Nitrofurantoin

J01X - Other antibacterials ATC J01XE01 Small molecule approved 1953 Oral Parenteral Natural product

JFDA label: NITROBACT-100

Mechanism of Action

Inhibitor of DNA — DNA inhibitor

Target	Action	Gene / class
DNA efficacy	INHIBITOR

Indications

Approved

Cystitis, acute uncomplicated
Nitrofurantoin macrocrystals (Furadantin, Macrodantin)
Nitrofurantoin monohydrate/macrocrystals (Macrobid)

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: curated · openfda-label.

Bacteria

Organism	Activity	MIC
Citrobacter amalonaticus	Active	—
Citrobacter diversus	Active	—
Citrobacter freundii	Active	—
Enterococcus faecalis	Susceptible	32.0 mg/L
Escherichia coli	Susceptible	32.0 mg/L
Klebsiella oxytoca	Active	—
Klebsiella ozaenae	Active	—
Staphylococcus aureus	Active	—
Staphylococcus epidermidis	Active	—
Staphylococcus saprophyticus	Susceptible	32.0 mg/L
Streptococcus agalactiae	Active	—
Escherichia coli	Resistant	64.0 mg/L
Klebsiella pneumoniae	Resistant	64.0 mg/L

Class profile

gramStatus	Both
spectrumBreadth	Moderate
atypicalCoverage	No
isBactericidal	1
moaCategory	Multiple targets (nitro group reduction causes DNA/RNA/protein damage; urinary tract only)
pdIndex	Time-dependent
postAntibioticEffect	None
mrsaCoverage	0
resistanceMechanisms	Nitroreductase mutations (nfsA,nfsB),Efflux pumps

Contraindications

Source: Lexicomp

Anuria, oliguria, or significant impairment of renal function (creatinine clearance [CrCl] Note: The manufacturer’s contraindication in patients with CrCl Because of the possibility of hemolytic anemia caused by immature erythrocyte enzyme systems (glutathione instability), the drug is contraindicated in pregnant patients at term (38 to 42 weeks gestation), during labor and delivery, or when the onset of labor is imminent Absolute
also contraindicated in neonates younger than 1 month of age Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Not Known ECG changes (nonspecific ST/T wave changes, bundle branch block)

Nervous system disorders (14)

Not Known Bulging fontanel (infants) · chills · confusion · depression · dizziness · drowsiness · headache · malaise · numbness · paresthesia · peripheral neuropathy · pseudotumor cerebri · psychotic reaction · vertigo

Hepatobiliary disorders (4)

Not Known Cholestatic jaundice · hepatic necrosis · hepatitis · increased serum transaminases

Renal and urinary disorders (1)

Not Known Urine discoloration (brown)

Blood and lymphatic system disorders (10)

Not Known Agranulocytosis · aplastic anemia · eosinophilia · glucose-6-phosphate dehydrogenase deficiency anemia · granulocytopenia · hemoglobin decreased · hemolytic anemia · leukopenia · megaloblastic anemia · thrombocytopenia

Immune system disorders (3)

Not Known Anaphylaxis · angioedema · hypersensitivity (including acute pulmonary hypersensitivity)

Metabolism and nutrition disorders (1)

Not Known Hyperphosphatemia

Gastrointestinal disorders (12)

Not Known Abdominal pain · anorexia · Clostridium difficile associated diarrhea · constipation · diarrhea · dyspepsia · flatulence · nausea · pancreatitis · pseudomembranous colitis · sialadenitis · vomiting

Skin and subcutaneous tissue disorders (7)

Not Known Alopecia · erythema multiforme · exfoliative dermatitis · pruritus · skin rash (eczematous, erythematous, maculopapular) · Stevens-Johnson syndrome · urticaria

Musculoskeletal and connective tissue disorders (4)

Not Known Arthralgia · lupus-like syndrome · myalgia · weakness

Eye disorders (3)

Not Known Amblyopia · nystagmus · optic neuritis

Infections and infestations (1)

