Saw this article in the Straits Times this morning, and was reminded that I had wanted to follow up on the issue of drug resistance in Neisseria gonorrhoeae. There has not been a case of “super gonorrhoea” in Singapore to my knowledge, but it is a matter of time before such cases appear locally.

Neisseria gonorrhoeae is a Gram-negative coccoid bacterium (a microscope view below) that is the cause of the sexually-transmitted disease gonorrhea as well as other disease manifestations such as septic arthritis, gonorrhea throat (which presents as sore throat), disseminated gonococcemia, and gonococcoal keratoconjunctivitis (which presents as red eye). The bacterium was discovered in 1879 by German physician Dr Albert Ludwig Sigesmund Neisser.

Gram stain from a urethral swab – intra- (and extra-) cellular Neisseria gonorrhoeae.

It is an ancient disease of humans, with a (perhaps outdated) argument that the first description can be found in 黄帝内经 (the Yellow Emperor’s Classic of Medicine) which dates back to 2,600 BC. The Greek physician Aelius Galenus was believed to have named the disease gonorrhea (after “gonos” – semen and “rhoea” – flow) because he mistook the flow of pus from the urethra for “involuntary flow of semen”. The disease is also mentioned in the Bible (Leviticus 15:2 “Speak unto the children of Israel, and say unto them, when any man hath a running issue out of his flesh, because of his issue he is unclean.”), although of course, this could similarly refer to chlamydial urethretis.

It is the second most common notifiable sexually transmitted infection in Singapore, with 1,872 cases in 2016.

A variety of compounds were used to treat gonorrhea with mixed success until the discovery of antibiotics, with first sulfa drugs and then penicillin being used with resounding success. The picture below, available on Wikipedia, expresses the situation then better than a thousand words. I was told an apocryphal story by an old American physician that penicillin was preferentially used – because of its scarcity during World War II – to treat soldiers with gonorrhea and syphilis rather than those with infected war injuries, as the former could return to the battlefield (the latter would normally be shipped home). I was subsequently unable to substantiate this story, however,

As with many other pathogens, Neisseria gonorrhoeae soon developed resistance to many of the different antibiotics used in its treatment. This is detailed in an excellent article by Unemo and Shafer in Clinical Microbiology Reviews in 2014, and I include their nice timeline of drug use and resistance, along with the mechanisms of drug resistance, below.

Screenshot of a figure from Unemo & Shafer, Clin Microbiol Rev 2014.

Penicillin was the mainstay of gonorrhea treatment until the 1970’s, when the spread of plasmid-mediated penicillinases put the final nail in the coffin of a drug that had already seen multiple treatment failures worldwide as a consequence of cumulative chromosomal mutations that reduced the affinity of penicillin-binding proteins to penicillin as well as those that reduced penetration or increased efflux of the drug from the bacterium.

Tetracyclines (i.e. doxycycline) fared a little better, but by the 1980s, the story of tetracycline resistance mirrored that of penicillin resistance, with the emergence and spread of a plasmid-mediated tetM on top of background chromosomal mutations that resulted in high-level tetracycline resistance. tetM belongs to a common bacterial family of ribosomal protection proteins that directly dislodges tetracycline molecules that bind to and affect the ribosomes in bacteria.

The fluoroquinolones became widely used in the 1980s to treat gonorrhea and other sexually-transmitted infections, but as with other bacteria, resistance to this class of antibiotics soon developed in the form of chromosomal mutations that resulted in fluoroquinolone target modifications. These fluoroquinolone-resistant bacteria arose in multiple locations globally and spread rapidly, resulting in fluoroquinolones being removed from the published treatment guidelines for gonorrhea by the end of the first decade of the 21st century. More than 70% of N. gonorrhoeae isolates in Singapore are resistant to ciprofloxacin, a situation that has remained unchanged for more than a decade. The situation is little better in the region.

Screenshot of a table from the WHO Western Pacific Region report on gonococcal resistance. Figures are from the year 2015.

“Super gonorrhea” as used in the press defines cases of gonorrhea where the current combination treatment regimen of an extended-spectrum cephalosporin (commonly ceftriaxone) and the macrolide azithromycin have failed. These cases are rare at present, but there is little reason to believe that such extensively drug-resistant (XDR) gonococcal strains will not spread, given the history of gonococcal antibiotic resistance as outlined above. Ceftriaxone resistance is mediated by a combination of chromosomal mutations that both reduce the affinity of penicillin-binding proteins to the drug as well as increase the speed at which the drug is pumped out from the bacterium, whereas azithromycin resistance is caused both by drug extrusion and chromosomal mutations that modify the target site.

Unlike the case with other Gram-negative bacteria, there are still a fair number of drugs that can be used against “super gonorrhea”. The challenge is that gonorrhea like many sexually transmitted infections has conventionally been treated in an outpatient setting, and there is an implicit paradigm that such treatment should be short-term – preferably single dose (to avoid the issue of non-adherence) – cheap, safe and effective. The issue is that these other drugs are either less effective (i.e. gentamicin single dose has a pooled cure rate of only 91.5% and will need to be combined with a second effective drug) or expensive (ertapenem, tigecycline, and newer-generation fluoroquinolones). Clinical trials will also need to be performed for the newer drugs, and suitable combinations that are applicable for an outpatient setting will need to be developed.