Alexander Fleming known as the “Father of Antibiotics” while receiving Nobel Prize for the discovery of Penicillin in 1945 had forecasted in his acceptance speech, “But I would like to sound one note of warning the time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non‐lethal quantities of the drug and make them resistant”. Today humanity is witnessing his golden words turning into a harsh and bitter reality with under-, over- and misuse of antimicrobials leading to the emergence of resistance among bacteria and other micro-organisms. Day is not far when a minor injury, disease or surgery could result into the death of a person as a result of untreated infection due to antimicrobial resistance (AMR). Currently, at least 700,000 people die each year due to drug-resistant diseases, including 230,000 people who die from multidrug-resistant tuberculosis (WHO, 2019). British government appointed antimicrobial resistance review committee chairman Jim O’Neil predicted in 2016 that by the year 2050 there could be an estimated 10 million deaths annually as a result of AMR and it could cost the world economy a whopping 100 trillion dollars. An ever-growing list of infections such as pneumonia, tuberculosis, systemic infections and gonorrhoea are becoming harder and sometimes impossible to treat as antimicrobials continue to become less effective. Resistance has also rapidly emerged to sulphonamides, penicillins, tetracyclines, macrolides, fluoroquinolones and cephalosporins.
Though some critics term these figures projected by Jim O’Neil as exaggerated, fact of the matter is that as per World Health Organization (WHO, 2020) high rates of resistance against antibiotics frequently used to treat urinary tract infections, sepsis, sexually transmitted infections and some forms of diarrhoea have already been reported world-wide, indicating that we are steadily running out of effective antibiotics. For instance, the rate of resistance to Ciprofloxacin, an antibiotic commonly used to treat urinary tract infections has increased from 8.4% to 92.9% for Escherichia coli and from 4.1% to 79.4% for Klebsiella pneumoniae in countries reporting to the Global Antimicrobial Resistance and Use Surveillance System (GLASS). WHO-GLASS has further reported that the resistance in Klebsiella pneumoniae, that can cause life-threatening infections, to the last resort treatment i.e., carbapenem antibiotics has spread to all regions of the world. K. pneumoniae is a major cause of hospital-acquired infections such as pneumonia, bloodstream infections and infections among newborn and intensive-care unit patients. Colistin is the only last resort treatment for the life-threatening infections caused by carbapenem resistant Enterobacteriaceae i.e., E. coli, Klebsiella, etc. However, astonishingly bacteria resistant to colistin have also been detected in several countries and regions, causing infections for which there is no effective antibiotic treatment available at present (WHO, 2019). Thus the world is fast heading towards what some people call as ‘antibiotic apocalypse’ and others term as ‘post-antibiotic era’ as a fall-out of multi-drug resistant or pan-resistant micro-organisms known in common parlance as ‘superbugs’. Superbugs exhibit super-resistance and like super-computers and self-automated AI machines turn uncontrollably and unimaginably hostile, wreaking havoc to the ailing lot like tuberculosis patients suffering from multi-drug resistant, extensively drug resistant and totally drug resistant forms of tuberculosis.
Need of the hour is to take adequate prevention, management and control measures well in time to stop the spread of resistance among microbes though many scientists believe it to be an evolutionary process wherein micro-organisms are believed to mutate to resistant forms as a result of natural selection and environmental survival pressure created by antibiotics or the constrained environment. Intrinsic or acquired mutations allow them to survive and live on to reproduce. Then they pass this trait to their offsprings, which would be a completely resistant generation. Bacteria are remarkably adaptable organisms with an innate ability to circumvent damage if exposed to a toxic environment (Floris et al, 2020). Since the development of the first antibiotic less than a century ago, there has been an exponential growth in antimicrobial resistance that is disproportionate to the rate at which antibiotics are introduced. In 2019 WHO identified 32 antibiotics in clinical development that address the WHO list of priority pathogens, of which only six were classified as innovative. Since 1990, only three novel-class antibiotics have been launched (pleuromutilins, lipoglycopeptides, and oxazolidinones), although many derivatives of older classes were also launched (Baker et al, 2018).
