When the Clap Hits Back: Antimicrobial Resistance Threats in Neisseria gonorrhoeae

March 26, 2018

The CDC is warning about the possibility of gonorrhea becoming "untreatable." In part 1 of a 3-part series, we will discuss the long history of antimicrobial treatment for gonococcal infections, and find out why antimicrobial resistance in Neisseria gonorrhoeae has been classified as an urgent threat to public health.

Neisseria gonorrhoeae renderingNeisseria gonorrhoeae rendering from CDC.

Imagine a man in his early 20s who visits his primary care physician with complaints of urethral discharge, dysuria and a sore throat. He mentions having been in Japan a few days before, where he had a protected vaginal intercourse and oral sex with a female partner. His physician sends him home with amoxicillin and refers him to an STD clinic. A urine specimen collected during this visit is positive for Neisseria gonorrhoeae by PCR. Unsurprisingly, at his STD clinic visit, the patient reports no resolution of any symptom despite having been on amoxicillin for 10 days. At this visit, he finally gets a shot of ceftriaxone intramuscularly, and his urinary symptoms subside. However, his throat is still inflamed and his pharyngeal cultures are persistently positive for the star of today's show (in case you haven't figured out, it's N. gonorrhoeae, shown at right). Over the next two months, he makes two additional trips to the clinic, during which increasing doses of ceftriaxone are administered. That means 2 more painful shots on top of the sore throat that just won't go away, even with a treatment that is supposed to work like a charm. At the third visit, he is administered 1 g of ceftriaxone, after which his symptoms are resolved and his pharyngeal culture is negative for N. gonorrhoeae.

This case isn't hypothetical—it actually took place in Sweden in 2010. The good news is this gentleman was finally cured, and fortunately there are not too many case reports of ceftriaxone treatment failure, all of which had been exclusively pharyngeal infections. The bad news is, although we have yet to see a case of ceftriaxone treatment failure in the US or Canada similar to the one mentioned above, the global outlook of antimicrobial resistance in N. gonorrhoeae suggests that it is only a matter of time. Antimicrobial resistance in N. gonorrhoeae has been categorized by the CDC as an "urgent threat," alongside other horrific organisms such as Clostridioides difficile and carbapenem-resistant Enterobacteriaceae. Some readers may wonder what makes N. gonorrhoeae so exceptionally threatening that it warrants its own bullet point. To address this question, we need to go back in time and examine the tumultuous relationship between people and one of the one of the oldest known human diseases.

Human beings, which are the only known hosts of N. gonorrhoeae, have been fighting the organism and its associated diseases, also known as "the clap," throughout recorded history, with special mention in ancient Chinese writings and the Book of Leviticus. Remedies ranging from peppers and plant extracts to metallic compounds were used in conjunction with procedures such as hyperthermia and urethral irrigation in attempts to relieve symptoms. The antimicrobial era for the treatment of gonorrhea started when sulfanilamide was discovered in 1935. Despite the sulfanilamide elixir tragedy in 1937, sulfonamide compounds were still enthusiastically welcomed among the medical community and quickly became a mainstay in treatment of gonococcal infections.

Sign advertising penicillin to cure gonorrhea in the 1940sSign from the 1940s advertising penicillin to treat gonorrhea Source.

The success of sulfonamides, however, did not last long, as the organism developed widespread resistance to these agents within the first ten years or so, resulting in treatment failures. Further research into sulfonamide resistance revealed the expected effect of selective pressure, where the use of popular sulfonamide-based antimicrobial regimens resulted in selection of organisms that had developed multiple mechanisms to antagonize the antimicrobial effects of these agents. These included the ability to synthesize more of the drug target molecules to dilute the inhibitory effects, or acquisition of mutations that prevented the drugs from binding to their targets. Fortunately, penicillin was there to save the day. This then-magical drug had been around for a while, but it was not until the early 40s when major pharmaceutical companies started to ramp up production of the drug to get ready for D-day during World War II (see photo, right). Penicillin was quickly adopted as a treatment of choice for gonorrhea and remained effective throughout the next few decades despite a continuous and insidious increase in MICs. The discovery of infectious isolates harboring plasmid-mediated beta-lactamases in 1976 and subsequent worldwide spread of such plasmids rendered penicillin unsuitable as an empirical treatment. Several chromosomal elements conferring resistance to penicillin that arose during the last few years of the penicillin era were the last nails in the coffin for a cure once thought to be forever effective.

Throughout the next few decades, scientists and clinicians were hard at work trying to seek the next ideal treatment option. New agents thought to be effective as empirical treatment such as tetracycline, spectinomycin, fluoroquinolones, and an oral extended-spectrum cephalosporin (ESC) cefixime, swiftly came and went as the organism navigated its way to acquire a literal alphabet soup of genetic elements and mutations to help it survive whichever drug humans had in store for it.

