The World Health Organization (WHO) has named antibiotic resistance (AR) an international public health crisis in the 21^st century based on estimates from available surveillance studies. The actual burden of AR is difficult to quantify in some regions of the world due to lack of personnel, equipment, and financial resources. That said, based on current data, AR is projected to cause millions of premature deaths by 2050, with an accumulated loss to the global economy of trillions of dollars.

Historical review

The fortuitous discovery of penicillin by Fleming in 1928 heralded in the antibiotic era that revolutionised medicine and saved countless lives. Once physicians saw how effective these so-called “magic bullet” drugs were in their patients, they began prescribing antibiotics not only for bacterial infections, but also for minor ailments and viral infections. Unfortunately, successful treatment using the B-lactam antibiotic penicillin was short lived due to the spread of a plasmid-mediated enzyme penicillinase in Staphylococcus aureus. Even though penicillin-resistance spurred initiatives to develop additional B-lactam drugs, new classes of natural antibiotics, and semi-synthetic antimicrobials during the so-called “golden era” between 1960-2000, resistance occurred to these antibiotics as well. This comes as no surprise since antibiotics and AR genes have existed for thousands of years as microbes evolved. Archaeologists have found traces of the antibiotic tetracycline in the bones of ancient Sudanese Nubian skeletons as far back as 350-550 A.D.

Many susceptible bacteria are exposed to antibiotics that are produced-naturally by other bacteria and fungi. As part of evolution, these susceptible bacteria develop mechanisms of resistance based on the activity of resistance genes that overcome the action of antibiotics. Discovery of resistance genes have been found to be widespread in the environment, verifying the origin of these genes in reservoirs of soil bacteria that are intrinsically resistant to antibiotics, i.e., environmental resistomes. In 2012, multi-drug resistance (MDR) bacteria were isolated in the Lechuguilla Cave, an underground ecosystem within Carlsbad Cavern National Park in New Mexico (a UNESCO World Heritage Site) that dates back at least four million years ago. One of these isolates, Paenibacillus was found to be resistant to 18 frequently used antibiotics of last resort to treat superbugs, well before antibiotics were used for human, animal, and agricultural use. Although this discovery suggests that human overuse and misuse of antibiotics are not solely responsible for the emergence of AR, they no doubt contribute significantly to the antimicrobial resistant pandemic.

Current practices responsible for increased bioburden of antibiotic resistance

Overuse and misuse of antibiotics for human and animal consumption, poor infection prevention and control practices, large scale waste disposal by pharmaceuticals, and wastewater reservoir of resistance genes and organisms all contribute to the bioburden. In a point prevalence survey on healthcare associated infections in Europe, 35 per cent of hospitalised patients in 2011 were receiving antibiotics and according to one U.S. study in acute care hospitals, a mean of 59.3 per cent of all patients received at least one dose of an antimicrobial agent during their hospital stay. In affluent countries, excessive and unnecessary prescriptions occurred in the community, whereas in developing countries, excessive use was due to over-the-counter drugs and loose regulatory systems. In hospital settings, the intense and prolonged use of drugs is probably the main contributor to the emergence and spread of highly AR healthcare-acquired infections, whereas in the community, failure to complete antibiotic prescription supplies and self-medication appear to contribute to AR. Over 50 per cent of antibiotics have been reported to occur in food-producing animals and aquaculture for growth promotion and treatment of diseases. Although this practice has been banned in Europe since 2006, some countries continue this practice.

Mechanisms of antibiotic resistance

Misuse and overuse of antibiotics accelerate selective pressure for transfer from bacteria carrying resistance genes to susceptible bacteria via mobile genetic elements called plasmids, transposons, and integrons. Expression of these genes can 1) affect cell wall permeability that prevents penetration of antibiotics into bacteria, 2) modify protein porin channels that restrict antibiotic entry into bacteria, 3) create efflux pumps that move antibiotics out of bacterial cells, 4) modify antibiotic binding sites in the bacteria, 5) develop alternative metabolic pathways, and 6) produce enzymes like B-lactamases that degrade or modify antibiotics.

To date, there are more than 1,000 different B-lactamases. Genes encoding B-lactamases are termed bla followed by the name of the specific enzyme (e.g., bla_KPC). Several Gram-negative bacteria carrying resistance genes that express one or more B-lactamases, are a major clinical threat due to their multi-drug resistance and rapid global spread. Compounding the problem, more than one mechanism of resistance may be responsible for antibiotic resistance in these organisms.