WHO has declared that AMR is one of the top 10 global public health threats facing humanity. It requires urgent multisectoral and multi-dimensional action in order to achieve the United Nations Sustainable Development Goals (SDGs). Superbugs are omnipresent in the biosphere Continued resistance is rapidly eliminating treatment options for patients, and the cost burden to treat a multidrug-resistant infection is steadily climbing, reaching more than $2.2 billion annually in the United States. Universally, the market consumption rate of antibiotics is assessed to range from 0.1 to 0.2 million tons yearly (Wise, 2002). Antibiotics are extensively used in medical, veterinary, and agricultural platforms for therapeutic, prophylactic, metaphylactic and growth-promoting purposes. The overall quantity of antibiotics used worldwide in agriculture is estimated to range between 63,000 and 240,000 tons, with beta‐lactam antibiotics like penicillins, cephalosporins, and carbapenems being the largest group of antibiotics consumed (50%–70%) by humans (Kumar & Pal, 2018).
Many strategies for avoiding, inhibiting, or bypassing resistance mechanisms in pathogens have been attempted. The most notable successes in such endeavors have been with the β-lactam antibiotics. Clavulanic acid and related compounds are potent inhibitors of β-lactamase enzymes and are frequently used in combination with the β-lactam antibiotics. These combinations have been highly effective but bacteria have found a way to outsmart us: a number of β-lactamases that are refractory to inhibition by clavulanate have appeared. To date, research to extend this approach to other classes of antibiotics has not been successful (Davies & Davies, 2010). Antibiotic resistance has been found in most bacteria, but several bacteria are particularly problematic and are becoming common among hospital-acquired infections that include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae commonly referred to as ESKAPE pathogens (Floris et al, 2020). In 2017, the WHO published a list of bacteria where new antibiotics to tackle them are needed urgently and grouped them according to their priority as critical, high and medium, with a view to encourage research and development of new antibiotics.
AMR can be overcome to a large extent by referring to nature to develop naturally derived agents with antibacterial activity on novel targets such as bacteriophages, Odilorhabdins (ODLs), peptidic benzimidazoles, quorum sensing (QS) inhibitors and metal-based antibacterial agents and by deactivating the mechanism of resistance, like the action of the β-lactamase inhibitor antibiotic adjuvants (Breijyeh et al, 2020). Strategies relying on phage therapy, probiotics, CRISPR technology, faecal transplantation and host immune response biomarkers are also being explored as novel approached to combat AMR. Innovative vaccine technologies, such as reverse vaccinology, novel adjuvants, and rationally designed bacterial outer membrane vesicles, together with progress in polysaccharide conjugation and antigen design, have the potential to boost the development of vaccines targeting several classes of multidrug-resistant bacteria (Das et al, 2017). Furthermore, new approaches to deliver small-molecule anti-bacterials into bacteria, such as hijacking active uptake pathways and potentiator approaches, along with a focus on alternative modalities, such as targeting host factors, blocking bacterial virulence factors, monoclonal antibodies, and microbiome interventions, all have a significant potential to counter AMR (Baker et al, 2018).
Unless and until adequate prevention and control measures are not adopted in a concerted fashion by all the stakeholders, it is not possible to combat AMR through novel and innovative approaches. A mix of conventional and novel approaches alone is going to yield best results. Measures need to be taken at international, national, community, hospital level as well as at individual level by healthcare workers including doctors, nurses, pharmacists and by the patients in order to control the problem of AMR effectively. All stakeholders need to join hands and act in an integrated and collaborative manner complementing and supplementing each other in their efforts towards preventing and controlling AMR. All our hospitals need to devise their own infection control and antibiotic use policies besides framing standard treatment guidelines for infectious diseases and constituting Drugs and Therapeutics Committees and formulating Hospital Formularies (Geer, 2017). There is a need to conduct culture tests for determining antimicrobial sensitivity first and then only prescribing antibiotics. Rampant sale and use of antimicrobial drugs that have been listed and notified in 2013 under Schedule H1 of the Drugs and Cosmetics Act, over-the-counter sans any prescriptions written by qualified physicians and their indiscriminate sale by unqualified pharmacists at retail sale outlets need to be curbed with tough regulations and strict law enforcement. Need of the hour is to implement this provision strictly on war-footing basis failing which it will be impossible to avert AMR. Indiscriminate sale and use of antibiotics cannot be taken lightly anymore. Jammu and Kashmir government must come up with a robust and comprehensive action plan of its own for the containment of AMR as soon as possible. Other measures that the government needs to take for the prevention and control of AMR have been enumerated in another article of mine published in 2017 on “Averting Antibiotic Apocalypse in J&K”.
(Author teaches at the Department of Pharmaceutical Sciences, University of Kashmir)