Emerging pathogens and antibiotic resistance make STIs an urgent challenge

The landscape of sexually transmitted infections (STIs) has been shifting rapidly in recent years, with prevalence rates of certain STIs climbing and new diseases taking a toll. There is a disproportionate disease burden among high-risk populations such as pregnant women, sexually active adolescents, men who have sex with men (MSM), and HIV-infected individuals. In some of these populations, STI co-infections are much more frequent than they are in the general population.¹

Testing for STIs has always been complex due to the asymptomatic occurrence of some of the most common infections, such as herpes simplex virus (HSV) 1 and 2. There are at least 50 million individuals infected with HSV2 in the United States, of which only 10 percent to 25 percent have been diagnosed.² Diagnostic difficulties are compounded further due to the rapid emergence of antibiotic resistance, with STIs like N. gonorrhoeae and M. genitalium evolving into STI “superbugs.” Prevention of these superbugs warrants the need for widespread antimicrobial resistance surveillance.

Some STIs that were thought to be well contained, such as syphilis, are reemerging. With nearly 28,000 known cases in the U.S. in 2016, a 17.6 percent increase compared to 2015, syphilis prevalence is on the rise.³

For clinical labs working to diagnose STIs, these emerging trends and newer diseases can be extremely confounding.

Molecular detection of STIs

Molecular testing offers sensitive and faster STI diagnosis compared to culture-based and other conventional assays, thereby improving patient outcomes. Higher-sensitivity detection of trichomoniasis, which is commonly underdiagnosed because of the low sensitivity of wet mount microscopy methods, is now possible due to the adoption of molecular platforms. Even for diseases such as genital herpes where the infection cannot be cured, higher sensitivity improves patient and partner management.

In some cases, however, FDA-cleared molecular tests are not available. There is a pressing need for a molecular test for M. genitalium, a fastidious organism for which culture takes far too long to yield medically actionable results. In select labs, M. genitalium is diagnosed by molecular testing of urine or urethral, vaginal, or cervical swabs, typically using in-house PCR assays that can be validated as laboratory-developed tests (LDTs).⁴ Data generated using these LDTs indicates a 1.1 percent to 3.3 percent prevalence rate for M. genitalium in the general population.^5,6 However, the true prevalence may be severely underestimated.

Antibiotic resistance

For many STIs, it is as critical to detect markers of drug resistance as it is to perform pathogen identification. N. gonorrhoeae and M. genitalium, in particular, have very high rates of antibiotic resistance. The CDC made it a priority to fund projects designed to tackle gonorrhea resistance as an urgent threat. The CDC also recently updated its treatment guidelines to slow the emergence of cephalosporin resistance, which will greatly limit treatment options and could cripple gonorrhea control efforts.⁴

The substantial decline in the capability of laboratories to perform essential gonorrhea culture techniques required for antibiotic resistance/susceptibility testing is a major challenge to monitoring emerging antimicrobial resistance in N. gonorrhoeae.⁷ Molecular testing has been piloted as a means of identifying antibiotic resistance markers, with those results guiding treatment paths for patients. A recent study at the University of California, Los Angeles, demonstrated the use of a rapid genotyping assay to predict whether N. gonorrhoeae strains were susceptible or resistant to ciprofloxacin.⁸ The study led to reduced reliance on broad-spectrum antibiotics and increased use of more targeted therapies that led to improved patient outcomes.

The need for genotypic resistance marker typing is even more pronounced for M. genitalium, as its slow growth rate obviates a phenotypic antibiotic susceptibility testing approach. M. genitalium exhibits a remarkable capacity to develop antimicrobial resistance—specifically to the macrolide azithromycin—very rapidly after introduction of treatment.^9,10 In fact, there are high rates of macrolide resistance reported in the U.S. already for M. genitalium, with some areas recording resistance rates as high as 50 percent.¹¹ One school of thought is that syndromic management of non-gonococcal urethritis using macrolide antibiotic treatments causes strains containing macrolide mutations to predominate, resulting in drug resistance.¹² This has already led to European STI treatment guidelines advocating for the detection of macrolide resistance-mediating mutations in all M. genitalium positive cases.¹³

Looking ahead

Emerging STIs and high rates of associated antibiotic resistance are poised to become major public health threats, caused in part by the syndromic management activities that lead to overuse of broad-spectrum antibiotics. There is a critical need for resistance typing for gonorrhea that might become untreatable, if resistance emerges to the current dual therapy regimen.

