Primary Care Corner with Geoffrey Modest MD: STI Infection Therapy WHO Guidelines

By Dr. Geoffrey Modest

Because of growing antibiotic resistance, the World Health Organization (WHO) published updated guidelines for the treatment of sexually-transmitted infections: see http://www.who.int/mediacentre/news/releases/2016/antibiotics-sexual-infections/en/.  See end of this blog for links to other relevant blogs on STIs, antibiotic resistance, etc.

Details:

• 131 million people are infected with chlamydia, 78 million with gonorrhea and 5.6 million with syphilis
• All have increasing antibiotic resistance, especially gonorrhea, where some strains do not respond to available antibiotics (see blogs at end). Quinolones are not recommended, as a result.
• There is a 7-fold increased risk of transmission of HIV in both ulcerative and nonulcerative lesions (also with other STIs, such as HSV-2, chancroid, trichomoniasis)
• There is increasing evidence of trichamonas being resistant to nitroimidazoles (and there really is no other rx)
• Syphilis has more resistance to azithromycin
• Chlamydia has more treatment failures to tetracyclines and macrolides

Gonorrhea (see http://www.who.int/reproductivehealth/publications/rtis/gonorrhoea-treatment-guidelines/en/ ) for details. I will highlight differences with the 2015 MMWR on STIs (see: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm )

• Genital and anorectal GC infections
  • Typically cause urethritis in men and mucopurulent discharge in women. Can be asymptomatic, esp in women. Pharyngeal and rectal infections are largely asymptomatic
  • Use local resistance data to determine the choice of therapy
  • If local resistance data not available, use dual therapy:
    • Ceftriaxone 250mg IM as a single dose plus azithromycin 1 g as a single dose, or
    • Cefixime 400mg orally as a single dose plus azithromycin 1 g as a single dose [MMWR: only use if ceftriaxone not available, increasing reports of cefixime resistance)]
  • If recent local resistance data are available, can use single therapy based on the local resistance pattern: [MMWR: no single treatment recommended: there are some data suggesting synergy of the dual therapy and perhaps slower development of resistance]
    • Ceftriaxone 250mg IM as a single dose
    • Cefixime 400mg orally as a single dose
    • Spectinomycin 2gm IM as a single dose
  • Oropharyngeal GC infections (MMWR noted treatment failure after single dose therapy and therefore prefer dual therapy. especially for pregnant women):
    • If local resistance data not available, use dual therapy:
      • Ceftriaxone 250mg IM as a single dose plus azithromycin 1 g as a single dose, or
      • Cefixime 400mg orally as a single dose plus azithromycin 1 g as a single dose [MMWR: this one is not recommended]
    • If recent local resistance data are available, can use single therapy based on the local resistance pattern:
      • Ceftriaxone 250mg IM as a single dose
    • Treatment failure:
      • If reinfection suspected, re-treat with above, reinforce sexual abstinence or use of condom, and provide partner Rx
      • Otherwise, contour treatment to GC susceptibility
      • Retreat with one of the following:
        • Ceftriaxone 500mg IM as a single dose plus azithromycin 2 g as a single dose, or
        • Cefixime 800mg orally as a single dose plus azithromycin 2 g as a single dose
        • Gentamicin 240 mg IM as a single dose plus azithromycin 2 gas a single dose
        • Spectinomycin 2g IM as a single dose (if not oropharyngeal GC) plus azithromycin 2 gas a single dose
        • MMWR: treat as dictated by susceptibility testing. Options include: can try gemifloxacin 320 orally plus azithro 2gm, or single doses of gentamicin 240 mg IM plus azithro 2gm; and get test-of-cure 7-14 days later, preferably by culture. No comment on the double dose treatment proposed by WHO noted above (doubling the dose of cephalosporin and azithro). They also place treatment of sex partners as priority right away, not mentioned in WHO until likely reinfection.
      • GC ophthalmia neonatorum, use one of:
        • Ceftriaxone 50 mg/kg (max of 150mg) IM as single dose, or
        • Kanamycin 25 mg/kg (max of 75mg) IM as single dose, or
        • Spectinomycin 25 mg/kg (max of 75mg) IM as single dose
      • Use topical ocular prophylaxis for all neonates to prevent GC and chlamydia eye infections, as determined by cost and local resistance
        • Tetracycline hydrochloride 1% eye ointment
        • Erythromycin 0.5% eye ointment [MMWR: this is recommended med]
        • Povidone iodine 2.5% solution (water-based, not alcohol-based)
        • Silver nitrate 1% solution
        • Chloramphenacol 1% eye ointment
      • MMWR also suggests treatment for adult gonococcal conjunctivitis with ceftriaxone 1 gm IM plus azithro 1 g orally, both in a single dose

Chlamydia (see http://www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/ )

• Can be asymptomatic in men and women
• Uncomplicated genital chlamydia [MMWR recommends the same 2 primary treatments, adds levofloxacin 500mg orally once a day for 7 days, and has ofloxacin as 300 mg bid for 7 days. Does not include tetracycline. And again pushes more for treatment of sex partners]
  • Azithromycin 1 g orally as a single dose (most convenient dosing), or
  • Doxycycline 100mg orally twice a day for 7 days (cheapest treatment). These 2 are the major recommendations
  • Tetracycline 500 mg 4 times a day for 7 days, erythromycin 500mg orally twice a day for 7 days, ofloxacin 200-400 mg orally twice a day for 7 days (alternative regimens)
• Anorectal chlamydia
  • Priority is doxycycline 100mg bid for 7 days, secondary would be azithromycin 1gm orally as a single dose
• Genital chlamydia in pregnant woman [MMWR also recommends azithro as primary, then options of amoxacillin or a variety of erythromycin-based therapies similar to WHO]
  • Use azithromycin over amoxicillin (500mg orally 3 times a day for 7 days), and that over erythromycin, regimens as above
• LGV (lymphogranuloma venereum)
  • Doxycycline 100mg bid for 21 days preferred, can do azithromycin 1 g orally weekly for 3 weeks
• Neonatal chlamydia conjunctivitis (ophthalmia neonatorum) [MMWR prioritizes the erythromycin regimen]
  • Azithromycin20 mg/kg/day orally once a day for 3 days (preferred), or erythromycin 50 mg/kg/day, orally in 4 divided doses for 14 days
• Neonatal ocular prophylaxis
  • Same as for GC above

