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 Is it really the “end of antibiotics”? Antibiotic resistance and what can be done.

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 Is it really the “end of antibiotics”? Antibiotic resistance and what can be done.

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I would like to dig deeper into this topic.

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"Rational use of antimicrobials, regulation on over-the-counter availability of antibiotics, improving hand hygiene and improving infection prevention and control are the major recommended approaches" - National Library of Medicine

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Introduction

Antimicrobial resistance (AMR) including multidrug resistance (MDR), is on the rise among many microorganisms in health-care facilities as well as in community [ 1]. Reported data suggests that almost 2 million cases of infection with resistant bacteria have been reported in the United States (US) every year leading to $20 billion incremental direct healthcare cost [ 2]. Estimates of European Medicines Agency (EMA) and European Centre for Disease Prevention and Control (ECDC) reported a toll of 25,000 deaths per year as a direct consequence of a MDR infection with total cost of €1.5 billion [ 3]. In Canada, hospitalization caused by resistant infections resulted in higher economic burden with excess cost of $9-$14 million [ 1]. Study by Indian Network for Surveillance of Antimicrobial Resistance (INSAR) group, India reported prevalence of 41% with methicillin resistant Staphylococcus aureus (MRSA) [ 4]. High prevalence of Gram-negative bacterial resistance has also been reported in India [ 5]. World Health Organization (WHO) estimates that worldwide 3.7% of new cases and 20% of previously treated cases are estimated to have MDR-TB [ 6].

The path of antibiotic development is challenged at every step by the emerging microbial resistance. Emergence of MRSA, resistant Pseudomonas aeruginosa have already compromised the most effective treatments [ 7]. Recent reports have witnessed changing susceptibility pattern and spreading trend in AMR [ 8- 10].Development of superbug like New Delhi metallo-β-lactamase 1 (NDM-1) positive Enterobacteriaceae have further complicated the management of such infections [ 11].

Urgent threats with Clostridium difficile, carbapenem-resistant Enterobacteriaceae (CRE) and drug-resistant Neisseria gonorrhoeae have been reported by US Centers for Disease Control and Prevention (CDC) [ 2]. Thus AMR is a major point of concern as it is associated with high death rates and fear of progression to the pre antibiotic era; also has potential to hamper infectious disease control programmes; increase in health care costs and diminish health-care gains achieved so far [ 6].This review discusses various measures that can be taken to combat AMR with major emphasis on antibiotics resistance.

Call for action

The global threat of AMR calls for the collaborative action for developing effective strategies in combating AMR. CDC recommends 12 steps to prevent antimicrobial resistance in a healthcare setting [ 12].

We herein discuss the effective strategies for combating AMR. The collaborative approach is required at different levels. Different measures for combating AMR can be directed at international, national, community, hospital, individual and patient level. [] summarizes these approaches.

1. International Measures

As a global problem, AMR is now well accepted by various stakeholders. In the year 2011, WHO theme was on combating antimicrobial resistance. It was one of the major attempts to draw international attention and need of combined efforts to alleviate the problem of AMR [ 13]. Some of the WHO recommended approaches are listed below: [ 14]

Increased collaboration between governments, nongovernmental organizations, professional groups and international agencies

New networks that undertake surveillance of antimicrobial use and AMR

International approach for control of counterfeit antimicrobials

Incentives for the research and development of new drugs and vaccines

Forming new, and reinforcing existing programmes to contain AMR.

2. National Strategies
2.1 National committee with intersectoral coordination and regulatory actions
Establishment of national committee to monitor impact of antibiotic resistance and provide intersectoral co-ordination is required. WHO recommends that such committee would formulate AMR policy; provide guidance on standards, regulations, training and awareness on antibiotic use and AMR. Developing indicators to monitor and evaluate the impact of AMR prevention and control strategies would be amongst priority objectives at national level [ 15].Further WHO advises that having a registration scheme for all dispensing outlets, making prescription-only availability of antimicrobials, legal binding on all manufacturers to report data on antimicrobial distribution and incentives for rational use of antimicrobials can help contain AMR [ 15].

Establishing and implementing national standard treatment guidelines, having essential drug list (EDL), enhancing coverage of immunization are other essential strategies desired at national level [ 14].
2.2 National Antimicrobial Resistance Policy, India
A national policy for containment of AMR was introduced in 2011. The policy aims to understand emergence, spread and factors influencing AMR, to setup antimicrobial program, to rationalize the use of antimicrobials and to encourage the innovation of newer effective antimicrobials. In addition, some major action points identified in national policy were; establishing AMR surveillance system, strengthening infection prevention and control measures and educate, train and motivate all stake holders in rational use of antimicrobials [ 16]. WHO estimates that less than 50% of all countries are implementing basic policies for appropriate use of medications [ 17].

