Gonorrhea,a common sexually transmitted infection,is increasingly threatened by antibiotic resistance,prompting a critical search for new treatments. Recent data from the Robert Koch Institute indicates rising case numbers in Germany and internationally,even as diagnostic methods improve [[1]]. Now,the U.S. Food and Drug Governance has approved two novel oral antibiotics-zoliflodacin and gepotidacin-offering a potential breakthrough in combating this evolving public health challenge.
Growing Antibiotic Resistance Complicates Gonorrhea Treatment: Could Two New Drugs Offer a Breakthrough?
Gonorrhea, caused by the bacterium Neisseria gonorrhoeae, remains one of the most common bacterial sexually transmitted infections (STIs). Both in Germany and internationally, rising case numbers have been observed in recent years, as shown by data from the Robert Koch Institute here. Men who have sex with men (MSM), young adults, and individuals with multiple sexual partners are particularly affected. This increase is due to both a real intensification of transmission and improved diagnostics, including wider use of sensitive nucleic acid amplification tests (NAAT) and targeted screenings that now more frequently detect asymptomatic – especially extragenital – infections. Rising STI rates highlight the ongoing need for prevention, testing, and effective treatment options.
The Challenge of Resistance
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A growing concern is the increasing difficulty in treating gonorrhea. Neisseria gonorrhoeae exhibits significant and dynamic antibiotic resistance worldwide, leading the World Health Organization to classify the pathogen as a high-priority germ in 2017. Resistance has been documented against all historically used classes of antibiotics according to the RKI. Surveillance in Germany also shows a growing resistance problem: while ceftriaxone currently remains highly effective, increasing minimum inhibitory concentrations are being observed, particularly in isolates from the pharynx. High rates of resistance persist against fluoroquinolones and azithromycin, meaning these drugs are no longer recommended for initial treatment. Isolated treatment failures under standard therapy demonstrate that the therapeutic options are increasingly shrinking.
Diagnosis and Therapy According to Current Guidelines
The current German-language S2k guideline recommends low-threshold testing for individuals with symptoms and those in at-risk groups, particularly MSM, people with multiple sexual partners, and those with a known STI exposure. Testing should be performed on urogenital, rectal, and pharyngeal samples, depending on sexual practices. NAAT diagnostics are the primary method used. If treatment failure is suspected, symptoms persist, or as part of resistance monitoring, a culture with resistance testing is essential.
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Ceftriaxone is considered the first-line therapy for gonorrhea. The recommended dosage is a single injection of 1.5 g, administered intramuscularly or intravenously. This monotherapy is used for patients with confirmed infection as well as those with a clinical suspicion, provided reliable treatment adherence can be ensured, particularly with regard to follow-up if symptoms persist. If no pathogen is detected and adherence is uncertain, the guideline recommends combination therapy with azithromycin in a single oral dose of 1.5 g to treat any potential co-infection. Testing for Chlamydia trachomatis should always be performed concurrently to allow for targeted additional therapy if co-infections are present. The guideline also emphasizes the importance of partner treatment, a test-of-cure control, and involving patients in structured STI care and counseling services to prevent reinfection and further transmission.
New Antibiotics as a Response to Increasing Resistance
Given the globally increasing development of resistance, there is an urgent need for new anti-gonorrheal agents. In December 2025, the U.S. Food and Drug Administration (FDA) approved two new oral drugs for the treatment of gonorrhea for the first time in decades according to an FDA announcement. These approvals represent a significant step forward in combating this growing public health threat.
Zoliflodacin is an orally available antibiotic from the first drug class of spiroketal topoisomerase inhibitors, selectively inhibiting bacterial DNA gyrase through a previously unused binding mechanism. A Phase III study published in The Lancet showed that a single oral dose achieved high microbiological cure rates in uncomplicated urogenital gonorrhea and was not inferior to the combination therapy of ceftriaxone plus azithromycin. Zoliflodacin also demonstrated overall good tolerability. The most frequently reported treatment-related side effects in the Zoliflodacin group (619 patients) were headache (10%), neutropenia (7%), and leukopenia (4%).
Gepotidacin is a novel triazaacenaphthylene antibiotic candidate that also works on bacterial topoisomerases, but at a different site than classic fluoroquinolones. A randomized Phase III study, also published in The Lancet found, achieved comparable clinical and microbiological success rates with the combination therapy of ceftriaxone plus azithromycin. The oral application (2 doses at intervals of 10 to 12 hours) and the favorable safety profile make the substance particularly attractive for outpatient use.
A Glimmer of Hope
Whether and when Zoliflodacin and Gepotidacin will also be available in Europe depends on the approval procedures of the European Medicines Agency (EMA). Given the increasing resistance and limited therapeutic alternatives, there is a clear need for new anti-gonorrheal substances in Germany as well. Should these drugs be approved, they could represent an important addition to the current standard parenteral therapy, especially in the outpatient setting. Whether and in what role they will be incorporated into future guidelines will largely depend on further data on efficacy in extragenital infections and under real-world conditions. However, against the background of the current resistance situation, they could become a relevant component in the future therapy of gonorrhea.
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