Lill-Karin Skaret, a 67-year-old
grandmother from Namsos, Norway, was traveling to a lakeside
vacation villa near India’s port city of Kochi in March 2010
when her car collided with a truck. She was rushed to the Amrita
Institute of Medical Sciences, her right leg broken and her
artificial hip so damaged that replacing it required 12 hours of
surgery.
Three weeks later and walking with the aid of crutches,
Skaret was relieved to be home. Then her doctor gave her
upsetting news. Mutant germs that most antibiotics can’t kill
had entered her bladder, probably from a contaminated hospital
catheter in India. She risked a life-threatening infection if
the bacteria invaded her bloodstream -- a waiting game over
which she had limited control, Bloomberg Markets magazine
reports in its June issue.
“I got a call from my doctor who told me they found this
bug in me and I had to take precautions,” Skaret remembers. “I
was very afraid.”
Skaret was lucky. Eventually, her body rid itself of the
bacteria, and she escaped harm from a new type of superbug that
scientists warn is spreading faster, further and in more
alarming ways than any they’ve encountered. Researchers say the
epicenter is India, where drugs created to fight disease have
taken a perverse turn by making many ailments harder to treat.
India’s $12.4 billion pharmaceutical industry manufactures
almost a third of the world’s antibiotics, and people use them
so liberally that relatively benign and beneficial bacteria are
becoming drug immune in a pool of resistance that thwarts even
high-powered antibiotics, the so-called remedies of last resort.
Medical Tourism
Poor hygiene has spread resistant germs into India’s
drains, sewers and drinking water, putting millions at risk of
drug-defying infections. Antibiotic residues from drug
manufacturing, livestock treatment and medical waste have
entered water and sanitation systems, exacerbating the problem.
As the superbacteria take up residence in hospitals,
they’re compromising patient care and tarnishing India’s image
as a medical tourism destination.
“There isn’t anything you could take with you traveling
that would be useful against these superbugs,” says Robert Moellering Jr., a professor of medical research at Harvard
Medical School in Boston.
The germs -- and the gene that confers their heightened
powers -- are jumping beyond India. More than 40 countries have
discovered the genetically altered superbugs in blood, urine and
other patient specimens. Canada, France, Italy, Kosovo and South
Africa have found them in people with no travel links,
suggesting the bugs have taken hold there.
Post-Antibiotic Era
Drug resistance of all sorts is bringing the planet closer
to what the World Health Organization calls a post-antibiotic
era.
“Things as common as strep throat or a child’s scratched
knee could once again kill,” WHO Director-General Margaret Chan
said at a March medical meeting in Copenhagen. “Hip
replacements, organ transplants, cancer chemotherapy and care of
preterm infants would become far more difficult or even too
dangerous to undertake.”
Already, current varieties of resistant bacteria kill more
than 25,000 people in Europe annually, the WHO said in March.
The toll means at least 1.5 billion euros ($2 billion) in extra
medical costs and productivity losses each year.
“If this latest bug becomes entrenched in our hospitals,
there is really nothing we can turn to,” says Donald E. Low,
head of Ontario’s public health lab in Toronto. “Its potential
is to be probably greater than any other organism.”
Promiscuous Plasmids
The new superbugs are multiplying so successfully because
of a gene dubbed NDM-1. That’s short for New Delhi metallo-beta-
lactamase-1, a reference to the city where a Swedish man was
hospitalized in 2007 with an infection that resisted standard
antibiotic treatments.
The superbugs are proving to be not only wily but also
highly sexed. The NDM-1 gene is carried on mobile loops of DNA
called plasmids that transfer easily among and across many types
of bacteria through a form of microbial mating. This means that
unlike previous germ-altering genes, NDM-1 can infiltrate dozens
of bacterial species. Intestine-dwelling E. coli, the most
common bacterium that people encounter, soil-inhabiting microbes
and water-loving cholera bugs can all be fortified by the gene.
What’s worse, germs empowered by NDM-1 can muster as many
as nine other ways to destroy the world’s most potent
antibiotics.