3. Action at Community Level

Globally, infectious diseases still continue to be significant cause of morbidity and mortality, affecting more the countries where health services are not sufficiently accessible [ 18]. Kardas et al., in a review of antibiotic misuse in the community reported that at community level, more than one third of patients were non-compliant to the antibiotic regimen and one quarter kept the unused antibiotics for use in future [ 19]. This indicates a poor antibiotic-taking behavior [ 19]. Review on population perspective of AMR by Lipsitch et al., suggests that prevention of AMR in an individual suffering from infection is one of the basic method to prevent further spread of resistance to the wider community [ 20]. The increasing rate of resistance among community acquired infections like upper and lower respiratory tract infections, bacterial diarrhea, typhoid fever are not matched by development of newer antibiotics [ 21]. Thus there is urgent need for reforms at community level for curtailing AMR. Different measures directed to control and prevent AMR at community levels are the need of an hour.
3.1 Rational use of antibiotics
Irrational use of medicines is a serious global problem. In developing countries, at primary level, less than 40% patients in public sector and less than 30% patients in private sector are treated in accordance with standard treatment guidelines [ 17].This mandates public and professional education towards rational use of antibiotics.
3.2 Over-the-counter (OTC) antibiotics
Measures that preserve efficacy of antimicrobials are mainly directed towards the hospitals and drug providers and missing antibiotic use without prescription. In systematic review of non-prescription antimicrobial use, Morgan et al., reported that non-prescription use of antimicrobials varied from as low as 3% in northern Europe studies to 100% in African studies [ 22]. This implies urgent need for regulatory control on OTC use of antibiotics.
3.3 Guidelines for use of antibiotics at local levels
About use of antibiotics in common situations, Bhagwati A. discussed that an empirical antibiotic therapy should be started considering the clinical condition of the patient and prevalent pathogen and resistance pattern in a locality. Appropriate change in antibiotic is required as per the sensitivity of microbe. Antibiotic guidelines are therefore must to optimize antibiotic selection with their dosing, route of administration and duration of therapy [ 21].
3.4 Standards of hygiene
Use of alcohol-based hand rubs or washing hands has proven efficacy in prevention of infection [ 12, 23]. This factor can restrict the spread of infection and thereby the AMR. Willingness to put up with high standards of hygiene is the need of an hour.
3.5 Other approaches
These include identifying residents with MDR infections and use of standard treatment regime for their management, vaccination, infection prevention strategies and ban on OTC sale of antimicrobials [ 12, 16].

4. At Hospital or health care setting

A person or a patient in a health care facility is at higher risk of infection with common pathogens. For control and containment of AMR, experts recommend some of the measures as discussed herein.
4.1 Infection prevention and control within health-care facilities [1,24]
Infection prevention and control measures are designed to reduce the spread of pathogens including resistant ones within healthcare facilities and to the wider community. This can prevent further infections and AMR spread [ 1]. Recommended measures to prevent and control infection in a health-care facility [ 1, 12, 16, 24- 26].

Establishing an infection prevention and control committee (IPC).

Good hand hygiene practices.

Effective diagnosis and treatment of infection.

Rational antimicrobial use.

Surveillance of antibiotic resistance and antibiotic use.

Improving the antimicrobial quality and supply chain.

Good Microbiology Practices.

Surveillance of Antibiotic resistance and antibiotic use

All over the world, surveillance is considered as strength of the programmes directed towards AMR. The objective of surveillance is to facilitate the containment of antibiotic resistance. It is a useful tool that generates data on antimicrobial use and AMR which is essential in updating national EDLs and formulating infection control policies. It may also help in improving antimicrobial prescribing and development of empirical therapy or standards treatment guidelines [ 25, 26].National policy on AMR in India recommend three types of surveillances which include comprehensive surveillance, sentinel surveillance, and point prevalence [ 16].

Good Microbiology Practices

From accurate collection, handling of specimens to the speedy reporting with standard microbiology practices may help in prevention of AMR spread. Testing with international standards, reporting of resistance pattern to IPC and monitoring the sterilization and disinfection activities underlie the good microbiology practices [ 16, 24].

