Saq065 amrau report Internal V11

1.3 The problem of antimicrobial resistance

The term ‘antimicrobial resistance’ is used to describe microorganisms that have developed the ability to resist the antibiotics or other antimicrobials that have been in use. When antibiotics were first introduced in the 1930s and 1940s, they were regarded as ‘miracle drugs’ because they brought about significant reductions in mortality due to bacterial diseases that had high fatality rates, offered faster recovery from infectious illnesses and were used extensively during World War II to treat injuries. Antibiotic use then expanded into prophylactic applications, where antibiotics are given to prevent an infection – for example, during surgery, when normally sterile body tissues are exposed to non-sterile areas such as the mouth or gut. With the advent of transplant surgery that requires artificial immunosuppression of the patient to prevent rejection of the transplant, antibiotics became essential for preventing and treating infections in people whose immune system was not able to combat infections from bacteria that exist in the normal environment.

However, within several years of the introduction of antibiotics, bacteria began to develop mechanisms to combat the antibiotics in use. In the presence of the antibiotic, these bacteria gained a selective advantage and then became predominant in the changed environment. Bacteria have a number of means of sharing genetic material, sometimes between unrelated species, and this led to further expansion of the resistant strains. All antibiotics in common use for human health have been impacted by this phenomenon. Figure 1 shows the time lag between clinical introduction and first appearance of resistance for a range of antibiotics.¹²

Although some antibiotics enjoyed several decades of use before resistance was seen, for others the time difference has been much shorter. Some antibiotics, notably vancomycin, were highly valued because of their ability to treat infections that had become resistant to other commonly used antibiotics. The level of vancomyin resistance now seen is a cause for significant concern, and some types of bacteria that carry this resistance, such as vancomycin-resistant enterococci, have changed their profile from being organisms of little concern in human health to a cause of significant morbidity and mortality, particularly in hospital settings.

If antibiotics continue down the path that has been observed for the previous several decades and lose their clinical power, diseases that once had a high fatality rate and are now regarded as being of minor health concern in developed societies have the potential to become serious health threats once again. The risk associated with many medical and surgical procedures that have become relatively commonplace will also dramatically increase.

In addition to the obvious cost to human health, there are large financial implications for society, because relatively low-cost therapies will be replaced with high-cost drugs and other interventions to achieve better health outcomes.

1.3.1 Emergence of antibiotic resistance

The emergence of AMR is determined by a complex (and largely uncertain) interaction of environmental, epidemiological, clinical and behavioural factors.¹³ There is overwhelming evidence that the use and overuse of antibiotics has been a powerful selector of resistance.¹⁴ AMR occurs when antibiotic levels that would normally prevent the growth of or kill a particular bacterium become ineffective because of a change in the bacterium. An antibiotic is no longer clinically effective when this occurs at a therapeutic dose for treatment of infection.

There are two stages in the emergence of antibiotic-resistant bacterial strains:

1. 
   Genetic mutation or gene acquisition – resistance arises due to a mutation(s) in the DNA sequence of the relevant gene(s) in the bacterial chromosome, or because the existing antibiotic resistance gene is transferred into the bacterium from another resistant bacterium (gene acquisition or horizontal gene transfer).
   
2. 
   Selective advantage – once a resistance gene or mutation is present (and expressed), the cells containing it are able to grow in the presence of the antibiotic and therefore increase in numbers at the expense of susceptible cells. Naturally resistant organisms are also favoured. The total amount of antibiotic used is a general indicator of the selection pressure and continuous exposure to an antibiotic provides the strongest selection pressure.
   

Figure 1: Time lag between an antibiotic being introduced to clinical use and the first appearance of resistance

1.3.2 Spread of antibiotic resistance

Resistant bacteria can move from one environment to another (e.g. animal to human or vice versa). Such spread can occur through direct contact (e.g. between animal and human) or indirectly (e.g. in food or water). The global spread of resistant organisms is well documented, and presumably due to movement of hosts or contaminated products between locations (including between continents).¹⁵

Resistance due to mutations in the bacterial genome is spread by transmission of the bacterium, whereas horizontal gene transfer allows for resistance to be spread between commensal and pathogenic bacteria and vice versa, and also between different species of bacteria. The most frequent mechanism underpinning AMR is horizontal gene transfer between a resistant bacterium and a susceptible one. This occurs in the absence of selection.²

Figure 2: Relationship between total antibiotic consumption and Streptococcus pneumoniae resistance to penicillin in 20 industrialised countries

1.3.3 Factors contributing to antimicrobial resistance

Antibiotics are a key contributor to the development and spread of AMR, but it is important to realise that AMR is driven by both appropriate and inappropriate use of antibiotics. Some issues of particular concern include:

• 
  the inappropriate use of antibiotics, such as taking antibiotics to treat an upper respiratory tract infection that is caused by a virus
  
• 
  a lack of compliance with appropriate antibiotic therapy, such as missing doses or ceasing a course of antibiotics before cure, in which case, bacteria are exposed to less-than-effective doses of the active agent, which facilitates their ability to develop and spread resistance
  
• 
  treatments that are prolonged beyond cure, leading to resistance in commensal bacteria, which can be transferred to pathogenic bacteria
  
• 
  prolonged use of prophylactic antibiotics
  
• 
  the use of antibiotics in primary industries.
  

More antibiotics are used on animals in Australia and other developed nations than for human treatments. According to the JETACAR Report, approximately 700 tonnes of antibiotics are imported each year into Australia, and 550 tonnes (78%) are used as ‘growth promoters’ in food animals or for the treatment of sick animals.¹¹⁰ This report discusses the linkages that were reported between the use of some antibiotics in animals and the increase in resistance in bacteria isolated from humans; spread was thought to occur either by direct contact or via the food chain. The report also describes work that has been done in Australia since the late 1990s to address these linkages.

Much work has also been done to look at the association between the level of use of antibiotics in different countries, and the incidence of resistant bacteria that are isolated. Figure 2 provides data from a study that looked at total antibiotic use in 20 industrialised countries by defined daily dose per 1000 population per day, and showed how increased antibiotic consumption correlated with a higher percentage of Streptococcus pneumoniae isolates that were resistant to penicillin.¹⁶

1.3.4 Cross-resistance and co-selection

Many mutations or single transferable antibiotic resistance genes confer resistance to some or all members of an antibiotic family. Exposure to one antibiotic can select for resistance to other antibiotics of the same class (cross-resistance). Resistance can be selected across structurally unrelated antibiotic classes by co-selection. The fragments of genetic material that carry antibiotic resistance determinants often carry more than one resistance gene and determine resistance to more than one antibiotic group. When this genetic material transfers between bacteria, all the resistance genes are transferred together (co-transfer).² Exposure to one class of antibiotic may then select for resistance to an unrelated class.