Explore the latest advancements in the management and prevention of sexually transmitted infections (STIs).
This CME covers common STIs, including Gonorrhea, Syphilis, Chlamydia, Trichomoniasis, HIV, Genital Herpes Simplex, Human Papilloma Virus (HPV), and Mycoplasma genitalium.
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Reviewed and edited by Harish Moorjani MD
This article highlights the latest advancements in the management and prevention of adult sexually transmitted infections (STIs). We’ll explore updated treatment recommendations, promising new therapies and vaccine developments for some common STIs.
Gonorrhea
According to the Centers for Disease Control (CDC), there were 601,319 reported cases of gonorrhea, caused by Neisseria gonorrhoeae, (a gram-negative diplococcus bacterium) in the U.S. in 2023, a decrease of 7% from 2022.[1,2] Globally, in 2022, the World Health Organization (WHO) estimated that there were 82 million gonorrhea infections.[3]
Gonorrhea typically presents with a white, yellow or greenish vaginal or urethral discharge. More serious disease such as pelvic inflammatory disease, conjunctivitis (also seen in newborns if the mother is infected), pharyngitis, and disseminated infection with the possibility of arthritis, skin lesions, meningitis or endocarditis.
There are three major updates in the treatment of gonorrhea. The first is the concerning emergence of drug-resistant Neisseria gonorrhoeae, unresponsive to ceftriaxone therapy. Ceftriaxone-resistant isolates increased in China from 2.9% in 2017 to 8.1% in 2022.[4] In 2020 the CDC increased the standard dosage of ceftriaxone for uncomplicated gonorrhea from 250mg to 500mg due to increasing resistance.[5]
Zoliflodacin, a new oral antibiotic to treat gonorrhea is in phase 3 clinical testing and in vitro has shown effectiveness in strains resistant to ceftriaxone and azithromycin. Zoliflodacin inhibits the bacterial enzyme type II topoisomerase, which is needed for bacterial function and reproduction.[6,7]
Two types of vaccines are currently being tested to prevent gonorrhea. One is the meningococcal B vaccine (already in use to prevent Neisseria meningitidis meningitis), to see if there is cross reactivity with Neisseria gonorrhoeae, as both organisms are Neisseria species.[8]
The second potential vaccine is in pre-clinical testing and creates an immunogenic response against small polysaccharide–protein outer membrane vesicles (OMVs). OMVs are naturally created by many gram-negative bacteria using their bacterial cell membrane as the outer sphere of the OMV which is then extruded from the bacteria. OMVs, after being released from the bacteria, then carry proteins to host cells which can result in biochemical changes in the host that allow the bacteria to better survive and multiply. OMVs have antigens on their surfaces from the bacterial cell membrane that can be used in a vaccine to induce immunity.[9]
![OMV formation in gram-negative bacteria[10]](https://static.wixstatic.com/media/ad4816_a00328ed49614c2787f20c9e8813ab1e~mv2.png/v1/fill/w_800,h_528,al_c,q_90,enc_auto/ad4816_a00328ed49614c2787f20c9e8813ab1e~mv2.png)
Syphilis
Syphilis is a systemic bacterial infection caused by the spirochete Treponema pallidum. In 2023, the CDC reported there were 209,253 cases of syphilis in the U.S., an increase of 84% from 2018, and the highest number of cases reported since 1950.[1,2] The WHO estimated that in 2022 there were eight million infections world-wide.[12]
A syphilis vaccine has so far eluded scientists.[13]
The treatment for uncomplicated primary and secondary syphilis in non-pregnant adults remains a single dose of benzathine penicillin G. For penicillin-allergic non-pregnant patients, doxycycline is recommended. Although azithromycin has in the past been effective in treating syphilis, due increasing resistance, it is no longer recommended.[14]
Pregnant women who are allergic to penicillin should undergo desensitization for penicillin G prior to treatment.[14,15,16] The treatment of pregnant women with syphilis differs from non-pregnant women and clinicians are advised to use the link below to get more information.
