Chapter 1: Antibiotic Resistance: The State of Play Today

In 1842, Edwin Chadwick published an influential report: the Report from the Poor Law Commissioners on an Inquiry into the Sanitary Conditions of the Laboring Population of Great Britain. It described the terrible social, environmental and living conditions experienced by the majority of people in England and Wales. The impact of this report was far-reaching and profound. It led to the Public Health Act (An Act for Promoting Public Health) being passed through the Houses of Parliament at Westminster in order to improve public health and to ensure

What Chadwick had recognised was that rapid industrialisation was transforming British society. Urbanisation was taking place on an unimaginable scale. Row upon row of cheap, poorly built housing sprang up as homes for the poorly paid factory workers who were needed to produce the factory goods. In sharp contrast, these goods were sold to generate the wealth and money that built the impressive town halls and municipal building that represented prosperity and define our city landscapes to this day. The lack of sanitation and abject poverty experienced by most factory workers inevitably resulted in the “4 Ds”: Dirt, Disease, Deprivation and Death. This pervasive squalor and the cramped living conditions, combined with poverty, was a perfect breeding ground for infections (Figure 1.1).² 

The Chadwick Act, as it became known, was a significant milestone for public health. The health of the British nation needed to improve. The problems caused by the ravages of disease and unmanaged sewage was not restricted to the poor and destitute slum dwellers. These problems affected the entire society and even the wealthy were not immune. The Chadwick Act set out the need for “The State” to play an active role in improving public health. The treasury provided funding to organise and run national and local boards of health that were accountable to the Treasury. Superintending inspectors and officers were appointed and individual town halls could request inspections if the death rates in their local areas were too high. Ultimately, the Act led to investment in the Victorian public sewerage systems and, at last, the public health of the nation started to improve.

It is easy to mistake Chadwick's motives as straightforward philanthropy. In fact, his motivation was money. The argument he used to negotiate his Act through parliament was an economic one. Chadwick reasoned that improving the health of the poor would result in fewer men (and women), who were used to populate the industrial workforces, dying from infectious diseases. This would result in a reduction in the numbers of families and widows left destitute after the main, male breadwinner had died. In turn, this would reduce the number of penniless, desperate relatives, widows and families seeking poor-relief and ending up in Victorian workhouses because they had no alternative. Money would be saved in the long term. Improving public health was cost effective.

In many regards, the Chadwick Act was a response to the crisis caused by a plethora of common endemic and epidemic diseases, such as syphilis, gonorrhoea, whooping cough, scarlet fever, smallpox, dysentery, diphtheria, tuberculosis, measles, the plague, typhoid, typhus and influenza, that regularly ravaged industrial Britain. These diseases were not confined to the British Isles or even to industrialised nations. Infectious diseases were, and are, a global concern. They affect humanity across every society and habitable continent. Even today, infectious diseases recognise no boundaries nor borders. Human, as well as animal migration facilitate their deadly spread across the globe and throughout history they have been accompanied by a devastating loss of human life.

Looking back at statistics gathered more than 100 years ago at the beginning of the twentieth century, infectious diseases caused by microbial pathogens were responsible for the majority of human disease and death (Table 1.1).

However, the next 100 years were a pivotal time span in a battle to rid the world of infections. The twentieth century is considered a golden age for public health. The scientific adventurers, visionaries and pathfinders, such as Antonie Van Leeuwenhoek, Louis Pasteur, Robert Koch and Joseph Lister, ensured that by the turn of the twentieth century there was a much better understanding about the microbial causes of infection and disease. Knowledge about the relatively “simple” microbes, bacteria, fungi and virus, as well as the more complex parasites, such as trypanosomes and plasmodia that are responsible for malaria and sleeping sickness, had expanded. Humanity had entered an era where the importance of infection control was understood, better sanitation measures were adopted and vaccination programmes were implemented.

When it comes to public health, another game changer arrived in 1928. Fleming's discovery of penicillin heralded the arrival of the golden age of antibiotic discovery. These new, miracle drugs that could combat infections and target disease-causing bacteria and microbes led to the utopian view that death from infectious diseases, such as tuberculosis, pneumonia and diphtheria, would be relegated to history—an uncomfortable memory associated with an annihilative past. Scientific progress and discovery had saved the day. Scientists were inspired to hunt for new microbes, brew broths of bacteria and purify antibiotic products that could inhibit the growth of human pathogens. Any compound that showed potential as an antibiotic drug was quickly tested on animals and shortly afterwards it made its way into clinical use. The impact of infectious disease was altered significantly. A short course of an antibiotic is an effective treatment. Diseases caused by bacterial infections that had been firmly placed in the top ten were relegated down the killer lists. In developed countries, a quick glance at the mortality statistics suggests that the battle is being won; chronic diseases, which include heart disease and cancer, have overtaken infectious diseases as the most likely cause of death, and access to rapid improvements in healthcare provision has resulted in concomitant dramatic increases in life expectancy.

Sadly, the global optimism that infections were to be relegated to the past didn't last. Even now, at the beginning of the 21st century, infectious diseases are still a significant threat in developing countries (Figure 1.2).

Diseases believed to be vanquished to the past, such as tuberculosis and gonorrhoea, are becoming more and more difficult to treat and cure. In addition, the last decades have shown that society doesn't just have to contend with battling infectious diseases from the past. New infections are continuing to emerge that present significant implications for human health. As science and technology continues to develop, we seem to be unwittingly exposing ourselves to new pathogens, including bacterial ones. It is essential that society remains on high alert: emerging and re-emerging diseases need to be tracked and monitored.

