Nitrofurans Nitrofurantoin

Chemistry and Mechanism of Action

A number of 5-nitro-2-furaldehyde derivatives, called nitrofurans, are used in the treatment and/or prophylaxis of microbial infections, primarily in the urinary tract. Recent evidence suggests that the reduction of the 5-nitro group to the nitro anion results in bacterial tox-icity. Intermediate metabolites modify various bacterial macromolecules that affect a variety of biochemical processes (e.g., DNA and RNA synthesis, protein synthesis); this observation may explain the lack of resistance development to these drugs. Evidence also indicates that the nitro anion undergoes recycling with the production of superoxide and other toxic oxygen compounds. It is presumed that the nitrofurans are selectively toxic to microbial cells because in humans, the slower reduction by mammalian cells prevents high serum concentrations.

Antibacterial Spectrum and Resistance

Nitrofurantoin (Furadantin, Macrodantin) is primarily active against gram-negative bacteria (E. coli, P. mirabilis is variable) and some susceptible gram-positive organisms, such as S. aureus and Enterococcus faecalis. In vitro activity is demonstrated against Staphylococcus saprophyticus and Staphylococcus epidermidis, but it may not be helpful in predicting patient response; the same applies for certain species of Klebsiella and Citrobacter. Most Proteus (indole positive), Serratia, and Pseudomonas spp. are resistant. Development of resistant strains is virtually unknown, and cross-resistance with other antimicrobials has not been reported.

Absorption, Metabolism, and Excretion

Nitrofurantoin is administered orally and is rapidly and almost completely absorbed from the small intestine; only low levels of activity are achieved in serum because the drug is rapidly metabolized. Relatively high protein binding (about 70%) also affects serum levels, reducing potential for systemic toxicity and alteration of intestinal flora. Relative tissue penetration is much lower than other antimicrobials for UTIs, and therefore, nitrofurantoin is not indicated in the therapy of infections such as pyelonephritis and renal cortical or per-inephric abscesses. Nitrofurantoin is rapidly excreted by glomerular filtration and tubular secretion to yield effective urinary levels. In moderate to severe renal dysfunction, toxic blood levels may occur while urinary levels may be inadequate. The drug is inactivated in the liver.

Nitrofurazone (Furacin) is used topically and is not readily absorbed from the skin.

Clinical Use

The singular indication for nitrofurantoin is the treatment and long-term prophylaxis of lower UTIs caused by susceptible bacteria; it is not used as a bacterial suppressant. It is often used prophylactically post intercourse in women with chronic UTIs. Although serum drug concentrations are low, concentrations (100-200 ^g/mL) are found in urine that are well above the minimum inhibitory concentration for susceptible bacteria. The bacteriostatic or bactericidal activity of nitrofuran-toin is concentration dependent; a urinary concentration greater than 100 ^g/mL ensures bactericidal activity. Because nitrofurantoin lacks the broad tissue distribution of other antimicrobial agents, urine cultures should be obtained before and after therapy. Alkalinization of the urine increases urinary concentrations of the drug but decreases its antibacterial efficacy; acidifying agents, including cranberry juice, can be useful.

Nitrofurazone, a topical antibiotic, is occasionally used in the treatment of burns or skin grafts in which bacterial contamination may cause tissue rejection.

Adverse Effects and Drug Interactions

Nausea and vomiting are the most commonly observed adverse effects. Pulmonary hypersensitivity reactions can result in chronic morbidity, usually after therapy lasting at least 6 months. Findings can include chronic desquamative interstitial pneumonia with fibrosis. Resolution may not occur with discontinuation of therapy; fever is absent. Reactions may also be acute or suba-cute. Patients may present acutely with findings resembling acute respiratory distress syndrome. Infiltrates (especially at the base of the lung) and/or effusions may develop but are usually reversible when the drug is stopped; fever is a common finding. In contrast, resolution of pulmonary disease may require several months, especially in subacute reactions, with which fever is not frequent. These reaction types have all been reported as contributing factors in mortality. When a patient taking nitrofurantoin develops pulmonary symptoms, a suspicion of drug-associated toxicity must be entertained.

Intrahepatic cholestasis and hepatitis similar to that seen in chronic active hepatitis can rarely occur; fatalities have been reported. Nitrofurantoin can interfere with immature red blood cell enzyme systems found in babies less than 1 month of age and in nursing infants. This leads to cellular damage and anemia. Nitro-

furantoin use is also contraindicated in pregnant women near term.

In vitro antagonism between nitrofurantoin and the quinolones has been shown, but a demonstration of clinical relevance warrants further study. Certain drugs used in treating gout, which inhibit tubular secretion, can affect UTI therapy by raising serum levels of nitro-furantoin with concomitant diminished urinary levels.

Nitrofurazone is a relatively safe topical agent. Skin sensitization has been reported.

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