STANDARD TREATMENT — The treatment of choice for uncomplicated urogenital gonorrhea is a single IM injection of ceftriaxone. When treatment with ceftriaxone is not possible, a single oral dose of cefixime can be used. In patients with a severe cephalosporin allergy, administration of single doses of IM gentamicin and oral azithromycin is an alternative.3,4

Neisseria gonorrhoeae has developed resistance to various antibiotics, including penicillins, fluoroquinolones, tetracyclines, and azithromycin. Resistance to ceftriaxone is uncommon in the US, but rates of ceftriaxone-resistant N. gonorrhoeae have been increasing rapidly in Asia.5

Co-infection with Chlamydia trachomatis is common in patients with gonorrhea; if chlamydial infection has not been excluded, a 7-day course of oral doxycycline should be added to ceftriaxone or cefixime.3,4

PHARMACOLOGY — Gepotidacin, a triazaacenaphthylene, and zoliflodacin, a spiropyrimidinetrione, both block bacterial DNA replication by inhibiting two bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Fluoroquinolones also inhibit bacterial type II topoisomerases, but they bind to the enzymes differently6; cross-resistance between fluoroquinolones and the new drugs has not been observed.

Both gepotidacin and zoliflodacin have activity in vitro against ceftriaxone-resistant strains of N. gonorrhoeae.7,8 Neither drug has been shown to have activity in vivo against C. trachomatis.

CLINICAL STUDIES — Gepotidacin – FDA approval of gepotidacin for the new indication was based on the results of an open-label trial (EAGLE-1) in 628 patients ≥12 years old with suspected uncomplicated urogenital gonorrhea. Patients were randomized to receive either two 3-g oral doses of gepotidacin 12 hours apart or combination treatment with a single 500-mg IM dose of ceftriaxone and a single 1-g oral dose of azithromycin (addition of azithromycin to ceftriaxone is no longer recommended for treatment of gonorrhea). Among the 406 patients who were infected with a ceftriaxone-susceptible strain of N. gonorrhoeae, the rate of confirmed urogenital bacterial eradication at the test-of-cure visit (day 4-8), the primary endpoint, was noninferior with gepotidacin compared to ceftriaxone plus azithromycin (92.6% vs 91.4%).9

Other Infection Sites – Few patients in the EAGLE-1 trial had confirmed rectal or pharyngeal gonorrhea; the rates of bacterial eradication of rectal and pharyngeal infection were 100% (26/26) and 78% (14/18), respectively, with gepotidacin, and 80% (12/15) and 94% (16/17) with ceftriaxone plus azithromycin.9

Zoliflodacin – FDA approval of zoliflodacin was based on the results of an open-label trial in 930 patients ≥12 years old with suspected uncomplicated urogenital gonorrhea. Patients were randomized 2:1 to receive either a single 3-g oral dose of zoliflodacin or combination treatment with a single 500-mg IM dose of ceftriaxone and a single 1-g oral dose of azithromycin. Among the 744 patients who were infected with a ceftriaxone- or azithromycin-susceptible strain of N. gonorrhoeae, the rate of confirmed urogenital bacterial eradication at the test-of-cure visit (day 4-8), the primary endpoint, was noninferior with zoliflodacin compared to ceftriaxone plus azithromycin (90.9% vs 96.2%).10

Other Infection Sites – In the open-label trial, rates of bacterial eradication with zoliflodacin were also similar to those with ceftriaxone plus azithromycin among 114 patients with confirmed rectal gonorrhea (87.3% vs 88.6%) and 81 patients with confirmed pharyngeal gonorrhea (79.2% vs 78.6%).10

ADVERSE EFFECTS — Gepotidacin – The most common adverse effects of gepotidacin in the EAGLE-1 trial were diarrhea (49%), nausea (24%), abdominal pain (8%), vomiting (6%), and flatulence (6%). Hypersensitivity reactions, including anaphylaxis, have been reported.

Gepotidacin causes concentration-dependent QT-interval prolongation; use of the drug for treatment of gonorrhea should be avoided in patients with a history of QT-interval prolongation, relevant cardiac disease, severe renal (eGFR <30 mL/min/1.73 m²) or hepatic (Child-Pugh C) impairment, or at least two of the following three risk factors: a body weight of 45-60 kg, moderate renal impairment (eGFR 30-59 mL/min/1.73 m²), and moderate hepatic impairment (Child-Pugh B).

