Rise of the Desi Superbug

A recent article on Indian superbug NDM-1 reminds you of early Naipaul’s biased, but riveting writing.

WrittenBy:Anand Ranganathan
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On May 8, 2012, Indian business newspaper Mint carried a two page article on NDM-1, syndicated from Bloomberg and reprinted untouched by Indian editors. Titled “Superbugs spread to 40 nations threatening India medical tourism”, the piece by Jason Gale and Adi Narayan paints a devastating picture of what lies in store for the world if the NDM-1 menace goes unchecked. Lucid and well-written, it is till date the most comprehensive report on NDM-1 to have appeared in the main press. Fortuitously, its comprehensive nature allows one to debate, paragraph-by-paragraph, the many arguments and predictions it professes. But first, a little calm before the storm.

Our gut and our skin is colonised by 800 different species of bacteria. While we are made up of 10 trillion cells, there are roughly a quadrillion (1,000 trillion) bacteria living and feeding on our bodies. We adjust a little on the sofa and shed a million of them. Brush our teeth, and an equal number find themselves without food and shelter!

Out of these quadrillion bacteria, one family is Staphylococcus aureus, or Staph, that mainly colonise our nose and upper respiratory tract. In fact, at any given point, roughly 20% of the human population – that’s 1.4 billion people – is carrying Staph.

Now Staph is a bug – just like Klebsiella pneumonia is a bug that resides in our mouth and intestines – and is quite harmless except when our immune system and its ability to fight pathogens is compromised, while convalescing in a hospital from a severe injury, for example. Then it may proliferate on a wound or laceration, or get into our lungs through ingested dribble and cause nuisance. It still is, however, just a bug – pop in a few antibiotics and watch it cower back to its doghouse. But with time, and with our over-dependence and overuse of antibiotics, the bugs have become superbugs, i.e. have acquired resistance to many of the antibiotics that earlier wiped them out easily.

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Figure 1. Staphylococcus aureus. Photo credit: Janice Haney Carr, CDC

The first superbug to be isolated and identified was MRSA, or Methillicin Resistant Staphylococcus Aureus, in 1961 by Patricia Jevons of the Cross Infection Reference Laboratory, Colindale, London. (Curiously, it wasn’t named CL-1 – for Colindale London-1.) In those days, Staph was routinely treated with penicillin – a beta-lactam antibiotic characterised by a four-membered ring (Figure 2), until it acquired resistance rendering the penicillin useless. A new type of beta-lactam, Celbinin, also called Methillicin, was then employed for killing the penicillin-resistant Staph. But the bug overcame that hurdle, too, and soon, Methillicin-resistant Staph was raging all over England like wild fire. And that is how a simple, friendly bug became a superbug, fifty years before India got its very own NDM-1 (named after New Delhi).

How did it happen?

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Figure 2. Beta-lactam antibiotics. The four-membered lactam ‘square’ is circled in red.

Methillicin acted by destroying PBP, the one Staph protein machine that helped build its cell wall. Without the cell wall the Staph couldn’t survive, of course; no cell can. But soon, the cunning Staph let in through its barbed wires a different PBP, called mecA,  which was unbending to Methillicin. Poor Methillicin bumped off as much of the Staph PBP as it could, but it still couldn’t prevent the bug from exploiting the immigrant PBP for building its cell wall. Staph survived, and thrived.

Fifty years later MRSA is still raging across the world. The 2005 report of the European Centre for Disease Prevention and Control paints a gruesome picture, with a number of countries detecting MRSA in a quarter of all samples tested. In 2010, the situation has marginally improved in some countries, like the UK and Ireland, while for many like Portugal, it has deteriorated: more than half of the 1,633 Staph samples tested were found to be MRSA (Figure 3).

There exists no alarmist newspaper report or a travel advisory for thousands of medical tourists who’d like to catch some sun in Lisbon while they get their hips and other body parts replaced, enlarged, set straight, or removed entirely. Many of them may return with an aquiline nose and a pocketful of MRSA.

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Figure 3: MRSA affected countries in Europe. Top panels: left – 2005 data; right – 2010 data.

