Volume 10 Issue 1
A Peer Reviewed Article
Globally, the medical profession is increasingly facing the problem of antimicrobial resistance. As antibiotic therapy continues to be a mainstay of curing infections, both developed and developing nations are dealing with the hard reality that its effectiveness is decreasing. A comprehensive global approach is thought to be the most effective way of slowing the progression of antimicrobial resistance. Broadly, there is a need to have stricter controls on the use of antibiotics not only in clinical practice, but also in the wider community, and in animal husbandry. This review focuses on the importance of developing a multifaceted solution that considers healthcare delivery, public health measures, pharmaceutical research, agriculture and global advocacy. The incorporation of antibiotic stewardship programs into hospital guidelines, the introduction of regulations dealing with non-prescription access to antibiotics and monitoring or banning the use of antibiotics in animal husbandry are necessary strategies to assist in combating antimicrobial resistance. Further, this article explores existing national and international campaigns that aim to raise awareness of antimicrobial resistance, and discusses current approaches in encouraging research and the development of new antibiotics.
The discovery of antibiotics in the 20th century heralded dramatic changes in clinical practice. Among others, antibiotics were able to contain and treat infections in a more effective manner, and provided prophylactic cover when need- ed, allowing for complex procedures to be conducted in a safer environment. Yet, as a consequence of such extensive antibiotic use, resistance to these very drugs is a public health problem that the medical profession is increas- ingly facing. The threat of moving towards an era where the effectiveness of these drugs on which modern medicine is premised, could be permanently compromised, is a concerning one.  Resistance that develops in one part of the world, often rapidly spreads to others, causing difficulty in infection prevention and control.
Judicious use of antibiotics is imperative in halt- ing the current trend of increasing antimicrobial resistance, and the solution should be multi-faceted, in recognition of the contributions of various stakeholders. Drivers of antimicrobial resistance include improper use of antibiotics in clinical practice, non-prescription access to antibiotics globally and the use of antibiotics in agriculture.  The introduction of antibiotic stewardship pro- grams into clinical practice has been associated with significantly reduced rates of antimicrobial resistance in some instances, and should be implemented globally where possible. Addition- ally, while non-prescription access to antibiotics is often endemic in developing nations, solutions which take into account the unique social, cultural and political context of these countries are likely to lead to the desired outcome of reducing the driver for resistance. Regulations for antibiotic use in other sectors are important, as are measures to encourage the pharmaceutical industry to invest in antibiotic research and development.
The Phenomenon of Antibiotic Resistance
Globally, the widespread use of antibiotics by doctors and health professionals has become a true characteristic of modern medicine. The implications of a “post-antibiotic era” due to the development of antimicrobial resistance would truly be far-reaching. Research currently suggests that there may be upwards of 20,000 potential anti- microbial resistance genes in the world. The overuse of antibiotics is the major driver of selection pressure that contributes to the development of resistance.
The rates of antimicrobial resistance development around the world are concerning, particularly for the treatment of common bacterial infections, such as respiratory, gastrointestinal and urinary tract infections. From an Australian perspective, the main antibiotic resistant organ- isms found are vancomycin-resistant enterococci, methicillin-resistant Staphyloccocus aureus (MRSA), multi-resistant Escherichia coli (E. coli), multi-resistant Streptococcus pneumoniae and multi-resistant Neisseria gonorrhoeae.[5,6] For in- stance, the incidence of MRSA in comparison to all reported S. aureas infections within the Australian community has doubled from 10 to 20% between 2001 and 2010.
Globally, antimicrobial resistance is even more concerning. A study in Bolivia found that 76% and 44% of commensal E. coli from healthy chil- dren was resistant to nalidixic acid and ciproflox- acin respectively.[1,8] A study on Shigella isolates conducted in the Andaman and Nicobar Islands in India found that the number of drug resistance patterns, including resistance to newer genera- tion antibiotics, had more than tripled between 2000 and 2011. Furthermore, fluoroquinolo- nes, a synthetic antibiotic, which heralded prom- ising results in relation to overcoming resistance has shown reduced efficacy in less than 30 years after its introduction.
