Extremely high doses of ceftriaxone for gonorrhea in some parts of China

Doctors at a hospital in Hangzhou, China, conducted a study screening for drug-resistant gonorrhea for six months in 2019. During that time, they analyzed 70 samples/swabs from people with gonorrhoea. Among these 70 people, seven (10%) had high-level resistance to ceftriaxone and 37% had resistance to another drug, cefixime. The latter drug is taken orally, but in the current era it is not the preferred treatment for gonorrhea in many countries because of resistance.

Prior to seeking care at the hospital, all seven patients (six men, one woman) had been treated with derivatives of penicillin (called cephalosporins), but this therapy had failed. These antibiotics were all structurally related to ceftriaxone, hence the high-level resistance to this latter antibiotic.

To overcome high-level resistance to ceftriaxone, doctors treated four of the seven people with a high dose of ceftriaxone: 2 grams given intravenously for one or two days. Three of them were subsequently cured. The fourth person was retreated with another course of ceftriaxone but did not return to the hospital for a checkup to see if he was cured. The remaining patients were treated with other antibiotics. One person was given a 12-day regimen of cefuroxime (Ceftin) and was cured. Two other patients were treated with other antibiotics; however, they did not return to the hospital for a checkup, so doctors were unable to find out if they were cured.

The seven people were infected with a strain of gonorrhea that has also been found in Europe, Japan, North America and other parts of China.

The importance of this study is at least as follows:

• It documents that higher doses of ceftriaxone than those used in North America or Europe are being prescribed in parts of China for the treatment of gonorrhea.
• Treatment with high-dose ceftriaxone was extended beyond a single dose for some people.
• It showed that the same strains of gonorrhea-causing bacteria can spread to people on different continents.

The use of high doses of ceftriaxone in Hangzhou is not an anomaly, as explained below.

A review in Beijing

In another study, doctors in Beijing reviewed records collected from seven hospitals in five provinces between 2013 and 2017. They focused on 1,686 people who had been diagnosed with gonorrhea. On average, throughout the study, 10% of samples were resistant to ceftriaxone, according to lab tests. A total of 1,401 participants received intravenous ceftriaxone as treatment. Most people in the study received doses of 1,000 mg or greater, as a single dose. Commonly administered doses included the following:

• 2,000 mg
• 3,000 mg
• 4,000 mg
• 6,000 mg

All of these were given intravenously. There were no reports of treatment failure throughout the study period. The doctors thought that the lack of treatment failure occurred because all participants were treated with extremely high doses of ceftriaxone. The Beijing doctors noted that these doses of ceftriaxone are higher than what is recommended for routine use in Chinese guidelines for sexually transmitted infections. The doctors advanced the following reasons for the use of very high-dose ceftriaxone:

• Most ceftriaxone produced for the Chinese market comes in doses of 1,000 and 2,000 mg.
• “There is a sense from most clinicians that domestically manufactured ceftriaxone is less potent than the drug manufactured in other nations, which may have prompted the decisions to give higher doses when prescribing domestically produced ceftriaxone.”
• “Patients who were previously diagnosed with N. gonorrhoeae or other sexually transmitted infections would be prescribed higher ceftriaxone dosage than those with primary infections in this study.”
• “Patients who were already using antibiotics for their infection [at the time they sought care at the hospitals] would be prescribed a higher dosage of ceftriaxone than those who did not use antibiotics at initial presentation. The physicians probably regarded these patients as experiencing clinical treatment failure, so they would prescribe a high dosage.”

The Beijing doctors warned that the safety of using such high doses of ceftriaxone is not known. In addition to the treatment of gonorrhea, ceftriaxone is also used for serious bacterial infections of the abdomen, bone, brain, lungs, skin, urinary tract and so on. The most recent Canadian prescribing information for ceftriaxone notes that “there is limited experience with daily doses of 3 to 4 grams administered as a single dose or two equally divided doses. The total daily dose should not exceed 4 grams.”

Another consequence of using such high doses as reported in China is the effect on the balance of gut bacteria. It is plausible that excessive doses of ceftriaxone (or other antibiotics) could lead to the overgrowth of bacteria that can cause serious infections in people. However, doctors were not able to assess this possibility in their study.

Historically, strains of gonorrhea or other sexually transmitted infections resistant to antibiotics do not stay in one region but eventually spread throughout the world. Gonorrhea that has become used to extremely high doses of ceftriaxone in parts of China may spread and become harder to treat in other countries where much lower doses of ceftriaxone are used.

—Sean R. Hosein

REFERENCES:

1. Yan J, Chen Y, Yang F, et al. High percentage of the ceftriaxone-resistant Neisseria gonorrhoeae FC428 clone among isolates from a single hospital in Hangzhou, China. Journal of Antimicrobial Chemotherapy. 2021 Mar 12;76(4):936-939. 
2. Han Y, Yin Y, Dai X, et al. Widespread use of high-dose ceftriaxone therapy for uncomplicated gonorrhea without reported ceftriaxone treatment failure: Results from 5 years of multicenter surveillance data in China. Clinical Infectious Diseases. 2020 Jan 1;70(1):99-105. 
3. Sandoz Canada. Ceftriaxone sodium for injection BP. Product monograph. 6 January 2022.
4. Baker RE, Mahmud AS, Miller IF, et al. Infectious disease in an era of global change. Nature Reviews Microbiology. 2022 Apr;20(4):193-205. 
5. Lewis DA. Global resistance of Neisseria gonorrhoeae: when theory becomes reality. Current Opinion in Infectious Diseases. 2014 Feb;27(1):62-7.