- Gonorrhea-causing bacteria have been gradually developing the ability to resist antibiotics
- Researchers tested a new antibiotic called gepotidacin in people with uncomplicated gonorrhea
- Gepotidacin, taken orally, was highly effective and generally well tolerated
The germs that cause gonorrhea (N. gonorrhoeae) are most commonly spread during condomless anal, oral and vaginal intercourse. These germs can also be passed from mother to child during the birthing process.
Gonorrhea does not always cause symptoms. However, in people who were assigned male at birth (AMAB), gonorrhea can cause discharge from the penis as well as a burning sensation while urinating. If left untreated, the germs that cause gonorrhea can affect the testicles and prostate.
People assigned female at birth (AFAB) who have gonorrhea can develop a burning sensation while urinating, discharge from the vagina, pain in the lower abdomen, and vaginal bleeding between periods or after sex. What’s more, gonorrhea can contribute to pelvic inflammatory disease, infertility and other complications.
Gonorrhea causes inflammation in delicate wet tissues, and such inflammation can act as a portal, or gateway, for other sexually transmitted infections (STIs), including HIV.
These symptoms, complications and risks for other infections underpin the need for sexually active people to get regular checkups and screening for STIs such as gonorrhea.
Treatment
Since 1945, a range of treatment options—antibiotics—were developed for gonorrhea. However, the germs that cause this infection have gradually developed the ability to resist many antibiotic treatments.
A scientific advisory panel to the Public Health Agency of Canada (PHAC) has released interim guidance for the treatment of gonorrhea.
In adults (and in young people 10 years of age and older), the advisory panel recommends the following treatment “for all uncomplicated infections (urethral, endocervical, vaginal, rectal and pharyngeal)”:
- the antibiotic ceftriaxone 500 mg given as an intramuscular injection in a single dose
In many countries, ceftriaxone has become the leading treatment for gonorrhea.
In Canada, the previously mentioned scientific advisory panel noted that “alternative treatment options, which are required if access to intramuscular injection is not available, if the individual refuses the injection, or if the individual is severely allergic to [cephalosporins—the class of antibiotic to which ceftriaxone belongs], are currently under review.” In the meantime, should ceftriaxone not be an option, PHAC recommends the following alternative antibiotics:
- cefixime 800 mg orally in a single dose + doxycycline 100 mg orally twice daily for seven consecutive days
- cefixime 800 mg orally in a single dose + azithromycin 1 g orally in a single dose
- azithromycin 2 g orally in a single dose + gentamicin 240 mg in a single intramuscular dose
- gentamicin 240 mg in a single intramuscular dose + doxycycline 100 mg orally twice daily for seven consecutive days
The panel states that doxycycline should not be used in pregnancy and in people who are lactating. They also state that gentamicin should not be used during pregnancy.
Other recommendations from the scientific advisory panel related to the management of gonorrhea can be found here. PHAC also has a Gonorrhea Guide.
Enter gepotidacin
Gepotidacin is the first new oral antibiotic being tested for the treatment of gonorrhea since the 1990s. In clinical trials, two doses of 3,000 mg, taken 10 to 12 hours apart (for a daily total of 6,000 mg) was highly effective against uncomplicated gonorrhea. Side effects were mostly gastrointestinal (diarrhea and nausea) and generally mild and temporary.
Gepotidacin is approved in the U.S. for the treatment of uncomplicated urinary tract infections. It is not approved for the treatment of gonorrhea.
Gepotidacin is not yet approved in Canada. It belongs to a new class of drugs called triazaacenaphthylene antibiotics.
An important clinical trial – Eagle 1
Researchers recruited 628 participants with uncomplicated gonorrhea for a clinical trial called Eagle 1. Participants were from the following countries:
- Australia
- Germany
- Mexico
- Spain
- U.K.
- U.S.
Participants were randomly assigned to receive one of the following regimens:
- gepotidacin tablets 3,000 mg orally twice daily (12 hours apart) in one day
- ceftriaxone 500 mg via intramuscular injection + azithromycin 1 g orally (both drugs administered once)
Participants were mostly AMAB (89%), most of whom were gay or bisexual men who had sex with men (gbMSM). On average, participants were in their 30s. The major ethno-racial groups were White (74%) and Black (15%).
