Figure 1: Case Courtesy of Dr. Peter M. Martin
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.
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.
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.
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 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 studies12,13 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 classes3,4 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.
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.
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:
If you are prescribing azithromycin, remember:
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.
The Emergency Medicine Resident Simulation Curriculum for Pediatrics (EM ReSCu Peds) is here! This free ebook contains 16 EM resident-tested, peer reviewed cases covering essential pediatric content identified through a robust modified Delphi process [1] with experts across the United States. Each chapter contains robust supporting materials to help educators prepare, execute, and debrief cases with residents at every level to help supplement the clinical experience.
We request some basic demographic about you and how you plan to use the educational cases in the download form to provide us with necessary insights whether there is a need for such a resource.
Cases were created and iteratively peer reviewed by members of 10 organizations represented in a national collaborative of EM, PEM, and simulation experts. Participating organizations included:
In total, EM and PEM physicians from 44 institutions participated in the development process of this educational resource aimed at preparing EM residents to care for critically ill children.
A 35-year-old male with a history of diabetes and pericarditis, status post pericardiectomy 3 years ago, presented with a painful lesion on his anterior chest wall. One month prior, the patient reported a bump at his sternotomy scar base which extruded a piece of suture when squeezed and subsequently healed. Two days ago, the patient developed diffuse right-sided chest pain. During the past 24 hours, an enlarging, erythematous, painful, non-draining lesion developed at the base of his scar. He reports subjective fever. He denies shortness of breath, exertional chest pain, nausea, and vomiting.
A 25-year-old male who was previously healthy presents to the emergency department with a painful left posterior ear mass. The mass began as a “pimple” and has been increasing in size for the last 6 months. He has an associated headache, dizziness, and malaise. He denies fever, trauma, drainage, known insect bite, dysphagia, dyspnea, trismus, and hearing loss. He emigrated to the United States from Honduras 8 months ago. He was seen in the emergency department 4 months prior for a similar complaint, which was diagnosed as lymphadenopathy by point-of-care ultrasound.
A 42-year-old patient is brought in by EMS after jumping off of a two-story building. The primary survey is intact and the secondary survey demonstrates swelling, ecchymosis, and tenderness to the right heel. You obtain foot x-rays and see the following images (Image 1. Lateral view of the right foot. Author’s own images).
A 3-year-old female with a history of epilepsy presents with a rash that began one day ago. The patient started becoming fussy four days ago, saying, “I don’t feel good,” and not wanting to play outside with her siblings or finish her meals. Family noticed the patient rubbing her eyes frequently and crying when she went to the bathroom. She felt warm so they gave her Tylenol and Motrin at home. Yesterday, they noticed a rash was starting to develop with itchy, painful red spots. This morning, the rash progressed to involve some blisters on the face, chest, and back.
Medications include Tylenol, Motrin, and lamotrigine, which was started by her neurologist three weeks ago. Family history is significant for epilepsy on the father’s side of the family.