In 2008, the acronym “ESKAPE” pathogens (Enterococcus, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp or Escherichia coli) was proposed to highlight those pathogens that often escape the effects of antibiotics. Several of these organisms are on the WHO and CDC list of Critical Global Antimicrobial Resistant Threats. These organisms are increasingly multi-drug resistant (MDR), extensively-drug resistant (XDR) or pan-drug-resistant (PDR).

Multi-drug resistant organisms of global concern

Three of the ESKAPE pathogens will be briefly discussed, i.e., S. aureus, K. pneumoniae and A. baumannii that display resistance due to mecA and bla_NDM, respectively, as well as two emerging pathogens, mcr-1 in E. coli and the yeast, Candida.auris. By the 1960s, the first strains of methicillin-resistant S. aureus (MRSA) emerged and now are a common cause of both HAI and community-acquired infections (CAIs). In 2011 in the U.S. alone, MRSA was estimated to cause more than 80,000 invasive infections, only 14,000 occurring in the hospital. In Europe, several countries implemented national action plans to reduce the spread of MRSA in healthcare facilities. Based on data generated by the European Antimicrobial Resistance Surveillance Network between 2015-2018, many countries reported a significant decrease in MRSA although globally, MRSA remains a serious, high priority pathogen.

Klebsiella pneumoniae, a common intestinal bacteria that can cause life-threatening infections such as pneumonia and septicemia, is a global concern. Resistance mediated by extended-spectrum beta-lactamases (ESBLs) affects all penicillin’s, cephalosporins including third-generation cephalosporins, and aztreonam. Prevalence of ESBLs among clinical isolates varies from country to country and between institutions, ranging from <1.0 per cent to 42 per cent for some European isolates from patients in ICU. In institutions experiencing a high proportion of cephalosporin-resistance, treatment of severe K. pneumoniae infections usually relied on last-resort carbapenems until the first K. pneumoniae carrying a blaKPC gene encoding a carbapenemase enzyme, capable of hydrolyzing all B-lactams including carbapenems was identified in the U.S. in 1996. Since then, carbapenem-resistant (CR) K. pneumoniae rapidly emerged as the most common cause of carbapenem and multi-drug-resistant infections in Enterobacteriaceae (CRE) and other organisms worldwide. This can be attributed in part to international travel, patient-to-patient transmission, and interspecies horizontal transfer of KPC-resistant genes. Colonisation of CRE in the GI tract is important as a reservoir for dissemination in healthcare facilities and may precede infection. Multiple antibiotics or long-term treatment are risk factors for CRE. A known history of CRE carriage in the past 12 months prior to hospitalisation and epidemiological linkage to a person known to be a carrier should prompt pre-emptive isolation, active screening, and contact precautions. 

In 2008, a novel bla_NDM gene that encoded for a zinc-dependent, metallo-B-lactamase was detected in a Swedish patient infected with a carbapenem-multi-drug resistant K. pneumoniae organism. He was thought to acquire the infection in India, although the exact origin of this so-called plasmid-mediated, New Delhi metallo-B-lactamase resistance gene has not been confirmed. bla_NDM has spread globally by horizontal gene transfer to other Gram-negative organisms including other ESKAPE organisms such as A. baumannii and E. coli, imparting resistance on these organisms to most antibiotics except tigecycline and colistin. Only a few therapeutic options remain for treatment of infections due to carbapenemase-resistant organisms, one being an old and rather toxic antibiotic, colistin. Infection control and interventions targeted to prevent dissemination of these almost untreatable pathogens are greatly needed.

Since the late 1980’s, carbapenem-resistant (CR) A. baumannii, has become increasingly prevalent worldwide and causes significant HAIs, raising serious concerns about the remaining and extremely limited antibiotic options for treatment. Carbapenem-resistance can result from the over-expression of OXA, IMP, VIM, SIM or, more recently, New Delhi Metallo-Beta-Lactamase (NDM)-type carbapenemases. Today, carbapenem-resistant A. baumannii appears to only be susceptible to colistin and tigecycline, although data supporting the efficacy of such tigecycline regimens is limited. Colistin-resistant isolates, now increasing worldwide, are thought to be mediated by modification of the bacterial cell membrane resulting in interference with the drug’s ability to bind bacterial targets.

