Resistance hounds antibiotics

December 6, 2019 0 By S Harachand

Researchers warn that the post-antibiotic era is now upon us. The post-antibiotic era is a scenario in which all antibiotic medicines lose their powers. In such a situation, there will be no surgeries, no cancer therapy, and certainly no organ transplants. Even a minor injury, like that from a fall, can prove fatal.

If antibiotics lose their effectiveness, it would spell “the end of modern medicine”, according to England’s chief medical officer, Sally Davies.

Antibiotic drugs form the fundamental pillars of modern medicine. This unique class of medications is perhaps the greatest gift of modern science to humankind.

Unfortunately, the emergence of resistant microbes is increasingly rendering these critical and lethal weapons virtually ineffective.  

To make matters worse, very few new antibiotics are on the development horizon: The research pipeline of antibiotics has been running dry for decades.

Even so, bacterial infections throughout the world are becoming resistant to the drugs most often used to treat them.

In a way, it is natural for the remarkably resilient bacteria that cause diseases to develop ways to evade the drugs meant to kill or weaken them. This phenomenon of antibiotic resistance is spreading far and wide unabated, making even comparatively new antibiotics useless.

For example, third generation cephalosporins are today often useless against common bacteria like Escherichia coli, and fluoroquinolones are no longer the treatment of choice for gonorrhoea.

Around 25,000 people die in the European Union and 23,000 in the USA every year from infections caused by resistant bacteria. 

The increase in resistance is largely attributed to the widespread use of antibiotics. Antibiotic use goes unchecked throughout the world, irrespective of whether a country is rich or poor.

A new study published in the BMJ shows that nearly 25% of the time, antibiotics are inappropriately prescribed. Similarly, researchers from Public Health England came up with a finding last year that up to 23.1% of prescriptions for antibiotics made in primary care may be inappropriate. Further, no clinical justification was documented in a third of all the prescriptions.

Treatment failures because of multidrug-resistant bacteria, once rare and limited to hospitals, now occur very commonly in hospitals and are found increasingly in the community as well.

The scenario of post-antibiotics apocalypse is not distant, point out researchers. It is here, it is now.

“This serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country.”

India: Last line first

Even though antibiotic resistance is a global phenomenon, India is at the centre of this catastrophe. Antibiotics are freely available in the country and anybody can buy any antibiotic without the need for a prescription. Clinicians prescribe antibiotics rampantly. Hospitals use these precious drugs indiscriminately. There are no effective regulations on the use of antibiotics in livestock.

These practices, compounded by poor sanitation, are suspected to be creating a fertile ground for super-resistant pathogens.

Superbugs having New Delhi metallo-beta-lactamase-1 (NDM-1) were first reported in a Swedish patient who had been admitted to a hospital in New Delhi in 2008. However, the controversial carbapenem-resistant NDM-1 bugs, with their origin attributed to India, are increasingly being detected in many parts of the world.

India carries one of the largest burdens of drug resistance in the world. Nearly 400,000 people in the country may be dying due to antimicrobial resistance (AMR) every year, according to Nicholas Day, professor and director of the Mahidol Oxford Tropical Medicine Research Unit, Thailand.

Infections, mostly contributed by Gram-negative strains of bacteria, make the situation particularly grave. Isolates from the country have shown that these organisms harbour multiple resistance mechanisms to different classes of antibiotics. The rates of extended-spectrum beta-lactamase (ESBL) in E.coli and Klebsiella are as high as 80%. 

“Several publications have documented that 80% of Europeans who visit India for pleasure become ESBL carriers,’’ says a leading microbiologist from India, preferring anonymity.

Carbapenem resistance is as high as 60-80% in some commonly encountered nosocomial pathogens like Acinetobacter and Klebsiella species.

Resistance to colistin is creeping in, but no one knows the actual numbers as the tests of susceptibility to this high-end antibiotic can be done only by broth micro-dilution, method which is expensive, labour intensive, technically demanding and time-consuming, he adds. 

