Nitrofurantoin for urinary tract infections

Q. What are the advantages and disadvantages of using nitrofurantoin to treat and prevent urinary tract infections (UTIs) in women?A. One-half of all women will develop at least one UTI in their lifetime, and 25%–46% of these individuals will experience a recurrence within one year. (1-4) Anatomic and genetic factors, sexual intercourse, pregnancy, estrogen deficiency, use of spermicides, indwelling catheters, and antibiotic use in the previous month all contribute to the risk of developing a UTI.(1) Recurrence is highest in patients with diabetes, urinary retention or incontinence.(5) In North America, billions of dollars are spent each year to manage this common infection.(2)Advantages of nitrofurantoinIn most countries, nitrofurantoin is considered a first-line antibiotic for treating uncomplicated UTIs, with about 25 million prescriptions filled worldwide annually.(6) It is popular because of lower rates of resistance compared with quinolone or sulfonamide antibiotics (estimated to be 2%, 20% and 15% worldwide, respectively).(7)Moreover, nitrofurantoin does not share cross-resistance with other common antimicrobials used to treat UTIs, and the incidence of rash is much lower with nitrofurantoin than trimethoprim-sulfamethoxazole.(1) As well, nitrofurantoin has little effect on gastrointestinal or vaginal flora.(2)Limitations of nitrofurantoin in impaired renal functionSince therapeutic concentrations of nitrofurantoin are achieved only in the urine and it is eliminated primarily by glomerular filtration, reductions in the glomerular filtration rate (GFR) could potentially lead to treatment failure.(8) In addition, the risk of systemic adverse effects may rise in renally-impaired patients, due to elevated nitrofurantoin serum concentrations.(9)In most countries, nitrofurantoin is not recommended or is contraindicated in patients with a GFR of < 60 mL/min.(9) However, this standard was largely based on smaller older studies that lacked consistent clinical efficacy endpoints and measured the amount of nitrofurantoin in the urine rather than urinary drug concentrations.(10)Results of a recent population-based retrospective study of Ontario women (mean age 79 years) with a UTI and renal dysfunction showed a similar risk of nitrofurantoin treatment failure in patients with relatively high or relatively low GFRs (median 69 and 38 mL/min, respectively).(9) Failure was defined as either the need for a second antibiotic or a hospital visit within 14 days of treatment. The authors concluded that mild to moderate reductions in GFR do not justify avoidance of nitrofurantoin.(9) Primary limitations of this study included lack of compliance data and restriction to an older population cohort.Similarly, an epidemiologic study of European women (age ≥ 18 years) with a UTI found that nitrofurantoin therapy was not associated with a higher risk of ineffectiveness in those with moderate renal impairment (GFR 30–50 mL/min).(8) However, a significant association was seen between this degree of renal impairment and pulmonary adverse events leading to hospitalization (0.16% of patients).(8)Acute pulmonary hypersensitivity reactions to nitrofurantoin (e.g., fever, chills) tend to resolve within days after nitrofurantoin discontinuation.(11) On the other hand, chronic exposure to the drug can lead to irreversible pulmonary fibrosis.(12) Pulmonary fibrosis caused by nitrofurantoin may be more prevalent in elderly patients, who typically experience symptoms of dyspnea, dry cough and fatigue.(12) In addition to potential pulmonary toxicity, nitrofurantoin has been linked to peripheral neuropathy; it appears to be more common in patients during long-term prophylactic therapy or in those with renal insufficiency.(8,10)In clinical practice, some physicians routinely prescribe nitrofurantoin in patients with a GFR 30 mL/min.(12)ConclusionGiven its relatively low cost, efficacy against common pathogens and low impact on promoting bacterial resistance, nitrofurantoin 100 mg twice daily should continue to be a first-line therapy for uncomplicated UTIs. Treatment duration should be a minimum of five days, since clinical efficacy is diminished if given for only three days (i.e., cure rates fall from 79%–92% to 61%–70%).(13) For postcoital UTI prophylaxis, a single 50–100 mg dose should be taken within 24–48 hours.(4)For long-term prophylaxis in younger patients with recurrent UTIs, the suggested regimen is 50 mg or 100 mg at bedtime.(4) Such proactive use of nitrofurantoin could prevent future loss of efficacy of the valuable quinolones, which are needed to manage other serious infections.(7) Since nitrofurantoin exhibits poor tissue penetration, it is not indicated for upper UTI or complicated UTI.(2) Other antibiotics with a full systemic action are preferred in these cases.Asymptomatic bacteriuria should be managed conservatively in older women, since it is often transient and resolves without drug intervention.(5) Vaginal (but not oral) estrogen or cranberry-containing products can effectively reduce the number of symptomatic UTI episodes.(5,14)Postcoital voiding, front-to-back wiping, increased fluid intake and proper use of sanitary napkins can also decrease the risk of developing a UTI.(2,14) These strategies can be discussed with patients at the time of dispensing nitrofurantoin prescriptions.Glenn Schoepp is manager, St. Anthony’s Clinic Pharmacy, Victoria, BC; and clinical instructor, University of British Columbia.ReferencesTrestioreanu AZ, Green H, Paul M, et al. Antimicrobial agents for treating uncomplicated urinary tract infection in women. Cochrane Database Syst Rev 2010;10:CD007182.Dielubanza EJ, Schaeffer AJ. Urinary tract infections in women. Med Clin N Am 2011;95:27-41.Aydin A, Ahmed K, Zaman I, et al. Recurrent urinary infections in women (abstract). Int Urogynecol J 2015:26:795-804.Cupp M. Prevention of recurrent urinary tract infections. Pharmacist’s Letter 2011;27:DD270224.Mody L, Juthani-Mehta M. Urinary tract infections in older women: a clinical review (abstract). JAMA 2014;311:844-54.Kallen AJ, Welch HG, Sirovich BE. Current antibiotic therapy for isolated urinary tract infections in women. Arch Intern Med 2006;166:635-9.McKinnell JA, Stollenwerk NS, Jung CW, et al. Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis. Mayo Clin Proc 2011;86:480-8.Geerts AFJ, Eppenga WL, Heerdink R, et al. Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infections and renal impairment in primary care. Eur J Clin Pharmacol 2013;69:1701-7.Singh N, Gandhi S, McArthur E, et al. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women. CMAJ 2015;187:648-56.Oplinger M, Andrews CO. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for evidence (abstract). Ann Pharmacother 2013;47:106-11.Broes MJ, Roelofs BF, Mudde AH, et al. Pulmonary toxicity resultingfrom the use of nitrofurantoin [abstract]. Ned Tijdschr Geneeskd 2012;156):A4990.American Geriatrics Society 2015 Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Amer Geriatr Soc 2015;63:2227-46.Huttner A, Verhaegh EM, Harbarth S, et al. Nitrofurantoin revisited: a systemic review and meta-analysis of controlled trials (abstract). J Antimicrob Chemother 2015;70:2456-64.Wang CH, Fang CC, Chen NC, et al. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systemic review and meta-analysis of randomized controlled trials (abstract). Arch Intern Med 2012;172:988-96.

Nitrofurantoin for urinary tract infections

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Glen Schoepp