Colistin has also been used as a last resort antibiotic for life-threatening infections in humans caused by numerous MDR members of the Enterobacteriaceae family. Since discovery in 2015 of plasmid-mediated resistance in E. coli due to a mobilised colistin resistance gene (mcr-1) in a pig in China, mcr genes have been detected in multiple members of the family Enterobacteriaceae including K. pneumoniae. Colistin has been used worldwide for prophylaxis or treatment in veterinary medicine to manage respiratory conditions, and as growth promoters in cattle herds in several countries. To date, there are at least nine known colistin-resistance mcr genes with worldwide distribution, mostly in animal and environmental samples and to a lesser extent, in human clinical samples.

Although the focus of this article has been on antibiotic resistance, we need not forget that multi-drug resistance can also occur in fungi. Candida auris is an emerging species of yeast that has become a serious global health threat characterised by colonisation of skin, persistence in the healthcare facilities, and antifungal resistance. C. auris first described in 2009 from a single isolate, has since been reported in more than 25 countries worldwide. Most isolates sent to CDC have been resistant to fluconazole, and up to one-third were resistant to amphotericin B, usually considered a last-resort treatment. Although most C. auris isolates are susceptible to echinocandins, resistance may develop while patients are on treatment. The mechanisms of Candida auris anti-fungal drug resistance are not well understood but may be due to ergosterol mutations or by an efflux pump. C. auris is also a significant public health issue because it is difficult to identify with standard laboratory methods that may lead to incorrect treatment, and it spreads easily in hospitals and long-term care facilities.

Approaches to addressing global antimicrobial resistance

Are we headed to a post-antibiotic era? Over the past two to three decades, we have not only been confronted with an increase in multi-drug-resistant microorganisms (MDROs) causing serious and sometimes life-threatening infections but also with a significant decrease in the number of new antimicrobial agents to treat these infections. Fortunately, since 2014 several new antibiotics, most modifications of known antibiotic classes, have been approved due to the initiatives set forth by a global action plan.

In summary, antimicrobial resistance is a global issue that cannot be ignored. In order to understand the gravity of antimicrobial resistance, we need to address the reasons behind the dramatic increase in antimicrobial resistance and the consequences facing us, as well as potential solutions to the problem. In May 2015, the World Health Assembly endorsed a global action plan and a One Health approach to promote best practices by enhancing prevention and control of infections, avoiding emergence and spread of antibiotic resistance by optimal use of antibiotics in humans and animals, investing in research and development of new antimicrobials, classes of drugs, and vaccines, delinking payments for antibiotics from the volume used and if not compliant, institute a pay or play policy requiring pharmaceutical companies to pay a charge if they do not have active antibiotic R&D programme, and investing in research and development of diagnostic laboratory tools, e.g., rapid point-of-care tools, for optimal patient management.

References available upon request.

Traditionally, the public is not used to viewing nurses as leaders, and not all nurses begin their career with thoughts of becoming a leader. As a result, nurses have automatically been assigned the backseat in decision making in the healthcare industry. This has led to a recurrent gap in expected patient care outcomes across most healthcare systems especially in the developing world despite them forming the largest cadre in any health system. Nurses and midwives make up more than 50 per cent of the health workforce and deliver almost 80 per cent of hands-on care. This is according to reports by Annette Kennedy, president of the International Council of Nurses (ICN).

A good example is the primary healthcare setting that forms the entry point for most patients and, therefore, the most in number. A typical health system, especially in the developing world, has a nurse or midwife as the lead of the primary health facility. When they are posted into the various primary healthcare units, they are expected to carry out both the functions of the caregiver across all services to the community as well as be the administrator and facility manager. Unfortunately, as they go through nursing school, the leadership skills and competencies of how to manage a complex health system are rarely part of the curriculum for the same nurses and midwives posted to these facilities immediately after graduation. Rarely do they receive these necessary skills or competencies as part of professional career development in the already complex health system. With this background coupled with severely restricted resources, poor infrastructure, knowledge deficit on required standards of care and poor problem-solving skills, the patient suffers the most with poor outcomes recorded most of the time with the blame lying on the same nurse or midwife by both the community and the health system leaders.

