What is the next step in managing vaginal discharge when all tests for sexually transmitted infections (STIs), bacterial vaginosis (BV), candidiasis, and Mycoplasma genitalium are negative?

Management of Vaginal Discharge with Negative Infectious Workup

Immediate Next Step: Retest for Bacterial Vaginosis

When all standard tests are negative, the most important next step is to retest for bacterial vaginosis using Gram stain (Nugent criteria), as standard clinical testing misses 20-30% of BV cases, and BV remains the most common cause of vaginal discharge (40-50% of identified cases). 1

Why BV Testing Should Be Repeated

• Laboratory testing fails to identify the cause of vaginitis in a substantial minority of women, making missed BV the most likely explanation for persistent symptoms with negative initial testing 2, 3
• Gram stain has 90% sensitivity and is the most specific diagnostic method for BV, superior to clinical criteria alone 1
• Up to 50% of women with BV meeting diagnostic criteria are asymptomatic, meaning the infection can be present even without classic symptoms 2, 1
• Point-of-care tests (pH, whiff test, wet mount) are rarely performed in community practice settings (only 15-21% of cases), leading to missed diagnoses 4

Specific Diagnostic Algorithm

Step 1: Verify Initial Testing Was Adequate

• Confirm that Amsel criteria were properly assessed (3 of 4 required: homogeneous white discharge, clue cells, pH >4.5, positive whiff test) 3
• Check if vaginal pH was actually measured—this simple test is often omitted but helps differentiate BV/trichomoniasis (pH >4.5) from candidiasis or non-infectious causes (pH <4.5) 1
• Verify that wet mount microscopy was performed, as its sensitivity is only 40-80% and interpretation varies significantly 3

Step 2: Order Confirmatory Testing

• Obtain Gram stain with Nugent scoring as the gold standard for BV diagnosis when wet mount is equivocal 3, 5
• Consider nucleic acid amplification testing (NAAT) for comprehensive vaginitis panel, as molecular testing can detect microbiome-based BV, Candida species, and Trichomonas in a single test 3
• DNA probe testing for Gardnerella vaginalis has similar sensitivity and specificity to Gram stain 6

Step 3: Perform Bacterial Culture

• If empirical treatment has failed, bacterial culture should be performed to detect potentially pathogenic microorganisms beyond the typical vaginitis causes 5
• Culture can identify less common bacterial pathogens including Haemophilus influenzae, beta-hemolytic streptococci, Streptococcus pneumoniae, and Staphylococcus aureus, which account for 5.6% of vulvovaginitis cases 5
• These atypical bacteria are found with highest prevalence in children and postmenopausal women 5

Consider Aerobic Vaginitis

• If clue cells are absent and Gram stain is negative for BV, consider aerobic vaginitis as an alternative diagnosis 3
• The Infectious Diseases Society of America recommends treating confirmed aerobic vaginitis with ampicillin or amoxicillin-clavulanate 3
• Do not treat asymptomatic patients with incidental bacterial findings and no clue cells, as this leads to inappropriate antibiotic use 3

Evaluate for Non-Infectious Causes

Only after infectious causes are truly excluded, consider:

• Mechanical, chemical, allergic, or other non-infectious irritation of the vulva, particularly if there are objective signs of external vulvar inflammation with minimal discharge 2
• Atrophic vaginitis in postmenopausal women (pH typically <4.5) 6
• Inflammatory vaginitis, which may improve with topical clindamycin and steroid application 6
• Irritant or allergic vaginitis accounting for 5-10% of cases 6

Critical Pitfalls to Avoid

• Do not diagnose BV without clue cells unless confirmed by Gram stain, as this may lead to treating the wrong condition 3
• Avoid empirical treatment without proper diagnosis—in one study, 42% of women with vaginitis symptoms received inappropriate treatment, and those without infections who received empiric treatment were more likely to have recurrent visits within 90 days 4
• Among 120 women without BV, TV, or VVC, 34% were prescribed antibiotics/antifungals unnecessarily 4
• Of 170 women with laboratory-diagnosed vaginitis, 47% received one or more inappropriate prescriptions 4

Special Consideration: Recurrent BV

• BV has a 50-80% recurrence rate within one year, which may explain persistent symptoms despite previous treatment attempts 1
• If BV is confirmed on retesting, treat with metronidazole 500 mg orally twice daily for 7 days (cure rate 80-90%) 1
• The 7-day regimen has higher cure rates (95%) compared to single-dose metronidazole 2g (84%) 3