Nitrofurantoin Toxicity Research Articles

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SESSION TITLE: Drug-Induced Lung Injury Pathology Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Nitrofurantoin is a common antibiotic prescribed for urinary tract infections. Acute pulmonary toxicity from nitrofurantoin can present in many ways that can be confused with a COPD exacerbation. This case gives us insight into a unique diagnosis of acute nitrofurantoin pulmonary toxicity on a patient who became immediately symptomatic after taking the medication. CASE PRESENTATION: An 80 y/o patient with COPD and DM presented to the hospital due to sudden onset shortness of breath. His symptoms began immediately after starting nitrofurantoin for an UTI. His symptoms were chest tightness, cough with sputum production, and body shakes. On admission, the patient was hemodynamically stable, but hypoxic requiring 10L NC to maintain an oxygen saturation of 90%. Laboratory evaluation demonstrated an elevated white count (12K/uL), eosinophils (5.6%), AST/ALT (209/380 U/L), and a lactic acid of 3.1 mmol/L. His sputum culture, coccidioidomycosis, viral panel, and blood cultures were negative. A CTA of his lungs showed emphysematous changes with bilateral ground glass opacities and no pulmonary embolism. Physical exam was relevant for end expiratory wheezing. The patient was started on bronchodilators and steroids for a COPD exacerbation on admission but failed to respond to treatment. Pulmonology was consulted for the persistent hypoxia. We found after chart review that the patient had prior admissions for COPD exacerbations that correlated with him starting nitrofurantoin as an outpatient. We decided to stop treating him for a COPD exacerbation, resume his home inhalers, and stop the nitrofurantoin. The patient was titrated off his oxygen within 24 hours and all his laboratory values were normalized. A follow up CT Chest showed resolution of the ground glass opacities. DISCUSSION: Nitrofurantoin toxicity is described in literature as hepatoxicity, pulmonary fibrosis, and rarer instances of acute pulmonary toxicity such as the case reported here (1). Our case highlights how nitrofurantoin toxicity can mimic a COPD exacerbation and if this diagnosis is not considered, patients have prolonged hospitalization or improper treatment. Most cases of pulmonary toxicity from nitrofurantoin usually respond well to stopping the antibiotic, like our patient (2). While nitrofurantoin has an excellent safety profile, it is important to be aware that there have been fatalities from pulmonary toxicity from nitrofurantoin (3). CONCLUSIONS: Pulmonary toxicity from nitrofurantoin can easily mimic a COPD exacerbation or a pneumonia. The symptoms from an acute toxicity usually occur within several hours to days of taking the antibiotic. When patients are admitted for acute hypoxia and infectious workup is negative, there needs to be a thorough review of medications and if nitrofurantoin is listed, it should be discontinued and listed to not be used again. Reference #1: Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015 Sep;70(9):2456-64. doi: 10.1093/jac/dkv147. Epub 2015 Jun 11. PMID: 26066581. Reference #2: Khan TMA, Ansari Y, Siddiqui AH, Matthew H, Siddiqui F. Nitrofurantoin-associated Acute Pulmonary Toxicity Mimicking Severe Sepsis with Significantly Elevated Procalcitonin. Cureus. 2019;11(8):e5516. Published 2019 Aug 29. doi:10.7759/cureus.5516 Reference #3: Livanios K, Karampi ES, Sotiriou A, Tavernaraki K, Styliara P, Kainis E. Nitrofurantoin-induced acute pulmonary toxicity. Respirol Case Rep. 2016;4(1):25-27. Published 2016 Jan 14. doi:10.1002/rcr2.131 DISCLOSURES: No relevant relationships by Adnan Abbasi No relevant relationships by Bhargav Patel

How Common Are Pulmonary and Hepatic Adverse Effects in Older Adults Prescribed Nitrofurantoin?