5. At Personal / Patient level
5.1 Role of Physician
Along with providing direct patient care, complying with local infection control and antibiotic use policies and timely notifying resistant cases to IPC, the physician can play a major role in combating AMR [ 24]. Identifying and preventing situations that may act as nidus for infection may help curtail unnecessary infections and thereby AMR [ 12].
5.2 Role of Nurses/health care providers
Since nurses/health care providers are in direct contact with the patients, they are amongst those related in either spread or control of infection and AMR. Educating nurses and health care providers about the AMR and aseptic practices may help in control of spread of infections. Moongtui et al., have reviewed the role of nurses in preventing AMR and reported the initiatives by Thailand like having Master's programme in infection control nursing with other short training courses and involvement of nurses in AMR prevention and control programme [ 27].
5.3 Role of Pharmacist
McCoy et al., in their review discussed the Pharmacist-directed antibiotic stewardship programs (ASPs) as an approach to improve the utilization of antibiotics. Pharmacists can counsel patients with viral infections about the ineffectiveness of antibacterials and can recommend appropriate OTC medication for supportive care. Referral to physician is must if a bacterial infection is suspected. Above all, most importantly, addressing patient and clinician concerns related to antimicrobial and understanding of the appropriate use of these agents, pharmacist can be an essential arm in preventing AMR [ 28]. Pharmacist is the key person to educate patients about antimicrobial use and the importance of complying with the prescribed treatment regime. This may help to reduce the unnecessary use of antibiotics.
5.4 At patient level
(a) Aseptic protocol for any procedures.

Parameswaran et al., reported that MDR microbes caused 30.2% of the catheter-related blood-stream infections and empirical treatment had no role in prevention of such infections [ 29]. This mandates use of aseptic protocol to minimize local or systemic infections associated with any procedures.

(b) Breaking the chain of infectivity [ 12].

By simple means like covering mouth while coughing or sneezing, infection spread can be reduced.

(c) Compliance to the antimicrobial regime and antibiotic.

Improved compliance definitely can improve the rate of infection control. Patient education on compliance with antibiotics is must [ 30]. Using established regimes for prophylactic use of antibiotics in high risk cases and for the shortest duration possible can minimize risk of AMR [ 31].

6. Other Measures
6.1 Pharmaceutical promotion
WHO recommends that pharmaceutical firms should strictly adhere to the standards of drug promotion, direct-to-consumer advertising and advertising the internet [ 14]. There is need to identify and prohibit any incentives promoted by pharmaceutical companies that possibly encourage inappropriate antimicrobial use.
6.2 Antibiotic use in animals
Use of antibiotic avoparcin in food of the animals in Europe was the cause of development of vancomycin-Resistant Enterococci (VRE) and consequent colonization in human intestine, thus highlighting its importance [ 16]. WHO specifically called for stricter legislation to minimize antimicrobial usage in animals. Improved sanitation, provision of probitotics or nutritional supplements in feed and vaccination for common animal diseases can help reduce the antimicrobial use in animals [ 25].
6.3 Rapid understanding of the AMR mechanisms
In their review, Bergeron and Ouellette suggested that genotyping of bacteria and identification of resistant genes in bacteria can impact the treatment of infections and contribute to the control of AMR [ 32].
6.4 Innovation in new drugs and technology
Concerns of increased antibiotic resistance lead to the urgent need of concentrating on the issue of new drugs and vaccines development to combat AMR. Collaborated efforts of national, international, government and academic networks are needed to identify new classes of antibiotics and diagnostic technologies [ 15].Providing research funding for development of new antimicrobials to pharmaceutical companies for diseases of public health importance can advance the new drug development.

In summary, it is necessary to enforce essential actions to be taken by government to inspire change by all stakeholders related to AMR as described in WHO policy package for combating AMR [ 13]. This policy package refers to:

Dedicate to a comprehensive, financed national plan with accountability of each one involved and engagement of civil societies

Improve and strengthen surveillance and laboratory capacity and facilities

Make sure uninterrupted wide access to essential medicines of assured quality

Regulate and encourage rational use of medicines, even in animal husbandry, and ensure proper patient care

Improvise on infection prevention and control

Promote and pursue innovations and research and development for new tools

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Strategies to Combat Antimicrobial Resistance

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The global burden of antimicrobial resistance is rising and is associated with increased morbidity and mortality in clinical and community setting. Spread of antibiotic resistance to different environmental niches and development of superbugs have further ...

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This occurs often when patients

1. stop their treatment early

2. save the antibiotics

3. use them in the future

4. are misdiagnosed an antibiotic

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These are important in our daily lives, saving humans and animals alike with all types of bacterial infections

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Some bacteria do not die after taking antibiotics. This can lead to either: replication occurring, when the bacteria grow and multiply, or gene transfer, when genetic materials are transferred between resistant bacteria and cells in the body.

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1. There is a good chance you will develop resistance to the antibiotic, meaning you will not be able to take the same one again.

