Randomized trial shows zoliflodacin cures over 90% of uncomplicated gonorrhea infections — Evidence Review
Published in The Lancet
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Table of Contents
A new international trial suggests that a single-dose oral antibiotic, zoliflodacin, is as effective as current standard injections for treating gonorrhea, offering a potential alternative as resistance to existing therapies increases. Related research generally supports zoliflodacin’s efficacy for genital and rectal infections, though some concerns remain around its effectiveness in pharyngeal cases and resistance development (1,2,3,4).
- The new study’s findings align with previous phase 2 trials, which found high cure rates for urogenital and rectal gonorrhea using zoliflodacin, but noted less consistent results at the pharyngeal site (1).
- Preclinical and in vitro analyses have shown that zoliflodacin remains effective against multidrug-resistant Neisseria gonorrhoeae strains, with low rates of resistance selection at recommended doses, supporting its role as a valuable new oral agent (2,3).
- Meta-analyses and systematic reviews confirm that while ceftriaxone-based regimens remain highly effective, new oral antibiotics like zoliflodacin are promising for future treatment options, though more robust data—especially for extragenital infections—are needed (5).
Study Overview and Key Findings
The rise of antibiotic resistance in Neisseria gonorrhoeae has made the search for new, effective treatments urgent. Traditional regimens, such as injectable ceftriaxone combined with oral azithromycin, are becoming less reliable due to increasing resistance, especially in certain regions. The recently published phase 3 trial provides timely evidence for an alternative: a single-dose oral therapy that could streamline treatment delivery and improve accessibility, particularly in low-resource or community-based settings. Notably, the study also monitored the emergence of resistance during the trial period—an important consideration given the global trends in antimicrobial resistance.
| Property | Value |
|---|---|
| Study Year | 2025 |
| Journal Name | The Lancet |
| Authors | Alison Luckey, Manica Balasegaram, Lindley A Barbee, Teresa A Batteiger, Helen Broadhurst, Stephanie E Cohen, Sinead Delany-Moretlwe, Henry J C de Vries, Jodie A Dionne, Katherine Gill, Chris Kenyon, Rossaphorn Kittiyaowamarn, Drew Lewis, John P Mueller, Vimla Naicker, Seamus O’Brien, John P O’Donnell, Nittaya Phanuphak, Elizabeth Spooner, Subasree Srinivasan, Stephanie N Taylor, Magnus Unemo, Zinhle Zwane, Edward W Hook, Keisha De Gouveia, Thembisa Makowa Mkhize, Samantha Siva, Lindy Gumede, Ranmini Kularatne, Venessa Maseko, Shabashini Reddy, Patience Kwedza, Ravesh Singh, Lisha Sookan, Danielle Travill, Kittipoom Chinhiran, Sarinthorn Mongkolrat, Chatnapa Duangdee, Jantawan Satayarak, Siriporn Nonenoy, Supanat Thitipatarakorn, Joseph V Woodring, Wannee Chonwattana, Supawadee Na-pompet, Waropart Pongchaisit, Suwan Sriviriyakul, Tanyaporn Wansom, Aaron Ermel, Lora Fortenberry, Catherine L Cammarata, Rebecca Lillis, Alison Cohee, Ejovwoke Dosunmu, Godfred Masinde, Paula Dixon, Julia C Dombrowski, Olusegun O Soge, Elske Hoornenborg, Alje van Dam, Vicky Cuylaerts, Irith Debaetselier, Angèle Gayet-Ageron, Sarah M. McLeod, Alita Miller, Sarah Cohen, Hilary Johnstone, Lebogang Tshehla, Emilie Alirol, Carmen Au, Cherine Bajjali, Esther Bettiol, Pierre Daram, Amalia Droal, Varalakshmi Elango, Christophe Escot, Markus Heep, Karin Hergarden, Daniel Iniguez, Gabrielle Kornmann, Jean-François Louvion, Manon Manuelli, Jessica Renaux, Mary-Ann Richardson |
| Population | People with uncomplicated urogenital gonorrhea |
| Sample Size | n=900 |
| Methods | Randomized Controlled Trial (RCT) |
| Outcome | Cure rates of gonorrhea infections |
| Results | Zoliflodacin cured over 90% of infections at genital sites. |
Literature Review: Related Studies
To contextualize the new findings, we searched the Consensus paper database, which contains over 200 million research articles. The following queries were used to identify relevant studies:
- zoliflodacin gonorrhea treatment efficacy
- oral antibiotics gonorrhea infection cure
- genital infections zoliflodacin clinical trials
Summary Table of Key Topics and Findings
| Topic | Key Findings |
|---|---|
| How effective is zoliflodacin for treating gonorrhea, especially compared to standard therapies? | - Zoliflodacin shows high cure rates for urogenital and rectal gonorrhea, similar to ceftriaxone, but is less effective for pharyngeal infections (1,5). - Standard treatments with ceftriaxone remain highly effective, but resistance is rising, highlighting the need for alternatives (5,9). |
| What is the risk of resistance development with zoliflodacin? | - In vitro and clinical studies indicate low rates of resistance emergence with recommended single-dose zoliflodacin regimens, but certain rare strains may require higher dosing (2,3,4). - Surveillance and tailored diagnostics may be needed to detect predisposed strains and guide effective use (4). |
| How does zoliflodacin compare to other emerging oral antibiotics? | - Gepotidacin, another oral antibiotic, has shown similar high efficacy rates in early-phase trials (7). - Solithromycin was less effective and associated with more adverse events than the current standard, suggesting zoliflodacin may be a more promising alternative (8). |
| What is the safety and tolerability of zoliflodacin and similar regimens? | - Zoliflodacin is generally well tolerated, with most adverse events being mild and gastrointestinal in nature (1). - Some alternative regimens, such as solithromycin or gentamicin/azithromycin, are associated with more frequent or severe gastrointestinal side effects, limiting their routine use (6,8). |
How effective is zoliflodacin for treating gonorrhea, especially compared to standard therapies?