In the United States of America (USA), during the early summer of 1976 the country celebrated its bicentennial anniversary of the signing of the Declaration of Independence on the 4th of July 1776. Nearly three weeks later, on the 21st of July 1976, more than 2000 members of the Pennsylvania American Legion of war veterans celebrated this historic event during their annual three-day convention at the Bellevue Stratford Hotel, Philadelphia. Nearly two weeks later, the Center for Disease Control (CDC) in Atlanta Georgia was alerted: four veterans had died from suspected pneumonia after attending the convention. A cluster of cases soon followed. Veterans were reporting symptoms of mild cough, fever and, in some cases, a deadly progressive pneumonia. By the end of the epidemic, 182 members of the legion were diagnosed with this mysterious disease and 29 deaths were reported. This disease wasn't restricted to veterans. Another 39 people who had been in close vicinity to the hotel developed a similar disease and five additional deaths followed. A “new” airborne infectious disease had been identified. It took another six months—from the time the outbreak had been detected—before the bacterial perpetrator of the disease was identified. The bacterium responsible for this disease was Legionella pneumophila, just one of more than 50 species of Legionella that have since been isolated and, luckily, only a small fraction of these species cause human infection. Legionella are ubiquitous in the natural environment. They are found in freshwater systems, including lakes, rivers and thermal springs. But, Legionnaires’ disease is not associated with exposure to the bacteria found in these natural freshwater systems. The Legionella that cause human disease need man-made water systems and they are effectively spread through modern ventilation systems. Legionella have been shown to survive temperatures of 54 °C and below 20 °C. In cool conditions, the bacteria hibernate while they wait for conditions that are more favourable for growth.³  The result is that the stagnant water and low water pressure associated with hotels, ferries and cruise ships has meant that travel is an important risk factor for Legionnaires’ disease.

In these modern times, human impact on the global environment also means that we are exposing ourselves to previously hard-to-reach insects and animals that harbour unknown infectious agents. Travel and tourism to tropical rainforests and remote wilderness, as well as economic development in mining and deforestation, have presented opportunities for humans to come into contact with habitats harbouring microbes that we hadn't been exposed to in the past. Suburbanisation is also a problem. In the early autumn of 1975, two mothers from Old Lyme, Connecticut, needed medical attention. A strange outbreak of arthritis and juvenile arthritis was affecting their families and their town. Word about this mysterious outbreak of unexplainable symptoms reached the Connecticut State Department of Health, and the Yale School of Medicine sprang into action and launched an investigation that culminated in the characterisation of Lyme disease. In the USA and in the United Kingdom (UK) increasing suburbanisation and the reversion of agricultural land to forests had brought people into contact with deer that carry ticks infected with Borrelia burgdorferi, the bacterial cause of Lyme disease. This disease is transmitted to humans via the bite of an infected deer tick (members of the Ixodidae family) that causes a skin rash at the site of attack. In the majority of cases, and if the disease is diagnosed at an early stage, it can easily be treated by antibiotics. But if treatment is delayed it can result in serious systemic, unpleasant side effects that affect the joints, heart and central nervous system.⁴  New infectious diseases are not only a problem of the twentieth century. They are constantly being discovered and it seems as if the list of new infections is going to keep growing in the foreseeable future (Figure 1.3).

As a 21st century society living in the developed world, the collective memory about the mortality and morbidity caused by diseases associated with the past is fading. In part, this is due to some notable successes in the push to rid the world of deadly infectious diseases. Smallpox was an infectious disease caused by the Variola virus that has ravaged mankind. It was highly infectious and it spread on water droplets coughed and sneezed from the noses and mouths of infected people. It appeared in North-east Africa more than 12 000 years ago and migrated across the globe, arriving in Europe sometime between the fifth and seventh centuries. Smallpox was taken to the new world by the Spanish and Portuguese conquistadors, where it decimated the local population and ultimately contributed to the collapse of the Aztec and Inca empires. Smallpox affected all levels of society and in the eighteenth century in Europe, 400 000 people died annually of smallpox, one-third of survivors went blind and most survivors were left with terrible, disfiguring scars as a result of oozing pustules that were a symptom of this disease.

However, those that survived smallpox had one significant favourable outcome: they gained immunity to subsequent infections. It was this phenomenon that led to one of the greatest developments in public health: inoculation. Edward Jenner is reputed to be the first leading proponent of vaccination to prevent smallpox. Since then, a global campaign under the guardianship of the World Health Organisation to eradicate smallpox using an international vaccination campaign has been a triumph. Smallpox was finally declared “eradicated” in 1977.⁵  Polio is another potentially fatal viral disease that was globally endemic until the 1950s. This disease is also spread through person-to-person contact, entering the body through the mouth and leaving the body in faeces. The majority of people infected with polio have little or no signs of illness and never know they are infected. They carry the virus in their intestines and spread it silently by shedding it into water systems, allowing it to enter the next victim. Paralysis occurs as the virus attacks the nervous system, causing a crippling and potentially fatal infectious disease. It was the apparent randomness of the infection profile that spread fear within communities before safe and effective vaccines arrived in the 50s and 60s. Even today, there is no cure for this disease. Instead, there is a prevention strategy to eradicate polio using an immunisation programme to vaccinate every child until transmission stops and the world is polio-free. This battle has been hard-fought and is almost won.

The development of more stable polio vaccines, financial investment and a concerted global effort to combat the challenges of conflict, political instability, hard-to-reach populations and poor infrastructure has ensured that, at long last, the majority of the globe has been declared polio-free. Nigeria became the last country to be declared polio-free in September 2015, leaving Pakistan and Afghanistan as the only countries where polio remains endemic.

The battle to rid the world of polio emphasised that constant and consistent vigilance, combined with focused effort and commitment, is vital to ensure we can remain one step ahead in our battle with infectious diseases. During the campaign to eradicate polio from Nigeria in 2003, unfounded rumours about the efficacy of the polio vaccine swept through northern Nigeria and the immunisation programme was suspended. What followed in that region was another deadly polio outbreak. If a vaccination programme is to work, then enough people in a population or community must be immunised so that the virus cannot infect new hosts and, as a consequence, the disease dies out. This is called herd immunity (Figure 1.4).

