A Balancing Act: CDC Updates to Treatment Guidelines for Gonorrhea and Impact on Treatment of Chlamydia

Sexually transmitted infections (STIs) are common reasons patients seek health care in the United States. Unfortunately, cases are on the rise. Since 2014, cases of gonorrhea and chlamydia have increased 63% and 19%, respectively.

Previously, Pharmacist Consult covered common first-line treatment options for a variety of STIs. Since that article was published in July 2020, a few things have changed. Specifically, the treatment of gonorrhea.

On December 18, 2020, the Centers for Disease Control and Prevention (CDC) published an update to the 2015 treatment guidelines for gonococcal infection (gonorrhea). The changes could have a noticeable impact on how clinicians and patients approach treatment of this common STI.

Gonorrhea is caused by a bacteria called Neisseria gonorrhoeae. Patients with gonorrhea typically do not have just gonorrhea. Co-infection with another bacteria, Chlamydia trachomatis (you guessed it, the cause of chlamydia), is also common.

Previously, the first-line recommended treatment for gonorrhea was a combination of two antibiotics – ceftriaxone and azithromycin. These two antibiotics were given once: ceftriaxone as a single injection into the muscle (intramuscular injection) and azithromycin as a single oral dose. This was recommended as a strategy to prevent N. gonorrhoeae from becoming resistant to ceftriaxone (rates of resistance among similar antibiotics prior to the recommendation were increasing) as well as to treat any possible co-infection with C. trachomatis – two birds with one stone.

N. gonorrhoeae has become resistant to a variety of antibiotics. In the 1980s, penicillin and tetracycline became no longer recommended for treatment due to resistance. In 2007 and again in 2012, ciprofloxacin and cefixime became no longer recommended. Thus, penicillin, tetracycline, ciprofloxacin, and cefixime are no longer recommended. However, ceftriaxone has retained its activity (able to be used for treatment) up to this point.

Though N. gonorrhoeae resistance to ceftriaxone has remained relatively low, N. gonorrheoae and other bacteria have demonstrated increased resistance to azithromycin (Figure 1), and this increase began around the time this dual-therapy recommendation was implemented.

Studies have connected increased resistance to azithromycin with increased exposure to azithromycin via treatment of patients with gonorrhea. In an effort to preserve the effectiveness of azithromycin for other infections, the updated guidelines have removed azithromycin from the treatment of gonorrhea. Additionally, studies of ceftriaxone doses that demonstrate optimal treatment of the bacteria has led to a larger recommended dose from 250 mg to 500 mg. This results in a new recommendation of a single dose of ceftriaxone 500 mg intramuscularly for the treatment of gonorrhea (Table 1).

Table 1. Changes to Gonorrhea Treatment Recommendations

STI	2015 CDC Recommendations	New 2020 CDC Recommendations
Gonorrhea	Ceftriaxone 250 mg IM x 1 dose + Azithromycin 1 g by mouth x 1 dose	Ceftriaxone 500 mg IM x 1 dose (if > 150 kg or 300 lbs: 1 g is recommended)
Chlamydia co-infection unknown	Monitor – azithromycin typically treats chlamydia	Doxycycline 100 mg by mouth 2 times a day x 7 days

Great! This means that patients only need a single drug instead of two to treat their STI – but what about patients with unknown or potential chlamydia co-infection?

Previously, clinicians and patients did not need to worry – azithromycin adequately treated chlamydia. Clinicians simply needed to monitor culture results to ensure that if chlamydia was present that it would be susceptible to azithromycin – the patient’s end of the bargain (aside from abstaining from sexual contact) was more or less complete.

If co-infection with chlamydia cannot be ruled out, it is recommended to treat with doxycycline 100 mg by mouth 2 times daily for 7 days. Although this an effective treatment (especially with directly observed therapy), this new recommendation raises concerns for real-world compliance and successful treatment.

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Figure 1. Percentage of Neisseria gonorrhoeae isolates with elevated minimum inhibitory concentrations (MICs) to ceftriaxone, cefixime, and azithromycin — Gonococcal Isolate Surveillance Project, United States, 2009–2018

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This updated recommendation means that two main strategies for further treatment can take place after patients receive their dose of ceftriaxone:

1. Sending patients home without a prescription and calling one into their pharmacy after the test is positive.
2. Sending patients home with a physical prescription or calling one into their pharmacy before the test is positive.

In an effort to streamline workflow, clinicians may opt for strategy number 2. However, due to a potential lack of health literacy, this leaves the possibility of patients mistakenly filling and taking their doxycycline despite a negative result for chlamydia.

But what’s the big deal?

Patients must do this all the time for other medications. True, but chlamydia is a communicable disease. If it is not treated properly, it can spread to other people leading to an increase in cases. It is imperative that it is treated appropriately so as to prevent unnecessary treatment in other individuals. Although it is not the intention of this recommendation, if not executed properly by clinicians and patients, it is plausible that rates of resistance to doxycycline (as well as treatment failures of chlamydia) may increase if non-compliance is high.

