Authors: Lauren Busch, Pharm.D. Candidate 2022, Michelle Tulchinskaya, Pharm.D. Candidate 2022, and Yvonne Burnett, Pharm.D., BCIDP
Sexually transmitted infections (STIs) or sexually transmitted diseases (STDs) in the U.S. are on the rise with an all-time high reached for the sixth consecutive year. According to the most recent STI surveillance report by the Center for Disease Control and Prevention (CDC), more than 2.5 million cases of chlamydia, gonorrhea, and syphilis were reported in 2019.1 Chlamydia and gonorrhea testing reached its lowest point in early April 2020, which is associated with the rise of the COVID-19 pandemic, with 27,659 chlamydia and 5,577 gonorrhea cases potentially missed.2 Stigma still remains as a major barrier to treatment as well. Knowledge and understanding of STIs help identify the issues and controversies contributing to the stigma created by STI diagnosis and treatment.3 The CDC’s STI treatment guidelines have been updated in July of 2021 with several new recommendations regarding gonorrhea, chlamydia, pelvic inflammatory disease, trichomoniasis, and Mycoplasma genitalium treatment.4 In addition, the CDC provides a thorough discussion of STIs that allow the healthcare team to gain the necessary understanding of the underlying factors surrounding STI stigma.3 As the guidelines had not been previously updated since 2015, it is important for clinicians to be aware of the several new recommendations in order to best serve their patients.
CDC guidelines have previously recommended ceftriaxone 250 mg intramuscularly (IM) plus azithromycin 1 g orally for the treatment of uncomplicated gonococcal infections of the cervix, urethra, and rectum due to high rates of chlamydia co-infection and in order to delay resistance of Neisseria gonorrhoeae to cephalosporins.5 However, the new CDC guidelines recommend ceftriaxone monotherapy as a single 500 mg IM dose (1 g if patient ≥ 150 kg). If chlamydia coinfection has not been ruled out, then doxycycline 100 mg orally twice daily for 7 days should be added. The removal of azithromycin from the treatment regimen is due to increasing concern for growing rates of resistance to azithromycin by N. gonorrhoeae as well as M. genitalium, Shigella, and Campylobacter. Azithromycin is also no longer equally recommended as the preferred treatment for chlamydia alongside doxycycline as discussed below. The increased dose of ceftriaxone is thought to be necessary for N. gonorrhoeae isolates with elevated minimum inhibitory concentrations (MICs). Data shows that even though 250 mg of ceftriaxone is >99% effective in curing anogenital gonorrhea, a higher dose is needed for strains with a higher MIC.4 Ceftriaxone also needs to have a concentration above the MIC for a longer amount of time when treating pharyngeal gonorrhea compared to urogenital gonorrhea, and a 500 mg dose of ceftriaxone allows for about 50 hours above an MIC of >0.03 mcg/mL.6-8
Though other single-dose injectable cephalosporin regimens have been shown to be effective against uncomplicated urogenital and anorectal gonococcal infections in the past, the pharmacokinetics of these regimens have not been evaluated and are at a disadvantage when compared to ceftriaxone 500 mg. Cefixime is still a single oral dose alternative regimen in the new guidelines; however, it is now recommended without azithromycin and the recommended dose has increased to 800 mg.4 From 2006-2011, the minimum concentrations of cefixime needed to inhibit in vitro growth of the N. gonorrhoeae strains circulating increased, demonstrating that cefixime effectiveness may be decreasing.9 Therefore, cefixime should only be used as an alternative if ceftriaxone is not available. Additionally, an alternative regimen for patients allergic to cephalosporins is gentamicin 240 mg IM plus azithromycin 2 g orally as a single dose.4
The preferred treatment regimen for chlamydia among adolescents and adults is now doxycycline 100 mg orally twice daily for 7 days.4 Azithromycin 1 g orally in a single dose, previously a recommended regimen, is now only recommended as an alternative regimen for pregnant patients.4,5 This change is due to concern regarding the efficacy of azithromycin in treating rectal chlamydia infections.4 The presence of rectal chlamydia cannot be predicted based on sexual practices. Inadequately treated rectal Chlamydia trachomatis infection can increase the risk for transmission and put women at risk for repeat urogenital C. trachomatis infection through autoinoculation from the anorectal site. Treatment failure among men was higher for azithromycin than doxycycline, and other studies found that for rectal chlamydia infection among men who have sex with men (MSM) reported microbiologic cure of 100% with doxycycline vs. 74% with azithromycin.10-15 Azithromycin may be used when non-adherence to doxycycline is a concern, but might require post-treatment evaluation and testing due to lower effectiveness in treating rectal infection. Erythromycin is also no longer recommended as an alternative agent due to the frequency of gastrointestinal adverse effects that can result in non-adherence.4
