Fosfomycin and Nitrofurans

Mechanism

💊 Generic and Commercial Names

Fosfomycin trometamol (Monurol), fosfomycin sodium (Fosfocina), nitrofurantoin (Furantoína).

🔬 Pharmacological Group

Narrow-use urinary antiseptics. An early-stage cell wall synthesis inhibitor (fosfomycin) and a multi-target disruptor (nitrofurantoin).

Mechanism of Action

Their selectivity is based on rapid active elimination in the urine:

• Inhibition of the MurA Enzyme by Fosfomycin: It is a structural analogue of phosphoenolpyruvate (PEP). It binds covalently and irreversibly to the cysteine residue (Cys-115) of the active site of the cytoplasmic enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). By blocking this enzyme, it prevents the synthesis of UDP-N-acetylmuramic acid (basic metabolic precursor of early-course bacterial peptidoglycan), inhibiting the synthesis of the wall in its initial phase.
• Multi-Target Genomic Disruption by Nitrofurantoin: It is reduced intracellularly by bacterial flavoprotein enzymes (nitrofuran reductases) to highly reactive chemical intermediates and free radicals that non-specifically damage ribosomal proteins, block bacterial protein translation, and induce massive breaks in the double strands of chromosomal cellular DNA. By having multiple mechanisms of action directed simultaneously, the development of resistance by common bacteria is extremely rare.

Pharmacokinetics

Key Pharmacokinetics

Antimicrobial Spectrum

• Fosfomycin: Excellent bactericidal activity against Gram-positive (MRSA, VRE) and Gram-negative multidrug-resistant ESBL and AmpC producers (such as ESBL-producing E. coli from the community).
• Nitrofurantoin: Excellent spectrum of low urinary course against E. coli(including most ESBL producers), enteric Gram-positive cocci (susceptible streptococci and enterococci). It is not active against Pseudomonas aeruginosa or Proteus mirabilis.

Indicators and dose

Dosage and Adjustment

• Fosfomycin Trometamol (uncomplicated low UTI): 3 g orally in a single dose for healthy adults (a second sachet of 3 g can be repeated after 48 hours in complex cases).
• Nitrofurantoin (uncomplicated low UTI): 100 mg every 12 hours orally for 5 to 7 consecutive days.
• Adjustment in Kidney Failure:
  • Cl_cr < 30 mL/min: Nitrofurantoin is absolutely contraindicated. Oral Fosfomycin Trometamol loses efficacy due to reduced dural clearance, preferring management with systemic course alternatives.

Security

Contraindications and ADRs

• Contraindications: Moderate to severe kidney failure; glucose-6-phosphate dehydrogenase deficiency; end of pregnancy (weeks 38-42 due to risk of neonatal hemolytic anemia).
• Adverse Effects (ADR):
  • Uselessness of Nitrofurantoin in Renal Failure: If the glomerular filtration rate falls below 30 mL/min, nitrofurantoin is not adequately filtered into the urine, which causes two direct clinical problems:
    1. Analgesic ineffectiveness due to urinary concentrations lower than the MIC of the pathogen.
    2. Systemic plasma accumulation that drastically increases the risk of toxicity.
  • Acute and Chronic Pulmonary Fibrosis: Acute transient immune-mediated pulmonary toxicity (fever, progressive dyspnea, eosinophilia in sputum), or irreversible cumulative chronic fibrosing course in prolonged treatments greater than 6 months.
  • Hepatotoxicity: Chronic autoimmune hepatitis or transaminasitis.