Nitrofurantoin
Encyclopedia
Nitrofurantoin is an antibiotic
which is marketed under the following brand names; Furadantin, Macrobid, Macrodantin, Nitrofur Mac, Nitro Macro, Nifty-SR, Martifur-MR, Martifur-100 (in India), Urantoin, and Uvamin (in Middle East). It is usually used in treating urinary tract infection
. Like many other drugs, it is often used against E. coli.
It is sometimes described as being appropriate to use in pregnant patients (along with other agents such as sulfisoxazole or cephalexin). This is in contrast to agents such as trimethoprim
and ciprofloxacin
which may not be appropriate for pregnant women.
(MIC) is 32 μg/mL or less. The peak blood concentration of nitrofurantoin following an oral dose of nitrofurantoin 100 mg, is less than 1 μg
/mL and may be undetectable; tissue penetration is negligible; the drug is well concentrated in the urine: 75% of the dose is rapidly metabolised by the liver, but 25% of the dose is excreted in the urine unchanged, reliably achieving levels of 200 μg/ml or more. For this reason, nitrofurantoin cannot be used to treat anything other than simple cystitis
.
At the concentrations achieved in urine, nitrofurantoin is bacteriocidal.
Nitrofurantoin and the quinolone
antibiotics are mutually antagonistic in vitro. It is not known whether this is of clinical significance, but the combination should be avoided.
Resistance to nitrofurantoin may be chromosomal or plasmid mediated and involves inhibition of nitrofuran reductase. Acquired resistance in E. coli continues to be rare.
Nitrofurantoin and its metabolites are excreted mainly by the kidneys. In renal impairment, the concentration achieved in urine may be subtherapeutic. Nitrofurantoin should not be used in patients with a creatinine clearance of 60 mL/min or less. However a retrospective chart review may suggest that nitrofurantoin is not contraindicated in this population.
, since its reduced form is highly reactive. This is made possible by the rapid reduction of nitrofurantoin inside the bacterial cell by flavoprotein
s (nitrofuran reductase) to multiple reactive intermediates that attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules within the cell. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal activity.
Nitrofurantoin is only clinically proven for use against E. coli
or Staph. saprophyticus
. It may also have in vitro activity against:
and is used in the treatment of infections caused by these organisms.
Only a minority of Enterobacter species and Klebsiella species are sensitive to nitrofurantoin; nitrofurantoin has no activity against
Nitrofurantoin must never be used to treat pyelonephritis
, renal abscess
, and pyeloempyema because of extremely poor tissue penetration and low blood levels. Urinary catheter infections may be treated with nitrofurantoin if there are no systemic features; the catheter must be changed after 48 hours of antibiotics and treatment is ineffective if the catheter is not replaced or removed.
. It can also cause pulmonary fibrosis
. All these side effects are much more common in the elderly.
Patients should be informed that nitrofurantoin colours urine a dark orange-brown; this is completely harmless.
Neonates (babies up to the age of one month) have immature enzyme systems in their red blood cells (glutathione
instability) and nitrofurantoin must therefore not be used because it can cause haemolytic anaemia. For the same reason, nitrofurantoin should not be given to pregnant women after 38 weeks of pregnancy, or who are about to give birth.
Nitrofurantoin is contraindicated in patients with decreased renal function (CrCl < 60mL/min) due to systemic accumulation and subtherapeutic levels reached in the urinary tract. However a retrospective chart review may suggest that nitrofurantoin is not contraindicated in this population.
