Gepotidacin in cystitis: new oral class, dose and QT

A 29-year-old woman comes to the consultation with burning on urination, a constant urge to urinate and lower abdominal pain for two days. She has no fever, no back pain and no discharge, and the pregnancy test is negative. This is the third episode in the year. She is allergic to sulfa, and the last urine culture, from four months ago, grew Escherichia coli resistant to fluoroquinolone. The urine dipstick shows positive nitrite and leukocytes. She asks whether there is a new antibiotic, which she read had been approved in the United States. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. Gepotidacin (brand name Blujepa) is an oral antibiotic from a new chemical class, the triazaacenaphthylenes, approved by the FDA for uncomplicated cystitis in women and, later, for uncomplicated urogenital gonorrhea in selected situations. The text explains the indication, the dose, the interactions, the risk of prolonging the QT interval and what the studies showed. It does not replace the urine culture, the local guideline or your institution's protocol. If you play the case of the day on NEXO, you will recognize the challenge: deciding with clues that arrive in sequence.

Key points

• The FDA approved Blujepa on March 25, 2025 for uncomplicated cystitis in women aged 12 or older weighing at least 40 kg.
• On December 11, 2025, the FDA added uncomplicated urogenital gonorrhea, for people who have few or no alternatives.
• For cystitis, the dose is 1500 mg, two 750 mg tablets, twice a day, after a meal, for 5 days.
• Gepotidacin prolongs the QT interval in a dose-dependent way; the label asks to avoid use with strong CYP3A4 inhibitors, severe renal impairment and severe hepatic impairment.
• In the two phase 3 studies, it was non-inferior to nitrofurantoin, with diarrhea in 16 percent of patients.
• It also inhibits acetylcholinesterase, which matters in anesthesia with succinylcholine and in people who use anticholinergics.

Why this is a reasoning scenario

Cystitis is one of the most common infections in clinical practice, and almost every health professional will treat it many times. Even so, choosing the antibiotic has become harder. E. coli causes about 75 percent of infections, and resistance to the usual oral options is rising (Scangarella-Oman and colleagues, 2025a). When a drug from a new class appears, practical questions come up: who it is for, what dose to use, which drugs it interacts with and when it is not the best choice.

The scenario is good for training because it brings together clinical history, microbiology and pharmacology. You need to confirm that the infection really is uncomplicated, read the old urine culture, remember the allergies and check the medication list because of QT and CYP3A4. The post on signs, symptoms and history helps organize the history taking, and the post on differential diagnosis reminds you of the causes that mimic cystitis.

What the scene teaches

The scene trains six habits. The first is separating uncomplicated cystitis from pyelonephritis and from complicated infection. The second is ordering a urine culture when the infection is recurrent or there was resistance before. The third is knowing the approved indication and the age and weight limits. The fourth is reviewing drugs that prolong the QT or inhibit CYP3A4. The fifth is advising the patient about diarrhea and taking the drug with food. The sixth is knowing when to reassess.

What is not at stake

The text does not discuss prevention of recurrent cystitis or compare all oral options. The final choice depends on the urine culture, the availability of the drug, the cost and local resistance. The post on clinical decision making helps you think about when to order a culture before treating.

Uncomplicated cystitis and resistance

It is estimated that 50 to 60 percent of adult women will have at least one urinary tract infection in their lifetime (Scangarella-Oman and colleagues, 2025a). In the EAGLE studies, uncomplicated cystitis was defined by the presence of at least two symptoms, such as dysuria, frequency, urgency or lower abdominal pain, with nitrite or pyuria in the urine (US label of Blujepa, 12/2025). Patients with signs of complicated or upper infection, such as pyelonephritis or urosepsis, were excluded (US label of Blujepa, 12/2025).

The burden of resistance

In the phase 3 studies, among the E. coli isolates from the microbiological population, 28 percent were resistant to fluoroquinolones, 28 percent were resistant to sulfamethoxazole-trimethoprim and 15 percent produced extended-spectrum beta-lactamase (ESBL) (Scangarella-Oman and colleagues, 2025a). A quarter of the Klebsiella pneumoniae isolates were resistant to nitrofurantoin (Scangarella-Oman and colleagues, 2025a). Data from the United States cited in one of these studies show that 22 percent of patients with cystitis received an antibiotic to which the germ was resistant (Ramírez and colleagues, 2026).

