Nitrofurantoin and CrCl: How Low Can You Go?

The 2015 Beers Criteria for Potentially Inappropriate Medication Use in Older Adults includes an updated recommendation for nitrofurantoin use in patients with impaired renal function.

Although the drug was previously contraindicated in individuals with a creatinine clearance (CrCl) <60 mL/min, the updated Beers Criteria lowered the renal function breakpoint to CrCl <30 mL/min.¹ This means that a greater number of older patients can now receive nitrofurantoin for treatment of their infections.

Nitrofurantoin is a nitrofuran antimicrobial that is active against many Gram-positive and Gram-negative organisms, including resistant strains of Escherichia coli. It achieves very high urinary concentrations while limiting systemic exposure, making it an ideal targeted medication for the treatment of urinary tract infection (UTI).

The Infectious Diseases Society of America (IDSA) Uncomplicated Cystitis Guidelines recommend nitrofurantoin as an appropriate first-line regimen in patients with uncomplicated UTI. ²

When the drug was first approved several decades ago, its prescribing information included a warning against use in patients with CrCl <40 mL/min. Subsequent prescribing information updates in 2003 changed the breakpoint to CrCl <60 mL/min without much reason.³

Several recent publications questioning the evidence for this change, along with several retrospective studies investigating the use of nitrofurantoin in patients with impaired renal function, prompted the Beers Criteria update.

Where did the original change from a contraindication of CrCl <40 mL/min to CrCl <60 mL/min come from?

Clinical Evidence

A 2013 review article attempted to uncover the clinical evidence supporting this change, but it found minimal applicable results.³ Four trials conducted between 1958 and 1971 mentioned that patients with “poor” renal function who received nitrofurantoin had much lower urinary excretion of drug compared with those with normal renal function, leading to a hypothesis that efficacy would be compromised.

The many limitations of these 4 trials included:

• Each study included very low numbers of patients with “poor” renal function (range 6-18 patients each).
• There was no standardized definition of “poor” renal function, and Scr values were oftentimes missing.
• Many patients would have met the definition of “end stage renal disease” and should not have received the medication.
• Most were single-dose studies using older formulations of nitrofurantoin. Current formulations have a much higher bioavailability.
• While the authors concluded that patients with “poor” renal function had lower urinary concentrations of drug, the tables and charts presented data that some subjects with “poor” renal function actually had the same concentrations.
• No clinical outcomes were assessed.

Retrospective Trial Evidence

To date, only 3 retrospective trials have looked at patients with impaired renal function who were treated with nitrofurantoin.

The first body of literature to review nitrofurantoin use in impaired renal function occurred in 2009 and included hospitalized Canadian patients stratified by a modified CrCl >50 mL/min (n=234) or modified CrCl ≤50 mL/min (n=122).⁴

Clinical cure, which was defined as receipt of 5 to 10 days of nitrofurantoin therapy with no initiation of UTI antibiotics or relapse of symptoms within 14 days, were similar in both groups (CrCl > 50 mL/min 78% cure vs. CrCl ≤ 50 mL/min 71% cure). Adverse events were rare yet similar in the groups (8% vs. 7%, respectively), and they included gastrointestinal disturbances or headache.

The authors concluded that nitrofurantoin appears to be safe in patients with impaired renal function.

Another retrospective study conducted in 2013 investigated the safety and efficacy of nitrofurantoin in outpatient Danish women to build upon the results of the previous study and attempt to elicit rates of rare serious adverse events.⁵

The women were assigned to receive nitrofurantoin (n=21,317) or trimethoprim (n=7926) if they were aged 18 years or older, received a prescription for 1 of those antibiotics for 3 to 10 days, and did not receive any additional antibiotics in the previous 6 months. Of the cohort, 186 nitrofurantoin and 82 trimethoprim subjects were categorized as having moderate or severe renal impairment (CrCl <50 mL/min). Overall treatment ineffectiveness, which was defined as receipt of a second antibiotic within 1 month of the study drug, did not differ between groups (14.4% nitrofurantoin vs. 16.6% trimethoprim).

Although a higher rate of ineffectiveness was observed as renal function declined, renal impairment was not significantly associated with treatment ineffectiveness. The risk of adverse reactions was significantly higher in nitrofurantoin patients with impaired renal function compared with trimethoprim patients with impaired renal function (adjusted HR for nitrofurantoin 4.1, adjusted HR for trimethoprim unable to be calculated due to low number of events). The most common adverse reaction for nitrofurantoin included pulmonary reactions (n=32) and blood dyscrasias (n=3) in the 3 month follow-up.

The authors concluded that nitrofurantoin may be effective in women with impaired renal function, though a higher rate of adverse events may occur.

The third study was a retrospective review of Canadian women aged 65 years or older who received 1 of 4 antibiotics as an outpatient for a UTI: nitrofurantoin, ciprofloxacin, norfloxacin, or trimethoprim/sulfamethoxazole.⁶

Patients were stratified into 1 of 2 study arms: impaired renal function (median CrCl=38 mL/min, n=9223) and normal renal function (median CrCl=69 mL/min, n=182,634). Treatment failure was defined as receipt of a second antibiotic or hospitalization for a UTI, both within 14 days of the initial antibiotic.

In patients with impaired renal function, the authors discovered that a second antibiotic was prescribed more frequently for the nitrofurantoin group than the others (13.8% nitrofurantoin, 6.5% ciprofloxacin, 6.5% norfloxacin, 12.6% trimethoprim/sulfamethoxazole). Similar results were seen among patients requiring hospitalization (2.5% nitrofurantoin, 1.1% ciprofloxacin, 1.2% norfloxacin, 2.1% sulfamethoxazole/trimethoprim). However, a similar risk of treatment failure was also seen in patients with normal renal function.

The authors concluded that although the quinolones had better outcomes overall, there was no increased risk of treatment failure in patients receiving nitrofurantoin who had impaired renal function, compared with those with normal renal function. Therefore, the contraindication of avoiding nitrofurantoin in CrCl <60 mL/min is not justified.

Conclusion

With the revised Beers Criteria and the large subsequent retrospective reviews, there is adequate data to indicate that nitrofurantoin can safely and effectively be used in patients with CrCl >30 mL/min. Nevertheless, nitrofurantoin use in this population should be limited to short-term treatment only (≤7 days), as more serious adverse events have been seen with longer use. In fact, long-term use of nitrofurantoin for UTI suppression or prophylaxis should be avoided.

Compared with other urinary tract antibiotics, nitrofurantoin has several disadvantages, which mainly involve the need for longer courses of therapy and higher rates of treatment failure.¹ However, the drug’s lack of systemic exposure, lack of allergic cross reactivity with other classes of antibiotics, and retained activity against some resistant bacterial strains make it a valuable option in the oral antibiotic armamentarium.

References

• The American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatric Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015 Nov;63(11):2227-46. doi: 10.1111/jgs.13702. Epub 2015 Oct 8.
• Gupta K, Hooten TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar 1;52:e103-e120.
• Oplinger M, Andrews CO. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for evidence. Ann Pharmacother. 2013;47:106-111.
• Bains A, Buna D, Hoag NA. A retrospective review assessing the efficacy and safety of nitrofurantoin in renal impairment. Can Pharm J. 2009;142:248-252.
• Geerts AFJ, Eppenga WL, Heerdink R, et al. Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care. Eur J Clin Pharmacol. 2013;69:1701-1707.
• 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 Jun 16;187(9):648-56. doi: 10.1503/cmaj.150067. Epub 2015 Apr 27.