Antimicrobial Resistance (AMR) – A global threat is here to stay!

By Vasan Sambandamurthy, PhD

Associate Research Director, Biocon Limited.

Antimicrobial resistance (AMR) represents a global catastrophe that threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi.

AMR is an evolutionary response to antimicrobial exposure and resistance arises through mutation or through the acquisition of resistance gene(s) from other bacteria in a process called horizontal gene transfer (HGT).

In the pre-antibiotic era, the case fatality rate for Staphylococcus aureus bacteria was 80% and 97% of patients with endocarditis died due to lack of treatment. Before the advent of antibiotics, wound infections were often treated by amputation. In fact during World War I, 70% of amputations were performed as a result of wound infection. The discovery and development of antibiotics have profoundly altered the fate of patients with such infections, facilitating advances in modern medicine such as increasingly complex surgery, transplantation and chemotherapy.

Cost to the Society

Unfortunately, the global emergence of antibacterial drug resistance in healthcare settings and in the community threatens the enormous gains made by the availability of antibiotic therapy. The Centers for Disease Control and Prevention (CDC) estimates that 2 million illnesses and 23,000 deaths are caused by drug-resistant bacteria in the United States each year. The annual impact of antibiotic resistant infections on U.S. economy is estimated to be $20 – $35 billion with an additional cost to society for lost productivity of $35 billion / year. This results in 8 million additional days in hospitals each year, higher hospital cost
and re-admissions. With a declining choice of antibiotics, we have entered a “post-antibiotic” era. In Nigeria, for instance, as many as 88% of Staphylococcus aureus infections cannot be treated with methicillin. The AMR problem also seems to be acute in the ‘BRIC’ states: Brazil, Russia, India and China. Multidrug resistance among the ‘ESKAPE’ organisms – encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter sp. – is of particular concern because they are responsible for many serious infections in hospitals and result in – severe illness, increased recovery time, increased medical expenses and increased risk of mortality.

Mortality attributable to AMR every year in comparison to other major causes of death

Fighting back against AMR: The four core actions to prevent

What gaps in our knowledge need addressing?

1. Fundamental understanding of how to minimize the selection of antimicrobial resistance along with the knowledge of how to optimize antimicrobial use.
2. Improved targeting through rapid infection diagnostics should be enabled – this has been slow to be implemented due to technical and financial barriers as well as innovation adoption.
3. Discovery of new drugs is urgently required along with the research on the quality of currently used antimicrobials.
4. The understanding of how to effectively reduce the prevalence of resistant organisms and their transmission
5. Continued research to generate new insights into basic mechanisms of resistance, gene transfer, and adaptive bacterial evolution.

Beyond antibiotics – alternative strategies for prevention and treatment

Understanding the scientific basis of antimicrobial resistance is essential to combating this public health threat. There is no single solution and several, synergistic, overlapping, and complementing approaches will be needed, with a strong overarching shared goal to ensure and sustain access to effective antimicrobial therapies. These include:

1. Drug Derivatives: Modification of known antimicrobial agents – new β-lactamases or efflux pump inhibitors.
2. Novel agents: Whole cell or target based antibiotic discovery using new tools such as combinatorial chemistry and genomics.
3. Anti-virulence Drugs: Antibodies or small molecules blocking or inhibiting virulence factors.
4. Bacteriophages or enzybiotics: delivery of bacteriophages or phage-lytic enzymes.
5. Evolutionary biology approaches: Aimed at targeting the ecology/evolution of AMR, including inhibitors of plasmid transfer of resistance, gene silencing antisense oligomers.

In conclusion, AMR has to be recognized as a major international collaborative science program to provide the solutions needed by the society. To put it into perspective, the Large Hadron Collider project cost about £6 billion and the International Space Station cost £96 billion to build. It is estimated that the research to address the problem of AMR probably requires an investment that is somewhere between the two.

References:

1. National action plan for combating antibiotic-resistant bacteria. White House Report. March 2015.
2. Antibacterial antibodies gain traction. NRDD 14:737-8 (2015).
3. Holmes AH et al., Understanding the mechanisms and drivers of antimicrobial resistance. Lancet (2015).
4. Perry JA. Bioessays 36: 1179–1184 (2015).
5. Antibiotic resistance threats in the United States, 2013. CDC Report 2014.