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THE COMING ANTIBIOTIC ARMAGEDDON

If all this sounds alarming and terrible, it is meant to be
Updated Feb 02, 2020 01:38pm

Antibiotics are prescribed in 70 percent of patient encounters in Pakistan. Over-the-counter availability of the drugs allows many to buy antibiotics with no prescription at all. If antibiotic overuse remains the norm and bugs continue to develop immunity against the drugs, a dark future awaits us...

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Her name is Mehreen and she is 27. She has an unnerving habit of looking straight into the eyes of strangers during conversation until they get uncomfortable and look away. It is a wonderful thing, this assertion of her fearlessness, her right to the space she moves in.

She comes from a prosperous family that owns a 2-kanal (1,210 square yards) house in Defence Housing Authority next to a major academic institution. But at the moment, her job as vice president of a human resources company that operates in seven countries, her myriad family connections and her Ivy League education have all become irrelevant; for Mehreen is sick.

The fact of the matter is, Mehreen is dying.

Lying on the private bed of a large private hospital in Lahore, she stares at the ceiling with jaundiced eyes. Her body has been overwhelmed by septic shock — a state in which her blood vessels have widened to form tunnels incapable of supporting life-sustaining pumping pressure, resulting in a lack of oxygen supply to vital organs; her heart has weakened to less than 15 percent of its pumping capacity; her liver and lungs are drowning in her own body fluids. This is the frightening prequel to the inevitable collapse of her body’s organ systems, possibly culminating in death.

All this is the result of an infection that started inside her gut; her killer: a tiny stubborn bug that took residence in her body months ago.

Like Hitchkock’s Psycho silent at the keyhole, the bug waited in the shadows of her intestines for the right moment to strike; and the moment came when Mehreen picked up a pack of over-the-counter antibiotics from the drug store on her way home from gym. She had bad zukaam (flu) that was ‘just not going away’ and her doctor decided to prescribe a third-generation antibiotic for what was certainly no more than a common cold.

And now, in less than 48 hours, Mehreen will be dead.

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Once upon a time you were a bug.

Some 3.7 billion years ago or so, you crawled out of a warm chemical soup composed of cooled gases and electrified clays.

You were a microscopic organism that — via kinetic movements and natural selection — withstood trillions of biochemical and electromagnetic interactions between particles of matter called molecules. Baked by the heat of a young sun, you made building blocks of proteins called amino acids, which began to come together in the right configuration. You were attacked by acids and alkalis, salts and heavy metals; nevertheless, you persisted.

Despite tremendous odds, because of tremendous odds, pieces of you gelled (call it love at millionth sight) and you became the composite you: the first stirring of Life on Earth.

Human beings are mostly bugs, over 100 trillion of them. From the inside of your mouth and intestines to the tip of your little toe, you are covered with this layer of benign microbes that makes you virtually invincible, possibly invisible, to billions of disease-causing pathogens.

With your awakening, came more attacks by nature and other organisms, which, too, were rapidly coming alive. Through trial and error, over billions of years, you figured that you could grow a tough outer membrane — skin — to protect your soft insides. You developed horns, nails and teeth to fight; flagella, tails and legs to escape danger if need be.

You negotiated with other peace-minded microorganisms and reached an effective deal worthy of envy by Pakistani political parties: these foreign bugs could live on and inside you, provided they paid rent in the shape of food or protection from more dangerous or pathogenic microbes. They were your friends and neighbours, ever ready to provide succour; and they covered every part of you.

Human beings are mostly bugs, over 100 trillion of them. From the inside of your mouth and intestines to the tip of your little toe, you are covered with this layer of benign microbes that makes you virtually invincible, possibly invisible, to billions of disease-causing pathogens.

This Cloak of Invisibility is called your ‘microbiota’ (all the genes in these bugs collectively called the ‘microbiome’) and it is one of the most exciting areas of research in medicine today.

We know that this symbiotic swarm of living things on our body reached this balance over a staggering amount of time. Enough time to reach an ecological homeostasis, a wonderful balance of give and take. We protect each other from hostile pathogens, we regulate each other’s metabolism. The bacteria in our microbiome help digest our food, fortify our immune system and produce vitamins to help correct our nutritional deficiencies. They even drive our craving for dark chocolate!

