Future considerations and practice implications

According to the Centers for Disease Con­trol and Prevention (CDC), antibiotic-resistant infections result in more than 2 million infections and 23,000 deaths per year in the United States. Huemer and colleagues estimate that these infections lead to over 700,000 deaths worldwide. Since the discovery of multidrug-resistant infections, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci, concern has grown regarding antibiotic resistance among sexually transmitted infections (STIs). This concern is especially significant for gonorrheal infections because antibiotic resistance already exists. Chlamydia, Myco­plasma genitalium, and syphilis also run the risk of antibiotic resistance.

Understanding anti­biotic resistance and future considerations regarding STI treatments and preventives can help nurses understand the implications for clinical practice.

Antibiotic resistance and persistence

Both antibiotic resistance and antibiotic persistence pose a threat to infection outcomes. Antibiotic resistance developed as a result of antibiotic misuse and overuse. It’s also attributable to naturally occurring characteristics within bacteria or mutations at the chromosomal level within the bacteria. Antibiotic persistence, a newer concept, refers to the ability of susceptible bacteria to survive despite adequate exposure to antibiotics.

Antibiotic resistance can develop through a number of actions at the bacterial level. Bacteria can acquire methods for restricting access of the antibiotic through the cell membrane or develop “pumps” within the cell wall to remove the antibiotic after it enters the cell. Bacteria also can develop the ability to destroy the antibiotic via enzymes or proteins or acquire the ability to bypass the effects of the antibiotic altogether.

Antibiotic resistance is a well-documented phenomenon, while antibiotic persistence is less well understood and probably underreported. Either scenario leads to treatment failure that perpetuates further antibiotic resistance. The slow rate of new drug development to combat resistance to current antibiotics further complicates STI treatment.

Neisseria gonorrhoeae

Gonorrhea is the second most commonly reported STI in the United States. Since 2009, when rates of gonorrheal infections were historically low, rates of infection have increased by 118%. Disparities in infections remain notable, with over half of all infections seen in those between ages 15 and 24 years. Rates of infection have increased in both males and females, most age groups, and across most racial and ethnic groups. Since 2013, rates of infection have remained higher in men than women, with a third of new cases occurring in men who have sex with men (MSM). The CDC recommends that sexually active women younger than age 25 and all sexually active MSM receive annual testing for gonorrhea or more frequently (every 3 to 6 months) if they have multiple or anonymous sex partners.

Symptoms

Initial gonorrheal infections can be asymptomatic. Symptoms first manifest as localized inflammation such as cervicitis, urethritis, and proctitis (inflammation of the rectal lining) with accompanying discharge. Pharyngitis, a localized infection, occurs with oral exposure to gonorrhea. Untreated infections can progress to disseminated gonorrhea, which can lead to septic arthritis. In pregnancy, a risk exists for transmission during delivery, which can infect the eyes of the neonate and, in extreme cases, lead to blindness. Most concerning, however, is that some gonorrheal infections remain asymptomatic, resulting in further spread of the infection.

Treatment

Among STIs, gonorrhea has the highest rate of antibiotic resistance worldwide. In 1993, four recommended antibiotics existed for treatment within the United States, including ceftriaxone and cefixime. By 2007, due to antibiotic resistance first noted in Hawaii and the U.S. Pacific coast, the recommended available antibiotic treatments dropped to two. Currently, the CDC recommends only one antibiotic to treat gonorrhea in adults and adolescents with uncomplicated infection of the cervix, urethra, rectum, or pharynx—a single injectable dose of 500 mg ceftriaxone (a cephalosporin) for those weighing <150 kg and 1 g ceftriaxone for those weighing >150 kg.

Tien and colleagues report that outside of the United States, especially in the Western Pacific region, resistance to cefixime, ceftriaxone, or both, has been detected at ≥5%. As of December 2022, the CDC hasn’t received any verified clinical reports of treatment failures to cephalosporins in the United States. However, the need exists for other treatment options.

Recently, late-stage clinical trials have begun for a newer drug, zoliflodacin, which may prove as effective as the current recommended treatment for uncomplicated urogenital gonorrhea. Zoliflodacin’s mechanism of action is the inhibition of microbial biosynthesis, which differs from current treatment modalities. Given as a single oral dose, zoliflodacin has proven effective in treating urogenital and rectal infections but less successful for pharyngeal infections. The U.S. Food and Drug Administration fast-tracked zoliflodacin for development as an oral treatment for gonococcal infections. Of note, zoliflodacin has proven effective in treating ureaplasma species, M. genitalium, Chlamydia trachomatis, and Chlamydophila pneumoniae. As with any STI, partners require treatment and anyone who tests positive for gonorrhea should receive repeat testing 3 months after treatment.

