Brooklyn Pruett, PharmD and Lisa C. Hutchison, PharmD, MPH
Nitrofurantoin (Macrobid®) is a broad-spectrum antibiotic with gram-positive and gram-negative activity commonly used for treatment and prevention of urinary tract infections (UTIs).1 Nitrofurantoin is excreted into the urine by the kidneys where it achieves therapeutic concentrations. Once in the urine, nitrofurantoin inhibits bacterial protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis. Adverse effects of nitrofurantoin include pulmonary toxicity, hepatic dysfunction, peripheral neuropathy, hemolytic anemia, and Clostridium difficile-associated diarrhea.
Previously, nitrofurantoin was on the American Geriatrics Society (AGS) Beers Criteria of medications potentially inappropriate for use in older adults. The guideline recommended to avoid nitrofurantoin in geriatric patients with a creatinine clearance less than 60mL/min due to lack of efficacy.2 The recommendation also stated to avoid use for long-term suppression of UTI because of the potential for pulmonary toxicity, hepatotoxicity, and peripheral neuropathy. However, in the 2015 AGS Beers Criteria the threshold for creatinine clearance concern was decreased to 30mL/min for nitrofurantoin because of questions about the old evidence regarding nitrofurantoin excretion and new, albeit low quality, evidence for effectiveness.3
Two studies support use of nitrofurantoin in older women for treatment of UTI. The most recent study was a retrospective cohort study that compared use of nitrofurantoin and trimethoprim in women with renal impairment and a UTI.4 Inclusion criteria were women greater than 18 years of age who received a prescription for nitrofurantoin or trimethoprim for a treatment of a UTI which was defined as (1) no antibacterial treatment six-months prior to receiving either treatment, (2) at least a one- year medication history prior to the antimicrobial starting date, and (3) a six-month follow up medication history after starting the antimicrobial therapy. Exclusion criteria included patients with antibacterial use less than three days or greater than ten days. The primary outcome was treatment failure defined as starting a second antibiotic for treatment of a UTI within one month. The secondary outcome was hospitalization due to adverse effects.
For nitrofurantoin, the overall incidence for ineffective treatment was 14.4% as compared to 16.6% for trimethoprim. The occurrence of treatment failure increased with decreased renal function, but this was not statistically significant. Adverse events that occurred included pulmonary reactions (painful respiration, pleural effusion), and blood dyscrasias. For nitrofurantoin users the risk of an adverse event was significantly higher in patients with renal impairment, defined as a GFR less than 50 mL/min/1.73m2. These results indicate that nitrofurantoin reaches therapeutic effects in the urine for bactericidal activity at least as effective as trimethoprim. However, results also suggest that adverse events were significant in renal impaired patients.
Based on these findings and reconsideration of the old data, the 2015 AGS Beers Criteria panel of experts changed the recommendation so nitrofurantoin is considered inappropriate for treatment of UTI when the patient has a creatinine clearance less than 30mL/min (instead of 60mL/min). The use of nitrofurantoin for long-term suppression of UTI is still considered potentially inappropriate given the risk for toxicity.
1. Macrobid® . North Norwich, NY: Norwich Pharmaceuticals, Inc; 2009.
2. Resnick, Barbara, and James T. Pacala. “2012 Beers Criteria.” Journal of the American Geriatrics Society 60.4 (2012): 612-13. The American Geriatrics Society. Web. 15 Jan. 2016. http://www.americangeriatrics.org/files/documents/beers/2012AGSBeersCriteriaCitations.pdf
3. “American Geriatrics Society 2015 Updated Beers Criteria for Potentially
Inappropriate Medication Use in Older Adults.” Journal of the American Geriatrics Society 63.11 (2015): 2227-246. Accessed 15 Jan. 2015. http://onlinelibrary.wiley.com/store/10.1111/jgs.13702/asset/jgs13702.pdf?v=1&t=ijkhj451&s=034b8ee90406aeba02f3ceb2d969e01d3b9c7e7c
4. Geerts, Arjen F. J., et al. “Ineffectiveness and Adverse Events of Nitrofurantoin in Women with Urinary Tract Infection and Renal Impairment in Primary Care.” European Journal of Clinical Pharmacology Eur J Clin Pharmacol 69.9 (2013): 1701-707. Web. http://link.springer.com.libproxy.uams.edu/article/10.1007%2Fs00228-013-1520-x