After decades without meaningful advances in gonorrhea treatment, the approval of new oral antibiotics marks a turning point in the fight against the infection.

Phase 3 clinical trials show that zoliflodacin and gepotidacin — recently approved in the US for the treatment of uncomplicated urogenital gonorrhea — produced cure rates comparable to the standard regimen of intramuscular ceftriaxone, which is currently the cornerstone of international guidelines.

For the first time in decades, oral administration is again a real option for treating gonorrhea. But the advance comes with a clear warning: without proper diagnosis, active surveillance, and rational use, the innovation could speed up exactly the problem it seeks to solve — antimicrobial resistance.

The gap in creating new therapeutic options was not accidental. The lack of new oral agents reflects a broader stagnation in developing antibiotics effective against resistant bacteria over recent decades, worsened by the high cost of research, limited financial returns and the rapid emergence of resistance.

In the specific case of gonorrhea, the pathogen’s high adaptive capacity and the lack of sustainable incentives for drug development slowed progress further, pushing treatment toward injectable regimens as the only viable option.

The global context helps underscore the importance of this moment. Neisseria gonorrhoeae already shows resistance to virtually every class of antibiotics used since penicillin was introduced. Oral fluoroquinolones, macrolides, and cephalosporins were abandoned after documented treatment failures. Since 2020, intramuscular ceftriaxone has, in practice, become the only first-line recommendation in many countries, reflecting the scarcity of effective options.

According to infectious disease specialist Alexandre Cunha, a member of the Brazilian Society of Infectious Diseases (SBI) committee on bacterial resistance, that history explains why the arrival of new drugs must be treated cautiously. “What is a solution today — therapeutic innovation with new antibiotics — can become a problem if those drugs are not used sparingly. The history of gonorrhea shows that indiscriminate use accelerates resistance,” he said.

That background helps explain why approval of the new antibiotics was treated as urgent in countries such as the US, where there are already reports of more frequent treatment failures, while in Brazil the debate is more preventive than reactive. The continued susceptibility to ceftriaxone creates a strategic opportunity to incorporate innovation without repeating, on an accelerated timeline, the cycle of resistance seen elsewhere.

This tension between scientific progress and public health risk runs through the current debate and is especially clear when we look at the clinical and epidemiologic behavior of gonorrhea.

An Efficient Pathogen and a Vulnerable System

Gonorrhea remains one of the most incident sexually transmitted infections (STIs) worldwide and often remains a silent infection. In women it is frequently asymptomatic until complications such as pelvic inflammatory disease and infertility arise. In men, although urethritis is usually symptomatic, asymptomatic colonization of the oropharynx and rectum is common and plays an important role in both transmission and the development of resistance.

This clinical profile makes timely diagnosis central and at the same time one of the main bottlenecks in disease control. Molecular nucleic acid amplification tests are the gold standard for detection, but they do not provide information about antimicrobial susceptibility. In cases of treatment failure, culture with susceptibility testing is still essential, although it is seldom available in routine clinical practice.

In Brazil, these limitations are compounded by structural weaknesses. Gonorrhea is not a nationally notifiable disease, which makes it difficult to establish precise incidence estimates. Resistance surveillance depends on sentinel initiatives, such as SenGono, which reveal an ambiguous picture: high resistance to ciprofloxacin and tetracyclines, but continued high susceptibility to ceftriaxone, a therapeutic agent whose effectiveness must be preserved.

At this point, infectious disease specialist Renata Maronna Praça Longhi, a faculty member in the medical school at the Federal University of Grande Dourados, Dourados, Brazil, broadens the focus of the debate to the health system as a whole. “Today the top priority for sexually transmitted infections is improving diagnosis, especially ensuring earlier diagnosis. We still see many cases of syphilis, gonorrhea and HIV diagnosed late, which shows the need to ease access, ensure proper reception and invest in screening,” she said.

That observation helps explain why new therapeutic options, although necessary, do not solve the problem on their own.

What Changes With the New Antibiotics

In practice, the main benefit of the new drugs is simplification of healthcare management. Oral treatment could expand access in lower-complexity services, reduce barriers to care, and make treatment easier in settings where giving injectables is limited.

Clinical data, however, set clear limits. Zoliflodacin and gepotidacin showed high effectiveness for uncomplicated urogenital gonorrhea, but they had lower cure rates for pharyngeal infections, which are a critical point in transmission dynamics and resistance. Regulatory agencies have adopted cautious indications, reflecting concerns about safety and appropriate use.

The lower effectiveness for pharyngeal infections is not a mere technical detail. The oropharynx is recognized as one of gonococcus’s main silent reservoirs, playing a central role in both transmission and the emergence of resistance. Historically, it is in that site that treatment failures first appear, reinforcing the need for caution in expanding use of oral regimens.

This is precisely where enthusiasm for innovation meets its limits. For Márcio Fernandes, Coordinator of the Sexually Transmitted Infections Committee of the SBI, the relevance of these drugs is in expanding the therapeutic armamentarium, not in indiscriminately replacing the current standard.

“We learned from HIV that individualized therapy makes all the difference to therapeutic success. But to individualize, you need options. That does not mean trivializing use. These drugs did not come to perform miracles,” he said.

The debate becomes even more complex with adoption of new pharmacologic prevention strategies. Postexposure prophylaxis with doxycycline — doxycycline postexposure prophylaxis (DoxiPEP) — has been shown to reduce the incidence of syphilis and chlamydia, but it has limited effectiveness against gonorrhea because of N gonorrhoeae’s preexisting resistance to tetracyclines.

According to Longhi, that nuance needs to be made explicit. “Today we talk about combined prevention, which includes condom use, preexposure prophylaxis for HIV, vaccination against HPV and hepatitis B and, more recently, doxycycline as PEP for bacterial STIs. In the case of gonorrhea, that protection is lower, about 50%-60%, which reinforces the need for caution and monitoring,” she said.

The introduction of new oral antibiotics, therefore, occurs in an ecosystem already stressed by multiple interventions.

Innovation, Behavior, and Stewardship

The arrival of new therapeutic options puts clinicians back at the center of the strategy to contain antimicrobial resistance. Unlike the hospital setting, where prescribing last-resort antibiotics typically goes through infection control committees, gonorrhea is mostly treated in primary care, creating a particularly sensitive area for antimicrobial stewardship — the set of strategies aimed at rational, evidence-based antibiotic use. Often clinical practice involves rapid, empirical decisions without laboratory support or institutional checks.

“If these antibiotics are used outside their indications, in the short-to-medium-term, we will see resistance to them too,” warned Fernandes. For him, the path is to treat these drugs as reserve resources, linking access to strict guidelines, continuing medical education and active epidemiologic surveillance.

Cunha reinforces the point by noting that the problem is not limited to self-medication. “Today it is much harder to buy antibiotics without a prescription than in the past. The bigger challenge is educational: prescribing only when indicated, using the narrowest effective spectrum, remains the golden rule,” he said.

In this context, Longhi’s view helps broaden the frame. For her, the antibiotic is only the final step in a much broader response. “New oral antimicrobials expand the therapeutic arsenal, but they do not replace comprehensive care. Without coordination between appropriate treatment, partner management and a system capable of welcoming and following these patients, the antibiotic by itself has limited impact,” she said.

Daniela Barros is a journalist from Brazil, specializing in social journalism at the Pontifical Catholic University of São Paulo in São Paulo, and a master’s student in the Department of Social Medicine at the Ribeirão Preto Medical School in Ribeirão Preto, Brazil. She has been involved in medicine for 23 years and has contributed to several specialized publications.

This story was translated from the Medscape’s Portuguese edition.