Not Known Superinfection (eg, Pseudomonas or Candida)

General disorders and administration site conditions (1)

Not Known Fever

Respiratory, thoracic and mediastinal disorders (7)

Not Known Acute pulmonary reaction (symptoms include chills, chest pain, cough, dyspnea, fever, and eosinophilia) · cough · cyanosis · dyspnea · pneumonitis · pulmonary fibrosis (with long-term use) · pulmonary infiltration

Other (1)

Not Known Hepatotoxicity (idiosyncratic) (Chalasani, 2014)

Dosing

Source: Lexicomp

Cystitis, acute uncomplicated, treatment: Nitrofurantoin monohydrate/macrocrystals (Macrobid): Oral: 100 mg twice daily for 5 days (Gupta 2011; Gupta 2007). Nitrofurantoin macrocrystals (Furadantin, Macrodantin): Oral: 50 to 100 mg every 6 hours; administer for 7 days or at least 3 days after obtaining sterile urine. UTI, prophylaxis: Nitrofurantoin macrocrystals (Furadantin, Macrodantin): Oral: 50 to 100 mg once daily at bedtime.

(For additional information see "Nitrofurantoin: Pediatric drug information") UTI, treatment: Infants, Children, and Adolescents: Nitrofurantoin macrocrystals (Furadantin, Macrodantin): Oral: 5 to 7 mg/kg/day in divided doses every 6 hours (maximum: 400 mg daily). Administer for 7 days or at least 3 days after obtaining sterile urine. Adolescents: Nitrofurantoin monohydrate/macrocrystals (Macrobid): Oral: 100 mg twice daily for 7 days UTI, prophylaxis: Infants, Children, and Adolescents: Nitrofurantoin macrocrystals (Furadantin, Macrodantin): Oral: 1 to 2 mg/kg/day as a single daily dose or divided every 12 hours (maximum: 100 mg daily) (Bradley 2016)

Avoid use; alternative agents preferred. Refer to adult dosing.

CrCl ≥60 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. CrCl Manufacturer's labeling: Use is contraindicated. Alternate dosing: Limited data suggest nitrofurantoin is safe and effective for short-term treatment of uncomplicated UTI in patients with CrCl 30 to 60 mL/minute (Oplinger 2013; Santos 2016; Singh 2015). The Beers Criteria recommends avoiding use in geriatric patients ≥65 years with a CrCl

There are no dosage adjustments provided in the manufacturer's labeling. Contraindicated in patients with a previous history of cholestatic jaundice or hepatic dysfunction associated with nitrofurantoin.

Warnings & Precautions

Source: Lexicomp

Hepatic reactions

Rare, but severe and sometimes fatal hepatic reactions (eg, cholestatic jaundice, hepatitis, hepatic necrosis) have been associated with use (onset may be insidious); discontinue immediately if hepatitis occurs. Monitor liver function tests periodically. Use is contraindicated in patients with a history of nitrofurantoin associated cholestatic jaundice or hepatic dysfunction.

Optic neuritis

Postmarketing cases of optic neuritis have been reported.

Peripheral neuropathy

Has been associated with peripheral neuropathy (rare); risk may be increased in patients with anemia, renal impairment (CrCl • Pulmonary toxicity: Acute, subacute, or chronic (usually after 6 months of therapy) pulmonary reactions (possibly fatal) have been observed; if these occur, discontinue therapy immediately. Monitor closely for malaise, dyspnea, cough, fever, radiologic evidence of diffuse interstitial pneumonitis or fibrosis.

Superinfection

Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Disease-related concerns:

Hemolytic anemia

Use caution in patients with G6PD deficiency; may be at increased risk for hemolytic anemia. Discontinue therapy if occurs.

Renal impairment

Urinary nitrofurantoin concentrations are variable in patients with impaired renal function. The manufacturer contraindicates use in CrCl Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Sedatives

Effects may be potentiated when used with other sedative drugs or ethanol. Special populations:

Elderly

Use in elderly patients, particularly females receiving long-term prophylaxis for recurrent UTIs, has also been associated with an increased risk of hepatic toxicity and peripheral neuropathy. Monitor closely for toxicities during use.