Year of the nurse

As the world makes another attempt at achieving universal health coverage by 2030 and WHO declaring the year 2020 as the year of the nurse and midwife, it is the perfect time to turn the tables and invest in the nurses and midwives to have a lasting impact and better patient outcomes. After all, it is estimated that the world needs 9 million more nurses and midwives to achieve UHC by 2030. Even though not mentioned, the world needs the nurses to be more empowered in their positions than they are currently for the said UHC to be achieved otherwise the same scenario would replay over and over. For the transformation of the healthcare system to occur, the nurses and midwives must become part of the decision-makers and be full partners alongside the rest of the healthcare professionals and not be viewed sorely as implementers all the time.

For nurses to function in this role as partner and decision-maker, there is a need to focus on a few critical aspects. These are:

1. Leadership skills and competencies:

It is necessary to invest in the nurse to acquire knowledge, skills and competencies in leadership to effectively handle the complex health system through the nursing school curriculum and as part of professional development. Working in teams, collaboration across disciplines, patient advocacy, knowledge on standards of quality and safety improvement, monitoring and evaluation of patient care and overall administrative competencies would be part of the curriculum. This would empower them to take the lead in identifying gaps in patient care, develop improvement plans and making the necessary changes to achieve set goals alongside the rest of the team successfully.

2. Team member in health policy development and validation:

As implementors of most of the policies put in place in the health system, nurses and midwives possess great potential to provide value during health policy development and validation. Non-compliance to set policies and standards is a recurrent challenge in the health system and this is partly because there is poor involvement of the implementors during development and validation leading to little or no buy-in. Being part of the team that develops health policies ensures better chances of buy-in and adherence to the policies, which automatically improves patient outcomes. As such, more nurses and midwives should intentionally be given a chance to serve actively on advisory committees, commissions and health boards where policy decisions are made to advance health systems and, in the process, improve patient care. In addition, they should be empowered with knowledge and skills to effectively handle this role.

3. Innovation opportunity:

As 80 per cent of frontline workers, it is inevitable that nurses will always face challenges at work and as such have the highest opportunity to find creative ways to ensure patient care is not disrupted. This is especially common in severely resource-restricted zones, especially in the developing world with poor infrastructure. In the developed world, the challenges present themselves as a shortage of nursing staff, an influx of patients with complex conditions and unrealistic working hours. It is not unusual to find nurses improvising ways to make their work easier and better in the ever-challenging environment. More often than not, the improvised processes cost very little due to the already complex situation and as such would reduce the burden of health finance in the health system if the production of the innovations was made commercial.  This can be an opportunity for the relevant stakeholders to invest in these creative ways to promote the nurses work and, therefore, offer them a global platform to be viewed as much more than just implementors.

Achieving universal health coverage in 10 years may be an uphill task but it is not impossible. Investing in the nurses and midwives who form the largest cadre of human resources in the health sector is one strategy that will have an impact. At the end of the day, most patients will still access the primary healthcare unit and it is still the nurse/midwife who will care for them or determine the care they will get.

Imagine if each nurse/midwife in the primary healthcare setting of the health system is empowered to identify gaps in the system, plan for improvement, identify innovative ways to solve the gaps in the ever-changing healthcare environment that can be scaled up, use the lessons learnt to influence policy changes and lead the way to sustainable gains, the transformation of the health system would occur seamlessly.

The year of the nurse and midwife 2020 provides a platform for stakeholders to intentionally shift their focus to this priceless resource and strategise on how to maximise the gains that can be achieved in the next 10 years if the investment is made to empower, improve and transform the nurse/midwife.

A significant share of health spending is at best ineffective and at worst, wasteful. One-fifth of health spending could be channelled towards better use.’ Organization for Economic Cooperation and Development (OECD), 2018.

Health Economics is not about money, it concerns the most effective and efficient allocation of scarce resources to meet a specified goal. Our goal in healthcare is the cure or mitigation of disease, but we cannot afford to fix everything so our goal as clinicians and as administrators is also to obtain the maximum cost-benefit from the treatments and strategies we employ for patient care. In this we would also be following Hippocrates’s dictum, primum non nocere, ‘first, do no harm’.

