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Monday, April 15, 2024

The Last Drug That Can Fight Gonorrhea Is Starting to Falter

To an unfamiliar eye, the press release from the Massachusetts Department of Public Health two weeks ago looked pretty routine. Its language was a little unnerving, maybe, but phrased carefully: Analysts had discovered a resident with a strain of gonorrhea that showed “reduced response to multiple antibiotics,” but that person—and a second with a similar infection—had been cured.

To a civilian, the announcement may have felt like bumping over a little wave in a boat: a moment of being off-balance, then back to normal. To people in public health and medicine, it felt more like being on the Titanic and spotting the iceberg.

Here is what the news actually said: A disease so old and basic that we barely think about it, even though it affects almost 700,000 Americans a year, is overcoming the last antibiotics now available to treat it. If it gains the ability to evade those drugs, our only options will be desperate searches for others that aren’t approved yet—or a return to a time when untreated gonorrhea caused crippling arthritis, blinded infants as they were born, and made men infertile through testicle damage and women via pelvic inflammatory disease.

The wearying thing, to professionals, is that they saw the iceberg coming. Gonorrhea is not like Covid, a new pathogen that took us by surprise and required heroic research efforts and medical care. It’s a well-known foe, as old as recorded history, with a predictable response to treatment and an equally predictable record of gaining antibiotic resistance. 

Nevertheless, it is getting ahead of us. The Massachusetts discovery “is alarming,” says Yonatan Grad, an infectious-disease physician and researcher and associate professor at the Harvard T.H. Chan School of Public Health. “It is an affirmation of a trend that we knew was happening. And the expectation is, it’s going to get worse.”

A bit more detail on the announcement: The Massachusetts department said that the person had been diagnosed with a novel strain of gonorrhea that was carrying a constellation of traits never before detected in one bacterial sample in the US. Those traits included a genomic signature—previously seen in patients in the UK, Asia, and one person in Nevada—called the penA60 allele. But genomic analysis showed that it also exhibited, for the first time, full resistance to three antibiotics and some resistance to three more. One of those is the drug of last resort in the US: an injectable cephalosporin antibiotic called ceftriaxone. 

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In 2020, the CDC declared that physicians should only administer ceftriaxone against gonorrhea because all the other antibiotics historically used against the infection had lost effectiveness. Fortunately, the substantial dose recommended by the CDC still worked for this patient. It also cured the second person, whom the health department says has no connection to the first and was carrying the same strain with the same resistance pattern. But to experts, that reduced susceptibility indicated ceftriaxone could also be on its way out.

“This situation is both a warning and an opportunity,” says Kathleen Roosevelt, director of Massachusetts’ Division of STD Prevention and HIV Surveillance, emphasizing that rates of gonorrhea are at historic highs across the US. To try to curb that trend, her agency pushed out instructions to every frontline health care professional in the state, asking them to extensively interview patients who test positive, encourage those who’ve received treatment to come back to be sure they’re cured—and, crucially, change the way clinics test patients for infection to begin with.

That last request hints at why the emergence of gonorrhea has been so hard to control. The bacterium is very good at amassing mutations that protect it against antibiotics. It churned through sulfa drugs, the first antibacterials, in the 1940s; penicillin and tetracycline, some of the earliest antibiotics, by the 1980s; and fluoroquinolones such as Cipro by the mid-2000s. Until two years ago, successful treatment relied on administering azithromycin, a macrolide introduced in the mid-1980s, alongside ceftriaxone—but in revised CDC guidelines in 2020 the agency removed azithromycin from the regimen because resistance to it had spiked. As early as 2012, academic and CDC researchers warned in the New England Journal of Medicine that “untreatable gonococcal infection” was on the way.

Aside from being good at protecting itself, gonorrhea poses a challenge that other bacterial infections—pneumonia, for instance—do not. Because it can be a stigmatized disease, people may be reluctant to go to their regular physicians, and so public health departments set up freestanding clinics. That imposed the need to deliver a cure in one dose—first pills, then the ceftriaxone shot—in case people didn’t come back. 

Public clinic use isn’t universal, of course. Gay and bisexual men who take PrEP, pre-exposure prophylaxis against HIV, must be tested for STDs periodically to keep their prescriptions, and that is equally likely to happen in private offices or group practices. And the Massachusetts department says it learned of its first case via primary care. But public funding for sexual health has been repeatedly cut—by 40 percent since 2003, according to the National Academies of Sciences, Engineering, and Medicine. And primary care practitioners aren’t equally thorough in interrogating their patients’ sex lives. 

“We know that clinicians often aren’t super comfortable talking about sexual health, and patients aren’t either,” says Elizabeth Finley, director of communications at the National Coalition of STD Directors, the professional association for STD chiefs such as Roosevelt. “So recommendations to be tested can get skipped over, or requests aren’t heard.”

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The possibility that people at risk would want to keep their sexual health separate from the rest of their medical care, and might not be diligent about coming back to clinics, drove a change in testing that accidentally paved the way for gonorrhea to surge. In the 1990s, clinics began switching from traditional ways of identifying bacteria—take a swab, swish it over a plate, incubate the culture until something grows—to nucleic-acid rapid tests that were more sensitive  and delivered faster results. But the unintended consequence of never culturing the bacteria was losing sight of how it was gaining resistance—because ascertaining drug susceptibility, or sequencing for genomic information, requires having an organism to test.

Once that problem became evident, separate surveillance programs were set up to cope. The Massachusetts case came to light thanks to a program established in 2013; it requires that every positive test be reported to the state’s department within 24 hours and any bacterial isolate be sent to a state lab. The CDC runs the Gonococcal Isolate Surveillance Project, which tracks the emergence of resistance in 32 cities and one military base by funding health departments to collect at least 25 bacterial samples a month from men who have tested positive. (A separate program tracks the disease in women.)

It’s a keyhole view into the problem, perhaps displaying the part of the iceberg above the water. It was developed before sequencing became cheap and widely accessible and doesn’t deliver as much information as researchers and clinicians would like. “It’s become a surrogate,” says Margaret Hammerschlag, a physician-researcher and the program director of pediatric infectious diseases at SUNY Downstate Health Sciences University in Brooklyn. “I have no idea what’s going on with gonorrhea in my hospital, but because one of the sites is in New York City, they are generating data for here.”

Rising resistance, rising rates of a still-stigmatized disease, lagging technology: Together they make gonorrhea a hard problem, one that has to be faced in a time of deep disease fatigue. Newer antibiotics—zoliflodacin, from Entasis Therapeutics, and gepotidacin, made by GSK—have both been in clinical trials for years, but neither is available yet. Older drugs are under consideration, but before using them health authorities would have to determine whether other bacteria residing in patients’ bodies might develop resistance as well. (One of the drugs being tested—ertapenem, belonging to a last-resort class called carbapenems—is already losing effectiveness against gut bacteria like E. coli that cause grave hospital infections.) Grad has been working for several years to turn the search for resistance inside out by mining genomes to identify signatures of drug susceptibility instead of resistance and developing a diagnostic test to indicate which older drug might still work.

It all presents a lesson that we could have learned from the Covid pandemic: For a pathogen, surveillance—noticing its emergence and monitoring where it moves—isn’t sufficient to control disease. We leave ourselves vulnerable unless we build the capacity to respond to it and treat it as well. 

“Systems get the outcomes they’re designed to get,” Finley says. “In the US, we have not optimized the way we respond to sexually transmitted infections. So we have multiple breakdowns in public health: the emergence of these pathogens, an underfunded system, and an issue that we’re not willing to talk about. It’s just a perfect storm.”

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