Molecular assay predicts Neisseria gonorrhoeae susceptibility

The emergence of untreatable Neisseria gonorrhoeae infections has caused great concern.^1-4 Untreated or inadequately treated Neisseria gonorrhoeae infection is associated with many health consequences including pelvic inflammatory disease and infertility, neonatal blindness,⁵ and an increased risk of HIV transmission and acquisition.^6-8 And treatment with ceftriaxone may be a major driver of ceftriaxone resistance.⁹

Building on our previous discussion of multi-drug resistant gonorrhea and the potential utility of a laboratory-developed molecular assay to determine ciprofloxacin susceptibility [MLO. 2016;48(12):30], we here report on the implementation and outcomes, including costs and the frequency of clinical cure.

gyrA genotyping and targeted therapy

The use of antibiotics previously thought to be ineffective may slow the emergence of ceftriaxone resistant infections by alleviating the selective pressure.¹⁰ The use of ciprofloxacin 500 mg orally as an alternative to a 250 mg ceftriaxone injection for the treatment of Neisseria gonorrhoeae infections has been made possible by the development of a rapid genotypic assay for the determination of mutation at codon 91 of the gyrase A (gyrA) gene of Neisseria gonorrhoeae; a non-mutated (wild-type) gyrA genotype reliably predicts full susceptibility to ciprofloxacin.¹¹

In 2007, we developed a real-time polymerase chain reaction assay for gyrA genotyping remnant nucleic acid amplification DNA specimens,¹² which was verified in accordance with Clinical Laboratory Improvement Amendments.¹³ In November 2015, that assay was implemented at the University of California Los Angeles for genotyping all remnant Neisseria gonorrhoeae positive nucleic acid specimens.¹⁴ The results of the gyrA genotyping are available to clinicians within twenty-four hours and are reported in the patient’s medical record.

At the University of California Los Angeles, the use of gyrA genotyping has decreased the use of ceftriaxone for the treatment of Neisseria gonorrhoeae infections from 94 percent prior to assay implementation to 78 percent after; there was also a concomitant increase in the use of targeted ciprofloxacin therapy.¹⁴ Notably, the use of electronic reminder notification sent to providers with genotype results and treatment recommendations further augmented the use of ciprofloxacin targeted therapy, from three percent prior to reminder notifications to 18 percent after.¹⁵

Cost issues and other concerns

Given those results as well as the numerous potential benefits of gyrA genotyping and targeted therapy, further implementation of the assay in other health systems is warranted. An important consideration for future implementation, however, is the financial costs of gyrA genotype testing. A recent analysis of the direct costs of the gyrA genotyping program at the University of California Los Angeles noted that the costs vary by the prevalence of resistant infections, frequency of testing, and assay performance.¹⁶ In settings where there is a high frequency of testing (an average of 17 tests per day), with a presumed ciprofloxacin resistance rate approaching 25 percent (the national estimate¹⁷), as well as a 30 percent rate of infections with indeterminate genotype results, the cost of gyrA genotyping with genotype-based targeted therapy was only $12.41 more expensive per case than recommended two-drug ceftriaxone and azithromycin therapy.¹⁶ That cost difference may not be prohibitive given that there are other factors that must be considered.

For example, that analysis did not take into consideration the theoretical decrease in ceftriaxone-resistant infections expected with use of ciprofloxacin as an alternative regimen, nor did it take into account other potential benefits of oral therapy over injection therapy. Those benefits may include a reduction in the number of accidental needle stick injuries, an increase in the proportion of patients treated, and improved partner treatment.

One valid concern about the gyrA testing program is the lack of studies demonstrating effective treatment with ciprofloxacin among wild-type Neisseria gonorrhoeae infections. A prior study demonstrated ciprofloxacin to be 99 percent effective in treating phenotypically susceptible Neisseria gonorrhoeae infections,¹⁸ but that was not done in conjunction with genotype analysis. A clinical trial is currently underway at the University of California Los Angeles, which is evaluating patient outcomes among those with wild-type Neisseria gonorrhoeae infections treated with ciprofloxacin 500 mg orally.¹⁹ The preliminary test-of-cure data are unpublished, but are promising; between 7 and 21 days post treatment with ciprofloxacin 500 mg orally for wild-type Neisseria gonorrhoeae infections, 11 of 11 patients with repeat testing had a negative Neisseria gonorrhoeae nucleic acid amplification test result.

The view from here

In all, the use of gyrA genotyping to promote targeted oral ciprofloxacin therapy appears to be a promising strategy. The use of gyrA genotyping in conjunction with electronic reminder notifications successfully increased the proportion of patients treated with targeted oral ciprofloxacin therapy at the University of California Los Angeles. The costs of implementing the assay are considerable; however, in high frequency testing centers such as commercial laboratories, the costs of the assay may not be prohibitive given the other potential benefits. Finally, preliminary data on patient outcomes among those with wild-type Neisseria gonorrhoeae infection treated with ciprofloxacin are encouraging. Thus, gyrA genotyping for the promotion of targeted ciprofloxacin therapy is a step towards expanding our antimicrobial toolbox for treating an infection that is rapidly becoming untreatable.

Acknowledgments: This research was supported by the United States National Institutes of Health grants R21AI117256, NIH R21AI109005.

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Lao-Tzu Allan-Blitz is a fourth-year medical student at the David Geffen School of Medicine, University of California, Los Angeles.

Jeffrey Klausner, MD, MPH, is a professor of medicine in the Division of Infectious Diseases and the Program in Global Health at the David Geffen School of Medicine, University of California, Los Angeles.