veterinary antibiotics, including nitrofurantoin, have been found in chicken in Vietnam
, China
, Brazil
, and Thailand
. The European Union banned the use of nitrofurans in food producing animals by classifying it in ANNEX IV (list of pharmacologically active substances for which no maximum residue limits can be fixed) of the Council Regulation 2377/90. The Food and Drug Administration
(FDA) of the United States has prohibited furaltadone since February 1985 and withdrew the approval for the other nitrofuran drugs (except some topical uses) in January 1992. The topical use of furazolidone
and nitrofurazone
was prohibited in 2002. Australia prohibited the use of nitrofurans in food production in 1992. Japan did not allocate MRLs for nitrofurans leading to the implementation of a "zero tolerance or no residue standard". In Thailand, the Ministry of Health
issued in 2001 Proclamation No. 231 MRL of veterinary drug in food which did not allocate MRL for nitrofurans. The Ministry of Agriculture and Cooperatives had already prohibited importation and use of furazolidone and nitrofurazone in animal feed in 1999 which was extended to all nitrofurans in 2002. Several metabolites of nitrofurans, such as furazolidone, furaltadone and nitrofurazone cause cancer or genetic damage in rats.
because of risk of extravascular hemolysis
resulting in anemia
.
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
which is marketed under the following brand names; Furadantin, Macrobid, Macrodantin, Nitrofur Mac, Nitro Macro, Nifty-SR, Martifur-MR, Martifur-100 (in India), Urantoin, and Uvamin (in Middle East). It is usually used in treating urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
. Like many other drugs, it is often used against E. coli.
Use
Resistance to other antibiotics has led to increased interest in this agent.It is sometimes described as being appropriate to use in pregnant patients (along with other agents such as sulfisoxazole or cephalexin). This is in contrast to agents such as trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...
and ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
which may not be appropriate for pregnant women.
Pharmacology
Organisms are said to be susceptible to nitrofurantoin if their minimum inhibitory concentrationMinimum inhibitory concentration
In microbiology, minimum inhibitory concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. Minimum inhibitory concentrations are important in diagnostic laboratories to confirm resistance of microorganisms...
(MIC) is 32 μg/mL or less. The peak blood concentration of nitrofurantoin following an oral dose of nitrofurantoin 100 mg, is less than 1 μg
Microgram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...
/mL and may be undetectable; tissue penetration is negligible; the drug is well concentrated in the urine: 75% of the dose is rapidly metabolised by the liver, but 25% of the dose is excreted in the urine unchanged, reliably achieving levels of 200 μg/ml or more. For this reason, nitrofurantoin cannot be used to treat anything other than simple cystitis
Cystitis
Cystitis is a term that refers to urinary bladder inflammation that results from any one of a number of distinct syndromes. It is most commonly caused by a bacterial infection in which case it is referred to as a urinary tract infection.-Signs and symptoms:...
.
At the concentrations achieved in urine, nitrofurantoin is bacteriocidal.
Nitrofurantoin and the quinolone
Quinolone
The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
antibiotics are mutually antagonistic in vitro. It is not known whether this is of clinical significance, but the combination should be avoided.
Resistance to nitrofurantoin may be chromosomal or plasmid mediated and involves inhibition of nitrofuran reductase. Acquired resistance in E. coli continues to be rare.
Nitrofurantoin and its metabolites are excreted mainly by the kidneys. In renal impairment, the concentration achieved in urine may be subtherapeutic. Nitrofurantoin should not be used in patients with a creatinine clearance of 60 mL/min or less. However a retrospective chart review may suggest that nitrofurantoin is not contraindicated in this population.
Mechanism
The mechanism of action of nitrofurantoin is unique and complex. The drug works by damaging bacterial DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, since its reduced form is highly reactive. This is made possible by the rapid reduction of nitrofurantoin inside the bacterial cell by flavoprotein
Flavoprotein
Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin: the flavin adenine dinucleotide or flavin mononucleotide ....
s (nitrofuran reductase) to multiple reactive intermediates that attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules within the cell. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal activity.
Uses
The normal adult dose of nitrofurantoin is 50 to 100 mg four times daily for seven days. If a long-acting preparation (e.g., Macrobid) is used then the dose is 100 mg twice daily. The pediatric dose is 5–7 mg/kg/day in four divided doses. or when in 25 mg/5ml oral suspension then pediatric dose is 3 mg/kg/day in four divided doses. Nitrofurantoin should be taken with food, as this improves the absorption of the drug by 45%.Nitrofurantoin is only clinically proven for use against E. coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
or Staph. saprophyticus
Staphylococcus saprophyticus
Staphylococcus saprophyticus is a coagulase-negative species of Staphylococcus bacteria. S. saprophyticus is often implicated in urinary tract infections. S. saprophyticus is resistant to the antibiotic novobiocin, a characteristic that is used in laboratory identification to distinguish it from S...
