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{{Vaginitis}}
{{Vaginitis}}


{{CMG}}; {{AE}}{{CZ}}, {{DN}}
{{CMG}}; {{AE}}{{CZ}}, {{DN}}, {{AKI}}


==Overview==
==Overview==
Vulvovaginitis is a common condition for which women seek medical care accounting for approximately 10 million office visits every year. It is defined as symptoms that cause itching, irritation, burning and abnormal vaginal discharge. The three common causes of vaginal discharge in reproductive age group include: most common being Bacterial Vaginosis followed by Candida vulvovaginitis and Trichomoniasis. All the patients with vulvovaginitis present with common symptoms like vaginal discharge, itching and dysuria. Diagnosis of vulvovaginitis requires a complete history of the description of the symptoms and sexual history as they aid in diagnosis. Physical examination of the external genitalia and speculum examination should focus on documenting the nature of the discharge present, the presence of any vulvar and labial lesions, foreign body, presence of cervical inflammation, cervical lesions, and any cervical motion or adnexal tenderness with a bimanual examination. It is essential to rule out pelvic infammatory disease and cervical lesions as the cause of vaginal discharge. Estimation of vaginal pH and vaginal smear wet mount examination is the initial diagnostic test which helps in differentiation of the common etiologies. Treatment of vulvovaginitis includes medical therapy targeted against the causative pathogen and a counseling on hygiene, voiding techniques and sexual practices . Prognosis is good in most patients but minority of patients have recurrence.
[[Vulvovaginitis]], a common condition for which women seek medical care, accounts for greater than 10% of visits made to providers of women's health care.<ref name="pmid21084788">{{cite journal| author=Quan M| title=Vaginitis: diagnosis and management. | journal=Postgrad Med | year= 2010 | volume= 122 | issue= 6 | pages= 117-27 | pmid=21084788 | doi=10.3810/pgm.2010.11.2229 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21084788  }} </ref> It is characterized by symptoms that cause [[itching]], [[irritation]], [[Burning during urination|burning]], and abnormal [[vaginal discharge]]. The three most common causes of vaginal discharge in women within the reproductive age group are [[Bacterial vaginosis|bacterial vaginosis]], [[vulvovaginitis|candida vulvovaginitis]], and [[trichomoniasis]]. All patients with [[vulvovaginitis]] present with common symptoms like [[vaginal discharge]], [[itching]], and [[dysuria]]. Diagnosis of [[vulvovaginitis]] requires a detailed history of the patient's [[symptoms]], as well as her sexual history, both of which facilitate an accurate diagnosis. Physical examination of the [[external genitalia]] and [[speculum]] examination should focus on documenting the nature of the [[discharge]], the presence of any [[Vulvitis|vulvar]] or [[Labial commissures|labial]] lesions, [[foreign body]], presence of [[cervical inflammation]], [[cervical lesions]], and any [[Cervical motion tenderness|cervical motion]] or adnexal tenderness with a bimanual examination. It is essential to rule out [[pelvic inflammatory disease|pelvic inflammatory disease]] and cervical lesions as the cause of [[vaginal discharge]]. Estimation of vaginal [[pH]] and [[vaginal smear]] [[wet mount]] examination constitute the initial diagnostic test, which helps differentiate among common etiologies. Treatment of [[vulvovaginitis]] includes medical therapy targeted against the causative pathogen and counseling on [[hygiene]], voiding techniques, and sexual practices. The [[prognosis]] is good in most patients, though a minority of patients experience recurrence.


