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Nitrofurantoin: Side Effects

Nitrofurantoin is a synthetic nitrofuran that belongs to a group of organic substances characterized by a heterocyclic ring consisting of four carbon atoms and one oxygen atom. Its mechanism of action is not understood. Nitrofurans enter bacterial cells and interact with several enzymes; thereby inhibiting bacterial growth. Nitrofurantoin is active against many Gram-positive and Gram-negative bacteria. It is particularly useful in treating urinary pathogens, including Escherichia coli, Klebsiella species, and Proteus species. However, Pseudomonas aeruginosa is almost always resistant.

After almost complete absorption from the gastrointestinal tract, nitrofurantoin produces high urinary concentrations. Blood and tissue concentrations are low. Nitrofurantoin has been used almost exclusively in the treatment and prophylaxis of urinary tract infections. Because of the severity of its adverse effects it should not be used as first choice.

General adverse effects

Harmless gastrointestinal adverse effects are most frequent with nitrofurantoin. Polyneuropathy occurs mainly in patients with renal insufficiency, in whom nitrofurantoin is contraindicated. Rarely, hemolytic anemia and hepatitis occur. Adverse events that are believed to be due to hypersensitivity include rashes, generalized urticaria, and acute pulmonary reactions. Although there are some in vitro data suggesting that nitrofurantoin may be a mutagen, a carcinogenic effect has not been proven in vivo. Teratogenic effects of nitrofurantoin have not been reported. High-dose oral nitrofurantoin may influence spermatogenesis and sperm motility.

Frequency

Drug-related adverse events are rare with nitrofurantoin and occur in fewer patients than with co-trimoxazole or trimethoprim, for example. The frequency of certain adverse reactions varies in different geographical areas. Lung reactions are more prevalent in Scandinavia and South Africa than in the UK, whereas polyneuropathies or gastrointestinal reactions are more frequent in the UK than in Sweden. These discrepancies are unexplained.

Nitrofurantoin: Organs and Systems

Cardiovascular

Except for cardiovascular collapse in anaphylactic shock, adverse cardiovascular events seem to be extremely rare with nitrofurantoin. In experimental animals, cardiotoxic effects have been described.

Respiratory

Acute respiratory reactions to nitrofurantoin include dyspnea, cough, interstitial pneumonitis, and pleural effusion, while interstitial pneumonitis and fibrosis are common chronic reactions. Nitrofurantoin causes acute lung injury more often than any other drug. Since the first well-documented case of an acute lung reaction in 1962, several hundred further observations have been published. The frequency of acute severe pulmonary disease has been estimated to be one in every 5000 first administrations. Women aged 40-50 years are mainly affected.

The acute lung reactions are not dose-related, and sensitization occurs at the earliest 1-2 weeks after the onset of exposure during the first course of therapy. Symptoms develop 2-10 hours after administration and consist of severe dyspnea, tachypnea, non-productive cough, high fever (usually with chills), cyanosis, and chest pain. Occasionally, arthralgia, backache or headache, vomiting, rash, collapse, and anaphylactic shock accompany the pulmonary symptoms. Lung findings include dense crackles or moist rales, predominantly at the lung bases.

X-ray examination may be normal, but more often shows bilateral interstitial lower lobe infiltrates, often with pleural effusion. In one case, transient reverse ventilation-perfusion mismatch was documented by scintigraphy. Initially the leukocyte count is normal or raised, with neutrophilia and lymphopenia. Later, eosinophilia is common. When nitrofurantoin is withdrawn, clinical symptoms subside rapidly, usually within 1-3 days. However, minor X-ray changes can still be found 2 months later. Re-exposure to nitrofurantoin 50 mg re-induces the syndrome. Single cases of death due to heart failure have been reported in debilitated patients.

Acute lung reactions to nitrofurantoin are extremely rare in children. Lung tissue findings in acute reactions have shown minor vasculitis, granulomatous vascu-litis (hypersensitivity angiitis), proliferation of endothelial cells, and empty alveoli. Rapidly progressing bronch-iolitis obliterans with organizing pneumonia (BOOP) has been reported.

Chronic lung reactions are 10-20 times less frequent than acute reactions and mainly involve older patients. Reactions serious enough to require hospitalization occur in one out of 750 long-term users. Acute reactions do not seem to predispose to the later occurrence of chronic reactions. During long-term treatment, dyspnea and usually a non-productive cough without fever develop. Restrictive respiratory impairment is common. X-rays show interstitial infiltrations, often in the middle and basal lung regions. Fibrotic changes, alveolar exudates, and pleural effusions are rare. Histologically, chronic interstitial pneumonitis with varying degrees of fibrosis most often is found, and in some instances desquama-tive alveolitis.