To determine the frequency of serious pulmonary and hepatic adverse events (AEs) in persons aged 65 and older prescribed nitrofurantoin. Retrospective electronic health record (EHR) audit of nitrofurantoin prescriptions and associated AEs. Urban academic medical center. All inpatients and outpatients aged 65 and older prescribed nitrofurantoin from January 1, 2010, to December 31, 2014. The number of nitrofurantoin prescriptions and pulmonary and hepatic AEs associated with nitrofurantoin use was acquired by data extraction from EHRs. Of 3,400 individuals aged 65 and older prescribed nitrofurantoin during the study period, 641 were identified as possibly having one of five targeted symptoms or disease complications (pulmonary and hepatic) associated with nitrofurantoin. After a detailed chart audit, 89% were deemed to have no adverse reaction, 7% had a minor side effect or allergy, and 3.9% met criteria for suspicion of a nitrofurantoin-induced AE, five of whom were rated as being highly suspicious for nitrofurantoin toxicity; four of the five were identified with pulmonary toxicity and one with hepatotoxicity. Four of five of these individuals used nitrofurantoin chronically. Nitrofurantoin was prescribed for 3,400 individuals aged 65 and older during the 5-year study period. Serious side effects appeared to be uncommon, but chronic use appeared to be at greater risk.

Incidence and Genetic Bases of Nitrofurantoin Resistance in Clinical Isolates of Two Successful Multidrug-Resistant Clones of Salmonella enterica Serovar Typhimurium: Pandemic "DT 104" and pUO-StVR2.

In this study, the incidence and genetic bases of nitrofurantoin resistance were established for clinical isolates of two successful clones of Salmonella enterica serovar Typhimurium, the pandemic "DT 104" and the pUO-StVR2 clone. A total of 61 "DT 104" and 40 pUO-StVR2 isolates recovered from clinical samples during 2008-2014 and assigned to different phage types, were tested for nitrofurantoin susceptibility. As previously shown for older isolates, all newly tested pUO-StVR2 isolates were highly resistant to nitrofurantoin (minimal inhibitory concentration [MIC] of 128 μg/ml), while 42.6%, 24.6%, and 32.8% of the "DT 104" isolates were susceptible, showed intermediate resistance or were highly resistant, with MICs of 8, 64, and 128 μg/ml, respectively. The genetic bases of nitrofurantoin resistance were established by PCR amplification and sequencing of the nfsA and nfsB genes encoding oxygen-insensitive nitroreductases. pUO-StVR2 isolates shared identical alterations in both nfsA (IS1 inserted into the coding region) and nfsB (in frame duplication of two codons). "DT 104" isolates with intermediate or high resistance had a missense mutation affecting the start codon of nfsA, while a single resistant isolate carried an additional frameshift mutation affecting nfsB. Complementation studies, performed with wild-type nfsA and nfsB, cloned independently and together into low and high copy-number vectors, confirmed NfsA and NfsB as responsible for nitrofurantoin toxicity. The same alterations persisted along time in isolates of each clone belonging to different phage types. Accordingly, changes leading to nitrofurantoin resistance have probably occurred before phage type diversification.

Nitrofurantoin-Induced Granulomatous Interstitial Pneumonia

Nitrofurantoin-induced lung toxicity is relatively common, but rare histologic patterns sometimes occur that may make diagnosis difficult. We present the case of a 69-year-old woman taking prophylactic nitrofurantoin for urinary tract infections, who developed granulomatous interstitial pneumonia. She improved with cessation of nitrofurantoin, without other therapy. To our knowledge, this is the fourth reported case of granulomatous interstitial pneumonia associated with nitrofurantoin, and the first to show complete resolution with cessation of the drug alone, without steroids. It is important to recognize that idiosyncratic reactions to nitrofurantoin can produce a wide spectrum of histologic patterns. Of these patterns, granulomatous interstitial pneumonia is a rarely evidenced manifestation (possibly because few cases undergo a confirmatory lung biopsy). Recognition of granulomatous interstitial pneumonia as a manifestation of nitrofurantoin toxicity can aid in early identification of the reaction and prompt withdrawal of the drug, both of which are essential to prevent long-term complications.

Desferal Protection against Acute Nitrofurantoin Toxicity in Albino Rat Lungs

Desferal Protection against Acute Nitrofurantoin Toxicity in Albino Rat Lungs

Severe nitrofurantoin lung disease resolving without the use of steroids

We report a case of an elderly woman who developed a severe, chronic pulmonary reaction to nitrofurantoin therapy that she had taken continuously for three years to prevent urinary tract infections. The patient was taking no other drug known to cause lung disease but the diagnosis was delayed by failure to recognize the association between nitrofurantoin and adverse drug reactions affecting the lung. When originally seen, the patient was unable to care for herself due to dyspnea. Bronchoscopy with biopsy ruled out other causes of her pulmonary disease. Immediate withdrawal of nitrofurantoin led to substantial, sustained improvement and disappearance of symptoms over several months without administration of corticosteroids. Nitrofurantoin toxicity should always be considered in any person taking that drug who develops bilateral infiltrates.