Pediatric

Use is contraindicated in children Other warnings/precautions:

Appropriate use

Pyelonephritis: Not indicated for the treatment of pyelonephritis or perinephric abscesses.

Pregnancy & Lactation

Pregnancy

FDA category B

Caution

Safe for treating UTI in T1 and T2. Avoid in T3 (particularly 38+ weeks). Not recommended as prophylaxis throughout T3

Lactation

Contraindicated RID 5.0%

Nitrofurantoin is excreted in breast milk. The relative infant dose (RID) of nitrofurantoin is 5% when calculated using the highest breast milk concentration located and compared to an infant therapeutic dose of 6 mg/kg/day. In general, breast-feeding is considered acceptable when the relative infant dose is The therapeutic use of nitrofurantoin is contraindicated in neonates (

Monitoring

Efficacy	Culture and susceptibility testing; clinical resolution (temperature, WBC, CRP, procalcitonin)
Toxicity	Renal function (dose adjustment in renal impairment); hepatic function for hepatically cleared agents; signs of C. difficile infection (diarrhoea)
Clinical pearl	Culture results guide de-escalation to narrower-spectrum therapy. Review antibiotic appropriateness at 48–72 h (antimicrobial stewardship).
Counseling	Complete the full course. Report persistent diarrhoea, rash, or lack of improvement after 48–72 h.

Chemistry & Properties

Formula	C8H6N4O5
Molecular weight	238.16 g/mol
IUPAC name	1-[(E)-(5-nitrofuran-2-yl)methylideneamino]imidazolidine-2,4-dione
CAS	67-20-9
PubChem CID	6604200
InChIKey	`NXFQHRVNIOXGAQ-YCRREMRBSA-N`
logP	0.07 (XLogP -0.5)
Polar surface area	118.05 Å²
H-bond acceptors / donors	6 / 1
Drug-likeness (QED)	0.35
Lipinski violations	0

SMILES

O=C1CN(/N=C/c2ccc([N+](=O)[O-])o2)C(=O)N1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP2B6	Inhibitor	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
mitochondrial pyruvate carrier 1 like (MPC1L)	Inhibitor	pIC50 5.5
mitochondrial pyruvate carrier 2 (MPC2)	Inhibitor	pIC50 5.5

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)MRP2 (Substrate)P-gp (Substrate)

Drug–drug interactions (97, DDInter)

Interacting drug	Severity	Management
Leflunomide	major
Nitrous acid	major
Teriflunomide	major
Adalimumab	moderate
Asparaginase Escherichia coli	moderate
Balsalazide	moderate
Benznidazole	moderate
Benzocaine (topical)	moderate
Bortezomib	moderate
Brentuximab vedotin	moderate
Cabazitaxel	moderate
Carboplatin	moderate
Carfilzomib	moderate
Certolizumab pegol	moderate
Chloramphenicol	moderate
Chloroquine	moderate
Cinchocaine (topical)	moderate
Cisplatin	moderate
Clofarabine	moderate
Cocaine (nasal)	moderate
Cocaine (topical)	moderate
Crizotinib	moderate
Dapsone	moderate
Dapsone (topical)	moderate
Dinutuximab	moderate
Disulfiram	moderate
Docetaxel	moderate
Elotuzumab	moderate
Epirubicin	moderate
Eribulin	moderate
Etanercept	moderate
Ethinylestradiol	moderate
Etoposide	moderate
Fluconazole	moderate
Fludarabine	moderate
Golimumab	moderate
Hydroxychloroquine	moderate
Idelalisib	moderate
Infliximab	moderate
Interferon alfa-2a, Recombinant	moderate

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Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
NITROBACT-100	Capsule 100 mg	25 cap	Reda Jardaneh Drug Store	3.300