Several times a week Brad Spellberg struggles with a difficult decision. A patient stumbles into his emergency room in southern California suffering from familiar symptoms: pressure when she urinates, pain in her side, fever and nausea. Based on these clues Spellberg can quickly diagnose the problem as a kidney infection, but the trouble lies in deciding what he should do next. He knows the patient is hurting and of course he wants to help, but more than his patient’s health hangs in the balance.
Like any emergency room clinician Spellberg has two disparate options. The first is to treat the patient with a powerful antibiotic called carbapenem, administered intravenously. It would wipe out a variety of bacteria that might be causing the infection, but there is a catch. Deploying this precious resource may make it less likely he can use it to treat a future patient. The drug would kill susceptible bacteria but it would also fuel resistance by allowing the few microbes that are able to survive carbapenem to thrive and multiply. Spellberg’s second option is to send the patient home with a lower-level class of drug, a quinolone. The stakes of his decisions are high. If a relatively mild bacterium is behind the patient’s infection, a quinolone would neutralize it and the patient would recover. But if the infection is caused by a drug-resistant pathogen, the patient would not recover without carbapenem and the untreated infection may worsen.
Spellberg’s catch-22 comes down to an issue of timing. He will not know exactly what bug is causing the patient’s infection for several days because there are no fast, cheap diagnostic tests available. So it will take three days for lab workers to identify the patient’s assailant. Spellberg cannot wait that long to make his choice. His dilemma, sadly, is not uncommon. Across the country doctors are struggling with the same issues he faces as the chief medical officer at the Los Angeles County + University of Southern California Medical Center.
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Such situations now represent a key front against encroaching antibiotic resistance. And there is alarming evidence that we are quickly losing ground. In August, for example, the World Health Organization issued new guidance on sexually transmitted diseases. It said that the standard drugs used to treat gonorrhea are often no longer effective due to escalating resistance. Now WHO recommends employing two drugs against the bacterium that causes the infection. Moreover, earlier WHO analysis concluded that antibiotic-resistant pathogens are now present in every part of the world—jeopardizing a century of medical advances.
The threat of antibiotic resistance has become so dire that the United Nations General Assembly is holding a meeting to discuss it this month in New York City. Although WHO has been sounding the alarm on antibiotic resistance for years, this month’s high-level U.N. meeting represents only the fourth time in the international body’s history that its General Assembly—a global deliberative body that primarily grapples with issues like war and economics—has held a meeting to tackle a health topic. (The other three were HIV, noncommunicable diseases and Ebola.) The meeting “is a clear recognition that this is a worldwide threat to everyone and worldwide action is what we need to address it,” says Ezekiel Emanuel, chair of medical ethics and health policy at the University of Pennsylvania.
The pressure to hold such a high-level meeting has grown in recent years, even as unnecessary or incorrect antibiotic use in health care settings and agricultural production has exacerbated the problem. For example, when agricultural producers treat their healthy livestock or fish with antibiotics to help speed their growth and keep them healthy in subpar conditions, they are simultaneously fueling resistance that can sideline the drugs for human use.
A New Urgency
The September 21 U.N. meeting will come on the heels of some particularly bad news about superbugs. Last November an analysis published in The Lancet Infectious Diseases reported that scientists had detected resistance to a last-line antibiotic called colistin in meat animals and people in China—likely from use of colistin in livestock to speed agricultural production. The resistant gene was found on a plasmid, a length of DNA that can be easily transferred between different strains of bacteria. Then, more bad news: In recent months we have seen the spread of this colistin resistance gene emerging rapidly in various areas around the globe.
Colistin-resistant Escherichia coli has surfaced in more than 30 countries, including in a patient in the U.S. One strain of E. coli in the U.S. has actually proved resistant to both carbapenem and colistin (but fortunately that strain appears to be susceptible to some other antibiotics). “The fact we are so concerned about colistin resistance is a sign of how desperate we are,” says Lance Price, a microbiologist and director of the Antibiotic Resistance Action Center at The George Washington University. “It’s a shitty drug. It’s toxic and doctors don’t like to use it, but now they have to use it because it’s the only thing that treats some of these drug-resistant infections.”