Doctors use colistin without knowing whether it will work or not. This non-specific use of colistin has led to selection pressure, resulting in the emergence of bacteria which are inherently resistant to colistin, like Burkholderia cepacia and Proteus species.

Today, colistin is the last resort to treat MDR infections and hence it is important to preserve the efficacy of this crucial antibiotic. But the drug is being grossly misused in the country.

Oral formulations of colistin are used to treat diarrhoea, irrespective of whether the infection occurs to chicken, pigs or children. Presently, there are no rational indications for oral colistin in humans. Administration of colistin via oral route is akin to “carpet bombing”. Such use could lead to colistin-resistant Gram negative infections. 

No repository; dearth of data 

India banned the use of colistin and its formulations for food producing animals, poultry, aqua farming and animal feed supplements in July. Before the prohibition came, the drug was being used extensively in the poultry industry as a growth promoter and a prophylactic.

Studies in some western countries found 30 percent of their chicken harbouring multidrug-resistant organisms. The percentage could be far higher in India.

The presence of colistin-resistant bacteria has been found in fresh food samples collected from various outlets in the southern Indian city of Chennai by researchers from the Apollo Cancer Institute, Chennai and Christian Medical College, Vellore, recently. This leaves ample chances for these resistance-conferring genes to be transmitted to bacteria inside humans. 

India is yet to implement systematic, nationwide surveillance of AMR pathogens in clinical settings, animals, and the environment, even though it started National Action Plan on AMR in 2017. It is one of the very few countries in the world without national surveillance data on resistant pathogens, according to World Health Organization’s (WHO) recently published AMR surveillance data from 169 member countries. 

Plans are afoot to set up a biorepository for drug-resistant microbes at National Centre for Microbial Resource (NCMR), Pune, the government announced in October.  

Unlike drugs that treat other diseases, the odds of misuse are pretty high with antibiotics. Unfortunately, the impact of such misuse is not always limited to the single patient.

Scoping Report on AMR in India 2017 found that the resistance level is high to broad-spectrum antibiotics belonging to fluoroquinolones and cephalosporins including the widely used ciprofloxacin and ofloxacin and third-generation ceftriaxone.

Antibiotics: A problem of plenty

Even as a large number of generic antibiotics are released into the Indian healthcare system, the quality of these drugs remains largely untested. Dozens and dozens of substitutes are available for each antibiotic. Experts say nowhere else in the world can one see 30 or 40 meropenems. They find it difficult to believe that all of them are equally potent. All these drugs require to be tested to ascertain their quality, but there is no national-level mechanism in place for the purpose. 

The quality of antibiotics is a critical issue because the suboptimal bioavailability of these drugs helps foster resistance.

A study published in the British Journal of Clinical Pharmacology in 2018 found that, of the 118 systemic antibiotic fixed-dose combination (FDC) formulations marketed in India, just 36% were approved and 64% had no record of regulatory approval. Less than 5% were approved by the Medicines and Healthcare Products Agency (MHRA) or European Medicines Agency (EMA) or the US FDA.

Even multinational companies were found to manufacture unapproved formulations and these accounted for 19% of FDC and single-drug formulation sales annually. The authors wanted MNCs to explain the sale of products in India without the approval of their own national regulators, and in many cases, even the approval of the Indian regulator.

Two out of three healthy persons in India have antibiotic-resistant organisms in their digestive tracts, indicate a study by the Indian Council of Medical Research (ICMR), based on analysis of stool samples of 207 individuals who had not taken any antibiotics for at least a month and did not suffer from any chronic illness.

Slow offtake of “stewards” 

A growing body of evidence shows that the smart use of antibiotics is an effective way to control the spread of resistant bacteria.

Antimicrobial Stewardship (AMS) programmes play an important role in ensuring that antibiotics are used only when appropriate. They involve many factors, such as leadership, commitment, accountability, education, training and communications, as well as robust auditing and feedback. 