Giant Cell Interstitial Pneumonia Associated with Nitrofurantoin

A case of giant cell interstitial pneumonia (GIF) that occurred in association with exposure to nitrofurantoin is presented. While the diagnosis of GIP is confirmed by histopathology, this diagnosis can be supported by the findings of bizarre multinucleated giant cells (MGC), elevated T lymphocytes, and a low T lymphocyte helper/suppressor ratio in the bronchoalveolar lavage fluid (BALF). Recognition of GIP as a rare manifestation of nitrofurantoin toxicity is important because prompt therapy may be associated with a favorable outcome.

GIANT CELL INTERSTITIAL PNEUMONIA ASSOCIATED WITH NITROFURANTOIN

A case of giant cell interstitial pneumonia (GIF) that occurred in association with exposure to nitrofurantoin is presented. While the diagnosis of GIP is confirmed by histopathology, this diagnosis can be supported by the findings of bizarre multinucleated giant cells (MGC), elevated T lymphocytes, and a low T lymphocyte helper/suppressor ratio in the bronchoalveolar lavage fluid (BALF). Recognition of GIP as a rare manifestation of nitrofurantoin toxicity is important because prompt therapy may be associated with a favorable outcome.

The labile iron pool in hepatocytes: prooxidant-induced increase in free iron precedes oxidative cell injury.

The labile iron pool (LIP) represents the nonferritin-bound, redox-active iron that has been implicated in oxidative stress and cell injury. Here we examined whether alterations in LIP can be detected in cultured murine hepatocytes and whether increases in LIP are related to the oxidative damage inflicted by the redox cycling drug nitrofurantoin (NFT). Early changes in LIP were monitored with the metal-sensitive fluorescent probe calcein (CA), the fluorescence of which is quenched on binding to iron. Short-term exposure (<1 h) to NFT reduced the CA fluorescence signal by 30%, indicating that the amount of LIP-associated iron had increased. Prolonged exposure (2 h) to NFT caused oxidative cell injury. The addition of the cell-permeable ferrous iron chelator 2,2'-bipyridyl not only prevented the quenching of CA fluorescence but also partially protected from NFT toxicity. It is concluded that reductive stress-induced increase in LIP is an essential event that precedes oxidative cell damage in intact hepatocytes.

Antioxidant and Cytoprotective Properties ofd-Tagatose in Cultured Murine Hepatocytes

d-Tagatose is a zero-energy producing ketohexose that is a powerful cytoprotective agent against chemically induced cell injury. To further explore the underlying mechanisms of cytoprotection, we investigated the effects ofd-tagatose on both the generation of superoxide anion radicals and the consequences of oxidative stress driven by prooxidant compounds in intact cells. Primary cultures of hepatocytes derived from male C57BL/6 mice were exposed to the redox cycling drug nitrofurantoin (NFT). Lethal cell injury induced by 300 μM NFT was completely prevented by high concentrations (20 mM) ofd-tagatose, whereas equimolar concentrations of glucose, mannitol, or xylose were ineffective. The extent of NFT-induced intracellular superoxide anion radical formation was not altered byd-tagatose, indicating that the ketohexose did not inhibit the reductive bioactivation of NFT. However, the NFT-induced decline of the intracellular GSH content was largely prevented byd-tagatose. The sugar also afforded complete protection against NFT toxicity in hepatocytes that had been chemically depleted of GSH. Furthermore, the ketohexose fully protected from increases in both membrane lipid peroxidation and protein carbonyl formation. In addition,d-tagatose completely prevented oxidative cell injury inflicted by toxic iron overload with ferric nitrilotriacetate (100 μM). In contrast,d-tagatose did not protect against lethal cell injury induced bytert-butyl hydroperoxide, a prooxidant which acts by hydroxyl radical-independent mechanisms and which is partitioned in the lipid bilayer. These results indicate thatd-tagatose, which is a weak iron chelator, can antagonize the iron-dependent toxic consequences of intracellular oxidative stress in hepatocytes. The antioxidant properties ofd-tagatose may result from sequestering the redox-active iron, thereby protecting more critical targets from the damaging potential of hydroxyl radical.

