Antimicrobial resistance | Lesson

Tutorial

Opportunistic bacterial infection and bacterial resistance are topics that are all too familiar in recent years, both in hospital and community medicine. The following makes reference to some of the important bugs with regard to this area and illustrates the basic principles of resistance.

Since the large scale introduction of penicillin in the 1940s, humans have enjoyed unprecedented health and wellbeing with regard to bacterial infection. With the introduction of antibiotics, the equilibrium between human and pathogen became suddenly and massively destabilised relative to evolutionary trends up to that point, which in essence was the entirety of human history up to the 1940s. Therefore it is not surprising that natural selection continues to attempt to rebalance the scales in this regard.

In contrast to media propaganda, so called ‘killer bugs’ do not have an agenda other than to achieve what all organisms evolve towards, sustained survival. While they are not ‘out to get’ anyone, they are out to survive. Indeed, resistant strains of Staphylococcus aureus existed in nature long before the commercial introduction of penicillin, just not at the same frequency as today.

As per Darwinian laws of natural selection, shifts in environmental or molecular trends convey selective pressures on organisms i.e. pressures that result in the inevitable survival of bugs with advantageous mutations. That is to say that it is normal and predictable that bacteria (as well as all biological organisms), mutate and adapt to environments that threaten their survival i.e. environments laden with antimicrobial drugs, chemicals, soaps, detergents etc. It is important to keep this in mind because minimising this selective pressure helps prevent further mutational change.

The two major components with regard to drug resistant pathogens can be classified into two areas:

(a) the selective pressures that bring about mutational change and

(b) those that propagate and spread such resistant strains.

The former (a) pertains to widespread use of antibacterial agents which are ubiquitous in the modern world. They exist in large quantities and in every realm of human living, from animal feed in the agricultural sector to children’s toys. It is difficult to find soap or household cleaning products that do not have the word ‘antibacterial’ stamped on the label. Such widespread integration of these chemicals has contributed to the development of drug resistant mutations within bacteria.

Industry is not without blame and corporations are guilty of taking advantage of peoples’ insecurity while using the ‘fear factor’ to entice sales of such products.

Misuse of antibiotics by both doctors and patients is an integral part of this problem also, and doctors carry a large burden of blame in this regard. Inappropriate prescribing, choosing the wrong antibiotic drug class relative to the clinical complaint, and unwarranted sustained courses of therapy are serious contributing factors that doctors must address and improve on dramatically.

Perceived pressures on many primary care doctors to prescribe a drug also contribute to this problem. Many such cases relate to patients who present with simple viral infections. In this context, explaining that an antibiotic will not be of benefit and may be harmful will help alleviate this pressure in many cases. In this context communication between doctor and patient is integral. It has been shown that where resistance has occurred, the continued use of the particular antimicrobial agent serves only to amplify the frequency of this strain in a population.

Patients have a responsibility also and they must be warned against self medicating with antibiotics and ensuring they finish prescribed courses as advised and directed.

The second component (b) is with regard to the factors that lead to the proliferation of resistant strains. These factors are mainly behavioural and environmentally-driven and relate to the contact spread of bacteria. Simple contact precautions such as hand-washing and basic barrier nursing techniques are essential in this regard. While such steps are simple in principle, they have proven to be extremely difficult to adequately implement on a large scale in many countries including Ireland and the UK. Other key recommendations include adequate cleansing of stethoscopes in between patient examinations and minimising contact with patients who are carriers of resistant strains. A change in hospital dress code should be implemented with short sleeved scrub tops replacing traditional shirts and ties. While on an individual basis it may be difficult to appreciate how such simplistic measures serve to tackle this problem, the answer lies in this realm and the effectiveness of adequately implemented contact recommendations should not be underestimated.

A range of bugs have become all too familiar in the hospital environment as a result of the combination of factors (a) and (b). Development of new antibiotics is not the answer, as resistance will naturally occur in time to any chemotherapeutic agent. As such, antibiotics may help buy time, but in the interim the continued misuse of these drugs serves only to promote the development of new resistant isolates. The answer, as demonstrated by the Dutch and Scandinavian models, is through strict contact precautions, hand-washing and associated barrier nursing.

Pathogens

MRSA

Methicillin/Multidrug Resistant Staphylococcus Aureus (MRSA) refers to strains of Staphylococcus aureus (S. aureus) which are resistant to beta-lactam antibiotics including methicillin and flucloxacillin, as well as cephalosporins and other common antibiotics. S. aureus, a gram positive coccus, is a common normal commensal in the community and it normally does not convey a threat to individuals. However, by virtue of the factors described above, MRSA isolates have thrived, particularly in the hospital environment, and have resulted in substantial mortality and morbidity.

