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Must We Avoid Nitrofurantoin with Impaired Renal Function?

Acute uncomplicated cystitis is becoming more difficult to treat in the setting of increasing antimicrobial resistance. In the 2010 IDSA Guideline, nitrofurantoin (Macrobid) is now listed as the first-line choice, surpassing ciprofloxacin and sulfamethoxazole/trimethoprim from the previous iteration.

For tested E. Coli strains at my institution in 2012, the susceptibility to common agents is as follows:

  • Ciprofloxacin 61%
  • Levofloxacin 72%
  • Sulfamethoxazole/trimethoprim 69%
  • Nitrofurantoin 97%
The reality of resistance hits close to home for me and may be similar in your institutions.

Why not just prescribe 5 days nitrofurantoin for all patients with acute uncomplicated cystitis?
  1. The American Geriatrics Society's Beers Criteria for Potentially Inappropriate Use in Older Adults recommends against using nitrofurantoin in this age group.
  2. Nitrofurantoin is contraindicated in patients with creatinine clearance < 60 mL/min.
Let's tackle each of these concerns.

Inclusion in Beers Criteria
Darrell Hulisz, PharmD explores the reason for nitrofurantoin's inclusion in the Beers Criteria in a recent Medscape article. He concludes, "It is generally accepted that nitrofurantoin may be ineffective for UTIs in the elderly because age-related declines in renal function result in subtherapeutic concentrations in the urinary tract. However, the recommendation to avoid the drug in the elderly is not because it causes nephrotoxicity. Although not well-documented, it is plausible that the risk for other toxicities from nitrofurantoin, such as pulmonary fibrosis, would increase secondary to drug accumulation." 

Who experiences adverse reactions and how common are they?
  1. Concern exists for an associated increased risk for serious adverse reactions in patients with renal impairment (possible older adults). 
  2. Pulmonary toxicity, hepatotoxicity, and hemolytic anemia are rather rare occurrences, and are often linked to prolonged treatments (6 months or longer). [1] 
  3. Published cases of peripheral neuropathy associated with nitrofurantoin in patients with renal insufficiency have occurred most often with treatments lasting beyond the 5-day period recommended by the IDSA. [1]
Bottom Line: Adverse effects tend to occur in those on therapy longer than 5 days.

Use with Reduced Renal Function
Is it really true that nitrofurantoin is not effective when CrCl drops below 60 mL/min? 

When nitrofurantoin was originally FDA-approved in 1988, the CrCl lower limit was 40 mL/min. It was changed to 60 mL/min in 2003 with little explanation. The contraindication seems to be based on a few studies from the 1950s and 1960s addressing urinary recovery of this drug in patients with various degrees of renal function. [2] These 40+ year-old studies had significant flaws, some not even listing clear methodologies or how many patients were included. They also didn't report clinical efficacy.
    Newer Data
    Two more recent studies evaluated clinical efficacy.
    • A retrospective chart review of 356 patients (mostly older adults) was conducted in 2009 that assessed the efficacy and safety of nitrofurantoin in patients with renal impairment. The study concluded that nitrofurantoin cure rates for UTI and adverse events were similar between those with and those without renal impairment. [3] 
    • In a cohort of 21,317 women, nitrofurantoin treatment was not associated with a higher risk of ineffectiveness in women with UTI and moderate renal impairment (30-50 ml/min/1.73 m2). The authors did, however, find a significant association between renal impairment (<50 ml/min/1.73 m2) and pulmonary adverse events leading to hospitalization (HR 4.1, 95% CI 1.31-13.09). AIn absolute terms, only 4 out of 187 (2.1%) patients had adverse effects in the group with poor renal function and it is unclear if patients with with the lowest CrCl had more adverse events. [4]
    Application to Clinical Care
    While both recent studies had some important limitations, they still suggest that patients with an estimated creatinine clearance >40 mL/min are probably ok to receive a 5-day course of nitrofurantoin. This is different from the current 60 mL/min mark stated in the Beers Criteria and Macrobid package insert. Cure rates and adverse reactions were generally similar to patients with normal renal function.


       
    Bryan Hayes, PharmD 
    (@PharmERToxGuy)
    Clinical Assistant Professor, University of Maryland (UM) Clinical Pharmacy Specialist, EM and Toxicology



    References
    1. Guay DR. An update on the role of nitrofurans in the management of urinary tract infections. Drugs 2001;61:353-64. [PMID 11293646]
    2. Oplinger M, et al. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for the evidence. Ann Pharmacother 2013;47(1):106-11. [PMID 23341159]
    3. Bains A, Buna D, Hoag NA. A retrospective review assessing the efficacy and safety of nitrofurantoin in renal impairment. Can Pharm J 2009;142:248-52.
    4. Geerts AF, 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 May 10. [Epub ahead of print] [PMID 23660771]

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