When the new Centers for Disease Control and Prevention (CDC) recommendations¹ regarding the treatment of uncomplicated gonorrhea (and indirectly chlamydia) debuted like a slice of antibiotic resistance doom, it felt like another “gift” had arrived from 2020. Intramuscular (IM) ceftriaxone dosing has increased from 250 mg to 500 mg (or 1 g for weight ≥150 kg). Empiric chlamydia coverage switched from a single dose of 1 g of azithromycin to doxycycline 100 mg PO BID for 7 days. Being deferential to CDC expertise, many providers accepted them uncritically. Compliance rates with a switch from a 1-time to a 7-day regimen are not addressed, especially worrisome for a condition that can be minimally or asymptomatic. 

Case

A young woman presents with new and concerning discharge after an unprotected encounter. Her pregnancy test is negative. After agreement for empiric treatment, the patient then refuses empiric treatment when told about the new guidelines (2 injections and 14 chances for esophagitis). Patient specifically asks for the old regime or will just leave against medical advice.

Why a higher dose of ceftriaxone for gonorrhea?

It is important to note that the evidence of ceftriaxone, cefixime, and azithromycin resistance for gonorrhea is substantial.² Observational data from across the United States and world demonstrate worsening resistance patterns. Many of our pharmacy colleagues are working on obtaining 500 mg/2 mL ceftriaxone for injection vials, so it can be given in single injection (or two for morbidly obese patients). While this guideline may be existentially troubling, this change is practically feasible and should become standard of care.

Read more about the Trick of the Trade on administering IV instead of IM ceftriaxone for gonorrohea.

Why no mention of the single-dose azithromycin option for chlamydia?

The evidence basis for the change to doxycycline for treatment of chlamydia co-infection coverage is substantially weaker. It is also decidedly mute on the risks of partial or non-compliance with treatment. The question then becomes: How profound is the treatment effect and how does it balance against its risks?

The guideline states, as evidence for the doxycycline switch:

“A recent investigation comparing children who received twice-yearly azithromycin with children who received placebo found that the gut’s resistome, a reservoir of antimicrobial resistance genes in the body, had increased determinants of macrolide and nonmacrolide resistance, including beta-lactam antibiotics, among children receiving azithromycin (10).³ A higher proportion of macrolide resistance in nasopharyngeal Streptococcus pneumoniae was demonstrated in communities receiving mass administration of oral azithromycin (11).⁴ Azithromycin resistance has been demonstrated in another STI, Mycoplasma genitalium, and sexually transmissible enteric pathogens (e.g., Shigella and Campylobacter) (12–14)^5-7. In addition, evidence supports increasing concern for the efficacy of azithromycin to treat chlamydial infections, especially rectal infections (15,16)^8,9.”

Citations 10 and 11 speak in generalities of resistance patterns, with citation 11 being a secondary analysis of a mass azithromycin treatment trial of young children in Niger. Citations 12-14 discuss rates of coinfection treatment failure – an important consideration, but only secondarily relevant. That leaves 2 citations (15 and 16)– one a meta-analysis and one a small poster that isn’t even available online related to known anorectal chlamydia.

That really leaves the meta-analysis⁸ to answer our question: how best do we protect the reproductive health of our patients in the setting of diagnostic uncertainty?

The meta-analysis

The meta-analysis is somewhat messy with substantial heterogeneity in many relevant subgroups.⁸ A single study comprises the majority of the evidence that shows doxycycline superiority in non-gonococcal urethritis.¹⁰ It was from 2011 and revealed that while doxycycline may be better for chlamydia treatment, azithromycin was better for coinfection treatment (such as shigella or mycoplasma). And to top the whole thing, the doxycycline superiority line reads:

“We found a pooled efficacy difference in favor of doxycycline of 1.5%… to 2.6%.”

In men with symptomatic urethritis, the superiority of doxycycline increases to 7% (an NNT of 14). If you ignore the heterogeneity and pool everyone, we arrive with an overall NNT for doxycycline over azithromycin of 38 (fixed effects model size was a 2.6% advantage). If the above study¹⁰ was removed, the pooled difference would have been non-significant with an NNT of at least 50.

Having thought perhaps they just didn’t include all the evidence, a secondary literature review was undertaken. A few small case studies¹¹ and older observational studies^12,13 were found, which showed a potential treatment failure rate of azithromycin of up to 8%, but comparable rates with doxycycline.¹² That’s it. There is also genuine concern that use of azithromycin may induce resistance not only for itself but other antibiotic classes^3,4 but this concern is based on fecal biome sampling from toddlers and requires a couple of steps to be relevant to our question. Doxycycline, an essential medication in its own right, for treatment of tick-borne disease, ascending genital tract infections, COPD exacerbation and MRSA, also requires our stewardship.

Medication compliance questions

Given patient non-compliance with filling and completing ED prescriptions approach rates of 20%,^14,15 the recommendation for a 7-day course of doxycycline for chlamydia over single-dose azithromycin is fraught with peril. Additionally, consider that the patient may be relatively asymptomatic, placing them even more at risk for medication non-compliance for the 7-day course of doxycycline. Contrast this with the risks of pelvic inflammatory disease and infertility if untreated.

Conclusion

Given the sparse, heterogenous literature, we should have strong reservations about recommending doxycycline for patients for whom chlamydia has not been excluded. New gonorrhea treatment recommendations should be followed and efforts made to stock appropriate concentrations of ceftriaxone. A single-dose of azithromycin may be a reasonable alternative for your patient for non-gonococcal disease, after considering and discussing the risks and benefits. Pregnant patients require close follow up but should also continue to receive azithromycin.