==Synopsis==
==Classification==
Based on the etiology vaginitis is classified into the following:
*[[Candida Vulvovaginitis]]
*[[Bacterial vaginosis]]
*[[Trichomoniasis]]
*[[Atrophic vaginitis]]
*Aerobic vagnitis


===Symptoms and Examination===
==Differential Diagnosis==
{| class="wikitable" style="border: 2; background: none;"
The differential diagnosis for patients presenting with [[vaginal discharge]] includes the following considerations:
|-
 
{| Class="wikitable" style="border: 2; background: none;"                                                      
! rowspan="2" |Common Presentation
! rowspan="2" | Disease  
! rowspan="2" | Disease  
! colspan="6" rowspan="1" | Symptoms
! colspan="6" rowspan="1" | Symptoms
! rowspan="2" | Examination Findings  
! rowspan="2" | Physical Examination Findings  
|-
|-
! rowspan="1" | Discharge || Dysuria || Vaginal odor || Dyspareunia || Genital skin lesion || Genital pruritus
! rowspan="1" | Discharge || Dysuria || Vaginal odor || Dyspareunia || Genital skin lesion || Genital pruritus
|-
|-
| rowspan="5" |'''Vaginitis'''
| [[Candida Vulvovaginitis]] ||✔  ||✔ ||✔ || ✔
| [[Candida Vulvovaginitis]] ||✔  ||✔ ||✔ || ✔
||✔  ||✔✔   
||✔  ||✔✔   
|
|
*Vulvar  edema, fissures, excoriations
*Vulvar  edema, [[fissures]], [[excoriations]]
*Thick curdy vaginal discharge
*Thick, [[curdy]] [[vaginal discharge]]
|-
|-
| [[Bacterial Vaginosis]] ||✔||||✔||          <small>—</small>  
| [[Bacterial Vaginosis]] ||✔||<small>—</small>
||✔||          <small>—</small>  
||                <small>—</small>  
||                <small>—</small>  
||<small>—</small>  
||<small>—</small>  
|
|
* Fishy-odor from the [[vagina]]
* Fishy odor from the [[vagina]]
* Thin, white/gray homogeneous [[vaginal discharge]]
* Thin, white/gray homogeneous [[vaginal discharge]]
* Lack of significant vulvovaginal inflammation
* Lack of significant vulvovaginal [[inflammation]]
|-
|-
| [[Trichomoniasis]] ||✔||✔|| ✔
| [[Trichomoniasis]] ||✔||✔|| ✔
Line 38: Line 48:
|| ✔
|| ✔
|
|
* Strawberry cervix: petechial haemorrhages on the ectocervix, specific to trichomoniasis
* Strawberry [[cervix]]: [[petechial haemorrhages]] on the [[ectocervix]], specific to [[trichomoniasis]]
* Frothy, mucopurulent, yellow-green or gray vaginal discharge
* Frothy, [[mucopurulent]], yellow-green or gray [[vaginal discharge]]
|-
|-
| [[Atrophic Vaginitis]] ||✔||✔|| ✔
| [[Atrophic Vaginitis]] ||✔||✔|| ✔
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||✔||✔
||✔||✔
|
|
*Pale and dry vaginal epithelium
*Pale and dry vaginal mucosa
*Increased friability of the vaginal epithelium with patchy erythema and petechiae  
*Increased [[friability]] of the [[vaginal]] [[mucosa]] with patchy [[erythema]] and [[petechiae]]
*Sparsity of pubic hair, fusion of the [[labia minora]], narrow and a shortened vagina
*Sparsity of [[pubic hair]], fusion of the [[labia minora]], narrow and a shortened [[vagina]]
|-
|-
|Aerobic Vaginitis
|Aerobic Vaginitis
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|✔
|✔
|
|
*Vaginal mucosa is red and inflamed, severe ecchymotic bleeding points and ulcers can be seen in severe cases
*[[Vaginal mucosa]] is red and [[inflamed]], severe [[ecchymotic]] bleeding points and [[ulcers]] can be seen in severe cases
