by Raees ul Hamid Paul
Striking a cautionary note at the end of his Noble speech on December 11, 1945, Alexander Fleming had said, “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 make them resistant.”
Our malpractices with antimicrobials have opened up Pandora’s Box and the evil, antimicrobial resistance (AMR) is out there, creating the pandemonium. The data which has emerged from several countries across the globe is carrying a very horrendous message: the world is virtually running out of antibiotics and we are possibly heading towards an antibiotic apocalypse. AMR, a buzzword in the clinical jargon is a looming threat to the global health, food security and development. Although strenuous efforts are being put in to design and discover new antimicrobial agents to keep up with the pace of anticipated escalation of AMR, we must realize that there are not much antimicrobial agents in the pipeline and the tap is running dry. The World Health Organization last week observed World Antibiotic Awareness Week (13-19th November) with the aim of reaching out to the general masses to avoid imprudent use of antibiotics. This year’s theme was “Take advice from a qualified healthcare professional before taking antibiotics”.
In JK where misuse of antibiotics is rampant, there is no reason to be complacent about that our infectious disease healthcare might be in a hunky dory situation. The situation is so alarming that it should literally send shivers down our spine. According to a report by DAK (GK, March 11, 2017), more than 70% of antibiotics are either prescribed unnecessarily or given improperly and an astounding >80% of infections are resistant to even last resort antibiotics which should set off the alarm bells for all of us. Recently Civil Society Forum Kashmir (CSFK) had to step in to raise concerns about this humongous healthcare related issue (RK, September 12, 2017).
Global burden of AMR
Currently, global burden estimates put around 700,000 people losing their battle annually to drug resistant infections. If the existing trend continues, the figures extrapolated are that by 2050, resistant bugs will account for 10 million annual deaths. The most notorious among these superbugs is MDR-TB, which accounted for 250,000 deaths in 2015, according to a WHO report. It’s believed that George Orwell succumbed to a TB infection caused by a drug resistant strain of tuberculosis bacillus while he was writing his dystopian novel, 1984. Apart from high mortality, AMR is associated with significant morbidity, longer hospital stays and rising healthcare costs.
How do microbes evade antimicrobial drugs?
Microbes withstand the onslaught of antibiotics by producing antibiotic cleaving enzymes such as several types of beta-lactamase which are easily disseminated by horizontal transfer of resistance cassettes harboring these genes for such enzymes, mutating the genes which lead to modification of drug targets so that the drug loses its affinity for the target enzyme or protein, employing expulsive strategies facilitated by specific groups of cell membrane bound transporters called efflux pumps. These transporters are fuelled largely by energy either from ATP or proton motive force (PMF). The most common among these is overexpression of ATP-binding cassette transporters (ABC-efflux pumps). Resistance in tuberculosis mainly arises through point mutations and there is no evidence of any role of horizontal gene transfer yet. Further, some bacteria have evolved very fascinating and deceptive strategies to evade the action of antibiotics like production of decoy mechanisms, the same way decoy flare mechanisms used by war planes to ward off the heat seeking rockets. High throughput sequencing of bacterial genomes has revealed that bacteria harbor around 20K resistance conferring genes belonging to approximately 400 different classes.
Non- therapeutic applications of antibiotics leading to AMR
Among the non-clinical uses of antimicrobials, agriculture, animal husbandry, aquaculture and waste disposal from drug manufacturing companies serve as the biggest environmental reservoirs of AMR. Resistance is brewing up in these farms and spreading off-site. According to one estimate, around 80% of all the antibiotics by weight sold in US are given to the livestock. Colistin is the “antibiotic of last resort” which is used as a salvage therapy if the patient doesn’t respond to standard therapy. Although this antibiotic was introduced back in 1950’s, its clinical application was limited by its toxicity to the humans. Due to its unrestricted use for agriculture and livestock, it has led to spread of resistant strains to human beings. What is intriguing is that in a span of just 18 months after discovery of mcr-1 gene in China in 2015, which confers resistance to colistin, it has spread across the globe. In China, 25% of the hospital patients were carrying mcr-1 harboring resistant bacterial strains. With regard to fungal pathogens, the azole fungicide usage in agriculture is one of the predominant environmental reservoirs of azole resistance in aspergillosis in the western world and Asia including India.
How often resistance translates into clinical failure?
A resistance in microbe can be viewed in two different ways depending on the person handling it. For a clinician, antimicrobial resistance is treatment failure even after administering proper dosage of an antibiotic. Accordingly, this category is referred to as clinical resistance. For a microbiologist, resistance is the failure of breakpoint drug concentration to inhibit the growth of a microbe under in vitro conditions, the category known as microbiological resistance.
