Nitrofurantoin

Urinary tract infections Uses of nitrofurantoin include the treatment of uncomplicated urinary tract infections (UTIs) and prophylaxis against UTIs in people prone to recurrent UTIs. The efficacy of nitrofurantoin in treating UTIs combined with a low rate of bacterial resistance to this agent makes it one of the first-line agents for treating uncomplicated UTIs as recommended by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. In meta-analyses of clinical trials, nitrofurantoin has shown clinical UTI cure rates of 79 to 92% and bacterial eradication rates of 80 to 92%. Treatment with nitrofurantoin for 7days was not more effective than treatment for 5days, whereas treatment for 5days was superior to treatment for 3days (which showed clinical cure rates of 61–70%). As a prophylactic against UTIs, nitrofurantoin was similarly effective to other antibiotics, with a UTI risk ratio of 0.38. Taken daily long-term as a prophylactic, there were no differences in effectiveness between different doses of nitrofurantoin (50mg/day, 75mg/day, 100mg/day, or 50mg twice daily). because of extremely poor tissue penetration and low blood levels. As such, nitrofurantoin is not recommended for eradication of chronic bacterial prostatitis. In any case, in men with antibiotic-refractory or relapsing chronic bacterial prostatitis, prophylactic nitrofurantoin may be useful in preventing UTIs and managing symptoms. However, supporting data were lacking as of 2020. • Escherichia coli Many or all strains of the following genera are resistant to nitrofurantoin: There is a potential risk of hemolytic anemia in the newborn when used near time of delivery. Newborns of women given this drug late in pregnancy had a higher risk of developing neonatal jaundice. Evidence of safety in early pregnancy is mixed as of 2017. A 2015 meta analysis found no increased risk from first trimester use in cohort studies that was a slight increase of malformations in case control studies. ==Contraindications==

Nitrofurantoin is contraindicated in patients with decreased renal function (CrCl < ) due to systemic accumulation and subtherapeutic levels reached in the urinary tract. Many of the severe side effects of this drug are more common in the elderly and those with renal impairment, as this causes the drug to be retained in the body and reach higher systemic levels. Thus, the drug is not recommended for the elderly population according to 2012 AGS Beers Criteria. Nitrofurantoin is also contraindicated in babies up to the age of one month, as they have immature enzyme systems in their red blood cells (glutathione instability), so nitrofurantoin must not be used because it can cause haemolytic anaemia. Nitrofurantoin is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) because of risk of intravascular hemolysis resulting in anemia. ==Adverse effects==

The most common side effects of nitrofurantoin are nausea, headache, and flatulence. Less common adverse events (occurring in less than 1% of those taking the drug) include: Chronic pulmonary reactions caused by nitrofurantoin include diffuse interstitial pneumonitis, pulmonary fibrosis, or both. It is important to recognize nitrofurantoin as possible cause of symptoms and discontinue the drug when the suspicion of pulmonary side effects arises as it can be reversible if the drug is stopped early. Neuropathy Neuropathy is a rare side effect of taking nitrofurantoin. Patients may experience numbness and tingling in a stocking-glove pattern, which may or may not improve upon discontinuation of the drug. Gut microflora Nitrofurantoin has been found to modify the gut microbiota composition. Effects in three clinical studies have included increased abundance of Actinobacteria, Bifidobacterium species, and Clostridium species, decreased abundance of Faecalibacterium species, and no changes. However, this was based on a single study in which only two cases occurred. Other sources state that nitrofurantoin has a low risk of Clostridioides difficile infection. ==Interactions==

Nitrofurantoin has historically been reported to be a disulfiram-like drug and to produce alcohol intolerance-type reactions when combined with alcohol. However, subsequent clinical studies failed to replicate these findings and the earlier results have been deemed erroneous. ==Pharmacology==

Organisms are said to be susceptible to nitrofurantoin if their minimum inhibitory concentration is 32 μg/mL or less. The peak blood concentration of nitrofurantoin following an oral dose of nitrofurantoin 100mg is less than 1μg/mL and may be undetectable. Its bioavailability is about 90% and the urinary excretion is 40%. 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 200μg/mL or more. In studies of dogs, the majority of urinary excretion is through glomerular filtration with some tubular secretion. There is also tubular absorption which is increased with urine acidification. 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. Mechanism of action Nitrofurantoin is concentrated in the urine, leading to higher and more effective levels in the urinary tract than in other tissues or compartments. With a oral dose, plasma levels are typically less than while in the urine it reaches . The drug works by damaging bacterial DNA, since its reduced form is highly reactive. respiration, pyruvate metabolism and other macromolecules within the cell. Nitrofurantoin exerts greater effects on bacterial cells than mammalian cells because bacterial cells activate the drug more rapidly. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal activity. The broad mechanism of action for nitrofurantoin is likely responsible for the low development of resistance to its effects, as it affects many different processes important to the bacterial cell. ==History==

A method for preparing nitrofurantoin was patented in 1952. It has been available for the treatment of lower UTIs since 1953. ==Society and culture==

Brand names Nitrofurantoin is marketed under many names in countries worldwide. ==Animal feed==

Residues from the breakdown of nitrofuran veterinary antibiotics, including nitrofurantoin, have been found in chicken in Vietnam, China, Brazil, and Thailand. The European Union prohibited 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. ==References==