In short, they know our deepest darkest secrets.

Yet, once in a while, a pathogen breaks through the barriers of skin and the microbiota. It is dangerous and may cause severe infection with spread of the bug throughout the body. Fortunately, in most cases, it is detected by our immune system — a multipronged army of specialised cells — that chases, contains and kills these invaders. The body is quite vigilant and diligent, as it turns out.

Scientists are scrambling to produce new effective antibiotics but the bugs are rapidly evolving to become resistant to them | Malika Abbas/White Star
Scientists are scrambling to produce new effective antibiotics but the bugs are rapidly evolving to become resistant to them | Malika Abbas/White Star

In rare instances, though, the immune system is not able to control the infection; usually because our immunity is compromised due to disease (diabetes, chronic kidney or liver disease, for example), unfavourable environment (extreme cold, smog), breaks in protective barriers (heat or traumatic damage to skin) or because the invading army is just too big and powerful.

This is when an antibiotic (a drug against said bacteria) might come in very handy and may even be lifesaving.

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Alexander Fleming discovered the first known modern antibiotic — Penicillin — in 1928. This ushered in the golden age of antibiotics. Suddenly we had a magical drug that could cure the worst infections in the world: tuberculosis, cholera, leprosy, the much-feared Black Death (bubonic plague). Doctors, nurses, medics and others began dispensing these drugs by the handfuls. Hundreds of thousands of people were saved from what would previously have been certain death.

However, much like the process of evolution (which gave rise to your own defences) bacteria — which divide and grow in numbers much more quickly than humans do — began self-selecting for antimicrobial resistance via natural selection. A bacterium with a gene that confers resistance against the antibiotic would be able to survive and birth more of its kind; the others would die out.

Did you know the World Health Organization has singled out Pakistan for an entirely separate treatment category? It is not because we are wonderfully unique, but woefully so: In 2016 thousands of cases of the world’s most dangerous strain of Salmonella Typhi — the bacterium that causes typhoid fever — were documented in Pakistan.

Therefore the same antibiotic that worked for, say, leprosy 10 years ago would become ineffective against it over time.

This has given rise to a full-blown arms race between the microbial world and the human world. Scientists are scrambling to produce new effective antibiotics; the bugs are rapidly evolving to become resistant to them.

And the bugs are winning.

Enter Pakistan:

Antibiotic abuse and the plethora of problems that follows it is one of the largest challenges facing the world today, but the issue is at a whole different scale in Pakistan where:

(a) Antibiotics are available over the counter without a doctor’s prescription,

(b) A pharmacist, hakeem, or your ‘samajhdar chaacha’ (wise uncle) can recommend and therefore dispense an antibiotic at the first twitch in your nostril.

(c) Antibiotic stewardship programmes (ASPs) — that dictate a hospital’s institutional use of specific and privileged antibiotics — and solid foundational training in the dangers of overuse are often nonexistent even in major cities (as noted in the 2018 GARP-Pakistan [Global Antibiotic Resistance Partnership] Situation Analysis Report On Antimicrobial Resistance in Pakistan).

(d) Complete absence of national surveillance programs for antibiotic use in livestock has led to indiscriminate use of antibiotics in farm animals and poultry for therapeutic, prophylactic and growth promotion purposes. This has added significantly to antimicrobial resistance (AMR) in bacteria isolated from these animals. Rates and mode of their transmission between humans and animals remain to be established, according to the GARP-Pakistan report.

Result:

Did you know the World Health Organization has singled out Pakistan for an entirely separate treatment category?

It is not because we are wonderfully unique, but woefully so: In 2016 thousands of cases of the world’s most dangerous strain of Salmonella Typhi — the bacterium that causes typhoid fever — were documented in Pakistan. Indeed, this bug is resistant not just to the first and second-line antibiotics but also third line (drugs that may be useful, but have doubtful or unproven efficacy). In fact, there are only one or two classes of antibiotics left with efficacy against this XDR (extensively drug-resistant) typhoid.