Several mechanisms for the adverse lung effects of nitrofurantoin have been proposed. The pathogenesis of the acute lung reactions may be allergic (type III reactions). However, there is also evidence that a cytotoxic immune mechanism (type II reactions), cell-mediated immunity (type IV reactions), or direct toxic injury to lung tissue through the production of oxygen radicals may be involved. In chronic lung reactions, the causative role of nitrofurantoin is less evident. It is supported by analogy and by the clinical course. Sometimes the skin test is positive, even in chronic lung reactions.

Lymphocyte transformation tests give variable results. A polyclonal hypergammaglobulin-emia is always present, with IgG predominating. Precipitating serum antibodies have not been found. Recent data have supported a toxic pathogenesis similar to that of the herbicide paraquat.

After nitrofurantoin withdrawal, the clinical symptoms regress rapidly. However, in most cases X-ray findings abate slowly and resolution is incomplete in at least 50% of patients. Occasional deaths due to cardiopulmonary failure have also been reported. The therapeutic benefit of corticosteroids is controversial, but the bulk of experience and anecdotal reports suggest that they are useful.

Atypical courses have been rarely described. A mixed type of reaction can occur: after an initial short fever peak, the patient becomes either afebrile or subfeb-rile, despite continuing to take nitrofurantoin and unabated activity of the lung process, or a typical chronic reaction converts to a typical acute reaction on re-exposure to nitrofurantoin after withdrawal. Acute reactions can occur without clinical symptoms, and can be recognized only on X-ray. Single cases of pulmonary hemorrhage, eosinophilic pneumonia, and interstitial giant cell pneumonia have also been reported.

In nitrofurantoin-induced pulmonary toxicity, in which high-resolution computed tomography initially showed a widespread reticular pattern and associated distortion of the lung parenchyma, thought to represent established and irreversible fibrosis, follow-up scans after drug withdrawal nevertheless showed resolution of pulmonary changes. These findings have been corroborated by a report of two middle-aged women who developed respiratory symptoms after prolonged treatment with nitrofurantoin. Both had impaired lung function and abnormal CT scans, and lung biopsies showed features compatible with bronchiolitis obliterans organizing pneumonia. Their condition improved when nitrofurantoin was withdrawn and glucocorticoid treatment was given.

In a patient with nitrofurantoin-induced pulmonary toxicity, in whom high resolution CT scans initially showed a widespread reticular pattern and associated distortion of the lung parenchyma, thought to represent established and irreversible fibrosis, follow-up CT scans after withdrawal of the drug showed resolution of the pulmonary changes.

• An 82-year-old woman developed a productive cough after having taken nitrofurantoin 50 mg/day for 4 years. She had impaired lung function and abnormal CT scans, and lung biopsies showed features compatible with bronchiolitis obliterans organizing pneumonia. The condition improved when nitrofurantoin was withdrawn and she was given a glucocorticoid. • In a 58-year-old woman who took nitrofurantoin 100 mg/day for 11 months, pulmonary toxicity occurred, with bilateral interstitial infiltrates in the lower zones of the chest X-ray and loss of lung volume. High resolution CT scans showed ground-glass opacification in the mid-thoracic region, with patchy fibrosis and traction bronchiectasis. After withdrawal of nitrofurantoin and administration of prednisone, a chest X-ray 3 months later showed resolution of the pulmonary changes.

Nervous system

More than 140 cases of toxic polyneuropathy have been reported. The frequency depends on dose, tissue concentration, and renal function: in up to 90% of cases polyneuropathy occurred in patients with renal insufficiency. Symptoms usually start 9-45 days (at the earliest 3 days) after beginning nitrofurantoin. The neuropathy starts peripherally, predominantly affects the limbs, and remains more severe distally. Initially, there is sensory loss with paresthesia. Later, motor loss develops, often with severe muscle atrophy. As a rule, no further deterioration occurs after withdrawal of nitrofurantoin, and there may be total regression (34% of cases) or partial regression (45% of cases). In some severe cases there is residual disability. The motor loss resolves more slowly and less completely than the sensory impairment. Single cases of retrobulbar optic neuritis, lateral rectus muscle palsy, and facial nerve palsy have been reported.

The lesions comprise degeneration of the myelin sheath of the nerves and nerve roots, with degeneration of the corresponding anterior horn cells and muscle fibers. The pathogenesis is unclear. Impairment of glutathione reductase has been considered. Even in healthy people, nitrofurantoin 400 mg/day for 2 weeks causes a significant increase in motor nerve conduction time. If strict attention is paid to the contraindication of renal insufficiency, the risk of polyneuropathy can be reduced. Careful controls for the initial symptoms of paresthesia can prevent the development of severe disablement.

