When the Clap Hits Back Part II: What Clinical Labs Can Do To Prevent the Spread of Antimicrobial-Resistant Neisseria gonorrhoeae

May 28, 2018

Immediately after I discussed the threat of untreatable gonorrhea in my previous blog post, Public Health England reported treatment failure in an individual who just returned to the United Kingdom (UK) from southeast Asia, where he had a sexual contact. The patient was treated with 1 g of ceftriaxone, a dose twice that recommended for treatment of uncomplicated anogenital infection in the UK, which resolved this patient’s genital infection. However, his throat specimens collected for test of cure were persistently positive for Neisseria gonorrhoeae by culture. The report did not mention whether this patient’s initial treatment included oral azithromycin, but it may not have mattered since subsequent susceptibility testing demonstrated that the organism had an azithromycin MIC of >256 µg/mL, indicating high-level resistance. The ceftriaxone MIC in this isolate was 0.5 µg/mL, which exceeded both EUCAST and CLSI clinical breakpoints for resistance (>0.125 µg/mL and >0.25 µg/mL, respectively). An attempt to treat this patient with an alternative regimen with spectinomycin, for which the MIC was within the susceptible range, also failed. Despite the lack of clinical breakpoints for ertapenem, this intravenous (IV) antimicrobial was chosen as a last resort because of its low MIC of 0.032 µg/mL. Fortunately, this patient’s pharyngeal infection was successfully treated with a 3-day course of IV ertapenem.
 
The report shook the field of gonorrhea treatment and control and received a lot of media coverage for a good reason: ceftriaxone and azithromycin are part of the only reliable empirical regimen we have been holding on to for the past decade. Even the case from Sweden discussed in the first installment of this blog series involved isolates with maximum ceftriaxone MICs of 0.125 µg/ml, which were still considered susceptible according to CLSI clinical breakpoints, and the patient was successfully treated with 1 g of IV ceftriaxone.
 
The N. gonorrhoeae isolate in the more recent report was the first one that displayed both ceftriaxone and azithromycin MICs in the resistant range, according to clinical breakpoints from both CLSI and EUCAST. Moreover, this UK case was also the first case of true treatment failure, even after administration of high doses of ceftriaxone. Ertapenem successfully eradicated the infection in this patient, but routine IV treatment is not a practical solution. Compliance has always been a challenge when it comes to treatment of gonorrhea, and it also plays a vital role in the prevention of disease transmission and antimicrobial resistance.
 
The currently recommended regimen has been successful partly because we can administer the whole course of empirical treatment in a single clinic visit. Just imagine how many more cases of gonorrhea would go untreated and how many more transmission events would occur should a multiday course of IV antibiotics be needed for the treatment of gonococcal infections. Antimicrobial resistance in N. gonorrhoeae is no longer a looming threat, but a real problem that rears its ugly head time and again.
 
The central question for laboratorians is whether there is anything we can do to detect and help prevent the spread of drug-resistant N. gonorrhoeae. The answer is yes! Clinical laboratories can help control the spread of infection caused by these isolates by providing drug susceptibility information. We can do this by performing susceptibility testing in-house or sending isolates to a reference laboratory to help clinicians choose the right antimicrobials, especially in cases of treatment failure.

The Role of Clinical Laboratorians in Antimicrobial-Resistant Gonorrhea Prevention

Report all gonorrhea cases. Something every clinical laboratory can do is comply with local or state public health regulations that require clinical laboratories to report results of any diagnostic test positive for gonorrhea. For example, the state of California (according to Title 17 CCR §2505) requires laboratories to report positive tests for gonorrhea, among other sexually transmitted diseases (STDs), including syphilis and Chlamydia trachomatis infections, to local public health agencies. In Los Angeles County, results must be submitted to the L.A. County Department of Public Health within 1 working day after the health care provider, or other person authorized to retrieve the report, has been notified. Note that this notification does not need a patient’s consent and is not a violation of Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule. Once a report is received, public health professionals will conduct personal index or contact interviews to help the patient manage their infection and provide treatment and prevention counseling. A timely submission from the clinical laboratory after diagnosis is key to the success of this personal-level intervention.
 