*Erosions, hyperaemia, scattered bleeding points and ulcers can be demonstrated on the cervix
*[[Erosions]], [[hyperaemia]], scattered [[bleeding points]] and [[ulcers]] can be demonstrated on the [[cervix]]
|-
|-
|Chlamydia
| rowspan="2" |'''Cervicitis'''
|[[Chlamydia infection|Chlamydia]]
|✔
|✔
|✔
|✔
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|✔
|✔
|
|
*Cloudy, yellow mucoid discharge from the cervical os<ref name="pmid16669564">{{cite journal| author=Miller KE| title=Diagnosis and treatment of Chlamydia trachomatis infection. | journal=Am Fam Physician | year= 2006 | volume= 73 | issue= 8 | pages= 1411-6 | pmid=16669564 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16669564  }}</ref>
*Cloudy, yellow mucoid [[discharge]] from the [[cervical os]]<ref name="pmid16669564">{{cite journal| author=Miller KE| title=Diagnosis and treatment of Chlamydia trachomatis infection. | journal=Am Fam Physician | year= 2006 | volume= 73 | issue= 8 | pages= 1411-6 | pmid=16669564 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16669564  }}</ref>
*Friable appearance of cervix<ref name="pmid16669564">{{cite journal| author=Miller KE| title=Diagnosis and treatment of Chlamydia trachomatis infection. | journal=Am Fam Physician | year= 2006 | volume= 73 | issue= 8 | pages= 1411-6 | pmid=16669564 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16669564  }} </ref>
*Friable appearance of [[cervix]]
*[[Cervical motion tenderness]] may be present<ref name="abc">Chlamydia CDC Fact Sheet. CDC.http://www.cdc.gov/std/chlamydia/stdfact-chlamydia-detailed.htm#_ENREF_3. Accessed on January 11, 2016</ref>
*[[Cervical motion tenderness]] may be present<ref name="abc">Chlamydia CDC Fact Sheet. CDC.http://www.cdc.gov/std/chlamydia/stdfact-chlamydia-detailed.htm#_ENREF_3. Accessed on January 11, 2016</ref>
*Clear or white urethral discharge in men<ref name="pmid16669564">{{cite journal| author=Miller KE| title=Diagnosis and treatment of Chlamydia trachomatis infection. | journal=Am Fam Physician | year= 2006 | volume= 73 | issue= 8 | pages= 1411-6 | pmid=16669564 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16669564  }} </ref>
*Testicular tenderness and swelling may be present<ref name="abc">Chlamydia CDC Fact Sheet. CDC.http://www.cdc.gov/std/chlamydia/stdfact-chlamydia-detailed.htm#_ENREF_3. Accessed on January 11, 2016</ref>
|-
|-
|Gonnorrhea
|[[Gonorrhea]]
|✔
|✔
|✔
|✔
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|
|
*[[Mucopurulent discharge|Mucopurulent]] [[urethral]],  [[cervical]] or [[vaginal]] discharge
*[[Mucopurulent discharge|Mucopurulent]] [[urethral]],  [[cervical]] or [[vaginal]] discharge
*Positive cervical motion tenderness
*Positive [[cervical motion tenderness]]
*Friable cervical mucosa
*Friable [[cervical]] [[mucosa]]
*Abdominal pain with negative [[rebound tenderness]]
*[[Abdominal pain]] with negative [[rebound tenderness]]
**Lower abdominal pain (consistent with [[PID]])
**Lower [[abdominal pain]] (consistent with [[PID]])
**Right upper quadrant pain ([[Fitz-Hugh-Curtis syndrome]])
**Right upper quadrant pain ([[Fitz-Hugh-Curtis syndrome]])
*Labial edema and Bartholin’s gland enlargement and tenderness [[Bartholinitis|(Bartholinitis]])
*[[Labial edema ]]and [[Bartholin’s]] gland enlargement and tenderness [[Bartholinitis|(Bartholinitis]])
|}
|}