Clones and mechanisms

The ST131 clone of E. coli, multidrug-resistant and spread worldwide, is present in up to 30 percent of clinical isolates across various infections (Scangarella-Oman and colleagues, 2025b). In the EAGLE studies, among the isolates tested by molecular typing, the most frequent clones were ST131, ST1193 and O25b:H4 (Scangarella-Oman and colleagues, 2025b). ESBLs are usually carried on plasmids that carry other resistance genes, which limits several classes of antibiotics at the same time (Scangarella-Oman and colleagues, 2025b).

Applying it to the patient

The patient in the scene has recurrent cystitis, a sulfa allergy and a previous isolate resistant to fluoroquinolone. This rules out sulfamethoxazole-trimethoprim and makes fluoroquinolone a poor choice. She has no fever or back pain, which points to a lower infection. Before considering the new drug, it is worth collecting a urine culture, since the infection is recurrent and there has been resistance. The post about diagnostic uncertainty helps decide when to treat before the result.

Gepotidacin: a new class against old targets

Gepotidacin inhibits two bacterial enzymes that control DNA winding, DNA gyrase and topoisomerase IV (US label of Blujepa, 12/2025). Fluoroquinolones act on the same enzymes, but in a different way. Two fluoroquinolone molecules bind near the two DNA cleavage sites, while gepotidacin binds to the enzymes as a single molecule (Osheroff, 2026). Unlike fluoroquinolones, which cause breaks in both DNA strands, gepotidacin causes mostly single-strand breaks (Osheroff, 2026).

Why quinolone resistance does not carry over directly

Gepotidacin retains activity against fluoroquinolone resistance caused by target mutations (Osheroff, 2026). In addition, in most uropathogens it inhibits both enzymes in a balanced way (Scangarella-Oman and colleagues, 2025a). Therefore, a mutation in a single enzyme does not greatly reduce susceptibility to gepotidacin (Scangarella-Oman and colleagues, 2025a). This feature explains the interest in it for germs that no longer respond to quinolones.

Activity in the laboratory

In a study with 3250 enterobacteria isolates from urinary tract infection, the minimum inhibitory concentration that inhibits 90 percent of isolates (MIC90) was 4 µg/mL for E. coli (Hackel and colleagues, 2025). For Klebsiella pneumoniae and Enterobacter cloacae, the MIC90 was 32 µg/mL (Hackel and colleagues, 2025). Among the E. coli, 99.8 percent had a MIC of up to 16 µg/mL, versus 88.6 percent of the K. pneumoniae (Hackel and colleagues, 2025). In other words, activity is better against E. coli than against other enterobacteria.

The germs of the indication

The American label lists five germs for the cystitis indication: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus and Enterococcus faecalis (American Blujepa label, 12/2025). Germs outside this list are not part of the approved indication, even if the laboratory shows activity.

Regulatory situation: FDA and other agencies

United States. The FDA approved Blujepa on March 25, 2025, under NDA 218230, as a new molecular entity, with priority review (Drugs@FDA, NDA 218230). The original indication is for adult women and girls aged 12 or older, weighing at least 40 kg, with uncomplicated cystitis caused by the susceptible germs on the list (American Blujepa label, 12/2025). On December 11, 2025, a supplement added the indication of uncomplicated urogenital gonorrhea (Drugs@FDA, NDA 218230). This second indication applies to patients aged 12 or older, weighing at least 45 kg, who have few or no treatment alternatives, and the label says it is based on limited safety data (American Blujepa label, 12/2025).

Other countries. This text describes only the situation in the United States, checked against primary sources on October 24, 2026. Registration, indication and availability in other countries depend on the local agency, and it is worth checking before use.

Responsible use

The label asks that the drug be used only when the bacterial infection is proven or strongly suspected, to reduce the emergence of resistance (American Blujepa label, 12/2025). When culture and susceptibility testing are available, they should guide the choice; without them, local epidemiology helps with the empirical choice (American Blujepa label, 12/2025). A new class is a valuable resource, and using it without need speeds up the loss of that resource.

Contraindication and warnings

The American label lists one contraindication and several warnings (American Blujepa label, 12/2025):

• Contraindication: history of severe hypersensitivity to Blujepa.
• QT prolongation, dependent on dose and concentration.
• Acetylcholinesterase inhibition, with effects such as dysarthria, syncope, cramps, excessive salivation and sweating.
• Hypersensitivity reactions, including anaphylaxis.
• Clostridioides difficile infection, which should be considered in any diarrhea after antibiotics.