ROLES OF DT DIAPHORASE IN THE GENOTOXICITY OF NITROAROMATIC COMPOUNDS IN HUMAN AND FISH CELL LINES

The genotoxicity of nitroaromatic compounds was examined in two cultured cell lines, namely, a human hepatoma cell line, HepC2, and a brown bullhead fibroblast cell line, BB. Furthermore, the role of the quinone-reducing enzyme DT diaphorase [NAD(P)H:(quinone acceptor) oxidoreductasel was examined with respect to its influence on the genotoxic effects of model nitroaromatic pollutants. The nitroreductive characteristics of these two cell lines were examined using an acetylated cytochrome c reduction assay for enzymatic nitroreductase activity. Subsequently, the influence of DT diaphorase on the genotoxicity of two model nitroaromatics, 4-nitroquinoline 1-oxide (4NQ) and nitrofurantoin (NF), revealed that DT diaphorase was the predominant 4NQ reductase in cytosols of both cell lines, but played a lesser role in NF reduction in both species. Despite these interspecific similarities, results revealed marked qualitative differences between the two species in terms of the influence of DT diaphorase on quinone-mediated genotoxicity. When pre-treated with the DT diaphorase inhibitor dicoumarol, HepC2 cells exhibited an exacerbation of genotoxicity in the presence of 4NQ, indicating a protective influence of the enzyme. In contrast, 4NQ genotoxicity in BB cells was reduced in the presence of dicoumarol, indicating a deleterious effect of DT diaphorase activity. Conversely, dicoumarol pretreatment was moderately protective against NF-mediated genotoxicity in HepC2 cells but exacerbated NF toxicity in BB cells. This study illustrates the manner in which functionally analogous enzymes may have markedly distinct influences on xenobiotic toxicity in different cellular systems.

High-resolution computed tomography of drug-induced lung disease

In order to determine the potential clinical utility of high-resolution CT (HRCT) in the assessment of drug-induced lung disease, we reviewed the chest radiographs and HRCT scans of 23 patients and five normal controls. The radiographs and HRCT scans were reviewed separately in random order by two independent observers who were not aware of the relative numbers of patients and controls. Abnormal findings were detected in the affected patients in 17/23 radiographs compared to 23/23 HRCT scans. The patients included five cases of bleomycin toxicity, five cases of nitrofurantoin toxicity, two cases each of penicillamine, busulphan, BCNU and amiodarone toxicity, and one case each of cyclophosphamide, procainamide, mitomycin and methotrexate toxicity. The HRCT appearances could be grouped into four categories according to their dominant pattern and distribution of disease. These include fibrosis with or without consolidation (n = 12), ground-glass opacities (n = 7), widespread bilateral consolidation (n = 2), and bronchial wall thickening with areas of decreased attenuation (n = 2). The results of this study indicate that HRCT is more sensitive than the radiograph in the detection of drug-induced lung disease. The appearances demonstrated by HRCT reflect the pathological mechanisms of drug-induced lung disease.

Combined nitrofurantoin toxicity to liver and lung

Nitrofurantoin is an antibiotic commonly used for prophylaxis and treatment of urinary tract infections. Pulmonary and hepatic toxicity are rare side effects of this agent. The simultaneous occurrence of pulmonary fibrosis and chronic active hepatitis in a patient undergoing long-term nitrofurantoin therapy is reported. The presence of pulmonary toxicity was evidenced by infiltrates on chest radiographs and impaired diffusion capacity during pulmonary function tests. Prolonged elevation of liver enzyme concentrations together with the presence of increased antibody titers (anti-smooth muscle antibody, antinuclear antibody) was suggestive of chronic hepatitis, a diagnosis corroborated by liver biopsy findings. After discontinuation of nitrofurantoin therapy, the patient had a full recovery. The infiltrates initially found on chest radiographs disappeared, and laboratory parameters normalized without the need for corticosteroid therapy. (Gastroenterology 1992 Apr;102(4 Pt 1):1396-9)

