Rise of the Resistance

The growing issue of antibiotic resistance

Today is European antibiotic awareness day. The European center for disease control (ECDC) has published more worrying statistics on the seemingly inexorable rise of multi-resistant gram negative bacteria (here) and is pushing the viewpoint that resistance is everyone's problem.

Sadly, awareness remains low in the public as a whole, although recent press releases from the UK Department of Health and Centers for Communicable Disease Control in the US have led to front page stories.

As a small contribution to public awareness of this problem, I spoke recently on local BBC Radio Coventry and Warwickshire and wrote about it for the public-facing website of my university. I have reproduced that text here.

Rise of the Resistance

“Take care, not antibiotics”, we are urged by NHS England as the flu season comes upon us again. In one of many new experiences since I started at Warwick, in the new Division of Microbiology and Infection, I found myself on BBC local radio talking about some of the background to this slogan and the threat of antibiotic resistance in bacteria. This is a subject close to my heart. As a clinical microbiologist at Heartlands Hospital, I routinely deal with the problems posed to patient care by antibiotic-resistant bacteria; as a researcher, I am trying to understand the spread of antibiotic resistance.

Antibiotic resistance – a cause for concern?

My media interview on the BBC came about as a result of comments from Dr Srinivasan at the Centers for Disease Control and Prevention (CDC) in America. In an interview with Frontline, he stated that both humans and livestock have been overmedicated to such a degree that bacteria are now resistant to antibiotics. This led to a proliferation of media coverage suggesting that we’ve reached a point where antibiotics no longer work.

Antibiotic resistance is a significant cause for concern in the US. Every year, at least two million people become ill with drug-resistant infections. But it’s also a problem globally. A number of medical organisations, including the World Health Organisation (WHO), have warned that the overuse of antibiotics and the resulting evolution of resistant bacteria are causing a public health crisis.

Understandably people found these news reports very alarming. But antibiotics are still wonder drugs, saving hundreds of thousands of lives without question every year. Even penicillin remains incredibly effective in the infections we use it for. However we are seeing more antibiotic resistance than we did 30 years ago and this poses a serious risk to human health. The spread of resistant bacteria in hospitals is a major issue for patients' safety and it’s a problem in hospitals across the UK and Europe.

However, the good news is that many countries are implementing measures to stem this. In the UK as well as launching the “Take care, not antibiotics” public health campaign, the Department of Health published an antibiotic resistance strategy in September. This recommended that we limit the use of antibiotics and fund research not only to develop new antibiotics but also to help us understand why resistance spreads.  

Researching antibiotic resistance

My entry point into the fascinating complexity of this subject is through a bacterium intimately connected with influenza. The bacterium is called Haemophilus influenzae because it was originally found in the lungs of people who had died from the flu. Haemophilus influenzae is not the cause of flu, which is a viral illness. However, much of the mortality from the flu results from the fact that the virus renders a patient’s lungs much more susceptible to bacterial infection. This means that if you have a nasty case of the flu you can become vulnerable and more likely to pick up something else, for example, pneumonia, of which H. Influenzae is an important cause and it’s this that can kill.

A lethal synergy

This relationship between the influenza virus and H. influenzae, is a lethal synergy. It has been observed in clinical cases and elegantly demonstrated in animal models of disease, most recently by Wong and colleagues in the US. Immunisation against H. influenzae type b, or Hib, has been highly successful in virtually eliminating serious illnesses caused by H. influenzae in children. However, not all strains of the bacterium are covered by the vaccine and it is these non-vaccine strains which cause serious disease in an increasingly elderly population. Diseases caused by H. influenzae and other respiratory bacteria, notably Streptococcus pneumoniae, account for up to 75 per cent of the antibiotic consumption in the developed world.

Clever creatures

In common with many other bacteria, H. influenzae has become increasingly antibiotic-resistant in the past few decades. The principal reason for this in Haemophilus is that it has acquired a large segment of DNA, known as a genetic element, with genes encoding resistance to common antibiotics. Bacteria are clever. They can, and do, freely and promiscuously exchange DNA and genetic elements with other members of the same species and other, often very distantly-related, species.

Bacteria have been sharing genes for millennia, but the use and abuse of antibiotics in healthcare, veterinary medicine and agriculture has undoubtedly led to a new breed of super resistant bacteria, resulting in the problems that we face today. The evolution of antibiotic resistance is natural selection in action. The presence of an antibiotic in a person, animal or ecosystem such as waste-water plant, kills all the vulnerable (susceptible) bacteria, leaving open the habitat for resistant bacteria. The presence of the antibiotic can itself promote the sharing of genes and because genetic elements often carry genes for resistance to many antibiotics, this drives the evolution of multiple antibiotic-resistant bacteria.

My research focuses on a particular genetic element, known as an ICE (integrating and conjugating element). This was first detected in H. influenzae but it is stably present in many bacterial species which are separated from H. influenzae by millions of years of evolution. Not all of the elements carry antibiotic resistance genes, rather they seem to be efficient capture and transfer mechanisms for genes which will benefit bacteria in whichever environment they happen to inhabit.

I am using RNA sequencing technology to explore the transfer of this genetic element in response to antibiotics and other stresses common to H. influenzae’s lifestyle, such as the presence of free oxygen radicals and competing bacteria. As the genetic element is present in so many bacterial species, insights gained in this species are likely to apply to a wide range of antibiotic resistant bacteria of profound relevance to human and animal health.

The future of antibiotics

Furthering our understanding of how antibiotic resistance genes spread and what triggers the spread, is vitally important in preserving the utility of the antibiotics in current use. There has been an alarming dearth of new antibiotics developed in recent decades. However, new developments may now be restarting with government and commercial initiatives. Understanding how resistance arises and spreads may enable the conservation of the efficacy of these new antibiotics as long as possible. It may also lead to more intelligent antibiotic design. Potentially the antibiotics of the future will be less likely to cause the spread of resistance.

My research, and that of others working in this field, will help to underpin the strategy outlined by the UK Chief Medical Officer in September to deal with the serious threat of antibiotic resistance to human health. It’s possible that with this work the “end of antibiotics” needn’t become a reality.