Untreatable Killers
NDM-1 is changing common bugs that drugs once easily
defeated into untreatable killers, says Timothy Walsh, a
professor of medical microbiology at Cardiff University in
Wales. Or as in Skaret’s case, the gene is creating silent
stowaways poised to attack if they find a weakness -- or that
can pass harmlessly when the body’s conventional microbes win
out.
Cancer patients whose chemotherapy inadvertently ulcerates
their gastrointestinal tract are especially vulnerable, says
Lindsay Grayson, director of infectious diseases and
microbiology at Melbourne’s Austin Hospital.
“These bugs go straight into their bloodstream,” Grayson
says. Newborns, transplant recipients and people with
compromised immune systems are at higher risk, he says.
Six infants died in a small hospital in Bijnor in northern
India from April 2009 to August 2010 after NDM-1-containing
bacteria resisted all commonly used antibiotics.
India Vulnerable
India is susceptible because it has many sick people to
begin with. The country accounts for more than a quarter of the
world’s pneumonia cases. It has the most tuberculosis patients
globally and Asia’s highest incidence of cholera.
Most of India’s 5,000-plus drugmakers produce low-cost
generic antibiotics, letting users and doctors switch around to
find ones that work. While that’s happening, the germs the
antibiotics are targeting accumulate genes for evading each
drug. That enables the bugs to survive and proliferate whenever
they encounter an antibiotic they’ve already adapted to.
India’s inadequate sanitation increases the scope of
antibacterial resistance. More than half of the nation’s 1.2
billion residents defecate in the open, and 23 percent of city
dwellers have no toilets, according to a 2012 report by the WHO
and Unicef.
Uncovered sewers and overflowing drains in even such modern
cities as New Delhi spread resistant germs through feces,
tainting food and water and covering surfaces in what Dartmouth
Medical School researcher Elmer Pfefferkorn describes as a fecal
veneer.
Tap Water
Germs with the NDM-1 gene existed in 51 of 171 open drains
along the capital’s streets and in two of 50 samples of public
tap water, Walsh found in 2010.
Abdul Ghafur, an infectious diseases doctor in Chennai,
southern India’s largest city, sees patients every week who
suffer from multidrug-resistant infections. He and others who
used to successfully combat infections with such common
antibiotics as amoxicillin now must use more-expensive ones that
target a broader range of germs but typically cause greater side
effects. Some infections don’t respond to any treatment, evading
all antibiotics, he says.
That’s bad news because the more frequently the NDM-1 gene
is inserted into different bacteria, the more likely it will
enter virulent forms of E. coli, sparking outbreaks that may be
impossible to subdue, says David Livermore, who heads antibiotic
resistance monitoring at the U.K.’s Health Protection Agency in
London.
Black Death
The gene 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.
“It’s a matter of time and chance,” says Mark Toleman, a
molecular geneticist at Cardiff University. 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, Toleman says.
“There is a tsunami that’s going to happen in the next year
or two when antibiotic resistance explodes,” says Ghafur, 40,
seated at a polished wooden table in a consulting room in
Chennai as patients fill 20 metal chairs in the waiting area,
forcing others into the corridor.
“We need wartime measures to
deal with this now.”
R.K. Srivastava, India’s former director general of health
services, says the government is giving top priority to
antimicrobial resistance, including increasing surveillance of
hospitals’ antibiotics use.
Name Shame
At the same time, it’s trying to preserve the country’s
health-tourism industry. Bristling that foreigners coined a name
that singles out their capital to describe an emerging health
nightmare, officials say the world is picking on India for
troubles that impede all developing nations.
When Indian researchers joined international teams studying
the NDM-1 gene, the government questioned the data and methods
of the scientists, among them Chennai microbiologist Karthikeyan
K. Kumarasamy.
“These bacteria were present globally,” says Nirmal K.
Ganguly, a former director general of the Indian Council of
Medical Research and one of 13 members of a government task
force created in September 2010 to respond to the NDM-1 threat.
“When you are blamed, the only reaction is that you put
your back to the wall and fight.”
Ulterior Motive?
S.S. Ahluwalia, a former deputy opposition leader in the
upper house of India’s parliament and a member of the Bharatiya
Janata Party, says Western rivals want to muscle in on the
medical tourism industry. Josef Woodman, founder of the
guidebook “Patients Beyond Borders,” values the industry
globally at $54 billion a year.
