Before the development of antibiotics, an infection could more often than not lead to critical illness, loss of a limb or even death. Common infections could potentially be deadly or life threatening. However, the development of penicillin changed the trajectory of the human race and the ability to survive infections. This has allowed for new possibilities and a brighter future[1]. Penicillin also paved the way for newer antibiotics and had a direct impact on life expectancy. Some studies have shown that the average life expectancy prior to antibiotics was forty-seven. Through the use of antibiotics, life expectancy increased significantly[2]. Furthermore, after the development of antibiotics, the leading cause of death shifted from communicable disease (infectious diseases) to non-communicable disease (cardiovascular disease, cancer, and stroke)[3]. With many deadly infectious diseases now curable, there was no question as to why penicillin was initially hailed as a “miracle drug.”[4]
When penicillin came to the market, it was used broadly and was capable of treating many types of infections, including sexually transmitted, skin and soft tissue, respiratory, and blood stream infections as well as many other diseases. The utilization of penicillin during World War II had a profound impact on saving the lives of American soldiers as it was capable of treating a variety of diseases that those in combat might face, such as blood stream infections (sepsis) or infections secondary to injury (wound infections) and surgical operations (post-surgical infections)[5].
Penicillin’s success and excellent track record prioritized the commercial production of this compound, which lead to 4 million sterile packages of penicillin per month during World War II[6]. However, as the use of penicillin intensified and rose to meet the demand of the peoples’ need for a miracle, an almost paradoxical phenomenon had occurred, known scientifically as antimicrobial resistance. A bacteria’s ability to survive, now depended on outmaneuvering its newly introduced arch nemesis, penicillin. This is a naturally occurring biological mechanism and part of an evolutionary process that empowers bacteria to adapt and subsequently survive. Natural selection of more resistant bacteria was inevitable. This means that bacteria that are resistant to penicillin survive and multiple, while the more sensitive bacteria, or bacteria inhibited by penicillin, diminished resulting in more dangerous untreatable bacteria. Many of the ways bacteria “learned” to survive was through development of antibiotic resistance genes harbored by the bacteria. When a bacteria mutated and developed these resistance genes, it was now resistant. Further exacerbating this was the ability of microbes to share their newly learned defense mechanisms with other bacteria, spreading resistance rapidly and dangerously.
In an almost ironic and prophetic prediction, the concept of antibiotic resistance was noted by the creator of the miracle drug, Alexander Fleming[7]. In 1945, in an interview with a major national newspaper, Alexander Fleming warned the world that the misuse of penicillin could lead to antimicrobial resistance, quoted infamously: “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism.[8]”
Close to eighty years after penicillin was first introduced, antimicrobial resistance has intensified to an unprecedented level. Even newly developed antibiotics cannot escape bacteria’s ability to evade and survive. The media refers to these highly resistant microbes as “superbugs,” capable of defying even the most powerful antibiotic. The Centers for Disease Control and Prevention (CDC) notes that 2.8 million antibiotic-resistant infections occur in the U.S. each year with more than 35,000 people dying as a result[9]. Side effects of antibiotics such as Clostridioides difficile lead to an additional 3 million infections with 48,000 deaths. In addition to the CDC, the World Health Organization (WHO), and the United Nations (UN) have now identified antimicrobial resistance as a global and public health concern. The WHO has implemented the Global AMR response in an effort to combat this rising threat[10]. The UN has warned that if no action is taken, drug resistance disease can lead to 10 million deaths by each year by 2050 and force up to 24 million people into extreme poverty by 2030[11]. Furthermore, the CDC estimates the cost of antimicrobial resistance is $55 billion every year in the United States ($20 billion for health care and about $35 billion for loss of productivity)[12] [13] [14].
One of the most alarming statistics published by the CDC is that roughly 1 in 3 antibiotics, or 30 percent shouldn’t have been prescribed in the first place. When taking into consideration in appropriate antibiotic selection, dosing, and duration, in appropriate prescribing may be as high as 50 percent[15]. This translates to 47 million excess prescriptions each year[16]. According to the CDC 98% of infections, such as rhinitis and sinusitis are viral, in which case antibiotics would not be effective in treating. However, these infections are often treated with antibiotics, exacerbating antimicrobial resistance[17]. Although there are many other contributors to antimicrobial resistance the most striking contribution is misuse of antibiotics by highly trained healthcare providers, especially in the United States[18]. Clinicians are expected to practice medicine within the confines of evidence-based practice guidelines. It is therefore, odd to see prescribing habits as it pertains to antibiotics, off base, and inappropriate.
Addressing the underlying cause for inappropriate and poor antibiotic prescribing is complex and is multifactorial. Why is it, despite outstanding evidence on the indications and appropriate utilization of antibiotics, do we find close to 50 percent of antibiotic use is either unnecessary or used inappropriately [19] [20] [21]? Possible reasons for this behavior include lack of education specific to infectious disease, the tradition of prescribing as opposed to evidence- base prescribing, cognitive influences such as defensive medicine and fear of liability, time constraints and pressure by the patient, fatigue and burnout, as well as misinformation.
