WHO Guidelines for the

Treatment of STIs

Robert Paulino-Ramirez, MD, HIVS, DTM&H

WHO Consultant
Workshop on Enhancing and Innovating Comprehensive HIV/STI
Services for Adult and Adolescents of KP in the Caribbean
Trinidad & Tobago, May 2018
WHO STIs Guidelines

•  Neisseria gonorrhoeae
•  Chlamydia trachomatis
•  Genital Herpes
Simplex
•  Treponema pallidum
 Grading of Recommendations
Assessment, Development and
Evaluation (GRADE)
Level Description
High We are very confident that the true effect lies close to that of the
estimate of the effect
Moderate We are moderately confident in the effect estimate; the true effect
is likely to be close to the estimate of the effect, but there is a
possibility that it is substantially different.
Low Our confidence in the effect estimate is limited; the true effect may
be substantially different from the estimate of the effect
Very low We have very little confidence in the effect estimate; the true
effect is likely to be substantially different from the estimate of the
effect
Treatment of Treponema pallidum
(Syphilis)

Available at:

http://www.who.int/reproductivehealth/
publications/rtis/syphilis-treatment-guidelines/
en/
 Early syphilis
(primary, secondary, early latent < 2 years )
Adults and Adolescents Pregnant Women
Benzathine penicillin G 2.4 million units IM, Benzathine penicillin G 2.4 million units
single dose. IM, single dose.

Strong recommendation, very low quality evidence

Alternative Procaine penicillin G 1.2 million Procaine penicillin G 1.2 million units
units IM once daily x 10-14 days IM once daily x 10-14 days

Penicillin Doxycycline 100 mg twice daily Erythromycin 500 mg four times daily
allergy or x 14 days or x 14 days* OR
stock out Ceftriaxone 1 g IM, QD x 10-14 Ceftriaxone 1 g IM, once daily x
days or 10-14 days* OR
in special circumstances in special circumstances Azithromycin 2
Azithromycin 2 g QD x 1 g, Single dose*
*with precaution
Conditional recommendation, very low quality evidence
 Summary of evidence - early syphilis
•  Very low quality evidence
•  7 randomized and 18 non-randomized studies
–  evaluating benzathine penicillin G, procaine penicillin, ceftriaxone, azithromycin and
doxycycline (with or without tetracycline).
•  Average serological cures with benzathine penicillin G 2.4 megaU, single dose IM
estimated at 840 per 1000 people
•  No difference in serologic cure rates: single dose of benzathine penicillin G versus two
weekly injections
•  Treatment with benzathine penicillin G and procaine penicillin - not captured in
published studies but based on historical and successful use
 Summary of evidence - early syphilis
•  Similar numbers cured when treated with ceftriaxone, azithromycin or doxycylcine
•  Resistance to azithromycin for treating syphilis
–  Limited data – azithromycin resistant strains reported in specific settings
–  Will remain largely unknown as capacity to monitor AMR in syphilis is not
available
–  STI GDG concern about azithromycin resistance in other conditions and in syphilis
•  Acceptability of injection versus oral medication : 10-20% refuse injection ; HCP
averse to providing injections
•  Concern of impending global shortage of benzathine penicillin
•  Benefits of treatment with benzathine penicillin G versus no treatment is largely
based on 70 years of successful treatment of syphilis
 Summary of evidence – early syphilis
(pregnant women)
•  Quality of the evidence very low.
•  Few studies (10 non-randomized studies), very few pregnant women included, stage
of syphilis (whether early or late) was unknown.
•  Evidence from successful historical use of benzathine and procaine penicillins and
erythromycin was used to inform the judgements about the benefits of different
medicines.
•  Recommendations for non-pregnant women with early syphilis were used to inform
the recommendations for pregnant women except for doxycycline
•  Benefits were large for using benzathine penicillin compared to no treatment.
•  Differences in medicines in terms of benefits and harms were trivial.
 Summary of evidence – early syphilis
(pregnant women)
•  Prevention of mother-to-child transmission was a critical outcome.
–  Penicillins cross the placental barrier, while azithromycin and
erythromycin do not
•  increased chance of mother-to-child transmission of syphilis not impacted
by the latter two medicines
•  There was no evidence for adverse effects, transmission to partner,
antimicrobial resistance (AMR), HIV transmission or acquisition, or STI
complications.
•  No specific research evidence for the other factors (acceptability, feasibility,
equity and costs) for pregnant women
 Late Syphilis
(infection of more than two years’ duration without
evidence of recent treponemal infection)
Adults and Adolescents Pregnant Women
Benzathine penicillin G 2.4 megaU IM x 3 Benzathine penicillin G 2.4 megaU IM
consecutive weeks 3 x consecutive weeks
Strong recommendation, very low quality evidence
Alternative Procaine penicillin G 1.2 Procaine penicillin G 1.2 megaU IM
megaU IM once daily x 10-20 once daily x 20 days
days
Penicillin Doxycycline 100 mg twice Erythromycin 500 mg four times daily x
allergy or daily x 30 days 30 days (with caution)
stock out
Conditional recommendation, very low quality evidence

