Sherrie Rice
April 2025—For Neisseria gonorrhoeae, the pipeline of antibiotics is running dry, and antimicrobial resistance is a global threat.
“It’s just a matter of when it’s going to happen,” says Olusegun O. Soge, PhD, MSc, associate professor of global health and of medicine and adjunct associate professor of laboratory medicine and pathology at the University of Washington. The U.S. does not have ceftriaxone resistance now, but “it’s a matter of time. It’s going to get here.”
Dr. Soge, a microbiologist with expertise in molecular diagnostics for infectious diseases, has been part of national gonococcal antimicrobial resistance surveillance for more than 20 years. Knowing what he knows from colleagues in Cambodia, Vietnam, and other parts of the world where resistance to ceftriaxone is at high levels, he says he doesn’t know “whether we’re doing enough to track antimicrobial resistance from where it emerges and to deal with it before it comes to the U.S.” (Ouk V, et al. JAC Antimicrob Resist. 2024;6[2]:dlae053; Zhu X, et al. MMWR Morb Mortal Wkly Rep. 2024;73[12]:255–259; Lan PT, et al. Lancet Reg Health West Pac. 2024;48:101125). He spoke last year on this and related laboratory approaches in a sexually transmitted infection session at the ADLM annual meeting.
Work is being done in the U.S., Dr. Soge said, but he fears what is being done globally may not be working. “That’s my concern. And the world is a global village.” As a professor of global health and with the recent lesson of COVID-19, he feels compelled “to sound the alarm that we need to think beyond this country.”
The number of gonorrhea cases reported to the Centers for Disease Control and Prevention is not the actual number of cases, Dr. Soge said. “It’s underreported every year because of the stigma.”
In 2022, 648,056 cases were reported to the CDC, down 9.2 percent from 2021. “Which is good, but it’s not the actual number of cases,” he said, which is likely closer to 1 million.
Treatment remains complicated, and the reason is that N. gonorrhoeae has progressively developed resistance to all recommended antimicrobials. The only effective first-line treatment the CDC recommends now is ceftriaxone.
The sequential development of resistance is not a surprise, Dr. Soge said, citing a 2017 commentary predicting such (Hook EW. Clin Infect Dis. 2017;65[6]:924–926). “It’s just a matter of survival. You want to kill them; they want to live,” he says. N. gonorrhoeae is among the bacteria that the CDC has designated as urgent antibiotic resistance threats.
A report of a novel strain of multidrug nonsusceptible N. gonorrhoeae in Massachusetts was published last year (Reimche JL, et al. Lancet Infect Dis. 2024;24[3]:e149–e151). In their correspondence, the authors presented the details of two U.S. cases of the penA 60.001 allele identified in multilocus sequence type 8123, an emerging international multidrug nonsusceptible N. gonorrhoeae lineage. The cases responded to ceftriaxone, but isolates from the first of the two cases demonstrated in vitro nonsusceptibility to ceftriaxone and nonsusceptibility or resistance to first-line drugs recommended previously.
U.S. patients with failed treatment for gonorrhea “might be anticipated in the near future,” the authors write, owing to high rates of gonorrhea, rapid evolution of N. gonorrhoeae resistance, and increasing case reports of penA 60.001 allele associated with treatment failures. They added, “Although ceftriaxone was still effective, these primary care cases are a warning to clinicians and public health officials to scale up clinical awareness, surveillance, and laboratory detection, including culture and gradient strip antimicrobial susceptibility tests and advanced molecular diagnostics, to delay the arrival of extremely drug-resistant gonorrhea until new treatments or vaccines are developed.”
Said Dr. Soge, “They have screened thousands of other specimens and since then they’ve not found any other case.” The strain of N. gonorrhoeae they reported was novel to the U.S. but genetically similar to isolates identified in the U.K. “So where did that strain come from? How did the person get the strain? It’s still a mystery,” Dr. Soge said. “And that’s the world of gonococcus—some things remain a mystery.”
The World Health Organization has a global action plan to control the spread and impact of N. gonorrhoeae antimicrobial resistance, and part of it is to strengthen antimicrobial resistance surveillance globally, Dr. Soge said.
