Gonorrhea guide: Treatment and follow-up

Treatment and follow-up guidance for Neisseria gonorrhoeae infections

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Management and treatment

General advice

N. gonorrhoea is able to develop AMR, making successful treatment a challenge. Adults and adolescents should be treated with combination therapyFootnote 1.

The use of two medications with different mechanisms of action is thought to improve treatment efficacy as well as to prevent or potentially delay the emergence and spread of antimicrobial-resistant gonorrhea.  

The appropriate combination therapy will depend on the site of infection (e.g., pharyngeal infection is harder to eradicate) and probability of resistance (e.g., more likely in gbMSM).

The recommended combination therapy includes a third generation cephalosporin with either azithromycin or doxycycline. Azithromycin is preferred over doxycycline, due to significant rates of tetracycline resistance and concerns about adherence with multiday treatment. This combination therapy is also effective for chlamydia, which is frequently associated with gonococcal infectionsFootnote 2Footnote 3Footnote 4Footnote 5.

Avoid monotherapy in order to help prevent resistance. Monotherapy with azithromycin is not recommended due to macrolide resistance and treatment failuresFootnote 6Footnote 7.

Assess each case individually to guide decision-making and consult an experienced colleague or infectious disease specialist when necessary.

Choose treatment according to local epidemiologic data where available. Refer to local and P/T public health officials for specific information about AMR patterns in the region and follow P/T guidelines.

Treatment indications

Treat all cases confirmed by

Consider treatment in suspected cases as follows:

Note: Advise people and partners to abstain from unprotected sexual contact for at least seven days after treatment is complete and until signs and symptoms have resolved.

Medication-specific considerations

Cephalosporins

While an  estimated 10% of patients report a history of penicillin allergy, in reality, only less than one percent are truly allergicFootnote 8Footnote 9Footnote 10. Approximately 80% of those with a penicillin allergy lose their sensitivity to it after 10 yearsFootnote 8. Cross-reactivity between beta-lactam antibiotics, such as penicillins and cephalosporins, may arise, due to similarities in their chemical side-chain structures. The side-chain structures of cefixime and ceftriaxone differ from those of penicillin, hence there is a negligible risk of cross-reactivity. As such, it is considered safe to give cefixime or ceftriaxone to patients with an IgE-mediated reaction to penicillin (anaphylaxis, hives)Footnote 11Footnote 12Footnote 13Footnote 14Footnote 15Footnote 16.

Advise the patient that the risk of a reaction to cefixime and ceftriaxone is low and it is similar to giving an antibiotic to an individual who does not have any drug allergies. If treatment should be initiated, ensure the setting has the capacity to respond to an IgE-mediated reaction with epinephrine. Do not prescribe cefixime or ceftriaxone to persons with a history of allergy to cephalosporins or with severe non-IgE-mediated reactions to penicillins (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, interstitial nephritis or hemolytic anemia).

Always take a comprehensive medical and allergy history and check with local jurisdiction for available guidelines or protocol for the assessment and management of penicillin allergy.  

Azithromycin

Refer the health advisory issued by Health Canada about azithromycin and risk of cardiovascular complications and death.

There are significant gastrointestinal side effects associated with high dose azithromycin. Repeat dose if vomiting occurs within one-hour post-administration. Increasing drug resistance may impact effectiveness of this medication.

Doxycycline

Doxycycline is contraindicated in pregnant and breastfeeding females.

Treatment

The following treatment options are recommended in the absence of contraindication. Consult product monographs for contraindications and side effects

The treatment recommendations will be covered in the following sections:

Recommended treatment for uncomplicated anogenital and pharyngeal infection

Adults and youth nine years of age and over Footnote 15Footnote 16Footnote 17Footnote 18Footnote 19Footnote 20Footnote 21Footnote 22Footnote 23Footnote 24Footnote 25Footnote 26.