The situation is not very dissimilar for the United States. The CDCP (Centre for Disease control and Prevention) believes around 100,000 deaths are caused every year through hospital-acquired superbug infections. Compare that to the 100-odd deaths through our very own NDM-1 and you begin to wonder why, if the scare of the superbug is so real, there is a beeline of Indians wanting to get treated in America. European Centre for Disease Prevention and Control has an excellent interactive portal for anyone interested in these superbugs and their spread across Europe (http://ecdc.europa.eu/en) and it is high time south-Asia had something similar.

MRSA can be treated with a host of antibiotics that do not have in their chemical structure the four-membered lactam ring, like Vancomycin, Linezolid, and Clindamycin (Figure 4).

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Figure 4. Antibiotics for treating MRSA superbug.

MRSA is, of course, one of many hundreds, perhaps thousands, of superbugs that roam our streets and hospitals. They obey no rules, follow no national boundaries, and have no passports. Each one is dangerous, and can cause death if not treated in time.

Regrettably, though, while all superbugs are equal, some are more equal than others.

In December of 2009, a Swede was enjoying a little of our hospitality when he fell ill. After enjoying a little of our hospitals, too, he returned to his native country, where he was identified as the first carrier of NDM-1, an Indian superbug (Antimicrob. Agents Chemo, 2009, 53, p.5046). NDM-1 stands for New Delhi Metallo-beta-lactamase-1, for the evil Dilli gene that bored into the otherwise friendly and easily treatable Klebsiella pneumonia, turning it from Emraan Hashmi to Rajnikant in no time. The metallo-beta-lactamase, also called carbapenemase, was an illegal immigrant – just like mecA was in the MRSA story – and it rendered the pneumonia bug resistant to an antibiotic called Carbapenem. There was nothing usual about the way it sneaked in – concealed in a loop of DNA called plasmid – a ‘horizontal gene transfer’ route used in thousands of bug-to-superbug makeovers; and there was nothing unusual in a carbapenemase sneaking in to Klebsiella pneumonia in the first place (more on that later). But the fact that it was an Indian superbug, and one that dared to snarl at a foreigner when the poor fellow was wading through scum and ‘faecal veneer’ (this extraordinarily thoughtful phrase courtesy of Mint, May 8, 2012) was enough for all hell to break loose. Since then, numerous NDM-1 cases have been reported from all around the world – the bugs are different in many instances but they all carry the NDM-1 carbapenemase.

In 2010, while describing the medical history of an English patient infected with NDM-1, the team of UK scientists that originally reported the superbug, in their wisdom, though it fit to end a report with the following comment: ‘Patients coming back after treatment abroad “…could facilitate rapid spread of NDM-1 with potentially serious consequences.”’ (Journal of Hospital Infection, 2010, 75, p. 239). This in a country where 50 males and 32 females had MRSA as the underlying cause mentioned in their death certificates (UK Office of National Statistics, 2011).

In another research report of 2010, that was otherwise stringently scientific in its experimental procedures and their interpretation, the same team concluded: “Several of the UK patients had undergone elective, including cosmetic, surgery while visiting India or Pakistan. India also provides cosmetic surgery for other Europeans and Americans, and NDM-1 will likely spread worldwide. It is disturbing, in context, to read calls in the popular press for UK patients to opt for corrective surgery in India with the aim of saving the NHS (National Health Service, UK) money. As our data shows, such a proposal might ultimately cost the NHS substantially more than the short-term saving and we would strongly advise against such proposals.” (Lancet Infect Dis., 2010, 10, p.597)

Quite right. Let the English patient with a defective hip and a clogged heart not suffer at the hands of an Indian doctor who is more capable, with a delivery that is ten times less costly, in a hospital which is more welcoming and courteous. Let him, instead, await his turn for a couple more years, in the delightful company of MRSA and other less-advertised but equally dangerous superbugs.

The Americans were more circumspect and less willing to believe in the Orwellian aphorism. In commenting on their NDM-1 cases they noted: “…The superbugs are all bad…Is NDM-1 more worrisome than MRSA? It’s too early to judge…A decade ago, New York City hospitals were the epicentre of infections with other bacteria resistant to carbapenem antibiotics. Those bacteria, which had a different mutation, were troubling, but did not explode into a public health emergency.” (New York Times, August 11, 2010)

So what was it that prompted from the Americans a more nuanced response towards the desi superbug, in total contrast to their complaining cousins across the pond? Yes, you guessed it – their own battles with Carbapenem Resistant Klebsiella Pneumoniae or CRKP for short, as dangerous as NDM-1, if not more.