Because syphilis during pregnancy can lead to severe adverse complications to the fetus
or newborn, stock-outs of benzathine penicillin for use in antenatal care should be
avoided.
 Summary of evidence – late syphilis
•  Very low quality of evidence
•  Most studies include patients with early or late syphilis; stage of syphilis not
reported
•  One study included over 300 people diagnosed with late syphilis: Evaluated
benzathine penicillin G 2.4 MU given once IM and azithromycin 2 g given once
orally.
–  Serological cure was low (33–39%);
•  Another study included 135 pregnant women treated for late syphilis. This study
found that 99% of women with the double dose of benzathine penicillin G were
cured.
 Summary of evidence – late syphilis
•  Historically, multiple doses of benzathine penicillin G (once a week for three weeks)
or procaine penicillin 1.2 MU (once daily for 20 days) have been successful for
serological and clinical cure of syphilis.
•  PMTCT is a critical outcome.
–  Penicillins cross the placental barrier, while azithromycin
and erythromycin do not, meaning that there is an
increased chance of congenital syphilis with treatment
with the latter two medicines.
 Key Message: Congenital syphilis
•  Infants with confirmed congenital syphilis or infants who are clinically normal, but
mother with syphilis was not treated, inadequately treated (including treated within
30 days of delivery) or treated with non-penicillin regimen:
–  Aqueous benzyl penicillin 100,000-150,000 U/kg/day intravenously for 10-15
days
–  Procaine penicillin 50,000 U/kg/day single dose intramuscularly for 10-15
days
•  In infants who are clinically normal and the mother had syphilis and was adequately
treated with no signs of re-infection:
–  closely monitor the infants over treatment
–  Benzathine penicillin G 50,000 U/kg/day single dose intramuscularly

Conditional recommendation, very low quality evidence

Summary of evidence - congenital syphilis
•  Quality of the evidence was very low.
•  Nine non-randomized studies and historical use of the medicines to treat and prevent
confirmed or suspected congenital syphilis.
•  Small sample sizes of most studies and very low rates of follow-up of babies after
treatment.
–  follow-up ranged from six months to one year.
–  Treatments - aqueous benzyl penicillin, procaine penicillin and benzathine
penicillin G
–  Ceftriaxone was not assessed.
•  Most studies of infants with confirmed congenital syphilis or infants whose mothers
received inadequate or no treatment - 100% cures with no adverse effects
 Laboratory diagnosis
Direct Detection methods

Dark-field microscopy
–  The most specific method for dx of early stages of syphilis
–  Must be performed immediately
–  Cons- requires specialized equipment and training
–  Sensitivity is less than 50%

Direct Fluorescent Antibody (DFA)

–  ñsensitivity and specificity
–  Cons- requires specialized equipment, fluorescein conjugate
not commercially available
 Laboratory diagnosis (2)
Direct Detection methods
NAATs
–  Detects T. pallidum by PCR
–  Commercial PCR tests are still costly
Non-Treponemal Tests
 Laboratory diagnosis (3)
Non-treponemal
VDRL and RPR
–  Not highly specific due to cross reactions
–  Can be negative in latent syphilis
–  Primary and secondary syphilis can be negative due to a
prozone reaction (Ag-Ab)
–  Quantitative non-treponemal can be used to monitor
response to treatment (titres ê after effective Tx)
Treponemal
 Laboratory diagnosis (4)
Treponemal
Treponema pallidum haemagglutination assay (TPHA), treponema
pallidum particle agglutination assay (TPPA), and Fluorescent
Treponemal antibody absorbed (FTA-ABS)
–  Highly specific
–  They do not differentiate btw venereal syphilis from
endemic syphilis (yaws and pinta)
–  Remains positive (85%) for patient’s lifetime
–  Do not differentiate ACTIVE vs TREATED syphilis
 Laboratory diagnosis (5)
Newborns
–  Should be tested monthly until three months to confirm
negative results