While taking nitrofurantoin after urinary tract surgery, a 10-year-old girl developed diplopia and ptosis. A sleep test confirmed ocular myasthenia. Her signs and symptoms resolved after drug withdrawal.

Single cases of benign intracranial hypertension (pseudotumor cerebri), with and without ocular palsy, have been reported. Uncharacteristic general symptoms, with dizziness, cephalalgia, or drowsiness, are more frequent.

Trigeminal neuralgia and cerebellar symptoms have been attributed to nitrofurantoin.

Sensory systems

One case of crystalline retinopathy has been associated with long-term nitrofurantoin.

Psychological, psychiatric

Rarely, concomitant dysphoric, euphoric, or even psychotic reactions have been reported in patients taking nitrofurantoin.

Metabolism

One case of hyperlactatemic metabolic acidosis together with hemolytic anemia due to glucose-6-phosphate dehydrogenase deficiency has been reported.

Hematologic

Some cases of hemolytic anemia associated with glucose 6-phosphate dehydrogenase deficiency have been described in patients taking nitrofurantoin.

Single cases of nitrofurantoin-induced (or enhanced) hemolytic anemia have occurred in patients with deficiencies of other erythrocyte enzymes (enolase or glutathione peroxidase), as have isolated cases of methemoglobinemia.

Nitrofurantoin produces oxidant stress and cellular damage by different mechanisms. It can disturb folate metabolism, leading to a megaloblastic component in pre-existing (mostly hemolytic) anemia, which responds to folic acid treatment.

There have been single cases of thrombocytopenia and a severe hemorrhagic diathesis with deficiency of coagulation factors due to a nitrofurantoin-induced hepatic disorder. Furthermore, nitrofurantoin experimentally inhibits ADP-induced platelet aggregation.

Allergic agranulocytosis or neutropenia have been proven in only a few cases. Pancytopenia is also rarely seen.

Mouth and teeth

Some cases of parotitis, rarely proven by rechallenge, have been associated with nitrofurantoin. The symptoms disappear after withdrawal.

Gastrointestinal

Gastrointestinal symptoms are the most common adverse effects of nitrofurantoin. Nausea and anorexia have been most often reported, whereas abdominal pain and diarrhea are rare. These effects are dose-related and usually harmless. The manifestations occur mostly after absorption of the drug and are mediated by the central nervous system. Measures that delay absorption, such as sugar coating or the use of a macrocrystalline form of the drug, reduce these adverse effects.

Liver

Hepatic reactions to nitrofurantoin are rare, and different forms can be distinguished. They can be associated with fatal liver necrosis.

Data from The Netherlands suggest that acute reactions are more common than chronic ones. Acute hepatic reactions may be hepatocellular or cholestatic. In the vast majority of subjects, symptoms appear within the first 6 weeks of nitrofurantoin treatment, and in half of the patients they occur within the first week of treatment. Jaundice is most common, followed by abdominal pain, malaise, and nausea. Hepatomegaly has been reported in nearly 50% of cases, fever in 30-65%, eosinophilia in 15-50%, and a rash in 12-60%. An immunological patho-genesis has been proposed, but experimental data point to a toxic mechanism involving the formation of glutathione-protein mixed disulfides and/or protein alkylation. The prognosis after withdrawal of the drug is good, but fatal courses have been reported when the drug is continued or, rarely, even after it has been discontinued.

Chronic active hepatitis, icteric or anicteric, has been described, almost always in women taking long-term nitrofurantoin. Most patients develop symptoms after a period of about 6 months of nitrofurantoin use. Fever (0-24%), rash (0-3%), and eosinophilia (9-23%) occur rarely compared with acute cases. There is hepatomegaly in 30-60% of chronic cases. Sometimes a broad spectrum of autoimmune reactions, a lupus-like syndrome, or mild cholestasis can be present. Some of these cases have occurred in combination with lung reactions of the protracted acute or chronic type, or in patients with ascites and liver cirrhosis. The clinical symptoms usually improve after withdrawal, but a few cases with extensive hepatocellular necrosis have necessitated liver transplantation or ended fatally. The histological changes can persist. Re-exposure to nitrofurantoin has reproduced the pathological liver tests.

Granulomatous hepatitis, with a rash or isolated increases in serum transaminase activities, can occur in patients with lung reactions. In the protracted acute and in chronic lung reactions liver injury (such as chronic active hepatitis) is more frequent than in acute reactions. Such cases usually show a broad spectrum of serological autoimmune reactions (lupus-like syndrome).