An extensive review of the literature addressing the possible reasoning behind overprescribing antibiotics by healthcare providers using tools such as PubMed, Google Scholar and statistical data published by the CDC, found that the root causes for this problem can be established, which may in turn, provide opportunities for strategic interventions to change the prescribing habits of clinicians.
It is estimated that one percent of physicians report that they are infectious disease physicians[22] [23]. When including midlevels such as nurse practitioners and physician assistants, this percentage is even lower. Furthermore, according to researchers, close to 80 percent of counties in the United States do not have a single infectious disease specialist[24]. It is, therefore, easy to postulate that lack of infectious disease expertise in most areas in the United States, can ultimately lead to inappropriate antibiotic prescribing, due to insufficient guidance on how to diagnosis and treat infectious diseases.
Another possible cause for overprescribing antibiotics, is the disregard for the underlying evidence and a tendency to rely on tradition or non-evidence-based practices. In an article published by BMJ Open, primary care physicians admitted to prescribing medications outside of evidence-based guidelines due to heavy workload, and lack in training and support from their respective institutions. Clinicians in this study also admitted to having the lack of knowledge and skills in searching and applying evidence to make clinical decisions[25]. Furthermore, according to an article published by The American Family Physician, may clinicals have misconceptions about evidence-based medicine, referring to it as “cookbook” medicine and inflexible. The article also notes that clinicians’ inability to determine what evidence-based medicine is, and how to distinguish it from other claims made by researchers is also problematic[26]. It is apparent that many clinicians do not rely on evidence-based medicine to make clinical decisions, and subsequently may prescribe antibiotics subjectively.
Defensive medicine, or the practice of medicine in a way to minimize risk of medical malpractice liability, is also a driver in inappropriate antibiotic prescribing. A recent article published in Antimicrobial Resistance & Infection Control in 2019, divides determinants of antibiotic prescribing into intrinsic and external categories. Intrinsic determinants include understanding the evidence and attitudes towards evidence-based prescribing as noted above. This also includes qualifications and expertise, and years in practice. External determinants include other considerations, such as patient expectations[27]. Many studies have been published that conclude that patient expectation to receive antibiotics may influence the prescriber and inadvertently or intentionally lead to overprescribing, despite the evidence to prescribe in that scenario[28]. Furthermore, time constraints, high workload, and the expectation to see as many patients as possible in a given timeframe, can also result in doctors pursing the path of least resistance, which in many cases, is prescribing antibiotics rather than taking the time to explain why it may not be indicated[29]. It is also important to note, that patient satisfaction is directly correlated with the likelihood of medical malpractice suits being brought against the clinician[30]. Many clinicians may feel compelled to prescribe, in order to satisfy the patient, and avoid complaints[31]. Fear of bad reviews by the patient, and fear of “playing it safe” may lead to irrational antibiotic prescribing.
Another important factor in overprescribing antibiotics is the impact of physician burnout. Physician burnout refers to physical and mental exhaustion, depersonalization and lack of efficacy expressed by physicians, typically due to excessive hours spent, and dissatisfaction in work related expectations[32]. In an article published by BMJ Open, researchers concluded that burnout is correlated with increased defensive medicine and the likelihood of overprescribing[33].
Lastly, and arguably one of the most important factors behind physician overprescribing, is misinformation. This was especially exemplified during the outbreak of COVID-19. Clinicians were quick to prescribe antibiotics for COVID-19 when the evidence was clearly lacking. This included hydroxychloroquine and azithromycin, which many clinicians believed had activity against this virus, as well as ivermectin. Clinicians were misinformed of the evidence of these antimicrobials in the setting of COVID-19. Some literature demonstrated benefits of these antimicrobials, however only in a limited case by case scenario, such as coinfections with COVID-19 and other pathogens[34] [35]. Other literature showed benefit of these antimicrobials but were poor studies that could not be generalized. However, many healthcare providers were misinformed of the limitations of the studies that showed benefit of using these antimicrobials and instead assumed the evidence was sufficient. It is therefore no surprise that the CDC notes that, “experts are concerned that the pandemic could undo much of the nation’s progress on antibiotic resistance, especially in hospitals”[36].
It is unfortunate, that a large contributor to antimicrobial resistance, is caused by so many dedicated to helping others. As demonstrated, the reason why healthcare providers often overprescribe is complex, and second to multiple factors. As this issue progresses, and resistance exacerbates, hopefully more light will be shed on the determinates of this problem, so that serious solutions can be put in place, which will lead to a pathway to a safer future.
About the Author
Dr. Ari Frenkel is a board certified infectious disease and internal medicine physician. His experience includes medical director of infectious disease for RCCH (Regional Care Partners), a corporate hospital system that had 14,000 employees and 2,000 doctors across 16 hospitals throughout the United States. Dr. Frenkel also served as a medical director in the nursing home and rehab setting and is well versed on infectious diseases pertaining to long term care. Due to the rising global threat of antimicrobial resistance, Dr. Frenkel dedicated his career to solving this predicament. He co-founded Arkstone Medical Solutions, a biomedical technology company that uses artificial intelligence and machine learning to democratize infectious disease expertise across many clinical settings. Using this technology, thousands of physicians and healthcare facilities now have access to the tools they need to provide antimicrobial stewardship and better care to their patients.
References
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