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Antimicrobial resistance (AR), the phenomenon whereby microbes gradually develop resistance to agents used to eradicate them, is rapidly becoming a severe and urgent threat to global public health. Thanks to AR, a wide range of infections – even those once considered routine – are developing ultimately life-threatening potential by becoming increasingly difficult to treat until eventually untreatable, and consequently rates of healthcare-associated infections (HAIs), morbidity and mortality are increasing. Unfortunately, as AR rises and our arsenal of antimicrobial weaponry falls, some of the greatest achievements of modern medicine – such as organ transplantation and other complex surgeries, as well as cancer chemotherapy – may be invalidated.
By Elizabeth Srejic
Antimicrobial resistance (AR), the phenomenon whereby microbes gradually develop resistance to agents used to eradicate them, is rapidly becoming a severe and urgent threat to global public health.1 Thanks to AR, a wide range of infections – even those once considered routine – are developing ultimately life-threatening potential by becoming increasingly difficult to treat until eventually untreatable,2-3 and consequently rates of healthcare-associated infections (HAIs), morbidity and mortality are increasing.4-5 Unfortunately, as AR rises and our arsenal of antimicrobial weaponry falls, some of the greatest achievements of modern medicine – such as organ transplantation and other complex surgeries, as well as cancer chemotherapy – may be invalidated.6
Resistant microbes, along with antimicrobial drugs, are wending their way into a variety of settings and reservoirs – humans, flora, fauna, industry and environment, to name a few – where they provoke resistance by indiscriminately pressuring pathogenic and benign microbes.7-8 Healthcare facilities, in particular, are becoming “breeding grounds” for increasingly tenacious pathogens9 and major distributors of antimicrobial agents that spread readily via a variety of vectors and vehicles.
Unfortunately, worsening AR is stoking the emergence of “superbugs,” or strains of bacteria that resist more than one type of structurally unrelated drug.10 Superbugs, which are among the most dangerous microbes becoming resistant to drugs, infect more than 2 million people nationwide and kill at least 23,000 individuals each year, according to the Centers for Disease Control and Prevention (CDC).11
“It’s not hyperbole/overstatement to say that the threat of AR is one of the most serious problems facing not only the United States but really the world,” says Arjun Srinivasan, MD, associate director for healthcare-associated infection prevention programs in the Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases. “Being unable to treat infections threatens the lives of hundreds of thousands of people who acquire pneumonia, urinary tract (UTIs) and other common infections in the United States every year. And consider how dependent we are upon antibiotics for surgery – from routine procedures to advanced surgeries like organ transplantation – and to care for patients who are undergoing immune suppressive therapies like cancer chemotherapy or bone marrow transplant therapies. AR and an inability to treat infections really puts at risk not just the lives of patients who get common infections, but really fundamentally threatens our ability to deliver the type of medicine that we’ve come to take for granted today.”
Terms describing microbial resistance to drugs are technically discrete but commonly used interchangeably. “Antimicrobial resistance” refers to drug resistance across different types of microbes (bacteria, parasites, viruses and fungi) as well as the classes of drugs used to eradicate these microbes (antibiotics, anti-parasitics, antivirals and antifungals). “Antibiotic resistance” is a narrower term describing resistance specifically in bacteria (which are killed by antibiotics). Although these two terms differ in scope, both will be abbreviated as “AR” in this article unless otherwise indicated.
