Is it appropriate to prescribe metronidazole (antibiotic) and fluconazole (antifungal) to a patient with a suspected bacterial, protozoal, or fungal infection?

Can You Prescribe Metronidazole and Fluconazole Together?

Yes, you can and sometimes should prescribe metronidazole and fluconazole together, particularly when treating mixed anaerobic bacterial and fungal infections, or when metronidazole therapy unmasks or exacerbates underlying candidiasis.

Primary Clinical Scenario: Metronidazole-Induced Candidiasis

The FDA label for metronidazole explicitly states that "known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candicidal agent" 1. This is the most direct evidence supporting concurrent use:

• Metronidazole suppresses anaerobic bacteria (including protective vaginal flora), which can allow Candida overgrowth 2, 3
• When candidiasis emerges or worsens during metronidazole therapy, adding fluconazole is appropriate and necessary 1
• This scenario is particularly common in bacterial vaginosis treated with metronidazole, where subsequent vulvovaginal candidiasis may develop

Mixed Infections Requiring Dual Coverage

In critically ill patients with suspected or confirmed mixed infections:

• Intra-abdominal sepsis may involve both anaerobes (requiring metronidazole) and Candida species (requiring fluconazole) 4
• Pelvic infections can similarly have mixed bacterial-fungal etiology 2
• The IDSA guidelines recommend empiric antifungal therapy in critically ill patients with risk factors for invasive candidiasis, which may overlap with anaerobic infection risk factors 4

Safety Considerations

There are no documented drug-drug interactions between metronidazole and fluconazole:

• The FDA label for metronidazole lists multiple drug interactions (warfarin, phenytoin, lithium, disulfiram, alcohol) but does not mention azole antifungals 1
• Fluconazole's CYP450 interactions (primarily CYP3A4 and CYP2C9 inhibition) do not significantly affect metronidazole metabolism 5
• Metronidazole is metabolized primarily by the liver to 5 metabolites, with minimal CYP-mediated metabolism 6

Practical Prescribing Algorithm

When to use both medications:

1. Metronidazole prescribed first, candidiasis develops: Add fluconazole 150 mg single dose for uncomplicated vulvovaginal candidiasis, or 400 mg daily for more severe infections 4

2. Mixed anaerobic-fungal infection suspected (e.g., complicated intra-abdominal infection in ICU patient):

   • Start metronidazole 500 mg IV/PO every 8 hours for anaerobic coverage 2, 3
   • Add fluconazole 800 mg loading dose, then 400 mg daily for empiric Candida coverage 4
   • Adjust based on culture results at 48-72 hours 4

3. High-risk ICU patients: Consider empiric coverage for both anaerobes and Candida if multiple risk factors present (recent surgery, broad-spectrum antibiotics, central lines, parenteral nutrition) 4

Important Caveats

• Metronidazole has no activity against aerobic bacteria or fungi and must be combined with other agents for mixed infections 2, 7
• Monitor for metronidazole-specific adverse effects (peripheral neuropathy, disulfiram-like reaction with alcohol, reversible neutropenia) regardless of fluconazole co-administration 1, 7
• Avoid alcohol during metronidazole therapy and for at least one day after completion 1
• In pregnant women, metronidazole is acceptable for anaerobic infections, but fluconazole should be used cautiously (amphotericin B deoxycholate preferred for invasive candidiasis) 4

Duration of Therapy

• Metronidazole: Typically 7-14 days for anaerobic infections 2, 3
• Fluconazole: 14 days after first negative blood culture for candidemia, or single dose for uncomplicated vulvovaginal candidiasis 4
• Do not discontinue metronidazole prematurely even if candidiasis develops; treat both conditions concurrently 1