Nitrofurantoin and Renal Function: Does Evidence Support the Creatinine Clearance Cutoff?
In our previous column,1 we discussed the importance of properly estimating renal function when determining medication dosing, particularly in elderly patients. This column will focus on the clinical application of that renal function estimation in a common clinical scenario: the use of nitrofurantoin for the treatment of a urinary tract infection (UTI). Let’s start by revisiting our case.
Case Report
A 77-year-old woman with a past medical history of hypertension, hyperlipidemia, and osteoarthritis presents with concern for a 3-day history of dysuria and flank pain. The patient weighs 52 kg, is 157.5 cm tall, and her serum creatinine level is 0.7 mg/dL. Using the Cockcroft-Gault equation, her creatinine clearance (CrCl) is estimated at approximately 58 mL/min. Urinalysis has been performed and is suggestive for a UTI. You make the presumptive diagnosis of uncomplicated cystitis and send a urine sample for culture. You wish to start the patient on empiric antibiotics, but she has a history of intolerance to sulfa drugs (nausea, swelling, rash), ciprofloxacin (itching, rash), and cephalexin (rash). Because you and the patient both desire outpatient treatment, the remaining oral antibiotic options include fosfomycin and nitrofurantoin. Are both of these agents viable treatment options?
The Evidence
Nitrofurantoin is recommended by the Infectious Diseases Society of America as a first-line treatment option for uncomplicated cystitis.2 Its availability as a generic, its history of clinical experience, and its low rates of resistance make nitrofurantoin an attractive option for the treatment of uncomplicated cystitis. However, the prescribing information indicates that nitrofurantoin is contraindicated in patients with a CrCl of less than 60 mL/min due to an increased risk of adverse effects but more importantly due to reduced efficacy, since nitrofurantoin is concentrated in the urine. Without adequate renal filtration, urine drug concentrations do not reach therapeutic levels, increasing the chances for clinical failure. Is this cutoff of 60 mL/min based on sufficient clinical evidence that warrants avoiding it in this patient?
Oplinger and Andrews3 sought to answer this question in a review article published in 2013. In addition to reviewing the medical literature, they also looked at drug package inserts, pharmacology textbooks, and other resources. The authors noted that the package insert for Macrodantin from 1988 indicated that the medication was to be used when the CrCl exceeded 40 mL/min. Interestingly, they noted the package insert for Macrobid from 2003 had updated the CrCl cutoff to 60 mL/min.
The authors found 2 studies that evaluated urinary recovery of nitrofurantoin, the results of which suggested subtherapeutic urinary concentrations of the medication in patients with reduced renal function. However, in studies involving patients with bacteriuria as well as renal dysfunction, including some of the same patients who had achieved inadequate urinary concentrations of nitrofurantoin, the clinical cure rate for Escherichia coli infection when using nitrofurantoin was consistently high and was similar to that of patients without renal dysfunction. Importantly, patients with an estimated CrCl as low as 40 mL/min still achieved a high rate of clinical cure, a rate similar to that of patients with normal renal function.
Oplinger and Andrews concluded that from the available evidence, which had limitations, there was not sufficient evidence to substantiate a CrCl of at least 60 mL/min for initiation of nitrofurantoin, because this contraindication had been based almost exclusively on the recovery of nitrofurantoin in the urine. Instead, given the number of studies showing a high rate of clinical cure with nitrofurantoin in patients with renal dysfunction, the evidence suggests that the medication can be effectively used in patients with a CrCl of 40 mL/min or higher.
Furthermore, the authors did not note an increased risk of adverse effects with nitrofurantoin use in patients with a CrCl of 40 to 60 mL/min compared with those with normal renal function.
Clinical Application
Traditionally, it has been recommended that nitrofurantoin be avoided in patients with a CrCl less than 60 mL/min because of safety and efficacy concerns. However, the available evidence does not support a CrCl cutoff of 60 mL/min, since this limit is based primarily on pharmacokinetic drug studies. Studies evaluating the clinical cure rate with nitrofurantoin show similar efficacy when patients’ CrCl is as low as 40 mL/min compared with patients with normal renal function.
Due to the limitations of these data, nitrofurantoin likely should not be used widely in patients with a CrCl of 40 to 60 mL/min when other medication are viable; while nitrofurantoin appears to remain effective, preference should be given to agents with clearly documented clinical efficacy in this setting.
However, in cases occurring where local resistance rates are high, or in patients with a history of clinical failure or a history of intolerance to other medications, nitrofurantoin appears to be a viable option.
When nitrofurantoin is employed in these settings, patients should be monitored closely for toxicity as well as for clinical cure to ensure that the therapy is safe and effective.
Outcome of the Case
In the case presented above, our patient’s estimated CrCl is 58 mL/min. While nitrofurantoin is labeled as being contraindicated in patients with a CrCl of less than 60 mL/min, the evidence suggests that the medication can retain its efficacy in patients with a CrCl of 40 mL/min.
Given the increased costs associated with fosfomycin (which represents a viable treatment option), the patient elects to initiate nitrofurantoin, 100 mg twice daily for 7 days. She will be scheduled for a follow-up visit in 1 week to ensure that her symptoms have resolved and that a clinical cure has been attained.
Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.
Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.
References:
- Dietrich EA, Davis K. The importance of accurately estimating renal function when determining dosing. Consultant. 2016;56(3):270-271.
- Gupta K, Hooton 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;52(5):e103-e120.
- Oplinger M, Andrews CO. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for the evidence. Ann Pharmacother. 2013;47(1):106-111.