Which means, once our luck runs out and the bug develops resistance to these last two classes, Pakistani patients, regardless of their wealth and social status, will die if they acquire typhoid.

In recent years we have (inadequately) talked about ‘climate change (better termed the ‘climate emergency’), Lahore’s ‘Smog Apocalypse’ and the ongoing wildfire crisis raging across the world. But we are still not talking about the giant elephant in the room — The Post-Antibiotic Era, when all bacterial infections become completely and irrevocably resistant to current antibiotics.

What will we do then?

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The story of damage from excessive antibiotic use and abuse does not end with drug resistance, however.

Remember your friendly neighbourhood bugs — your microbiota — that protects you from pathogens and nourishes you?

Guess what happens to them when you hammer your body with one antibiotic after another?

You virtually wipe them out.

Physicians and patients both need to be whistleblowers on the Antibiotic Armageddon | Emaan Rana/White Star
Physicians and patients both need to be whistleblowers on the Antibiotic Armageddon | Emaan Rana/White Star

Every single time you do a course of antibiotics or take one ‘kabhi kabhi’ (sometimes) after acquiring belly cramps from street food, or the flu, or common cold (which, by the way, antibiotics do not work against; most stomach, nasal and sinus infections are caused by viruses), you decimate your microbiome.

Physicians need to counsel their patients and junior doctors that not every cough or cold deserves an antibiotic. Not every fever or back pain is a urine or kidney infection.

Not every patient that hits the emergency room’s door with diarrhoea needs a broad-spectrum concoction of four third-line antibiotics. Suddenly, your antibiotic use has, paradoxically, left you defenceless against very dangerous organisms. This is precisely what happened to the unfortunate Mehreen.

The antibiotic killed a large chunk of beneficial bugs in her intestines, allowing a deadly pathogen called Clostridicum Difficile or C Diff. to exude a poisonous membrane that coated her colon.

Over a few weeks, it grew and grew with no powerful ‘good’ bacteria in place to prevent its colonisation. To top it off, this C Diff. was multi-drug-resistant as well: first- and second-line antibiotics failed to eradicate it. It multiplied until it became a hydra of disease with heads and limbs in all parts of her body, causing severe sepsis, then septic shock.

Mehreen died.

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Yet more issues besides drug resistance and overgrowth of pathogenic organisms rise from antibiotic abuse.

The gut microbiota helps regulate our metabolism and programmes our immune system. Once you mess with it, cut out large swathes of it, you’ve disrupted an ecosystem that has evolved over millions of years.

Indeed, there is evidence that peculiarities of the microbiome and lack of diversity in it are linked with obesity, development of autoimmune disease, including rheumatoid arthritis and Type 1 diabetes, as well as other illnesses such as asthma and anxiety disorder. Some scientists have recently discovered that some skin bacteria may in fact help protect against skin cancer!

So what happens when you abuse antibiotics?

You increase the risk of all these diseases.

Raise your hand if you want terrible metabolism, skin cancer, obesity and mood disorder. No one?

6

If all this sounds alarming and terrible, it is meant to be.

Physicians and patients both need to be whistleblowers on the Antibiotic Armageddon.

Physicians need to counsel their patients and junior doctors that not every cough or cold deserves an antibiotic.

Not every fever or back pain is a urine or kidney infection.

Not every patient that hits the emergency room’s door with diarrhoea needs a broad-spectrum concoction of four third-line antibiotics.

Here are a few things physicians could tell our patients:

  • Get vaccinated regularly and on schedule as per the guidelines issued by the World Health Organization, especially the ones pertaining to Pakistan.

  • Get vaccinated against typhoid. This cannot be stressed enough. A typhoid conjugate vaccine (TCV) is commercially available, which can prevent this particular strain from doing damage to your body. In fact, the TCV was recently added to Pakistan’s routine vaccination schedule.

  • Get vaccinated against all available strains of viral hepatitis.

  • Please do not use antibiotics unless prescribed by a doctor.

  • Raise your voice as responsible citizens and demand that the government ban over-the-counter availability of antibiotics. These should be dispensed only on a doctor’s prescription.