“When we talk about antibiotic stewardship, what we want to make sure is that we are not using antibiotics with no good reason,” says Dr Michael-Alice Moga, Assistant Professor, Department of Critical Care Medicine, The Hospital for Sick Children, Toronto.

A patient may be put on a broad-spectrum antibiotic in situations where the clinician is not sure what is going on with the patient. But the very moment he gets more information, he needs to stop it or switch.

“You may have put someone on antibiotics suspecting an infection. But as soon as you have evidence that there wasn’t an infection, you need to stop them. In case the evidence comes back showing an infection, then you need to use the narrowest spectrum of antibiotics possible to cover just that bug instead of one with broad-spectrum activity,” she explains.  

However, a lot of doctors find it hard to see the collateral impact. They want to be doubly sure and keep the patient on a broad-spectrum antibiotic for 10 or 14 days, because that is the more immediate thing they see. If thousands of doctors do the same thing thousands of times, according to Dr Moga, we are certainly going to pay for that 5 or 15 years down the road.

Clinicians need to be alerted about the consequences. Already, a lot many instances of antibiotic resistance are getting reported from every part of the world. So, if clinicians are not going to change the way they are carrying on, things are going to get worse.

Besides, they must realize that all antibiotics have potential side-effects, and they are exposing the patient to unnecessary risks. Obviously, there are all sorts of reasons why doctors need to be very thoughtful about how they use antibiotics.

“Do we give cancer drugs willy-nilly to everyone?” asks Dr Subramanian Swaminathan, senior consultant, ID, BGS Gleneagles Global Hospitals, Bengaluru. “Doctors should take personal responsibility while using antibiotics. When we don’t do it for ourselves, we don’t give it to other people. Physicians need to understand that these are toxic things.” 

Still, adds Dr Moga, the role of antibiotics in critical care settings is important. But it should be minimised.

Adoption of AMR practice is abysmally low even in bigger healthcare organisations (HCO). Experts see several challenges in implementing AMR protocols in hospitals in India. 

A conflict of interest is the first and foremost barrier. Pharmacies are usually a hospital’s biggest source of revenue. Less consumption of medicines means less earnings to the organisation. 

Moreover, AMS has not been made mandatory by any accreditation agency. Most hospitals are anyway not accredited.

Apart from the lack of any compulsion, HCOs are also not motivated to invest money to set up and run AMS programmes.  

“All organisations, including health care organisations, function and thrive on sufficient funding for specific projects. There is no obvious “return on investment” on antimicrobial stewardship. Healthcare professionals in most places have failed to provide a sustainable business plan for AMS,” observes Dr Anup R Warrier, Lead – Infectious Diseases, Infection Control and Antimicrobial Stewardship, Aster DM Healthcare – India Units.

Clinical governance is an essential part of a good AMS programme. In the Indian healthcare industry, clinical governance is still in its infancy and will never mature until people start paying for quality instead of quantity in clinical care. 

Sadly, a tremendous amount of resources is wasted on “measuring” the quality of care, with no strategy on how to address any “lack of quality”. AMS will thrive where the hospital team has successfully developed a business case around it and where there is a strong clinical governance system, he adds.  

A paucity of ID experts is another problem. Even if some healthcare organisation wants to implement AMR protocols, very few qualified people are available to run it. As a specialty, infectious disease is still looking for acceptability among the physicians. 

Specialists, as a matter of fact, develop in response to the demand, says Dr Anup. And demand is in proportion to how much revenue there is in the specialty. ID is a “cerebral” specialty with no procedures involved. The contribution of ID, when calculated by the number of consults and patients, does not justify more clinicians entering this specialty.

However, there has been a significant change in the scenario in the last 10 years. National Accreditation Board for Hospitals & Healthcare Providers (NABH) and Joint Commission International (JCI) have fuelled this change to some extent, he points out. 

