High-dose ceftriaxone for gonorrhea in Japan

As mentioned earlier in this issue of TreatmentUpdate, in the past two decades, gonorrhea has become less susceptible to several antibiotics, including ceftriaxone, the standard of care for gonorrhea today. Although cases of ceftriaxone resistance are relatively rare in Europe and North America, it seems likely that in the years ahead it may become more common.

Raising the dose

Ceftriaxone is the preferred treatment for gonorrhea in Canada and many high-income countries. To ensure its success in treating gonorrhea, public health authorities in many countries and regions have increased the recommended dose for adults and adolescents with uncomplicated gonorrhea as follows:

• Japan – 1 gram given as a single intravenous dose
• Europe – 1 gram given as a single intramuscular injection with 2 grams of azithromycin taken orally
• United States – 500 mg given as a single intramuscular injection
• United Kingdom – 1 gram given as a single intramuscular injection

At press time, the preferred treatment for gonorrhea in Canada was ceftriaxone 250 mg given as a single intramuscular dose, accompanied by another antibiotic, azithromycin, given in pill form also as a single dose. Given that reports suggest that azithromycin-resistant gonorrhea is spreading across Canada, it is likely that at some point in the future guidance for gonorrhea treatment will be updated.

In Japan

In Japan, ceftriaxone is administered via intravenous infusion when used for gonorrhea treatment, while in North America and Western Europe this drug is usually given via intramuscular injection. Japanese researchers cited data from the 1990s that suggest that when 1 gram of ceftriaxone is administered via intramuscular injection or intravenously, the result is that levels in the blood are similar.

Researchers in Tokyo have been investigating the impact of different antibiotic regimens for the treatment of gonorrhea. The researchers were interested in the ability of antibiotics to cure gonorrhea in the throat and rectum. They compared the following regimens:

• ceftriaxone – 1 gram given intravenously as a single dose
• ceftriaxone – 1 gram given as above along with either of the following antibiotics taken orally: azithromycin 1 gram (also as a single dose) or doxycycline 100 mg twice daily for seven consecutive days

The combination regimen was used in cases where both gonorrhea and chlamydia were diagnosed.

The researchers recruited 320 people—208 of whom were given ceftriaxone alone and 112 of whom were given combination therapy with ceftriaxone and an oral antibiotic.

In comparing the two regimens, the researchers found no differences in rates of cure.

Later in this report we highlight some issues with the study.

Study details

Researchers enrolled 320 participants, all of whom were gay, bisexual or other men who have sex with men (MSM). The men underwent screening for gonorrhea of the throat and/or rectum and for chlamydia. Visits to the study clinic were done every three months between 2017 and 2020.

Participants returned to the study clinic at least two weeks after they received treatment to have swabs done to check if gonorrhea and/or chlamydia was cured.

All gonorrhea infections were symptom free.

On average, the men were 30 years old (ranging between 18 and 57 years).

Results

Researchers found that both regimens were highly effective, with 98% of participants cured with ceftriaxone alone and 96% cured with combination therapy. This difference in cure rates was not statistically significant.

Cure rates did not differ whether gonorrhea was in the throat or the rectum.

Treatment failure

Treatment for gonorrhea failed in nine cases, distributed as follows:

• ceftriaxone alone – four cases: three in the throat and one in the rectum
• ceftriaxone + oral antibiotic – five cases: three in the rectum and two in the throat

In all nine cases, researchers analysed the genetic information from strains of gonorrhea isolated from the men. The researchers were not able to find genetic markers of resistance to ceftriaxone in any of these cases. They therefore re-treated all the men with another round of ceftriaxone (without any oral antibiotics) at a dose of 1 gram given as a single intravenous dose.

Subsequently, the researchers found that eight of the nine men were cured. Again, investigation found that the ninth man did not have ceftriaxone-resistant gonorrhea, so he was given a third course of this drug and was cured.

Adverse events

In general, intravenous ceftriaxone seemed to have been well tolerated, with only one person developing an allergic reaction (graded as moderate intensity by the researchers). This occurred two hours after his infusion. The man was successfully treated with oral corticosteroids and recovered.

Bear in mind

This was not a randomized clinical trial and its findings are not definitive; however, the study is still important, as it compared two regimens. Despite its limitations, this study suggests that 1 gram of ceftriaxone with or without oral antibiotics is, in most cases, effective at treating gonorrhea.

—Sean R. Hosein

REFERENCES:

1. Aoki T, Mizushima D, Takano M, et al.  Efficacy of 1 g ceftriaxone monotherapy compared to dual therapy with azithromycin or doxycycline for treating extragenital gonorrhea among men who have sex with men. Clinical Infectious Diseases. 2021 Oct 20;73(8):1452-1458. 
2. Hanao M, Aoki K, Ishii Y, et al. Molecular characterization of Neisseria gonorrhoeae isolates collected through a national surveillance programme in Japan, 2013: evidence of the emergence of a ceftriaxone-resistant strain from a ceftriaxone-susceptible lineage. Journal of Antimicrobial Chemotherapy. 2021 Jun 18;76(7):1769-1775.