There was a benzathine penicillin G shortage in early 2024 at which time the CDC recommended treating only pregnant women and neonates with congenital syphilis with benzathine penicillin. The recommendation was to treat everyone else with doxycycline, but as of September 2024 the shortage had ended and benzathine penicillin G is again the recommended antibiotic for all.[14,17]
Chlamydia
Chlamydial infection, caused by Chlamydia trachomatis is the most frequently reported bacterial infectious disease in the U.S. In 2023 there were 1,648,568 reported cases of chlamydia, a decrease of 6% from 2018.[1,2] In 2020, the WHO estimated there were 129 million chlamydial infections worldwide.[18]
Doxycycline is first line treatment in adults, with azithromycin and levofloxacin as alternatives, although levofloxacin should not be used routinely due to potential adverse quinolone side effects.[19] In pregnant women, azithromycin is first line therapy with amoxicillin as an alternative.
Expedited partner therapy for chlamydial infections is permissible in 47 states and potentially allowable in three, although not specifically legislated for in those three states. This allows patients to be given prescriptions for their partners, to try to reduce disease transmission and complications.[20]
There is an experimental chlamydia vaccine currently called CTH522 which has completed a phase 1 trial. In that trial, there were 3 intramuscular injections at 0, 1 and 4 months followed by intranasal administration at 4.5 and 5 months. The vaccine induced anti-CTH522 IgG seroconversion in 100% of the fifteen subjects.[21]
Trichomoniasis
An estimated 2.6 million people in the U.S. are infected with trichomonas, caused by the flagellated protozoan parasite Trichomonas vaginalis.[22] According to the WHO, in 2020 there were approximately 156 million new cases worldwide of T. vaginalis infections among people aged 15–49 years old.[23]
Trichomoniasis is typically asymptomatic in men but may occasionally cause urethritis or prostatitis symptoms. Women may be asymptomatic or present with a yellow-green vaginal discharge.
The medication of choice is oral metronidazole, with tinidazole as an alternate drug. Men can be treated with a single dose of metronidazole while women are generally treated for 7 days.[22] Treatment recommendations are different when breast feeding or during pregnancy and providers are advised to review current recommendations.
There is no current human vaccine for trichomoniasis but there is basic science research underway to try to develop one.[24]
Click here for further information on Trichomonas infections including during pregnancy and while breast feeding.
HIV
There are two new developments with respect to HIV (human immunodeficiency virus) treatment and prevention.
A phase1/2 trial was completed with five patients using the drug EBT-101, a CRISPR derived gene editing therapy designed to cure HIV. It was well tolerated by the subjects. However, three of the patients developed a rebound serum HIV viral load, indicative of a return of their HIV disease. While EBT-101 at this dose did not succeed, further research into this type of therapy will continue, possibly at higher doses of EBT-101.[25]
In 2022, the antiviral lenacapavir was approved by the FDA for treatment for patients with multiple drug-resistant HIV. One of the advantages of lenacapavir is that it only needs be administered subcutaneously once every 6 months.[26]
In July 2024, a phase 3 study for pre-exposure prophylaxis (PrEP) of HIV compared every 6-month subcutaneous lenacapavir versus daily oral HIV PrEP. It was reported that no cases of HIV developed in 2,134 women who received subcutaneous lenacapavir. Lenacapavir’s zero HIV conversion rate compared to 1.5%-1.8% new cases of HIV in the oral PrEP groups. Lenacapavir’s 100% effectiveness in the phase 3 study is felt to be a major step forward in drug compliance and effective prevention of HIV.[27]
However, the cost of lenacapavir may be an issue as it currently costs tens of thousands of dollars more per year than oral HIV PrEP medications. FDA approval is now being sought to allow use of subcutaneous lenacapavir for HIV PrEP.[26]
Genital Herpes Simplex
An estimated 491 million people worldwide ages 15-49 (13% of the total population) have had a herpes simplex virus type 2 (HSV-2) infection, the main cause of genital herpes.[28] In 2018, among people aged 14-49 the CDC estimated that there were 572,000 new genital herpes infections in the U.S.[29] Although much less common, herpes simplex virus type 1 (HSV-1), typically seen in the mouth or on the lips, can also cause genital herpes.
