Nitrofurantoin


Article Author:
Francis Squadrito


Article Editor:
Daniel del Portal


Editors In Chief:
Casey Ciresi


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Orawan Chaigasame
Carrie Smith
Abdul Waheed
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James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
2/28/2019 9:43:20 PM

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.


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Nitrofurantoin - Questions

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A 31-year-old female presents with complaints of shortness of breath, fever, dyspnea on exertion, cough, and pleuritic chest pain. Chest radiographs show bilateral pulmonary infiltrates. The patient states that she started an antibiotic for recurrent urinary tract infections 8 days ago. What antibiotic is most commonly associated with this presentation?



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A urinary culture is performed on a patient with an uncomplicated urinary tract infection. The culture grows Proteus bacilli. Which antibiotic would be an inappropriate choice to treat this pathogen?



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Which of the following drugs is used to treat urinary tract infections but has no activity against Proteus?



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A 26-year-old female presents with symptoms of a urinary tract infection. A urinary culture is performed. Nitrofurantoin is ineffective against which pathogen?



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A patient was started on an antibiotic for a urinary tract infection. She continued taking the antibiotic for 4 months because of recurrent dysuria. Now she presents with dyspnea and a dry cough. She denies any weight loss or smoking. What is the most likely etiology of these new symptoms?



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A patient is admitted to the hospital and has a history of chronic renal insufficiency. The patient requires treatment for an infection. The patient has a creatinine clearance is less than 35 ml/min. What medication is contraindicated in this patient?



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A patient forgets to take a dose of her nitrofurantoin for a urinary tract infection. She calls your office and asks what she should do with the missed dose. What do you recommend?



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A patient is admitted to the hospital for acute renal failure. What medication is contraindicated in this patient?



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A 66-year-old female is found to have aplastic anemia. The patient was recently started on an antibiotic. What antibiotic is known to be associated with aplastic anemia?



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Which urinary tract antibiotic is not active against Proteus and is associated with pulmonary side effects?



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A 17-year-old female with no medical problems is diagnosed with an uncomplicated urinary tract infection. Which of the following antibiotics is considered to be a first-line therapy for the treatment of cystitis in this patient?



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Which of the following drugs is used to treat urinary tract infections but has no activity against Proteus?



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A patient undergoing treatment for an infection develops symptoms that are determined to be an adverse event from the antimicrobial drug he is receiving. He has nausea, dyspepsia, paresthesias, difficulty breathing, cough, pleuritic chest pain, pulmonary infiltrates, and neutropenia. Which of the following drugs is the likely culprit?



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What is the most common serious complication of the long-term use of nitrofurantoin?



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A 23-year-old pregnant female at 39 weeks gestation presents with symptoms of a urinary tract infection. Urinalysis confirms a diagnosis of cystitis. Why is nitrofurantoin contraindicated in this patient?



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You have a patient is starting a course of nitrofurantoin for a bladder infection. Which of the following is to be included in your counseling points with her?



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Nitrofurantoin - References

References

Asadi Karam MR,Habibi M,Bouzari S, Urinary tract infection: Pathogenicity, antibiotic resistance and development of effective vaccines against Uropathogenic Escherichia coli. Molecular immunology. 2019 Feb 18;     [PubMed]
Gianvecchio C,Lozano NA,Henderson C,Kalhori P,Bullivant A,Valencia A,Su L,Bello G,Wong M,Cook E,Fuller L,Neal JB 3rd,Yeh PJ, Variation in Mutant Prevention Concentrations. Frontiers in microbiology. 2019;     [PubMed]
Gardiner BJ,Stewardson AJ,Abbott IJ,Peleg AY, Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems. Australian prescriber. 2019 Feb;     [PubMed]
Ghazvini H,Taheri K,Edalati E,Sedighi M,Mirkalantari S, Virulence factors and antimicrobial resistance in uropathogenic Escherichiacoli strains isolated from cystitis and pyelonephritis Turkish journal of medical sciences. 2019 Feb 11;     [PubMed]
Kornfält Isberg H,Melander E,Hedin K,Mölstad S,Beckman A, Uncomplicated urinary tract infections in Swedish primary care; etiology, resistance and treatment. BMC infectious diseases. 2019 Feb 13;     [PubMed]
Tuem KB,Desta R,Bitew H,Ibrahim S,Hishe HZ, Antibacterial Resistance Patterns of Uropathogens isolated between 2012-2017 from a Tertiary Hospital in Northern Ethiopia. Journal of global antimicrobial resistance. 2019 Jan 24;     [PubMed]
Croker R,Walker AJ,Goldacre B, Why did some practices not implement new antibiotic prescribing guidelines on urinary tract infection? A cohort study and survey in NHS England primary care. The Journal of antimicrobial chemotherapy. 2018 Dec 22;     [PubMed]
Hanlon JT,Perera S,Drinka PJ,Crnich CJ,Schweon SJ,Klein-Fedyshin M,Wessel CB,Saracco S,Anderson G,Mulligan M,Nace DA, The IOU Consensus Recommendations for Empirical Therapy of Cystitis in Nursing Home Residents. Journal of the American Geriatrics Society. 2018 Dec 24;     [PubMed]

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