Indication/infection Preferred treatment Alternative treatment

Anogenital infection
(urethral, endocervical, vaginal, rectal) in adults and youth ≥ 9 years of age

  • Ceftriaxone 250 mg IM in a single dose [A-l] PLUS azithromycin 1 g PO in a single dose [B-ll]

OR

  • Cefixime 800 mg PO in a single dose [A-l] PLUS azithromycin 1 g PO in a single dose [B-ll]
Note: This regimen is considered an alternative therapy for gbMSM
  • If there is macrolide resistance or contraindication to macrolide use
  • Ceftriaxone 250 mg IM in a single dose [A-l] PLUS doxycycline 100 mg PO BID x 7 days [B-III]

OR

  • Cefixime 800 mg PO in a single dose [A-l] PLUS doxycycline 100 mg PO BID x 7 days [B-III]

Pharyngeal infection
in adults and youth ≥ 9 years of age

  • Ceftriaxone 250 mg IM in a single dose [A-l]
    PLUS azithromycin
    1 g PO in a single dose [B-Ill]
  • Cefixime 800 mg PO in a single dose [A-l]
    PLUS azithromycin
    1 g PO in a single dose [B-ll]

Note:

Considerations in children
Consult with a pediatric specialist or an experienced colleague and relevant clinical guidelines when a gonococcal infection is diagnosed in a child.
Note: Suspected sexual abuse of children must be reported to the local child protection agency.

Pregnancy or breastfeeding

Pregnant people should receive the same treatment (ceftriaxone or cefixime plus azithromycin) as other non-pregnant individuals and monitored for complications. In cases of cephalosporin allergy or other contraindications, consult with an infectious disease specialistFootnote 27.

Notes:

HIV coinfection

People with HIV infection should receive the same treatment as those without HIV infection.

Alternative treatment in case of penicillins or cephalosporins allergy OR cephalosporins and/or macrolides resistance

In case of documented allergy to penicillins/cephalosporins (refer to section above regarding medication-specific considerations cephalosporins) or resistance to macrolides, refer to the alternative treatment recommendations for adults and youth below.

Cephalosporins allergy or resistance or severe non-IgE-mediated reaction to penicillins

Azithromycin 2 g in a single oral dose [A-I] PLUS gentamicin 240 mg IM in two separate 3-mL injections of 40 mg/mL solution [B-II]Footnote 28

Notes:

Quinolone treatment regimens

This combination therapy/regimen should only be used if quinolone susceptibility is demonstrated or regional/local quinolone resistance rates are under 5% and a TOC can be assuredFootnote 29Footnote 3.

OR 

  • Azithromycin 2 g in a single oral dose [A-I] PLUS gemifloxacin 320 mg in a single oral dose [B-II]Footnote 28

Notes:

Contraindications to macrolides and cephalosporins

This regimen is recommended for people with macrolide and cephalosporin-resistant N. gonorrhoeae, or a history of anaphylactic reaction to macrolides and cephasloporins or contraindications to cephalosporins.

Gentamicin 240 mg IMFootnote 33Footnote 34 in two separate 3-mL injections of 40 mg/mL solution [B-II] PLUS
Doxycycline
100 mg orally twice daily for 7 days (unless contraindicated or there is documented tetracycline resistance) [B-III]

Notes:

Resistance to both cephalosporin and azithromycin with failure or contraindications to previously noted regimens

Ertapenem has in-vitro activity but optimum dose/duration is undefined. Given the broad spectrum nature of this antimicrobial, use of this agent should be restricted to exceptional situationsFootnote 35Footnote 36Footnote 37Footnote 38.

Complicated infections associated with N. gonorrhoeae

Epididymitis / epididymo-orchitis and  PID

If epididymitis/epididymo-orchitis or PID (upper genital tract infection) are suspected, refer to STI-associated syndromes.

Gonococcal ophthalmia and disseminated infections in adults and youth 9 years or olderFootnote 39Footnote 40

Consult an infectious diseases specialist for guidance on management.

Hospitalization is indicated for meningitis and as well as for initial management of other disseminated infections.

Situation/Infection Preferred initial therapy while awaiting consultation with an experienced colleague
Arthritis

Ceftriaxone 2 g IV/IM daily for 7 days [A-II]

PLUS azithromycin 1 g PO in a single dose x 1 dose [B-lll]

Meningitis

Ceftriaxone 2 g IV/IM daily for 10–14 days [A-II]

PLUS azithromycin 1 g PO in a single dose x 1 dose [B-lll]

Endocarditis

Ceftriaxone 2 g IV/IM daily for 28 days [A-II]

PLUS azithromycin 1 g PO in a single dose x 1 dose [B-lll]

Ophthalmia

Ceftriaxone 2 g IV/IM in a single dose [A-II]

PLUS azithromycin 1 g PO in a single dose [B-lll]

Notes:

Gonococcal infection in the neonates

Neonates born to mothers with untreated N gonorrhoeae infection at the time of delivery should be tested and treated immediately without waiting for test results. They should be managed by or in consultation with a paediatric infectious disease specialist or an experienced colleague.

