Sexually Transmitted Infections - Frequently Asked Questions

An Antimicrobial Stewardship Program FAQ.

These guidelines were produced by Sinai Health-University Hospital Network ASP in collaboration with infectious diseases physicians, clinical pharmacists and public health experts, including previous team members from Public Health Ontario.

Gonorrhea

Open all

Why was the ceftriaxone dosage increased to 500 mg?

The rationale for increasing the ceftriaxone dose for the treatment of gonorrhea is threefold:

Increasing prevalence of non-susceptible clones:
- Although cephalosporin MICs are generally low in Canada, the number of isolates with decreased susceptibility is rising. In Ontario, 1.12 per cent of isolates had decreased susceptibility to ceftriaxone (MIC ≥ 0.125 mg/L) in 2020, up from 0.23% in 2016¹.
Optimizing treatment of pharyngeal infection:
- The minimal dose for eradicating pharyngeal gonorrhea is currently unknown. Pharyngeal infections are often asymptomatic but may contribute to transmission and are harder to cure microbiologically, even when strains are susceptible⁴. Proposed explanations include suboptimal drug concentrations in oropharyngeal tissues and horizontal transfer of genetic material with commensal Neisseria species, thereby promoting resistance5. A higher fT > MIC may be required, but this has not yet been demonstrated in pharmacokinetic studies (animal or human).

Why was azithromycin removed for combination therapy?

Combination therapy with azithromycin was previously based on the theoretical benefit of preventing resistant strains. However, azithromycin’s ecological impact on other microorganisms (such as Streptococcus pneumoniae and Mycoplasma genitalium) is now recognized^6,7.

Additionally, resistance to azithromycin among N. gonorrhoeae persists. In Ontario, the proportion of NG isolates considered non-susceptible to azithromycin (generally defined as MIC ≥ 2 mg/L) ranged from 3.6 to 15 per cent between 2016 and 2020¹. These figures approach the five per cent resistance threshold that the World Health Organization uses to recommend against the empiric use of an antibiotic.

What is the rationale for cefixime 800 mg PO as an alternative treatment?

For uncomplicated gonococcal infections, the original recommended dose of cefixime was 400 mg in a single oral dose⁸. Due to the global rise in the proportion of isolates with decreased susceptibility in the late 2000s and early 2010s, some guidelines removed cefixime, while others increased the dose to 800 mg as an alternative.

A pharmacokinetic study of 25 healthy volunteers found that after a single 800 mg dose, Cmax and AUC plateaued, but concentrations in pharyngeal fluid were almost undetectable⁹. Higher dosing may increase the chance of target attainment, but isolates with MICs as low as 0.12 mg/L have been linked to treatment failure, regardless of dose or anatomic site¹⁰.

Cefixime should be reserved for patients unable to receive intramuscular injections and only if pharyngeal gonorrhea is excluded. Test of cure is strongly recommended.

Chlamydia

Open all

Should doxycycline always be preferred over azithromycin? Can we still give azithromycin in select patient populations?

We favour universal doxycycline use due to data from RCTs and observational studies showing it to be more effective for rectal chlamydia in both men and women^11-13. Rectal chlamydia is often asymptomatic and may act as a reservoir for transmission. In women, there is also a possibility of transmission between anatomic sites via autoinoculation.

Azithromycin remains the preferred treatment in pregnancy due to the teratogenic risk associated with tetracyclines. It may also be considered for patients unlikely or unable to adhere to a seven-day treatment course. While some evidence suggests imperfect adherence may not greatly impact on treatment success^14,15, the data is conflicting¹⁶.

Syphilis

Open all

Can penicillin G sodium (aqueous penicillin G) replace penicillin G benzathine?

No. Due to the slow replication of the organism (~30–33 hours), prolonged treponemicidal concentrations are required²⁰. Penicillin G benzathine (PGB) is formulated to be long-acting; it is slowly absorbed and hydrolyzed to penicillin G. One dose of 2.4 million units of PGB yields treponemicidal concentrations lasting as long as three to four weeks²⁰. Therefore, the two forms are not interchangeable.

For neurosyphilis, are three IM injections of penicillin G benzathine needed in addition to 10 to 14 days of intravenous penicillin therapy?

Intravenous penicillin for 10 to 14 days is the recommended treatment. Penicillin G benzathine (PGB) does not achieve treponemicidal levels in the CSF. Since the treatment duration is comparatively shorter than for non-neurologic late latent syphilis, one to three additional doses of PGB should be considered.

Can pregnant patients be treated with antibiotics other than penicillin?

