inappropriate selections, insufficient dosing, and unclear obedience to medication guidance). However, human medication in the population and clinics, in animal farming and agricultural sectors, and in the environment are the four major sectors that influence the emergence of antibiotic resistance, according to research findings [18][19][68,69]. AMR may lead to increases in-patient death rates and the duration of hospitalized stay and has numerous social and financial consequences. Any drug-resistant microbes necessitate physical separation from the community to prevent infection, resulting in lost work and family periods for patients. Additionally, the patient could be charged with further physician visits and hospitalization, as well as potential second-line therapies, laboratory examinations, and other diagnostic expenses [20][21][3,70].

5.1. New Antibiotics

Plazomicin is a chemically synthesized aminoglycoside [22][71] that inhibits bacterial protein synthesis and has dose-dependent bactericidal efficacy in vitro [23][72]. Plazomicin was certified by the FDA in 2018 for the treatment of cUTI and pyelonephritis at a dosage of 15 mg/kg IV, QD. The FDA package insert for plazomicin mentions nephrotoxicity and ototoxicity as potential adverse effects. Plazomicin is more effective than other aminoglycosides against colistin-resistant Enterobacterales (including those with MCR-1 genes), with 89.5% of isolates susceptible (compared to amikacin, gentamicin, and tobramycin, which are effective against 16.8%, 47.4%, and 63.2 percent of isolates, respectively) [24][73]. In two clinical studies, plazomicin 15 mg/kg IV, QD was compared to meropenem 1 g IV, TID [25][74], and levofloxacin 750 mg IV, QD in patients with complicated urinary tract infections (UTI) for up to 10 days [26][75]. Eravacycline is a tetracycline-class fluorocycline. It suppresses bacterial protein production, just like other tetracyclines. Eravacycline was authorized by the FDA in 2018 for the treatment of cIAI at a dosage of 1 mg/kg IV, BD for a total of 4 to 14 days. According to surveillance studies [27][84], eravacycline is active against E. coli (MIC50/90: 0.12/0.5), including ESBL E. coli (0.25/0.5), and K. pneumonia (0.25/0.5), including ESBL K. pneumoniae (0.06/0.5) [27][84]. Temocillin is a derivative of ticarcillin, a penicillin antibiotic that primarily targets PBP3 and was developed and marketed in the United Kingdom in the 1980s, but was quickly abandoned due to its lack of activity against Gram-positive bacteria, non-fermenters (such as A. baumannii and P. aeruginosa), and anaerobes [28][85]. Given the increasing prevalence of infections caused by Enterobacterales that are resistant to third-generation cephalosporins, there has been increased interest in this antibacterial drug in recent decades as a carbapenem-sparing alternative. ESBL and AmpC do not affect temocillin, whereas OXA-48 and MBL do [28][29][30][31][85,86,87,88]. Cefiderocol is a catechol-substituted siderophore that has recently been discovered [32][89]. In 2019, the FDA authorized it at a dosage of 2 g IV. Cefiderocol has a MIC50/90 of 2/8 mg/L for Enterobacterales with ESBL and AmpC [33][90]. It is active against >90% of Enterobacterales isolates. It also kills over 90% of Acinetobacter spp. and Pseudomonas aeruginosa isolates [34][91], including carbapenem-resistant strains [35][92]. E. coli and Klebsiella spp. were the most frequent pathogens in this investigation (There was no information supplied on their sensitivity to third-generation cephalosporins), with P. aeruginosa accounting for 7%. A recently published RCT compared cefiderocol 2 g IV, TID in 145 patients with meropenem 2 g IV, and TID in 146 nosocomial pneumonia patients and found similar mortality at day 14, 12.4% vs. 11.6% [36][93].