POC Tests
–  Rapid results, no refrigerated storage, or lab equipment
–  Sensitivity 93-98%
–  Immunochromatographic strips
–  Cons- do not differentiate ACTIVE vs TREATED syphilis
Treatment of Neisseria gonorrhoeae

Available at:
http://www.who.int/reproductivehealth/
publications/rtis/gonorrhoea-treatment-
guidelines/en/
 Genital and Anorectal gonococcal
infections
Dual Therapy Single Therapy
Ceftriaxone 250 mg intramuscular (IM) as Single therapy (one of the following, based
a single dose PLUS azithromycin 1 g on recent local AMR data confirming
orally as a single dose OR susceptibility):

Cefixime 400 mg orally as a single dose Ceftriaxone 250 mg IM as a single dose OR

PLUS azithromycin 1 g orally Cefixime 400 mg orally as a single dose
as a single dose OR
Spectinomycin 2 g IM as a single dose
Conditional recommendation, low quality evidence
Recent local AMR data should determine the choice of therapy (for both dual therapy
and single therapy). Where recent local AMR data is not available, dual therapy is
recommended.
Good practice statement
 Oropharyngeal gonococcal infections
Dual Therapy
Ceftriaxone 250 mg IM as a single dose PLUS
azithromycin 1 g orally as a single dose
Cefixime 400 mg orally as a single dose PLUS
azithromycin 1 g orally as a single dose
Single Therapy
(based on recent local AMR data
confirming susceptibility):
Ceftriaxone 250 mg IM as a single
dose

*Treatment failures have been observed and therefore dual therapy is suggested over
single therapy.
Conditional recommendation, very low quality evidence
 Retreatment after treatment failure
•  If reinfection is suspected, retreat with a WHO-recommended regimen,
reinforce sexual abstinence or condom use, and provide partner
treatment.
•  If treatment failure occurred after treatment with a regimen not
recommended by WHO, retreat with a WHO-recommended regimen.
•  If treatment failure occurred and AMR data are available, retreat
according to susceptibility.
•  If treatment failure occurred after treatment with a WHO-recommended
single therapy, retreat with WHO-recommended dual therapy.
•  If treatment failure occurred after a WHO-recommended dual therapy,
retreat with one of the following dual therapies:à

Conditional recommendation, very low quality evidence

 Retreatment after treatment failure
(dual therapy options)
Dual Therapy (after Tx Failure
Ceftriaxone 500 mg IM as a single dose PLUS azithromycin 2 g orally as a single dose
OR
Cefixime 800 mg orally as a single dose PLUS azithromycin 2 g orally as a single dose
OR
Gentamicin 240 mg IM as a single dose PLUS azithromycin 2 g orally as a single dose
OR
Spectinomycin 2 g IM as a single dose (if not an oropharyngeal infection) PLUS
azithromycin 2 g orally as a single dose.
*Reinfection should be distinguished from treatment failure, AMR data should be
obtained when possible, and the WHO-recommended regimens should be used.
Conditional recommendation, very low quality evidence
 Gonococcal Ophthalmia neonatorum
Single Therapy Single Therapy (AMR data available)
Ceftriaxone 50 mg/kg (maximum 150 mg) (based on recent local AMR data
IM as a single dose OR confirming susceptibility):
Kanamycin 25 mg/kg (maximum 75 mg) Ceftriaxone 250 mg IM as a single dose
IM as a single dose OR
Spectinomycin 25 mg/kg (maximum 75
mg) IM as a single dose
*Choice of treatment may depend on the cost and quality of the medicine in different
settings and on equity considerations. Side-effects should be monitored.
Conditional recommendation, very low quality evidence
Gonococcal Ophthalmia neonatorum
§  Tetracycline hydrochloride 1% eye ointment OR
§  Erythromycin 0.5% eye ointment OR
§  Povidone iodine 2.5% solution (water-based; NOT alcohol-based!) OR
§  Silver nitrate 1% solution OR
§  Chloramphenicol 1% eye ointment
Choice of treatment may depend on the AMR, cost and quality of
the medicine in different settings and on equity considerations. Side-effects
should be monitored.
Conditional recommendation, low quality evidence
For all neonates, topical ocular prophylaxis is recommended for the prevention
of gonococcal and chlamydial ophthalmia neonatorum
Strong recommendation, low quality evidence
Key changes since 2003 WHO guideline
•  Quinolones no longer recommended!
•  Dual therapy, including ESC, is preferred over single therapy
•  Single therapy should be based on recent local AMR data
•  Separate treatment recommendations for oropharyngeal gonorrhoea
•  Recommendations of retreatment after treatment failure
•  New topical medications for prophylaxis of ophthalmia neonatorum

