A
OMICS A Journal of Integrative Biology Volume 24, Number 3, 2020
ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2020.0008
Review Article
It Is Time to Revitalize the Antibiotic Pipeline:
Systems Ecology Can Help
Semra Sardas,1 Ayse Seyma Buyuk,2 and Ayfer Beceren3
Abstract
Antimicrobials have been known for millennia, but innovative antibiotics are currently in short supply. New
antimicrobial discoveries are being threatened by planetary scale loss of biodiversity that has important impacts
on species and ecosystems. This expert review underscores that microorganisms in nature and their diversity are
essential cornerstones to revitalize the antibiotic innovation and discovery pipeline. The recent rise of systems
ecology and planetary health offers new and actionable potentials in this regard. Without a systems scale focus
and appreciation of systems ecology, the global threats to human and planetary health from inappropriate use of
antibiotics and antimicrobial resistance will continue to escalate with serious consequences to all life on the
planet. With acutely pressing research and development needs to revitalize antibiotic treatment and novel
diagnostic tools for personalized medicine, national health systems ought to work across knowledge silos not
only within but also across the ministries, for example, health, agriculture, environment, economy, trade, and
social services ministries that collectively impact on systems ecology and by extension on health innovations
including the antibiotic discovery pipeline. Such systems vision can also help to revitalize antibiotic discovery
pipeline as most antibiotics have natural origins or have designs inspired or based on molecules in the envi-
ronment and microorganisms that produce antibiotics. Above all, our audience and responsibility include every
person who has an interest in his or her own health, in the health of his or her fellow human beings and all life
on the planet, and in the health of future generations.
Keywords: antibiotics, systems ecology, national innovation systems, systems pharmacy, drug discovery,
planetary health
Introduction
NTIBIOTICS SPECIFICALLY, AND ANTIMICROBIALS BROADLY, have been the cornerstones of modern thera- peutics especially since the past century. With increased and often inappropriate antibiotic use, however, the rise of the antibiotics era has coincided with the development of anti- biotic resistance. Inappropriate antibiotic use and resistance to antibiotics constitute a dual threat to national health sys- tems and planetary health at the same time.
Resistant pathogens result in complications in therapeutics, and increase all hospital drug expenditures by 20%–50%. Rational therapeutics and personalized medicine symbolized in the motto ‘‘the right drug, at the right time, and at the right dose’’ are antidotes to containing and reversing the trends on antibiotic resistance. In this context, the primary health care in a large number of countries has the highest rates of anti-
biotic prescriptions for systemic use, and oftentimes for re- spiratory tract infections. Inappropriate antibiotic use contributes to the increase in bacterial resistance both by disturbing the patients’ healthy microbiome that might oth- erwise counteract the pathogens and by selecting for the most resistant members of a bacterial population. Use of antibi- otics for time intervals shorter than the prescription or at suboptimal doses also contributes to the resistance progress (Ceyhan et al., 2010; Usluer et al., 2005; Yates, 1999).
Insofar as antibiotic resistance is concerned, the U.S. Centers for Disease Control and Prevention (CDC) has al- ready cautioned that annually 25,000 deaths in the European Union (EU) and >23,000 deaths in the United States occur due to antibiotic resistance (CDC Report, 2017). Chair of the ‘‘Review on Antimicrobial Resistance’’ O’Neill reported that, in 2050, the predicted death caused by cancer is esti- mated as 8.2 million, whereas the antibiotic resistance-
Departments of 1Toxicology and 2Clinical Pharmacy, Faculty of Pharmacy, Istinye University, Istanbul, Turkey. 3
Department of Toxicology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey.
SYSTEMS ECOLOGY CAN REVITALIZE ANTIBIOTIC PIPELINE 125
related deaths that are now 700,000 will effect 10 million lives (O’Neill, 2018).
No doubt, now is the time to act. There is a need for planetary scale awareness on antibiotic resistance and the current lack of effective responses, both in public and private domains, that are collectively threatening the antibiotic dis- covery and innovation pipeline.