Penicillin is the antibiotic of choice for treating syphilis in pregnancy because it is the only antibiotic with evidence supporting its effectiveness in treating fetal infection and preventing congenital syphilis²⁰. Alternatives such as doxycycline and azithromycin are not recommended due to the teratogenicity of tetracyclines and the emergence of macrolide-resistant strains of T. pallidum.

Can cephalosporins be used for patients with penicillin allergy?

There is emerging evidence that ceftriaxone can be an alternative, especially for neurosyphilis (excluding late-stage disease)²⁰. However, comparative randomized trials are lacking. Consult Infectious Diseases for advice on alternative treatments.

Table 1. Comparison between Canadian, American, European and British STI guidelines

Guideline recommendations	CDC 2021¹⁷	PHAC 2025²¹	TPH 2018²²	European	BASHH
Gonorrhea First-line	Anogenital or pharyngeal: Ceftriaxone 500 mg IM once^b	Anogenital or pharyngeal: Ceftriaxone 500 mg IM once AND Azithromycin 1 g PO once	PHO 2018²³ Anogenital or pharyngeal: Ceftriaxone 250 mg IM once AND Azithromycin 1 g PO once	2020²⁴ Anogenital or pharyngeal: Ceftriaxone 1 g IM once AND Azithromycin 2 g PO once^c	2020²⁵ Anogenital or pharyngeal: Ceftriaxone 1 g IM once
Select alternative(s)	Anogenital: Cefixime 800 mg PO once -- Gentamicin 240 mg IM once AND Azithromycin 2 g PO once No reliable alternatives for pharyngeal gonorrhea	Anogenital or pharyngeal: Cefixime 800 mg PO once AND Azithromycin 1 g PO once -- Gentamicin 240 mg IM/IV once AND Azithromycin 2 g PO once	Anogenital or pharyngeal: Cefixime 400 mg PO once AND Azithromycin 1 g PO once -- Gentamicin 240 mg IM/IV once AND Azithromycin 2 g PO once -- Azithromycin 2 g PO once (least preferred)	Anogenital: Ceftriaxone 1 g IM once -- Cefixime 400 mg PO once AND Azithromycin 2 g PO once^c -- Gentamicin 240 mg IM once AND Azithromycin 2 g PO once^c Pharyngeal: Ceftriaxone 1 g IM once	Anogenital or pharyngeal: Cefixime 400 mg PO once AND Azithromycin 2 g PO once -- Gentamicin 240 mg IM once AND Azithromycin 2 g PO once -- Azithromycin 2 g PO once
Chlamydia (non-LGV) First-line	Doxycycline 100 mg PO bid for 7 days	Doxycycline 100 mg PO bid for 7 days -- Azithromycin 1 g PO once	Doxycycline 100 mg PO bid for 7 days -- Azithromycin 1 g PO once	2015 (under review)²⁶ Urogenital: Doxycycline 100 mg PO bid for 7 days -- Azithromycin 1 g PO once Rectal and pharyngeal: Doxycycline 100 mg PO bid for 7 days	Updated 2018²⁷ Doxycycline 100 mg PO bid for 7 days
Alternative(s)	Azithromycin 1 g PO once -- Levofloxacin 500 mg PO daily for 7 days	Levofloxacin 500 mg PO daily for 7 days		Urogenital: Erythromycin^d 500 mg PO bid for 7 days -- Levofloxacin 500 mg PO daily for 7 days Rectal and pharyngeal: Azithromycin 1 g PO once	Erythromycin^d 500 mg PO bid for 10-14 days