* ESC= Extended-spectrum cephalosporins

 Laboratory diagnosis
Culture or Gram stain
Lower sensitivity, a negative gram stain should not be considered
sufficient for ruling out infection in asymptomatic men*
*Workowski KA, Bolan GA. Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR Recommendations
and reports : Morbidity and mortality weekly report Recommendations and reports. 2015;64(RR-03):1-137.
NAATs
–  Preferred
–  Highly sensitive (>90%) (higher to culture >85%) and
specific
–  Can be performed in urine, vaginal and urethral swabs
 Research Implications
1.  Limited recent randomized clinical trials (RCTs) ⇒ conduct adequate RCTs of
new drugs (possibly old) and different dual therapies (men and women, incl.
key populations and extragenital samples)
2.  Report cure and side-effects, but also e.g. transmission to partners, HIV
transmission and acquisition, quality of life, in vitro AMR, patient values,
preferences, acceptability, compliance, equity and feasibility
3.  Follow-up studies with patients who had treatment failure
4.  Pharmacokinetic/pharmacodynamic studies
5.  Enhance surveillance of AMR, incl. treatment failures
6.  Rapid point-of-care tests (ideally with molecular AMR prediction)
7.  Prevalence, prevention and treatment of ophthalmia neonatorum
8.  New treatment options
9.  Rationale drug use, availability and conservation
10.  Vaccine
Treatment of Chlamydia trachomatis

Available at:

http://www.who.int/reproductivehealth/
publications/rtis/chlamydia-treatment-
guidelines/en/
 Genital Chlamydia (Cervix, Urethal)
Adults and Alternatives Pregnancy
adolescents
Azithromycin 1 g -  Tetracycline 500 mgs PO 4 a)  Azithromycin 1 g PO single
PO single dose OR times a day x 7 days dose OR

Doxycycline 100 mg -  Erythromycin 500 mg PO 4 b) Amoxicillin 500 mg PO TID x 7

PO BID x 7 days times a day x 7 days days OR

-  Ofloxacin 200-400 mg BID x c) Erythromycin 500 mg 4 times x

7 days 7 days

Conditional recommendation, Moderate quality a)  Strong recommendation,

evidence moderate quality evidence
b)  Conditional recommendation,
low quality evidence
c)  Conditional recommendation,
low quality evidence
 Anorectal Chlamydia
Adults and adolescents Remarks
Doxycycline 100 mg PO BID x 7 days OR *Doxycycline not to be used in
pregnant women
Azithromycin 1 g PO single dose
Conditional recommendation, low quality evidence
 Lymphogranuloma venereum (LGV)
Adults and adolescents Remarks
Doxycycline 100 mg PO BID x 21 days OR When none of them are
available then use:
Azithromycin 1g PO, weekly x 3 weeks Erythomycin 500 mg PO 4
times a day x 21 days.