Pelvic Inflammatory Disease
The recommended treatment of pelvic inflammatory disease (PID) was updated to include metronidazole, while previously it was optional.4,5 Metronidazole has been shown to more effectively eradicate anaerobic organisms in the upper genital tract, which helps prevent long-term side effects such as infertility and ectopic pregnancies.16 A new recommended parenteral regimen consists of ceftriaxone 1 g intravenously (IV) every 24 hours plus doxycycline 100 mg orally or IV every 12 hours plus metronidazole 500 mg orally or IV every 12 hours.4 Cefotetan plus doxycycline and cefoxitin plus doxycycline are still recommended parenteral regimens; however, clindamycin plus gentamicin is now only recommended as an alternative parenteral regimen along with ampicillin/sulbactam and doxycycline.4,5 The guidelines recommend transitioning to oral therapy, after 24-48 hours of clinical improvement with parenteral therapy, with a single dose of ceftriaxone 500 mg IM plus doxycycline 100 mg PO BID and metronidazole 500 mg PO BID for a total treatment duration of 14 days.4 The updated guidelines recommend doxycycline with the addition of metronidazole as these regimens have demonstrated improved prevention of long-term complications associated with PID.4,5
Recommendations for the treatment of trichomoniasis have also changed between the 2015 and 2021 guidelines. Previously, metronidazole 2 g orally or tinidazole 2 g orally as a single dose was preferred, with metronidazole 500 mg orally twice daily for 7 days as an alternative regimen.5 Now, the guidelines recommend metronidazole 500 mg PO BID for 7 days for women and metronidazole 2 g PO as a single dose only for men with tinidazole 2 g PO as a single dose as the alternative for both men and women.4 The change in recommendations comes from new data that demonstrates multi-dose metronidazole is more effective than the 2 g-single dose in women.17 There is currently no data comparing the different dosing regimens of metronidazole in men, so the 2 g-single dose is still preferred in this population.4
The treatment ofMycoplasma genitalium was only addressed in the setting of urethritis, cervicitis, and PID in the previous guidelines. The 2015 guidelines stated azithromycin 1 g PO was preferred over the 7-day PO doxycycline course; however, azithromycin resistance was identified to be on the rise. Moxifloxacin 400 mg daily PO for 7 days was also mentioned as a treatment with a few cases of success, but was not yet tested in clinical trials.5 The current CDC guidelines give the first official recommendations for the treatment of Mycoplasma genitalium. The guidelines recommend against the use of a single dose of 1 g azithromycin due to high rates of macrolide resistance with treatment failures. Treatment should use macrolide resistance-guided therapy. If macrolide sensitive, doxycycline 100 mg PO BID for 7 days, followed by a 1 g PO dose of azithromycin, then azithromycin 500 mg PO daily for 3 more days is recommended. If the strain is resistant to macrolides, doxycycline 100 mg PO BID for 7 days followed by moxifloxacin 400 mg PO daily for 7 days is recommended. If resistance testing is not available (currently not available in the U.S.), it is recommended to treat as if the M. genitalium is macrolide resistant. Doxycycline is included in treatment regimens because it is thought to reduce the organism load and help with clearance of the organism. The new guidelines state that PID treatment regimens are not effective against M. genitalium; therefore, after initial treatment of PID with doxycycline 100 mg PO BID for 14 days, if M. genitalium is detected, moxifloxacin 400 mg PO daily for 14 more days is recommended. The guidelines also updated to recommend a newly FDA-cleared nucleic acid amplification test (NAAT) to test for M. genitalium in men with recurrent non-gonococcal urethritis, women with recurrent cervicitis, and to be considered for women with PID.4
Overall, the 2021 CDC STI treatment guidelines contain several updates regarding not only treatment recommendations, but also diagnostic and screening recommendations.4 Clinicians must be aware of these new updates to best treat their patients due to evolving resistance patterns and new evidence since 2015. The updated guidelines also emphasize the importance of primary prevention of STIs through assessing behavior risk and biologic risk and routinely asking about sexual histories using effective counseling skills.4 With the COVID-19 pandemic potentially hindering patients’ access to screening and treatment, clinicians must be prepared with the knowledge of new treatment recommendations and with effective counseling strategies for when patients are able to seek care.