Additionally, M. genitalium has already become a difficult bacterium to treat on a syndromic basis. In the ideal clinical setting, specific diagnostic tests for M. genitalium would be as readily available as tests for C. trachomatis and N. gonorrhoeae, and detection of both N. gonorrhoeae and M. genitalium would be accompanied or followed by molecular detection of drug resistance-mediating mutations. Due to the unique aspects of these two STIs, a precision-based treatment approach guided by their resistance profile post-diagnosis might be more useful than the current syndromic approach.

Even when they are not antibiotic-resistant, STIs represent an urgent area of clinical and diagnostic need. The emergence of new STIs, combined with the re-emergence of infections long thought to have been overcome, make this a dynamic and important field. Molecular testing must continue to improve for this segment of public health, in order to provide reliable results for an increasing number of sexually transmitted pathogens with faster turnaround times and more robust workflows.

REFERENCES

1. Hayes R, Watson-Jones D, Celum C, van de Wijgert J, Wasserheit J. Treatment of sexually transmitted infections for HIV prevention: end of the road or new beginning? AIDS. 2010;24(suppl 4): S15-S26.
2. Beauman JG Genital herpes: a review. Am Fam Physician. 2005;72(8):1527-1534.
3. Centers for Disease Control and Prevention. The State of STDs—Infographic (webpage). Updated September 26, 2017. https://www.cdc.gov/std/stats16/infographic.htm
4. Centers for Disease Control and Prevention. 2015 Sexually Transmitted Diseases Treatment Guidelines. https://www.cdc.gov/std/tg2015/default.htm
5. Manhart LE, Holmes KK, Hughes JP, Houston LS, Totten PA. Mycoplasma genitalium among young adults in the United States: an emerging sexually transmitted infection. Am J Public Health 2007;97(6):1118-1125.
6. Sonnenberg P, Ison CA, Clifton S, et al. Epidemiology of Mycoplasma genitalium in British men and women aged 16-44 years: evidence from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Int J Epidemiol.2015;44(6):1982-1994.
7. Centers for Disease Control and Prevention. The growing threat of multidrug-resistant gonorrhea. https://www.cdc.gov/cdcgrandrounds/archives/2012/May2012.htm
8. Allan-Blitz L-T, Humphries RM, Hemarajata P, , et al. Implementation of a rapid genotypic assay to promote targeted ciprofloxacin therapy of Neisseria gonorrhoeae in a large health system. Clin Infect Dis. 2017;64(9) 1268–1270.
9. Jensen JS, Bradshaw C. Management of Mycoplasma genitalium infections—can we hit a moving target? BMC Infect Dis. 2015;15(1):343.
10. Unemo M, Jensen JS. Antimicrobial-resistant sexually transmitted infections: gonorrhea and Mycoplasma genitalium. Nature Reviews Urology. 2017;14(3):139-152.
11. Getman D, Jiang A, O’Donnell M, Cohen S. Mycoplasma genitalium prevalence, coinfection, and macrolide antibiotic resistance frequency in a multicenter clinical study cohort in the United States. J Clin Microbiol. 2016;54(9):2278–2283.
12. Horner P, Blee K, Adams E. Time to manage Mycoplasma genitalium as an STI: but not with azithromycin 1 g! Curr Opin Infect Dis. 2014;27(1):68-74.
13. Jensen JS, Cusini M, Gomberg M, Moi H. 2016 European guideline on Mycoplasma genitalium infections. J Eur Acad Dermatol Venereol. 2016;30(10):1650-1656.

Anjana Bhattacharya, PhD, serves as Global Product Manager for Women’s Health at Luminex, with responsibility for its ARIES GBS and HSV 1&2 assays.