In pregnancy	Azithromycin 1 g PO once Alternative: Amoxicillin 500 mg PO tid for 7 days	Azithromycin 1 g PO once -- Amoxicillin 500 mg PO tid for 7 days -- Erythromycin^d 2 g/day PO in divided doses for 7 days -- Erythromycin^d 1 g/day PO in divided doses for 14 days	Azithromycin 1 g PO once -- Amoxicillin 500 mg PO tid for 7 days -- Erythromycin^d 2 g/day PO in divided doses for 7 days	Azithromycin 1 g PO once Alternatives: Amoxicillin 500 mg PO tid for 7 days -- Erythromycin^d 500 mg PO qid for 7 days	Azithromycin 1 g PO once, followed by 500 mg PO daily for 2 days -- Amoxicillin 500 mg PO tid for 7 days -- Erythromycin^d 500 mg PO qid for 7 days -- Erythromycin^d 500 mg PO bid for 14 days
PID Select first-line (outpatient)	Ceftriaxone 500 mg IM AND Doxycycline 100 mg PO bid for 14 days AND Metronidazole 500 mg PO bid for 14 days	Ceftriaxone 500 mg IM once AND Doxycycline 100 mg PO bid for 14 days May add: Metronidazole 500 mg PO bid for 14 days	Ceftriaxone 250 mg IM once AND Doxycycline 100 mg PO bid for 14 days May add: Metronidazole 500 mg PO bid for 14 days	2017¹⁸ Ceftriaxone 500 mg IM once AND Doxycycline 100 mg PO bid for 14 days AND Metronidazole 500 mg PO bid for 14 days -- Levofloxacin 500 mg PO daily for 14 days AND Metronidazole 500 mg PO bid for 14 days -- Moxifloxacin 400 mg daily for 14 days	2019²⁸ Ceftriaxone 1 g IM AND Doxycycline 100 mg PO bid for 14 days AND Metronidazole 500 mg PO bid for 14 days -- Moxifloxacin 400 mg daily for 14 days
Select first-line (inpatient)	Ceftriaxone 1 g IV q24h AND Doxycycline 100 mg IV/PO bid AND Metronidazole 500 mg IV/PO bid (transition to oral doxycycline and metronidazole to complete 14 days of therapy)	None provided	None provided	Ceftriaxone 1 g IV q24h AND Doxycycline 100 mg IV/PO bid AND Metronidazole 500 mg IV/PO bid (transition to oral doxycycline and metronidazole to complete 14 days of therapy) -- Clindamycin 900 mg IV q8h AND Gentamicin 3-6 mg/kg IV q24h (transition to oral clindamycin 450 mg PO qid to complete 14 days)	Ceftriaxone 2 g IV q24h AND Doxycycline 100 mg IV/PO bid AND Metronidazole 500 mg IV/PO bid (transition to oral doxycycline and metronidazole to complete 14 days of therapy) -- Clindamycin 900 mg IV q8h AND Gentamicin 2 mg/kg IV once, followed by 1.5 mg/kg IV q8h (transition to oral clindamycin 450 mg PO qid to complete 14 days)
Select alternative(s) (outpatient)	Levofloxacin 500 mg PO daily for 14 days AND Metronidazole 500 mg PO bid for 14 days -- Moxifloxacin 400 mg daily for 14 days	Levofloxacin 500 mg PO daily for 14 days May add: Metronidazole 500 mg PO bid for 14 days	Levofloxacin 500 mg PO daily for 14 days May add: Metronidazole 500 mg PO bid for 14 days	Ceftriaxone 500 mg IM once AND Azithromycin 1 g PO weekly x 2 doses	Ceftriaxone 1 g IM AND Azithromycin 1 g PO weekly x 2 doses
Select alternative(s) (inpatient)	Clindamycin 900 mg IV q8h AND Gentamicin 2 mg/kg IV once, followed by 1.5 mg/kg IV q8h; 3-5 mg/kg IV q24h can be substituted	None provided	None provided	None commercially available in Canada	None commercially available in Canada
^aOnly products commercially available in Canada are displayed ^bIf weight ≥ 150 kg, increase dosage to 1 g ^cCan be given in 2 doses 6-12 h apart to limit gastrointestinal side effects ^dDosage refers to erythromycin base; of note, the only dosage form available in Canada is 333 mg