It is important to differentiate between colonisation and infection in relation to clinical practice as this distinction carries important implications for treatment as well as future triaging and management of co-morbidities.

Eradication of the commonly colonised sites (e.g. groin, axilla and nose) on admission is achieved using topical preparations (e.g. chlorohexidine, nasal bactroban etc).

MRSA infections vary from wound/surgical site infections to respiratory tract and septicaemia. Results from a CDC study in 2010 showed that invasive MRSA infections in healthcare settings in the USA are declining. While this seems to correlate broadly with trends in Ireland, MRSA remains disproportionately prevalent with MRSA isolates (as a proportion of S. aureus isolates) existing in Ireland at approximately 27%. This is in contrast to Holland and Scandinavian countries where they are less than 1%.

Glycopeptides, which include vancomycin, are routinely used in the treatment of MRSA infections. In recent years there has been a corresponding trend in the emergence of resistant strains which are termed Vancomycin Intermediate Staphylococcus Aureus (VISA) and Vancomycin Resistant Staphylococcus Aureus (VRSA). The distinction between the two is based on the minimum inhibitory concentration of vancomycin required to inhibit growth in the laboratory.

Proliferation of such resistance has obvious clinical implications with regard to pathogenicity, however the control principles apply to these new resistant strains as to MRSA. Implementation of environmental control strategies (i.e. hand-washing, barrier nursing etc) are the solution.

Carbapenem resistant Enterobacteriaceae

Carbapenem Resistant Enterobacteriaceae (CRE) represent yet another microbial niche that has become more prevalent in recent years. Members of Enterobacteriaceae include the Klebsiella species and E. coli.

Nosocomial opportunistic infection with CRE may result in varying presentations of disease from urinary tract infections to sepsis. A common mechanism of resistance in this context is through the production of Klebsiella pneumoniae carbapenemase (KPC) which inhibits the activity of carbapenems. Infections with CRE are difficult to treat and associated mortality rates are as high as 40-50%.

Clostridium difficile 

Other relevant bacterial infections include Clostridium difficile (C. diff). This is a spore forming gram positive anaerobic bacillus that produces two exotoxins. It results in pseudomembranous colitis, toxic megacolon, perforation, sepsis and death. It is a common cause of antibiotic associated diarrhoea and risk factors for associated infection include antibiotic exposure (especially broad spectrum), immuno-compromised states and GI surgery. There are various methods used to diagnose C diff. with varying sensitivities and specificities which include stool testing for the toxin, toxin ELISA, PCR and flexible sigmoidoscopy. Treatment is with oral metronidazole, vancomycin or fidaxomicin.

Multi-drug resistant tuberculosis

According to The WHO there were approximately 480,000 new cases of Multi-Drug Resistant Tuberculosis (MDR-TB) in 2014. MDR-TB is resistant to the two main anti-TB drugs, isoniazid and rifampicin. In keeping with selective pressures that continue to drive mutational change in the microbial realm, Extensively Drug Resistant Tuberculosis (XDR-TB) has emerged . XDR-TB is a type of TB that is resistant to at least four of the core anti-TB drugs and it has been identified in 105 countries. It is estimated that 9.7% of people with MDR-TB have XDR-TB.

Malarial resistance

As of July 2016, resistance to the first line treatment for Plasmodium falciparum malaria (artemisinin-based combination therapies – ACTs) was reported in five countries (Cambodia, Lao People’s Democratic Republic, Myanmar, Thailand and Vietnam). While patients in most regions with these resistant infetions recover fully with appropriate treatment, P. falciparum has become resistant to almost all available antimalarial drugs along the Cambodia-Thailand border.

Global surveillance

As per the ‘Antimicrobial Resistance Global Report on Surveillance’ (published by the WHO 2014), a major recurring obstacle in tackling the ongoing and evolving challenges of antimicrobial resistance are gaps in data (www.who.int). These extend from gaps in information on pathogens of significant public health importance worldwide due to a lack of standards for methodology, data sharing and coordination. Worringly, the report concludes that global surveillance of antibiotic resistance is neither coordinated nor harmonised. As a result of these concerning conclusions, the global action plan for resistance as set out includes ‘the development of tools and standards for harmonized surveillance of antibiotic resistance in humans as well as for integrated surveillance in food-producing animals and the food chain’. Other endeavors include ‘collaboration between antimicrobial resistance surveillance networks and centres to create or strengthen coordinated regional and global surveillance.

As always there is a constant evolutionary interplay between humans and all tiers of the microbiological world, as such evolution will continue. However, having the tools to help predict potential evolutionary shift and adaptation through development of initiatives as outlined by the WHO is therefore crucial to developing a more balanced approach to dealing with antimicrobial resistance.