The medications recommended in the treatment of genital herpes simplex are acyclovir, famciclovir, or valacyclovir. Recommended therapies for an initial infection are below.
Recommended therapy for recurrent infections:
EBT-104 is an investigational CRISPR-editing therapy for herpes simplex, still in pre-clinical investigation. It has been reported that a single dose reduced herpes virus DNA by over 99.99% in laboratory cells[25] and significantly decreased viral shedding in a rabbit keratitis (corneal infection) model.[30]
Human Papilloma Virus (HPV)
There are about 200 viruses that can cause an HPV infection. Some cause genital or oropharyngeal warts and some high-risk types can cause cancer, typically of the cancers of the vulva, vagina, mouth/throat, penis and rectum.[31] About 90% of HPV infections are effectively eliminated by the immune system within two years, but some continue on to become cancerous. It is estimated by the CDC that about 13 million Americans become infected each year and about 36,500 people per year are diagnosed with a cancer caused by HPV infection.[32,33] In 2019, it was estimated by the WHO that HPV caused approximately 620,000 cancer cases in women and 70,000 cancer cases in men worldwide.[31]
The CDC recommends two doses of HPV vaccine for all adolescents at age 11 or 12 years, that has been found to be over 90% effective at preventing HPV warts and induced cancers.[34]
Mycoplasma genitalium [35]
Mycoplasma genitalium has been found to be the cause in 15% to 40% of cases of urethritis in men. In women with cervicitis, M. genitalium has been found in 10% to 30% of cases and found in 4% to 22% of women who have pelvic inflammatory disease.
M. genitalium is an extremely slow-growing organism and culture can take up to six months. The nucleic acid amplification test (NAAT) is considered the test of choice.
There is increasing macrolide resistance to M. genitalium and azithromycin is only recommended as first line therapy if macrolide sensitivity testing is available. Otherwise, the recommended treatment is doxycycline followed by moxifloxacin, each for 7 days. There appears to be a lack of consensus regarding the dosing schedule of azithromycin in pregnancy or when breast feeding. Moxifloxacin and doxycycline are contraindicated during pregnancy. In some areas of the world, pristinamycin is a second line drug for pregnant patients, but it is not available in the U.S. and data is limited as to safety. Clinicians are advised to review the latest information before treating pregnant women.[36,37]
Summary
Sexually transmitted infections affect millions of people each year. Increasing antibiotic resistance, especially for gonorrhea, may present therapeutic challenges. A new antibiotic to treat gonorrhea, zoliflodacin, is currently in clinical trials. The incidence of syphilis is rising, but benzathine penicillin G is still the drug of choice.
For HIV pre-exposure prophylaxis, an every 6-month injection of lenacapavir has been found to be very effective. It is still waiting FDA approval in the U.S. for that indication and is more expensive than oral prophylaxis, which may be an issue limiting use.
Vaccines, such as the HPV vaccine and ones being developed and tested for gonorrhea and chlamydia may be crucial in the future to help control global STI incidence.
