Opinion | Gonorrhea, Then and Now

Last month, an article in Nature about a novel oral treatment for gonorrhea brought good news for anyone who might one day contract the sexually transmitted infection (STI), which was recently estimated to infect roughly 80 million people every year.

The report on zoliflodacin, which is not yet approved in any country, was also heartening because the drug’s phase III testing was “the largest global trial ever conducted for a new treatment against gonorrhea,” according to Pierre Daram, PhD, MBA, the STI Treatment Project leader for the Global Antibiotic Research and Development Partnership (GARDP). GARDP is the Geneva-based non-profit that led the trial, and its direct involvement represents an important turning point in the ongoing battle against drug-defying microbes.

Nonetheless, I found the title and sub-title of the Nature piece, “‘Ground-breaking’: first treatment targeting ‘super-gonorrhoea’ passes trial: Antibiotic could turn the tide on drug-resistant form of the infection — if it’s used wisely,” both hopeful and sobering. Why?

At the same time we urgently need new drugs to treat Neisseria gonorrhoeae, we also need better messaging around condoms. After all, although hardly foolproof, they are still quite effective in preventing STIs.

And yet: condom-less sex is back, especially among men who have sex with men (MSM). My UCLA colleague Pamina Gorbach MHS, DrPH, whose research focuses on bio-behavioral dynamics of sexual health, recently confirmed this: “For women and hetero males, they [condoms] serve the dual purpose of preventing pregnancy and STIs and HIV. But for the MSM community in the U.S., HIV PrEP [pre-exposure prophylaxis with anti-viral pills or injections] has been a real game-changer.”

This leads to an urgent question: In this latest era of sexual liberation, how can we encourage people who risk getting gonorrhea to consider the greater global good of using condoms in order to prevent its possible antibiotic melt-down?

Gonorrhea’s Ups and Downs

As a former history major, I’ve always been interested in cycles of infection. Here’s what I recently learned from decades of data from the CDC: After peaking in 1975 at 464 infections per 100,000 Americans, gonorrhea’s incidence was down to 98 by 2009. Then, 12 years later in 2021, it had more than doubled to 214 cases per 100,000.

More than 710,000 reported cases in 2021 also show its 28% rise over just 5 years, thus firmly establishing gonorrhea as our country’s second most common STI after chlamydia.

Experts believe that many factors account for gonorrhea’s latest rebound, which has disproportionately hit young people ages 15 to 24, gay and bisexual men, and racial and ethnic minority groups. For one thing, STI-associated stigma and socio-economic barriers to care are perennial issues hindering treatment. Casual, one-time hook-ups and the dangerous mix of sex plus recreational drugs are also fueling transmission. Finally, experts wonder, is a lessening fear of HIV prompting less concern about unprotected sex?

Meanwhile, ever lurking in the shadows, is N. gonorrhoeae‘s growing antibiotic resistance.

The Problem With Modern Diagnostics

Working as a medical resident in Chicago in the late 1970s, I saw many classic cases of gonorrhea. Men with a gooey, urethral discharge or chronic urinary stricture. Women with red-hot pelvic inflammation or post-infectious scarring leading to an ectopic pregnancy or infertility. Scattered pustules or septic arthritis due to bloodborne spread of the fastidious, Gram-negative diplococci found in aspirated pus or cloudy drops of synovial fluid that a microbiology tech would then try to grow on a chocolate agar plate.

Today’s trainees may not have seen those culture plates, but they are still seeing plenty of patients whose genital, rectal, and throat swabs are PCR-positive for N. gonorrhoeae.

The good news? With the advent of PCR testing, the organism became easier to detect. The bad news? Using PCR tests, especially in patients on HIV PrEP who are tested for gonorrhea every 3 months, it is now hard to distinguish an active infection from one that’s gone. Nor do PCR tests inform us about antibiotic susceptibility.

Both of these issues can lead to antibiotic overuse, which further jeopardizes today’s remaining regimen for uncomplicated gonorrhea.

Waning Antimicrobial Weapons

This leads us back to the historical context. Ever since the 1930s and 1940s, when sulfa drugs were only briefly effective against N. gonorrhoeae, the organism has displayed ongoing antibiotic resistance. For the next several decades, its eradication required ever-higher doses of penicillin. Then drugs in the fluoroquinolone (FQ) class replaced penicillins and tetracyclines, until FQ-resistant strains emerged in Asia and the Pacific Basin and later spread worldwide.

By 2007, FQs were dropped from all CDC regimens and third-generation cephalosporins like ceftriaxone combined with azithromycin later became WHO’s treatment of choice for genital and anorectal infections.

But that was then. Now extremely drug-resistant (XDR) strains are signaling a slowly unfolding global crisis.

Scoping the Future

Like Gorbach, my UCLA colleague Paul Adamson, MD, MPH, is another STI researcher as well as a clinician who is currently focused on gonorrhea in global settings. In another few weeks, he’ll start a 3-month stint at the Sexual Health and Promotion Clinic at Hanoi Medical Center, Vietnam’s first facility to offer HIV PrEP. While there, the infectious diseases doctor will not only characterize local strains of N. gonorrhoeae but will begin to correlate clinical presentations and patient behaviors with antibiotic resistance.

Adamson was enthusiastic when he heard the news of zoliflodacin; at the same time, he felt a need to protect it. “It seems like it’s as effective as ceftriaxone and azithromycin, so that’s exciting,” he said, “but you also want to hold it for cases in which you can’t use ceftriaxone. I fear that will be really hard to do.”

His concern stemmed from the fact that relatively few isolates of N. gonorrhoeae are cultured these days — yet a culture is still the only way to identify ceftriaxone-resistant strains in individual patients.

Daram sees things differently. As he told me over email, GARDP’s aim “is to limit the clinical use [of zoliflodacin]…to the targeted disease only.” He’s hoping this tactic will largely rein in future resistance to the novel agent.

“Wouldn’t that be great?” I thought while reading his message. Yet, all the while, I kept thinking about condoms.

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