A July 2016 report from the U.S. Centers for Disease Control and Prevention (CDC) painted a dire picture of an ages-old public health scourge that had lately been considered in check. The disease is gonorrhea, and the agency’s surveillance system for monitoring antibiotic resistance in lab samples found steeply rising rates of resistance to the last two available antibiotics—azithromycin and ceftriaxone—that can cure the sexually transmitted infection. Among lab samples studied for Neisseria gonorrhoeae, the microbe that causes gonorrhea, resistance to azithromycin shot up between 2013 and 2014 from 0.6 percent to 2.5 percent, while resistance to ceftriaxone rose from 0.4 percent to 0.8 percent.
Although at first glance those numbers may seem negligible, they confirm a disquieting trend: In the last 20 years, N. gonorrhoeae has grown increasingly impervious to treatment. Public health officials in the U.S. and around the globe have also reported the emergence of resistance to third-generation cephalosporins (including ceftriaxone), the antibiotic of last resort for the disease—a sign that the specter of untreatable disease is on the horizon. In 2015, there were nearly 400,000 cases of gonorrhea recorded in the U.S.—representing a 13 percent increase compared with the previous year. The real U.S. caseload may actually be closer to 800,000, because fewer than half of gonorrhea infections are diagnosed. The World Health Organization (WHO) estimates 78 million new infections each year.
“The confluence of emerging drug resistance and very limited alternative options for treatment creates a perfect storm for future gonorrhea treatment failure in the U.S.,” noted Jonathan Mermin, director of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and Tuberculosis Prevention. “History shows us that bacteria will find a way to outlast the antibiotics we’re using to treat them. We are running just one step ahead in order to preserve the remaining treatment option for as long as possible.”
Yonatan Grad, an assistant professor in the Harvard Chan School’s Department of Immunology and Infectious Diseases, is equally alarmed. “For a high-prevalence disease like gonorrhea, these numbers are very disturbing. Not only are a large number of people affected—as many as one out of every three cases in the U.S. is resistant to at least one antibiotic—but the trajectory of resistance is on a steep incline,” says Grad, a physician-scientist who did postdoctorate work in the School’s Department of Epidemiology from 2010 to 2014, focusing on pathogen evolution and spread. “From a public health perspective, the fear is that we may soon encounter complete resistance to treatment.”
Understanding how microbes adapt and move through populations and why drug-resistant infections unfold differently in different patients is key to combating the threat. Grad is tackling the problem by joining modern genomic tools with computational methods.
His work offers new ways to track and treat drug-resistant infections. And in doing so, he is carving a path toward preserving antibiotics’ potency. In July 2015, Grad’s innovative approach was recognized by the Doris Duke Charitable Foundation with a prestigious Clinical Scientist Development Award, which aims to support promising junior physician-scientists as they transition to independent careers.
TAMING “SUPERBUGS”
In any battle, “Know thy enemy” is sage advice, but it is especially relevant in the global fight against antibiotic-resistant pathogens. According to the CDC, each year in the United States alone, at least 2 million people become infected with antibiotic-resistant bacteria. Some 25,000 people die as a direct result of these infections, while many more succumb to complications tied to antibiotic resistance, such as the need to shift to other treatment options that may carry severe side effects. In addition to this significant human toll, antibiotic resistance increases health care costs by an estimated $20 billion per year, according to the CDC.
Although antibiotic resistance may seem like a new problem, Alexander Fleming, the Nobel Prize–winning scientist who discovered penicillin nearly nine decades ago, predicted its rise. In a 1945 interview with The New York Times, he warned: “The greatest possibility of evil…is the use of too-small doses, so that, instead of clearing up the infection, the microbes are educated to resist penicillin.” He added: “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.”
Now, some 70 years after Fleming’s cautionary message, his fears have been realized on a worldwide scale. National and international public health organizations, including the CDC and the WHO, have recently called for decisive steps to quell the antibiotic resistance crisis.
Against this backdrop, some of the most worrisome drug-resistant diseases are sexually transmitted infections. This past October, the CDC issued a report stating that the total combined cases of gonorrhea, chlamydia, and syphilis reported in 2015 were the highest number ever recorded in the U.S.
REFINING DIAGNOSIS
One approach to this problem starts with how gonorrhea is diagnosed. “Currently, we very rarely test the antibiotic susceptibility profile of gonococcal infections, other than as part of surveillance or in cases of treatment failure,” Grad explains. “Instead, we diagnose the presence of the infection in a way that doesn’t provide the susceptibility profile and then treat patients empirically. Part of the issue is timing. We want to treat patients when they present for care, but the tests to determine the susceptibility profile take several days and rely on obtaining, culturing, and testing a bacterial specimen—and also require patients to return to the clinic to receive proper treatment.”
There are no approved rapid diagnostic tests that signal which particular drugs a given strain of N. gonorrhoeae will succumb to. Current guidelines therefore recommend empirical treatment—using a one-time dose of drugs (now a combination of two antibiotics) that, in theory, should eliminate infection in the vast majority of patients. But with the rise of resistance and a development pipeline for new antibiotics that has run dry, the therapeutic toolkit for gonorrhea has reached its limit.
