Nitrofurantoin in renal impairment

A 74 year old female patient presents to clinic describing dysuria and urinary frequency that started within the last few days.  She has no vaginal discharge or irritation and has no CVA tenderness, fevers, chills, flank pain, nausea, or vomiting.  The diagnosis of uncomplicated UTI is made based on clinical suspicion and you decide to prescribe some antibiotics.  She weighs 72 kg and her SCr is 1.4 mg/dL.  Using the Cockcroft-Gault equation,
her ClCr is estimated to be 40 mL/min.  She has a sulfa allergy (and it's a real one).  Is nitrofurantoin a viable option in this patient?

About nitrofurantoin

Nitrofurantoin (Macrobid, Macrodantin) is an older antibiotic that is approved for the treatment of uncomplicated cystitis.  It is partially eliminated by the kidneys (only about 40% - glomerular filtration and active tubular secretion) and otherwise metabolized in other tissues.  Nitrofurantoin has poor penetration into the renal parenchyma, making it useless for pyelonephritis or perinephric abscesses, and it is not approved for any complicated UTIs.  It is a particularly attractive option for uncomplicated cystitis because resistance of E. coli to nitrofurantoin is almost zero.

What is the concern in a patient like this?

The issue with using nitrofurantoin in renal dysfunction is that the FDA-approved prescribing information for nitrofurantoin states that a ClCr <60 mL/min is a contraindication for use but this does not seem to be based on any sturdy evidence.  There were a few studies from the 1960s that collected nitrofurantoin in the urine and plotted it against concentration-time curves and came to the conclusion that it did not meet adequate urinary concentrations in azotemic patients.  These studies were rife with limitations such as unclear calculation of ClCr, failure to report urine concentrations, reporting concentrations after only one dose, and not reporting clinical outcomes among other issues.  

What the evidence tells us about use in renal impairment

In more recent years, some studies have tested using nitrofurantoin in renal impairment with the best piece of evidence coming from CMAJ in 2015.  This study was a retrospective cohort study that looked at the treatment of four different antibiotics and compared patients with relatively lower eGFR (median 38 (IQR 27-52) mL/min per 1.73 m2) with patients with relatively higher eGFR (median 69 (IQR 56-82) mL/min per 1.73 m2).  They looked at clinical outcomes suggestive of treatment failure.  Here are the main findings:

• Treatment failure was not higher with nitrofurantoin compared to TMP/SMX, regardless of lower or higher eGFR.
• Treatment failure was higher with nitrofurantoin compared to ciprofloxacin, but this occurred in both the lower and higher eGFR groups.
• Nitrofurantoin was the most commonly prescribed antibiotic, regardless of lower or higher eGFR (~40% in both groups).
• Interesting considering the mean age of patients was 75-80 years old

Beers criteria 2015 update

To help us with the conflict between the prescribing information (contraindicated at ClCr <60 mL/min) and the evidence (comparable effectiveness as low as ClCr 30 mL/min or greater), the Beers criteria revised their recommendation for nitrofurantoin.  Currently, their recommendation is to avoid nitrofurantoin in ClCr <30mL/min or for long-term suppression of bacteria.

Back to the patient case

As this patient has an uncomplicated UTI, IDSA guideline recommended first line therapy generally includes (in no particular order) SMX/TMP, nitrofurantoin, fosfomycin, and pivmecillinam.  Pivmecillinam is not available in the U.S. but fosfomycin is, and may be an option for this patient.  SMX/TMP is not an option given her "real" sulfa allergy.  With a ClCr of 40 mL/min, nitrofurantoin is also a viable choice.  Fluoroquinolones are not first line, despite often being efficacious, due to their high risk of collateral damage.

References
Singh N et al. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women. CMAJ  2015;187(9):648-56.

American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc  2015;63(11):2227-46.

image by Hey Paul Studios