MRSA Resistance to Anti-biotics

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Discuss how MRSA became resistant to antibiotics and became such a prevalent organism associated with British hospitals. Explain how MRSA is treated and touch upon the wider implications for antibiotics and the future of healthcare.

Introduction

It may be argued that micro-organisms are the most successful life form on the planet partly due to their pervasive presence and their utilisation of any available food source, including humans. The ubiquitous presence of micro-organisms and their astronomic numbers give rise to many mutations that account for rapid evolutionary adaptation and in part for emerging antibiotic resistance (Evans and Brachman 1998). Bacteria have evolved numerous structural and metabolic virulence factors that enhance their survival rate in the host. Once such bacteria is Meticillin Resistant Staphylococcus aureus (MRSA).

What is MRSA and why did resistance occur?

The genus Staphylococcus are non-motile, Gram-positive cocci, measuring 0.5-1.5µm in diameter and are commonly found in the nose and on skin. They can occur singly, in pairs, short chains or in grape like clusters. There are several species but Staphylococcus aureus has been a significant pathogen for humans for many years. It is different from other Staphylococci because it produces the enzyme coagulase. Potential virulence factors include surface proteins, which promote colonisation and membrane damaging toxins that can either damage tissue or invoke other disease symptoms. Before the emergence of antibiotics, the mortality rate for Staphylococcus aureus infections was 80% (Fedtke et al 2004). The versatile organism has developed a resistance to Meticillin due to its mobile genetic element the mecA gene, which is found in the Staphylococcal cassette chromosome mec (SCCmec) and this mediates the resistance to ?-lactam antibiotics such as Meticillin (Greenwood 2000).

Of the current antimicrobial resistant organisms, Meticillin-resistant Staphylococcus aureus (MRSA) is probably the most challenging in a hospital setting. MRSA first came to the public’s attention, here in the UK, in the 1980’s when the first epidemic strain, Epidemic Meticillin-resistant Staphylococcus aureus (EMRSA was identified. Subsequently a further sixteen epidemic strains have been recognised. Each strain has its own genetic makeup and display resistance to different antibiotics. EMRSA -15 and EMRSA -16 are the most common strains found in the UK, accounting for 96% of all MRSA bacteraemia. Worryingly, a new strain, EMRSA – 17 was identified in 2000. Not only did it display resistance to the previously recognised antibiotics but also Fusidic acid, Rifampicin, Tetracycline and sometimes Mupirocin.

Evolution and natural selection have produced the mechanism through which micro-organisms can adapt to their ever changing environment, including resistance to natural and man made antibiotics. Bacteria including Staphylococcus aureus are adept at infecting and colonising humans and also aid other microbes to cause infection by producing anti-inflammatory molecules, which allow microbes to evade the body’s immune system (Fedtke et al 2004). They are also able to hide in biofilms and proteins called defensins.Therefore bacteria successful in these evasive strategies are able to pass these strategies down the generations in a process called horizontal gene transfer (Bush 2004). However, this is not a new phenomenon. As far back as 1940, the journal Nature published an article describing the discovery of an enzyme that destroyed Penicillin called Beta-lactamase.

Two mechanisms are used by Staphylococcus aureus to cause infection (Roghmann et al 2005). These are toxin production and tissue invasion. Toxin production is exemplified in gastroenteritis resulting from consuming Staphylococcal enterotoxins in food and tissue invasion is demonstrated in the classical abscess comprised of pus contained in a fibrin wall and surrounded by inflamed tissues.

Why a hospital problem?

Staphylococci are the classic hospital acquired bacteria and Staphylococcus aureus is the commonest cause of surgical site infection. For years, glycopeptides, such as Vancomycin have been the first choice for serious Staphylococcus aureus infections. Now clinicians are facing strains with reduced susceptibility to glycopeptides, with no decline in virulence (Dancer 2003).

Within the hospital environment there are recognised high risk areas/departments where patients are at greater risk of infection. Two such areas are intensive care units and burns units. Examples of factors associated with higher risk MRSA acquisition are previous antibiotic therapy and frequent admissions. The more often a patient is admitted to hospital the greater the chance of exposure to MRSA and being prescribed antibiotics. Patients and their pre-disposing factors,,for example, being immunocompromised,and having wounds make them more susceptible to acquiring MRSA, In addition the healthcare workers and the environment are also potential reservoirs of MRSA. The environment as a reservoir has been more difficult to assess (Dancer 2004), although work done by Rayner 2003 confirmed that MRSA has been isolated on patient equipment.

The term risk factors, which are often used in relation to MRSA, apply to the strength of association between the organism and the odds of going onto develop an infection.

The factors responsible for increasing resistance are complex and varied as are the potential strategies for overcoming the problem. Inappropriate prescribing and overuse of antimicrobials by clinicians may be driven by lack of understanding of the problem and inadequate surveillance for resistance.

Poor prescribing and increasing resistance however not the only issue in the management of Staphylococcus aureus. This is where medical microbiologists are pivotal in the appropriate use of antimicrobials. They can provide clinicians with laboratory reports that contain a restricted number of antimicrobial sensitivities, as well as advising on the correct method and appropriate specimen to obtain. This saves time and resources. Therefore the patient should receive the appropriate antimicrobial treatment at an earlier stage.

However, it needs to be acknowledged that prescribers prefer and adhere more closely to policies that take an educational rather than a restrictive approach. Some view policies as rigorous and fixed and relate better to guidelines, that are seen as more flexible and acknowledge that some patients will fall outside of the recommendations (Binyon 2000). There are also legal aspects to consider, as it is more difficult to justify action taken outside a policy than a guideline.