Biology will perhaps never behave like mathematics. Does every case of resistance lead to abysmal treatment failure? The relationship between resistance which we often determine in the laboratory and the clinical outcome is not a deterministic one. A very strange approximation was made by Rex and Pfaller while analyzing the clinical outcomes in large data sets which they termed as “90-60 rule”. As per this approximation, though infections with in vitro resistant microbes can be treated ~90% of the time, however, we can still expect favorable clinical outcomes ~60% of the time in infections with resistant microbes. However, this rule is still far from general acceptability and wide recognition among the quarters of healthcare community and infectious disease specialists. Studies have reported ample number of cases where the pathogen isolated demonstrated in vitro resistance, however, the patients showed clinical improvement with the same drug. This anomaly is accounted by the rationale that apart from the drug’s intrinsic toxicity to the pathogen, host factors including the immunological status of the patient and pharmacokinetic-pharmacodynamic parameters also play a key role in determining the clinical outcome of antibiotic therapy. For instance, a patient with a sound immune status will clear the infection relatively easily than a patient with some immunological deficit, as it would be concerted action of antibiotic and immune system on the microbe in the former, resulting in greater likelihood of favorable clinical response. So, the points which we should infer here are: first even if the pathogen is susceptible, it may not always lead to a favourable clinical outcome, second AMR can’t always lead to clinical failure. Many of these factors have been taken into consideration and led to new treatment modalities proposed by IDSA (Infectious Disease Society of America) and ESCMID (European Society for Clinical Microbiology and Infectious Diseases).
How to contain AMR?
As per WHO, three anthropogenic causes-underuse, overuse and misuse of antibiotics can lead to resistance. Such is the gravity of the problem that some experts are giving radical suggestions, like introducing antibiotics with some nasty side effects. They argue that the relatively harmless nature of antibiotics to animal or human body is one of the prime reasons for their irrational use, unlike others like anticancer drugs which make people vomit and lose hair.
Underuse of antibiotic leading to resistance is somewhat enigmatic. Researchers are challenging the “finish your antibiotic” medical advice dogma and arguing that putting a patient on long term therapy and multiple courses even if he/she may feel resolution of symptoms while yet to complete his regimen, may actually increase the risk of resistance. Although, it can be conceded that taking the complete course of antibiotics is necessary to clear the infection and resolution of symptoms mayn’t always be suggestive of complete clearance of infection. However, there is no empirical evidence to back this notion that stopping antibiotic will lead to resistance, claims Oxford Professor Tim Peto. He and his collaborative team said that this is an “urban myth” that perhaps got ingrained in the minds of the people since the Nobel speech of Alexander Flemming in 1945, in which he told an imaginative and emotive story of a man with throat infection who undertook incomplete course of antibiotics. Although, he himself recovered from the illness but transmitted the infection to his wife who died as the bug had now become resistant. Interestingly, the bug which Flemming was talking about, Streptococcus pyogenes has never been found to become resistant to penicillin (Martin J Llewelyn, British Medical Journal, 2017). In one of the large meta-analysis cited by Peto, longer duration and multiple courses of certain antibiotics were associated with higher odds for resistance development.
Some others strongly vouch for providing more incentives to drug manufacturing companies so that they can passionately work on discovery of new antimicrobial agents. Former British Conservative Minister and leading economist Lord O’ Neill, best known for coining the term BRIC, suggested that antibiotic should be taxed to fund to pursue more aggressive research in the field of AMR and looking for new drug candidates.
As a major step towards fighting evolution of superbugs, McDonalds, the World’s biggest fast-food chain would stop using chicken treated with highest priority critically important antibiotics (HPCIA), a special list of antibiotics prioritized by WHO to be used prudently for containing AMR. Burger King too is contemplating to join the fray by switching to use of antibiotic-free chicken. Likewise, pressure is mounting on other fast food giants to take the pledge of fighting superbugs by restraining their use of antibiotic treated chicken. Around 3 50,000 people signed an online petition to urge Kentucky Fried Chicken (KFC) to stop using antibiotic-fed chicken.
At the community level how can general masses contribute in mitigating the AMR? WHO has prescribed a set of dos and don’ts? Antibiotic is not the solution to every damn infection. They can’t get us rid of the cold and flu. There is an urgent need to stop the menace of OTC use of antibiotic which is going on in our society. Maintaining hand hygiene, preparing food hygienically, limiting close contact with others while a person is sick, refraining from sharing antibiotics, practicing safer sex, updated vaccination and above all, always seeking advice from a qualified healthcare professional.
At hospital level, there is an urgent need to implement antimicrobial stewardship programs. These stewardship programs are coordinated efforts involving the general physicians, infectious disease specialists, microbiologists, pharmacologists and the infection control persons, to improve the treatment outcomes of antimicrobial therapy while minimizing the risk of its unintended ramifications like toxicity and emergence of AMR. Further it’s incumbent upon the healthcare professionals to stick to the standard treatment protocols of IDSA and ESCMID while managing infectious diseases.
Let’s take the pledge to be guardians of these “saviors of humanity”, lest we plunge ourselves into dark ages of healthcare.
(Author is a doctoral fellow in the Department of Medical Microbiology PGI, Chandigarh. PGI is a nodal coordinating center and WHO collaborating center for antimicrobial resistance in bacterial and fungal pathogens.)