Dose, interactions and QT

In uncomplicated cystitis, the recommended dose is 1500 mg, or two 750 mg tablets, taken orally, twice a day, about 12 hours apart, for 5 days (American Blujepa label, 12/2025). The tablets should be taken after a meal, to reduce gastrointestinal intolerance (American Blujepa label, 12/2025). If the patient forgets a dose, she should take it as soon as possible, without doubling the dose to make up for it (American Blujepa label, 12/2025). For gonorrhea, the regimen is different: 3000 mg followed by another 3000 mg dose about 12 hours later (American Blujepa label, 12/2025).

Why this dose

The dose of 1500 mg twice a day for 5 days was chosen from pharmacokinetic and pharmacodynamic models, animal studies and a phase 2a study in women with cystitis (Scangarella-Oman and colleagues, 2022). In animal and laboratory models, the index that best predicts efficacy is the ratio between the area under the free drug curve over 24 hours and the MIC (American Blujepa label, 12/2025). In healthy volunteers, single doses of 100 to 3000 mg were generally well tolerated, and food delayed the peak without changing total exposure (Tiffany and colleagues, 2022).

Renal and hepatic function

The table summarizes what the label says about renal function, hepatic function and interactions in cystitis.

Situation	Guidance in cystitis	Source
eGFR of 60 to 89 or 30 to 59 mL/min	No dose adjustment	(American Blujepa label, 12/2025)
eGFR below 30 mL/min, including on dialysis	Avoid use	(American Blujepa label, 12/2025)
Mild or moderate hepatic impairment (Child-Pugh A or B)	No dose adjustment	(American Blujepa label, 12/2025)
Severe hepatic impairment (Child-Pugh C)	Avoid use	(American Blujepa label, 12/2025)
Moderate CYP3A4 inhibitor	No dose adjustment	(American Blujepa label, 12/2025)
Strong CYP3A4 inhibitor	Avoid use	(American Blujepa label, 12/2025)
Strong CYP3A4 inducer	Avoid use	(US label of Blujepa, 12/2025)

The reason to avoid use in severe renal impairment appears in the pharmacokinetic studies. Compared with normal renal function, the area under the curve of gepotidacin increased 1.5-fold in moderate renal impairment and 1.9-fold in severe or end-stage renal impairment without hemodialysis (Hossain et al., 2020). In people with end-stage renal disease, the increase was 2.4-fold before hemodialysis and 4.1-fold after (Hossain et al., 2020). The label also says that intermittent hemodialysis is unlikely to remove much of the drug (US label of Blujepa, 12/2025).

The QT interval

In a study of healthy volunteers, intravenous gepotidacin prolonged the Fridericia-corrected QTc by a mean of 12 ms with 1000 mg and 22 ms with 1800 mg, doses and route that are not the approved ones (US label of Blujepa, 12/2025). The peak concentration with 1000 mg intravenously is about 1.2 times the steady-state peak with 1500 mg orally twice a day (US label of Blujepa, 12/2025). For this reason, the label calls for avoiding the drug in people with a history of long QT, relevant heart disease, use of antiarrhythmics or of other drugs that prolong the QT (US label of Blujepa, 12/2025). If use cannot be avoided in these risk groups, the label advises correcting electrolytes and doing an electrocardiogram before and during treatment, when indicated (US label of Blujepa, 12/2025).

Other interactions

Gepotidacin may increase exposure to digoxin, and the label suggests considering measuring the serum level (US label of Blujepa, 12/2025). It should be avoided with drugs heavily metabolized by CYP3A4 in which small changes in concentration cause serious effects (US label of Blujepa, 12/2025). Because it inhibits acetylcholinesterase, it may prolong the effect of succinylcholine in anesthesia and reduce the effect of systemic anticholinergics and of nondepolarizing neuromuscular blockers (US label of Blujepa, 12/2025). The post about interprofessional clinical reasoning shows why pharmacy helps review this list.

Applying it to the patient

The patient in the scene is 29 years old and weighs more than 40 kg, and the infection appears to be lower and uncomplicated. Before prescribing, it is necessary to ask about drugs that prolong the QT, about azole antifungals and other strong CYP3A4 inhibitors, about fainting and about heart disease. If she uses any of these drugs, gepotidacin is no longer a good choice. It is also worth warning that diarrhea is common, that the tablets should be taken after eating and that she should return if fever, low back pain or intense diarrhea appears. The post about diagnostic pause reminds you to check the medication list before closing the prescription.