===Diagnosis and Treatment===
===Diagnosis and Treatment===
The following table summarizes the diagnosis and management of common [[vaginitis]] conditions:<ref name="pmid26042815">{{cite journal| author=Workowski KA, Bolan GA, Centers for Disease Control and Prevention| title=Sexually transmitted diseases treatment guidelines, 2015. | journal=MMWR Recomm Rep | year= 2015 | volume= 64 | issue= RR-03 | pages= 1-137 | pmid=26042815 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26042815  }}</ref>
{| class="wikitable" style="border: 2; background: none;"
{| class="wikitable" style="border: 2; background: none;"
|-
|-
Line 99: Line 109:
!rowspan="2" | Treatment
!rowspan="2" | Treatment
|-
|-
! rowspan="1" | pH|| Saline Wet mount preparation|| Gold Standard test
! rowspan="1" | pH|| Saline [[Wet mount]] preparation|| Gold Standard test
|-
|-
| [[Candida Vulvovaginitis]] ||Normal|| Hyphae and pseudohyphae can be demonstrated || Culture
| [[Candida Vulvovaginitis]] ||Normal|| [[Hyphae]] and [[pseudohyphae]] can be demonstrated || [[Culture]]
|
|
*In patients with normal pH and positive microscopy, culture is not neccessary and treatment can be initiated
*In patients with normal [[pH]] and positive microscopy, [[culture]] is not neccessary and treatment can be initiated
*In patients with normal pH and negative microscopy, culture for candida is done
*In patients with normal [[pH]] and negative microscopy, [[culture]] for [[candida]] is done
|
|
* Topical Azoles for uncomplicated infection
* Topical [[Azoles]] for uncomplicated infection
* Oral Fluconazole one dose of 150mg for complicated infection
* Oral [[Fluconazole]] one dose of 150mg for complicated infection
|-
|-
| [[Bacterial Vaginosis]] ||>4.5|| Clue cells are demonstrated||Gram Stain to determine the relative concentration of lactobacilli, G. vaginalis, Prevotella, Porphyromonas, peptostreptococci and Mobiluncus  
| [[Bacterial Vaginosis]] ||>4.5|| [[Clue cells]] are demonstrated||[[Gram stain]] to determine the relative concentration of [[lactobacilli]], [[Gardnella vaginalis]], [[Prevotella]], [[Porphyromonas]], [[peptostreptococci]] and [[Mobiluncus]]
|
|
Amsel’s criteria: Presence of three out of four criteria is required to make the diagnosis of BV
Amsel’s criteria: Presence of three out of four criteria is required to make the diagnosis of [[Bacterial Vaginosis]]
*Vaginal fluid pH >4.5
*Vaginal fluid [[pH]] >4.5
*>20% of epithelial cells are “clue” cells (cells with unclear borders, dotted with bacteria)
*>20% of “[[clue]]” cells (cells with unclear borders, dotted with bacteria)
*Milky homogenous, adherent vaginal discharge
*Milky [[homogenous]], adherent [[vaginal discharge]]
*Positive “whiff” test, which is an amine or “fishy” odor noted after the addition of 10% potassium hydroxide
*Positive “[[whiff]]” test, which is an amine or “fishy” odor noted after the addition of 10% [[potassium hydroxide]]
*Correlation of the criteria and gram stain is performed to aid diagnosis
*Correlation of the criteria and [[gram stain]] is performed to confirm diagnosis
|
|
*Metronidazole 500 mg orally twice a day for 7 days OR  
*[[Metronidazole]] 500 mg orally twice a day for 7 days OR  
*Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days OR  
*[[Metronidazole]] gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days OR  
*Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days
*[[Clindamycin]] cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days
|-
|-
| [[Trichomoniasis]] ||Normal||
| [[Trichomoniasis]] ||>4.5||
*Motile Trichomonads
*Motile [[Trichomonads]]
*Positive Whiff test
*Positive [[Whiff test]]
|| Nucleic acid amplification test(NAAT)
|| [[Nucleic acid amplification test]] ([[NAAT]])
|
|
*NAAT is highly sensitive for the diagnosis of Trichomonas vaginalis.
*[[NAAT]] is highly sensitive for the diagnosis of [[trichomonas vaginalis]].
*Treatment is initiated after confirmation of the diagnosis
*Treatment is initiated after confirmation of the diagnosis
|
|
*Metronidazole 2g or Tinidazole 2g in a single dose
*[[Metronidazole]] 2g or [[Tinidazole]] 2g in a single dose
|-
|-
| [[Atrophic Vaginitis]] ||Normal|| Vaginal smear cytology shows increased parabasal cells||Leftward shift of the vaginal maturation index
| [[Atrophic Vaginitis]] ||Normal|| Vaginal smear [[cytology]] shows increased parabasal cells||Leftward shift of the vaginal maturation index
|
|
*Diagnosis requires the correlation of clinical presentation and vaginal cytology findings.
*Diagnosis requires the correlation of clinical presentation and vaginal [[cytology]] findings.
*Other causes causing atrophic changes in the vagina should be ruled out.
*Other causes causing atrophic changes in the [[vagina]] should be ruled out.
|
|
*Lubricants and moisturizers for mild symptoms
*Lubricants and moisturizers for mild symptoms
*Topical or Oral estrogen therapy for moderate to severe symptoms
*Topical or oral [[Estrogen-replacement therapy|estrogen]] therapy for moderate to severe symptoms
|-
|-
|Aerobic Vaginitis
|Aerobic Vaginitis
|Increased
|Increased
>6
>6
|Numerous leukocytes are present
|Numerous [[leukocytes]] are present
|No gold standard confirmative  test but excessive growth of aerobes on culture helps in diagnosis when the vaginal smear findings are indeterminate
|No gold standard confirmative  test but excessive growth of [[aerobes]] on culture helps in diagnosis when the [[vaginal smear]] findings are indeterminate
|Microscopic diagnosis is made by Lactobacillus grade( LBG) and the severity is scored based on number of leucocytes, proportion of toxic leucocytes and parabasl epitheliocytes, and background flora
|Microscopic diagnosis is made by [[Lactobacillus]] grade (LBG) and the severity is scored based on number of [[leukocytes]], proportion of toxic [[leukocytes]] and parabasal epitheliocytes, and background flora
|
|
*Probiotics
*[[Probiotics]]
*Kanamycin and Clindamycin vaginal suppositories
*[[Kanamycin]] and [[Clindamycin]] [[vaginal suppositories]]
|}
|}
==References==
{{Reflist|2}}