“These reports are meant to destabilize India’s emergence
as a health destination,” says Ahluwalia, whose term ended in
April.
About 850,000 medical tourists traveled to India in 2010
for treatments from lifesaving cancer operations to cosmetic
surgeries, generating $872 million in revenue, according to the
Associated Chambers of Commerce and Industry of India, or
Assocham. The number of foreign patients is predicted to almost
quadruple by 2015, the trade body says.
Manish Kakkar, a doctor researching infectious diseases at
the New Delhi-based Public Health Foundation of India and a task
force member, says the government has its priorities wrong.
“We have been in a phase of denial,” he says. “Rather than
responding to the situation scientifically, we’ve completely
diverted attention, saying that it’s attacking our medical
tourism.”
‘That’s What’s Scary’
Kakkar and others worry about NDM-1 because unlike germs
such as VRE, short for the vancomycin-resistant enterococci bug
that can cause infection around a patient’s surgical incision,
NDM-1 is spreading beyond hospitals.
Two travelers from the Netherlands picked up an NDM-1 bug
in their bowels after visiting India in 2009 although they
hadn’t received medical care there, says Maurine
Leverstein-van Hall, a clinical microbiologist at the University Medical Center
in the Dutch city of Utrecht.
“That’s what’s scary,” she says. “It’s not just surgery or
being near a hospital. In some way, you get it through the food
chain or through the water.”
For now, it’s impossible to tell how common NDM-1
infections are or how often the mutant germs kill because
testing and surveillance are inadequate in developing countries,
says Keith Klugman, the William H. Foege chair of global health
at Emory University’s Rollins School of Public Health in
Atlanta.
‘Perfect Breeding Ground’
Cardiff’s Walsh estimates 100 million Indians carry germs
that harbor the NDM-1 gene, based on an extrapolation of studies
in New Delhi and from neighboring Pakistan.
“It’s not measured, and that’s the problem,” says Klugman,
who pinpoints India as the epicenter.
India’s jammed cities, poor sanitation and abundant
antibiotics produce an ideal incubator, Harvard’s Moellering
says.
“You have almost no control over the prescription of
antibiotics,” says Moellering, who has studied drug resistance
for four decades. “You have horrible sanitation problems in many
parts of the country. You have incredible poverty, and you have
crowding. When you put those four things together, it’s the
perfect breeding ground for multidrug-resistant bacteria.”
Antibiotics even pollute India’s rivers, streams and soil.
The bacteria that thrive in these places do so because they’ve
developed resistance to the drugs they encounter. People or
animals who ingest the water or soil may become colonized by the
resistant germs.
Mining Cipro
Until the government built a pipeline to a modern sewage
plant in 2010, the Patancheru Enviro Tech Ltd. treatment
facility on some days released the equivalent of 45,000 daily
doses of ciprofloxacin into the Isakavagu stream outside
Hyderabad in southern India, Swedish researchers reported in
2007. The plant treated wastewater from drug-making factories.
Residue from ciprofloxacin, a mainstay treatment for E.
coli infections, was so prevalent in river sediment downstream
that lead researcher Joakim Larsson of the University of
Gothenburg jokes, “Had ciprofloxacin been a little bit more
expensive, we could probably mine it from the ground.”
India’s antibiotics overload is forcing doctors to rely on
ever-more-powerful drugs. Many now turn to a class called
penicillin-based carbapenems to treat ailments as routine as
urinary tract infections, says Grayson, who was editor-in-chief
of medical text “Kucer’s The Use of Antibiotics” (Hodder
Arnold/ASM Press, 2010).
‘Antibiotic Stewardship’
NDM-1 has rendered even carbapenems useless, sometimes
leaving no way to fight infections. Two drugs potentially
capable of treating NDM-1 bacteria have toxic side effects in
some patients that include an increased risk of death.
“It’s an example of why we need to have good surveillance
and why we need to have good antibiotic stewardship,” says
Thomas R. Frieden, director of the U.S. Centers for Disease
Control and Prevention in Atlanta. “We are looking at the
specter of untreatable illness.”