Most types of resistant bacteria can be found on the Food and Drug Administration (FDA)'s finalized list of pathogens. This list of "qualifying pathogens" which are identified as having "potential to pose a serious threat to public health,” was released as part of the 2012 Generating Antibiotics Incentives Now (GAIN) provisions of the Food and Drug Administration Safety and Innovation Act (FDASIA), which aims to incentivize the development of new antibiotics by granting companies an additional five years of market exclusivity if they develop an antibiotic intended for a "qualified infectious disease," associated with any of these pathogens.12
The updated and finalized list of pathogens includes: Acinetobacter species, Aspergillus species, Burkholderia cepacia complex, Campylobac-ter species, Candida species, Clostridium difficile, Enterobacteriaceae, Enterococcus species, Mycobacterium tuberculosis complex, Neisseria gon-orrhoeae, Neisseria meningitides, non-tuberculous mycobacteria species, Pseudomonas species., Staphylococcus aureus, Streptococcus agalac-tiae, Streptococcus pneumoniae, Streptococcus pyogenes, Vibrio cholerae, Coccidioides species, Cryptococcus species, and Helicobacter pylori.13 Additionally, other resistant bacterial species cited in the literature include: extended-spectrum β-lactamase- and carbapenemase-producing coliforms such as extended-spectrum β-lactamase-producing Escherichia coli,14 Klebsiella pneumoniae and non-typhoidal Salmonella.15
Antibiotics may be classified as "narrow-spectrum" or "broad-spectrum" depending on the range of bacterial species they affect. Whereas a narrow-spectrum antibiotic targets a specific infection caused by a specific type of Gram-positive or Gram-negative microorganism, a broad-spectrum antibiotic is typically effective against a variety of microorganisms and infections. As such, narrow-spectrum antibiotics are generally appropriate when the causative organism is known, while broad-spectrum antibiotics are frequently used when the causative organism is unknown.16
Since narrow-spectrum antibiotics target specific bacteria, they spare more of the of the body’s normal flora, which means they are unlikely to cause super-infection, or widely contribute to resistance among other species present. However, one drawback of narrow-spectrum antibiotics is that choosing the wrong one will most likely not affect the target organism. Examples of common narrow-spectrum antibiotics are azithromycin, clarithromycin, clindamycin, erythromycin and vancomycin.17
Broad-spectrum antibiotics are useful in treating “super-infections” caused by more than one species, although using combinations of narrow-spectrum antibiotics may also be an effective therapy.18 Broad-spectrum antibiotics may also serve as effective second-line therapies when narrow-spectrum antibiotics fail.19 Furthermore, especially in cases where delaying treatment could be life-threatening, broad-spectrum antibiotics may be more advantageous than narrow spectrum antibiotics as they allow treatment to begin without definitively identifying the infecting pathogen.20 However, this characteristic causes them to be prescribed more often, meaning that they contribute more to AR than their narrow-spectrum counterparts.21
Another reason that broad-spectrum antibiotics contribute more strongly to AR than narrow-spectrum antibiotics is that they kill multiple species; however, they also stimulate all of them to develop resistance mechanisms every time they are used.22 Examples of broad-spectrum antibiotics include amoxicillin, levofloxacin, gatifloxacin, Streptomycin, tetracycline, and chloramphenicol.23
AR occurs in both spectra of antibiotic drugs, which are eventually defined by resistant organisms.24 Both spectra can also indiscriminately at-tack both harmful and beneficial bacteria within the body which disrupts the normal flora and gives opportunistic microbes a chance to establish themselves, which can lead to secondary infections such as Clostridium difficile (C. difficile) infection or Candidiasis.25
Microbes rely upon innate determinants of resistance to survive. These same mechanisms of resistance, which most often arise from genetic mutations, are what allow microbes to develop resistance to drugs; such resistance occurs through development of resistant genes which microbes share with other microbes and even with different species.26 Unfortunately, using antimicrobial drugs causes microbes to more rapidly develop resistance determinants which inhibit their demise.27-31
“When we use antibiotics, we expose bacteria to antibiotics, we select for the bacteria that can’t be killed by those antibiotics,” says Srinivasan. “So by using antibiotics we drive resistance. Many resistance genes can be shared readily among different types of bacteria so that the resistance becomes self-propagating. The bacteria divide, they share the resistance with other bacteria, and this leads to more use of antibiotics: it becomes a vicious cycle toward more and more resistance. And this transfer of resistance can be horizontal, meaning it can happen be-tween animals, between people.”