According to the World Health Organisation, there is quantitative evidence available regarding the harm caused to patients as a result of drug resistance in the treatment of tuberculosis – a common infection in developing countries.(8) Among the number of TB cases notified world- wide in 2010, it was estimated that there were 290 000 new cases of multi-drug resistant tu- berculosis (MDR-TB). A study conducted in Mozambique using data from the National Tu- berculosis Referral Laboratory detected 58.3% resistant strains to at least one anti-tuberculosis drug and 43.7% MDR-TB strains isolated in culture during 2011.[10,11] Furthermore, exten- sively drug-resistant tuberculosis (XDR-TB) has emerged, which is resistant to second-line drugs and its prevalence is estimated to be approxi- mately 10% worldwide.
These are but a few of the many examples of the implications of antimicrobial resistance. These show the immense speed at which antimicrobial resistance can develop, and they highlight the need for a concerted global effort to respond to it.
Addressing Antibiotic Use in Clinical Practice
The clinical environment, be it hospital or clinic, plays an important role in the management of antimicrobial resistance. These environments
are responsible for the appropriate provision and prescription of antibiotics, as well as for proper infection control. The first priority in managing any infection in a clinical environment is to control the transmission and spread of infection. This is essential since hospitals may sometimes con- tribute to the spread of nosocomial infections, through cross-infection between patients, and also through the horizontal transfer of antimi- crobial resistance. [13,14] The cornerstone of managing infectious patients in an environment such as this is curing the patient, while includ- ing the implementation of appropriate infection control measures, such as appropriate isolation and hand-disinfection practices. Once these measures have been implemented satisfactorily, the focus turns to antimicrobial treatments. Of- ten, there are guidelines for the appropriate use of the antibiotics, with variable levels of evidence for the recommendations. However, there is evidence that guidelines may be inappropriately adopted, as evidenced by the poor application of them with regards to urinary tract infections. In Australia, the Online Therapeutic Guidelines for antibiotics guides clinicians. 
Inappropriate prescribing can lead to increased antimicrobial resistance, more wastage of health resources, and a greater risk of adverse effects for patients. Misuse of antibiotics is partic- ularly common with respiratory presentations, where they are often wrongly prescribed for viral illnesses.
As a result, it has become essential to establish hospital or clinic-based antimicrobial policies, which may be known as antimicrobial steward- ship programs. Various hospital antibiotic policies have been implemented globally since the threat of antimicrobial resistance emerged; however it was McDougall and Polk who formally defined the aim of antimicrobial stewardship programs in 2005. The aim of the program is to regulate and monitor the prescription of antimicrobials in order to reduce further development of antimicrobial resistance, provide optimal patient care and decrease health costs. These policies are premised on the education of healthcare professionals; to empower them to prescribe antibiotics appropriately, and to support them in their practice. Occasionally these policies may be extend- ed to restrict the availability of certain antibiotics. 
Antimicrobial stewardship programs have been recommended by various international and national healthcare organisations. In 2007, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) developed comprehensive recommendations regarding optimal antimicrobial use in acute care hospitals, in the form of antimicrobial stewardship programs. In 2014, the Centres for Disease Control and Prevention (CDC) recommended all acute hospitals to implement an antibiotic stewardship program.
From an Australian perspective, the first National Antimicrobial Resistance Strategy was published in June 2015, and aims to guide governments, healthcare institutions and agricultural sectors, among others, in reducing the development of antimicrobial resistance. Additionally, every Australian hospital and day procedure service is now mandated to implement infection prevention and antimicrobial stewardship programs follow- ing the implementation of the National Safety and Quality Health Service Standards in 2013. In doing so, Australia is a global pioneer in mandat- ing requirements for better infection prevention and control.[22,23] Antimicrobial stewardship programs are important initiatives that are highly recommended by experts in the field.[1,5]
Education programs about antimicrobial stewardship can be used to great effect. This is evidenced by a significant reduction in antibiotic prescribing by GPs and non-medical prescribers in Derbyshire, England following a four-year initiative including educational seminars, antibiotic audits and ongoing GP support. The outcome was a lower than national average level of prescribing cephalosporins and quinolones. These programs are easy to organise and should continue to be encouraged. Empowering prescribers to make informed choices about antibiotic use is ultimately the aim of these initiatives.
The effectiveness of policies such as the anti- microbial stewardship program depends on the co-operation of the entire healthcare institution, including multi-disciplinary support. Hospitals and primary care establishments both seek to gain from integrating these policies to be a core aspect of current accreditation programs. Research has shown that codifying stewardship programs can successfully lead to a decrease in antibiotic use, while simultaneously reducing the burden of morbidity and mortality of infections. Evaluating the impact of existing antimicrobial stewardship programs is difficult, with no unifying metric to assess their effectiveness. Further- more, primarily observational studies have been conducted to assess the effectiveness of antimicrobial stewardship programs, which are Level III evidence according to Australian Government National Health and Medical Research Council NHMRC evidence hierarchy.