Expanding Our Arsenal
Keiji Fukuda, special representative of the WHO Director-General for Antimicrobial Resistance, says the coming U.N. meeting is designed to elevate the discourse on antibiotic resistance and signal this is a high priority. “The previous discussions have been held at the level of ministers of health and agriculture but this meeting will take this up to the level of prime ministers and presidents,” Fukuda explains. Yet the actions that are hoped for as a result of the meeting remain meager. No binding agreement is expected. What may be more realistic, Fukuda says, is a political declaration of commitment to coordinate further on this issue. “This may seem like a relatively easy thing, but to get that kind of cooperation on a worldwide basis is extremely difficult,” he says. The discussions will also hopefully include the recognition and commitment of financing to support such plans, he says.
Encroaching antibiotic resistance will not slow to keep pace with international diplomacy, however. It has been decades since a new class of antibiotics has been introduced—a needed innovation as more pathogens become resistant to existing antimicrobials. Researchers say that new antibiotics might not be the only option. Other weapons under development—likely to be used with antibiotics—include reintroducing tiny bacterial parasites called bacteriophages against some pathogens. Research teams are also looking into engineering souped-up antibodies to beat back specific infections or developing medications that would modulate a human’s immune response to a pathogen—because in some cases blocking inflammation will help alleviate much of the damage from infections. Another approach, Spellberg says, might be to employ iron-sequestration technologies that would passively starve microbes so they cannot grow in the body. Still other research pursued by Price and others zeros in on the gut microbiome, in the hope of designing probiotics that would change or help tamp down problematic bacterial colonization. “There’s not one silver bullet for combating antibiotic resistance,” Spellberg says. “Many things need to be explored so the solutions that are most promising will bubble to the surface.”
Already, drug resistance risks in our daily lives—outside of health care settings and farms—often go unrecognized but represent a growing concern. One little-discussed issue is community-acquired infections—situations in which people contract a superbug through food, drink or by touching a contaminated surface and then putting their hands in their mouths, Spellberg says. In such situations patients may unwittingly pick up superbugs that can reside in the gut without causing any issues for weeks or years. It is only when those superbugs go elsewhere in the body—the urinary tract, for example—that they can become dangerous or even deadly.
Unfortunately, this is already happening with alarming frequency. A recent small analysis found that about a third of patients with infections and resistance to major antibiotics (including penicillins and cephalosporins) did not have typical resistance risk factors such as exposure to a health care setting, prior use of antimicrobial drugs or international travel. That suggests they contracted their superbug infections in their own communities where the microbes apparently circulated, undetected.
There are already things that can be and are being done—with mixed results—to combat the increase in antibiotic resistance. One such measure is shortening the duration of drug treatment to the bare minimum required to end an infection. (Longer courses put selective pressure on the bacteria in the body, which can help resistance grow.) The Infectious Diseases Society of America, for example, has recently changed its guidelines for hospital- and ventilator-acquired pneumonia—shaving the recommended treatment time down to seven days or less based on new science showing that is long enough to treat the patient. Yet Spellberg worries that too often such recommendations only exist on paper, and have not yet been put into practice. He says consumers can help ensure the best future for our existing drugs by taking steps to protect themselves: washing their hands and vegetables, disinfecting surfaces, asking their doctors if antibiotics are truly necessary and getting vaccinated to prevent infections.
Yet perhaps the most intractable problem remains sparking investments to expand the arsenal against these microbes. “The basic issue is this research is needed but we don’t have the business models to facilitate or encourage this,” Fukuda says. Drugmakers often say that without a different incentive structure—perhaps government rewards for new classes of antibiotics—it does not make good business sense to invest in antibiotics when they could focus on projects that would command higher profits, such as new drugs to fight cancer. In Spellberg’s emergency room, however, patients simply cannot afford to wait.