If you are prescribing doxycycline, remember:

• Each pill should be taken with 6-8 oz of liquid, water preferred. 
• If taken with food, it decreases the risk of dyspepsia.
• One should sit upright for 30 minutes following each pill, especially those with history of GERD.
• If substantially sunexposed, sunscreen or full skin coverage should be recommended to prevent photosensitive reactions (which can be mild to quite severe).

If you are prescribing azithromycin, remember:

• Azithromycin can cause clinically significant increases of QTc even with a single dose, but typically only to those with multiple risk factors.¹⁶ Consider ECG if patient on QTc prolonging medications and/or coexisting electrolyte derangements discovered.
• The risk of treatment failure for chlamydia and other non-gonococcal coinfections is real. For men with symptomatic urethritis, that risk is substantially higher.
• Have a shared decision discussion about doxycycline versus azithromycin.
• While all patients should receive verbal and written follow-up instructions, close follow up should be emphasized, given that you are essentially contravening a CDC guideline.

Patient case resolution

You explain to your patient that the new guidelines should be followed for gonorrhea, and so she receives 500 mg of IM ceftriaxone. While the new guideline for doxycycline MAY be slightly more effective for the treatment of chlamydia, using shared decision making, she receives the old regimen (single-dose azithromycin). You verbally emphasize and document in the discharge instructions the importance they follow up with either their PCP, gynecologist, or the local sexually transmitted infection clinic for a recheck, if their symptoms don’t resolve within 7 days.

References

1. St. Cyr S, Barbee L, Workowski KA, et al. Update to CDC’s Treatment Guidelines for Gonococcal Infection, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1911–1916. DOI: http://dx.doi.org/10.15585/mmwr.mm6950a6external icon
2. https://www.cdc.gov/std/treatment-guidelines/toe/GCEvidenceTables2020.xlsx [Download file link]
3. Doan T, Worden L, Hinterwirth A, et al. Macrolide and nonmacrolide resistance with mass azithromycin distribution. N Engl J Med 2020;383:1941–50. PMID 33176084
4. Doan T, Arzika AM, Hinterwirth A, et al.; MORDOR Study Group. Macrolide resistance in MORDOR I—a cluster-randomized trial in Niger. N Engl J Med 2019;380:2271–3. PMID 31167060
5. Bachmann LH, Kirkcaldy RD, Geisler WM, et al. Prevalence of Mycoplasma genitalium infection, antimicrobial resistance mutations and symptom resolution following treatment of urethritis. Clin Infect Dis 2020;ciaa293. Epub March 18, 2020. PMID 32185385
6. Yousfi K, Gaudreau C, Pilon PA, et al. Genetic mechanisms behind the spread of reduced susceptibility to azithromycin in Shigella strains isolated from men who have sex with men in Québec, Canada. Antimicrob Agents Chemother 2019;63:e01679–18. PMID 30455248
7. Gaudreau C, Pilon PA, Sylvestre JL, Boucher F, Bekal S. Multidrug-resistant Campylobacter coli in men who have sex with men, Quebec, Canada, 2015. Emerg Infect Dis 2016;22:1661–3. PMID 27533504
8. Kong FY, Tabrizi SN, Law M, et al. Azithromycin versus doxycycline for the treatment of genital chlamydia infection: a meta-analysis of randomized controlled trials. Clin Infect Dis 2014;59:193–205. PMID 24729507
9. Dombrowski JC, Wierzbicki MR, Newman L, et al. A randomized trial of azithromycin vs. doxycycline for the treatment of rectal chlamydia in men who have sex with men. Presented at the National STD Prevention Conference, Atlanta, GA: September 14–24, 2020.
10. Schwebke JR, Rompalo A, Taylor S, et al. Re-evaluating the treatment of nongonococcal urethritis: emphasizing emerging pathogens randomized clinical trial. Clin Infect Dis. 2011 Jan 15;52(2):163-70. PMID 21288838
11. Bhengraj AR, Vardhan H, Srivastava P, Salhan S, Mittal A. Decreased susceptibility to azithromycin and doxycycline in clinical isolates of Chlamydia trachomatis obtained from recurrently infected female patients in India. Chemotherapy. 2010;56(5):371-7. PMID 20938174
12. Golden MR, Whittington WL, Handsfield HH, Hughes JP, et al. Effect of expedited treatment of sex partners on recurrent or persistent gonorrhea or chlamydial infection. New Engl J Med. 2005 Feb 17;352(7):676-85. PMID 15716561
13. Fortenberry DJ, Brizendine EJ, Katz BP, et al. Subsequent Sexually Transmitted Infections Among Adolescent Women With Genital Infection Due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis. Sex Transm Dis. 1999 Jan 1;26(1):26-32. PMID 9918320
14. Saunders CE. Patient compliance in filling prescriptions after discharge from the emergency department. Am J Emerg Med. 1987 Jul 1;5(4):283-6.
15. Ho J, Taylor DM, Cabalag MS, Ugoni A, Yeoh M. Factors that impact on emergency department patient compliance with antibiotic regimens. Emerg Med J. 2010 Nov 1;27(11):815-20. PMID 20513734
16. Hancox JC, Hasnain M, Vieweg WV, et al. Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: a narrative review based on the study of case reports. Ther Adv Infect Dis. 2013 Oct;1(5):155-65. PMID 25165550