Ertapenem seems similar in effectiveness to ceftriaxone for gonorrhea

The use of penicillin in the mid-1940s ushered in the era of powerful antibiotic therapy for a wide range of infections, including gonorrhea and syphilis. However, since that time, the bacteria that cause gonorrhea have been evolving the ability to resist first penicillin and subsequently other antibiotics.

As new antibiotics are not currently being developed at the same pace as they once were, scientists are reassessing older antibiotics approved for other conditions that have the potential to be repurposed as a treatment for gonorrhea.

About ertapenem

One older antibiotic that is very promising as a potentially repurposed treatment for gonorrhea is ertapenem (Invanz). This antibiotic was approved in Canada and other high-income countries about 20 years ago. It is used for the treatment of complicated abdominal, bone, brain, lung and pelvic infections, as well as for diabetic foot infections. Ertapenem can be administered both intravenously or via intramuscular injection in Canada and some other countries. For most infections in adolescents and adults, the usual dose is 1 gram per day for between five and 14 days. In the case of diabetic foot infections, the manufacturer, Merck, recommends a course of treatment that lasts between five and 28 days.

About 20 years ago, Merck facilitated the lab research to understand ertapenem’s effect on gonorrhea-causing bacteria. These experiments suggested that the drug was able to inhibit the growth of more than 600 isolates of gonorrhea-causing bacteria. Some of these bacteria were resistant to ciprofloxacin and ertapenem was active against these drug-resistant strains.

However, at the time these experiments were done, relatively low doses of ceftriaxone and another antibiotic, cefixime (taken in pill form), could be used to treat gonorrhea and were highly effective. Also, another antibiotic, azithromycin (which could also be taken in pill form) was also in use and largely still effective against gonorrhea (and syphilis). So ertapenem was bypassed in favour of these other drugs.

A clinical trial in the Netherlands

Recently, Dutch researchers published the results of a randomized, double-blind controlled trial in adults with uncomplicated gonorrhea (primarily anorectal and urogenital gonorrhea). The study, called Nabogo, tested the following antibiotics:

• ceftriaxone – 500 mg given as a single dose via intramuscular injection
• ertapenem – 1,000 mg given as a single dose via intramuscular injection
• gentamicin – 5 mg/kg of body weight (to a maximum of 400 mg) given as a single dose via intramuscular injection
• fosfomycin – 6 grams in a solution that was swallowed

Some participants also received placebo injections or placebo oral solution.

The researchers asked 2,160 people who had been diagnosed with gonorrhea to participate in the study. However, only 346 (16%) agreed to participate.

As ceftriaxone is the standard of care for gonorrhea, the effects of the other antibiotics were compared to it.

The researchers found that ertapenem was neither worse nor better than ceftriaxone (the technical statistical term used to describe this outcome is “non-inferior”). Gentamicin had a similar result, but there are concerns about its use. Fosfomycin proved to be poorly effective, and recruitment and assignment to this drug in the trial was quickly halted. Issues related to gentamicin and fosfomycin are discussed later in this report.

Although the study was small, it found that ertapenem was highly effective and should be studied in a larger trial.

Study details

Researchers with the Public Health Service in Amsterdam recruited people who tested positive using an assay that assessed their sample (urine or swabs of affected tissue) for the genetic information of the bacteria that causes gonorrhea. People who were immune suppressed were not recruited; this would have included people who were taking transplant medicines or HIV-positive people with a CD4+ count less than 200 cells/mm³.

The distribution of participants was as follows:

• ceftriaxone – 103 people
• ertapenem – 103 people
• gentamicin – 102 people
• fosfomycin – 38 people

The study was done between September 2017 and June 2020. Research staff administered the medicines; in the case of fosfomycin, they observed participants drinking the drug.

Most participants (90%) were gay, bisexual or other men who have sex with men (MSM). A total of 71 participants had HIV.

Among 272 HIV-negative people, 32% were using HIV pre-exposure prophylaxis (PrEP).

Between one and two weeks after initiating treatment, participants returned to the study clinic to have urine samples or swabs collected and analysed to find out if they were cured.

Participants were told to avoid sex until the study lab could confirm that they were cured. If they did have sex, they were encouraged to use condoms.

Participants kept diaries during the study to keep track of any adverse effects of treatment and any sexual activity.

Lab analysis found that all participants had gonorrhea that was susceptible to ceftriaxone.

