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.
“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.
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.
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.”
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.
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 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.
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 Britain’s Health Protection Agency in London.
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.
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.”
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.”
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.
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.”
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.”
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 Centers for Disease Control and Prevention in Atlanta. “We are looking at the specter of untreatable illness.”