The new phase 3 trial’s results are consistent with earlier studies demonstrating that zoliflodacin is highly effective for urogenital and rectal gonorrhea, achieving cure rates comparable to ceftriaxone-based regimens. However, prior evidence suggests efficacy at pharyngeal sites is less robust, and larger studies are still needed to confirm performance in these harder-to-treat locations (1,5).
- Previous phase 2 trials found 96% cure rates for urogenital and rectal infections with zoliflodacin, but only 50–82% for pharyngeal infections (1).
- The current standard, ceftriaxone (with or without azithromycin), remains highly effective but is threatened by emerging resistance (5,9).
- Systematic reviews highlight the urgent need for new oral agents as resistance trends threaten current regimens (5).
- The new study confirms zoliflodacin’s non-inferiority to standard therapy for genital sites, supporting its role as a potential alternative.
What is the risk of resistance development with zoliflodacin?
Findings from both clinical and laboratory studies indicate that zoliflodacin, when used at recommended doses, has a low risk of inducing resistance in Neisseria gonorrhoeae. However, rare strains with specific genetic substitutions may be predisposed to resistance, necessitating vigilance and possibly higher dosing or supplemental diagnostics (2,3,4).
- In vitro models show that single doses of ≥2–3 g are needed to suppress resistance adequately (3,4).
- Most clinical isolates remain susceptible to zoliflodacin, including multidrug-resistant strains (2).
- The phase 3 trial reported no emergence of resistance during the study period, but ongoing surveillance is recommended (2,4).
- Diagnostics targeting specific resistance markers may be required for optimal stewardship as zoliflodacin use increases (4).
How does zoliflodacin compare to other emerging oral antibiotics?
When compared to other novel oral agents, zoliflodacin demonstrates similar or superior efficacy and safety profiles in clinical trials. Gepotidacin has shown promising results, while other agents such as solithromycin have been less successful due to lower efficacy and higher rates of adverse events (7,8).
- Gepotidacin achieved ≥95% cure rates for uncomplicated urogenital gonorrhea in phase 2 studies (7).
- Solithromycin did not meet non-inferiority criteria compared to ceftriaxone plus azithromycin and was associated with more gastrointestinal side effects (8).
- These findings position zoliflodacin as one of the most promising oral candidates for future gonorrhea therapy.
What is the safety and tolerability of zoliflodacin and similar regimens?
Safety data from phase 2 and phase 3 trials indicate that zoliflodacin is generally well tolerated. Most side effects are mild and gastrointestinal, with few severe adverse events reported. In contrast, some alternative regimens, such as gentamicin or solithromycin combinations, are associated with higher rates of gastrointestinal or hepatic side effects (1,6,8).
- Zoliflodacin’s side effect profile is similar to or better than existing therapies, with most adverse events being mild (1).
- Non-cephalosporin regimens like gentamicin/azithromycin are effective but can cause significant gastrointestinal discomfort (6).
- Solithromycin was associated with a higher incidence of diarrhea and liver enzyme elevations (8).
- The tolerability of new oral agents will be crucial for their uptake in diverse patient populations.
Future Research Questions
Despite promising results, several areas require further investigation to ensure zoliflodacin and similar agents can be used safely and effectively across different populations and infection sites. Long-term surveillance, resistance development, extragenital efficacy, and real-world deployment challenges warrant ongoing research.
| Research Question | Relevance |
|---|---|
| How effective is zoliflodacin for pharyngeal and extragenital gonorrhea infections? | Prior studies highlight reduced efficacy at pharyngeal sites, a critical gap for comprehensive gonorrhea control (1,5). Expanded trials are needed to determine optimal regimens for these harder-to-treat locations. |
| What is the potential for resistance development to zoliflodacin in widespread clinical use? | In vitro and early clinical data suggest low resistance risk at recommended doses, but rare strains may be predisposed to resistance (2,3,4). Ongoing surveillance is essential as use expands to detect and mitigate resistance emergence. |
| How does zoliflodacin perform in populations with multidrug-resistant Neisseria gonorrhoeae? | Zoliflodacin is active against many resistant strains in vitro, but real-world effectiveness and resistance patterns in diverse global populations remain to be fully characterized (2,3). |
| What are the optimal dosing strategies for zoliflodacin to maximize efficacy and minimize resistance? | Laboratory models suggest single doses >2–3 g are needed to suppress resistance, especially for certain rare strains (3,4). Clinical trials to refine dosing for various infection sites and patient populations are needed. |
| How acceptable and feasible is single-dose oral zoliflodacin treatment in community and resource-limited settings? | The simplicity of oral therapy could improve access and adherence, but real-world studies are needed to assess feasibility, acceptability, and implementation challenges across different health systems (2,5). |