Antibiotic resistance

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25,000 deaths a year resulting from antibiotic resistance in Europe.

Resistance genes can be exchanged at very high frequency, up to one in 100 bacteria.

Antibiotics are drugs used to fight bacterial infections such as pneumonia, bronchitis, ear infections, meningitis, urinary tract infections, septicemia and sexually transmitted diseases. The discovery of antibiotics was a major milestone in medicine that has saved and continues to save millions of lives every year, but their effectiveness is threatened by the ability of bacteria to adapt and resist treatment. Antibiotics kill bacteria or stop them spreading. Resistant bacteria no longer respond to these drugs. This phenomenon is known as antibiotic or antibacterial resistance.

Infections in humans and animals caused by resistant bacteria are harder to treat than those caused by non-resistant (or "susceptible") bacteria. Some bacteria are resistant to several antibiotics; these are known as multidrug resistant (MDR) bacteria. In extreme cases – which fortunately are still very rare – bacteria can be resistant to all available antibiotics used in humans. These pan-resistant bacteria can lead to therapeutic failure. MDR bacteria that are a particular cause for concern are multidrug resistant Enterobacteriaceae (such as Escherichia coli and Klebsiella pneumoniae, bacteria in the digestive tract that cause a wide range of infections); methicillin-resistant Staphylococcus aureus; multidrug resistant tuberculosis bacilli; and Pseudomonas aeruginosa and Acinetobacter baumannii, bacteria that infect the lungs of cystic fibrosis patients and cause nosocomial infections (infections acquired in healthcare facilities or hospitals).

Causes and effets

Bacteria can become resistant to antibiotics either through mutation or by acquiring a resistance gene that confers resistance to one or more antibiotics. Bacteria are capable of exchanging genes. These exchanges are especially problematic when it comes to antibiotic resistance. While the acquisition of resistance through mutation is extremely rare – occurring in approximately one in every billion bacteria – resistance genes can be acquired much more frequently, by as many as one bacterium in every hundred.

Antibiotic resistance does not just affect disease-causing bacteria. The friendly, non-pathogenic bacteria that colonize us and make up our microbiome can also develop resistance, creating a reservoir of resistance genes that can then spread to pathogenic bacteria. Antibiotics fall into two categories: broad-spectrum antibiotics, which can kill a wide variety of bacterial species, and narrow-spectrum antibiotics, which target specific types of bacteria. If the bacterial species responsible for an infection has been identified, it is preferable to use a targeted antibiotic, as this will have a lesser impact on the microbiome and the development of resistance.

Taking antibiotics disrupts our microbiome and contributes to an increase in our reservoir of resistance genes. This is true for antibiotics prescribed for bacterial infections but it also applies when antibiotics are taken for viral infections such as colds or flu – on which they actually have no effect. The microbiome serves as a barrier to protect us against infections, so when the microbiome is disrupted (this is known as dysbiosis), the effectiveness of this barrier is reduced. Taking antibiotics for no reason is therefore harmful in two ways: it encourages colonization by resistant bacteria, increasing the risk of a subsequent infection that can be difficult to treat, and it also disrupts the microbiome.
Underdosage of antibiotics, which can occur when treatment is interrupted mid-course or with the use of counterfeit drugs sold in some low-income countries, can also encourage the selection of resistant bacteria.

A global phenomenon. Although antibiotic resistance can be observed in all countries, some are affected to a greater extent than others. One major contributing factor is the country's level of antibiotic consumption. Resistant bacteria are also found in animals and in the environment. Human medicine, veterinary medicine and environmental pollution by antibiotics therefore contribute to the increase in resistance. Moreover, resistant bacteria and resistance genes can also spread between humans, animals and the environment – so the use of antibiotics in veterinary medicine and the disposal of antibiotics in the environment can foster the emergence of new multidrug resistant bacterial strains.

Epidemiology

The European Center for Disease Prevention and Control (ECDC) estimates that 25,000 people die in Europe each year as a direct result of antibiotic resistance. A similarly high death rate has been observed in the United States by the Atlanta-based Centers for Disease Control and Prevention (CDC). There is a shortage of data for low-income countries, but the increase in resistance in these countries, together with difficulties accessing safe antibiotics (when antibiotics are actually needed), are probably responsible for a high number of deaths. Increasing antibiotic resistance will lead to a dramatic rise in these figures, as indicated in the report by Lord J. O'Neill on the impact of antimicrobial resistance by 2050.

Recognizing a looming crisis

On April 30, 2014, the World Health Organization (WHO) published its first global report on antimicrobial resistance – including antibiotic resistance – that emphasizes "this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country." It adds that if no action is taken, "the world is headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill". This international organization views antibiotic resistance as an emergency. On February 27, 2017, it published a list of bacteria for which new antibiotics are urgently needed.

In the early 2000s in France, the national plan to preserve the efficacy of antibiotics provided for surveillance of bacterial resistance to antibiotics under the aegis of Santé Publique France (previously the French Institute for Public Health Surveillance – InVS). In a report on the surveillance data published in November 2015, the French health authorities emphasized that "over time, the widespread, repeated use of antibiotics in human and animal healthcare is leading to an increase in bacterial resistance. Most antibiotics do not only act on their specific target, the bacterium responsible for the infection that needs to be treated, but also on other targets such as the commensal bacteria in the digestive tract, which are useful, non-pathogenic bacteria." Despite this plan, the level of antibiotic consumption in France remains particularly high. Twice as many antibiotics are prescribed by general practitioners in France as in Germany or the UK, two socio-economically comparable countries.