5.2. Beta-Lactam/Beta-Lactamase Inhibitor

Antibiotics that combine a cephalosporin or carbapenem antibiotic with a beta-lactamase inhibitor are listed below (BLI). The companion beta-lactam antibiotic can reach its objective, penicillin-binding proteins, via inhibiting beta-lactamases (PBPs). Tazobactam (partner to ceftolozane), avibactam (to ceftazidime), vaborbactam (to meropenem), and sulbactam are the BLIs that are coupled with the novel beta-lactam antibiotics described here (to imipenem-cilastatin). Another example is the use of sulbactam, which boosts imipenem’s action against most Enterobacterales (lowering the MIC by 2- to 128-fold) and P. aeruginosa (lowering the MIC by 8-fold) [37][94]. The addition of vaborbactam decreases the MIC 2- to > 1024-fold and increases meropenem’s effectiveness against most Enterobacteria species [37][94]. Ceftazidime/avibactam was authorized by the FDA in 2015 for the treatment of cIAI (in combination with metronidazole) and cUTI at a dosage of 2.5 g IV, TD, and was later extended to HAP/VAP in 2018. Ceftazidime/avibactam had similar potential adverse effects to ceftazidime alone, according to the FDA package insert. Ceftazidime/avibactam has the most clinical evidence among the “novel” antibiotics discussed in this paper. It was proven to be non-inferior to the best-available medication (mainly carbapenem) in treating cUTI caused by ceftazidime-resistant Enterobacterales and Pseudomonas aeruginosa [22](Table 1) [71]. Approximately 10% of the participants in this trial had cIAI. Ceftolozane/tazobactam is a combination of antipseudomonal cephalosporins and BLI tazobactam. In 2014, the FDA authorized this antibiotic combination (brand name Zerbaxa) for cUTI and cIAI indications at a dosage of 1.5 g IV, TD. In 2019, the indication was expanded to include HAP/VAP. Ceftolozane has already been shown to be effective against ESBL Enterobacterales and carbapenem-resistant P. aeruginosa [38][95]. Its effectiveness against carbapenem-resistant Acinetobacter spp. [39][96] and Enterobacterales [40][97] is modest. Meropenem/vaborbactam (Vabomere) was authorized by the FDA to treat cUTI at a dosage of 4 g (meropenem 2 g and vaborbactam 2 g) IV, TD. Carbapenem-resistant Enterobacterales, especially those that contain KPCs, benefit from the addition of vaborbactam. However, as previously stated, it has little activity against MBL and OXA-positive isolates [41][98]. Meropenem’s action against A. baumannii and P. aeruginosa is unaffected by the addition of vaborbactam [37][94].

6. Alternatives to Antibiotics

Antibiotic overuse in people and animals has contributed significantly to the rise of AMR and has also resulted in the buildup of these substances in the environment by selecting resistant bacteria and transforming the environment into a vast reservoir for AMR genes [42][99]. Furthermore, the abuse of antibiotics in animal production, as well as the EU restriction on their use in feed (Regulation EC/1831/2003), has resulted in a rise in the incidence of livestock disease and economic loss. Antimicrobial peptides are among the most effective antibiotic substitutes. Due to their capability to heal bacterial infections, especially those induced by multidrug-resistant diseases, many antimicrobial peptides have been reported, with varied activity spectra and mechanisms of action. Hundreds of AMPs have been found to exhibit antibacterial action in vivo against bacteria that are resistant to antibiotics [43][100]. A new piscidin-like peptide from black sea bass fish was recently revealed to have broad-spectrum antibacterial action against many bacteria, particularly Gram-positive infections [44][101]. Similarly, jelling-I, a tiny AMP made up of eight amino acids, kills Gram-negative and Gram-positive bacteria by compromising the cell membrane’s integrity [45][102]. Furthermore, another new defensin-like peptide with an antibacterial action against Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus carnosus, Nocardia asteroides, and one Gram-negative bacterium, Psychrobacter faecalis, was recently reported [46][103]. Antimicrobial lipids, such as medium-chain fatty acids (MCFAs) and monoglycerides, might be used instead of antibiotics. MCFAs are a key component of the innate immune system in mammalian breast milk, skin, and mucosa, and they can trigger the development of host defense peptides in humans and animals [47][104]. The antibacterial activity of lauric acid (LA) and its monoglyceride derivative, monolaurin (glycerol monolaurate, GML), is the greatest among MCFAs. Although the positive effects of MCFAs and LA are progressively becoming acknowledged, nothing is known about their content in insects. Because of their outstanding nutritional characteristics and possible impacts on animal health, insects have recently received a lot of interest as new alternative feed additives.