Use culture and molecular identification methods. Despite the availability of NAAT, which has become a standard of care for the diagnosis of uncomplicated gonococcal infections, clinical laboratories should still maintain the ability to perform gonorrhea culture for a few reasons. Recovery of organisms in culture from clinical specimens may be crucial for the diagnosis of some complicated or invasive gonococcal infections, as some clinical specimens (blood, joint fluids, rectal or throat swabs) may not have been validated on the molecular testing platform used in the laboratory. Additionally, prompt isolation of the organism in cases of treatment failure allows for phenotypic antimicrobial susceptibility testing, the results of which may have a tremendous impact on treatment plan and infection prevention strategy. However, most clinical laboratories have abandoned routine N. gonorrhoeae culture in favor of nucleic acid amplification tests (NAATs) because several commercial high-throughput platforms allow for shorter turnaround and less hands-on time for technologists.  Even if a CO2 incubator is unavailable, clinical laboratories may use commercial growth media with built-in CO2 generators, which allow for the cultivation of N. gonorrhoeae in an ambient air incubator.
 
Perform antimicrobial susceptibility testing. With the emergence of gonococcal isolates resistant to antimicrobials that are part of the standard empirical regimen, the latest update to the CLSI M100 document (28th edition supplement) mentions that laboratories should consider performing culture and susceptibility testing for clinical isolates associated with treatment failure. The CLSI recommends 4 antimicrobials for primary testing and reporting (ceftriaxone, cefixime, ciprofloxacin and tetracycline) (Table 1B in CLSI M100-S28); however, breakpoints for other antimicrobials are also available through CLSI. According to the M100 document, the disk diffusion method may be used for susceptibility testing. Unfortunately, for determination of MICs, the agar dilution method, which requires test medium to be made in-house with varying concentrations of antimicrobials, is the only other method currently recommended by the CLSI. From an epidemiological surveillance point of view, this limitation is a big concern since MIC data would allow for early detection of “MIC creep” before the organism becomes fully resistant to antimicrobials, yet agar dilution methods are generally too labor intensive for most clinical laboratories to perform.
 
Gradient diffusion, which may be more convenient for most clinical laboratories and was

Alphabet soup 1Gradient diffusion testing of an N. gonorrhoeae isolate with an elevated ceftriaxone MIC (0.25 ug/ml).

the method used to determine ceftriaxone, azithromycin and ertapenem MICs in the UK isolate mentioned above, has been evaluated as an alternative method to agar dilution for determination of MICs in N. gonorrhoeae. Most studies comparing the performance of gradient diffusion strips to that of agar dilution method had excellent categorical agreement and reproducibility for susceptibility to ceftriaxone, cefixime and ciprofloxacin between the 2 methods, with most of the variation within a 2-fold dilution. Although CLSI has not included gradient diffusion in its guidelines, this method of testing may be adopted by clinical laboratories to aid epidemiological surveillance and determination of susceptibility in cases of treatment failure.
 
Tracking antimicrobial resistance in N. gonorrhoeae is not an easy task for clinical laboratories. Growing the organism is easy to do, but susceptibility testing remains a challenge. Here in the US, instead of attempting to validate non CLSI-approved antimicrobial susceptibility methods, it is advisable (and may even be required) to report all cases of treatment failure to public health authorities and refer all isolates to local public health laboratories.
 
Stay tuned for my next and final blog post in this series, where I’ll discuss molecular approaches to predict antimicrobial susceptibility in N. gonorrhoeae and how they can be instrumental in an effort to track and control antimicrobial resistance in this organism.
 
Catch up with the first post, When the Clap Hits Back: Antimicrobial Resistance Threats in Neisseria gonorrhoeae. Read the final part in the series, When the Clap Hits Back Part III: Molecular Mechanisms of Resistance in Neisseria gonorrhoeae and How Molecular Tests May Save Us All.

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.