The warnings by various scholars aimed to increase the global awareness of antibiotic resistance over the past years so as to contain further emergence and spread of antibiotic resistance but have not always had success. The U.S. Food and Drug Administration (FDA) has noted, for example, that 1. Flouroquinolones should be avoided from patients with acute bronchitis, acute sinusitis, and uncompli- cated urinary tract infections who have options to undergo alternative treatments and they should be re- served for patients who cannot undergo alternative treatments in 2016 (FDA, 2016).
2. Restriction of quinolone and flouroquinolone usage was suggested by European Medicines Agency (EMA) in Europe in 2018, in nonbacterial infections, travel- er’s diarrhea, mild-to-moderate bacterial infections, and they should be used with special contexts such as patients with kidney disease, organ transplantations, and in elderly (EMA, 2019).
According to the Organisation for Economic Co-operation and Development (OECD) antimicrobial resistance report, Turkey, Korea, and Greece have higher incidence of antibi- otic resistance than other surveyed countries (OECD, 2018). Because antibiotic resistance is a shared concern of every region worldwide and can impact any individual, we share here our attempts and experience as scholars and university faculty to create and implement country-wide training pro- grams organized by the Turkish Ministry of Health, Rational Medicines Department, and the ways in which such efforts had impact on perceptions over antibiotic use and resistance in the field. Antibiotics resistance is a challenge to the health systems at national and planetary scale. Moreover, there are hitherto overlooked important linkages, as noted hereunder, between systems ecology, planetary biodiversity, and anti- biotic resistance. As such, we think that the present analysis article informs a broad readership in integrative biology, systems medicine and systems pharmacy, and planetary health.
Linkages Among Antibiotics, Biodiversity, and Systems Ecology
In May 2019, the Intergovernmental Science-Policy Plat- form on Biodiversity and Ecosystem Services (ISBES) warned that ‘‘around 1 million animal and plant species are now threatened with extinction’’ (D´ıaz et al., 2019). Al- though ecosystem covers both living and nonliving envi- ronment, biodiversity is the variety of life among living organisms from all sources. Loss of biodiversity has direct negative impacts on antibiotic discovery and availability. Biodiversity is essential for new drug discovery and avail- ability, particularly for antimicrobials and cancer therapeu- tics (Newman and Cragg, 2016). To improve the health outcomes, action has to be taken to reduce environmental damage (Whitmee et al., 2015). Hence, any effort to under-
stand and respond to antibiotic crisis through educational innovation ought to tackle planetary health and systems ecology at the same time. A brief look at the worldwide antibiotic use is an important step to contextualize attendant resistance and antibiotic discovery pipelines.
Worldwide Antibiotic Use
Turkey
Turkey is situated as a bridge between the EU, the Middle East, and Asia and can thus offer insights on antibiotic- related challenges and prospects within the broader world- wide pharmacy knowledge ecosystem. According to the WHO/Europe-ESAC Project, depending on the seasonal variation, the highest use of second- and third-generation cephalosporins and quinolones, intermediate-acting macro- lides, combinations of penicillins has been reported. Dis- tressingly, Turkey was the only country that has the oral use of third-generation cephalosporins (cefdinir and cefditoren). Total antibiotic use in 2011, expressed as defined daily doses in 1000 inhabitants per day, differed among 12 non-EU countries significantly, ranging from 15.3 to 42.3 (Versporten et al., 2014). Moreover, 88.5% of the aminoglycosides were used combined with glycopolypeptides and b-lactams (Usluer et al., 2005). Although the combination of the b- lactamase inhibitor and amoxicillin can manage some types of the resistance, this combination therapy should not be used as a first-line treatment; yet, it is widely used (Versporten et al., 2014). A prospective study conducted in 18 tertiary care hospitals by Usluer et al. (2005) in 2002 gives us further information about the inappropriate antibiotic prescription problem. Antibiotic prescription frequency was seen as 30.6% in 9471 hospitalized patients. Most commonly pre- scribed antibiotics were ampicillin–sulbactam, cefazolin, ceftriaxone, amikacin, ciprofloxacin, ornidazole, gentamicin, meropenem, cefuroxime, and vancomycin. In addition, the ratio of the combination therapy was 33% and third- generation cephalosporins (21.1%), aminoglycosides (30.8%), metronidazole–ornidazole–clindamycin (18.2%), penicillins (18.8%), quinolones (11.9%), carbapenems (10.9%), and glicopolypeptides (13.1%) were the most commonly used antibiotics in combination therapies. More than 40% of antibiotic prescriptions were given without a proven infection and 50% of the patients received inappro- priate antibiotic therapy. Intensive care units (ICU) had the highest antibiotic consumption ratios (surgical ICU 81%, medical ICU 52.5%); the 48.8% of the antibiotics were given for the treatment of an infectious disease but no reason was found for the antibiotic therapy in the 7% of the patients. (Usluer et al., 2005).