  • Encourage your hospitals and healthcare providers as well as your medical students and house staff to let go of the ‘sab chalta hai [everything goes]: this is Pakistan’ mentality. They should engage in ASPs and wash their hands before and after every patient encounter.

The above are common-sense measures that are standard counselling recommendations all across the world, and for good reason.

Your children’s lives literally depend on this.


The writer is a graduate of the Aga Khan University Medical College and the University of Florida. A diplomate of the American Boards of Medicine & Rheumatology, Dr Malik is currently Assistant Professor of Clinical Rheumatology at Shalamar Hospital & Medical College.

Header illustration by Samiah Bilal

Published in Dawn, EOS, February 2nd, 2020

A systematic literature review published in 2013 by Shehla Zaidi et al from Aga Khan University revealed a grim picture of Pakistani healthcare services. The review focused on health provider prescribing patterns and drug dispensing.

The researchers discovered:

EXCESSIVE PRESCRIPTION OF DRUGS

  • The average number of drugs prescribed per patient is three or more in Pakistan, as compared to an average of 2.39 in other low-to-middle-income countries (LMIC).

  • The private sector prescribed more (4.51) drugs per prescription
    compared to the public sector (2.77).

ANTIBIOTIC OVERUSE

  • Antibiotic overuse is one of the main reasons for excessive prescription with antibiotics prescribed in 70 percent of patient encounters in Pakistan as compared to 45 percent in other LMICs (a shocking statistic).

  • The prescription rate is significantly higher for antibiotics (62
    percent) and injections (48 percent) amongst private GPs as compared to the public sector, with rates of 54 percent and 22 percent
    respectively.

EXCESSIVE INJECTION USE

  • Pakistan has one of the highest rates of injection usage in the world with over 60 percent patient encounters involving an injection as compared to 23 percent in other LMICs.

  • Preference for injection usage is higher amongst general
    practitioners in rural areas (53 percent) as compared to urban areas (28 percent) while safe injection handling and disposal practices are weaker in rural areas.

INAPPROPRIATE USE OF MEDICATIONS

  • Treatment pattern for upper respiratory tract infections showed antibiotics being prescribed in an alarming 89 percent of prescriptions despite most such infections being self-limiting in nature.

  • Analysis of childhood diarrhoea management showed that there was sub-optimal prescription of ORS (oral rehydration salts) and overuse of antibiotics. Only 53 percent of GPs and 61 percent of specialists prescribed ORS in more than 50 percent of encounters, while 50 percent of GPs and 66 percent of specialists prescribed antimicrobials with interestingly no significant difference between GPs and specialists.

  • Management of tuberculosis also showed frequent variation from the recommended treatment. Only 3.4 percent GPs had knowledge of all Directly Observed Therapy Shortcourse (DOTS) components (standard therapy for TB), and only 35 percent able to correctly prescribe drugs, dose and duration for initial phase and 30 percent for continuation phase of the therapy.

— Compiled from Rational prescription & use: a snapshot of the evidence from Pakistan and emerging concerns by Shehla Zaidi, Noureen Aleem Nishtar

Antibiotic stewardship programmes (ASPs) are the heart of interventions designed to combat antibiotic misuse and promote proper infection control at healthcare institutes throughout the world.

Major strategies for ASPs include pre-authorisation of certain antimicrobial agents, formulary restriction of others and prospective audit with feedback, prescribing guidelines and, most importantly, awareness campaigns designed to educate healthcare personnel and the general public about the risks of irrational and excessive antibiotic use.

ASPs have shown a major impact on infection rates, resistance patterns, costs and clinical outcomes in many studies.

Given ASPs’ proven efficacy and major gains in many settings, it is imperative that such initiatives and efforts be implemented across Pakistan. Unfortunately, here, ASP initiatives have only recently been started and there is little to no published literature about antibiotic stewardship within Pakistan.

In March 2014, the Medical Microbiology and Infectious Diseases Society of Pakistan (MMIDSP) launched the Antibiotic Stewardship Initiative in Pakistan (ASIP) and initiated many ASP activities (talks, workshops, initiation of weekly ‘ASP Rounds’, awareness raising) that led to the inculcation of ASPs in many institutions in major Pakistani cities. A survey was carried out by MMIDSP among 757 general practitioners, paediatricians and other clinicians from September 2015 to May 2016 to gauge opinion on this (ASIP) initiative.