Results

The proportions of people cured of anogenital gonorrhea were as follows:

• ceftriaxone – 100%
• ertapenem – 99%
• gentamicin – 93%
• fosfomycin – 12%

Focus on the throat

Researchers were primarily interested in the ability of one course of treatment to eradicate gonorrhea from the anogenital or urogenital site. Some people had detectable gonorrhea in more than one place, for example, the anorectal region and the throat.

The researchers noted that the eradication of gonorrhea from the throat is more difficult than from other parts of the body. As a result, they decided to assess eradication of gonorrhea from the throat as a secondary (or less important) aim of the study.

The researchers stated that the ideal duration of time between initiation of treatment and getting a swab from the throat to assess if gonorrhea was cured there is not clear. In the study, this duration was between one and two weeks. It is possible that a longer duration may have been needed.

The proportions of people who had gonorrhea of the throat cured were as follows:

• ceftriaxone – 90% (38 out of 42 people) cured
• ertapenem – 88% (29 out of 32 people) cured
• gentamicin – 26% (9 out of 38 people) cured

Note: As mentioned earlier, fosfomycin proved to be poorly effective and recruitment and assignment to receive this drug in the trial were quickly halted. Issues related to gentamicin and fosfomycin are discussed later in this report.

Side effects

Antibiotics can cause temporary episodes of diarrhea, as they cause a shift in the balance of bacteria in the gut.

Diarrhea was reported by participants who received fosfomycin (87%), ertapenem (50%) and ceftriaxone (11%); it was rare in people who used gentamicin (2%).

One person who received ertapenem developed tightening of his throat. This was interpreted as an allergic reaction and he was given antihistamines in the emergency department of a hospital. He recovered.

In 14 participants the researchers noted “clinically relevant” declines in a measure of kidney health called eGFR (estimated glomerular filtration rate). That is, eGFR values declined by more than 25% in these people, more or less evenly distributed among the study medicines. However, none of the decreases in eGFR were deemed severe and most of the people recovered within a few weeks.

Focus on fosfomycin

The dose of fosfomycin used in the study was 6 grams in a single oral dose. However, this drug generally failed to cure participants of gonorrhea. As researchers noticed this partway through the study, they stopped recruiting people and assigning them to receive fosfomycin long before the overall study was completed.

The researchers stated that, based on past studies, it is plausible that fosfomycin taken repeatedly for several days might be able to cure people of gonorrhea. However, it is clearly not useful as a single-dose regimen. The researchers were interested in exploring single-dose regimens in the present study for ease of administration. Other researchers have found that not everyone who requires multiple treatments and assessments for sexually transmitted infections returns for further care and treatment. Such behaviour could lead to the spread of drug-resistant bacteria. Hence the focus on a single dose of treatment for gonorrhea in the present study and in most ongoing studies.

Focus on gentamicin

In a previous study, the combination of 240 mg of gentamicin with 1 gram of azithromycin was not as effective as the combination of ceftriaxone-azithromycin for gonorrhea clearance.

In the present study where the dose of gentamicin was adjusted by weight, participants received between 280 to 400 mg of this drug. However, the researchers found that despite this higher dose (compared to the one used in a previous study), gentamicin was inadequate for treatment of gonorrhea of the throat.

It is plausible that giving higher doses or longer courses of gentamicin could be more effective. However, the researchers cautioned that doing so “will probably increase the risk for serious [toxicity].” Gentamicin can injure the inner ears and kidneys.

Recruitment

The researchers stated that “a substantial proportion of eligible individuals declined to participate.” Many people who chose not to participate cited causes that inconvenienced them or interfered with their routines. Such causes included long wait times at the study clinic and/or having to make multiple study visits.

For the future

The present study, though well designed, was relatively small. The Dutch researchers stated that based on their results, ertapenem “might provide an alternative option for ceftriaxone susceptible gonorrhea.” There are many issues about the Nabogo trial to consider and these are discussed in the next report in this issue of TreatmentUpdate.

—Sean R. Hosein

REFERENCES:

1. de Vries HJC, de Laat M, Jongen VW, et al. Efficacy of ertapenem, gentamicin, fosfomycin, and ceftriaxone for the treatment of anogenital gonorrhoea (NABOGO): a randomised, non-inferiority trial. Lancet Infectious Diseases. 2022 Jan 19:S1473-3099(21)00625-3. 
2. Xu WQ, Zheng XL, Liu JW, et al. Antimicrobial susceptibility of ertapenem in Neisseria gonorrhoeae isolates collected within the China Gonococcal Resistance Surveillance Programme (China-GRSP) 2018. Infection and Drug Resistance. 2021 Oct 12;14:4183-4189.
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