Thursday, August 17, 2017

Gonococcus superbug: Current Status

Photo 1: Neisseria gonorrhoeae.
Source
Neisseria gonorrhoeae or what is commonly known as the gonococcus is sounding serious alarms all over the globe. In a post almost an year ago, I talked about how gonococcus is slowly rising to the status of true superbug. Gonococcus is responsible for a sexually transmitted disease called as Gonorrhea. Decades ago, this was absolutely treatable with a simple penicillin. However, they have now acquired several genes that makes it more untreatable.

Table 1: Resistance pattern of Gonococcus. Source
Here is the summary of current issue based on WHO reports in June. WHO has estimated that nearly 78 million people are infected with gonococcus. There are countries that are reporting their annual statistics and some countries that dont. The current recommended regimen for gonorrhea treatment is a combination of azithromycin and ceftriaxone. Table 1 shows a summary of number of countries in different WHO regions reporting gonococcal isolates with resistance to azithromycin and ciprofloxacin, and decreased susceptibility or resistance to extended-spectrum cephalosporin (Cefixime and/or ceftriaxone) for at least 1 year from 2009 to 2014. It should be noted that the report is based on data from 77 countries. Most African nations where the percentage of gonorrhea is expected to be higher has not reported. Interestingly, WHO has reported 3 confirmed cases of gonococcus that are resistant to all the anitbiotics tested. 

“These are cases that can infect others. It can be transmitted. And these cases may just be the tip of the iceberg, since systems to diagnose and report untreatable infections are lacking in lower-income countries where gonorrhea is a ctually more common.”
-Teodora Wi (Department of Reproductive Health and Research, WHO)

“To control gonorrhoea, we need new tools and systems for better prevention, treatment, earlier diagnosis, and more complete tracking and reporting of new infections, antibiotic use, resistance and treatment failures. Specifically, we need new antibiotics, as well as rapid, accurate, point-of-care diagnostic tests – ideally, ones that can predict which antibiotics will work on that particular infection – and longer term, a vaccine to prevent gonorrhoea.”
-Marc Sprenger, (Director of antimicrobial resistance, WHO)

By now you understand that gonorrhea is a serious issue and needs to be addressed qucikly. Vaccine is an excellent choice. But vaccine research in gonorrhea isn't so great and there are no candidates in sight that are ready to be launched. Howewer, there is a silver lining.

A study was recently published which retrospectivly looked into vaccine effectiveness of outer membrane vesicle meningococcal B vaccine (MeNZB) in a case-control study of patients at sexual health clinics aged 15–30 years. They found that the gonorrhea rate among teens and young adults who had received a meningitis B vaccine during an emergency campaign in the early 2000s was significantly lower than the rate seen in people of the same age who weren’t vaccinated. The estimated vaccine effectiveness of MeNZB against gonorrhoea was about 31%. Of course its a chance observation and some form of clinical trial needs to be done to have more credibitily for the claim and get a more realistic estimate. There are also similar reports of decline in gonorrhea rates follwing meningococcal vaccine in Cuba, and Norway.

There is a lot of effort currently in trying to come up with new antibiotics especially ones that can target such superbugs. A compound referred to as closthioamide has been shown to have promising results against drug resistant gonococcus.

Fig 1: Structure of Clostioamide.
Source
Closthioamide (CTA) was first discovered and isolated from Anaerobic Bacterium Clostridium cellulolyticum in 2010 which was initially tested as a possible compound against multi drug resistant Staphylococcus. It functions through attacking DNA gyrase. In brief, the researchers tested 149 strains isolated from patients, 8 WHO reference strains of of N. gonorrhoeae and 4 commensal Neisseria strains were tested. CTA performed really well against 146/149 (98%) of clinical gonococcal strains at ≤0.125mg/L. The study also noted that two N. perflava strains had the highest CTA MIC (>1 mg/L).

As the senior author of the study John Heap comments, "The imminent threat of untreatable antibiotic-resistant infectious diseases, including gonorrhoea, is a global problem, for which we urgently need new antibiotics. This new finding might help us take the lead in the arms race against antimicrobial resistance. We believe there are many undiscovered antibiotics out there in nature, but they are difficult to find and test. For example, the bacteria which produce closthioamide naturally make only tiny amounts that are not enough to test or use, so we had to chemically manufacture it ourselves by mimicking its natural structure. The next step will be to continue lab research to further assess the drug's safety and effectiveness. Despite showing tremendous promise, it will be a number of years before, and if, we can use the drug in real life human cases."

As of now there is no clear answer as to how to tackle the globally spreading true superbug "gonococci" is to be controlled. Perhaps the best method is the same as standard STD prevention methods.

References:

1. Wi T, Lahra M, Ndowa F, Bala M, Dillon J, Ramon-Pardo P et al. Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action. PLOS Medicine. 2017;14(7):e1002344. 

2. Petousis-Harris H, Paynter J, Morgan J, Saxton P, McArdle B, Goodyear-Smith F et al. Effectiveness of a group B outer membrane vesicle meningococcal vaccine against gonorrhoea in New Zealand: a retrospective case-control study. The Lancet. 2017; doi: 10.1016/S0140-6736(17)31449-6. [Epub ahead of print]

3. Miari V, Solanki P, Hleba Y, Stabler R, Heap J. In vitro susceptibility to closthioamide among clinical and reference strains of Neisseria gonorrhoeae. Antimicrobial Agents and Chemotherapy. 2017;:AAC.00929-17.

4. Lincke T, Behnken S, Ishida K, Roth M, Hertweck C. Closthioamide: An Unprecedented Polythioamide Antibiotic from the Strictly Anaerobic Bacterium Clostridium cellulolyticum. Angewandte Chemie. 2010;122(11):2055-2057.