Results
Overall, rates of cure were high—93% in people who received gepotidacin and 91% in people who received ceftriaxone + azithromycin. Analysis revealed that gepotidacin was what statisticians call “non-inferior” to ceftriaxone + azithromycin. This is a technical term that means that gepotidacin was neither better nor worse than ceftriaxone + azithromycin.
In all participants, urine samples and swabs of the urinary and genital tract were taken for analysis of STIs.
In a subgroup of participants, researchers collected and analysed urine and swabs from the rectum and throat four to eight days after treatment. They tested these samples and swabs for several STIs, including gonorrhea.
People who had a pre-treatment and subsequent swab that was positive for gonorrhea had another swab of the throat done at days 14 to 21 after taking treatment.
Different locations
Antibiotics sometimes have difficulty penetrating certain parts of the body. So, it is important to test fluids or samples from these parts (or compartments) to determine if gonorrhea has been wiped out. As mentioned earlier, subgroups of people had different parts of their body assessed for gonorrhea after treatment. The proportions that were cured were as follows:
Urinary tract
- gepotidacin – 100%
- ceftriaxone + azithromycin – 100%
Rectum
- gepotidacin – 100%
- ceftriaxone + azithromycin – 100%
Throat
- gepotidacin – 88%
- ceftriaxone + azithromycin – 100%
Side effects
Gepotidacin was generally well tolerated. Common drug-related side effects reported in the clinical trial were distributed as follows:
Diarrhea
- gepotidacin – 48%
- ceftriaxone + azithromycin – 7%
Nausea
- gepotidacin – 23%
- ceftriaxone + azithromycin – 3%
In general, these side effects occurred on the day the drug(s) were given and were largely resolved a day later.
Three people (less than 1%) prematurely left the study; all were receiving gepotidacin. These participants experienced the following adverse events:
- one participant – fainted 30 minutes after the first dose of gepotidacin
- one participant – visual difficulties, nausea, dizziness and diarrhea
- one participant – general discomfort, vomiting, dizziness and fever
All participants recovered from these episodes.
No one died as a result of gonorrhea treatment.
Bear in mind
The results from Eagle 1 are very promising for the future use of gepotidacin for the treatment of uncomplicated gonorrhea. However, there was only a small proportion of participants who had gonorrhea in the anus/rectum and/or throat.
For the future
One of the world’s leading STI researchers, Professor Magnus Unemo, PhD, at the University of Örebro in Sweden, reviewed the findings from Eagle 1 and made the following comments:
“Further gepotidacin studies should investigate higher numbers of women, adolescents, individuals with anorectal and [throat] infections, and diverse ethnicities.”
In addition to the above considerations, other issues that might affect the future deployment of gepotidacin in Canada could include at least the following:
- cost
- whether or not there will be restrictions on its use
Gepotidacin plus
In general, it is more difficult for bacteria to develop the ability to resist antibiotics when these drugs are used in combination rather than just one antibiotic alone. Gepotidacin is the first new antibiotic to be approved that has strong potential to treat gonorrhea. It is therefore important for health policy planners and prescribers to strive to find ways to minimize the development of resistance by gonorrhea-causing bacteria.
At this time, it is not clear which antibiotics have the potential to be used with gepotidacin. Experiments in the lab with antibiotics need to be done to assess if gepotidacin in combination with other antibiotics will result in greater activity than gepotidacin alone against gonorrhea. Such lab experiments are important because sometimes combinations of antibiotics can antagonize each other’s effects.
Professor Unemo has stated that combinations of gepotidacin with other antibiotics, such as those listed below, should be tested, as people with gonorrhea will likely also be coinfected with Mycoplasma genitalium and/or chlamydia (and these other antibiotics can affect those germs):
- gepotidacin + doxycycline
- gepotidacin + azithromycin
In addition, because doxycycline is increasingly used as post-exposure prophylaxis (PEP) after sexual exposure to reduce the risk of STIs, potential interactions between gepotidacin, doxycycline and other antibiotics need to be investigated.