Herd immunity relies on high levels of vaccination coverage to stop transmission and prevent outbreaks occurring. Even in developed countries, including the UK, we are not immune to the impact of rumours regarding the safety of vaccines. In the mid-1990s, uptake of the measles mumps and rubella (MMR) vaccine fell sharply as a result of misleading concerns about the safety of the MMR vaccine. Measles, mumps and rubella are contagious, viral infections with potential to cause long lasting, serious complications, such as viral meningitis, miscarriage and, in the case of rubella, birth defects caused by congenital rubella syndrome. Before mass vaccination started, measles was responsible for about 100 deaths in the UK each year. Fears about the safety of the MMR vaccine in the late 1990s led to a sharp drop in the uptake of the vaccine. The number of children with susceptibility to the viruses increased in parallel.⁶  The impact of this was apparent in the recent Welsh measles epidemic in 2013 (Table 1.2).

This epidemic centred round Swansea, a city in the south of Wales that had a low uptake of the MMR vaccination. Herd immunity requires about 95% vaccination coverage; in Swansea the uptake was 67.5%, which meant that there was not effective herd immunity within that community. By the end of the epidemic, there had been more than 1450 measles notifications, a total of 88 people had been hospitalised for complications caused by measles and one person died as a direct result of this infection. The majority of infections occurred in people who had not been vaccinated due to the scare associated with the safety of the MMR vaccine in the late 1990s. It is estimated that the cost associated with treating the sick and controlling the outbreak (including mass catch-up vaccination programmes) crept up towards half a million pounds.

Spurred on by the concerted efforts of 190 countries that signed up to fulfilling the 2000 Millenium Development Goals to reduce poverty and improve human development, investment into the research and development of new vaccines continues. The result is the development of life-saving childhood vaccines for bacterial pneumococcal and rotavirus infections, as well as an expansion of the global reach of existing vaccination programmes. Yet not all diseases have effective vaccination programmes and even with vaccination programmes some diseases are still proving difficult to eradicate.⁷  In underdeveloped countries, infectious diseases still have a lethal hold: the threat of infectious disease has not gone away (see Figure 1.2 with regards to the prevalence of infectious diseases for high income and low income countries). Lack of access to healthcare systems, effective infection control education, vaccination programmes and antimicrobial chemotherapy treatments, combined with poverty and poor sanitation, means that familiar infectious diseases including bacterial diseases still account for seven out of ten of the top mortality causes in underdeveloped countries.

Another disease that has haunted mankind throughout the millennia is tuberculosis (TB). Also known as the “white plague”, scrofula and consumption, this disease has cut short many lives throughout history, including those of the poets John Keats and Percy Bysshe Shelley, the novelists Emily Brontë, Robert Louis Stevenson and Edgar Allan Poe, as well as the composer Frédéric Chopin and actor Vivien Leigh. As early as the beginning of the nineteenth century, TB had gained notoriety among the medical professions on both sides of the Atlantic as one of the most lethal killer diseases. This disease is still a significant killer and it is caused by the bacterium Mycobacterium tuberculosis. This bacterium resides in the lungs and is spread by water droplets expelled by coughing and sneezing. TB can be an extremely debilitating and deadly disease, but it can also hide as a latent disease, where people are infected with the bacteria but show no symptoms. In these circumstances, the infected person is unable to transmit the disease. A vaccine to TB exists. The Bacillus Calmette–Guérin (BCG) vaccine has been around for more than 80 years and has been the subject of numerous trials and epidemiological studies conducted over several decades. Recent evidence suggests that it offers protection against M. tuberculosis infection.⁸  Yet, even with a protective vaccine, approximately one-third of the world's population has latent TB and are faced with a 10% lifetime risk of falling ill. This risk is greatly increased if you throw other factors into the mix, such as HIV, malnutrition, diabetes or tobacco use. In 2014, the World Health Organisation reported that 9.6 million people fell ill with TB and 1.5 million died from the disease. The majority of these cases are in South-east Asia and Western Pacific Regions, accounting for 58% of new cases, but Africa carried the most severe health burden, with 281 cases per 100 000 population in 2014 (compared with a global average of 133).⁹  Although the treatment regime is severe (a standard six-month course of four antibiotic drugs), TB can be a curable disease if the drugs are provided and taken properly, and if the bacterium causing the disease is susceptible to antibiotics. However, sticking to such a long and unpleasant treatment regime is difficult and of course, as a result, compliance is poor. One of the end results of non-compliance is that this disease continues to spread. This is not the only end result to non-compliance with antibiotic treatment. Alexander Fleming transformed modern medicine in 1928 when he discovered penicillin, but by 1945 Fleming was already sounding a note of caution. In his acceptance speech at the Nobel prize awards ceremony in 1945 Fleming stated:

Antibiotic or Antimicrobial Resistance (or AMR) is a natural phenomenon. On a primordial level, as long as microbes have been producing antibiotic compounds with the potential to destroy other microbes they have also been finding ways to protect themselves from those compounds. This is a necessary step to stop the production of antibiotics turning into a suicidal venture. A microbe that can protect itself from an antibiotic product has developed antibiotic resistance and “underdosing” or administering a sub-therapeutic dose, i.e., exposing a microbe to non-lethal quantities of antibiotic drugs, can make them resistant. This has been the case with TB. We are entering an era when significant cases of TB with resistance to a plethora of antibiotic drugs are starting to emerge. In 2014 it was estimated that 480 000 cases of multidrug-resistant TB (MDR-TB) occurred globally and only 123 000 were detected and reported.⁹  These figures are likely to continue to rise if nothing is put in place to tackle this issue. TB is one example of an “old” disease that has benefited from a vaccination prevention programme as well as treatment options. But now this disease is becoming increasingly resistant to our current arsenal of antibiotic drugs and, worryingly, it is not the only one.