Through environmental pollution both antimicrobial drugs and resistant bacteria are infiltrating land, companion animals, and food via agricultural and meat production systems.32-33 For example, using antibiotics in feed and to treat infections in livestock has given rise to an increasing number of microbes with resistance to multiple antimicrobials, and fresh produce may be contaminated by irrigation or wash water containing multidrug-resistant bacteria.34 Furthermore, livestock, fruits, and vegetables may also be contaminated by food handlers, farmers, and animal caretakers who carry resistant bacteria.35 As a result, opportunistic human pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and antimicrobial-resistant enterococci have been reported on produce and animal products,36-37 and resistance may be provoked in human gut microbiota and in foodborne bacteria through horizontal transfer of resistance genes.38
Another force that accelerates the development and spread of AR is negligent prescribing practices. Physicians may forgo diagnostic testing when the patient’s clinical signs and symptoms seem sufficient to identify the pathogen involved; also, testing is sometimes skipped because currently available diagnostic tests can delay, prolong, and/or raise the cost of treatment.39-40 Failure to establish the type or types of microbes involved can lead to errors or failures in treatment – including inappropriate or ineffective use of antibiotics. Furthermore, despite repeated warnings, some physicians reportedly prescribe unnecessary courses of antibiotics to pacify patients with viral infections or trivial infections known to typically clear up on their own, or they prescribe broad-spectrum antibiotics when narrow-spectrum choices would be effective. 41-42
“The way we prescribe antibiotics, which are generally known to be significantly overused and misused in hospitals, nursing homes, doctors’ offices, and in every other healthcare setting in which they’ve ever been studied, is a very important driving factor,” says Srinivasan. “What’s most important about this factor, in my opinion, is that it is potentially the most controllable one. Whereas several other factors that drive resistance – how microorganisms mutate, how fast they mutate, how they share genes – lie beyond our influence, our prescribing practices are very much within our power to influence.”
According to Srinivasan, failing to expand and comply with infection control programs is another way that humans accelerate the progression of AR. “The rate at which resistant organisms spread is an area within our influence. We aim to improve prescribing practices to slow the development and spread of well-known and emerging drug-resistant organisms and we also need really strong infection control practices to achieve this.”
According to Lammie and Hughes (2016), policymakers have advised that fighting AR requires a multifaceted, multi-sector approach necessitating political action; funding for research and development; and improved communication, cooperation, and collaboration among professional disciplines, organizations and other stakeholders in human, animal and environmental health.43 And some of the key strategic goals that have been proposed include stronger surveillance systems; antimicrobial stewardship programs (ASPs); infection control programs; developing, approving and producing new antimicrobial agents and vaccines; research and development in novel therapeutic approaches and rapid diagnostic tests; and implementing educational programs that target both professional groups and the public.44
Årdal and colleagues (2016) also called for a rigorous response across multiple sectors: “Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. The World Health Organization (WHO) alone will not be able to drive these actions. It will require a multi-sector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action.”45
Furthermore, Holmes et al. (2016) wrote: “To combat the threat to human health and biosecurity from antimicrobial resistance, an under-standing of its mechanisms and drivers is needed. Emergence of antimicrobial resistance in microorganisms is a natural phenomenon; yet antimicrobial resistance selection has been driven by antimicrobial exposure in health care, agriculture, and the environment. Onward transmission is affected by standards of infection control, sanitation, access to clean water, access to assured quality antimicrobials and diagnostics, travel, and migration. Strategies to reduce antimicrobial resistance by removing antimicrobial selective pressure alone rely upon resistance imparting a fit-ness cost, an effect not always apparent. Minimizing resistance should therefore be considered comprehensively, by resistance mechanism, microorganism, antimicrobial drug, host, and context; parallel to new drug discovery, broad ranging, multidisciplinary research is needed across these five levels, interlinked across the healthcare, agriculture, and environment sectors. Intelligent, integrated approaches, mindful of potential unintended results, are needed to ensure sustained, worldwide access to effective antimicrobials.”46
Srinivasan agrees that a multifaceted, multifactorial approach is necessary to combat AR: “All of these different groups have a critical role to play in combating AR. It is a big enough problem that no one group is going to be able to solve it on their own. Every group will have to play some part in it. On the policy front, policymakers are looking for ways that they can help drive improvements in antibiotic use in human and agricultural medicine, and ways to incentivize development of new drugs including vaccines so that we have new agents to combat resistant infections. Providers in the human, agricultural, veterinary, and other sectors are getting very engaged in our efforts to find the best ways to help improve antibiotic use and infection control. Patients can play a role by becoming informed – knowing when they might need antibiotics, not demanding antibiotics inappropriately – and providers can work with patients to help them understand which types of infections will and won’t be treated by antibiotics, and that antibiotics have certain side effects.”