First discovered in 1999 in North Carolina, CRKP has since been identified in more than a dozen states. A 2008 Centre for Disease Control report found that 8% of all Klebsiella pneumonia samples were CRKP positive, with New York and New Jersey being the worst hit.

It is bewildering, yet again, as to why the superbug wasn’t named NCC-1 – for North Carolina Carbapenemase-1. Perhaps the acronym was already usurped by National Cadet Corps? ‘Upset tummy’ isn’t as bloody-hell-poor-you as ‘Delhi belly,’ one has to admit.

In 2006, the CRKP superbug hopped from New York to Greece and then to Israel, where it struck in hospitals across the holy land – 22% of all pneumonia cases were carbapenem-resistant. The vengeance of this NDM-1 cousin lies unabated. As recent as 2010, more than 50% of all Greece samples were CRKP (Figure 5), with Italy following close behind.

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Figure 5. ECDPC Data for CRKP superbug, 2010.

Greece and Italy – something else other than their economic meltdown joins them at the hips. Yes, the inescapable rise of CRKP. But then again, it’s a western superbug, easier on the eye than our desi one. So no one shouts from the rooftops, no newspaper drenches its centrespread with an alarming story of national apathy, faecal veneer, and bureaucratic bungling. Could it be because NDM-1 and CRKP are not too alike after all, that they are chalk and cheese, one a gori-chitti angel while the other a kali-kaluti devil (like the infamous Benetton ad)?

Er, no.

The NDM-1 isolate that confounded the hapless Swede was also Klebsiella pneumonia (Lancet Infect Dis., 2010, 10, p.597), just like CRKP. It, too, possessed a carbapenemase, just like CRKP. The only difference being in the type of carbapenemase – metallo in the case of NDM-1, class A in CRKP. But a carbapenemase is still a carbapenemase, added metal or not – both rendered carbapenem useless, and could be killed only by non-lactam antibiotics like Colistin and Tigecycline (Figure 6). There is no doubt that these carbapenem-resistant superbugs are dangerous, perilous even, but to raise alarm over one while being hush-hush about the other…

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Figure 6. Antibiotics for treating NDM-1 and CRKP superbugs.

By 2013, medical tourism to India is expected to generate up to $ 3 billion in revenues. As of today, the western world is the favoured destination of the medical tourist, with more than 60% opting to visit America and Europe in search of cures. In 2011, President Obama told an audience: “…My preference would be that you do not have to travel to Mexico or India for cheap healthcare. I would like you to be able to get high quality treatment right here in the United States of America.”

If one were to be overly critical of the Mint article, one could declare the piece to be grandiloquent: “NDM-1 has rendered even carbapenems useless”; naughty: “The superbugs are proving to be not only wily but also highly sexed”; truthful: “You have horrible sanitation problems in many parts of the country. You have incredible poverty, and you have crowding”; affecting: “Even though he was being treated with a carbapenem, bacteria raged inside his tiny lungs and bloodstream”; conjectural: “100 million Indians carry germs that harbour the NDM-1 gene”; alarmist: “If this latest bug becomes entrenched in our hospitals, there is really nothing we can turn to”; more alarmist: “NDM-1 is changing common bugs that drugs once easily defeated into untreatable killers”; even more alarmist: “We are looking at the spectre of untreatable illness.”

When one Indian doctor reassures that “…We have a very senior person whose sole responsibility is to keep the whole hospital under infection surveillance 24/7”, the statement is challenged with, “How does the hospital—however good its surgeons and physicians—isolate itself when its patients, staff and food all come from outside, where they are exposed to this soup of resistance?”

Like the early Naipaul, it interviews everyone who agrees with the predetermined position, and no one who might present a more balanced, more nuanced perspective (remember those kind Americans?). And, of course, like the early Naipaul, it is riveting reading.

One particular thesis that the article presents, however, merits an immediate rebuttal, for it is so mind-bogglingly alarmist that, ironically, it takes all attention away from the article itself, forcing a size 48 font headline in the reader’s mind.