Europe
In contrast to northern European countries where antibiotic resistance rates remain low, in central and southern European countries, the rates of antibiotic resistance are reaching alarming levels. In 1997–2002, in the ESAC project, in which 15 original EU countries and a total of 32 countries partici- pated, systemic antibiotic usage data in the ambulatory care were obtained and grouped by active substance in the drug. Outpatient antibiotic use contradicted significantly in Eur- ope. According to the ESAC project, France had the highest
use of antibiotics in the ambulatory care and Netherlands had the lowest use. Antibiotic use was significantly different across Europe and antibiotic use was found low in northern, moderate in eastern, and high in the southern regions of Europe. Correlation was found between increased resistance to the microorganisms and consumption of the antibiotics. Although seasonal fluctuations of antibiotic use were high in eastern and southern European countries, the increase in antibiotic use during winter in northern European countries was <25%. Again, a correlation was found between outpa- tient antibiotic use and antibiotic resistance in Europe. Growing use of newer antibiotics, broad-spectrum antibiot- ics, for instance combination of clavulanic acid and amoxi- cillin, quinolones, and new macrolides to the detriment of the narrow-spectrum penicillins and cephalosporins was ob- served (Goossens et al., 2005).
A recent report from European Antibiotic Resistance Surveillance network program in 2011 demonstrates that the antibiotic resistance to the gram-negative pathogens in- creased with alarming findings of increasing resistance to fluoroquinolones, third-generation cephalosporins and car- bapanems Escherichia coli and Klebsiella pneumoniae (Versporten et al., 2014).
Non-EU countries
To build-up a sustainable network to assemble represen- tative, comparable, and valid data on antibiotic use in non-EU countries of the WHO European region, WHO/Europe- ESAC Project was conducted. According to the project results, the most commonly used antibiotic group in all countries was penicillins. However, the highest use of third- generation cephalosporins, the intermediate-acting macrolides, and the second-generation quinolones was also reported (Versporten et al., 2014).
United States
Similar to the whole world, United States has been facing antibiotic crisis. According to one retrospective study con- ducted at Johns Hopkins Hospital with 1194 beds, 1488 of the 5579 patients (27%) received antibiotics for at least 24 h. Third-generation cephalosporins (41%), cefepime (28%), and parenteral vancomycin (37%) were the most commonly prescribed antibiotics. Nineteen percent of the antibiotic treatments were not clinically indicated and most frequently because of the treatment of noninfectious lower respiratory tract conditions, such as congestive heart failure, or asymp- tomatic bacteriuria (Tamma et al., 2017).
Excessive antibiotic use has resulted in increasing antibi- otic resistance both at the population and individual level. Complications associated with excessive antibiotic usage have been observed in various studies. We should not forget that antibiotics are also used against serious cases such as in patients undergoing surgery, dialysis, chemotherapy, long- term immunosuppressive therapy, and organ transplantation. An observational study in the United States from 2013 to 2014 showed that systemically administered antibiotics (16.1%) were the most commonly implicated drug class groups responsible from the emergency department (ED) visits for the adverse drug effects compared within the all other drug classes. Approximately 53% of the drugs impli-
cated in ED visits were among the adolescents and children aged 19 years or younger. The adverse drug events related to antibiotics were estimated to be 48.9%. Compared with all other antibiotic classes, the hospitalization rate for ED visits because of the adverse drug events resulting from quinolone antibiotics was higher (14.5%) (Shehab et al., 2016; Ver- sporten et al., 2014).