According to WHO and Dar, et al. (2016), some of the ways that policymakers can do their part on national and international levels include improving surveillance methods that track the extent and causes of resistance; strengthening infection control and prevention policies; regulating and promoting appropriate use of medicines; making information widely available on the impact of AR and how the public and health professionals can help; rewarding innovation and developing new treatment options.47-48
Major political developments in the fight against AR include a global action plan released by the World Health Assembly and in 2015 and a National Action Plan for Combating Antibiotic-resistant Bacteria released by the White House the same year. The global action plan sets out five strategic objectives: to improve awareness and understanding of antimicrobial resistance; to strengthen knowledge through surveillance and research; to reduce the incidence of infection; to optimize the use of antimicrobial agents; and develop the economic case for sustainable in-vestment that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other inter-ventions,49 while the White House’s plan similarly proposes to strengthen national surveillance methods, advance the development and use of “rapid and innovative” diagnostic tests to identify and characterize resistant bacteria, accelerate basic and applied research and development for new antibiotics and other antimicrobial therapies, and improve international collaboration and capacities for AR prevention, surveillance, control and research and development by 2020.50
According to the WHO, clinicians and other healthcare workers can help to fight AR by enhancing infection prevention and control in hospitals and clinics; only prescribing antibiotics when they are truly needed; and prescribing the correct antimicrobial drugs for specific illnesses.51 Educating healthcare personnel may be particularly important among; a 57-study systematic review of clinicians' knowledge and beliefs about the importance and causes of AR and strategies to reduce resistance found most clinicians had heard of AR, 98 percent believed it was serious, 89 percent believed it was a problem globally, 92 percent believed it was a problem nationally and only 67 percent believed it was a problem for their practice.52 Also, 97 percent believed excessive antibiotic use and 90 percent believed patient non-adherence caused resistance, and most knew of strategies to reduce resistance including education. The researchers concluded that study subjects attributed responsibility for AR to patients, other countries and healthcare settings; and resistance was considered a low priority and a distant consequence of antibiotic prescribing.
WHO also states that patients and the public can help tackle resistance by: handwashing, and avoiding close contact with sick people to pre-vent transmission of bacterial infections and viral infections such as influenza or rotavirus; getting vaccinated and keeping vaccinations up to date; using antimicrobial drugs only when they are prescribed by a certified health professional; completing the full treatment course (which in the case of antiviral drugs may require life-long treatment), even if they feel better; and never sharing antimicrobial drugs with others or using leftover prescriptions.53
Educational outreach is also important among patients and the public; a study of educational programs that addressed the overuse of antibiotics for viral infections, the choice of antibiotic for bacterial infections such as streptococcal pharyngitis and UTI and the duration of use of antibiotics for conditions such as acute otitis media found that patient-based interventions, particularly the use of delayed prescriptions for infections for which antibiotics were not immediately indicated, effectively reduced antibiotic use by patients and did not result in excess morbidity; it also found that multi-faceted interventions combining physician, patient and public education in a variety of venues and formats were the most successful in reducing antibiotic prescribing for inappropriate indications.54
Furthermore, on the subject of fighting AR among patients and the public, McCullough, et al. (2016) wrote: “The public have an incomplete understanding of AR and misperceptions about it and its causes and do not believe they contribute to its development. These data can be used to inform interventions to change the public's beliefs about how they can contribute to tackling this global issue.” According to the results from the 54 studies included in the review, some participants had heard of AR, although most believed it referred to changes in the human body, and believed they were at low risk from AR; they also largely attributed worsening AR to the actions of others and thought that strategies to minimize resistance should be primarily aimed at clinicians.55
“The main message that I don’t think we get out to patients effectively enough is that you don’t want an antibiotic if you don’t really need an antibiotic,” says Srinivasan. “We really need to help people understand when antibiotics are not helpful. The most important of these is infections not caused by bacteria. Viruses that cause many common infections like the common cold are not killed by antibiotics, and if you take an antibiotic for a viral infection you’re exposing yourself to all of the downsides of antibiotics with zero benefits. In the medical literature, many studies show that for common infections like sinusitis, bronchitis and ear infections.”