Evidence: EAGLE-2, EAGLE-3 and beyond

The approval relied on two phase 3 studies, called EAGLE-2 and EAGLE-3, with 3136 randomized women (US label of Blujepa, 12/2025). Both were multicenter, double-blind and noninferiority studies, and compared gepotidacin 1500 mg twice a day for 5 days with nitrofurantoin 100 mg twice a day for 5 days (US label of Blujepa, 12/2025). The primary endpoint combined clinical cure and microbiological response at the test-of-cure visit, between days 10 and 13 (US label of Blujepa, 12/2025).

The main results

In the first study, the combined response was 51.8 percent with gepotidacin and 47.0 percent with nitrofurantoin (US label of Blujepa, 12/2025). In the second, it was 58.9 versus 44.0 percent (US label of Blujepa, 12/2025). Gepotidacin was noninferior in both studies (US label of Blujepa, 12/2025). Clinical cure alone was similar between the groups, and the difference appeared mainly in the microbiological response (US label of Blujepa, 12/2025). About 40 percent of the patients in each study had a history of recurrent infection (US label of Blujepa, 12/2025).

Response by pathogen

In the two studies combined, the combined response against E. coli was 55.1 percent with gepotidacin and 45.0 percent with nitrofurantoin (US label of Blujepa, 12/2025). For the other germs, the numbers were small (US label of Blujepa, 12/2025). With K. pneumoniae, the rates were similar in both groups, which the authors found unexpected (Scangarella-Oman and colleagues, 2025a). In analyses of isolates with characterized resistance mechanisms, gepotidacin maintained microbiological success in most categories, especially with multidrug-resistant E. coli (Scangarella-Oman and colleagues, 2025a).

Do symptoms improve quickly?

A pooled analysis of the two studies looked at the visit during treatment, between days 2 and 4 (Sheets and colleagues, 2026). More than 80 percent of patients in both groups had an early clinical response at that visit (Sheets and colleagues, 2026). Among those who had the visit on day 3, the early response was 89.0 percent with gepotidacin and 90.6 percent with nitrofurantoin (Sheets and colleagues, 2026). In an open-label phase 3b study without a comparison group, 54.4 percent of participants reported symptom improvement within 24 hours and 79.8 percent within 48 hours (Ramírez and colleagues, 2026). Without a control group, that study does not allow comparison with other antibiotics.

Adverse effects

In the two studies, serious adverse effects occurred in 1 of 1570 patients on gepotidacin, one episode of dysarthria, and in 1 of 1558 on nitrofurantoin (US label of Blujepa, 12/2025). Discontinuation due to an adverse effect occurred in 5 percent with gepotidacin and in 2 percent with nitrofurantoin (US label of Blujepa, 12/2025). The list below compares the most common effects.

• Diarrhea: 16 percent with gepotidacin and 3 percent with nitrofurantoin.
• Nausea: 9 and 4 percent.
• Abdominal pain: 4 and 2 percent.
• Flatulence: 3 percent and less than 1 percent.
• Headache: 2 and 3 percent.

Source of the list: (US label of Blujepa, 12/2025). Diarrhea was mild in 11 percent of patients, moderate in 5 percent and severe in less than 1 percent; it began in the first two days for most and lasted a mean of 4 days (US label of Blujepa, 12/2025).

And resistance during treatment?

In the two studies, 5.6 percent of patients treated with gepotidacin had isolates after the start of treatment with an apparent fourfold or greater increase in MIC (Weikel and colleagues, 2026). Most of these increases were not confirmed on repeat testing or involved germs genetically different from the initial one, which suggests colonization or a new infection (Weikel and colleagues, 2026). The authors conservatively considered one possible example of acquired resistance, with a mutation in the ParC D79G target (Weikel and colleagues, 2026). Resistance surveillance remains important after approval.

Pregnancy, lactation and older women

There are no data on use in pregnant women, and animal studies showed lower fetal weight and more fetal losses at exposures below the maximum human dose (US label of Blujepa, 12/2025). The patient in the scene had a negative pregnancy test, which matters for the choice. There are no data on passage into human milk (US label of Blujepa, 12/2025). In the cystitis studies, 22 percent of patients were 65 or older, with no overall differences in safety or efficacy, but the label notes that renal elimination requires attention in older women (US label of Blujepa, 12/2025).

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. Recurrent cystitis is a good exercise because an allergy, an old urine culture or a long-term medication changes management. The post on case-based learning explains why this format fixes knowledge, and the post on simulated consultations shows how to train the history taking.

Three exercises with cases

Change the kidney. Say what to do if the patient had an eGFR of 25 mL/min.

Change the medication list. Say what to do if she used an azole antifungal that is a strong CYP3A4 inhibitor.

