Introduction

  • Urinary tract infections (UTI) affect 150 million each year, with 50-60% of women developing at least one UTI in their lifetime.
  • Costs of these infections, ranging from societal to health care costs, are approximately $3.5 billion per year in the US alone.
  • Most commonly caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis.
  • Inadequate treatment can lead to recurring symptoms, disseminating infections, and increasing bacterial resistance.

Clinical Detail

CategoryDetails
Mechanism of ActionInactivation in bacterial ribosomal protein→inhibition of protein, DNA/RNA and cell wall synthesis
DoseAcute uncomplicated cystitis
Macrobid®: 100 mg twice daily
Macrodantin®: 50-100mg every six hours
Duration: 5 days for women, 7 days for men
Cystitis Prophylaxis
Macrobid®: 100mg once daily at bedtime
Macrodantin®: 50-100mg once daily at bedtime
Duration: 3-12 months; prolonged use has been associated with increased side effects
Susceptible bacteriaE. Coli, Klebsiella, Enterococcus (including VRE), Staphylococcus Saprophyticus, Enterobacter
FormulationNitrofurantoin 100mg capsule: ~$2-6
Nitrofurantoin suspension 25mg/5mL: ~$3
PK/PDDoes not reach therapeutic levels in serum or kidneys. Only concentrated in urine.
Taking with food increases absorption by 40%
Adverse EffectsPeripheral neuropathy, pulmonary toxicity (extended use)
Hepatic dysfunction, superinfection (C. Difficile), hemolytic anemia (caution if G6PD deficient)
Interactions and warningsAvoid use in CrCl < 30mL/min (decreased efficacy and increased risk of side effects)
Contraindicated in children < 1 month (risk of hemolytic anemia)
PregnancyContraindicated in pregnant patients at term (38-42 weeks gestation), during labor/delivery
• Increased risk of hemolytic anemia and jaundice developing in neonate

Indicated for asymptomatic bacteriuria in pregnant patients during first trimester
• Macrobid®: 100mg twice daily x 4-7 days
• Use if other antibiotics are contraindicated or cannot be utilized
• Consider alternative if pregnant patient has a G6PD deficiency
BreastfeedingAvoid in:
• Breastfeeding patients with premature infants or < 1 month of age
• Breastfeeding patients with infants of any age if patient has G6PD deficiency

Can consider:
• Breastfeeding patients with full-term infants > 1 month of age
CommentsDo not use for indication other than cystitis (pyelonephritis, prostatitis, bacteremia etc.)
Commonly resistant organisms: Proteus, Pseudomonas

Evidence

Author, yearDesign/sample sizeIntervention & ComparisonOutcome
Christiaens TC, 2002Prospective RCT-placebo controlled (n = 78)Nitrofurantoin 100mg QID vs placebo x 3 days in females with uncomplicated UTI w/ pyuriaCombined sx improvement and cure for Nitrofurantoin
Day 3: 27/35 (p = 0.08)
Day 7: 30/34 (p= 0.003)
Nitrofurantoin achieved higher rate of bacteriologic cure and symptomatic relief compared to placebo
Gupta K, 2007Prospective open label RCT (n = 338)Nitrofurantoin 100mg BID x 5 days vs Bactrim 1 DS tab BID x 3 daysClinical Cure: Nitrofurantoin 84% vs. Bactrim 79% (not significant)
Microbiological cure on day 3 of nitrofurantoin achieved in 127/130 (98%) of patients
Nitrofurantoin x 5 days = Bactrim x 3 days clinically and microbiologically
Iravani A et al. 1999Prospective double blind RCT (n = 521)Cipro 100mg BID x 3 days
Nitrofurantoin 100mg BID x 7 days
Co-trimoxazole DS BID x 7 days		Clinical resolution 4-10 days after therapy and at the 4-6 week follow-up was similar among the three treatment groups. (of note, normal dosing with Cipro is 500mg daily x3 days)
Ingalsbe ML, 2015Retrospective chart reviewMacrobid 100mg BID
Macrodantin 50-100mg QID
Treated for 5-14 days		Safety and clinical cure in males with UTIs and catheter-associated UTIs
A CrCl of ≥ 60 ml/min is suggested for men to achieve an 80% cure rate for most UTIs
Cure rate with specific organisms varied with CrCl but adverse events did not

Conclusions

  • Nitrofurantoin is a first line recommendation per IDSA for treatment of acute uncomplicated cystitis.
  • Most studies have demonstrated a clinical cure rate with nitrofurantoin of 88%-93% and a bacterial cure rate of 81% - 92%.
  • With high rates of efficacy, low risk of resistance, and lack of side effects, nitrofurantoin is an optimal first line agent for cystitis.
  • Due to the lack of therapeutic concentration outside of the urine, nitrofurantoin is not recommended for pyelonephritis, urosepsis, or prostatitis.

References

  • Flores-Mireles AL et al. Nat Rev Microbiol. 2015;13(5):269‐284.
  • Al-Badr A, et al. Sultan Qaboos Univ Med J. 2013;13(3):359‐367.
  • Macrobid®(Nitrofurantoin) [package insert]. Norwich Pharmaceuticals, Inc. North Norwich, NY. 2009.
  • Uncomplicated Cystitis and Pyelonephritis. Clin Infect Dis. 2011. 1;52(5):e103-20.
  • Nicolle LE et al. Clin Infect Dis. 2019 May 2;68(10):e83-e110.
  • Christiaens TC, et al. Br J Gen Pract. 2002;52(482):729‐734.
  • Gupta K, et al. Arch Intern Med. 2007;167(20):2207‐2212.
  • Iravani A, et al. J Antimicrob Chemother. 1999;43 Suppl A:67‐75.
  • Stein GE. Clin Ther. 1999;21(11):1864‐1872.
  • Ingalsbe ML, et al. Ther Adv Urol. 2015;7(4):186‐193.
Tags:nitrofurantoin cystitis urinary tract infection Macrobid