Refer to the Canadian Paediatric Society's article Preventing ophthalmia neonatorum for information about how to manage neonates born to mothers with untreated N gonorrhoeae infection.

Persistent and recurrent infection

Possible causes of persistent signs and symptoms after treatment:

Treatment failure

Treatment failure is defined as absence of reported sexual contact during the post-treatment period AND one of the following:

Recommended management of cephalosporin treatment failures

Counselling related to treatment

People diagnosed with gonorrhea and their partners should abstain from any sexual activity without barrier protection until treatment of the person and all current partners is complete (after completion of a multiple-dose treatment or for seven days after single-dose therapy) and symptoms have resolved.

Follow-up

Test of cure

TOC is recommended for all positive sites in all cases. Otherwise it is strongly recommended in the following situations:

Consider follow-up testing for cases of PID if N. gonorrhoeae was initially isolated.

The use of culture (where available) is recommended. Take samples three to seven days after treatment.

If NAAT is the only choice for TOC, the test should not be done for two to three weeks after treatmentFootnote 45Footnote 46 to avoid false positive results due to the presence of non-viable organisms.

Screening for reinfection

Repeat screening of people with a gonococcal infection is recommended six months post treatment, because of the risk of reinfectionFootnote 47.

Reporting and partner notification

National/provincial/territorial notification

Gonococcal infections are nationally notifiable and reportable by laboratories, physicians and designated health professionals to local public health authorities in all provinces and territories.

Local public health authorities should be promptly notified of suspected or confirmed treatment failures. The prompt notification of treatment failures will allow provincial and territorial (P/T) STI prevention and control programs to quickly identify emerging patterns of AMR in their jurisdictions. This will enable P/Ts to collaborate with the Public Health Agency of Canada to issue timely electronic alerts through the Canadian Network for Public Health Intelligence (CNPHI).

Partner notification

Case finding and partner notification are critical to the prevention and control of gonococcal infections. Notify, clinically assess, test and provide empiric treatment to all sexual partners of the index case within 60 days prior to symptom onset or date of specimen collection (if the index case is asymptomatic). Empiric treatment is indicated regardless of clinical findings and without waiting for test results)Footnote 4Footnote 42.

Extend the length of time for partner notification

Screen neonates born to mothers with gonorrhea, and treat as appropriate. Local public health authorities are available to assist with partner notification and help with referral for counselling, clinical evaluation, testing, treatment.

References

Footnote 1

Kidd S, Kirkcaldy R, Ye T, Papp J, Trees D, Shapiro SJ; Centers for Disease Control, Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Cephalosporin-Resistant Neisseria Gonorrhoeae Public Health Response Plan. CDC; August 2012. https://www.cdc. gov/std/treatment/ceph-r-responseplanjuly30-2012.pdf

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Footnote 2

Lyss SB, Kamb ML, Peterman TA, et al. . Chlamydia trachomatis among patients infected with and treated for Neisseria gonorrhoeae in sexually transmitted disease clinics in the United States. Ann Intern Med. 2003;139(3):178-185. doi:10.7326/0003-4819-139-3-200308050-00007

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Footnote 3

Tapsall JW. What management is there for gonorrhea in the postquinolone era?. Sex Transm Dis. 2006; 33(1):8-10. doi:10.1097/01.olq.0000194599.97426.a3

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Footnote 4

Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1-110. Erratum in: MMWR Recomm Rep. 2011 Jan 14;60(1):18.

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Footnote 5

World Health Organization. Guidelines for the management of sexually transmitted infections. 2003.

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Footnote 6

Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill. 2011;16(14):19833.

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Footnote 7

Soge OO, Harger D, Schafer S, et al. Emergence of increased azithromycin resistance during unsuccessful treatment of Neisseria gonorrhoeae infection with azithromycin (Portland, OR, 2011). Sex Transm Dis. 2012;39(11):877-879.

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Footnote 8

Centers for Disease Control and Prevention. Evaluation and diagnosis of penicillin allergy for healthcare professionals is it really a penicillin allergy? https://www.cdc.gov/antibiotic-use/community/for-hcp/Penicillin-Allergy.html. Reviewed 2017.