Drugmakers have been slow to respond with new medicines.
Most abandoned antibiotic discovery during the past decade, says
Karen Bush, a microbiologist at Indiana University in
Bloomington. She led teams that developed five bacteria-fighting
drugs beginning in the 1970s in laboratories that are now part
of AstraZeneca Plc (AZN), Bristol-Myers Squibb Co. (BMY), Johnson & Johnson
and Pfizer Inc. (PFE)
Companies instead pursued hypertension and high-cholesterol
drugs that patients take for a lifetime rather than a few weeks,
she says.
International Uproar
Kumarasamy, the Chennai microbiologist, says he thought he
was doing his country a favor when he helped track down the
cause of unexplained deaths inside India. Instead, he sparked an
international uproar over NDM-1.
Beginning in June 2000, Kumarasamy, now 36, studied
bacteria and went from hospital to hospital in Chennai to
collect specimens. He says he witnessed a steady increase in
difficult-to-treat infections. Patients were dying, and doctors
couldn’t identify what type of resistant germs killed them, he
says.
“No matter how skilled or intelligent the doctor is, they
are helpless when it comes to these infections,” he says over
lunch of rice and curry in a noisy Chennai food court. He didn’t
keep a tally of the deaths.
Kumarasamy, who received a Bachelor of Science degree from
Navarasam Arts & Science College in Tamil Nadu state in 1997,
says he began isolating bacteria from the blood, sputum, pus and
urine of patients and freezing the samples. He quit his lab job
in 2007 to study resistant germs for a doctorate in microbiology
at the University of Madras. He’s winding up his thesis on
carbapenem-resistant bacteria.
Festering Bedsores
Kumarasamy’s curiosity spiked in 2008 when he realized he
was dealing with something totally new. He reached out to Walsh,
whose Cardiff lab was at the forefront of international
antibiotic resistance research.
Around that time, Walsh was studying the case of a diabetic
stroke patient of Indian origin.
The man had festering bedsores
and had been transferred from New Delhi to his home in Sweden
for treatment. When bacteria cultured from his urine and feces
evaded more than a dozen drugs, including last-resort
carbapenems, Christian G. Giske, a clinical microbiologist at
Stockholm’s Karolinska University Hospital, sent the samples to
Walsh’s lab.
Stockholm Hotel
In a hotel room in the Swedish capital, Walsh and Giske
named the gene that made the bacteria immune to virtually all
these antibiotics New Delhi metallo-beta-lactamase-1.
Beta-lactams are a class of antibiotics that includes
penicillins, cephalosporins and carbapenems. Beta-lactamase is
an enzyme that destroys those drugs. Metallo-beta-lactamases are
so named because they contain zinc and destroy carbapenems, the
most powerful beta-lactams.
Kumarasamy, suspecting something similar in his own
specimens, asked Walsh to share the DNA sequence of this new
bacterial gene. Walsh did -- and Kumarasamy got a match.
Kumarasamy began visiting Chennai hospitals anew to look
for drug-resistant specimens.
He also got samples from
researchers in India’s northern Haryana state.
When his collection was added to those Walsh and his
colleagues were studying, the researchers discovered the same
NDM-1 gene from four countries: India, Pakistan,
Bangladesh and
the U.K. For most of the British patients, the link was recent
travel to India or neighboring Pakistan.
In Kumarasamy’s samples from inside India, many cases
emerged in people who hadn’t recently been hospitalized. That
suggested the bacteria were spreading in the community.
‘Unsung Hero’
“He is India’s unsung hero,” Walsh says.
The University of Madras initially thought so, too. It
feted Kumarasamy after he became the youngest scholar from the
155-year-old institution to have research appear in any
publication of the British medical journal “The Lancet.” His
August 2010 paper, in “The Lancet Infectious Diseases,” became
that publication’s most-read article that year.
The mood soured a few days later. Officials at India’s
Ministry of Health & Family Welfare balked at the gene’s name,
which threatened medical tourism’s public image.
“There was a lot of stress and tension, and I could not
sleep properly for two months,” says Kumarasamy, who says he
developed gastric reflux and heartburn.