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References
[1] Sexually Transmitted Infections (STIs). CDC. Last Reviewed: January 30, 2024 Retrieved from: https://www.cdc.gov/std/statistics/2022/default.htm
[2] National Overview of STIs in 2023. CDC. November 12, 2024. Retrieved from: https://www.cdc.gov/sti-statistics/annual/summary.html
[3] Multi-drug resistant gonorrhoea. WHO. July 4, 2024. Retrieved from: https://www.who.int/news-room/fact-sheets/detail/multi-drug-resistant-gonorrhoea
[4] Zhu X et al. Ceftriaxone-Resistant Gonorrhea — China, 2022. CDC Morbidity and Mortality Weekly Report. March 28, 2024 / 73(12);255–259, Retrieved from: https://www.cdc.gov/mmwr/volumes/73/wr/mm7312a2.htm?s_cid=mm7312a2_w
[5] Update to CDC's Treatment Guidelines for Gonococcal Infection, 2020. CDC-Morbidity and Mortality Weekly Report. December 18, 2020 / 69(50);1911–1916. Retrieved from: https://www.cdc.gov/mmwr/volumes/69/wr/mm6950a6.htm
[6] Positive Results Announced in Largest Pivotal Phase 3 Trial of a First-in-Class Oral Antibiotic to Treat Uncomplicated Gonorrhea. Businesswire. November 01, 2023. Retrieved from: https://www.businesswire.com/news/home/20231101634842/en/Positive-Results-Announced-in-Largest-Pivotal-Phase-3-Trial-of-a-First-in-Class-Oral-Antibiotic-to-Treat-Uncomplicated-Gonorrhea
[7] NIH Statement on Preliminary Efficacy Results of First-in-Class Gonorrhea Antibiotic Developed Through Public-Private Partnership. NIH. November 1, 2023. Retrieved from: https://www.niaid.nih.gov/news-events/nih-statement-preliminary-efficacy-results-first-class-gonorrhea-antibiotic-developed
[8] Exploring a Meningitis Vaccine for Gonorrhea Prevention. NIH. May 10, 2024. https://www.niaid.nih.gov/news-events/meningitis-vaccine-gonorrhea-prevention
[9] Johnson B. GSK’s gonorrhea vaccine receives fast-track designation to expedite clinical trials. Nature. 07 August 2023. Retrieved from: https://www.nature.com/articles/d41591-023-00069-9
[10] Roier S et al. A novel mechanism for the biogenesis of outer membrane vesicles in Gram-negative bacteria. Nat Commun. 2016;7:10515. Published 2016 Jan 25. Retrieved from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4737802/
[11] Gonococcal Infections Among Adolescents and Adults. CDC. Last Reviewed: September 21, 2022. Retrieved from: https://www.cdc.gov/std/treatment-guidelines/gonorrhea-adults.htm
[12] Syphilis. WHO. 21 May 2024. Retrieved from: https://www.who.int/news-room/fact-sheets/detail/syphilis
[13] Kojima N, Konda KA, Klausner JD. Notes on syphilis vaccine development. Front Immunol. 2022;13:952284. Published 2022 Jul 28. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365935/
[14] Primary and Secondary Syphilis. CDC Sexually Transmitted Infections Treatment Guidelines, 2021. Last Reviewed: July 22, 2021. Retrieved from: https://www.cdc.gov/std/treatment-guidelines/p-and-s-syphilis.htm
[15] Syphilis During Pregnancy. CDC Sexually Transmitted Infections Treatment Guidelines, 2021. Last Reviewed: July 22, 2021. Retrieved from: https://www.cdc.gov/std/treatment-guidelines/syphilis-pregnancy.htm
[16] Syphilis. CDC. Last Reviewed: October 3, 2024. Retrieved from: https://www.cdc.gov/std/treatment-guidelines/syphilis.htm
[17] Bachmann LH, Mena L. Clinical Reminders during Bicillin L-A® Shortage. CDC. February 26, 2024, updated September 9, 2024. Retrieved from: https://www.cdc.gov/sti/php/from-the-director/2023-07-20-mena-bicillin.html
[18] Sexually transmitted infections (STIs). WHO. 21 May 2024. https://www.who.int/news-room/fact-sheets/detail/sexually-transmitted-infections-(stis)