2. They destroy the gut microbiome, which makes you more prone to multiple chronic diseases and health conditions.

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Probiotics should always be taken when prescribed an antibiotic

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An article from New York Times by Dawn Mckeen discusses the negative effects of using antibiotics

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"AMR remains one of the top global public health threats facing humanity and was associated with the death of close to 5 million people globally in 2019" - WHO

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WHO has published its first global research agenda for the world's scientists to address the most urgent human health priorities to combat antimicrobial resistance (AMR). It outlines 40 research topics on drug-resistant bacteria, fungi and Mycobacterium tuberculosis that must be answered by 2030, in line with the Sustainable Development Goals.

The WHO Global Research Agenda for AMR in human health will catalyze innovation and implementation research, spanning the epidemiology, burden and drivers of AMR, context-specific and cost-effective strategies to prevent infections and emergence of resistance.

It will also involve the discovery of new diagnostic tests and improved treatment regimens, the identification of cost-effective methods to collect data and translate it into policy, as well as how to implement current interventions more efficiently in resource-limited settings. Ultimately, the generated evidence will inform policies and interventions to strengthen the response to antimicrobial resistance, particularly in low- and middle-income countries.

"Antimicrobial resistance is an urgent public health and economic challenge, and good quality research is a vital part of the response. To help preserve antimicrobials and save lives and livelihoods, this research agenda is a crucial tool for researchers and funders to prioritize research questions, and promptly and efficiently generate evidence that informs policy," said Dr Hanan Balkhy, WHO Assistant Director-General for AMR. "This first research agenda from WHO will provide the world's AMR researchers and funders with the most important topics to focus on and give the world its best chance to combat AMR," added Dr Silvia Bertagnolio, Unit Head in WHO AMR Division.

The research agenda was developed based on a review of over 3000 relevant documents published over the past decade. The review identified 2000 unanswered questions or knowledge gaps, which were further consolidated and prioritized by a large group of AMR experts to conclude with the 40 most pivotal research topics. A summary report containing the research priorities is available here.

AMR occurs when bacteria, viruses, fungi and parasites change over time and no longer respond to antimicrobial medicines making infections harder to treat and increasing the risk of disease spread, severe illness and death.

As a result, antimicrobial medicines become ineffective and infections persist in the body, increasing the risk of transmission to others. AMR remains one of the top global public health threats facing humanity and was associated with the death of close to 5 million people globally in 2019. Importantly, it is also a threat to the global economy, with impact on international trade, health care and productivity. If no action is taken, AMR could cost the world's economy US$ 100 trillion by 2050.

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WHO outlines 40 research priorities on antimicrobial resistance

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WHO has published its first global research agenda for the world's scientists to address the most urgent human health priorities to combat antimicrobial resistance (AMR).

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Should a government regulation be put in place?

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Should a government regulation be put in place?

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How can antibiotics be developed quicker?

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How can antibiotics be developed quicker?

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This could be a means of preventing resistance

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In terms of its effectiveness, this would be especially difficult due to the number of patients who often do not follow the instructions given when administered antibiotics.

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Bacteriophages are something that can replace antibiotics. Bacteriophages only attack specific bacteria while antibiotics attack the bad and the good bacteria in the gut. They are commonly found in bacteria.

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Has yet to be licensed

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" traditional procedures that are used for the prediction of antibiotic resistance today could be markedly improved by including a broader analysis of bacterial fitness, infection dynamics, horizontal gene transfer and other factors. This will lead to more informed preclinical decisions for continuing or discontinuing the development of drug candidates"

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Authors and Affiliations

1. AntibioTx A/S, Kemitorvet, Lyngby DK-2800, Denmark; and at The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby DK-2800, Denmark.,

Morten O. A. Sommer

2. and at The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby DK-2800, Denmark.,

Morten O. A. Sommer

3. Christian Munck is at The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby DK-2800, Denmark.,

Christian Munck

4. AntibioTx A/S, Kemitorvet, Lyngby, DK-2800, Denmark

Rasmus Vendler Toft-Kehler

5. Department of Medical Biochemistry and Microbiology, Uppsala University, Husargatan 3, Uppsala, SE-751 23, Sweden

Dan I. Andersson

Corresponding author

Correspondence to Dan I. Andersson.

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Prediction of antibiotic resistance: time for a new preclinical paradigm? - Nature Reviews Microbiology

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Risk assessment for the development of antibiotic resistance against a new drug candidate is of paramount importance in preclinical development. In this Opinion article, Sommeret al. propose a new preclinical paradigm for the prediction of antibiotic resistance. Predicting the future is difficult, especially for evolutionary processes that are influenced by numerous unknown factors.