Successful treatment now relies significantly on patient compliance. Both effective education and coordination with patients will be key. Clear verbal and written instructions and expectations will need to be communicated to patients to ensure successful treatment.

Additionally, these updated guidelines leave healthcare providers wondering: what do these gonorrhea recommendations mean for patients who are positive for chlamydia and negative for gonorrhea?

The guidelines for chlamydia treatment are not yet updated and the first-line recommendation still includes a one-time dose of azithromycin 1 g. A natural extension of the gonorrhea guidelines would imply that doxycycline for 7 days will now be the preferred treatment for chlamydia. An update to the chlamydia guidelines is now very much needed to clarify this.

Though some may view this update as controversial, it will still require a change in many clinicians’ approach to treatment. Emergency departments, primary care offices, and STI clinics will all need to re-think how to best provide proper care for these patients. The choice of drug for treatment will certainly take these guideline recommendations into account, however other patient-specific factors will also be determinants. There will certainly still be situations where azithromycin will be used, but the ultimate goal of this recommendation is to reduce overall use.

Table 2. Hypothetical Pro/Con Positions on Updated CDC Recommendations

Pro	Con
Single-drug treatment reduces drug utilization and costs to patient with gonorrhea only Decreased utilization of azithromycin, an important drug for treating pneumonia and infections in patients with true penicillin allergies	Increased resources dedicated for patient follow-up for patients with gonorrhea (with or without chlamydia) Opportunity for decreased adherence and (potentially) decreased treatment success Increased utilization of doxycycline, an important drug for treating pneumonia and skin/soft tissue infections

These updated guidelines represent compromise and an attempt to strike a delicate balance between individual treatment success, convenience, public health, and antimicrobial stewardship. And though these recommendations may complicate gonorrhea/chlamydia treatment, they are absolutely necessary to curb the rise of drug resistant gonorrhea.

References:

1. Sexually Transmitted Disease Surveillance 2018. Centers for Disease Control and Prevention (CDC). Accessible via: https://www.cdc.gov/std/stats18/default.htm. Last updated 28 July 2020.
2. Murdock, JL. Common First-Line STD Treatment Options. Pharmacist Consult. Accessible via: https://www.pharmacistconsult.com/common-first-line-std-treatment-options/. Published 27 July 2020.
3. Update to CDC’s Treatment Guidelines for Gonococcal Infection, 2020. Morbidity and Mortality Weekly Report (MMWR). Accessible via: https://www.cdc.gov/mmwr/volumes/69/wr/mm6950a6.htm?s_cid=mm6950a6_w. Published 18 December 2020.
4. Dicker LW, Mosure DJ, Berman SM, et al. Gonorrhea Prevalence and Coinfection With Chlamydia in Women in the United States, 2000. Sexually Transmitted Diseases: May 2003 – Volume 30 – Issue 5 – p472-475. Accessible via: https://journals.lww.com/stdjournal/fulltext/2003/05000/gonorrhea_prevalence_and_coinfection_with.16.aspx#:~:text=Chlamydial%20Coinfection,-The%20median%20chlamydia&text=The%20median%20chlamydia%20positivity%20in,(IQR%2042.5%E2%80%9352.9%25).
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6. Wind CM, de Vries E, Schim van der Loeff MF. Decreased Azithromycin Susceptibility of Neisseria gonorrhoeae Isolates in Patients Recently Treated with Azithromycin. Clinical Infectious Diseases, Volume 65, Issue 1, 1 July 2017, Pages 37–45, https://doi.org/10.1093/cid/cix249. Accessible via: https://academic.oup.com/cid/article/65/1/37/3828521. Published 24 March 2017.
7. Bacteria Culture Test. MedLine Plus | US National Library of Medicine. Accessible via: https://medlineplus.gov/lab-tests/bacteria-culture-test/. Last updated 30 July 2020.
8. Geisler WM, Uniyal A, Lee JY, et al. Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis Infection. N Engl J Med; 373:2512-252. doi: 10.1056/NEJMoa1502599. Accessible via: https://www.nejm.org/doi/full/10.1056/NEJMoa1502599#:~:text=For%20the%20treatment%20of%20chlamydia%20infection%2C%20the%20Centers%20for%20Disease,twice%20daily%20for%207%20days. Published 24 December 2015.
9. Understanding Health Literacy. Centers for Disease Control and Prevention (CDC). Accessible via: https://www.cdc.gov/healthliteracy/learn/Understanding.html. Last updated 24 November 2020.
10. Biggest Threats and Data -Antibiotic / Antimicrobial Resistance (AR / AMR). Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/drugresistance/biggest-threats.html. Last updated 28 October 2020.

David M. Kaylor, PharmD is a PGY1 Pharmacy Resident at UofL Health – UofL Hospital, Louisville, KY