[19] Chlamydial Infections. CDC. Last Reviewed: July 22, 2021. Retrieved from: https://www.cdc.gov/std/treatment-guidelines/chlamydia.htm
[20] Legal Status of Expedited Partner Therapy (EPT). July 16, 2024. Retrieved from: https://www.cdc.gov/sti/php/ept-legal-status/?CDC_AAref_Val=https://www.cdc.gov/std/ept/legal/default.htm
[21] Abraham S et al. Safety and immunogenicity of the chlamydia vaccine candidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet Infectious Diseases, Volume 19, Issue 10, 1091 - 1100. October 2019. Retrieved from: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30279-8/abstract
[22] Trichomoniasis. CDC. Last Reviewed: September 21, 2022. Retrieved from: https://www.cdc.gov/std/treatment-guidelines/trichomoniasis.htm
[23] Trichomoniasis. WHO. 16 October 2023. Retrieved from: https://www.who.int/news-room/fact-sheets/detail/trichomoniasis
[24] Nezhad G et al. Introduction of protein vaccine candidate based on AP65, AP33, and α-actinin proteins against Trichomonas vaginalis parasite: an immunoinformatics design. Parasites Vectors 17, 165 (2024). Retrieved from: https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-024-06248-y
[25] Johnson V. CRISPR-Editing EBT-101 Therapy Safe, Temporarily Suppresses HIV Infection. CGT Live. May 21, 2024. Retrieved from: https://www.cgtlive.com/view/crispr-editing-ebt-101-therapy-safe-temporarily-suppresses-hiv-infection
[26] Cox D, Barros Guinle MI. This preventive drug could be a 'game changer' in ending the HIV epidemic. NPR, Goats and Soda - Stories of Life In a Changing World. September 17, 2024. Retrieved from: https://www.npr.org/sections/goats-and-soda/2024/09/17/g-s1-23248/hiv-drug-aids-epidemic-lenacapavir
[27] Bekker LG et al. Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. NEJM. July 24, 2024. https://www.nejm.org/doi/full/10.1056/NEJMoa2407001
[28] Herpes simplex virus. WHO. 13 September 2024. Retrieved from: https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus
[29] About Genital Herpes. CDC. February 20, 2024. Retrieved from: https://www.cdc.gov/herpes/about/index.html
[30] Nadia A et al. CRISPR-Cas9-mediated genome editing delivered by a single AAV9 vector inhibits HSV-1 reactivation in a latent rabbit keratitis model. Molecular Therapy Methods & Clinical Development, Volume 32, Issue 3. Retrieved from: https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(24)00119-0
[31] Human papillomavirus and cancer, WHO. 5 March 2024. Retrieved from: https://www.who.int/news-room/fact-sheets/detail/human-papilloma-virus-and-cancer
[32] Clinical Overview of HPV. CDC. July 9, 2024. Retrieved from: https://www.cdc.gov/hpv/hcp/clinical-overview/index.html
[33] About HPV. CDC. July 3, 2024. Retrieved from: https://www.cdc.gov/hpv/about/index.html
[34] HPV Vaccine Recommendations. CDC, July 9, 2024, Retrieved from: https://www.cdc.gov/hpv/hcp/vaccination-considerations/index.html
[35] Mycoplasma genitalium. CDC. Last Reviewed: July 22, 2021. Retrieved from: https://www.cdc.gov/std/treatment-guidelines/mycoplasmagenitalium.htm
[36] Treatment of Mycoplasma genitalium infection in pregnancy: A systematic review of international guidelines. International Journal of Obstetrics & Gynecology. Volume166, Issue1, Pages 27-34. July 2024. Retrieved from: https://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.15469
[37]Mycoplasma genitalium. Australian STI Management
Guidelines for Use in Primary Care. Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). Last updated: April, 2024. Retrieved from: https://sti.guidelines.org.au/sexually-transmissible-infections/mycoplasma-genitalium/
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