7. Regulate the Sale and Use of Antibiotics through Prescription

In 1997, the worldwide interest in anti-toxins was USD 17 billion (GBP 10.6 billion), with around 818 billion remedies for respiratory plot contaminations. While the market is increasing in size (it was USD 15 billion in 1993), the quantity of treatments remains the same. Nonetheless, in the period 1980–1991, the all-out ascent in anti-microbial solutions in England was 46%, which was still lower than the pace of development in France [48][49][115,116]. The rise in anti-microbial costs could be impacted by various factors [49][50][51][116,117,118]. Two attributes of anti-toxin recommendation have appeared to raise the danger of obstruction choice, specifically the utilization of too few dosages or too long treatments [52][119]. The terrible implementation of the utilization of profoundly specific specialists presently cannot seem to be resolved as far as their natural impacts. Seventy-five percent of populace remedies are for respiratory infections [50][51][117,118]. The most widely recognized explanation for these is tonsillopharyngitis, along with bronchitis. Anti-microbials are given to around 90% of tonsillopharyngitis patients in both France and the United Kingdom. This creates 9 million solutions in France each year. The conference rate in France is several times that of the United Kingdom [49][50][116,117]. A quick indicative test for bunch A streptococci with 90% affectability is available [53][120]. However, it is not generally utilized and is not covered by the French medical care framework. For this reason, 35% of patients have been polluted with bunch A streptococci [54][121]; a fast test may save around 6 million anti-toxin solutions.

8. Global Action Plan on Antimicrobial Resistance

Procedures that are crucial for healthcare services would be inaccessible or dangerous without antibiotics, as detailed by the WHO [55][122]. Critical operations, cancer care, and prophylaxis during cesarean are examples of facilities that can no longer be administered efficiently without appropriate antibiotics. The foundation for improving WHO health programs recognize the building blocks of a healthcare system relating to administration, funding processes, medications and technology, health information programs, human resources, and the provision of health services [56][123]. With the scale and intensity of the antimicrobial resistance challenge, there has been some improvement in developing national initiative plans by member countries of the WHO [57][124]. The overarching aim of the action strategy is to assure the potential to cure and avoid contagious diseases by reliable and secure, quality-assured drugs, which are used sensibly and are available to anyone that needs them, and this should be continued as long as possible [58][125]. Antibiotics can be used in favor of better animal breeding methods to develop growth and prevent disease progressively. For each human and animal medication, it is necessary to gain even more knowledge of the extent of resistant strains and the usage of antibiotics. Public health services must optimize their use of antibiotics to decrease the impact of the disease. In line with the objectives for sustainable improvement, the focus should be put on improving sanitation and the availability of safe water, promoting handwashing habits, and better protection and treatment of infection in clinics [59][126].