Dr Anup sees more ID specialists in the country in the coming years as more and more HCOs “run” AMS and infection control programmes for NABH and JCI.   

“More and more large institutions are now investing in having ID specialists as part of their armamentarium for handling patients, especially in challenging situations such as transplant surgeries,” concurs Dr Swaminathan.

They now understand that stewardship in AMS can change outcomes. The government sector, however, remains unorganised.

Are clinicians resistant?  

The most difficult barriers to AMS practices, AMR leaders find, are often the clinicians themselves.

Doctors are not usually very AMR-savvy. Rather, most of them are somewhat averse to the concept of being questioned on their antibiotic choices. 

“Personally, I abhor taking a chance on antibiotic use and putting my surgical patient’s life in peril,” quipped a senior cardiac surgeon during a debate session in a recent conference on perioperative paediatric heart care. “I will go for the best available option for both peri-operative as well as post-operative care, rather than exposing my patient to any potential risk of infection.” 

Here, the practices in India are in contrast with that in the West. “In the West, it doesn’t matter what you do. You could be a neurosurgeon or a gynaecologist or whatever. But an understanding about infection control is mandatory. If you fail in infection control, you fail in your subject,” says Dr Swaminathan. 

So, all clinicians are expected to know the basic concept of infection control and AMS. Those kinds of initiatives are absolutely necessary, he says.  

Most of the clinicians, he points out, have a kind of contempt for infections and antibiotics. The problem is that they consider it as just an antibiotic.” “Well, it is not just an antibiotic. We are paying for this foolishness. The mindset needs to change,” he asserts.

Some AMR experts believe that, like in critical care, regulation of antibiotics in surgical specialties cannot be a top-down process, given the stakes are quite high. 

“The treating team often needs evidence that stepping down to a lower antibiotic will not affect the surgical outcome,” says Dr Sadia Khan, clinical microbiologist and former associate professor at Amrita Institute of Medical Sciences, Kochi.

In such cases, the message has to be conveyed by a peer rather than the regulator. Changes in prescribing behaviour cannot be brought about overnight, as, quite often, they warrant sustained inputs from antibiotic stewardship teams.

Nonetheless, ID specialists like Dr Anup say they encounter more friendliness, not hostility, among doctor specialists. In HCOs where ID departments have been thriving since long, many of the specialists are happy to leave the antimicrobial decisions to the ID teams.

In organisations where there is a culture of shared responsibility and teamwork, most of the clinicians are happy to solicit ID opinions, he avers, but hastens to add that the success of the ID consultant is dependent on his or her individual competence and the ability to develop and maintain interpersonal relationships. Humility, patience and friendliness, armed with knowledge, should get the ID physician sufficient support from other specialties, he says. 

Need for infection control; better diagnostics

Given the scale of the problem, AMR needs to be dealt with at different levels. Prevention of infection is one of the key goals of the programme. Hospitals, especially, critical care units, are the hotbeds of highly resistant superbugs.

Data from several critical units of tertiary care centres in India showed 7% of patients resistant to antibiotics. This also results in 5,98,000 neonatal deaths each year. 

Hence the onus is on hospitals to ensure that they take every possible means to stall nosocomial infection in critical care units.

“If we find that an infection is related to plastic such as catheters or a central line inside the body in critical care, what we do is we try to get as much plastic out as possible. If it is not there, it cannot get infected,” recommends Dr Moga, speaking on the AMR practices in Canadian critical care centres.

Simple things such as practising hand hygiene as a routine are some of the easiest things that can go a long way in decreasing the spread of infections.

Similarly, judicious use of antibiotics can be facilitated by appropriate selection of existing diagnostic tests. 

Point-of-care diagnostics may help clinicians avoid unnecessary treatments, rapidly select appropriate targeted therapies and inform the duration of treatment. Despite being essential to tackling antimicrobial resistance, very little progress is being made in this area.