Among those who returned the survey forms, 392 GPs and paediatricians (51.8 percent) answered on the usefulness of this activity and 495 (65.4 percent) also suggested measures to combat antibiotic misuse and antimicrobial resistance (AMR) in Pakistan.

The results were startling. Only:

  • 20.2 percent (one in five) of these 495 respondents suggested using ASPs to cull the epidemic of antibiotic abuse

  • 19.4 percent suggested a national and local antibiotic policy, with regulation and a ban on over-the-counter antibiotic use

  • 14.5 percent suggested awareness campaigns to educate GPs and the community about the dangers of antibiotic abuse

  • 12.5 percent suggested continuous medical education (CME) activities on the subject for health practitioners

  • 8.9 percent suggested taking appropriate history, examination and diagnostic tests before prescribing antibiotics

  • 8.3 percent suggested use of specific guidelines for antibiotic use against infectious diseases

These are alarmingly low numbers, which, to this writer, suggest a fundamental and systematic lack of formal education about global practices of antibiotic stewardship and infection control rampant among the Pakistani medical community.

The same survey, however, also noted that up to 98 percent of the respondents felt that the ASIP-related educational activities were very helpful and 91 percent reported that it would change their clinical practice, which reiterates the importance of awareness campaigns and education on the subject.

A survey of 11 major hospitals (five private and six public) in large cities carried out by MMIDSP over three months (January-April 2016), showed:

  • All five private but none of the public hospitals had some form of ASPs

  • 18 infectious disease (ID) physicians were available at the five private hospitals compared to no ID specialist at the public hospitals

  • Targeted APS activities were carried out at three out of five private and zero out of six public hospitals

Again, alarming numbers, made more concerning when we note lack of standardisation of quality metrics when it comes to defining what a state-of-the-art ASP might be.

Compiled from Situation Analysis Report on Antimicrobial Resistance in Pakistan: Findings and Recommendations for Antibiotic Use and Resistance presented by Dr Ejaz A. Khan

In May 2017, Pakistan’s Ministry of National Health Services, Regulations and Coordination submitted the newly drafted National Action Plan for Containment of Antimicrobial Resistance (NAP) to the WHO. The document was prepared after consultation with several concerned bodies, including representatives from the health, agriculture and veterinary sectors.

The major strategic priorities of the NAP include:

  1. Development and implementation of a strategy to improve national awareness and behaviour change regarding antimicrobial resistance (AMR)

  2. Establishment of an integrated national AMR surveillance system (use of antimicrobials and emerging resistance; human and animal)

  3. Improvement of infection prevention and control in healthcare settings, the community, animal health, food, agriculture and the environment

  4. Update and enforcement of regulations for human and veterinary antimicrobial use

  5. Phase-out of antimicrobial use for growth promotion and provision of appropriate alternatives (such as prebiotics, probiotics) in food animals

  6. Integration of AMR into all public health research agendas, including research on vaccines

  7. Estimation of the health and economic burden of AMR, for use in decision-making

The NAP has proposed several actions be initiated at the national level to combat AMR, but in this writer’s opinion, the most important of them are:

  • Acknowledge that there is an urgent need to initiate measures to tackle the growing hazards of antibiotic resistance and irrational use of antibiotics, and join international efforts to control this threat

  • Encourage and implement initiatives to improve infection control standards in hospitals

  • Include structured training in rational antibiotic usage and infection control in the medical curriculum at undergraduate and postgraduate levels

How successful the current government (whose most senior leader did establish a successful ‘model’ hospital, but has not yet been able to replicate that success elsewhere) will be at these goals remains to be seen.

That said, various institutions in Pakistan are currently developing intra-institution and regional guides on Hospital Acquired Infection Prevention and Control. One such guide (edited by Dr Maryam Riaz Tarar, Dr Shehnoor Azhar and Dr Javed Akram) was recently launched and distributed in Punjab in collaboration with the University of Health Sciences, Lahore.

UTM