. It may also have in vitro activity against:
- Coagulase-negative staphylococci
- Enterococcus faecalisEnterococcus faecalisEnterococcus faecalis – formerly classified as part of the Group D Streptococcus system – is a Gram-positive, commensal bacterium inhabiting the gastrointestinal tracts of humans and other mammals. It is among the main constituents of some probiotic food supplements. Like other species in the genus...
, - Staphylococcus aureusStaphylococcus aureusStaphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
, - Streptococcus agalactiaeStreptococcus agalactiaeStreptococcus agalactiae is a beta-hemolytic Gram-positive streptococcus.- Identification :The CAMP test is an important test for identification...
, - CitrobacterCitrobacterCitrobacter is a genus of Gram-negative coliform bacteria in the Enterobacteriaceae family.The species C. amalonaticus, C. koseri, and C. freundii use solely citrate as a carbon source...
species, - KlebsiellaKlebsiellaKlebsiella is a genus of non-motile, Gram-negative, oxidase-negative, rod-shaped bacteria with a prominent polysaccharide-based capsule. It is named after the German microbiologist Edwin Klebs...
species,
and is used in the treatment of infections caused by these organisms.
Only a minority of Enterobacter species and Klebsiella species are sensitive to nitrofurantoin; nitrofurantoin has no activity against
- AcinetobacterAcinetobacterAcinetobacter [asz−in−ée−toe–back−ter] is a genus of Gram-negative bacteria belonging to the Gammaproteobacteria. Acinetobacter species are non-motile and oxidase-negative, and occur in pairs under magnification....
species, - Morganella species,
- ProteusProteus (bacterium)Proteus is a genus of Gram-negative Proteobacteria.-Clinical significance:Three species—P. vulgaris, P. mirabilis, and P. penneri—are opportunistic human pathogens. Proteus includes pathogens responsible for many human urinary tract infections. P. mirabilis causes wound and urinary...
species, - ProvidentiaProvidentiaIn ancient Roman religion, Providentia is a divine personification of the ability to foresee and make provision. She was among the embodiments of virtues that were part of the Imperial cult of ancient Rome. Providentia thus figures in art, cult, and literature, but has little or no mythology as...
species, - SerratiaSerratiaSerratia is a genus of Gram-negative, facultatively anaerobic, rod-shaped bacteria of the Enterobacteriaceae family. The most common species in the genus, S. marcescens, is normally the only pathogen and usually causes nosocomial infections. However, rare strains of S. plymuthica, S. liquefaciens,...
species, or - PseudomonasPseudomonasPseudomonas is a genus of gammaproteobacteria, belonging to the family Pseudomonadaceae containing 191 validly described species.Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result, the genus Pseudomonas includes strains formerly classified in the...
species.
Nitrofurantoin must never be used to treat pyelonephritis
Pyelonephritis
Pyelonephritis is an ascending urinary tract infection that has reached the pyelum or pelvis of the kidney. It is a form of nephritis that is also referred to as pyelitis...
, renal abscess
Abscess
An abscess is a collection of pus that has accumulated in a cavity formed by the tissue in which the pus resides due to an infectious process or other foreign materials...
, and pyeloempyema because of extremely poor tissue penetration and low blood levels. Urinary catheter infections may be treated with nitrofurantoin if there are no systemic features; the catheter must be changed after 48 hours of antibiotics and treatment is ineffective if the catheter is not replaced or removed.
Adverse effects
Nitrofurantoin can cause nausea and vomiting, fever, rash, hypersensitivity pneumonitisHypersensitivity pneumonitis
Hypersensitivity pneumonitis is an inflammation of the alveoli within the lung caused by hypersensitivity to inhaled organic dusts. Sufferers are commonly exposed to the dust by their occupation or hobbies.-Pathophysiology:Hypersensitivity pneumonitis involves inhalation of an antigen...