Pancreas

A few cases of nitrofurantoin-induced acute pancreatitis, confirmed by rechallenge, have been reported.

Urinary tract

Nitrofurantoin-induced crystalluria, leading to obstruction of indwelling catheters, has been described in a few patients.

In rare cases, interstitial nephritis has been observed.

Skin

Allergic skin reactions occur in 1-2% of patients who take nitrofurantoin and comprise about 21% of all adverse reactions to nitrofurantoin. They often occur with other reactions, such as drug fever, lung, or liver reactions. The lesions can present as pruritus, as macular, maculopapular, or vesicular rashes, urticaria, angioedema, or erythema multiforme. The frequency of serious cutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis) after nitrofurantoin has been estimated to be 7 cases per 100 000 exposed individuals.

Sweet’s syndrome has been observed in association with a 7-day course of nitrofurantoin.

Transitory alopecia that has been reported in a few cases is dose-related.

Immunologic

About 20 cases of a lupus-like syndrome have been described, mostly in the Scandinavian literature. The clinical picture consisted of arthralgia or, rarely, exacerbation of a pre-existing rheumatoid arthritis and generalized lymphadenopathy, mostly associated with chronic lung and/or liver reactions, such as chronic active hepatitis. In patients with the lupus-like syndrome at least two immunological tests (antinuclear factor, rheumatoid factor, Coombs’ test, and antibodies against smooth muscle, thyroglobulin, thyroid cell cytoplasm, or glomeruli) were positive. The lymphocyte transformation test was always positive. However, the LE cell phenomenon was always negative. As in other allergic reactions to nitrofurantoin, circulating albumin IgG complexes were found by immunoelectrophoresis, with tailing of the albumin line. The syndrome regresses after withdrawal.

Long-Term Effects

Drug tolerance

Nitrofurantoin is effective against Enterobacteriaceae; the rates of resistance were below 2% in a single-center study and 3.5% in a multicenter study.

Mutagenicity

In vitro, nitrofurantoin acts as a mutagen by inhibiting DNA synthetase. In human fibroblast cultures it damages DNA. Treatment with nitrofurantoin for 12 months caused a significant increase in chromosome aberrations and sister chromatid exchanges in the lymphocytes of 69 children.

Tumorigenicity

Some studies have shown similar metabolism of nitrofurantoin and other (carcinogenic) nitrofurans. Formation of carcinogenic nitrofurantoin metabolites is therefore possible. However, a carcinogenic effect has not been proven for nitrofurantoin.

Second-Generation Effects Fertility

High-dose oral nitrofurantoin (10 mg/kg/day) transiently reduces the sperm count in 30% of patients. This is due to arrest of maturation. Depression of sperm motility or ejaculate volume can also occur at lower doses.

Teratogenicity

Only very small amounts of nitrofurantoin cross the placenta, and teratogenic effects are not known. Even when it is used in the first trimester, there have been no associated fetal malformations. No teratogenic effects have been associated with nitrofurantoin in Denmark, Finland, Norway, and Sweden, or in a Hungarian case-control survey.

Fetotoxicity

Hemolytic anemia occurred during the first hours of life in a full-term neonate whose mother had taken nitrofurantoin during the last month of pregnancy. It may therefore be wise not to prescribe nitrofurantoin at the end of pregnancy.

Lactation

Nitrofurantoin is actively transported into human milk, achieving concentrations greatly exceeding those in serum. Concern is warranted for suckling infants under 1 month old or for infants with a high frequency of glucose-6-phosphate dehydrogenase deficiency or sensitivity to nitrofurantoin.

Susceptibility Factors

Genetic factors

Glucose-6-phosphate dehydrogenase deficiency is decisive for the development of hemolytic anemia in patients taking nitrofurantoin.

Age

Nitrofurantoin is contraindicated during the last trimester of pregnancy and in neonates, because hemolytic anemia can result from immature enzyme systems.

Renal disease

The main risk factor for toxic reactions to nitrofurantoin, especially polyneuropathy and gastrointestinal symptoms, is impaired renal function.

Drug-Drug Interactions

Estrogens

Nitrofurantoin reduces the enterohepatic circulation of estrogens.

Nalidixic acid

Antagonism in antibacterial efficacy between nitrofurantoin and nalidixic acid has been observed.

Pyridoxine

Pyridoxine accelerates the renal elimination of nitrofurantoin.

Interference with Diagnostic Tests

Glucose measurements

Nitrofurantoin can produce spurious positive urine glucose concentrations or raised blood glucose concentrations if reducing reagents are used.

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