Although most gonorrhea treatment failures are reinfections, clinicians should consider treatment failure when symptoms persist beyond 3 to 5 days. In such cases, the CDC recommends retreating with the recommended dose of ceftriaxone. However, when treatment failure is truly suspected, such as a persistence of symptoms, providers should obtain appropriate clinical cultures and provide dual treatment with a single intramuscular dose of 240 mg gentamicin and a single oral dose of 2 g azithromycin.

The CDC recommends that any healthcare provider or health department suspecting a cephalosporin treatment failure or any N. gonorrhoeae infection with decreased cephalosporin sensitivity report it through the Suspected Gonorrhea Treatment Failure Consultation Form (bit.ly/4cF04iC).

Currently, the CDC monitors for antibiotic resistance through the Gonococcal Isolate Surveillance Project, which serves as the primary monitoring program for antimicrobial-resistant N. gonorrhoeae. Positive gonorrhea specimens collected from multiple participating sites throughout the United States are tested at antibiotic resistance laboratory networks for resistance to penicillin, tetracycline, gentamicin, ciprofloxacin, ceftriaxone, cefixime, and azithromycin. The CDC collates and analyzes the test results and provides susceptibility trends data to inform gonorrhea treatment recommendations.

Chlamydia trachomatis

According to Rodrigues and colleagues, C. trachomatis remains one of the most common global STIs with an estimated 129 million new cases each year. In the United States, as reported by the CDC, chlamydia is the most-reported STI with over 1.5 million cases per year. Similar to gonorrhea, those most impacted by the effects of chlamydial infections are people ages 15 to 24 years, MSM, and pregnant individuals. Disparities exist among racial and ethnic minority groups with rates for Black individuals six times that for White.

Symptoms

Initially, chlamydia infections can be asymptomatic. Some individuals remain asymptomatic while others, as the infection persists, develop cervicitis, urethritis, and proctitis. Discharge and dysuria can accompany the infection. Left untreated, infections can lead to fertility issues if the patient develops pelvic inflammatory disease (PID), epididymitis, and prostatitis.

Treatment

The CDC recommends that sexually active women younger than age 25 and all sexually active bisexual men and MSM receive testing for chlamydia annually or more frequently (every 3 to 6 months) if they have multiple or anonymous sex partners. Prompt testing and recognition of infection will enable early and effective treatment.

The current CDC treatment recommendation includes doxycycline 100 mg twice a day for 7 days. Alternative treatments include levofloxacin 500 mg once a day for 7 days or a single dose of 1 g azithromycin orally. The single dose of azithromycin remains the only recommended treatment for pregnant patients. However, experimental research in the United Kingdom demonstrated a potentially higher rate of treatment failure with azith­ro­mycin than doxycycline for nongenital chla­mydial infections.

A test of cure isn’t recommended unless the patient is pregnant or the provider has concerns about treatment adherence. This test of cure should occur no sooner than 4 weeks after treatment using nucleic acid amplification testing (NAAT).

The CDC recommends retesting all patients diagnosed with chlamydia about 3 months after treatment. The CDC also notes that treatment failure due to antibiotic resistance isn’t a concern at this time; the greater concern is reinfection as a result of new contacts or a partner not receiving treatment.

Syphilis

Increasing rates of syphilis (an STI caused by the bacteria Treponema pallidum) have been seen among all U.S. demographics; the highest rate of increase occurs in non-Hispanic American Indian and Alaskan Native populations. According to the CDC, MSM carry the highest burden of new syphilis infections, accounting for half of all primary and secondary cases of syphilis.

The CDC recommends annual screening for anyone who’s HIV positive, a sexually active MSM, transgender, or gender diverse based on reported sexual activity. More frequent testing, such as every 3 to 6 months, may be indicated based on risk factors such as history of incarceration or history of transactional sex work.

Symptoms

Syphilis infections can be categorized as primary, secondary, tertiary, early latent, latent, and congenital. Primary syphilis manifests as single or possibly multiple painless ulcers or chancres. Secondary syphilis may include rashes, mucosal lesions, and enlarged lymph nodes. If untreated, the infection can progress to tertiary syphilis, which includes gummatous lesions (tumors found on the liver or other body sites), tabes dorsalis (a symptom of neurosyphilis, which affects the spinal cord), and paresis. However, nearly all body systems can be affected by the infection.

Latent syphilis is asymptomatic and detected only via serologic testing. These infections are defined as early latent syphilis if contracted within the year and otherwise as unknown/late latent syphilis.