. It can also cause pulmonary fibrosis
Pulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...
. All these side effects are much more common in the elderly.
Patients should be informed that nitrofurantoin colours urine a dark orange-brown; this is completely harmless.
Neonates (babies up to the age of one month) have immature enzyme systems in their red blood cells (glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
instability) and nitrofurantoin must therefore not be used because it can cause haemolytic anaemia. For the same reason, nitrofurantoin should not be given to pregnant women after 38 weeks of pregnancy, or who are about to give birth.
Nitrofurantoin is contraindicated in patients with decreased renal function (CrCl < 60mL/min) due to systemic accumulation and subtherapeutic levels reached in the urinary tract. However a retrospective chart review may suggest that nitrofurantoin is not contraindicated in this population.
Use in food
Residues from the breakdown of nitrofuranNitrofuran
Nitrofurans are a class of drugs typically used as antibiotics or antimicrobials. The defining structural component is a furan ring with a nitro group.Members of this class of drugs include:* Furazolidone, antibacterial* Furylfuramide...
veterinary antibiotics, including nitrofurantoin, have been found in chicken in Vietnam
Vietnam
Vietnam – sometimes spelled Viet Nam , officially the Socialist Republic of Vietnam – is the easternmost country on the Indochina Peninsula in Southeast Asia. It is bordered by China to the north, Laos to the northwest, Cambodia to the southwest, and the South China Sea –...
, China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
, Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
, and Thailand
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
. The European Union banned the use of nitrofurans in food producing animals by classifying it in ANNEX IV (list of pharmacologically active substances for which no maximum residue limits can be fixed) of the Council Regulation 2377/90. The Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) of the United States has prohibited furaltadone since February 1985 and withdrew the approval for the other nitrofuran drugs (except some topical uses) in January 1992. The topical use of furazolidone
Furazolidone
Furazolidone is a nitrofuran antibacterial. It is marketed by Roberts Laboratories under the brand name Furoxone and by GlaxoSmithKline as Dependal-M.-Uses:It is used to treat diarrhoea and enteritis caused by bacteria or protozoan infections....
and nitrofurazone
Nitrofurazone
Nitrofurazone, 2-hydrazinecarboxamide, chemical formula C6H6N4O4, is a pale yellow crystalline compound.This bactericidal compound is used as an antibiotic most commonly in the form of ointments...
was prohibited in 2002. Australia prohibited the use of nitrofurans in food production in 1992. Japan did not allocate MRLs for nitrofurans leading to the implementation of a "zero tolerance or no residue standard". In Thailand, the Ministry of Health
Ministry of Public Health (Thailand)
The Ministry of Public Health , is a Thai government body responsible for the oversight of Public Health in Thailand.-External links:* - Official Website in Thai* - Official Website in English...
issued in 2001 Proclamation No. 231 MRL of veterinary drug in food which did not allocate MRL for nitrofurans. The Ministry of Agriculture and Cooperatives had already prohibited importation and use of furazolidone and nitrofurazone in animal feed in 1999 which was extended to all nitrofurans in 2002. Several metabolites of nitrofurans, such as furazolidone, furaltadone and nitrofurazone cause cancer or genetic damage in rats.
Precautions
Nitrofurantoin must be taken with food and in rare cases can cause bleeding in the stomach, vomiting and other gastrointestinal disruptions if these warnings are not adhered to. Nitrofurantoin is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiencyGlucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...
because of risk of extravascular hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
resulting in anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
.
Trade names
- Furadantin (U.S., UK)
- Macrobid (long acting preparation for twice daily dosing available in U.S., Canada, and UK)
- Macrodantin (U.S., UK)
- Furatin, Niftran(by Ranbaxy), Niftas(by Intas Pharmaceuticals) (India)
- Furanit
- Uvamin (Middle East)