Grad’s lab is seeking to identify ways to better control the disease and tamp down resistance. To do this, they are decoding N. gonorrhoeae genomes in bacterial isolates taken from different infected patients. In a March 2014 study published in The Lancet Infectious Diseases, Grad and his colleagues linked genetic differences among patient isolates to cephalosporin resistance. The researchers used samples from the Gonococcal Isolate Surveillance Project (GISP), a CDC-supported effort that began in 1986 to monitor antibiotic resistance in N. gonorrhoeae nationwide and that forms the basis for the CDC’s antibiotic treatment guidelines.
Those results, coupled with findings from a larger study by Grad’s group that looked at two other classes of antibiotics and published in October in the Journal of Infectious Diseases, could help speed the development of a rapid diagnostic test that differentiates N. gonorrhoeae strains based on their drug-resistance profiles.
Such a tool could reduce the uncertainty in current antibiotic treatment protocols. Instead of treating under the assumption that a patient is infected with the most common antibiotic-resistant strains, doctors could tailor treatments to the strains found in individual patients, and perhaps even bring previously shelved antibiotics back into use.
MAPPING AN EPIDEMIC
Grad and his co-authors also mined the GISP data to determine how closely related N. gonorrhoeae isolates are to one another. The researchers connected bacterial genomics with the demographic and geographic features of infected individuals—a crucial step in characterizing transmission patterns and potential disease outbreaks.
“Bacterial genomes carry a history that even the patients themselves may not know,” Grad says. “Being able to reconstruct that history through genome sequencing can be incredibly powerful for public health systems.” Such a genomic history could help public health experts track how the organism has been transmitted within and between communities, which could help guide surveillance efforts and identify disease outbreaks.
Now, as Grad extends his studies of antibiotic resistance in N. gonorrhoeae, he envisions basic insights that could apply to other drug-resistant bacteria.
“If we see a highly drug-resistant strain emerge in a patient in New York or Dallas or San Francisco, for example, where is it likely to appear next?” he asks. “How many undetected cases are there likely to be? How can a public health system most efficiently structure its surveillance and, ultimately, its interventions?”
One of the pathogens on which Grad is concentrating is methicillin-resistant Staphylococcus aureus (MRSA), which represents one of the most formidable antibiotic-resistant infections because of the microbe’s virulence and its ability to outwit many of the prescribed antibiotics in the medical arsenal. Grad’s new award from the Doris Duke Charitable Foundation will support research aimed at understanding why some people benefit from a form of MRSA control known as decolonization—which aims to remove MRSA from the body using antibacterial soap and ointment—and others do not.
“One of the things I find fascinating about infectious diseases is their heterogeneity,” says Grad. “Take respiratory viruses. Why do some people get a mild cold and others end up hospitalized when infected with the same virus? In this project on MRSA, we are examining an intervention that for some people is successful and for some people it’s not. We want to figure out why.”
Dyann Wirth, the Richard Pearson Strong Professor of Infectious Diseases and Chair of the Department of Immunology and Infectious Diseases at the Harvard Chan School, praises Grad’s scientific scope. “Yonatan is a rising star,” she says. “Because of his creativity, productivity, collaborative abilities, and focus on critically important questions, he is poised to make important contributions to biomedicine and public health.”
HEALING POWER
Grad’s interests haven’t always centered on infectious disease, or
even medicine. As an undergraduate at Johns Hopkins University, he was drawn to a variety of fields and started out studying chemistry, literature, and philosophy. Ultimately, he latched on to brain biology and joined the laboratory of renowned neuroscientist Solomon (“Sol”) Snyder. “I loved Sol’s group because it was full of people who were driven and excited about questions and ideas,” Grad recalls.
After completing his bachelor’s degree in 1996, he spent a year at Cambridge University studying human genetics on a Churchill Scholarship. He then enrolled in the MD-PhD program at Harvard Medical School (HMS), where he became increasingly convinced of the importance of computational biology. Grad joined George Church’s laboratory in the HMS Department of Genetics, where he explored computational and statistical methods to sift through mounds of genomic data.
Doctorate in hand, he returned to his third-year medical clerkships, rotating among the various clinical departments in the Harvard-affiliated medical centers and becoming immersed in day-to-day patient care. He found himself drawn to the field of infectious diseases—as a scientific and medical discipline—in part because it weaves together many of his own personal interests. “Infectious diseases arise through interactions between an individual and the world, so diagnosis is often based on understanding individual patients—their biology as well as their environment, behaviors, and risks—along with the biology and epidemiology of the pathogens,” he says.
For Grad, the clincher was that infectious-disease physicians often can eliminate an infection and return patients to their previous state of health. “Much of what we learn in clinical training is about ‘managing’ illness and health— ‘managing,’ rather than ‘curing,’” he says. “The word ‘cure’ is not something
I heard much during medical school or even in residency. When I did hear it, I was struck by its emotional power, both for patients and for doctors.”
Nicole Davis is a science writer and communications consultant specializing in biomedicine and biotechnology. She holds a PhD in genetics from Harvard University.
