In a 17‑year‑old female with persistent vaginal discharge and negative testing for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, bacterial vaginosis, and Candida species, what additional evaluations should be performed?

Evaluation of Persistent Vaginal Discharge After Negative Infectious Work-Up

In a 17-year-old female with persistent vaginal discharge and negative testing for common infectious causes, the next steps should include testing for Mycoplasma genitalium, Ureaplasma urealyticum, Group A β-hemolytic streptococci, and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae using nucleic acid amplification testing (NAAT), followed by evaluation for non-infectious causes including physiologic discharge, cervical pathology, and contact/chemical irritation. 1, 2, 3

Additional Infectious Etiologies to Consider

Mycoplasma and Ureaplasma Species

• Test for Mycoplasma genitalium and Ureaplasma urealyticum using NAAT or culture, as these organisms are frequently detected in women with vaginal discharge (prevalence of U. urealyticum up to 61.4% and M. hominis 16.5% in some populations), though their pathogenic role remains debated. 4
• M. genitalium is increasingly recognized as a cause of cervicitis and pelvic inflammatory disease, with measures of association with vaginal dysbiosis ranging from 0.4 to 6.1. 5

Group A β-Hemolytic Streptococci

• Obtain a full vaginal culture to detect Group A streptococci (Streptococcus pyogenes), which are isolated in 4.9% of adult women with recurrent vaginal discharge and are significantly associated with vulvovaginitis symptoms (p < 0.01). 6
• Group A streptococci are not detected by standard STI panels and require specific culture; other non-group B streptococci (groups C, F, G) have low isolation rates and unclear clinical significance. 6

Cervicitis Confirmation

• Perform NAAT testing for Chlamydia trachomatis and Neisseria gonorrhoeae from an endocervical or vaginal specimen, as these tests have sensitivity and specificity of 97.1%–100% and are superior to culture. 3
• Cervicitis may present with mucopurulent discharge that mimics vaginal discharge; examine for cervical friability, hyperemia, and mucopurulent exudate from the cervical os. 1
• Even when initial testing is negative, repeat NAAT testing is warranted if clinical suspicion for cervicitis persists, as false-negative results can occur. 7

Non-Infectious Causes to Evaluate

Physiologic Discharge

• Reassure the patient that physiologic vaginal discharge is normal in reproductive-age women and varies with hormonal fluctuations throughout the menstrual cycle; it does not require antimicrobial treatment. 2
• Physiologic discharge is typically clear to white, odorless, and associated with a vaginal pH ≤ 4.5 without inflammatory signs. 3

Mechanical, Chemical, or Allergic Irritation

• Inquire specifically about use of soaps, douches, perfumed products, tight clothing, and excessive manipulation or wiping of the vulvovaginal area, as these are common causes of non-infectious discharge with external vulvar inflammation. 2
• The presence of objective external vulvar inflammation with minimal discharge and no identifiable pathogens strongly points to mechanical, chemical, or allergic irritation. 2
• Instruct the patient to avoid compressing or manipulating the vaginal/vulvar area and to eliminate potential irritants (soaps, douches, tight clothing); this is more effective than antimicrobial therapy for non-infectious causes. 2

Cervical Pathology

• Perform speculum examination to inspect the cervix for ectropion, polyps, or other lesions that may produce discharge. 2
• Consider cervical cytology (Pap smear) if not up to date with screening guidelines, as cervical pathology must be excluded before labeling discharge as non-infectious. 2

Diagnostic Algorithm

Step 1: Confirm Negative Infectious Work-Up

• Verify that vaginal pH was measured from a vaginal specimen (not urine), as urine pH provides no diagnostic information for vaginitis; vaginal pH > 4.5 suggests bacterial vaginosis or trichomoniasis, while pH ≤ 4.5 suggests candidiasis. 3
• Confirm that wet mount microscopy was performed for clue cells (bacterial vaginosis) and motile trichomonads, and that KOH preparation was examined for yeast/pseudohyphae. 1, 3

Step 2: Order Additional Infectious Testing

• NAAT for M. genitalium and U. urealyticum (if available in your laboratory). 4, 5
• Full vaginal culture to detect Group A streptococci and other potential pathogens. 6
• Repeat NAAT for C. trachomatis and N. gonorrhoeae from endocervical or vaginal specimen, as initial testing may have been falsely negative. 3

Step 3: Evaluate for Non-Infectious Causes

• Detailed history of hygiene practices, product use, and sexual activity to identify potential irritants or mechanical causes. 2
• Speculum examination to assess for cervical pathology, ectropion, or signs of cervicitis. 1, 2

Step 4: Empiric Management if Testing Remains Negative

• If all testing is negative and discharge persists, consider a trial of eliminating potential irritants (soaps, douches, tight clothing) for 2–4 weeks. 2
• Re-evaluate in 3–6 months if discharge persists despite cessation of manipulation and elimination of irritants. 2

Red Flags Requiring Escalation

• Spontaneous discharge occurring without manipulation, unilateral or single-duct discharge, bloody or serous discharge, or a palpable vulvar or pelvic mass warrant further evaluation with imaging (ultrasound) and possible referral to gynecology. 2
• Development of fever, pelvic pain, or cervical motion tenderness suggests upper tract infection (pelvic inflammatory disease) and requires hospitalization and parenteral antibiotics. 7

Common Pitfalls to Avoid

• Do not assume all negative testing rules out infection; wet mount microscopy has low sensitivity for T. vaginalis (40–80%), and standard STI panels do not detect M. genitalium, U. urealyticum, or Group A streptococci. 3, 6
• Do not treat empirically with antimicrobials if testing is negative, as this contributes to antimicrobial resistance and does not address non-infectious causes; up to 42% of women with vaginitis symptoms receive inappropriate antimicrobial therapy. 2
• Do not confuse urine pH with vaginal pH; these are measured from distinct anatomic sites and are not correlated for vaginitis diagnosis. 3
• Do not overlook the possibility of co-infection; 14% of women with sexually transmitted agents harbor more than one organism, and 16% of women with bacterial vaginosis or candidiasis have concurrent sexually transmitted infections. 8