Currently, the CDC recommends an intramuscular shot of an ESC, ceftriaxone, plus one oral dose of azithromycin as an empirical treatment for uncomplicated or pharyngeal gonococcal infections. This double regimen has been working very well for the past decade, but clinical and public health microbiology laboratories are starting to see the ominous trend that was once observed during penicillin's heydays: the upward "creep" in cefixime and ceftriaxone MICs among N. gonorrhoeae isolates. Isolates with increased cefixime and ceftriaxone MICs have been popping up here and there all around the world. The alarming decrease in cefixime susceptibility from 2009 to 2011, and reports of treatment failures resulted in cefixime being removed from a lineup of agents recommended by the CDC for empirical treatment of gonococcal infections. For ceftriaxone, which remains a key player in the current empirical regimen, the prevalence of isolates with elevated ceftriaxone MICs (>0.125 μg/mL according to the CDC) in the US increased from 0.4% in 2013 to 0.8% in 2015.

The increase of ceftriaxone MICs among N. gonorrhoeae is particularly concerning, since a pharmacodynamic modeling using Monte Carlo simulations suggested that the standard dose of ceftriaxone for gonorrhea (250 mg) may fail to achieve adequate time of free drug above the MIC for organisms with ceftriaxone MICs of 0.125-0.25 μg/mL. Although there is currently no study that demonstrates a direct association between isolates with ceftriaxone MICs within this range and negative patient outcome, N. gonorrhoeae with ceftriaxone MICs 0.125-0.25 μg/mL were often isolated from cases of ceftriaxone treatment failure.

Tracking antimicrobial resistance trends in N. gonorrhoeae is not a trivial task, even in countries where a national reporting system is put in place to monitor susceptibilities among clinical isolates. Estimation of prevalence of resistance could be exceedingly challenging, as several factors could introduce bias into these studies. For example, surveillance of antimicrobial resistance in N. gonorrhoeae in the US is conducted by the Gonococcal Isolate Surveillance Project (GISP), which is a collaborative project between selected STD clinics in the US, public health authorities,  GISP regional laboratories, and the CDC. As previously mentioned, data from their 2015 report indicated a 0.8% prevalence of isolates with elevated ceftriaxone MICs in the US. This may seem trivial, but it is very likely that the increase in ceftriaxone MICs is largely underreported. A shift to molecular diagnosis as a standard of care resulted in abandonment of routine culture and susceptibility testing among clinical laboratories in the US, hence a lack of data on actual ceftriaxone MIC distribution among clinical isolates. Additionally, the potential loss in ceftriaxone's efficacy as a monotherapy in the treatment of gonococcal infections may have been masked by the effect of azithromycin, which is part of the current CDC recommendation. Method of sampling could affect the analysis as well. Although the enrollment protocol for GISP was designed to minimize bias by using systematic sampling (the first 25 men who attend a participating STD clinic each month), the surveillance does not include females, and only urethral isolates are collected. Moreover, there seems to be a relative oversampling from the western US, where resistant isolates often emerge, in comparison to the southern US States, where the disease prevalence is high but the resistance rate is reportedly low. With this these limitations, GISP surveillance results may be biased towards urethral isolates from the male population sampled and not representative of isolates from other sources in communities throughout the country.

As for the treatment of uncomplicated gonorrhea, the double regimen with azithromycin still works—for now. Although there has only been one case report of treatment failure following a dual antimicrobial regimen, azithromycin resistance among N. gonorrhoeae is on the rise.  Data from CDC's Gonococcal Isolate Surveillance Project (GISP) demonstrated an alarmingly increased prevalence of N. gonorrhoeae isolates with non-wild-type azithromycin MICs as defined by the CLSI (>2 μg/mL), from 0.6% in 2013 to 2.6% in 2015. Moreover, a fairly recent report from the Hawaii Department of Health described 8 N. gonorrhoeae isolates from 7 patients with high-level resistance to azithromycin (>256 μg/mL) and reduced susceptibility to ceftriaxone and cefixime (0.125-0.25 μg/mL). Nevertheless, all patients were successfully treated with a standard double regimen, as azithromycin resistance in N. gonorrhoeae does not necessarily indicate treatment failure. A possible explanation would be the fact that azithromycin is rarely used as a monotherapy for gonorrhea, and most azithromycin-resistant isolate are still susceptible to ceftriaxone. However, as the organism continues to develop resistance to ceftriaxone, we might end up with isolates highly resistant to both agents in the near future. Although new antimicrobials and combination regimens are being evaluated, it is imperative that we keep monitoring resistance trends, and devise a strategy to make sure our current empirical regimen stays effective for as long as possible and prevent gonorrhea from actually becoming "untreatable."

On my next blog post, we will discuss some of the challenges in antimicrobial susceptibility testing of N. gonorrhoeae, and why rapid molecular screening tests could serve as valuable tools to help us keep track of antimicrobial resistance in N. gonorrhoeae.

The above represents the opinions of the author and does not necessarily reflect those of the American Society for Microbiology.

Author: Peera Hemarajata

Peera Hemarajata
Peera Hemarajata is a diplomate of the American Board of Medical Microbiology and an Assistant Director at Los Angeles County Public Health Laboratories. His research interests include emerging infectious diseases, molecular assay development, antimicrobial resistance, and microbial genomics.