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Footnote 9

Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: an updated practice parameter [published correction appears in J Allergy Clin Immunol. 2008 Dec; 122(6):1237]. J Allergy Clin Immunol. 2008;122(2 Suppl):S1-S84. doi:10.1016/j.jaci.2008.06.00

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Footnote 10

Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273. doi:10.1016/j.anai.2010.08.002

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Footnote 11

Ahmed KA, Fox SJ, Frigas E, Park MA. Clinical outcome in the use of cephalosporins in pediatric patients with a history of penicillin allergy. Int Arch Allergy Immunol. 2012;158(4):405-410. doi:10.1159/000333553

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Footnote 12

Park MA, Koch CA, Klemawesch P, Joshi A, Li JT. Increased adverse drug reactions to cephalosporins in penicillin allergy patients with positive penicillin skin test. Int Arch Allergy Immunol. 2010;153(3):268-273. doi:10.1159/000314367

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Footnote 13

Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy. 2001; 31(3):438-443. doi:10.1046/j.1365-2222.2001.00992.x

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Footnote 14

Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis. Otolaryngol Head Neck Surg. 2007;136(3):340-347. doi:10.1016/j.otohns.2006.10.007

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Footnote 15

Chisholm SA, Mouton JW, Lewis DA, Nichols T, Ison CA, Livermore DM. Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink?. J Antimicrob Chemother. 2010; 65(10):2141-2148. doi:10.1093/jac/dkq289

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Footnote 16

Dunnett DM, Moyer MA. Cefixime in the treatment of uncomplicated gonorrhea. Sex Transm Dis. 1992;19(2):92-93.

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Footnote 17

Portilla I, Lutz B, Montalvo M, Mogabgab WJ. Oral cefixime versus intramuscular ceftriaxone in patients with uncomplicated gonococcal infections. Sex Transm Dis. 1992; 19(2):94-98.

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Footnote 18

Handsfield HH, McCormack WM, Hook EW 3rd, et al. A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. The Gonorrhea Treatment Study Group. N Engl J Med. 1991;325(19):1337-1341.

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Footnote 19

Barbee LA, Kerani RP, Dombrowski JC, Soge OO, Golden MR. A retrospective comparative study of 2-drug oral and intramuscular cephalosporin treatment regimens for pharyngeal gonorrhea. Clin Infect Dis. 2013;56(11):1539-1545.

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Footnote 20

Handsfield HH, Dalu ZA, Martin DH, Douglas JM Jr, McCarty JM, Schlossberg D. Multicenter trial of single-dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis. 1994; 21(2):107-111.

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Footnote 21

Bignell C, Garley J. Azithromycin in the treatment of infection with Neisseria gonorrhoeae. Sex Transm Infect. 2010;86(6):422-426. doi:10.1136/sti.2010.044586

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Footnote 22

Dan M, Poch F, Amitai Z, Gefen D, Shohat T. Pharyngeal Gonorrhea in female sex workers: Response to a single 2-g dose of azithromycin. Sex Transm Dis. 2006;33(8):512-515.

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Footnote 23

Gil-Setas A, Navascues-Ortega A, Beristain X. Spectinomycin in the treatment of gonorrhoea. Euro Surveill. 2010;15(19):pii/19568-pii/19569. Published 2010 May 13.

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Footnote 24

Ramus RM, Sheffield JS, Mayfield JA, Wendel GD Jr. A randomized trial that compared oral cefixime and intramuscular ceftriaxone for the treatment of gonorrhea in pregnancy. Am J Obstet Gynecol. 2001;185(3):629-632.

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Footnote 25

Donders GG. Treatment of sexually transmitted bacterial diseases in pregnant women. Drugs. 2000; 59(3):477-485.

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Footnote 26

Cavenee MR, Farris JR, Spalding TR, Barnes DL, Castaneda YS, Wendel GD Jr. Treatment of gonorrhea in pregnancy. Obstet Gynecol. 1993;81(1):33-38.

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Footnote 27

American Academy of Pediatrics. Gonococcal infections. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, ed. Red book®: 2018 report of the committee on infectious diseases. 2018th ed. American Academy of Pediatrics; 2018:355-65.

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Footnote 28

Kirkcaldy RD, Weinstock HS, Moore PC, et al. The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. Clin Infect Dis. 2014;59(8):1083-1091.