The next month, authorities at the ministry grilled the
eight Indian contributors to the “Lancet” report, including
lead author Kumarasamy, according to two co-authors who declined
to be identified because their employers don’t permit them to
speak to the media.
‘Batten Down the Hatches’
Officials questioned their data and chastised them for
sending specimens overseas without approval, saying the
researchers had violated a 13-year-old regulation, according to
two in the group.
The Indian Council of Medical Research says it requires
researchers to submit detailed proposals to send any bacterial
collections abroad. The process may take at least four months.
“The regulations were already in place,” says Sandhya
Visweswariah, a professor at the Indian Institute of Science in
Bangalore.
The researchers countered that the rules were nebulous and
were rarely enforced.
“It is suppression of scientific freedom,” Walsh says of
the government behavior. “They just try to batten down the
hatches and make everything very, very difficult and pretend
nothing has happened.”
Front-Page News
After front-page stories on the superbug appeared in Indian
newspapers, the government formed an antibiotic resistance task
force. It recommended in April 2011 that antibiotic use be
tracked in the country’s 100,000 hospitals to find excessive
prescribing. The group advised making it harder to get
antibiotics without a prescription by requiring pharmacists to
keep records for two years to aid audits and inspections.
Current rules make a prescription mandatory, but
regulations are rarely enforced and it’s easy to get potent
antibiotics, even intravenous ones, without a doctor’s assent.
The group advised enacting rules allowing drug inspectors to
immediately cancel the license of pharmacists dispensing
unprescribed antibiotics.
Task force member Ganguly says tracking antibiotic use will
be difficult.
“How do you regulate 1.2 billion people with so much
diversity?” he asks.
Dying Babies
While Kumarasamy was documenting NDM-1 in Chennai
hospitals, pediatrician Vipin Vashishtha was discovering how
deadly the gene can be.
In June 2010, new father Sanjeev Thakran, 28, rushed his
half-hour-old son in a car through monsoon-soaked streets to
Vashishtha’s Mangla Children’s Hospital in Bijnor. His wife,
Lalita, had delivered baby Tapas in a maternity hospital across
town three weeks early, and the infant was laboring for air.
Nurses in green scrubs warmed the 4-pound (1.8-kilogram)
newborn in a dome-covered crib and fed him milk and medicines
through a nasal tube. About 2 feet away, a frail-looking baby
was connected to a ventilator, Sanjeev Thakran says.
Vashishtha, seated on a leather swivel chair in his
consulting room, recalls thinking that Tapas might need only a
few days of intensive care. Instead, the baby spent weeks in and
out of the unit. Blood sometimes trickled from his nose and
shriveling umbilicus, according to medical records.
Even though he was being treated with a carbapenem, the
most powerful class of antibiotic, bacteria raged inside his
tiny lungs and bloodstream, eventually attacking membranes
covering his brain and spinal cord.
Incurable Scourge
Other infants in the eight-crib neonatal intensive care
unit were suffering, too. Vashishtha, 48, had tried several
antibiotics without success. When carbapenems didn’t work, he
says, he felt helpless because he knew he was dealing with a
potentially incurable scourge.
Tapas died 11 weeks after he was admitted. Lab results
identified the culprit a month later: NDM-1. The gene was in
bacteria known as Klebsiella pneumoniae. The germ exists in
people’s gastrointestinal tract and can cause pneumonia and
urinary-tract infections in hospital patients.
The lab also found two soil-borne species that normally
cause trivial infections but that were suddenly becoming
killers.
Tapas was one of 14 infants at the hospital who were
infected with NDM-1-containing bacteria over the course of 17
months. Six of the babies died. Among the eight survivors, half
developed meningitis, arthritis or water on the brain,
Vashishtha wrote to an Indian medical journal in February 2011.
‘Horrific Period’
“It was the most horrific period,” Vashishtha says as he
fixes his eyes on the playpen where he amuses children in his
office. “I was losing neonates at regular intervals. I suspected
we were dealing with something quite different, something quite
new.”
Vashishtha says he has improved infection control, walling
off part of the ICU for contagious, complicated cases.