From the standpoint of healthcare facilities, ways to combat AR include antimicrobial stewardship programs (ASPs) such as healthcare facility-wide preauthorization requirements and post-prescription reviews which are designed to inhibit inappropriate prescribing practices and reduce how long antibiotics are used.56 When implemented in healthcare facilities ASPs have been found to help thwart AR in hospitals and other healthcare settings.57
In a position statement released by the Society for Healthcare Epidemiology of America, the Infectious Diseases Society of America and the Pediatric Infectious Diseases Society of America, the authors wrote: “ASPs optimize antimicrobial use to achieve the best clinical outcomes while minimizing adverse events and limiting selective pressures that drive the emergence of resistance and may also reduce excessive costs attributable to suboptimal antimicrobial use. Therefore, AS must be a fiduciary responsibility for all healthcare institutions across the continuum of care.58 The position statement also suggests that ASPs should be required through regulatory mechanisms and monitored, and calls for research on ASPs, among other recommendations and endorsements.59
A systematic review that evaluated the effect of outpatient ASPs on prescribing, patient, microbial outcomes and costs in eligible 50 studies found medium-strength evidence that ASPs incorporating communication skills training and laboratory testing were associated with reductions in antimicrobial use.60 Any reported patient outcomes were not adversely affected and medication costs were generally lower with ASPs. The authors concluded low- to moderate-strength evidence suggested that ASPs in outpatient settings improved antimicrobial prescribing without adversely effecting patient outcomes. Also, a systematic post-prescription review performed by infectious disease physicians on the quality of in-hospital antibiotic use in surgical or medical wards of four hospitals found post-prescription review performed at days one and three to four resulted in higher quality of antibiotic use and lower antibiotic duration.61 Another study in a hospital with low baseline antibiotic use found implementation of an ASP was not only associated with lower total antibacterial drug use but also declining expenditures on these drugs.62 And a systematic review of studies of ASPs in an intensive care unit (ICU) setting identified reduced antibiotic use, length of ICU stay, and reduced cost of prescribing antimicrobial medications occurred with ASPs.63
From the standpoint of scientists and pharmaceutical companies, research and development are the chief means to combat AR. In particular, further investigating how specific mechanisms contribute to resistance; how to target cell wall synthesis, replication, transcription and protein synthesis in bacterial64-65 as well as other types of pathogens such as certain fungi;66 and factors such as physician prescribing behavior,67 in order to develop novel antimicrobial medications, vaccines alternative treatment options, policies, and educational programs represent key ways that this sector can participate in the fight against AR.
Regarding development of novel antimicrobial agents, the antimicrobial drug class is relatively limited in comparison to other classes68 even though the concept of untreatable disease is becoming increasingly compelling. In fact, pharmaceutical companies appear to be in no rush to develop new antimicrobial drugs69 even though expanding this narrow armamentarium could be helpful in the fight against AR. Their seeming disinterest may be due to economics: antimicrobial medications are generally a poorer return on investment than more profitable classes of drugs.70 Specifically, antimicrobial agents are taken for relatively short periods and discontinued once an infection clears up, whereas medications taken for chronic diseases are in many cases are taken daily for the rest of a person’s life.71
Clearly, the battle against AR is a tough and escalating crisis that will require participation across many sectors and nations throughout the globe. We can only hope that the world takes concerted action against this looming disaster before modern medicine as we know it is literally annihilated.
“Without urgent, coordinated action,” wrote the WHO in a 2014 surveillance report, “the world is heading toward a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill.”72
Elizabeth Srejic is a freelance writer.
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