Studies have shown a statistically significant immediate reduction in the use of broad-spectrum antibiotics following the implementation of formal antibiotic policies and programs, such as antimicrobial stewardship programs. For instance, a prospective 7-year study showed a statistically significant decrease of 22% in par- enteral broad-spectrum antibiotic use within a single teaching hospital. Furthermore, a 2005 Cochrane systematic review showed that hospital-based interventions aimed at improving antibiotic prescribing through stewardship pro- grams successfully reduced both antimicrobial resistance and the development of nosocomial infections. Within this review, 77% of studies included showed a significant improvement in at least one clinical outcome (such as in-hospital or 28 day mortality), and multiple studies showed over 10% reduction in resistance development between intervention and control groups. A retrospective cohort study conducted in a teaching hospital in North East Scotland found that implementation of antibiotic stewardship with fluoroquinolone and cephalosporin use resulted in a statistically significant decrease of prevalence of MRSA bacteraemia. A well-rounded steward- ship program may be associated with decreased use of broad spectrum antibiotics, a reduced risk of infection transmission within the hospital and a decreased level of antimicrobial resistance. Healthcare workers in hospitals and clinics are therefore encouraged to be aware of antimicrobial stewardship programs and help promote its aims.
Monitoring Antibiotic Use in the Community
Globally, access to antibiotics is not always governed by prescriptions from medical facilities. Pharmacies, friends and family can also be sources of drugs for those seeking self-medication. Non-prescription access to antibiotics is present worldwide, but most commonly in nations outside of Europe, North America and Australia. Developing nations in Asia and Afri- ca have been shown to have some of the highest rates of non-prescription access in the world.
For instance, the rates of antibiotic self-adminis- tration have been found to be as high as 74% in Sudan , 60% in China , and as low as 3%  in Northern European nations.
The strongest driver behind the prevalence of non-prescription access to antibiotics is the scar- city of medical resources in developing nations. As a result, minimally trained or unskilled person- nel often act as healthcare workers, and take on the role of antimicrobial prescribing. There are numerous problems associated with this status quo. Often, those dispensing the medications have little medical knowledge to guide them, which may lead them to select inappropriate antibiotics in light of local resistance patterns. Rates of adverse effects due to antibiotics are also more common, and are associated with the lack of medical screening for allergies in less than 17% of cases, as well as with a lack of knowledge of potential side effects. [29,35] In addition, many studies have shown consistently that these antibiotics are more likely to be administered as single dose therapies, as opposed to the full course. Potentially due to financial concerns, these drug regimens are popular in developing nations, but are associated with greater resistance potential.
Regulation and legislation are pivotal in combat- ing this issue. Limiting access of non-prescrip- tion antibiotics within the community is likely to reduce the rate at which antimicrobial resistance develops. Yet developing nations pose unique challenges. Often, the regulatory capacity of the nation might be limited, and legislation unen- forceable. Indeed, non-medical prescribers may well be the only access point to life-saving drugs that members of society with poor access to for- mal healthcare have. As a result, an outright ban on non-prescription sales is likely to cause more harm in the short-term. Hence, measures must be taken to ensure that drug restriction does not come at the expense of the health of patients. Advocacy and political leadership to ensure the incorporation of an antibiotic stewardship pro- gram into existing health infrastructure could be an effective start to safer antibiotic use.
In addition to addressing non-prescription antibiotic use, the key issues of infection control and prevention must also be addressed. For example, improving primary health care and basic health infrastructure may reduce the prevalence and spread of infections, thereby reducing the need for antibiotic use. Furthermore, vaccination programs remain as a key prevention strategy to avoid unnecessary antibiotic use in the future. In the United States for instance, the use of the pneumococcal conjugate vaccine against the drug-resistant Streptococcus pneumoniae has significantly reduced rates of infection, and as a consequence, the use of antibiotics as well. Yet, with high numbers of unvaccinated children in developing nations, there is a greater range of bacterial infections that require antibiotic use.  Finally, developing nations may lack social infrastructure, such as access to clean water and sanitation, which contributes to the spread of infections.
Addressing antimicrobial resistance at the community level needs to consider the social, economic and political structure unique to countries so that the best solution be identified and implemented.