A striking resistance evidence has been observed in nos- ocomial infections. Among the reported mechanically ven- tilated patients, the most common nosocomial infection is pneumonia. Also, for promoting the emergence of infections caused by the antibiotic-resistant pathogens, inadequate an- tibiotic therapy of the nosocomial infections seems to play a significant role. Although there are developments in im- proving the prevention, diagnosis, and treatment of the ventilator-associated pneumonia, it still remains a significant cause of hospital mortality. The estimated range for preva- lence of the ventilator-associated pneumonia is from 10% to 65%, with a high mortality rate. Increasing antibiotic resis- tance aggravates the treatment and, unfortunately, unneces- sary antibiotic treatments can result in colonization or infections caused by antibiotic-resistant pathogens and cau- ses the administration of inadequate antibiotic treatment prevailing in hospitals. Another study conducted between 1994 and 1998 in France reported that after the rational use of antibiotic policy, an important reduction of nosocomial in- fections due to antibiotic-resistant pathogens was observed from 37% to 15% (Geissler et al., 2003; Gruson et al., 2000; Ibrahim et al., 2001; Karabay et al., 2016).
Accurate prognostic assessments can lead to decreased unnecessary hospitalization and cost. To make safe decisions, accurate assessment of the risk stratification and disease se- verity is prerequisites. New measurable biomarkers reflecting apparent pathogenetic mechanisms to predict outcome and severity might improve patient prognoses and, most impor- tantly, clinical decision. Biomarkers including human growth hormone, prohormones, and cortisol have predictive poten- tial in various diseases. Apart from those biomarkers, com- pared with the white blood cells and C-reactive protein, procalcitonin was reported to have a better prognostic accu- racy. Therefore, it seems that we are in need of a robust diagnostic marker to guide the antibiotic therapy decisions (Schuetz et al., 2009).
Generating new molecules is an essential solution for the antibiotic resistance crisis. Unfortunately, that takes *10– 15 years until a new molecule can be used in the clinic and the average cost of that process is highly expensive. Many large pharmaceutical companies have discontinued antibi- otic research because of the economic factors and unavail- ability of compounds. In addition, many compounds were also disposed because of the unfavorable pharmacokinetics, poor potency, or revealed resistance. However, in future, because of the antibiotic resistance, many recent antibiotics will not be broadly used. Teixobactin, PC190723 (FtsZ in- hibitors), and the nanoparticles are the only antibiotics in development stages for >20 years. Clinical trials of these molecules have still not been completed due to insufficient responses caused by drug-resistant bacterial infections (Farrell et al., 2018). Plant-based natural products and/or their novel structures in antimicrobial discovery have promising implications for health and environmental appli- cations, however.
SYSTEMS ECOLOGY CAN REVITALIZE ANTIBIOTIC PIPELINE 127
Since there are very few molecules in the pipeline for disruptive innovation in the field of antibiotics development, physicians should bear in mind this predicament and must prescribe antibiotics rationally to provide optimal benefits from treatments. Therefore, the rational use of the antibiotic policy implementations has started globally. For example, the Turkish Ministry of Health, Rational Medication De- partment, has made efforts to establish antimicrobial stew- ardship programs due to high outpatient antibiotic use, and had successfully reduced the consumption and health ex- penditure in the short term. With rational antibiotic use pol- icy, certain intravenous and costly antibiotics require approval from infectious diseases specialist (IDS). In the first 72 h of an acute infection, Group-I antibiotics (amikacin, third-generation cephalosporins, isepamicin, parentheral quinolones, netilmicin, fluconazol, and amphotericin B) could be prescribed by any specialist; however, after 72 h, approval of an IDS is required. But Group-II antibiotics (ticarcillin–clavulonate, piperacillin–tazobactam, glycopep- tides, carbapanems, acyclovir, and amphotericin) could not be prescribed without approval of an IDS. The impact of the antibiotic restriction policy had positive impacts:
1. Within 1 year of implementation; appropriate use of the antibiotics rate increased to 95.5%, use of the third-generation cephalosporins decreased, antibiotic expenditure decreased by 18.5%, and the total saving was 332,000 dollars (Ozkurt et al., 2005).
