nitrofurantoin (Macrodantin, Macrobid)

Introduction

Tradename: Macrodantin.

Indications

• bacterial infections due to susceptible organisms
  • treatment of uncompliced urinary tract infection (UTI)
    • not as effective as ciprofloxacin
  • prevention of frequently occurring UTI when long-term therapy is necessary

Contraindications

• avoid in patients with creatinine clearance < 60 mL/min
  • not a good choice for elderly patients*
  • no loss in efficacy when creatinine clearance is 40 mL/min
  • may be safely used in elderly if eGFR > 30 mL/min provided duration of therapy < 8 days
• glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)
• 1st trimester of pregnancy
  • nitrofurantoin associated with birth defects in case control studies
  • not duplicated in studies of asymptomatic bacteriuria
• 3rd trimester of pregnancy
  • pregnant patients at term (38-42 weeks gestation), during labor & delivery, or when the onset of labor is imminent
• neonates under one month of age
• pyelonephritis: insufficient levels in renal tissue

* MKSAP17 recommends nitrofurantoin to treat cystitis in older women

pregnancy category = b

safety in lactation = +

Dosage

• 50 mg PO QID
• Pediatrics: 5-7 mg/kg/day divided QID

Tabs: 25, 50, 100 mg

Liquid: 25 mg/5 mL

Sustained-release: (macro-crystalline): Tradename Macrobid

• 100 mg PO BID

Max 400 mg/day.

Maintenance dose following dialysis.

Tabs: 100 mg.

Pharmacokinetics

• well absorbed orally
• macrocrystal absorbed slower than micro-crystal, causing less GI distress
• better absorbed when taken with food
• 20-60% bound to plasma proteins
• 50-70% metabolized by body tissue
• 50% eliminated unchanged in the urine
• more active in acid urine pH
• elimination 1/2life 20 minutes to 1 hour
• removed by hemodialysis
• less effective in patients with creatinine clearance < 40 < 60 mL/min* (NOT a good drug for treatment of UTI in the elderly)

* ref finds nitrofurantoin inferior to ciprofloxacin for treatment of cystitis in older women independent of renal function

elimination via kidney

elimination via liver

elimination by hemodialysis = +

1/2life = 0.3-1 hours

Monitor

• liver function tests periodically

Antimicrobial activity

Gram positive

• Streptococcus
  • Streptococcus group A
  • Streptococcus group B
  • Streptococcus group C
  • Streptococcus group G
  • Streptococcus pneumonia
• Enterococcus faecalis (+/-)
• Staphylococcus aureus (MSSA)

Gram negative

• Neisseria gonorrhoeae
• Escherichia coli
• Klebsiella species (+/-)
• Enterobacter species*

* Most strains of Proteus, Pseudomonas, Klebsiella & Enterobacter are resistant

Adverse effects

• common (> 10%)
  • chest pains
  • chills
  • cough
  • fever
  • difficulty breathing
  • dyspepsia
  • diarrhea
  • loss of appetite
  • nausea/vomiting
  • rash
• less common (1-10%)
  • sore throat, tiredness, weakness, drowsiness, headache, dizziness, numbness, paresthesias
• uncommon (< 1%)
  • hemolytic anemia in patients with G6PD deficiency, hepatitis, pruritus, arthralgias, hypersensitivity & in infants < 4 weeks of age
• pulmonary*
  • acute, subacute & chronic interstitial lung disease
  • acute
    • mean duration of exposure until symptom onset is 9 days
    • fever, chills, cough, dyspnea, hypoxemia, chest pain
    • eosinophilia (30%)
    • non-cardiogenic pulmonary edema, pleural effusion
    • reticulonodular changes on chest X-ray
    • oftens resolves with discontinuation, but will recur with repeat administration
  • chronic
    • onset months to years after prolonged exposure
    • pulmonary fibrosis (chronic)
    • ground glass opacities
    • glucocorticoids may be of benefit
• other
  • abdominal cramps, bladder irritation, peripheral neuropathy, gout, blood dyscrasia, hepatoxicity

* Pulmonary function testing:

• obstructive pattern with acute reaction
• restrictive pattern with chronic reaction

• drug adverse effects of nitrofurantoin

Drug interactions

• probenecid decreases renal excretion
• Mg+2-containing antacids decreases absorption
• quinolones (antagonistic)

• drug interaction(s) of antibiotics with warfarin

Mechanism of action

• may disrupt cell wall formation
• may interfere with bacterial carbohydrate metabolism
• bacteriostatic at low concentrations
• bactericidal at higher concentrations

More general terms

• 5-nitrofuran
• other antibiotic

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4509
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5915
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=61867