Open all

References

Canada PHAo. GC-AMR Laboratory Program 2022-05-09. 2022.
Connolly KL, Eakin AE, Gomez C, Osborn BL, Unemo M, Jerse AE. Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model. Antimicrobial agents and chemotherapy. 2019;63(3).
Canada PHAo. National Surveillance of Antimicrobial Susceptibilities of Neisseria gonorrhoeae Annual Summary 2019. Ottawa; 2019.
Barbee LA, St. Cyr SB. Management of Neisseria gonorrhoeae in the United States: Summary of Evidence From the Development of the 2020 Gonorrhea Treatment Recommendations and the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infection Treatment Guidelines. Clinical Infectious Diseases. 2022;74(Supplement_2):S95-S111.
Unemo M. Current and future antimicrobial treatment of gonorrhoea - the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infectious Diseases. 2015;15:364.
Malhotra-Kumar S, Lammens C, Coenen S, Van Herck K, Goossens H. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet. 2007;369(9560):482-90.
Seña AC, Bachmann L, Johnston C, Wi T, Workowski K, Hook EW, 3rd, et al. Optimising treatments for sexually transmitted infections: surveillance, pharmacokinetics and pharmacodynamics, therapeutic strategies, and molecular resistance prediction. The Lancet Infectious Diseases. 2020;20(8):e181-e91.
Inc. S-AC. Suprax. 2016.
Barbee LA, Nayak SU, Blumer JL, OʼRiordan MA, Gray W, Zenilman JM, et al. A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx. Sex Transm Dis. 2018;45(10):677-83.
Allen VG, Mitterni L, Seah C, Rebbapragada A, Martin IE, Lee C, et al. Neisseria gonorrhoeae Treatment Failure and Susceptibility to Cefixime in Toronto, Canada. Jama. 2013;309(2):163-70.
Páez-Canro C, Alzate JP, González LM, Rubio-Romero JA, Lethaby A, Gaitán HG. Antibiotics for treating urogenital Chlamydia trachomatis infection in men and non-pregnant women. The Cochrane database of systematic reviews. 2019;1(1):Cd010871.
Dukers-Muijrers NHTM, Wolffs PFG, De Vries H, Götz HM, Heijman T, Bruisten S, et al. Treatment Effectiveness of Azithromycin and Doxycycline in Uncomplicated Rectal and Vaginal Chlamydia trachomatis Infections in Women: A Multicenter Observational Study (FemCure). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;69(11):1946-54.
Chen L-F, Wang T-C, Chen F-L, Hsu S-C, Hsu C-W, Bai C-H, et al. Efficacy of doxycycline versus azithromycin for the treatment of rectal chlamydia: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy. 2021;76(12):3103-10.
Reedy MB, Sulak PJ, Miller SL, Ortiz M, Kasberg-Preece C, Kuehl TJ. Evaluation of 3-Day Course of Doxycycline for the Treatment of Uncomplicated Chlamydia trachomatis Cervicitis. Infect Dis Obstet Gynecol. 1997;5(1):18-22.
Bachmann LH, Stephens J, Richey CM, Hook EW, 3rd. Measured versus self-reported compliance with doxycycline therapy for chlamydia-associated syndromes: high therapeutic success rates despite poor compliance. Sex Transm Dis. 1999;26(5):272-8.
Khosropour CM, Manhart LE, Colombara DV, Gillespie CW, Lowens MS, Totten PA, et al. Suboptimal adherence to doxycycline and treatment outcomes among men with non-gonococcal urethritis: a prospective cohort study. Sex Transm Infect. 2014;90(1):3-7.
Workowski KA, Bachmann LH, Chan PA, Johnston CM, Muzny CA, Park I, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187.
Ross J, Guaschino S, Cusini M, Jensen J. 2017 European guideline for the management of pelvic inflammatory disease. Int J STD AIDS. 2018;29(2):108-14.
Wiesenfeld HC, Meyn LA, Darville T, Macio IS, Hillier SL. A Randomized Controlled Trial of Ceftriaxone and Doxycycline, With or Without Metronidazole, for the Treatment of Acute Pelvic Inflammatory Disease. Clinical Infectious Diseases. 2020;72(7):1181-9.
Justin D. Radolf ECTaJCS. Syphilis (Treponema pallidum). Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, PA: Elsevier; 2020. p. 2865-92.
PHAC 2025 - Gonorrhea guide: Treatment and follow-up - Canada.ca
Health TP. STI Treatment Reference Guide 2018.
Ontario) OAfHPaPPH. Ontario Gonorrhea Testing and Treatment Guide. Toronto, ON; 2018.
Unemo M, Ross J, Serwin AB, Gomberg M, Cusini M, Jensen JS. 2020 European guideline for the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS. 2020:956462420949126.
Fifer H, Saunders J, Soni S, Sadiq ST, FitzGerald M. 2018 UK national guideline for the management of infection with Neisseria gonorrhoeae. International Journal of STD & AIDS. 2020;31(1):4-15.
Lanjouw E, Ouburg S, de Vries HJ, Stary A, Radcliffe K, Unemo M. 2015 European guideline on the management of Chlamydia trachomatis infections. Int J STD AIDS. 2016;27(5):333-48.
Nwokolo NC, Dragovic B, Patel S, Tong CY, Barker G, Radcliffe K. 2015 UK national guideline for the management of infection with Chlamydia trachomatis. Int J STD AIDS. 2016;27(4):251-67.
Jonathan Ross MC, Ceri Evans, Deirdre Lyons, Gillian Dean, Darren Cousins, PPI representative United Kingdom National Guideline for the Management of Pelvic Inflammatory Disease (2019 Interim Update) [updated January 26, 2019.