Increasingly resistant to drugs

Data gaps, funding cuts, and reluctance to discuss it have made gonorrhoea less responsive to antibiotics. Positive gonorrhoea tests and STD cases in the US are now at an all-time high. The press release issued by the Massachusetts Department of Public Health two weeks ago may seem anonymous to the untrained eye. Analysts wrote the information in disturbing language, albeit carefully chosen. They tested and discovered a strain of gonorrhoea showing a “reduced response to several antibiotics” in a patient. Subsequently, they treated the patient and another person with a similar infection.

For a civilian, the announcement may feel like hitting a small wave on a boat: a moment of imbalance after which everything returns to normal. But for those in public health and medicine, it’s like sighting an iceberg on board the Titanic.

Hidden message

The real message hidden within the statement was an ancient and basic STD that we practically no longer considered dangerous. It affects almost 700,000 people every year in the United States alone. It is developing resistance against the latest antibiotics available to treat it. If it escapes these drugs, our only option will be to search for other unapproved drugs desperately. We may also have to return to a time when failure to treat the condition caused debilitating arthritis. It led to blindness in newborns and infertility due to testicular damage in men. It also resulted in pelvic inflammatory disease in women.

For the professionals, the most worrying aspect of the story is that they had foreseen the arrival of the iceberg. Gonorrhoea is not like COVID-19, a new pathogen that took us by surprise, requiring heroic efforts in research and therapies. It is a well-known enemy, as old as time, with a predictable response to treatment and an equally predictable history of antibiotic resistance.

Nonetheless, the disease is one step ahead of us. The discovery made in Massachusetts “is alarming,” emphasises Yonatan Grad, an infectious disease doctor, researcher, and associate professor at the T.H. Chan School of Public Health at Harvard. It affirms a trend we knew was underway. And the prediction is that the situation will get worse.”

Reduced options

The Massachusetts Department of Public Health reported that the patient cited in the release received a diagnosis of a new strain of gonorrhoea. This strain had several characteristics never before detected in a bacterial sample in the United States. These characteristics include the penA60 allele, a genomic signature already found in patients in the UK, Asia, and one person in Nevada. However, the genomic analysis also revealed that the strain appeared for the first time to be completely resistant to three antibiotics. It also showed some resistance to three others. Ceftriaxone, an injectable cephalosporin used as a last-resort drug in the United States, is one of these.

In 2020, the Centers for Disease Control and Prevention (CDC) declared that doctors in the country should only administer ceftriaxone against it since all other antibiotics historically used against the infection have lost their effectiveness. Fortunately, the dose recommended by the CDC worked in the patient’s case in Massachusetts. The drug also treated the second person, who the state Department of STD Health said was unrelated to the first patient but had the same strain with an identical pattern of resistance. Experts have tested and view the STD disease’s reduced sensitivity to the drug as a sign that ceftriaxone’s days may also be numbered.

The situation

“This situation is both a warning and an opportunity,” says Kathleen Roosevelt, director of the Massachusetts Division of STD Prevention and HIV Surveillance. She highlights that gonorrhoea rates are at historic highs in the United States. To limit the trend, the organisation has sent instructions to all front-line health workers in the American state. They are instructed to conduct in-depth interviews with patients who test positive. The goal is to encourage those undergoing treatments to make new visits, ensuring they are cured. This is key to changing the way clinics screen patients.

This last point, in particular, explains why it has proven difficult to control after testing. The bacterium that causes the disease accumulates mutations that protect it from antibiotics. In the 1940s, it managed to resist the first antibacterials, the sulphonamides; to some of the first antibiotics, such as penicillin and tetracycline in the 1980s and fluoroquinolones such as ciprofloxacin in the middle of the 2000s. Until two years ago, effective therapy was based on the administration of azithromycin. This is a macrolide introduced together with ceftriaxone in the mid-1980s. However, the CDC says, revised in 2020, that the agency removed azithromycin because resistance to the drug had increased. In 2012, academic and CDC researchers wrote in the New England Journal of Medicine that an “untreatable gonococcal infection” was coming.

Gonorrhea also involves complications other than bacterial infections, such as pneumonia. The stigma surrounding the disease may make people reluctant to contact their primary care physicians. This is why American public health departments set up independent clinics, and the need arose to provide a single-dose cure, first the pills, then the ceftriaxone injection.

Reluctance and little attention

People do not always turn to public clinics; they are not all around. Gay and bisexual men in the United States who take PrEP, the pre-exposure prophylaxis against HIV, must undergo periodic testing for STDs to maintain their prescriptions. This screening occurs just as frequently in private offices as in group studies. The Massachusetts Department of Health says it became aware of the first case through primary care. But public funding for sexual health has been repeatedly cut. Forty per cent since 2003, according to the National Academies of Sciences, Engineering and Medicine. And primary care physicians aren’t as conscientious about asking about their patients’ sex lives.

“We know that doctors often don’t feel comfortable talking about sexual health, and neither do patients,” says Elizabeth Finley, communications director of the National Coalition of STI Directors. The American professional association brings together those responsible for STIs and their testing. People saying to get checked may be ignored.

Healthcare

The possibility that people at risk may want to keep their sexual health separate from other medical care and may not regularly return to clinics is behind a change in screening that has accidentally paved the way for the rise in gonorrhoea. In the 1990s, clinics shifted from traditional methods of identifying bacteria. These involve taking a swab, running it on a plate, and incubating the culture until something grows. They shifted to rapid nucleic acid methods, which are more sensitive and have faster results.  Shelving the cultures had the unintended consequence of losing sight of how the bacteria developed resistance.

Once the problem became apparent, surveillance programs established in the United States brought the Massachusetts case to light. The program, created in 2013, mandates reporting any positive results to the state department within 24 hours. Subsequently, the isolated bacteria are sent to a state lab. The CDC runs the Gonococcal Isolate Surveillance Project. This project tracks the emergence of resistance in 32 American cities. It is located on a military base. The base funds health departments to collect at least 25 bacterial samples monthly from men who have tested STD positive. There is a separate program for women.

The growing issue

It’s like looking at the problem through a keyhole, a method that may only be able to show the big part of the iceberg. Researchers developed it before sequencing became cheap and widely accessible. It also provides less information than researchers and doctors would like.

Increased resistance, growing rates of a still stigmatised disease, and delay in technology. In a period of profound disease fatigue, addressing gonorrhoea becomes imperative due to its complexity and various contributing factors during screening. The new antibiotics – moxifloxacin, made by Entasis Therapeutics, and gepotidacin, made by GSK – have been in clinical trials for years, but neither is available. Older drugs have also been considered. But before using them, health authorities would need to determine whether other bacteria residing in patients’ bodies could develop resistance.

These cases represent a lesson we could have learned from the HPV virus period: surveillance of a pathogen—taking note of its appearance and monitoring where it moves—is not sufficient to control a disease: in order not to be vulnerable, it is necessary to develop the ability to react to and treat it.

Finley clarifies that systems produce the outcomes they were intended for. “In the United States, we have not optimised how we respond to STDs. There are several places where public health is not working. The finding of these pathogens, an underfunded system and a problem we’re unwilling to discuss: a perfect storm.”