Syphilis (see http://www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/ )

• Primary syphilis: painless chancre (may be extra-genital, at site of inoculation) after mean incubation of 21 days, and heals spontaneously in 3-10 weeks
• Secondary syphilis: generalized rash (varies widely, and I have seen a couple of cases looking just like pityriasis rosea), but typically palms and soles, symmetric, non-itchy. In moist areas (anus/labia), can be white-gray raised lesion of condyloma lata, which are teeming with treponemes (i.e., wear gloves…)
• latent syphilis: positive serology, no clinical signs/symptoms, and divided into early latent (<2yrs) or late latent (>2 years, or if unknown)
• If untreated, most remain in late latent stage, with 25% developing the late clinical sequelae of tertiary syphilis (can be >30 years after infection). Neurosyphilis can occur at any stage, even within the first few months: acute mental status changes, meningitis, stroke, cranial nerve dysfunction, auditory/ophthalmic/ocular abnormalities. Late neurosyphilis (tabes dorsalis, general paresis) occurs 10 to >30 years after infection
• MMWR basically agrees with below, though has additional recommendations for kids, treating tertiary and neurosyphilis, as well as coinfection with HIV (not different from non-HIV, though may have more clinical symptoms, such as neurosyphilis.
• Early syphilis (primary, secondary and early latent)
  • Benzathine penicillin G 2.4 million units IM once (preferred)
  • Procaine penicillin G 1.2 million unit IM for 10-14 days
  • In penicillin-allergic, or above not available: doxycycline 100mg orally bid for 14 days (cheaper and oral), or ceftriaxone 1 g IM daily for 10-14 days, or (last) azithromycin 2 g orally once only (if local susceptibilities support its use)
• Pregnant women with early syphilis
  • As above with emphasis on penicillin regimens
  • In those penicillin allergic: can use the erythromycin or ceftriaxone or azithromycin, as above. (Can’t use doxycycline in pregnancy, and erythromycin and azithromycin do not cross the placental barrier completely. So if use either of these, should treat the newborn soon after delivery)
• Late syphilis (infection >2 years, or syphilis of unknown duration without evidence of treponemal infection)
  • Benzathine penicillin G 2.4 million units IM once weekly for 3 injections, and interval between doses cannot exceed 14 days (preferred)
  • Procaine penicillin 1.2 million units IM daily for 20 days
  • If penicillin-allergic: doxycycline 100mg orally bid for 30 days
• Late syphilis (infection >2 years or syphilis of unknown duration without evidence of treponemal infection), in pregnant women
  • Benzathine penicillin G 2.4 million units IM once weekly for 3 injections, and interval between doses cannot exceed 14 days (preferred)
  • Procaine penicillin 1.2 million units IM daily for 20 days
  • If penicillin-allergic: erythromycin 500mg orally qid for 30 days. And treat the newborn
• Congenital syphilis
  • Aqueous benzyl penicillin 100,000-150,000 U/kg/day intravenously for 10-15 days (preferred)
  • Procaine penicillin 50,000 U/kg/day IM for 10-15 days
• Infants who are clinically normal but whose mothers had syphilis which was adequately treated
  • Risk of transmission depends on: maternal titers from non-treponemal tests (e.g. RPR), timing of maternal treatment and stage of maternal infection
  • If decide to treat: benzathine penicillin 50,000U/kg/day as single IM dose

Commentary:

Why is the WHO report important??

• It highlights the really major issue on increasing antibiotic resistance, and the WHO has really been at the forefront in studying this issue and publicizing pretty dire warnings
• We are seeing more international patients who may have been treated for an STI and we should know what are the acceptable regimens internationally
• In the US, I would go by the MMWR recommendations, though I think the suggestions of higher dose meds for treatment failure of gonorrhea make sense, but is supported only by successful reports in individuals who had failed a variety of treatments, and not from formal studies. In someone who is less likely to come back for test-of-cure, based on this I would probably use the higher dose regimen as per WHO. If they are very likely to return, it is reasonable to try the MMWR regimens with close follow-up. I am also still somewhat concerned about the treatment of syphilis in those with HIV, given early reports of failure, and still do use the longer regimen (2-3 shots for early syphilis), as per the relevant blog cited below.

For prior blogs, see https://stg-blogs.bmj.com/bmjebmspotlight/category/sti/ , which includes blogs detailing the increasing resistance of gonorrhea ( https://stg-blogs.bmj.com/bmjebmspotlight/2016/07/27/primary-care-corner-with-geoffrey-modest-md-gonorrhea-resistance-increasing/ ), a blog from the WHO highlighting that in 3 of the 6 regions of the world there is >25% resistance of gonorrhea to 3^rd generation cephalosporins (https://stg-blogs.bmj.com/bmjebmspotlight/2014/07/11/primary-care-corner-with-geoffrey-modest-md-whos-remarkable-scary-report/ ), a blog which questions the recommendation that those with syphilis and HIV get the same treatment as those without HIV (https://stg-blogs.bmj.com/bmjebmspotlight/2015/02/17/primary-care-corner-with-geoffrey-modest-md-syphilis-treatment-in-hiv-positive-patients/ , etc.