A laboratory dilemma; to authorise or not to authorise, that is the question?

You are busy reading the culture plates in the laboratory when you come across a sample from the Genitourinary Medicine (GUM) clinic growing a Neisseria gonorrhoeae reported as resistant to Ceftriaxone, Azithromycin, Doxycycline, Cefixime and Ciprofloxacin. What would you do? Would you authorise this as normal or would you do anything else? Hopefully this type of resistance pattern would ring alarm bells and prompt further work, but why?
 
The rising incidence of STIs
In 2015 there were about 435,000 Sexually Transmitted Infections (STIs) diagnosed in the UK. The majority of these were chlamydia at about 200,000. Worryingly the number of cases of gonorrhoea were over 41,200 (an increase of 53% since 2012) and syphilis 5,300 (76% increase since 2012). A lot of the increase is in men who have sex with men (MSM); 80% of gonorrhoea and 90% of syphilis has been in MSMs.

Global Incidence of gonorrhoea, 2005

Click for larger image

The current treatment regimen recommended by the British Society for Sexual Health and HIV (BASHH) is IM Ceftriaxone 500mg PLUS PO Azithromycin 1g as single doses. The incidence of Ceftriaxone resistance in the UK is currently very low at 0-0.2% but Azithromycin resistance is increasing and is now 1-1.6%. The WHO recommends changing empirical treatment when resistance reaches 5% but where would we go to next? How likely are we to reach a situation when we would need to change?
 
At present there is an outbreak of Azithromycin resistant Neisseria gonorrhoea in the UK. The outbreak originated in Leeds in November 2014 but has since spread to other areas of the UK. As of August 2016 there have been 48 cases with the same Azithromycin resistant strain of bacteria. This may not sound like a lot but the potential for wider spread is very worrying.
 
In addition to the ongoing outbreak, earlier this year the first case of gonorrhoea treatment failure was reported from the UK in the New England Journal of Medicine. The patient had acquired a strain of bacterium from Japan resistant to ALL of the commonly used antibiotics including Ceftriaxone, Azithromycin, Cefixime, Cefotaxime, Penicillin, Tetracycline and Ciprofloxacin. This resistant bacterium had multiple resistance mechanisms:

• Altered penicillin binding proteins reducing the binding of Ceftriaxone
• Enhanced efflux pump which pumps out Ceftriaxone and Azithromycin
• Altered porins in the cell membrane which reduce Ceftriaxone and Azithromycin entry into the bacterium

Together these mechanisms made the bacterium highly resistant to first-line Ceftriaxone and Azithromycin.
 
Why worry about gonorrhoea?
The most common presentation of gonorrhoea is urethral discharge, sometimes associated with abdominal pain and dysuria. The majority of infections are not debilitating but can cause some discomfort as well as embarrassment. However treatment is always recommended as there are a number of serious complications if gonorrhoea is left untreated.
 
The most common serious complications of untreated gonorrhoea are infertility and pelvic inflammatory disease but it can also cause severe septic arthritis and blood stream infections in an estimated 0.5-3% of patients. In pregnancy gonorrhoea can be transmitted to the baby causing opthalmia neonatorum which can lead to neonatal blindness.
 
So why is the newly reported resistance a problem?
It’s due to the number of cases and ease of spread of the disease. For example, in the 1970s the incidence of gonorrhoea in the USA was at its peak, with 500 cases per 100,000 population per year. That’s a lot of infections! In fact it’s 100 times more infections than meningitis in the UK last year which was only 5 per 100,000 cases. If we extrapolate these USA figures to the current UK population of 60 million, it would mean 300,000 cases per year (500 cases per 100,000). If we add an inability to treat gonorrhoea due to resistance, these numbers could go even higher, especially as the only drug left to treat antibiotic resistant N. gonorrhoea is Spectinomycin which is not only unlicensed in the UK but also very difficult to get hold of due to quality and supply issues.
 
So what can be done?
Public health messages about safe sex don’t seem to be working. Although the incidence of chlamydia seems to have plateaued the number of cases of other types of STI are increasing, especially gonorrhoea and syphilis. On top of this we are starting to run out of treatment options for gonorrhoea in particular.
 
The approach of Public Health England includes:

• A concerted effort to promote sexual health and change public attitude towards safe sex
• Robust contact tracing of cases of STIs especially for antibiotic resistant infections
• Ongoing surveillance of antibiotic resistance in STIs to detect and respond to outbreaks in a timely and effective manner
• Promotion of appropriate treatment of gonorrhoea with dual therapy and test of cure following treatment

 
So why does that test result you are looking at matter?
So let’s go back to the scenario at the start of this blog; the N. gonorrhoea resistant to Ceftriaxone, Azithromycin, Doxycycline, Cefixime and Ciprofloxacin and what to do about it. This is what I would do:

1. Confirm the identification of the bacterium; is it definitely N. gonorrhoea and is the growth pure?
2. Check the reported antibiotic sensitivities against the culture plates; is the reported resistance correct compared to the zone sizes
3. Test Ceftriaxone and Azithromycin sensitivity by MIC e.g. using Etest if available as this is much more accurate than disc diffusion and often shows that the original resistant result was incorrect
4. Repeat disc diffusion tests to confirm all sensitivity and resistance results
5. Alert the Duty Microbiologist to the result
6. Prepare the isolate for sending to the reference laboratory for further testing and confirmation
7. Consider how to write this up for the New England Journal of Medicine, as this is significant and extremely rare!

If the resistance results are confirmed the Duty Microbiologist should contact the GUM Consultant and suggest they consider notifying Public Health England. This may sound like passing the buck, however the notification is tricky. In order to notify PHE you need to disclose the patient’s details, simple…a Microbiologist can do that… but GUM is covered by specific legislation that protects patient anonymity, no one outside GUM knows the patient’s details…just a code. All GUM samples are coded rather than have patient identifying details. I suspect it would be up to the GUM Consultant to consider whether there was sufficient risk to others that might justify breaching patient confidentiality and reporting their details to PHE. But what about contact tracing, I hear you cry? This is different because there is no need to inform a contact of who the original case was so the patient’s confidentiality can be maintained. These confidentiality laws exist to encourage patients with STIs to seek treatment.
 
So you repeat the tests, check the MICs and realise that the microorganism is actually sensitive to both Ceftriaxone and Azithromycin! You heave a sigh of relief and calmly send the result through to the Consultant Microbiologist for authorisation. Another crisis averted…although resistance remains at large.
 
On the 21st September 2016 the United Nations held a general assembly to discuss the problem of antimicrobial resistance. The World agrees that something needs to be done, in fact it has been on the UK political agenda since “Getting ahead of the curve” in 2001, and although there maybe international agreement as to what needs to be done, no one knows exactly how to overcome the barriers to achieve this.

Prevention of STIs via safe sex messages is also vital, a message that the Thai restaurant chain "Cabbages & Condoms" loudly and proudly endorses ... conceptualised to provide funding for health projects, promote better understanding of STIs and acceptance of family planning ... They boast their food is guaranteed not to cause pregnancy!