Patient harm is estimated to be the 14th leading cause of global disease burden. This is comparable to the impact of diseases such as tuberculosis, while OECD evidence suggests that 15 per cent of hospital expenditure treats safety failures. The annual cost of common adverse events in England was calculated to be worth the equivalent of the yearly salary of 3,500 hospital nurses.

Patient harm also impacts the broader economy through partial or total incapacitation of workers and productivity losses. This is a difficult figure to calculate but we can be sure that it is significant, and some work has been done on the human capital and an individual’s contribution to Gross Domestic Product (GDP) lost through medical error. A human life is priceless, but in terms of economic contribution to GDP an American study found that whilst US$19.5 billion was the direct cost of treating medical error, a further US$20 billion was lost in productivity, and in long-term disability costs.

A strong economic case at a national level can, therefore, be made for investment in patient safety, as unintended patient harm exerts a burden on society and investing in the prevention of harm can create long term value. ‘Value’ is defined here in classical economic terms, as the net impact or effect in reducing patient harm per dollar invested, expressed mathematically as: Value = Patient Outcome / Cost.

Well-constructed studies from as long ago as 1998 identified medication error (50 per cent) as the most common type of unintended harm. The word unintended is important in this context and serves to distinguish between adverse events and complications. No healthcare intervention is completely devoid of risk. Another key concept is preventability, a medication error is not easy to prevent, but investments in smart pumps, Dose Error Reduction Systems (DERS), automated dispensing cabinets, and barcode medication administration systems have all been shown to make a difference to reduce error rates.

Below we take a very simple example of how health economics can be applied to intravenous infusions given by gravity and via smart pumps with DERS. Whilst we recognise that much of the Gulf Region operates at extremely high levels of integration, well beyond a simple DERS, this is a useful exercise as around 80 per cent of all patients admitted to hospital will have an IV infusion of some sort during their stay. Furthermore, WHO data indicates that two-thirds of all adverse events occur in low-to-middle-income countries, where highly integrated solutions may not attainable.

In Health Economics Cost-Effectiveness Analysis (CEA) we commonly use a comparator to rate the introduced technology against. In this case we have gravity delivery of IV infusions as the comparator to a smart pump with DERS, (we might call this the ‘do-nothing’ option, as it employs no technology in terms of rate/dose control, warning for empty or near empty infusions or pressure limiting / vein protection alarms).

Such comparisons take place through head-to-head studies, randomised controlled trials, or literature reviews. Gravity infusions and smart pumps are such long-established technologies that we can turn to the literature to compare their efficacy and efficiency; efficacy being how well a technology performs under ‘ideal conditions’, and efficiency being how well it performs in the ‘real world’.

A summary of the documented evidence for both technologies in terms of accuracy from the literature is given below:

For the appraisal of the value impact of gravity versus DERS smart pumps, we need to know how many times the procedure is undertaken. An average Adult Day Medicine Unit (DMU) would perform about 150,000 gravity infusions per annum. We cost the resources used by both techniques, and apply costs to some of the complications, if the evidence exists. We have followed the conventions of Health Economics by applying Monetary Units (MU) to all costs in ratios that are common to the healthcare market in our region. The smart pump cost reflects staff training time in new technology, initial capital investment, disposables costs, etc. Classically the capital investment for medical technology should be discounted over time as the initial, one time, the investment gives benefits over its lifecycle but in our model, we have included all costs in a disposables cost (5.5 MU) to make comparison simpler.

Above, we have taken very basic performance figures for the smart pump and DERS, ignored fixed costs such as cannula and dressing replacements, and chosen the very lowest costs for serious IV medication error and extravasation injury from the available literature.

An OECD Cost-Effective Incremental Factor of 5:1 is in-line with expectations of such programmes in terms of investment made and return. Furthermore, extravasation injuries have been estimated to cost up to £45,500 (56,000 MU) per incident in the UK NHS, and medication errors in Europe have been estimated at €6,700 per incident. (7200 MU). Using these numbers (35X56,000) + (840 X7200) would make the Cost-Effective Incremental Factor of the programme 12:1. The OECD has saluted programmes to reduce central line infections with cost-effective incremental factors of 3:1! 

Medication error causes suffering, and for that reason alone we cannot afford to ignore it but given that active medication safety initiatives and technology bring cost-benefits, there are also compelling hard-headed financial reasons for embracing it.