Gonorrhoea is a sexually transmitted infection caused by the Gram-negative bacteria Neisseria gonorrhoeae. It does not have a vaccination programme and it has also developed significant drug resistance. This infamous disease is becoming increasingly difficult to treat and cure. The World Health Organisation reports that gonorrhoea globally infects an estimated 106 million people every year (which represents a 21% increase since 2005). Symptoms include discharge and inflammation at the urethra, cervix, pharynx or rectum, and if it is left untreated this infection can lead to pelvic inflammatory disease and infertility in both women and men.

This bacterium was first treated successfully with penicillin G in 1943, but within 40 years it had developed resistance to this antibiotic (Figure 1.5). Neisseria gonorrhoeae is particularly well adapted at developing resistance to antibiotics. As a result, resistance to other first-line antibiotic treatments have followed quickly. At the moment, gonorrhea needs to be treated with a two-drug cocktail to eradicate the infection: either cefixime (an antibiotic taken orally) and azithromycin or ceftriaxone (antibiotics that have to be injected).

Worryingly, treatment failures with antibiotics in the drug cocktail commonly used to treat this disease are emerging. Cases of resistance to cefixime and ceftriaxone appeared in Japan between 1999 and 2002. Eight years later, in 2010, the first verified cefixime treatment failures were reported in Norway, the UK, Austria and France. However, a recent outbreak of gonorrhoea in Northern England attracted worldwide media coverage when it was reported that a strain of gonorrhea had been found with resistance to azithromycin, the other antibiotic used in the two-drug treatment.

This history of treatment failures shows that multidrug-resistant strains of Neisseria gonorrhoeae are emerging. In the age of easy international travel, we are faced with a worrying scenario of a public health disaster, where we have the emergence of untreatable gonorrhoea.¹⁰ 

As human beings, we share our individual human space with an incredible array of “friendly” commensal bacteria that exist on and in us. They cover our skin, inhabit our gut and are discretely placed inside our body cavities.² This diverse group of microbes have evolved with us and our environment can influence their distribution. We share a mutually beneficial relationship with the billions of microbes that start to colonise us from the moment we are born. We depend on them for many of our bodily functions, such as our defence against potential pathogenic infections and the mechanisms we use to metabolise our food to access the nutritional value. For many years, science has relied on conventional culturing techniques to understand the variety of the microbes that we share our life with. These days, advances in sequencing technology has revealed the complexity and diversity of the microbes (the microbiota) that make up our microbiome (Figure 1.6).¹¹ 

The human gut microbiota, in particular, is a complex microbial community that can interact with and influence human health. Research has indicated that different microbial communities found in the gut are associated with several diseases and disorders, including obesity, diabetes, allergies and inflammatory bowel diseases. In 2011, a paper was published by a group of scientists working as part of the Metagenomics of the Human Intestinal Tract (MetaHIT) Consortium. The consortium of scientists investigated the different microorganism compositions of samples obtained from the guts of a variety of individuals from different countries using modern genetic sequencing techniques. Their results suggested that humans can be divided into three groups based on their gut microbiota. The three types of gut microbiota or enterotypes vary depending on whether the majority of the bacteria enterotypes are either Bacteroides spp. (enterotype 1), or Prevotella spp. (enterotype 2) or Ruminococcus (enterotype 3).¹²  Now, our gut microbiota can be adversely affected by a prescription of antibiotics. As early as the Second World War it was clear that the penicillin used to treat Clostridium perfringens—the bacterium responsible for gas gangrene—could cause typhlitis, a disease that could actually be more lethal than the original gas gangrene itself. It didn't take long before it was clear that it wasn't just a dose of penicillin that caused typhlitis, a plethora of different antibiotics could cause this disease. The intestinal anatomy of patients suffering from typhlitis was examined and it was obvious that the gut lining had physically changed in some patients who had used antibiotics. Other symptoms included disabling antibiotic associated diarrhoea that was very hard to treat. Eventually, it was shown that the physical changes to the human gut and the antibiotic associated diarrhoea were caused by a bacterial pathogen C. difficile. Like most enteric bacterial pathogens, C. difficile and the toxins it produces can causes disease within a wide spectrum of severity, ranging from mild “nuisance” diarrhoea and a normal gut to severe diarrhoea and the formation of ulcerated and necrotised gut tissue.¹³  Most of the time the gastrointestinal tract resists becoming colonised by the bacteria we ingest as part of our day-to-day lives. This phenomenon is known as colonisation resistance. It is not entirely clear how gut microbiota provide colonisation resistance against infection. Perhaps they physically occupy gut space and prevent newly arrived microbes from interacting with cells that line the gut. Or they may interfere with and restrict the growth of potential pathogens by actively competing or withholding nutrients, or perhaps they just encourage the host to effectively combat bacterial infection. What is clear is that antibiotics taken to treat or prevent infections caused by bacterial pathogens can also destroy the bacteria that are part of our normal gut microbiota.

C. difficile infections are very difficult to treat. Antibiotics have been used as a first line treatment for bacterial infections since their discovery and commercial production. When it comes to treating C. difficile infections, the issue arises when the disease you need to treat is caused by the first line treatment that you would ordinarily turn to. One of the key features of this infection, severe diarrhoea, has other consequences. It releases C. difficile back into the environment, where it exists successfully in airborne particles or aerosols that contaminate surfaces, and are extremely hard to eradicate and can cause further infections (Box 1.1).