Thus, before gepotidacin can be launched against gonorrhea, some additional research is needed.
A brief history of gonorrhea treatment
As mentioned earlier, ever since the antibiotic era began early in the 20th century, gonorrhea-causing bacteria have gradually been developing the ability to resist every antibiotic deployed against it. Some examples are as follows:
Sulpha drugs
These antibiotics were introduced in the late 1930s, but within a decade high rates of resistance and treatment failure in cases of gonorrhea were reported.
Penicillin
This drug was introduced in the mid-1940s. A study in 1944 found that all strains of N. gonorrhoeae that were tested were susceptible to a low dose of penicillin. However, by the late 1960s, more cases of gonorrhea required many times the concentration of penicillin for effective treatment. Rates of gonorrhea resistant to penicillin are estimated by the Public Health Agency of Canada (PHAC) to be less than 7% in Canada.
Tetracyclines
This class of drugs, introduced in the 1950s, was useful for cases where penicillin resistance had developed or where people were allergic to penicillin. Over time, some strains of gonorrhea developed resistance to tetracycline. A recent report from PHAC suggests that rates of gonorrhea resistant to tetracyclines is high, between 30 and 60 per cent in Canada.
Ciprofloxacin and related drugs
The drug ciprofloxacin (Cipro) was introduced for the treatment of gonorrhea in the mid-1980s. It belongs to a class of drugs called fluoroquinolones. In the mid-80s, a relatively low dose of 250 mg was recommended to treat gonorrhea. Over time, gonorrhea-causing bacteria gradually developed the ability to resist this dose, so higher doses, up to 500 mg, were recommended. However, cases of gonorrhea were increasingly able to overcome this dosage. A related antibiotic, ofloxacin (400 mg), was sometimes used in place of Cipro. But by the mid-1990s, resistance to ofloxacin was also reported. Fluoroquinolones are no longer recommended for gonorrhea treatment. PHAC estimates that rates of gonorrhea resistant to fluoroquinolones range from 15 to 65 per cent in Canada.
Azithromycin
Azithromycin belongs to a class of antibiotics called macrolides. It was developed from an older antibiotic, erythromycin. In the 1990s it was used to treat both gonorrhea and syphilis. However, over time azithromycin treatment failures began to increase as the bacteria that cause syphilis and gonorrhea became resistant to it. PHAC estimates that about eight per cent of cases of gonorrhea are resistant to azithromycin.
Ceftriaxone and cefixime
Ceftriaxone and cefixime belong to a class of antibiotics called cephalosporins. Both of these drugs are highly effective. Ceftriaxone is the mainstay of gonorrhea treatment in Canada and many countries. According to PHAC, rates of gonorrhea with reduced susceptibility to ceftriaxone are extremely low—0.3 per cent.
In some years, such as 2022, no cases of ceftriaxone-resistant gonorrhea were detected. PHAC has recently raised the recommended dose of ceftriaxone to 500 mg (via intramuscular injection). At this dose, it will be difficult for gonorrhea-causing bacteria to develop resistance.
Rates of gonorrhea with reduced susceptibility to cefixime are extremely low as well, according to PHAC, also around 0.3 per cent.
PHAC has found that cases of extensively drug-resistant gonorrhea are rare, ranging between one and two cases in recent years.
Emerging resistance to ceftriaxone
As mentioned earlier, ceftriaxone is the mainstay of gonorrhea treatment in many countries. Although rates of gonorrhea resistance to ceftriaxone are extremely low in Canada, this is not the case in some parts of East Asia. Recent reports suggest that high rates of gonorrhea resistance to ceftriaxone have been reported in the following places:
- Vietnam – 27%
- Cambodia – 15%
- China – 8%
—Sean R. Hosein
Resources
TreatmentUpdate 245 – CATIE
Gonorrhea – CATIE
Gonorrhea Guide – Public Health Agency of Canada
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