*Doxycycline not to be use

during pregnancy
Conditional recommendation, very low quality evidence
 Ophtalmia neonatorum
Remarks
Azithromycin 20 mg/kg/day PO, one dose daily x 3 days, Strong recommendation due to
OR pyloric stenosis w use of
erythromycin in neonates.
Erythromycin 50 mg/kg/day PO, in 4 times daily x 14 days:
20 mg/kg/day, 30 mg/kg/day, OR 50 mg/kg/day

Trimethoprim 40 mg + Sulfa 200 mg PO BID x 14 days

Strong recommendation, very low quality evidence
ALL neonates topical ocular prophylaxis with: Apply for Chlamydia and
gonococcal infections.
-  Tetracycline hydrochloride 1% eye ointment OR
-  Erythromycin 0.5% eye ointment OR DO NOT USE ALCOHOL-
-  Povidone iodine 2.5% solution OR BASED POVIDONE IODINE
-  Silver nitrate 1% solution OR SOLUTION
-  Chloramphenicol 1% eye ointment
Strong recommendation, low quality evidence
 Laboratory diagnosis
•  NAATs are highly sensitive and specific
–  Used in vaginal, urine, and urethral swabs
–  Highly sensitive compared with Culture, DFA and
ELISA
 Research implications
1.  Potential for resistance to azythromycin, docycycline should
be further characterized.
2.  Studies comparing these regimens and dosages in RCTs
3.  Studies evaluating the use of amoxicillin 500 mg TID x 7
days
4.  Global incidence of chlamydia anorectal infections should
be determined
5.  Comparison of azithromycin over amoxicillin over
erythromycin dosages in pregnancy should be evaluated.
6.  RCTs should be conducted in LGV evaluating clinical and
microbiological cure.
7.  TMP/SMX use to be evaluated in ophthalmia neonatorum,
and the relationship with resistance in gonococcal infections.
Treatment of Genital Herpes Simplex
Virus

Available at:

http://www.who.int/reproductivehealth/
publications/rtis/genital-HSV-treatment-
guidelines/en/
 Genital HSV (First episode)
Adults and adolescents Remarks
Aciclovir 400 mg PO TID x 10 days OR Therapy should be provided for 10
days due to lost of follow-up
Aciclovir 200 mg PO 5 times x 10 days OR Aciclovir $
Valaciclovir $$$
Valaciclovir 500 mg PO BID x 10 days OR Famciclovir $$$$

Famciclovir 250 mg PO TID x 10 days * Same recommendation for HIV (+),

immunocompromised, severe
episodes, and pregnancy
Conditional recommendation, moderate quality evidence
Recommended Treatment over non Treatment * Same recommendation for HIV (+),
immunocompromised, severe
episodes, and pregnancy
Strong recommendation, moderate quality evidence
 Genital HSV (Recurrent episodes)
Adults and adolescents HIV (+) and Immunocompromised
Aciclovir 400 mg PO TID x 5 days, OR Aciclovir 400 mg PO TID x 5 days
800 mg BID x days, OR 800 mg TID x 2 days
Valaciclovir 500 mg PO BID x 5 days
Valaciclovir 500 mg PO BID x 3 days OR
Famciclovir 500 mg PO BID x 5 days
Famciclovir 250 mg PO BID x 5 days
Conditional recommendation, moderate quality evidence
Recommended Treatment over non Treatment * Same recommendation for HIV (+),
immunocompromised, severe episodes,
and pregnancy
Conditional recommendation, moderate quality evidence
 Genital HSV (frequent, severe or
distress)(4-6 times x year)
Adults, adolescents, and Pregnant HIV (+) and immunocompromised
Aciclovir 400 mg PO BID daily Aciclovir 400 mg PO BID daily, OR

Valaciclovir 500 mg PO QD daily Valaciclovir 500 mg PO BID daily, OR

Famciclovir 250 mg PO BID daily Famciclovir 500 mg PO BID daily

Conditional recommendation, low quality evidence
Recommended Treatment over non Treatment * Same recommendation for HIV (+),
immunocompromised, severe episodes,
and pregnancy

Conditional recommendation, moderate quality evidence

 Laboratory Diagnosis
•  Genital HSV is often Dx clinically
•  Lab Dx is required to differentiate HSV-1 and
HSV-2
•  Serological tests for HSV-2 antibodies
–  Abs within the first week and persist indefinitely
•  NAATs are largely preferred over Ab detection
or culture due to higher sensitivity.
 Research Implications
1.  RCTs comparing medicines vs placebo or comparing different
medicines to treat first or recurrent episodes
2.  Few data in key populations.
Thanks!!