The skin is another human environment that houses its own microbiome. Skin is a slightly acidic, dry environment with a surprisingly complex topography. Distinct microbial habitats are formed in cutaneous folds and crevices, as well as physical appendages, such as sweat glands, sebaceous glands and hair follicles. Staphylococcus epidermidis is one of the most commonly isolated microbes found on the surface of human skin.¹⁴  It usually exists in a commensal relationship with the host, secreting molecules that prevent infection by other potential pathogenic bacteria, such as S. aureus. This relationship between S. epidermidis and its human host is probably the result of a long-term co-evolutionary history with this bacterium. But this S. epidermidis has a dark side: it can become an opportunistic pathogen when it breaches the skin surface and enters the bloodstream. It is a leading cause of infections associated with the use of medical devices in seriously ill or immunocompromised patients.¹⁵ 

S. aureus is another bacterium carried by about a quarter of the population. This bacterium nestles near the mucous membranes found in the nasal passages, the groin and the perineum. It is also a commensal bacterium that can exist harmlessly as part of the microbiome. But it is also an opportunistic pathogen when it gets into the wrong place. S. aureus has developed processes that allow it to enter parts of our bodies, such as the skin, where it can cause impetigo, a highly infectious skin disease that spreads rapidly among children and families if robust hygiene practices are not used (Figure 1.7).

Left to itself, impetigo will usually clear up within 6–8 weeks, but antibiotics can markedly speed up and aid the recovery process. Now, impetigo is not a pleasant condition; it can be uncomfortable and itchy but, in general, it is not life threatening. S. aureus has developed chemical tricks that enhance its virulence. For example, it produces an enzyme called hyaluronidase that breaks down the glue that holds cells together. This allows it to attack the skin. It also produces haemolysin that allows it to break down red blood cells. If S. aureus is able to enter the blood stream, perhaps through a traumatic injury or as a side effect of an operation, it can cause septicaemia and even death. S. aureus used to be treated with penicillin, but resistance to penicillin had developed by the late 1960s and different antibiotics, including methicillin, had to be deployed to treat this potentially fatal disease. This strategic move introduced an unexpected side effect. A new strain of bacteria emerged: the infamous methicillin resistant S. aureus, (MRSA), which is one of the superbugs that has become resistant to antibiotics. Infections caused by MRSA have much less favourable outcomes compared to infections with methicillin susceptible S. aureus (MSSA)—S. aureus that can be effectively treated with methicillin. Patients infected with an MRSA strain of S. aureus have a 69% higher risk of developing complications than patients infected with the MSSA strain. They are more likely to develop sepsis and to lose limbs as a result. In fact, patients infected with MRSA are more likely to die (2–3 times greater risk) compared to patients with an MSSA infection.

MRSA is not the only pathogen that is causing us concern. In 2009, the concept of the ESKAPE pathogens emerged. The ESKAPE acronym was derived from the first letters of a suite of the most common pathogens that are resistant to many clinical antibiotics and are causing real concern among the clinical and scientific community. These pathogens are:

• Enterococcus faecium,

• Staphylococcus auerus,

• Klebsiella pneumoniae,

• Acinetobacter baumannii,

• Pseudomonas aeruginosa,

• Enterobacter.

In 2013, The Center for Disease Control (CDC) in America published a report that contained a list of the top eighteen drug-resistant threats to the USA that included many of the ESKAPE pathogens described above. These threats are categorised based on current levels of concern: urgent, serious and concerning.¹⁶ 

Many of the bacteria that make the ESKAPE list are responsible for healthcare associated infections (HCAI) or nosocomial infections. These are infections that occur in patients who receive care in a hospital or another healthcare facility. The infection may appear after the patient is discharged, but it was not present at the time of admission. Nosocomial infections are also infections experienced by healthcare staff that are caused by their work. The list produced by the CDC includes MRSA and MSSA, as well as diarrhoea caused by C. difficile infection or infections following surgery (Table 1.3).

Nosocomial infections are a significant financial burden to healthcare systems,³ patients and their families. They prolong hospital stays, create long-term disability and cause unnecessary deaths. Statistics suggest that HCAIs annually account for at least 37 000 attributable deaths in Europe and 99 000 deaths in the USA (Table 1.4).

In high income countries, the most frequent HCAI is a urinary tract infection often caused by catheter use. It is patients in intensive care units, the elderly and the very young that are the most susceptible to HCAIs and millions of patients are affected each year. Nosocomial infections in healthcare settings with limited resources affect up to one-third of operated patients. Of course nosocomial infections often require antibiotic treatment and, as a consequence, they present a growing problem when it comes to antibiotic resistance.

The current death toll ascribed to antibiotic resistance related disease is significant. In 2013, the CDC in the USA calculated that 23 000 deaths were attributable to antibiotic resistance in the USA and estimates for the European Union (EU) suggest that in 2011, 25 000 deaths were caused by antibiotic resistance. A conservative estimate is that, on a world-wide stage, antibiotic resistance has been responsible for 700 000 deaths. This situation is set to get worse as antibiotic resistance levels continue to rise. A recent review published in the UK calculated that if current antibiotic resistance levels increased globally by 40%, by 2050 antibiotic resistance will be responsible for an average 10 million deaths annually (Table 1.5 and Figure 1.8).