Antibiotic Use in Animal Husbandry
The development of antimicrobial resistance does not only occur in humans. The animal industry is also an important stakeholder in this global phenomenon. Widespread use of antibiotics in animal husbandry poses the risk of transmission of resistant bacteria from animals to humans. In many countries around the world, antibiotics are authorised for use in animals, and are available over the counter. Transmission from animals to humans may occur through exposure to animal products, or less commonly through environmental routes such as exposure to manure and biological solids. In the past two decades, increasing legislation has been introduced in specific countries to restrict the use of antibiotics in animal husbandry to address this problem.
For instance, the use of antibiotics in animal rearing was phased out in the European Union in 1999 and was associated with a reduction in antimicrobial resistance among faecal enterococci in animal populations, which proved that it was potentially possible to reverse the effects of antimicrobial resistance. In fact, rates of multi-drug resistant Enterococcus faecium in US poultry declined from 84% to 17%, after organic feed was implemented. Furthermore, international organisations such as the World Health Organisation, the United Nations Food and Agriculture Organisation and the World Organisation for Animal Health are currently working together to create guidelines regarding the appropriate use of antibiotics in animal rearing. The creation of a “No-Feed Antibiotics” label on consumer products could provide an incentive for the agricultural sector to reduce their use of antibiotics, particularly if this certification is produced in association with governmental departments of agriculture.
Antibiotics – The Way Forward in Antibiotic Development
In the 20th century, antibiotic discovery was at an all-time high. More than 20 classes of antibiotics were discovered in a span of just over 30 years, in what can be characterised as “the golden age of antibiotic discovery”. Since then however, antibiotic development has stalled dramatically. Indeed, there was a 32-year gap (1968 – 2000) between the discoveries of two novel antibiotic classes. During this time, the focus for pharmaceutical companies moved from discovering new classes of antibiotics to instead developing analogues, a decision associated with the reduced side effect profile of analogue drugs. Additionally, a new antibiotic has a relatively low profit potential, as compared to a drug of a different therapeutic class. This too, likely contributed to the decrease in interest in the pharmaceutical industry to fund and invest in antimicrobial research, especially as the regulations for approval for new classes of antimicrobials have become stricter. As a result of this decline in research and development into new antimicrobials, there has been a significant loss of knowledge and infrastructure in the industry with regards to antibiotic development and this is predicted to take time and effort to re-build.
There is a need for antibiotic development to be- gin anew. Suggestions currently being proposed and discussed at international conferences include revising the regulatory requirements for approval of medications, offering pharmaceutical-friendly patent protection and even providing direct financial investment. The European Medicines Agency has relaxed its current guide- lines for clinical antibiotic trials and the US Food and Drug Administration (FDA) is considering altering their regulations with regards to generic antibiotics.[1,39]
Other potential approaches include considering value-based pricing of new antibiotics, which could incentivise pharmaceutical companies to invest in drug development. This particular ap- proach promises developers a cut of the savings to healthcare costs that would be achieved if the current burden of morbidity and mortality of resis- tant infections is reduced by new drug discovery. 
Increasing Awareness Globally
Awareness about antimicrobial resistance is certainly building worldwide, with national campaigns such as the European Antibiotic Aware- ness Day, US Get Smart About Antibiotics Week, Canadian Antibiotic Awareness Week, and the Australian Antibiotic Awareness Week being established as annual traditions. Aiming to target both consumers and healthcare professionals, initiatives such as these impart knowledge on the necessity of using antibiotics prudently and judiciously, as well as on the need for co-operation to halt the trend of increasing resistance.
If left unchecked, the current trend of antimicrobial resistance suggests that a post-antibiotic era is not far off; a world where infections currently treated with antibiotics may carry a high level of morbidity and mortality. As discussed in this article, it is imperative that a multifaceted solution be raised where possible. These include incorporation of antibiotic stewardship programs into hospital guidelines, introduction of regulations to deal with non-prescription access to antibiotics, monitoring or banning the use of antibiotics in animal husbandry, global advocacy, and incentivisation of the pharmaceutical industry to engage in new antibiotic research.
Ultimately, if access to life-saving antibiotics is not to be compromised by the development of resistance, global co-operation is essential to this end. As the WHO World Health Day 2011 pro- claimed, when it comes to antimicrobial resistance, “no action today, no cure tomorrow” – the time to act is now.
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