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Nitrofurantoin
Authors

Francis J. Squadrito1; Daniel del Portal2.

Affiliations
1 Temple University Hospital
2 Temple University Hospital

Last Update: July 13, 2021.

Continuing Education Activity

Nitrofurantoin is an antibiotic medication that is used for the treatment of uncomplicated lower
urinary tract infection. It is effective against most gram-positive and gram-negative organisms.
Several major guidelines have declared nitrofurantoin as the first-line therapy for the treatment of
uncomplicated lower urinary tract infections. Increasing resistance to newer antibiotics coinciding
with increasing the prevalence of extended-spectrum beta-lactamase (ESBL) producing bacteria
has led to a resurgence in the use of nitrofurantoin. This activity outlines the indications,
mechanism of action, methods of administration, important adverse effects, contraindications,
monitoring, and toxicity of nimodipine, so providers can direct patient therapy successfully in
instances where nimodipine provides a benefit to patient care.

Objectives:

Describe the antibiotic mechanism of action of nitrofurantoin.

Outline the indications for using nitrofurantoin.

Summarize the contraindications and adverse effects of nitrofurantoin.

Review the importance of improving care coordination among the interprofessional team to
enhance the delivery of care for patients who can benefit from therapy with nitrofurantoin.

Access free multiple choice questions on this topic.

Indications
Nitrofurantoin is an antibiotic medication that is used for the treatment of uncomplicated lower
urinary tract infection. It is effective against most gram-positive and gram-negative
organisms. Nitrofurantoin was approved by the FDA in 1953 for treatment of lower urinary tract
infection. Nitrofurantoin is a synthetic antimicrobial created from furan and an added nitro group
and a side change containing hydantoin. Nitrofurantoin was widely used the for treatment of lower
urinary tract infections until the 1970s when trimethoprim-sulfamethoxazole and newer beta-
lactam antibiotics became available. More recently, several major guidelines have declared
nitrofurantoin as the first-line therapy for treatment of uncomplicated lower urinary tract
infections. Increasing resistance to newer antibiotics coinciding with increasing prevalence of
extended-spectrum beta-lactamase (ESBL) producing bacteria has led to a resurgence in use of
nitrofurantoin.[1][2][3][4][5]
Nitrofurantoin’s primary use has remained the treatment and prophylaxis of urinary tract
infections. Nitrofurantoin is advantageous in this role as it concentrates in the lower urinary tract
while maintaining a low serum concentration and also does not significantly affect bowel flora. The
predominant cause of urinary tract infections is periurethral colonization of bacteria from a fecal
reservoir, which then ascends the urinary tract. Researchers think that nitrofurantoin’s continued
effectiveness and minimal resistance patterns are in part attributable to its minimal effect on
bowel flora. Nitrofurantoin is effective against many gram-positive and gram-negative organisms.
Nitrofurantoin is bactericidal against most common urinary tract pathogens, including Escherichia
coli, Enterococci, Klebsiella, Staphylococcus saprophyticus, and Enterobacter. Its spectrum of
susceptibility also includes Shigella, Salmonella, Citrobacter, Neisseria, Bacteroides, group B
streptococcus, Staphylococcus aureus, and Staphylococcus epidermidis. Studies have shown the
effectiveness of nitrofurantoin does not differ between ESBL-producing E. coli and Non-ESBL-
producing E. coli strains. Resistance to nitrofurantoin remains relatively rare despite several
decades of widespread use. A population-based survey of in vitro antimicrobial resistance of
urinary E. coli isolates among United States outpatients showed resistance rate of 1.6%. A meta-
analysis for clinical cure demonstrated overall equivalence between nitrofurantoin and its
comparators when used for uncomplicated urinary tract infections. In long-term prophylaxis,
numerous studies demonstrated that nitrofurantoin is an effective prophylactic agent and
compares well to other antibiotics in this role.

Mechanism of Action
Nitrofurantoin’s mechanism action remains poorly understood since its discovery in the 1940’s.
Nitrofurantoin uses several mechanisms to achieve an antimicrobial effect. Nitrofurantoin is taken
up by bacterial intracellular nitroreductases to produce the active form of the drug via reduction of
the nitro group. Intermediate metabolites that result from this reduction then bind to bacterial
ribosomes and inhibit bacterial enzymes involved in the synthesis of DNA, RNA, cell wall protein
synthesis, and other metabolic enzymes.