Currently, rapid diagnostics being used for antibiotic stewardship programmes in tertiary care centres comprise tests to differentiate viral and bacterial infections, biomarkers like procalcitonin which can be used for de-escalating antibiotics, and molecular platforms which can detect the organism and resistance patterns from the blood and other samples directly. 

However, cost becomes a limiting factor in many setups, especially when it has to be borne by the patient, says Dr Sadia. Technical discordance with conventional methods also makes the treating team quite sceptical about the results obtained by these methods.

Of late, select Indian diagnostic firms have started commercialising AMR diagnostic products. MedGenome Labs, a genetic diagnostics company, has developed a quick test to analyse every single mutation present in any drug-resistant tuberculosis bacteria directly from sputum samples. This Bangalore-based firm is now in the process of bringing out such products for other infectious diseases as well.

Things are slipping… 

AMR can cause 10 million deaths annually by 2050, shows a UK government review. However, there is not enough information to show the global impact and cost of the phenomenon. 

“We may not have very good systematic data. But we have enough data to show that we are going in the wrong direction and things are slipping. If we wait for that kind of data, it will be too late to act.. by the time we get it,” informs Dr Swaminathan.

The impact of leaving AMR unchecked are wide-ranging and extremely costly.

Somewhat belatedly, the global community seems almost resolved to working out strategies to counter this most pressing public health problem.

The World Economic forum was quite honest in identifying AMR as a global risk beyond the capacity of any organization or nation to manage or mitigate by itself, points out Dr Sadia. 

Of course, ’One Health’ approach is an excellent way forward to the global community. 

India has all kinds of compelling reasons to go the extra mile in dealing with the menace. The country already bears the brunt of serving as the capital of AMR, along with similar distinctions in TB and HIV.

It is imperative for the country to put in a massive effort backed by strong political will to curb unbridled antibiotic practices. 

States like Telangana have come up with action plans to regulate antibiotic use in healthcare settings. But what is urgently required is a well-structured national-level policy to control the uncontrolled sale, prescription and use of these drugs in all clinical and non-clinical setups, coupled with strict monitoring to ensure the quality of antibiotics circulating in the country.

Clinical microbiologists argue that the current prescription practices are dictated, largely, by drug makers. Hence it is necessary to make it mandatory for doctors to attend CME programmes conducted by NGOs and NPOs without industry participation.

Irrational prescription practices should be dealt with using stringent laws. Heavy prescribers need to be tracked by making the clinicians’ identity — like his Aadhar number — mandatory with every prescription.  

AMR is a big challenge calling out for a huge resource allocation. “India cannot afford to hide behind the excuse of [being in a] “low resource” setting anymore. We need huge investments in diagnostics and clinical governance, in data analytics and in changing our financial model towards pay for performance,” notes Dr Anup. 

As for the problem of hospitals not having enough resources for an organisational level AMS programme is concerned, we should look at unit level or department level AMS activities.

One of the ways forward for India as a low-resource country is to focus on medical students, so that we can ensure that all “basic” doctors are trained in antimicrobial use in primary and secondary care syndromes. These trained doctors would not require “stewards” to help them prescribe antimicrobials appropriately in the future, he opines.

It is really scary to see doctors who do not understand the basic concepts of infection control, remarks Dr Swaminathan. “We need to change the way doctors are trained today at every level — undergraduate, post-graduate and sub-speciality. We need a curriculum change.”        

At the core of the issue is a lack of proper awareness. It is also the fundamental challenge in tackling this problem. 

Information about the use of antimicrobial agents and drug resistance can even be included in school curricula to promote awareness from an early age, as recommended by the WHO. 

Still, the target audience in human health, animal health and agricultural practices need to be identified for raising awareness on the health and economic impact of AMR. The language currently being used to communicate AMR is heavily scientific. This needs to be simplified for the community at large. 

“We need to tell this AMR story passionately and we need storytellers who can convey the horrors of the post-antibiotic era to the community,” says Dr Sadia. 

—With inputs from Divya Choyikutty