In the plan, too, is the building of additional laboratory capacity in low- and middle-income countries so testing can be performed not only to detect N. gonorrhoeae but also for antimicrobial resistance. “Right now, syndromic management is what is done in most low-income and middle-income countries. And early detection of ceftriaxone-resistant N. gonorrhoeae is important,” given it’s the only first-line treatment that is most effective for all gonorrhea cases, he said.
Surveillance now is dependent on culture, and most clinical laboratories don’t do N. gonorrhoeae culture, he said. “They’ve lost their culture capacity,” thanks to molecular tests that are far more sensitive and faster.
Antimicrobial resistance surveillance in the U.S. got its start at the CDC in 1986, with the Gonococcal Isolate Surveillance Project, or GISP, the goal of which was to monitor trends in antimicrobial susceptibilities so the CDC could have data on which to base its treatment recommendations. “Today we have the enhanced GISP, or eGISP,” Dr. Soge said, “and the Strengthening the U.S. Response to Resistant Gonorrhea,” or SURRG. At the time of his presentation last year, another name change was set to take place: Combatting Antimicrobial Resistant Gonorrhea and Other STIs, or CARGOS.
As of mid-2024, N. gonorrhoeae resistance data in the U.S. were available through 2022, and as of that year, the percentage of isolate with elevated MIC to ceftriaxone was less than 0.1 percent, cefixime was 0.1 percent, and azithromycin was 4.1 percent. “The world is not coming to an end,” Dr. Soge said.
Other antibiotics previously recommended for treatment of gonorrhea are ciprofloxacin, for which resistance was 31.4 percent in 2022; tetracycline, at 20.1 percent resistance; and penicillin, at 12.6 percent.
For ceftriaxone, Dr. Soge said, “we are not seeing a lot of isolates that have elevated MIC, but if you go to Cambodia, Vietnam, or other parts of the world, you are going to see very alarming high resistance rates.”
How to ensure sufficient data are gathered to guide effective prescribing is the question, Dr. Soge said, and that question raises another: What is done now for gonococcal culture in places that do not have CDC-supported surveillance programs?
He asks, “Is there a way we can partner with the commercial labs so that whenever they do culture they have a way of forwarding that to the public health lab so the public health lab can forward it to the CDC, or to the reference labs supported by CDC, to do antimicrobial resistance surveillance?” If so, resistance testing by agar dilution can be done, or perhaps it can be forwarded to one of the CARGOS sites that can do the Etest.
“This is something the CDC needs to be thinking about. It’s not just the sites that are supported,” he said. “How can we reach out to broaden collaboration with clinical labs” to expand N. gonorrhoeae resistance testing?
What more does Dr. Soge suggest?
- Make self-collection available. Dr. Soge and colleagues studied the sensitivity of patient-collected specimens (pharynx, rectum, urethra/urine, endocervix/vagina) and found the concordance between the self-collected specimen and the clinician-collected specimen to be 93 to 100 percent (Barbee LA, et al. Clin Infect Dis. 2021;73[9]:e3196–e3200). They showed also that male urine was 97 percent sensitive for recovery of N. gonorrhoeae compared with clinician-collected urethral swabs inoculated in the clinic and that delayed processing of urine (up to 22 hours) did not impact viability and culture recovery. “The self-collected vaginal swab is just fine for Neisseria gonorrhoeae culture, and clinics that don’t have the time for clinicians to do pelvic exams or collect specimens can have the patients collect their sample,” he said.
- Collect two samples for nucleic acid amplification testing and N. gonorrhoeae culture (Wind CM, et al. J Clin Microbiol. 2015;53[6]:1884–1890). NAAT is the predominant test for gonococcus diagnosis. If two samples are collected, a culture can be done with the second swab in the case of a positive NAAT result. “Those swabs in transport systems are fine; you can refrigerate them for 24 hours and some will be fine for more than 24 hours,” Dr. Soge said. Published papers have shown that the thinking that N. gonorrhoeae cannot be refrigerated is not true (Serra-Pladevall J, et al. J Microbiol Methods. 2018;145:37–39). “There’s a lot of things we’re learning now,” he said.
