Nystatin / Fluconazole

Mechanism

Pharmacological Class and Group

Antifungals with local and systemic action. Polyene antifungal with topical intestinal/mucosal action (Nystatin) and systemic triazole antifungal (Fluconazole).

Mechanism of Action

Both drugs interfere with the structural integrity of the fungal cell membrane, although they achieve this through different molecular targets:

• Nystatin: Polyene antifungal that physically binds to ergosterol, the predominant sterol in the membrane of yeasts (such as Candida albicans). Upon binding, it forms transmembrane hydrophilic channels or pores in the lipid double layer. This causes the massive release of intracellular cations (potassium, magnesium) and small organic molecules, destroying the energy gradient of the fungal cell and inducing bacterial lysis rapidly (fungicide).
• Fluconazole: Highly selectively inhibits the fungal enzyme of the cytochrome P450 pathway, lanosterol 14-alpha-demethylase. This enzyme catalyzes the conversion of lanosterol to ergosterol. Its inhibition stops the synthesis of the membrane component, causing the accumulation of abnormal methylated sterols and altering the permeability of the fungal membrane, which stops its cell replication (fungistatic).

Membrane Homeostasis in Oropharyngeal Candidiasis

Nystatin: Direct binding to Ergosterol Formation of transmembrane pores and lysis Fluconazole: Inhibition of 14-α-demethylase Ergosterol depletion and death

While nystatin acts purely by superficial contact on the oral mucosa without being absorbed systemically, fluconazole penetrates deeply into the lamina propria of the mucosa and the salivary glands after oral administration, controlling invasive fungal infection.

Pharmacokinetics

High Resolution Pharmacokinetics

• Nystatin: No absorption through the oral mucosa and the gastrointestinal tract. It is eliminated completely unchanged through feces. Its effect is purely superficial physical contact.
• Fluconazole: Rapid oral and complete intestinal absorption. Bioavailability greater than 90% (independent of gastric acidity and food intake).
  • Distribution: Excellent penetration into oral cavity tissues and saliva (where it reaches concentrations equivalent to or higher than plasma concentrations). Low binding to circulating plasma proteins (11-12%).
  • Metabolism: Marginal hepatic metabolism (less than 11%). It is a potent inhibitor of CYP2C9 and CYP2C19, and a moderate inhibitor of CYP3A4.
  • Excretion: Predominant renal excretion (80% of the drug is eliminated unchanged in urine).
  • Half-life (t_1/2): Prolonged, 30 hours, allowing single-daily dosages.

Indicators and dose

Clinical Indications and Off-Label Uses

• Oropharyngeal Candidiasis (Thrush): Initial treatment of choice in infants, adults with uncontrolled diabetes or mild immunosuppression (Nystatin suspension).
• Moderate to Severe Oropharyngeal Candidiasis / Esophageal Candidiasis: In HIV-infected patients, post-chemotherapy oncology patients or patients who do not respond to local topical therapy (systemic fluconazole).
• Prevention of Candidiasis in High-Risk Patients: Prophylaxis in severely neutropenic patients or patients undergoing head and neck radiotherapy.
• Mycotic Angular Cheilitis (off-label): Topical treatment of erythema and fissures in the corners of the mouth.

Dosage and Clinical Adjustment

Nystatin (Oral Suspension of 100,000 IU/mL):

• Adults and Children: 4-6 mL (400,000 to 600,000 IU) retained in the oral cavity as long as possible before swallowing, administered every 6 hours (4 times a day).
• Infants (Thrush): 1-2 mL applied directly to the lesions of the oral mucosa with a sterile applicator or gauze every 6 hours.
• Duration: Maintain treatment until 48 hours after the clinical disappearance of the lesions to avoid early relapses.

Fluconazole (Oral or Intravenous Route):

• Oropharyngeal Candidiasis: Loading dose of 200 mg on the first day, followed by 100 mg to 200 mg once daily orally for a minimum of 7 to 14 days.
• Esophageal Candidiasis: Loading dose of 200 mg on the first day, followed by 100 mg to 200 mg daily for 14 to 21 days (escalate to 400 mg/day in severe refractory cases).

Mandatory Adjustment in Renal Failure (Fluconazole):

• eGFR 50 mL/min/1.73 m²: No adjustment required (100% of dose).
• eGFR < 50 mL/min/1.73 m² (without dialysis): Administer a full loading dose on the first day, followed by a 50% reduction in the maintenance dose.
• Hemodialysis: Administer 100% of the usual dose immediately after completing each hemodialysis session.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to nystatin or fluconazole/related azoles.
• Concomitant use of Fluconazole with QT prolonging drugs metabolized by CYP3A4 (e.g., Terfenadine, Astemizole, Pimozide, Quinidine or Cisapride): Increased risk of fatal torsade de pointes-type ventricular arrhythmias.

Relative Contraindications

• Moderate to severe renal failure in treatment with fluconazole (requires mandatory dose reduction).
• Hepatotoxicity or marked elevation of basal transaminases (with fluconazole).

Adverse Effects (ADR) and Specific Toxicity

• Nystatin (Very safe because it is topical): Mild nausea or vomiting if large volumes of the suspension are swallowed, diarrhea, bad taste in the mouth (dysgeusia).
• Fluconazole (Common 1%-10%): Headache, nausea, diffuse abdominal pain, transient elevation of hepatic transaminases, morbilliform skin rash.
• Fluconazole (Uncommon to rare): Severe hepatotoxicity with fulminant acute liver failure (mainly in patients with severe underlying comorbidities), Prolongation of the corrected QT interval (QTc), toxic epidermal necrolysis (Lyell syndrome) or Stevens-Johnson.

Toxicity Alert: QTc Prolongation due to Interactions with Fluconazole

Fluconazole prolongs the QT interval on the electrocardiogram by blocking the cardiac potassium channel HERG, decreasing the intracellular potassium rectifying current during cardiac repolarization. This effect is exponentially enhanced when associated with drugs that inhibit its own hepatic metabolism (such as erythromycin or amiodarone), increasing the risk of lethal helical ventricular arrhythmias (torsade de pointes). It is mandatory to perform a baseline ECG if prolonged therapy with fluconazole is planned in polymedicated patients.

Drug Interactions of Clinical Relevance

• Oral Anticoagulants (Warfarin / Acenocoumarol): Fluconazole potently inhibits CYP2C9, blocking the clearance of the S isomer of warfarin, which drastically prolongs the prothrombin time (increase in INR) with a high risk of severe bleeding. Requires close monitoring and even reduction of basal anticoagulant.
• Statins (Atorvastatin, Simvastatin): Fluconazole moderately inhibits CYP3A4, increasing systemic levels of the statin with an increase in toxic myopathy or rhabdomyolysis.
• Phenytoin, Theophylline or Cyclosporine: Fluconazole significantly increases its serum levels, requiring therapeutic serum concentration monitoring.

Safety in Pregnancy and Breastfeeding

• Pregnancy:
  • Nystatin: Absolutely compatible (not systemically absorbed).
  • Fluconazole: Avoid. The continuous use of high doses during the first trimester is associated with the risk of specific congenital bone malformations (craniosynostosis, cleft palate). Only the use of a single dose of 150 mg is allowed in refractory vulvovaginal candidiasis, but the use of multiple prolonged doses in ENT is not recommended.
• Breastfeeding:
  • Nystatin: Absolutely compatible.
  • Fluconazole: Compatible with caution. It passes into breast milk reaching concentrations similar to those in plasma, so it should be reserved for essential indications.