9. Role of Pharmacists in Combating Resistance to Antimicrobials

Pharmacists are critical participants of the healthcare system and play a vital role in using medications and the delivery of medical guidance [60][127]. They are in an excellent position to recognize antibiotics better and educate their intelligent use in society and hospitals through direct communication with the patient [61][62][128,129]. The utilization of antibiotics among medical practitioners, patients in the various areas of the care community, and the general consumers is one of the significant results of improved pharmacists’ responsibilities [63][130]. Hospital pharmacists can supervise the clinical setting by controlling compliance with common treatment protocols, including the appropriate antibiotics prescribed by physicians through their formulation and testing [64][65][131,132]. In the context of antimicrobial stewardship, pharmacists and nurses can cooperate successfully to minimize antimicrobial usage and fight antimicrobial resistance [65][132]. Community pharmacists could convince patients that antibiotics are ineffective for viral infections, and they could suggest people consult with a registered physician for alternative therapy for a mild infection. They should be diligent in compliance with legislation and not allow antibiotics to be sold over the counter [64][131]. Academic pharmacists play an important part in teaching pharmacists and other medical professionals about the appropriate use of drugs and the concept of antimicrobial stewardship [66][133]. Pharmacists could also develop national legislation, regulations, and directives that encourage the proper use and application of antimicrobials, where available [67][134]. They could, in turn, cooperate in the development and facilitation of training and behavioral actions that help the appropriate use of antimicrobials with the support of society and health professional groups.

10. Types of Intervention

Interventions usually fall into six different categories: norms and standards (acknowledgment, directives, public scrutiny, limit OTC sales, control of prescription); information interventions (observation, response); support for decision-making (algorithm, etiology); sequence of distribution (decentralized supply, delivery of medications); economy (financial support, strategic pricing, wellbeing insurance); and management processes (necessary policy on medicine, programs for stewardship) [68][135]. The more successful they are when they plan the interventions, compared to a national facility or level, the closer they are geared towards the supplier/prescriber of antibiotics. It is also necessary to realize how one intervention can affect other circumstances. Persuasive intervention: Persuasive intervention is used to disseminate education services, to remember, audit, and discussion or educational provision. The ongoing training of medical professionals will help keep workers up-to-date, educate them about policies and improvements to pharmacotherapy, and encourage them to express perspectives and learn from discussions with their peers [69][136]. Passive education should preferably be paired with active interventions; passive education yields only modest results as an independent program [70][71][137,138]. Restrictive intervention: Restrictive interventions are initiatives that restrict the prescriber’s freedom to select such antibiotics. For example, targeted antibiotics may require approval by a specialist in infectious diseases and may be replaced by a pharmacist or be fully limited in the treatment [72][73][74][139,140,141].

11. Prescribing and Intervention Context

A few investigations depicted the context of interventions to deal with the availability of antibiotics in medical clinics, primary care, and pharmacies, including public, private, and casual suppliers. Some studies concentrated on drug stores, local-area drug specialists, and informal doctors in villages [68][135]. A better and faster decision by medical professionals associated with drug prescription may lead to substantial patient outcome changes and better use of healthcare costs. While there have been recent changes in the spread of evidence in practice, the prescription practice of medical professionals tends to differ. Due to this variance and the ability to damage the reputation of new medicines that often have a minimal benefit compared existing treatments [142], we must understand which interventions in the change of prescription are successful in improving patient results, thus minimizing healthcare costs [143].

12. Knowledge of Antimicrobial Resistance and Appropriate Antibiotics Use

Antibiotics have become a productive and proactive tool against many pathogens over the last four or five decades. The growth of antibiotic-resistant and propagated pathogens in the community is a significant problem globally that poses an important public health danger, particularly in developing areas, in the current era [75][76][144,145]. Concepts as to why and what should be done with antibiotic resistance are not the most significant basis for developing interventions to change prescriber execution in antibiotic prescriptions. A conceptual approach is required to choose and execute the procedures to change the medication [77][146]. The leading causes of antimicrobial resistance increase and spread may be self-medication, illegal prescription, improper use, and unnecessary use of such antimicrobial drugs [78][79][80][147,148,149]. This rise in antibiotic resistance gradually decreases their therapeutic efficacy and leads to more severe diseases with higher death rates. It will place a heavy strain on the global economy and various healthcare organizations [81][150]. Many studies accurately found that antibiotics had been appropriately administered to treat bladder or urinary tract infections (72% where n = 93), skin or wound infections (67% where n = 87), and gonorrhea (39% where n = 51) [82][151].