It is against this backdrop—a growing number of bacterial diseases that are not responding to the current arsenal of antibiotics we have at our disposal—that Dame Sally Davies, England's Chief Medical Officer, issued a statement that includes a stark warning about the catastrophe we face if we do not immediately address this threat. This is a situation that Edwin Chadwick, if he were alive now, would recognise. We are knocking at the door of an era when diseases such as syphilis, gonorrhoea, scarlet fever, dysentery, diphtheria, tuberculosis, measles, the plague, typhoid and typhus are becoming more and more difficult to treat and cure with antibiotics. In addition, we have the emergence of new diseases, such as Legionnaires’ disease and Lyme disease, that are presenting novel, modern day problems. These are global diseases affecting humanity on every habitable continent. The catastrophe is the terrible impact and burden that antibiotic resistance is likely to have on human life. But the catastrophe is also an economic one. Infections associated with antibiotic resistance require significant healthcare expenditures. Money needs to be spent on ordering the additional tests to understand the microbes that cause the growing number of antibiotic resistant infections. More intensive and longer lasting treatments with second line therapies—that often have nasty side effects and therefore need additional treatments—will have to be paid for. Patients and their families will experience other healthcare expenditures, such as lost income due to time taken off work because they will have developed an illness, either associated with the original infection or caused by the side effects of the second line treatments they have been forced to take. It will not be unusual for patients to die and this will have significant financial consequences for the families, relatives and dependents that they leave behind. The ultimate cost of antibiotic resistance is societal. Estimates suggest that if we keep our current rate of antibiotic resistance, by 2020 we will have lost 600 000 working age people. If current antibiotic resistance rates increase by 40%, then in 2020 this figure rises to 1 million and by 2050 we will lose an additional 4 million working age people as a direct result of antibiotic resistant infections. If rates remain unchanged in the fourteen Organisation for Economic Co-operation and Development (OECG) countries,⁴ there will be a contraction of gross domestic product (GDP) equal to 0.03% by 2020. If nothing changes and antibiotic resistance rates stay the same, the result will be a cumulative loss of about 2.9 trillion US dollars. But if the AMR rates increase by 40%, the impact is that by the year 2020 the GDP loss will double. The argument for addressing the growing problem of antibiotic or antimicrobial resistance has become an economic one.

Antibiotic resistance is a natural phenomenon, and Sir Alexander Fleming's prediction that antibiotic resistance would develop in pathogens that are capable of causing diseases is horribly accurate. Humans are playing a crucial role in the development and spread of antibiotic resistant microorganisms. The consumption of antibiotic drugs is strongly associated with the development of antibiotic resistant microbes. The more antibiotic products that are consumed, the more likely it is that antibiotic resistance is generated (Figure 1.9).

The reasons for this are multifaceted, but they include “underdosing”: exposing a microbe to non-lethal quantities of antibiotic drugs through poor compliance to the antibiotic treatment programme, as seen in the case of TB. Inappropriate prescribing of antimicrobials has also contributed to the problem. Antibiotics, such as penicillin, are effective against bacteria but they are not appropriate for infections caused by viruses: they do not work against these microbes. Prescribing antibiotics for a viral infection, such as the cold or flu, simply provides opportunities for bacteria to develop antibiotic resistance and will not help to cure a viral infection. What exacerbates this worrying situation is that when a bacterium develops antibiotic resistance to a drug such as penicillin, the changes in the bacterium's biology often makes the bacterium resistant to a score of other antibiotics too. Counterfeit and sub-standard antibiotics are also a growing problem in developing countries and 10% of the market in counterfeit antibiotics is directed towards European and North American countries. Just to make matters worse, in many countries there is very poor regulation of antibiotic drugs. A plethora of antibiotic drugs can be bought quickly and easily across the counter without a prescription (Figure 1.10).

Even countries that have successfully curtailed their use of antibiotics are not protected from antibiotic resistant bacteria. The rapid movement of large volumes of people through tourism and migration enables resistant bacteria to be trafficked around the globe. The spread pattern of MRSA is a classic example of this phenomenon. The first cases of MRSA emerged in the UK in 1959. By the end of the 1960s, MRSA had spread across Europe and by the end of the 1970s, it was firmly established as a global issue. Antibiotic resistant gonorrhoea and TB are also excellent examples of diseases with rapid, modern, global, migrating patterns.

Antibiotics are not fully metabolised by humans and animals, although some antibiotics are metabolised better than others.⁵ What this means is that after a dose of antibiotics has been consumed or injected, a large proportion of antibiotics is excreted back into the environment via urine and faeces. As antibiotics can be quite stable chemical compounds, they can happily remain in the environment at sub-therapeutic levels.⁶ The consequence is that environmental bacteria are encouraged to develop antibiotic resistance. The net result is that the problem spreads.

Ironically, the manufacture of antibiotics by pharmaceutical companies is also adding to the problem of antibiotic resistance. Significant levels of antibiotic residue are found in water systems close to these production plants and as the waste water moves away from the production plants, the concentration of antibiotics is reduced until it reaches the sub-therapeutic levels that encourage the development of antibiotic resistant bacteria throughout water systems.¹⁹ 

Serious concerns exist about how human consumption of antibiotics is adding to the problem of antibiotic resistance, but it may not be the main cause of this problem. In 2012, in 26 EU/European Economic Area (EEA) countries, 3400 tonnes of antimicrobials were sold for human use. Compare that to the 7982 tonnes sold for food-producing animals. The estimated biomass, expressed as 1000 tonnes, was 28 884 for humans and 55 421 for animals, respectively, although these figures varied significantly between countries.⁷

Animals develop infectious diseases too. Bacteria that respond successfully to antibiotic treatment cause many of these infectious diseases. So, of course, antibiotics are widely used to prevent or treat disease in the animals used for food. Disease is always a concern in the animal food industry, especially in modern agricultural production, where high density, close proximity animal husbandry in tight/constricted environments can lead to infections that can spread quickly and wipe out flocks. To combat this, antibiotics are used therapeutically to treat individual animals with a clinical disease. This therapeutic approach occurs in pets, horses and cattle. However antibiotics are often added to animal feed to prevent infection such as mastitis, a disease that dairy cows are prone to develop at the end of the lactation period. This is prophylaxis—an approach to provide a treatment to prevent a disease from occurring. Metaphylaxis is a different approach that is often used in animal husbandry. If one animal in a flock or herd shows signs of an infection not only is that animal treated with antibiotics but the whole herd is treated with the medicine to prevent the disease sweeping through the flock or the herd. Now, what is concerning about this approach is that many of the antibiotics that are used to treat animal infections are also used as human medicines.