According to the CDC, congenital syphilis, the transmission of the infection during pregnancy to the fetus, experienced a 422% rate increase from 2012 to 2019. Congenital syphilis is associated with increased risk of stillbirth and infant death, necessitating timely diagnosis and effective treatment. In pregnancy, screening should occur at the initial visit and at 28 weeks’ gestation. In the event of a positive rapid nontreponemal test, especially if concern exists about ongoing care, providers should administer treatment immediately. The CDC recommends testing the pregnant individual for syphilis if a fetal death occurs after 20 weeks’ gestation or in the event of a stillborn infant.

Treatment

The CDC recommends syphilis treatment with penicillin G benzathine administered intra­muscularly, with the number of doses determined by the stage of the infection. The FDA reports a shortage of penicillin G benzathine-injectable suspension products. During shortages, the CDC recommends treating nonpregnant patients with doxycycline. No proven alternate treatments exist for congenital syphilis, neurosyphilis, or pregnant patients.

Clinical evaluation and serologic testing should occur at 6 and 12 months after treatment. Failure of syphilis test titers to decrease by fourfold within 1 year after treatment for primary or secondary syphilis might indicate treatment failure or reinfection.

Antibiotic resistance hasn’t been seen with penicillin G benzathine, but T. pallidum resistance to macrolides such as azithromycin and erythromycin has occurred worldwide, including in southern Africa, Japan, and France.

Mycoplasma genitalium

M. genitalium accounts for approximately 40% of persistent or recurrent urethritis in men and between 10% and 30% of clinical cervicitis in women. The bacteria have a possible association with PID, infertility, endometritis, and endosalpingitis (inflammation of the lining of the fallopian tubes). Literature on associations with preterm birth and other pregnancy complications remains divided.

Symptoms

Many patients with mycoplasma infections experience no symptoms. Research conflicts exist regarding the association of the bacteria with symptomatology. Symptomatic rectal infections associated with mycoplasma have been seen in MSM. Due to the slow-growing nature of mycoplasma, the CDC doesn’t recommend cultures, so testing remains limited to NAAT on urine or swabs of the penile meatus, urethra, vagina, or cervix.

Treatment

M. genitalium has well-documented resistance to azithromycin and moxifloxacin. According to Wood and colleagues, doxycycline has poor efficacy as a treatment when used alone. The CDC currently recommends treatment based on macrolide resistance testing with a combination of doxycycline and azithromycin if no macrolide resistance exists or a combination of doxycycline and moxifloxacin if macrolide resistance does exist.

Unfortunately, commercial resistance testing for M. genitalium to macrolides and quinolones isn’t currently available in the United States. If sensitivity testing isn’t available, the CDC recommends a regimen of doxycycline followed by moxifloxacin. Research also has shown that the addition of metronidazole to doxycycline and ceftriaxone for treatment of PID may improve cure rates in the presence of mycoplasma. The CDC encourages healthcare providers who suspect treatment failure to report it to the Mycoplasma genitalium Treatment Failure Registry (bit.ly/4cIbulR).

Future considerations

Antibiotic resistance has prompted consideration of other STI treatments and prevention, including phage therapy and vaccines.

Phage therapy

Phage therapy involves using viruses that infect the specified bacteria, which causes the bacteria to burst or lyse. Currently, no studies have looked at the use of phages in the treatment of STIs, but they’ve been used successfully to treat dysentery caused by Shigella flexneri and Shigella sonnei. Bacteriophages also have been used as prophylaxis for S. flexneri and S. sonnei in Eastern Europe.

The use of bacteriophages to treat STIs remains theoretical due to various challenges. For example, little knowledge exists about phage pharmacokinetic activity in humans, methods and routes of administration, and optimal methods for use in the urogenital tract.

Vaccines

Evidence from research in other countries (including Cuba, Norway, and New Zealand) indicates that antimeningococcal B vaccines may prove effective against N. gonorrhoeae, but currently no vaccines are under development specific to gonorrheal infections. Vaccine development for C. trachomatis remained in the preclinical phase for years; one vaccine has entered Phase 1 trials.

Developing a T. pallidum vaccine has proven challenging because the bacteria is difficult to culture, making research on the spirochete nearly impossible. M. genitalium is an extremely slow-growing organism, which also complicates research efforts. Currently, vaccines aren’t a priority for development because effective treatments exist for STIs. However, increasing antibiotic resistance may prompt development.

Implications for clinical practice

Alternatives to antibiotic treatments for bacterial STIs aren’t feasible at this time. Management of these infections still requires prudent use of available antibiotics. Awareness of treatment failures and reporting concerns for antibiotic resistance to the CDC can help limit further development of resistance and raise awareness of possible newer antibiotic therapies.