Halfway through, the article says: “NDM-1 may even spread to the microbial cause of bubonic plague, the medieval scourge known as Black Death that still persists in pockets of the globe…Plasmids carrying the NDM-1 gene can easily be inserted into the genetic material of Yersinia pestis, the cause of plague, making the infection harder to treat.”

Bubonic. Pestis. Plague. Black Death. The mere words, their simple combinations, their easy sprinkling in a sentence, is enough to send shivers down a healthy man’s spine. In the case of a healthy European man whose ancestors suffered miserably in the Middle Ages, the shivers may proceed a little further down, buzzing and sparking through the leg and onto Mother Earth, creating a minor tremor in the continent. The tremors have already started their merry dance across the hungry and salivating press syndicates: “India May Foster Drug-Resistant Bubonic Plague,” The Inquisitr, May 8, 2012; “India Could Foster Drug-Resistant Bubonic Plague,” Newser, May 8, 2012.

This revolution will be syndicated!

Thankfully, though, both varieties of this dreadful disease – Bubonic and Pneumonic – are completely curable, through a host of antibiotics (Figure 7).

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Figure 7. First-line antibiotics for treating Plague. Notice the absence of a lactam ‘square.’

Look closely at the structures of these antibiotics – does anything strike you odd? Yes, none of them have that square, that four-membered lactam ring common to the dinner table antibiotic spread of the superbug family. True, an NDM-1 Yersinia pestis would be resistant to Carbapenem – as, recall, NDM is a carbapenemase – but it would matter little as this class of antibiotics is not used to treat plague at all! NDM Y. pestis is, therefore, as dangerous, and as treatable, as the traditional Y. pestis. Let’s hope this fact reassures Mint and Bloomberg readers who were already in the process of bolting from the country, hanging around T3 for the next flight out.

But why stop at Y. pestis; why not include the dreaded tuberculosis, too, now that the reader lies splayed on the mat waiting for the world to end by Christmas next? After all, more than half of the Indian population carries the Mycobacterium tuberculosis bug (Mtb) and the advantages for scare-mongering are enormous. Mtb spreads through air – the auto-wala spins his head round to check the fare meter and coughs, and congratulations! What’s more, the bug takes almost a year of dedicated pill-popping to clear off, and there already are multi-drug resistant strains floating around, with Dr Udwadia of Hinduja hospital, Mumbai having recently discovered ‘totally drug-resistant’ tuberculosis (Thorax, 2012, 67, p.286). But there’s the same problem here, too, unfortunately. None of the anti-TB drugs have that peculiar lactam square, and so, no matter how many NDMs bore into the Mtb bug, the drugs one would use to kill it will remain the same as for any Mtb infection. If at all the alarm bells need to toll and two-page articles printed, let it be on the scariest card the tarot reader can flip over: Totally Drug Resistant Tuberculosis. For this is the mother of all superbugs, this is what baby superbugs dream of becoming when they grow up. The word ‘Totally’ has an impact that ‘Bubonic’ must have had in the Middle Ages, and fingers have already started trembling on the kkkkeybboaawrdd.

The Mint article, though, is timely, and even with its alarmist, selective, scare-mongering, rogue-train-hurtling-down-the-tunnel reporting, it must be read and consumed by not just us but also those mandarins at the Ministry of Health and Human Welfare. No doubt, the NDM-1 superbug is scary, as all super bugs around the world are, but the health and sanitation statistics quoted in the Mint article are scarier.

The NDMC (New Delhi Municipal Corporation) cared-for island that is central Delhi has become a sun-kissed sanatorium for politicians and fat cats to formulate policies that affect those billion-odd who live on little more than land-fills and breathe the air that carries tuberculosis. Their multi-page health and hygiene achievements are not worth the newspaper they are printed on. Half-baked programmes, ill-defined goals, illegally approved hospitals and medical schools…the road to perdition is paved with hastily laid and crumbling foundation stones. It is through the miracle of an Indian’s immune system that the overwhelming majority of us are not dead yet.

The recent central Delhi diktat that forces private hospitals to take in at least 25% of poor people as patients is a great first step. The second, and a game-changer, would be to force at least 25% of our politicians to undergo treatment only at government hospitals.

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