- Industry investment in a transport medium that can support gonococcal viability for days. It would allow culture to be done on N. gonorrhoeae-positive NAATs even after several days of specimen collection, without compromising viability and culture recovery. Specimens can be transported over several days to the laboratory for N. gonorrhoeae culture.
- A combination NAAT plus viability assay, one that would report positivity for gonorrhea and that the N. gonorrhoeae infection is still viable and transmissible. “Right now, the only way we know something is viable is if we can get it to grow by culture. But we know the performance sensitivity of culture is very poor. So it would be nice to have a NAAT that combines detection and viability.”
- The CDC should partner with laboratories using total lab automation for culture-based testing. Lainhart, et al., evaluated the recovery of pathogens from urine cultures in the setting of the BD Kiestra TLA and in 2018 reported a 371 percent increase in N. gonorrhoeae recovery post-TLA. The high recovery rate was thought to be due to prompt and continuous incubation of culture plates, greater inoculation volume, and review of culture plates on high-resolution monitors (Lainhart W, et al. J Clin Microbiol. 2018;56[8]:e00546-18). “The CDC should partner with this laboratory,” Dr. Soge suggests, “and say: ‘For all the Neisseria gonorrhoeae isolate you recovered from your blood culture, can you forward it to our public health lab? We can then make sure we do surveillance of antimicrobial resistance with those.’”
- Make use of the Etest, which has been shown through the CDC program to be comparable to agar dilution methods (Raphael BH, et al. Sex Transm Dis. 2021;48[12S suppl 2]:S157–S160). Overall minimum inhibitory concentration concurrence was found to be greater than or equal to 95 percent. “Etest facilitates rapid detection and response to emerging resistant gonorrhea,” the authors wrote.
“It doesn’t take a lot of time,” Dr. Soge said of the test. “It’s not as laborious as the agar dilution.”
Rapid phenotypic N. gonorrhoeae antimicrobial susceptibility testing can’t stand alone for detection, he said. It has to be combined with a molecular assay (Hashemi MM, et al. J Clin Microbiol. 2020;58[12]:e01152-20; Melendez JH, et al. Diagn Microbiol Infect Dis. 2022;102[2]:115590).
Molecular tests for N. gonorrhoeae antimicrobial resistance detection are important, but there is no FDA-approved assay now. And there is no single molecular assay that can detect all the many genetic markers of resistance in N. gonorrhoeae.
The correlation between the detection of genetic markers and the actual MIC is not perfect, Dr. Soge said. “You can find the genetic markers there and it’s not expressed. You are not seeing an actual phenotypic resistance, so that’s something we need to pay attention to.”
Tickner, et al., in 2022 wrote of the need for a commercial test using the penA60 allele to identify ceftriaxone-resistant N. gonorrhoeae (Tickner JA, et al. Lancet Infect Dis. 2022;22[9]:1271–1272). They said the penA60 marker offers “a reliable target for molecular detection of the now predominant ceftriaxone-resistant FC428-like strains (in the absence of culture testing).”
When there’s a penA60, Dr. Soge said, the MIC to ceftriaxone is high—one or greater. In the U.S. there have been three such cases, he said, noting the difficulty of getting industry to develop an assay “when we do not see a lot of that resistance.”
On Dr. Soge’s wish list is a molecular assay that would help prevent ceftriaxone overuse. “If there’s an FDA-approved molecular assay that does a great job with fluoroquinolone, for instance, and someone can be treated with cipro instead of ceftriaxone, that would be amazing.”
For now, he said, “we still rely on culture for novel resistant mechanisms and for detection of antimicrobial resistance to new antibiotics that will be introduced,” one of which is zoliflodacin, which demonstrated clinical efficacy in phase three clinical trials. It is being developed as part of a public-private partnership between Innoviva Specialty Therapeutics and the Swiss not-for-profit Global Antibiotic Research and Development Partnership.
Sherrie Rice is editor of CAP TODAY.