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Footnote 29

Tapsall, John & World Health Organization. Anti-Infective Drug Resistance Surveillance and Containment Team. (‎2001)‎. Antimicrobial resistance in Neisseria gonorrhoeae / John Tapsall. World Health Organization. https://apps.who.int/iris/handle/10665/66963

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Footnote 30

Echols RM, Heyd A, O'Keeffe BJ, Schacht P. Single-dose ciprofloxacin for the treatment of uncomplicated gonorrhea: a worldwide summary. Sex Transm Dis. 1994;21(6):345-352.

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Footnote 31

Moran JS, Levine WC. Drugs of choice for the treatment of uncomplicated gonococcal infections. Clin Infect Dis. 1995;20 Suppl 1:S47-S65.

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Footnote 32

Moran JS. Ciprofloxacin for gonorrhea--250 mg or 500 mg?. Sex Transm Dis. 1996; 23(2):165-167.

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Footnote 33

Dowell D, Kirkcaldy RD. Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta-analysis. Sex Transm Infect. 2012; 88(8):589-594.

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Footnote 34

Hathorn E, Dhasmana D, Duley L, Ross JD. The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review. Syst Rev. 2014; 3:104. doi:10.1186/2046-4053-3-104

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Footnote 35

Quaye N, Cole MJ, Ison CA. Evaluation of the activity of ertapenem against gonococcal isolates exhibiting a range of susceptibilities to cefixime. J Antimicrob Chemother. 2014; 69(6):1568-1571.

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Footnote 36

Public Health England. Update on investigation of UK case of neisseria gonorrhoaea with high-level resistance to azithromycin and resistance to ceftriaxone acquired abroad. Health Protection Report. 2018; Volume 12 Number 14.

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Footnote 37

Unemo M, Golparian D, Limnios A, et al. In vitro activity of ertapenem versus ceftriaxone against Neisseria gonorrhoeae isolates with highly diverse ceftriaxone MIC values and effects of ceftriaxone resistance determinants: ertapenem for treatment of gonorrhea?. Antimicrob Agents Chemother. 2012;56(7):3603-3609. doi:10.1128/AAC.00326-12

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Footnote 38

Bharat A, Martin I, Zhanel GG, Mulvey MR. In vitro potency and combination testing of antimicrobial agents against Neisseria gonorrhoeae. J Infect Chemother. 2016;22(3):194-197

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Footnote 39

Committee on Infectious Diseases, American Academy of Pediatrics. Gonococcal infections. In: Pickering L, ed. Red book: 2012 report of the committee on infectious diseases. Vol 29th Edition. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012:336-344.

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Footnote 40

Bharat A, Martin I, Zhanel GG, Mulvey MR. In vitro potency and combination testing of antimicrobial agents against Neisseria gonorrhoeae. J Infect Chemother. 2016;22(3):194-197.

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Footnote 41

Belga S, Gratrix J, Smyczek P, et al. Gonococcal Conjunctivitis in Adults: Case Report and Retrospective Review of Cases in Alberta, Canada, 2000-2016. Sex Transm Dis. 2019;46(1):47-51.

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Footnote 42

Centers for Disease Control and Prevention (CDC). Update to CDC's Sexually transmitted diseases treatment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep. 2012;61(31):590-594.

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Footnote 43

Ota KV, Fisman DN, Tamari IE, et al. Incidence and treatment outcomes of pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections in men who have sex with men: a 13-year retrospective cohort study. Clin Infect Dis. 2009;48(9):1237-1243. doi:10.1086/597586

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Footnote 44

Donders GG. Treatment of sexually transmitted bacterial diseases in pregnant women. Drugs. 2000; 59(3):477-485.

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Footnote 45

Bachmann LH, Desmond RA, Stephens J, Hughes A, Hook EW 3rd. Duration of persistence of gonococcal DNA detected by ligase chain reaction in men and women following recommended therapy for uncomplicated gonorrhea. J Clin Microbiol. 2002;40(10):3596-3601.

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Footnote 46

Hjelmevoll SO, Olsen ME, Sollid JU, et al. Appropriate time for test-of-cure when diagnosing gonorrhoea with a nucleic acid amplification test. Acta Derm Venereol. 2012;92(3):316-319. doi: 10.2340/00015555-1275 [doi].

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Footnote 47

De P, Singh AE, Wong T, Kaida A. Predictors of gonorrhea reinfection in a cohort of sexually transmitted disease patients in Alberta, Canada, 1991-2003. Sex Transm Dis. 2007;34(1):30-36.

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