[[es:Vaginitis]]
[[es:Vaginitis]]
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[[pt:Vaginite]]
[[pt:Vaginite]]


[[Category:Infectious disease]]
[[Category:Gynecology]]
[[Category:Primary care]]


{{WH}}
{{WH}}
{{WS}}
{{WS}}
[[Category:Gynecology]]
[[Category:Emergency medicine]]
[[Category:Disease]]
[[Category:Up-To-Date]]

Latest revision as of 00:38, 30 July 2020

For patient information click here

Vaginitis Main Page

Patient Information

Overview

Classification

Bacterial Vaginosis
Candida vulvovaginitis
Trichomonas infection
Atrophic Vaginitis

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Dima Nimri, M.D. [3], Aravind Kuchkuntla, M.B.B.S[4]

Overview

Vulvovaginitis, a common condition for which women seek medical care, accounts for greater than 10% of visits made to providers of women's health care.[1] It is characterized by symptoms that cause itching, irritation, burning, and abnormal vaginal discharge. The three most common causes of vaginal discharge in women within the reproductive age group are bacterial vaginosis, candida vulvovaginitis, and trichomoniasis. All patients with vulvovaginitis present with common symptoms like vaginal discharge, itching, and dysuria. Diagnosis of vulvovaginitis requires a detailed history of the patient's symptoms, as well as her sexual history, both of which facilitate an accurate diagnosis. Physical examination of the external genitalia and speculum examination should focus on documenting the nature of the discharge, the presence of any vulvar or labial lesions, foreign body, presence of cervical inflammation, cervical lesions, and any cervical motion or adnexal tenderness with a bimanual examination. It is essential to rule out pelvic inflammatory disease and cervical lesions as the cause of vaginal discharge. Estimation of vaginal pH and vaginal smear wet mount examination constitute the initial diagnostic test, which helps differentiate among common etiologies. Treatment of vulvovaginitis includes medical therapy targeted against the causative pathogen and counseling on hygiene, voiding techniques, and sexual practices. The prognosis is good in most patients, though a minority of patients experience recurrence.