2. A country-wide survey at 15 hospitals with 8149 hospital beds, among the 12 major clinics, found the daily dose of the total antibiotics before the policy and after the policy was 7864.7 and 5926.2, respectively (Hoxsog˘lu et al., 2005).
3. After 8 years, in 25 centers, 1906 physicians’ opinions were as follows: ‘‘policy change was necessary’’ (77.7%), ‘‘cost effective,’’ (69.9%) and ‘‘reduced the unnecessary use of the antibiotics’’ (63.3%), and ‘‘improved the quality of the antibiotic usage by IDS consultation’’ (79.1%), whereas 49.2% of them felt that the approval of IDS results in delayed initiations (Karabay et al., 2016).
How Can Systems Ecology Help the Current Deficits in the Antibiotic Pipeline?
The ISBES Global Assessment Report, already noted, was prepared by 145 experts participating from 50 countries, based on a ‘‘systematic review of *15,000 scientific and government sources.’’ Accordingly, the catastrophic loss of biodiversity and decline of nature have never been as un- mistakable and profound throughout human history as in the past several centuries. The planetary ecosystem changes in- clude threats to world’s freshwater supplies, ocean acidifi- cation, among others (D´ıaz et al., 2019). Biodiversity has been noted as an important driver of drug discovery and availability, particularly for antimicrobials (Newman and Cragg, 2016). Alterations in the healthy microbiome by loss of biodiversity can pave the way for not only common complex diseases but also safety threats in pharmaceutical manufacturing plants, rise of antibiotic resistance, and hospital-acquired infections. Biodiversity loss can increase the risk for zoonotic infections that spread between animals
and humans and are often difficult to treat with available antimicrobials. The Planetary Health Commission highlights newly emerging diseases besides other several major con- cerns arising from ecological changes (Haines, 2016).
Conclusion
As it can be gleaned over the above data, antibiotic resis- tance is at all-time high in all parts of the world. However, rational strategies taken by countries seem to minimize the problem to some extent. Because the planetary biodiversity is increasingly threatened, pharmacy education ought to be expanded so as to include systems ecology to identify sus- tainable solutions to the antibiotic crisis. For this, the mindset on the narrow anthropocentric framing of health and drug discovery should also change as there is vast interdependency among human health and nonhuman life on the planet. Na- tional innovation systems around the world would be well poised to implement policies to cultivate cooperation among all ministries.
Absent a systems scale focus and without appreciation of systems ecology, the global threats to human and planetary health from inappropriate use of antibiotics and antimicrobial resistance will continue to escalate with serious conse- quences to all life on the planet. National health systems ought to work across knowledge silos not only within but also across the ministries, for example, health, agriculture, envi- ronment, economy, and trade and social services ministries that collectively impact on systems ecology and, by exten- sion, on health innovations including the antibiotic discovery pipeline.
Author Disclosure Statement
The authors declare they have no conflicting financial interests.
Funding Information
No funding was received for this article.
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Abbreviations Used
CDC ¼ U.S. Centers for Disease Control and Prevention ED ¼ emergency department
EU ¼ European Union
ESAC ¼ European Surveillance of Antimicrobial EMA ¼ European Medicines Agency
Consumption
FDA ¼ U.S. Food and Drug Administration ICU ¼ intensive care unit
ISBES ¼ Intergovernmental Science-Policy Platform on IDS ¼ infectious diseases specialist
Biodiversity and Ecosystem Services non- ¼ non-European Union
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Address correspondence to: Prof. Semra Sardas, PhD Vice Dean Department of Toxicology Faculty of Pharmacy Istinye University Topkap Campus Zeytinburnu, Istanbul Turkey 34010 E-mail: semrasardas@gmail.com; semra.sardas@istinye.edu.tr