Change the presentation. Say why gepotidacin is not suitable if she had fever and low back pain.

The limits of use of the game are described on the Economy page of NEXO. If you research the teaching of clinical reasoning, the page for Researcher explains how to get in touch. Professionals who write or review cases find information on Curator and on Creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Is gepotidacin a fluoroquinolone?

No. It acts on the same enzymes, but it belongs to another chemical class and binds in another way (Osheroff, 2026).

What is the dose in cystitis?

1500 mg twice a day, after a meal, for 5 days (US Blujepa label, 12/2025).

Is it used for pyelonephritis?

No. The studies excluded upper or complicated infection, and the indication is for uncomplicated cystitis (US Blujepa label, 12/2025).

Can men use it for cystitis?

The cystitis indication approved by the FDA is for female patients (US Blujepa label, 12/2025).

What is the most common adverse effect?

Diarrhea, in 16 percent of the patients in the cystitis studies (US Blujepa label, 12/2025).

Final checklist

• I confirmed uncomplicated cystitis, with no fever, low back pain or signs of upper infection.
• I collected a urine culture in a recurrent infection or one with previous resistance.
• I checked age, sex and weight of at least 40 kg.
• I reviewed medicines that prolong the QT interval and strong inhibitors or inducers of CYP3A4.
• I asked about fainting, heart disease and long QT.
• I checked the eGFR and liver function.
• I advised taking it after the meal and warned about diarrhea.
• I agreed on when to return if the symptoms get worse.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. GlaxoSmithKline. BLUJEPA (gepotidacin) tablets, for oral use. Prescribing Information. Revised 12/2025. Accessed 10/24/2026. Official source.
2. Hackel MA, Karlowsky JA, Sahm DF, West JM, Scangarella-Oman NE. In vitro activity of gepotidacin against urinary tract infection isolates of Enterobacterales, Enterococcus faecalis, and Staphylococcus saprophyticus. Antimicrob Agents Chemother. 2025. PMID 40372095.
3. Hossain M, Tiffany C, Raychaudhuri A, et al. Pharmacokinetics of Gepotidacin in Renal Impairment. Clin Pharmacol Drug Dev. 2020. PMID 32429000.
4. Osheroff N. Gyrase and Topoisomerase IV as Antibacterial Targets for Gepotidacin and Zoliflodacin: Teaching Old Enzymes New Tricks. Int J Mol Sci. 2026. PMID 41516368.
5. Ramírez M, Gupta K, Díaz-Regañón J, et al. Gepotidacin and Early Symptom Improvement in Uncomplicated Urinary Tract Infection: A Nonrandomized Clinical Trial. JAMA Netw Open. 2026. PMID 42809288.
6. Scangarella-Oman NE, Hossain M, Hoover JL, et al. Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections. Antimicrob Agents Chemother. 2022. PMID 34978887.
7. Scangarella-Oman NE, Butler DL, Breton J, et al. Efficacy and in vitro activity of gepotidacin against bacterial uropathogens, including drug-resistant phenotypes, in females with uncomplicated urinary tract infections: results from two global, pivotal, phase 3 trials (EAGLE-2 and EAGLE-3). Antimicrob Agents Chemother. 2025. PMID 40924001.
8. Scangarella-Oman NE, Butler DL, Breton J, et al. Efficacy and in vitro activity of gepotidacin against bacterial uropathogens, including subsets with molecularly characterized resistance mechanisms and genotypes/epidemiological clones, in females with uncomplicated urinary tract infections: results from two global, pivotal, phase 3 trials (EAGLE-2 and EAGLE-3). Antimicrob Agents Chemother. 2025. PMID 40924012.
9. Sheets AJ, Dennison J, Pogue JM, et al. Early Symptom Response in Patients With Uncomplicated Urinary Tract Infection Treated With Gepotidacin or Nitrofurantoin: Pooled Analysis From Two Pivotal Phase 3 Studies. Clin Infect Dis. 2026. PMID 41495938.
10. Tiffany C, Dumont EF, Hossain M, Srinivasan M, Swift B. Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects. Clin Transl Sci. 2022. PMID 35769034.
11. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. NDA 218230, Blujepa. Accessed 10/24/2026. Official source.
12. Weikel CA, Breton J, Butler D, et al. Characterization of isolates from two phase 3 uncomplicated urinary tract infection trials (EAGLE-2 and EAGLE-3) that show an apparent ≥4-fold increase in gepotidacin MIC between baseline and post-baseline visits. JAC Antimicrob Resist. 2026. PMID 42682990.