He can’t, however, control what happens outside his
hospital. Sewage from nearby homes flows in an open drain along
one wall of the two-story building.
Bijnor, like other small cities in Uttar Pradesh, lacks a
modern underground drainage system. During the rainy season,
it’s impossible not to wade through sewage water, the doctor
says.
‘Wash Hands Properly’
So far, Vashishtha has prevented more NDM-1 deaths. He
fumigates his wards every four weeks and applies fresh paint
every three months. He keeps hand-sanitizing liquid in his
office, along the corridors and next to every bed in intensive
care. Nurses must wash their hands with running water and soap
and scrub with an antimicrobial sanitizer before handling
patients.
“The first and foremost step to avoiding hospital-acquired
infection is to wash hands properly,” he says.
India’s major hospitals are marshaling tactics from common
cleanliness to computerized databases to outsmart resistant
bacteria and prevent more tragedies.
Artemis Health Institute, a private, 300-bed specialty
hospital in Gurgaon, southwest of New Delhi, employs an
infection-control officer who collects data every month on the
hospital’s four most troublesome bacteria to review patterns of
drug resistance. The officer, Namita Jaggi, also serves as
national secretary of a Buenos Aires-based group that collates
infection information worldwide.
‘Infection Surveillance 24/7’
About 3 miles (4.8 kilometers) away, cardiac surgeon Naresh Trehan’s medical complex, Medanta-The Medicity, requires
patients transferring from other hospitals to be screened for
resistant bacteria. This procedure, routine in some Nordic
countries, isn’t standard in India.
Medanta has a strict hand-washing policy and a 40-member
team to monitor infections, says Trehan, 65, who trained in
cardiac surgery at New York University and worked at Bellevue
Hospital in Manhattan before returning to India in 1988.
“We have a very senior person whose sole responsibility is
to keep the whole hospital under infection surveillance 24/7,”
he says.
Livermore at the U.K.’s Health Protection Agency says these
efforts may not be enough in a country where 626 million people
defecate in the open and that treats only 30 percent of the 10.1
billion gallons of sewage generated each day. Even the most
modern hospitals can’t exist as islands of cleanliness, he says.
“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?” he asks.
‘Hope for the Future’
Bush, the antibiotics researcher, has been investigating
novel ways to fight bacteria since 1977. She says combinations
of existing drugs, including an experimental compound from
AstraZeneca in late-stage patient studies, may neutralize some
carbapenem-destroying enzymes.
Should these mixtures pan out, they may help the superdrugs
regain at least some of their potency, potentially extending
their usefulness for a decade or more, she says.
A drug candidate from Basel, Switzerland-based Basilea
Pharmaceutica AG (BSLN) in early-stage trials shows some promise
against NDM-1, she says.
“What’s frustrating is to see that companies refused to
address the issue until the last few years,” Bush says. “There
are still some that are trying, and that’s the hope for the
future.”
‘Very Cautious’
Drugs that could once again tackle the world’s most
resistant germs would be a relief for people worldwide, Norway’s
Skaret among them. She spent more than six months fearing a
microbial time bomb until she learned that the NDM-1 supergerms
had passed from her system.
Even though she escaped physical harm, Skaret says, NDM-1
made her feel isolated. She says therapists, concerned about
their own exposure, refused to help her with rehabilitation to
recover from the car accident. Neighbors who delivered food were
careful not to get too close.
“When they heard about it, they were very cautious,” she
says.
If Walsh’s projection is accurate, 100 million Indians may
be carrying the NDM-1 gene unwittingly and doing little to
contain its spread. The number of countries reporting NDM-1 will
continue to grow as more bacteria pick up the gene and people
transport it around the globe.
To prevent a worldwide catastrophe, microbiologists
Kumarasamy and Walsh -- along with scores of scientists and
doctors inside and outside India -- are sounding an alarm.
“Combine sophisticated medicine, poor sanitation and heavy
antibiotic usage, and you have a rocket fuel to drive the
accumulation of resistance,” Livermore says. “That surely is
what India has created.”
I posted this lengthy article because this problem is not confined to India. It affects the whole world. The problem of the over use of antibiotics must be addressed before catastrophe strikes.