There is a surprising benefit associated with antibiotics. They stimulate growth if they are fed to poultry. For the poultry industry, the advantages are obvious: adding antibiotics to poultry feed increases the yield (size of the animal) and decreases the rearing time—the result is that profit margins increase. It is still not well understood how or why antibiotics have this effect on poultry. Theories include the idea that antibiotics knock out the poultry gut microbiome and allow the poultry to increase their absorbance of nutrients from their gut. Another theory suggests that perhaps antibiotic consumption results in fewer poultry bacteria. The poultry need to expend less time and energy fighting off potential infections and they invest that surplus energy into growing more quickly.

The problem with supplying antibiotics to poultry feed, either prophylactically or as growth enhancers, is that ultimately some animals will receive a sub-therapeutic dose. This allows opportunities for bacteria in poultry microbiomes to develop antibiotic resistance. Often these resistant bacteria end up being excreted in animal faeces and they end up contaminating the local environment. In some countries, droppings are collected and used as a cheap effective fertiliser for plant crops that are used for human consumption. This has the significant disadvantage of spreading resistant bacteria to new environments.

Antibiotics are also used in apiculture or beekeeping to control disease outbreaks such as foulbrood, a disease caused by the Paenibacillus larvae and Melissococcus plutonius. These diseases affect bee larvae and can lead to the destruction of the whole bee colony. The falling bee population is a global concern. Bees are responsible for pollinating many of the plant crops that the human population depends on across the globe. Fighting bee infections is a necessity. The USA, Canada and Argentina have used oxytetracycline to treat P. larvae infection but resistance to this antibiotic has already developed in bee populations. Other antibiotics that have been used to treat bee infections include erythromycin, chloramphenicol and fluoroquinolones. Honeybees are unable to use or metabolise these antibiotics themselves and high levels of these antibiotics can often be found in the honey they produce—and that humans consume—up to a year after the hive was treated.

Aquaculture is another global growth industry that is responding to increasing consumer demand, in this case for fish and shellfish. This industry also uses intensive farming methods. Fish are raised in stressful environments. They are exposed to a number of stressors, such as high fish density, closed compartmentalised farms and human handling. Being exposed to these stressors lowers the fish's natural immune responses making them vulnerable to bacterial infections, such as Aeromonas salmonicida, Vibrio anguillarum, Lactococcus garvieae and Flavobacterium spp. These infections can wipe out fish stocks and cause significant financial losses to the industry and ultimately increase prices on world-wide markets. The solution has been to adopt the use of prophylactic antibiotics—added to fish feed—to protect the farmed fish from these infections. Unsurprisingly, and par for the course, the use of antibiotics in aquaculture has led to antibiotic resistance developing in the pathogens that attack fish and shellfish stocks. The high-density fish farming environments that are used within the aquaculture farms has exacerbated this. Often, fish farms are situated in open bodies of water where bacteria with antibiotic resistance can leach into the wider natural environment through tidal movements and water currents. Antibiotic resistant pathogens can also be “picked up” by the migration and movement of wild fish that pass by fish farms, and they carry them further afield. Antibiotics are added to the fish feed that is sprinkled into the water. They can leach out of the feed into wider bodies of water, causing the concentration of antibiotics to plummet, especially if the farms are located in free running rivers or in open waters. This has the unfortunate effect of creating a situation where bacteria (including bacterial pathogens) are exposed to sub-therapeutic levels of antibiotics that can enable antibiotic resistance to develop. Antibiotic resistance that develops in the aquaculture industry can spread to human pathogens. Resistance to tetracycline that was found originally in the fish pathogen Vibrio anguillarum has also been identified in the food poisoning bacterium Salmonella enterica, and in 1993, an antibiotic resistant cholera outbreak in Latin America was due, in part, to the extensive use of antibiotics used in the Ecuadorian shrimp industry.

In 1969, in the UK, the Swann report recommended that if an antibiotic was used to treat human bacterial infections, they should not be added to animal feed. Many companies and many countries voluntarily signed up to this recommendation. Unfortunately, when it came to preventing antibiotic resistance, the outcome of this restrained use of antibiotics was not as successful as many had hoped for. To fall in line with the report recommendations, pharmaceutical companies and the agriculture industry swapped to different antibiotic pharmaceutical compounds that were not used for human medicine. But these new compounds were similar to the ones used to treat human infections. This meant that when the inevitable bacterial resistance developed in agricultural environments to these alternative antibiotic compounds, the bacteria had also developed resistance to the antibiotics used to treat human diseases. One such alternative drug is the antibiotic avoparcin that was added to animal feed. There are enough similarities between avoparcin and vancomycin to allow bacteria to develop resistance to both avoparcin and vancomycin. Now, this is a significant problem that is affecting human health because vancomycin is one of the few antibiotics that is left to treat an MRSA infection in humans. The idea that bacteria are developing widespread resistance to vancomycin—a so called antibiotic of last resort—is a worrying clinical development that is sounding alarm bells across the globe. In fact, it was such a worrying development that in the EU avoparcin and others like this drug, that showed worrying cross-resistance to treatment options being used in human medicine, were withdrawn voluntarily across the agricultural sector. In 2006, legislation in the EU was implemented that prevented the use of most antimicrobials as growth promoters added to animal feed. Sadly, outside of the EU it is not such a positive picture. Although the Food and Drug Administration (FDA) has proposed that the agricultural industry signs up to a voluntary code of conduct to begin to reduce their reliance on antibiotics, the USA still allows antibiotics to be added to animal feed as growth enhancers. In the USA, the amounts of antibiotics used in the animal industry outstrips the amount used by humans. Data from 2011 revealed that humans used 3.29 million kg a year compared with 13.5 million kg a year used in animals, which reflects the large poultry and livestock production of the USA. In other parts of the world, voluntary codes of conduct don't exist either, and antibiotic use is rife and unregulated.