Ideally a guideline will limit antimicrobial prescribing to situations where there is a clear indication for their use and that they should be administered for the shortest effective duration. The drug of choice should be appropriate, narrowest in spectrum and correct in dose and duration (SIGN 2000). Prophylactic antimicrobials should be only given for the recommended period. Emmerson (2000) argued that perhaps a guideline’s most important function is that of a vehicle for ensuring regular discussion amongst those concerned.

A study by Harrison (1998) found that approximately 20% of all prescribed antimicrobials relate to hospitalised patients. Of this 20%, 20-50% was unnecessary. His study also revealed that 25-50% of all hospital admissions receive an antimicrobial at some point during their stay. The study also made the point that even if numerous bacteria are killed during a single course of antimicrobials, if one mutant microbe remains in that patient; the possibility exists for the rapid establishment of a resistant population.

Current problems within the National Health Service exacerbate the issue. These problems include ‘hot’ bedding, overcrowding of wards, understaffing, inadequate cleaning, poor laundry services, patient relocation and poor isolation facilities. Dancer and Gemmill (2003) argue that erosion of hygiene standards emanated from the ready provision of antimicrobials.

Numerous guidelines have been written in order to attempt to control these problems. However sometimes what is good in theory is not so good in practice and there may be various explanations for this failure. Regardless of how sound the principles are, there may be insufficient resources to implement them. A prime example here is lack of isolation facilities in hospitals (Cooper 1999). There is a wide variance in which resistance is handled in different hospitals. Some hospitals isolate and treat the patient regardless as to whether or not the patient is colonised or infected. Therefore risk assessment in conjunction with the infection control team on a case-to-case basis is vital when resources are scarce.

Presently Vancomycin and Teicoplanin are used to treat MRSA infections. The majority of patients are colonised and are asymptomatic. They carry MRSA on skin or in the naso-pharynx. Patients who are found to be colonised in hospital settings are actively treated or decolonised. This is done by prescribing five days of a body wash used either in the bath or shower. The wash is also used to cleanse the hair. The wash includes chlorhexidine gluconate and is effective but known to dry out the skin with prolonged use. In conjunction with the body wash the patient is also prescribed a nasal cream which is applied 3 times a day for 5 days to both nares. The cream usually used is Bactroban which contains Mupirocin. For MRSA cases displaying intermediate or total resistance to Mupirocin, the cream of choice is Naseptin (BNF 2015).

Discussion

Antibiotic resistance may lead to routine infections being fatal. Antibiotics are losing their effectiveness at a rate that is both alarming and irreversible. The media talks of a post antibiotic era or antibiotic Armageddon.

So what of the future? Researchers are developing a vaccine. In order to achieve herd immunity, 85% of the population would require to be vaccinated and the vaccine would also have to provide protection against all the strains to which someone is likely to be exposed. However, limited vaccination of at risk groups may be possible (Farr 2004). Work is also ongoing in regard to lysostaphin, which is an enzyme that causes the cell wall in Staphylococcus aureus to rupture. It was first described 40 years ago. As it is specific to Staphylococcus aureus, it would not interfere with normal commensal flora. It could be used to reduce nasal carriage and subsequently reduce infection rates. Early clinical trials have been positive.

Assuming all the issues above were overcome, resistance still would not disappear. Thus there remains a need to continue with research into how and why bacterial mutations occur and into the development of new innovative drugs, vaccines and diagnostics. More resources need to be channelled into education of health care professionals, allied with effective infection control measures.

Every healthcare worker has a duty of care to comply with infection control policies. As long as infection control procedures are adhered to, hygiene improves and antibiotics are used prudently, there is the prospect of bringing MRSA under control in the hospital setting. However, we have to be aware that emphasising the importance of MRSA colonisation via policies and guidelines may result in accidental neglect of the factors that cause infection.

As MRSA will continue to spread in the wider community, via both humans and animals, some of the strains spread may be highly toxic and with an ageing population and increasing numbers of immuno-compromised patients, the danger will only increase. As more advances are made in medicine, these vulnerable populations will also increase. Those at most risk are those in long-term care homes, of which there is an ever-increasing number. While cross infection routes are relatively easily defined in a hospital setting, the situation in the community is not and because care homes are major feeders when it comes to hospital admissions, the impact on the crisis stricken NHS will continue.

Therefore MRSA screening was welcomed when introduced in 2013 across the UK following a nationwide study of the efficacy of screening patients on admission to hospital (HPS 2009). The aim of screening patients for MRSA is to identify patients that are colonised or infected with the organism. These patients can then be managed appropriately to reduce the risk of self-infection and of transmitting the organism to other patients.

As for MRSA rates being indicators of quality healthcare, they should be considered as tools that prompt further inquiry, rather than permitting judgements on quality of care.

Conclusion

MRSA has the capability to cause misery, morbidity and even fatalities under certain circumstances. The body is an incredibly complex machine; scientists are making striking advances in elucidating the precise molecular basis for the interaction between adherence surface structures of an organism and corresponding specific surface receptors on a host cell. Much more has still to be learned and microbiology will continue to play a huge part in research in order to understand the mechanisms of pathogenicity and the development of antibiotic resistance. This is essential for future treatment and prevention of infections allowing humans and micro-organisms to continue to co-exist.

Prevention and control of healthcare acquired infection demands the continual development of intervention strategies aimed at curtailing further antimicrobial resistance and reducing the spread of existing infection. Success however will only be achieved with a multi disciplinary approach at individual and organisational level. Infection prevention has to become an integral part of everyday healthcare practice (Fairclough 2006).

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