The Microbes Fight Back

Antibiotic Resistance

By Laura Bowater

The Royal Society of Chemistry

Copyright © 2017 Laura Bowater
All rights reserved.
ISBN: 978-1-78262-167-6

Contents

Chapter 1 Antibiotic Resistance: The State of Play Today,
Chapter 2 The Microbiologists,
Chapter 3 Public Health and Infectious Diseases,
Chapter 4 Microbial Makeup and Antibiotic Targets,
Chapter 5 What is Antibiotic Resistance?,
Chapter 6 Spreading Antibiotic Resistance?,
Chapter 7 Moving Forward While Looking Back,
Glossary,
Subject Index,

CHAPTER 1

Antibiotic Resistance: The State of Play Today

1.1 PRICEY PLAGUES

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

“more effective provision … for improving sanitary conditions of towns and populace places in England and Wales.“

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).

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.

1.2 THE ADVENT OF THE ANTIBIOTIC ERA

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.

1.3 NEW DISEASES

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 nC and below 20 °C. In cool conditions, the bacteria hibernate while they wait for conditions that are more favourable for growth. 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. 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).

1.4 VICTORIES WITH VACCINATIONS

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. 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. 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.

(Continues…)Excerpted from The Microbes Fight Back by Laura Bowater. Copyright © 2017 Laura Bowater. Excerpted by permission of The Royal Society of Chemistry.
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