Nearly all the classes of antibiotics currently used to treat human infections are also being used in food animals, including the newest classes of drugs, such as third- and fourth-generation cephalosporins, fluoroquinolones, glycopeptides and streptogramins.²⁰  Using antibiotic agents in agriculture has supported the intensification of modern food-animal production by allowing higher animal farming densities and the use of cheaper feed source. This has contributed to increased outputs and lower prices of meat to meet the demands of the modern consumer society. This is set against the fact that using antibiotics to support food-animal production has led to increasing levels of resistant bacteria appearing in animal reservoirs and the wider environment (Figure 1.11).

In developed, industrialised countries, antibiotic resistant bacteria can be transmitted to humans through direct consumption of animal products: the food-borne route through the ingestion of meat, fish and shellfish (shellfish can concentrate pathogenic bacteria from human and animal sewage discharges) that contain antibiotic resistant bacteria. Direct contact between animals and humans is another major route of transmission and MRSA can be spread this way. Bacteria with resistance and antibiotic residues from food-animal production are widely spread throughout the environment (mainly in manure). As a direct result of this environmental bacterial contamination, wild fauna can become reservoirs of antibiotic resistance and reintroduce resistant bacteria back into the food-animal chain and ultimately to humans. Demand for animal protein looks likely to increase for the foreseeable future and current projections suggest that the corresponding demand for antibiotics will increase by about 67% focused on developing countries (Figure 1.12).

The increasing levels of antibiotic resistant bacteria would not be such a threat if we had new, alternative antibiotic therapies in the pipeline to replace the antibiotics that are no longer effective. Currently, this is not the case. Shortly after the discovery of penicillin in 1928, a plethora of new antibiotics was discovered; this was the golden age of antibiotic discovery and it lasted for about 20 years. During this period, resistance to an antibiotic drug was a nuisance but it wasn't a significant problem. There always seemed to be a supply of alternative antibiotic drugs that could be used instead. But it didn't take long before novel compounds stopped being found. Instead, it was just the same old antibiotics that began to be discovered and rediscovered again and again. Not to be beaten by this, scientists turned their attention to improving the screening methods they used for discovering new antibiotics. They started to manipulate and chemically tweak the antibiotic drugs that had been discovered previously. New types and classes of semisynthetic and man-made antibiotics started to be produced.²¹  But the yield from these approaches was limited in both output and duration and new antibiotics were in short supply. The last major class of antibiotic was discovered in 1987. Since then, we have gone through a period where new approaches to drug discovery have been tried. These approaches have turned their back on the concept that the best place to look for a new antibiotic is to study the microbial world. Instead, the new approaches rely on automated techniques to screen vast libraries of different pharmaceutical compounds to find new drugs with potential antibiotic properties against pathogenic bacteria. Disappointingly, this approach has been surprisingly unsuccessful. The speed with which new antibiotics were found in the golden age of antibiotic discovery is only matched by the disappointing speed with which discovery and development of new antibiotic compounds has dried up.

Since the 1950s, investment in pharmaceutical research has been driven and underpinned by a profit model that depends on the exclusive market rights for any new product. Pharmaceutical companies will invest money in research and development if they know that they can recoup their investment and hopefully make additional profit returns when their new product comes to market. The more products that a pharmaceutical company can persuade doctors to prescribe and patients to buy and use, then the better the financial returns. Unfortunately, this profit model doesn't work with antibiotic drug discovery. The high costs involved in the initial drug discovery and development still remain, but there are problems when it comes to bringing the product to market. First of all, if an antibiotic works well—it is an effective treatment for a bacterial infection—in most cases it is prescribed as a short, restricted course of treatment (1–2 weeks). Having a drug that is effective in such a short period of time is great for consumers and patients. It is not so great for drug companies that need to sell large quantities of their product to recoup investment and make a profit. Secondly, with antibiotics, the more product that pharmaceutical companies persuade us to use, the quicker resistance develops to that product, and the quicker the product stops being effective and is therefore no longer prescribed. Again, this leads to a situation where there is less opportunity for drug companies to recoup their initial investment. Of course, we can always slow down the development of antibiotic resistance. If these new drugs are restricted and they are used sparingly—perhaps as a last resort—then the speed with which bacteria develop resistance will be slowed significantly. This will ensure that an alternative drug is available even when other antibiotic treatment options fail. It becomes the drug of last resort to be kept on the shelf until all other alternatives have failed. This is an aspirational position for the consumer market, but for a pharmaceutical company it is an extremely unattractive proposition. Why would it make an investment in the antibiotic market if the product it produces is designated a drug of last resort? This is one of the reasons why pharmaceutical companies are withdrawing investment in antibiotic drug development. Would a pharmaceutical company with a responsibility to generate profit for their shareholder invest in an antibiotic product that has a limited lifespan or is earmarked for restricted use? It simply doesn't make investment sense.

The optimism that followed some of the most influential scientific and medical discoveries has faded and has been replaced by a genuine 21st century fear about the future of infectious disease.

The discovery of antibiotics has transformed human lives. We have relied on antibiotics to cure bacterial infections and their use has transformed modern surgery by reducing the risk of developing potentially life-threatening infections. We have also used antibiotics to support the increasing demands placed on food production industries to ensure food security. Society relies on antibiotics, but as a result the manufacturing process used to synthesise the drugs, as well as their widespread use, is threatening their future effectiveness in human medicine. Antibiotics are the only class of drug to become clinically inactive the longer they are used. The good news is that society is at last waking up to this global concern. The World Health Organisation and governments across the globe are focusing attention on this multifaceted issue and a plethora of reports have been written and published describing the problem. Money is starting to be invested in order to tackle the growing threat of AMR and there is a growing understanding that there needs to be changes to legislation to underpin and support policy change to address this growing problem of antibiotic resistance.