Administration
Nitrofurantoin is only available as an oral medication. Nitrofurantoin’s optimal dosing remains
unknown since its use was approved before modern requirements for rigorous methods for drug
development. Current Infectious Disease Society of America guidelines recommend nitrofurantoin
monohydrate/macrocrystals dosage to be 100 mg twice daily for 5 days for the treatment of lower
urinary tract infections. A 7-day course of 100 mg twice daily is also considered acceptable. Courses
of less than 5 days are shown to be less effective and are no longer recommended. Dosing for long-
term prophylaxis of urinary tract infections is 50 mg to 100 mg once daily at bedtime. There are no
dosing adjustments for renal impairment as the drug is contraindicated in renal impaired patients.

Pharmacodynamics

Bioavailability of nitrofurantoin is considered to be 80% in healthy patients.  Nitrofurantoin is well

absorbed in the gastrointestinal tract with most absorption occurring in the proximal small bowel.
Studies have shown that therapeutic urinary concentrations of the drug are increased if
nitrofurantoin is taken with food. Serum concentrations are typically undetectable, although may
increase in patients with severe renal failure. Nitrofurantoin only achieves therapeutically active
concentrations in the lower urinary tract.

Adverse Effects
Nitrofurantoin is a relatively safe drug compared to alternatives. Comparator drugs such as
trimethoprim-sulfamethoxazole and ciprofloxacin often have more reported side effects than
nitrofurantoin. The most common reported side effects include nausea, vomiting, loss of appetite,
and diarrhea. These symptoms usually develop in the first week of therapy. Modern formulations,
specifically the macrocrystalline form of the drug, have less frequency of these effects due to
attempts by manufacturers to alter the crystal size, which effects gastrointestinal absorption.[6][7]
[8]

More severe reactions to nitrofurantoin exist. The most well known severe reaction is pulmonary
toxicity. Pulmonary toxicity caused by nitrofurantoin can be categorized into acute, subacute, and
chronic pulmonary reactions. The acute pulmonary reaction syndrome is characterized by sudden
onset of fever, chills, cough, myalgia, and dyspnea. Sub-acute pulmonary reactions also occur and
are characterized by persistent dry cough, dyspnea, and fever. This chronic, pulmonary reaction is
associated with the insidious onset of persistent dry cough and dyspnea. Acute, subacute, and
chronic pulmonary toxicity are reversible with immediate cessation of the drug. This effect
remains uncommon, with one study showing the calculated frequency for all pulmonary reactions
were only present in 0.001% of nitrofurantoin courses. Other rare adverse effects include hepatic
reactions such as cholestatic jaundice, hepatitis, and hepatic necrosis. The drug should be
ceased immediately in these cases. Peripheral neuropathy is another known rare adverse effect,
and is mostly associated with prolonged use in patients with poor renal function.

Contraindications
Nitrofurantoin should not be administered to patients with acute bacterial pyelonephritis as
nitrofurantoin does not reach therapeutic concentrations in the upper urinary tract, and
bacteremia often accompanies this disease.

Patients with anuria, oliguria, or significant impairment of renal function (defined as creatinine
clearance [CrCl] of less than 60 mL/min or clinically significant raised serum creatinine) should not
take nitrofurantoin. Of noted, the limit of CrCl less than 60 mL/minute has been challenged in the
literature as there is limited data for this cutoff; some studies show that an alternative creatinine
clearance threshold may be considered. A retrospective chart review suggests that a cutoff of CrCl
less than 40 ml/min would be more appropriate.

The drug is contraindicated in pregnant women at term (38 to 42 weeks gestation), during labor
and delivery, or when the start of labor is imminent; and is also contraindicated in neonates
younger than one month of age. This is because of the possibility of hemolytic anemia caused by
immature erythrocyte enzyme systems, specifically glutathione instability.

Nitrofurantoin is contraindicated in men with urinary tract infection as these infections are often
related to prostatitis, and nitrofurantoin does not penetrate prostatic tissue effectively.

Nitrofurantoin is identified in the Beers Criteria as a potentially inappropriate medication to be

avoided in patients 65 years and older due to its potential for pulmonary toxicity, hepatotoxicity,
and peripheral neuropathy, particularly when given longterm.

Enhancing Healthcare Team Outcomes

All healthcare workers including the primary care provider and nurse practitioner who prescribe
nitrofurantoin should know its indications, duration of treatment and adverse effects. The drug has
been around for decades and is relatively safe. Its lung toxicity is overstated and is infact very rare.
The drug is only available for oral use.
Review Questions

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Comment on this article.

References
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