Gepotidacin is a reversible acetylcholinesterase inhibitor; it can cause cholinergic adverse effects such as dysarthria, presyncope, muscle spasms, diarrhea, nausea, vomiting, abdominal pain, hypersalivation, and hyperhidrosis. Increased acetylcholine levels have been associated with serious adverse effects, including atrioventricular block, bradycardia, bronchospasm, seizures, and syncope.

Zoliflodacin – The most common adverse effects of zoliflodacin in the open-label trial were headache (10%), dizziness (3%), nausea (3%), and diarrhea (2%). Hypersensitivity reactions have been reported.

REPRODUCTION AND LACTATION — Gepotidacin – No data are available on the use of gepotidacin in pregnant or breastfeeding women. Administration of the drug to pregnant rodents was associated with fetal mortality and decreased fetal weight. Gepotidacin has been detected in the plasma of mice that were exposed to the drug through nursing.

Zoliflodacin – No data are available on the use of zoliflodacin in pregnant or lactating women, but administration of the drug to pregnant rodents was associated with fetal malformations and embryofetal loss, and administration to male rodents that mated with untreated females resulted in early pregnancy loss. In repeat-dose animal studies, zoliflodacin caused testicular toxicity and decreased spermatogenesis. Use of zoliflodacin during pregnancy should be avoided. Females with reproductive potential should undergo pregnancy testing before receiving the drug, and male patients with female partners who could become pregnant should use contraception for 3 months after treatment.

DRUG INTERACTIONS — Gepotidacin – Gepotidacin is a substrate of CYP3A4; drugs that inhibit CYP3A4 can increase gepotidacin serum concentrations and the risk of adverse effects, and drugs that induce CYP3A4 can decrease gepotidacin serum concentrations and its efficacy. For treatment of gonorrhea, use of gepotidacin with a moderate or strong inhibitor or inducer of CYP3A4 should be avoided.11

Gepotidacin can increase serum concentrations of drugs that are extensively metabolized by CYP3A4; use with sensitive CYP3A4 substrates with narrow therapeutic indices (e.g., quinidine, cyclosporine) should be avoided. It can also increase levels of digoxin.

Use of gepotidacin with other drugs that prolong the QT interval can result in additive effects and should be avoided.12 Inhibition of acetycholinesterase by gepotidacin may exaggerate the effects of succinylcholine-type anesthetics, may result in additive effects if the drug is used in combination with other acetylcholinesterase inhibitors, and may antagonize the effects of systemic anticholinergic drugs.

Zoliflodacin – Zoliflodacin is a substrate of CYP3A4; use with a moderate or strong CYP3A4 inducer can decrease its serum concentrations and efficacy and is contraindicated.11

DOSAGE, ADMINISTRATION, AND COST — Gepotidacin – The recommended dosage of gepotidacin for uncomplicated urogenital gonorrhea is two 3-g doses (four 750-mg tablets each) taken 12 hours apart. Gepotidacin should be taken after a meal to improve GI tolerability. Two 3-g doses of gepotidacin cost $760.13

Zoliflodacin – Zoliflodacin is administered as a single 3-g dose. To administer the dose, the contents of one granule packet should be mixed with water as described in the package insert. The entire dose of zoliflodacin should be consumed within 15 minutes after mixing. The cost of zoliflodacin is not yet available.

CONCLUSION — In randomized trials, the oral antibiotics gepotidacin (Blujepa) and zoliflodacin (Nuzolvence) were noninferior to IM ceftriaxone plus oral azithromycin for treatment of uncomplicated urogenital gonorrhea. Gepotidacin commonly causes GI adverse effects, and it can prolong the QT interval and cause cholinergic adverse effects. Zoliflodacin has the potential to cause reproductive toxicity. Ceftriaxone remains the drug of choice for treatment of urogenital gonorrhea in the US. Gepotidacin and zoliflodacin are active in vitro against ceftriaxone-resistant strains of Neisseria gonorrhoeae, but clinical data supporting their efficacy in treating such strains are lacking.

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