Today’s pearl summarizes the recent updates from the CDC’s Treatment Guidelines for Gonococcal Infection.
Which antibiotics and what doses should be used? How do we reach effective concentrations in all patients?
The new CDC recommendation for treating uncomplicated gonorrhea of the cervix/urethra/rectum/pharynx is ceftriaxone 500 mg IM (MMWR Dec 18, 2020).
- Patients ≥ 150 kg should receive ceftriaxone 1 gm IM.
- If chlamydial infection has not been excluded, add doxycycline 100 mg orally twice daily for 7 days. During pregnancy, azithromycin 1 gm as a single dose is recommended to treat chlamydia.
- Azithromycin is no longer needed if only gonorrhea is being treated.
Back in the day, we used ceftriaxone 125 mg IM. In 2010, it changed to 250 mg based on resistance patterns. Now, a decade later, we’ve increased again.
For patient in whom ceftriaxone is NOT an option, we can still use gentamicin 240 mg IM plus azithromycin 2 gm orally as a single dose.
Now for something a little more outside the guidelines. In a different post, I discussed the potential to use IV ceftriaxone in place of IM ceftriaxone for patients who either already have a peripheral IV in place or who refuse an IM injection. Based on data from the package insert, I believe this still holds true despite the higher dose of IM ceftriaxone now being recommended. And, it’s backed up by data from Japan who has been using this approach since 2008 (Aoki 2021). Below you can see the measured ceftriaxone serum concentrations obtained following IM and IV administration.
| Average Plasma Concentrations (mcg/mL) | ||||||||
| Ceftriaxone Dose/Route | 0.5 hr | 1 hr | 2 hrs | 4 hrs | 8 hrs | 12 hrs | 16 hrs | 24 hrs |
| 0.5 gm IM | 22 | 33 | 38 | 35 | 26 | 16 | ND | 5 |
| 1 gm IV | 151 | 111 | 88 | 67 | 43 | 28 | 18 | 9 |
| 1 gm IM | 40 | 68 | 76 | 68 | 44 | 29 | ND | ND |
| 2 gm IV | 257 | 192 | 154 | 117 | 74 | 46 | 31 | 15 |
#49
The PharmERToxGuy 
Hey! Can you comment on the switch to doxycycline as well. The language is a little muddled, whether 1gm azithro for empiric treatment is ever reasonable outside pregnancy or whether it should always be along with the 500mg of ceftriaxone. My concern is both patient compliance for empiric treatment as well as the evidence behind this. The CDC update links to this article: https://academic.oup.com/cid/article/59/2/193/2895398 which does not blow my mind in terms of efficacy of doxy (especially in females or asymptomatic patients). I think this is a potential public health disaster with people not taking (for the myriad reasons doxy is not well tolerated) or taking incompletely a regimen that seems like in many cases can still just be 1gm azithro empirically.
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The CDC does a much better job explaining it than I can: https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6950a6-H.pdf. The second section is on evidence and rationale. I agree it’s not the clearest explanation and there are serious adherence concerns.
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I apologize for imprecise language and punctuation, I typed that on my phone. I have deep concerns about the evidence basis, I sent this to a couple colleagues but have resigned myself to shared decision making. Interested in your thoughts:
When the new CDC recommendations (500mg IM ceftriaxone, doxy 100mg PO BID x 7 days) came out I felt uneasy about them but deferential to the CDC and accepted them uncritically. After a patient interaction, my concerns were realized — a young patient with concerning discharge and an unprotected encounter recently refused of empiric treatment when I told her about the new recommendations (2 injections and 14 chances for esophagitis). She specifically asked for the old regimen and I had some time so I went and read the whole update (https://www.cdc.gov/mmwr/volumes/69/wr/mm6950a6.htm) and the literature of its recommendations.
It left me with two huge questions.
First, the language is very vague in it’s recommendation. The update is explicitly for “Treatment Guidelines for Gonococcal Infection”. The top line language is similarly specific: “Treatment for coinfection with Chlamydia trachomatis with oral doxycycline (100 mg twice daily for 7 days) should be administered when chlamydial infection has not been excluded.” This guideline relates to patients who are clinically positive for gonorrhea (mostly by oil immersion microscopy looking for the gram (-) diplococci) — not our ED patients who come in with concern for possible STI. I’m not sure this is answering the question we are asking.
Secondly, I find the evidence basis for the change to doxycycline to be horribly wanting and blind to the risks of partial or non-compliance with treatment.
First, the direct language (from the article):
“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). A higher proportion of macrolide resistance in nasopharyngeal Streptococcus pneumoniae was demonstrated in communities receiving mass administration of oral azithromycin (11). Azithromycin resistance has been demonstrated in another STI, Mycoplasma genitalium, and sexually transmissible enteric pathogens (e.g., Shigella and Campylobacter) (12–14). In addition, evidence supports increasing concern for the efficacy of azithromycin to treat chlamydial infections, especially rectal infections (15,16).”
Citations 10-14 are either entirely irrelevant or secondarily relevant but do not directly relate to the recommendation itself. That leaves 2 citations, one a meta-analysis and one a small poster that isn’t even available online related to known rectal chlamydia.
That really leaves the meta-analysis to answer my question, which is how best do I protect the reproductive health of my patient in the setting of diagnostic uncertainty in the era of patient centered care?
Let me start by saying the meta-analysis is not on the level of a Cochrane review. The heterogeneity in the relevant subgroups is substantial. A single study comprises the majority of evidence that shows doxycycline superiority. And to top the whole thing, the top line ‘doxy is better’ stats are:
“We found a pooled efficacy difference in favor of doxycycline of 1.5% (95% confidence interval [CI], -.1% to 3.1%; I(2) = 1.9%; P = .435; random effects) to 2.6% (95% CI, .5%-4.7%; fixed effects). Subgroup analyses showed that the fixed effects pooled efficacy difference for symptomatic men was 7.4% (95% CI, 2.0%-12.9%), and the random effects was 5.5% (95% CI, -1.4% to 12.4%).”
Given the challenges we have in antibiotic compliance, when the choice is a single dose vs. 7 days of pills to treat something that can be largely asymptomatic (meaning higher likelihood for non-compliance), and the downside is PID and infertility, I have strong reservations about making this change.
Our Pharmacy is working on finding 500mg/2mL ceftriaxone so that part remains a single injection, but for the majority of my patients, I cannot in good conscience recommend doxy over azithro for empiric (and provocatively even potentially explicit treatment of) uncomplicated chlamydia, as in my patient above.
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Kory, agree with your thoughts here. I wasn’t a part of the group updating the recs, just sharing them as part of my educational pearls. Based on all I’ve read, I think a dose of azithromycin 1 gm is still reasonable. Of note, the incidence of vomiting with a 2 gm dose is almost a third. So, patients getting azithromycin may still need a second dose one week later, which is arguably also challenging from an adherence standpoint (though easier than BID doxy).
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