The CDC’s 2021 STI Treatment Guidelines provide the most up-to-date treatment and testing recommendations for adults and adolescents. The CDC also offers guidance on reporting suspected antibiotic resistance for gonorrhea and treatment failure of M. genitalium. In an attempt to improve access to guidelines, the CDC now offers a mobile app, which users can download for free to their smartphones. When combined with prevention, timely diagnosis, prompt treatment, and appropriate follow-up, nursing care can help mitigate antibiotic resistance to improve outcomes. (See Treatment guidelines.)

Erin Kiser is the medical officer at Medical Entrance Processing Station in Raleigh, North Carolina, and adjunct faculty for the Capstone College of Nursing, University of Alabama, in Tuscaloosa.

American Nurse Journal. 2025; 20(7). Doi: 10.51256/ANJ072506

References

Cater K, Międzybrodzki R, Morozova V, et al. Potential for phages in the treatment of bacterial sexually transmitted infections. Antibiotics. 2021;10(9):1030. doi:10.3390/antibiotics10091030

Centers for Disease Control and Prevention. About chlamydia. January 31, 2025. cdc.gov/std/chlamydia

Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2019. cdc.gov/antimicrobial-resistance/media/pdfs/2019-ar-threats-report-508.pdf

Centers for Disease Control and Prevention. Drug-resistant gonorrhea. February 15, 2024. cdc.gov/gonorrhea/hcp/drug-resistant

Centers for Disease Control and Prevention. Gonococcal Isolate Surveillance Project (GISP). April 15, 2025. cdc.gov/sti-statistics/gisp-profiles/index.html

Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021. Chlamydial infections. July 22, 2021. cdc.gov/std/treatment-guidelines/chlamydia.htm

Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021. Mycoplasma genitalium. July 22, 2021. cdc.gov/std/treatment-guidelines/mycoplasmagenitalium.htm

Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021. Syphilis. cdc.gov/std/treatment-guidelines/syphilis.htm

Centers for Disease Control and Prevention. U.S. STI epidemic showed no signs of slowing in 2021 – Cases continued to escalate. April 11, 2023. cdc.gov/media/releases/2023/s0411-sti.html#:~:text=Reported%20cases%20of%20the%20sexually%20transmitted%20infections%20%28STIs%29,cases%20%E2%80%93%20according%20to%20CDC%E2%80%99s%20final%20surveillance%20data.

Huemer M, Mairpady Shambat S, Brugger SD, Zinkernagel AS. Antibiotic resistance and persistence—Implications for human health and treatment perspectives. EMBO Rep. 2020;21(12):e51034. doi:10.15252/embr.202051034

Nishiki S, Arima Y, Kanai M, Shimuta K, Nakayama SI, Ohnishi M. Epidemiology, molecular strain types, and macrolide resistance of Treponema pallidum in Japan, 2017-2018. J Infect Chemother. 2020;26(10):1042-7. doi:10.1016/j.jiac.2020.05.022

Raccagni AR, Alberton F, Castagna A, Nozza S. Vaccines against emerging sexually transmitted infections: Current preventive tools and future perspectives. New Microbiol. 2022;45(1):9-27.

Rodrigues R, Marques L, Vieira-Baptista P, Sousa C, Vale N. Therapeutic options for Chlamydia trachomatis infection: Present and future. Antibiotics. 2022;11(11):1634. doi:10.3390/antibiotics11111634

Sanchez A, Mayslich C, Malet I, et al. Surveillance of antibiotic resistance genes in Treponema pallidum subspecies pallidum from patients with early syphilis in France.

Acta Derm Venereol. 2020;100(14):adv00221. doi:10.2340/00015555-3589

Taylor SN, Marrazzo J, Batteiger BE, et al. Single-dose zoliflodacin (ETX0914) for treatment of urogenital gonorrhea. N Engl J Med. 2018;379(19):1835-45. doi:10.1056/NEJMoa1706988

Tien V, Punjabi C, Holubar MK. Antimicrobial resistance in sexually transmitted infections. J Travel Med. 2020;27(1):taz101. doi:10.1093/jtm/taz101
Venter JME, Müller EE, Mahlangu MP, Kularatne RS. Treponema pallidum macrolide resistance and molecular epidemiology in Southern Africa, 2008 to 2018. J Clin Microbiol. 2021;59(10):e0238520. doi:10.1128/JCM.02385-20

Wood GE, Kim CM, Aguila LKT, Cichewicz RH. In Vitro susceptibility and resistance of Mycoplasma genitalium to nitroimidazoles. Antimicrob Agents Chemother. 2023;67(4):e0000623. doi: 10.1128/aac.00006-23

Key words: sexually transmitted infections, STIs, antibiotic resistance