Classification

Based on the etiology vaginitis is classified into the following:

Differential Diagnosis

The differential diagnosis for patients presenting with vaginal discharge includes the following considerations:

Common Presentation Disease Symptoms Physical Examination Findings
Discharge Dysuria Vaginal odor Dyspareunia Genital skin lesion Genital pruritus
Vaginitis Candida Vulvovaginitis ✔✔
Bacterial Vaginosis
Trichomoniasis
Atrophic Vaginitis ✔✔
Aerobic Vaginitis
Cervicitis Chlamydia
Gonorrhea

Diagnosis and Treatment

The following table summarizes the diagnosis and management of common vaginitis conditions:[4]

Disease Investigation Diagnostic Approach Treatment
pH Saline Wet mount preparation Gold Standard test
Candida Vulvovaginitis Normal Hyphae and pseudohyphae can be demonstrated Culture
  • In patients with normal pH and positive microscopy, culture is not neccessary and treatment can be initiated
  • In patients with normal pH and negative microscopy, culture for candida is done
  • Topical Azoles for uncomplicated infection
  • Oral Fluconazole one dose of 150mg for complicated infection
Bacterial Vaginosis >4.5 Clue cells are demonstrated Gram stain to determine the relative concentration of lactobacilli, Gardnella vaginalis, Prevotella, Porphyromonas, peptostreptococci and Mobiluncus

Amsel’s criteria: Presence of three out of four criteria is required to make the diagnosis of Bacterial Vaginosis

  • Vaginal fluid pH >4.5
  • >20% of “clue” cells (cells with unclear borders, dotted with bacteria)
  • Milky homogenous, adherent vaginal discharge
  • Positive “whiff” test, which is an amine or “fishy” odor noted after the addition of 10% potassium hydroxide
  • Correlation of the criteria and gram stain is performed to confirm diagnosis
  • Metronidazole 500 mg orally twice a day for 7 days OR
  • Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days OR
  • Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days
Trichomoniasis >4.5 Nucleic acid amplification test (NAAT)
  • NAAT is highly sensitive for the diagnosis of trichomonas vaginalis.
  • Treatment is initiated after confirmation of the diagnosis
Atrophic Vaginitis Normal Vaginal smear cytology shows increased parabasal cells Leftward shift of the vaginal maturation index
  • Diagnosis requires the correlation of clinical presentation and vaginal cytology findings.
  • Other causes causing atrophic changes in the vagina should be ruled out.
  • Lubricants and moisturizers for mild symptoms
  • Topical or oral estrogen therapy for moderate to severe symptoms
Aerobic Vaginitis Increased

>6

Numerous leukocytes are present No gold standard confirmative test but excessive growth of aerobes on culture helps in diagnosis when the vaginal smear findings are indeterminate Microscopic diagnosis is made by Lactobacillus grade (LBG) and the severity is scored based on number of leukocytes, proportion of toxic leukocytes and parabasal epitheliocytes, and background flora

References

  1. Quan M (2010). "Vaginitis: diagnosis and management". Postgrad Med. 122 (6): 117–27. doi:10.3810/pgm.2010.11.2229. PMID 21084788.
  2. Miller KE (2006). "Diagnosis and treatment of Chlamydia trachomatis infection". Am Fam Physician. 73 (8): 1411–6. PMID 16669564.
  3. Chlamydia CDC Fact Sheet. CDC.http://www.cdc.gov/std/chlamydia/stdfact-chlamydia-detailed.htm#_ENREF_3. Accessed on January 11, 2016
  4. Workowski KA, Bolan GA, Centers for Disease Control and Prevention (2015). "Sexually transmitted diseases treatment guidelines, 2015". MMWR Recomm Rep. 64 (RR-03): 1–137. PMID 26042815.


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