European Antibiotic Awareness Day is held every year on November 18. On this day in 2016, Santé Publique France, the French National Agency for Medicines and Health Products Safety (ANSM) and the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) published a report on antibiotic consumption and resistance in France.

Preventing and combating antibiotic resistance

Two strategies have been developed by scientists in the public and private sectors, clinicians and public health stakeholders to prevent this antibiotic resistance crisis and rule out the worrying prospect of a future without effective antibiotics.

  • First, it is vital to limit or even reverse the increase in antibiotic resistance and to control reservoirs of resistance. That is why we need to improve our understanding of how resistant bacteria and resistance genes are spreading at global level and unravel the methods used by these bacteria to replace susceptible bacteria. It is also crucial to characterize the mechanism of action of antibiotics and antibiotic combinations at the site of infection for all pathogenic bacterial species. This research will lead to more effective use of currently available antibiotics, thereby reducing consumption levels.
  • The second strategy involves searching for new antibiotics that are effective against resistant bacteria. Developing effective antibiotics is a long and increasingly complex process. A new antibiotic has to be able to kill bacteria while causing minimal unwanted side effects for patients. It must remain in our metabolism for long enough before being destroyed, and it must act at the site of infection. The emergence of bacteria that are resistant to the new antibiotic must be an extremely rare occurrence.

It is vital to avoid the misuse or excessive use of antibiotics, which speeds up the development of resistance. Public authorities, healthcare professionals and the healthcare industry must take the initiative in addressing this issue, but every individual also has a part to play. It should be emphasized that unnecessary antibiotic consumption has long-term negative effects both at individual level and for society as a whole. This effort to limit antibiotic consumption does not just apply to human medicine; it also concerns animals, especially livestock. According to WHO, half of all antibiotics used worldwide are given to animals. In several countries, livestock are constantly given low doses of antibiotics to speed up growth and promote weight gain. This practice, which is banned in the European Union, contributes to the development of resistance which can then be transmitted to humans. In France, the ÉcoAntibio Plan launched in 2011 has led to a 20% reduction in overall exposure of animals to antibiotics over a five-year period.

Hygiene remains a vital means of avoiding infections and the subsequent need for antibiotics. Although antibiotic resistance occurs all over the world, it is especially prevalent in countries with low levels of hygiene. In France, detailed checks for MDR bacteria carriage are carried out in hospitals as soon as a new patient arrives. These laboratory tests, together with stringent hygiene regulations, are helping to reduce outbreaks.

It is important to emphasize that vaccination against bacterial infections is a way of preventing the onset of disease and the subsequent need for antibiotics – which may ultimately prove ineffective in the event of antibiotic resistance. Vaccination also means that we can avoid the unwanted effects of antibiotics on our microbiome. Pneumococcal vaccination, for example, has led to a significant reduction in antibiotic resistance for this bacterial species.

Given the increase in antibiotic-resistant bacteria and the difficulties in developing effective new antibiotics, various alternative strategies are being investigated. Phage therapy has been the focus of renewed interest among the scientific community in the past few years. This alternative to antibiotics is a promising avenue for research. It involves eliminating bacteria by using specific viruses (called phages) to kill a given bacterial species. This targeted technique is a direct result of microbiologist Félix d'Hérelle's discovery of bacteriophages at the Institut Pasteur in 1917.

In May 2015, WHO launched a global action plan with the aim of preserving our ability to prevent and treat infectious diseases using safe, effective medicines. The plan sets out five objectives:

  • to improve awareness and understanding of antimicrobial resistance;
  • to strengthen surveillance and research;
  • to reduce the incidence of infection;
  • to optimize the use of antimicrobial medicines;
  • to ensure sustainable investment in countering antimicrobial resistance.

     

At the Institut Pasteur

The Institut Pasteur International Network, including the Institut Pasteur in Paris, is involved in all aspects of research into antibiotics and antibiotic resistance. Through this network, the Institut Pasteur is contributing to the global surveillance of resistance and developing research programs that will help scientists understand and model the spread of resistant strains and identify the link between resistance and virulence.

These programs draw on epidemiology, genomics and bioinformatics to describe these phenomena and unravel the mechanisms involved. Laboratories are also studying the mechanisms used by bacteria to exchange resistance genes. To find new antibiotics, Institut Pasteur teams are investigating the biosynthesis of the bacterial envelope, a target of many antibiotics, and looking for new targets. This knowledge will serve as a basis for finding active molecules, either in molecule libraries containing molecules with wide-ranging structures, or among natural products. The Institut Pasteur is also developing alternative strategies to tackle MDR bacteria such as phage therapy, antimicrobial peptides and the possibility of "hijacking" the CRISPR system, a bacterial immune system, to specifically kill resistant bacteria.

The Fighting Antibiotic Resistance research program involves more than 40 multidisciplinary teams from the Institut Pasteur International Network. These teams are working on a wide range of projects to tackle resistance, structured around seven main research areas:

  • Epidemiology – Global health and mathematical modeling of the spread of antibiotic resistance.
  • Genomics of antibiotic resistance and the horizontal transmission of genetic determinants.
  • In vitro and in vivo mechanisms of resistance.
  • The discovery of new targets and the characterization of drug targets.
  • Drug screening – and the discovery of new antibiotics.
  • Identification of "natural" compounds against MDR bacteria.
  • Alternative strategies to antibiotics.

The Institut Pasteur runs courses in connection with its mission to transfer knowledge:

Find out more
Antibiotic resistance: an emerging disease – video on the Institut Pasteur YouTube channel (Institut Pasteur and Sup'Biotech)Sup'Biotech)

 

Sources : WHO, Santé Publique France

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March 2017



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