Combined nitrofurantoin toxicity to liver and lung

Nitrofurantoin is an antibiotic commonly used for prophylaxis and treatment of urinary tract infections. Pulmonary and hepatic toxicity are rare side effects of this agent. The simultaneous occurrence of pulmonary fibrosis and chronic active hepatitis in a patient undergoing long-term nitrofurantoin therapy is reported. The presence of pulmonary toxicity was evidenced by infiltrates on chest radiographs and impaired diffusion capacity during pulmonary function tests. Prolonged elevation of liver enzyme concentrations together with the presence of increased antibody titers (anti-smooth muscle antibody, antinuclear antibody) was suggestive of chronic hepatitis, a diagnosis corroborated by liver biopsy findings. After discontinuation of nitrofurantoin therapy, the patient had a full recovery. The infiltrates initially found on chest radiographs disappeared, and laboratory parameters normalized without the need for corticosteroid therapy.

Nitrofurantoin-induced pulmonary toxicity: In vivo evidence for oxidative stress-mediated mechanisms

The present study was carried out to examine whether nitrofurantoin-induced pulmonary toxicity in normal rats was mediated via oxidant stress mechanisms. The relative importance of the cellular antioxidant enzymes in nitrofurantoin toxicity was also assessed. For this, the pulmonary toxicity induced by nitrofurantoin in rats was evaluated at various time intervals after a single subcutaneous injection. Data from this study showed that nitrofurantoin (200 mg/kg, s.c.) resulted in transient but measurable lung damage as evidenced by the increases in wet lung weight/body weight ratio and decreases in lung angiotensin converting enzyme activity. A transient decrease in GSH concentrations with a concurrent increase in GSSG concentrations as well as an increase in lipid peroxidation levels (measured by the formation of diene conjugates and thiobarbituric acid reactants) were also evident in lungs of nitrofurantoin-treated rats. In addition, nitrofurantoin did not alter the pulmonary Superoxide dismutase and glutathione peroxidase activities, but it did produce transient decreases in catalase and glutathione reductase activities. These data indicate that impairment of the ability of the lung to detoxify reactive oxygen species may play an important role in the development of nitrofurantoin-induced pulmonary toxicity. The results of the present study suggest that nitrofurantoin can damage the lungs of rats, probably through oxidative stress-mediated mechanisms. Also, our data have provided in vivo evidence for substantiating lipid peroxidation as a possible cause of lung damage.

A profile of nitrofurantoin toxicity and efficacy

A profile of nitrofurantoin toxicity and efficacy

Hospitalizations for Pulmonary Reactions following Nitrofurantoin Use

Acute pulmonary illness compatible with previously described nitrofurantoin toxicity and requiring hospitalization occurred three times among 16,101 first courses of therapy with nitrofurantoin. One case of fatal pulmonary fibrosis was ascribed to long-term use of nitrofurantoin among 742 observed recipients of ten or more prescriptions.

Nitrofurantoin toxicity occurring in children

Nitrofurantoin toxicity occurring in children

Quantitative study of natural antioxidant systems for cellular nitrofurantoin toxicity

The toxicity of nitrofurantoin was studied on human WI-38 fibroblasts: this chemical was lethal when added at concentrations higher than 5·10 −5 M in the culture medium. The protection afforded by anitoxidants was then tested: α-tocopherol gave at 10 −4 M a light protection in contrast to ascorbic acid which even became toxic at high concentrations. We also tested catalase, superoxide dismutase and glutathione peroxidase introduced intracellularly by the microinjection technique. On a molecular basis, glutathione peroxidase was 23-times more efficient than catalase and 3000-times more than superoxide dismutase. The results also showed that a similar range of enzyme concentrations was found for the protection against high oxygen pressure. This suggests that, in the case of both oxygen and nitrofurantoin toxicity, the peroxide derivatives are the most toxic intermediates of the free radical attacks.

Metabolic activation of oxygen by nitrofurantoin in the young chick

Anaerobic incubations containing nitrofurantoin, and NADPH-generating system, and chick hepatic microsomes produced an electron spin resonance spectrum identified as the nitro anion free radical. Aerobically, nitrofurantoin markedly stimulated oxygen consumption, superoxide formation, and NADPH oxidation in hepatic microsomal preparations from control and selenium-deficient chicks. The nitrofurantoin-stimulated oxidation of NADPH was inhibited by superoxide dismutase (SOD). The superoxide-dependent oxidation of NADPH did not appear to be mediated by an NADP • radical, as has been shown for lactate dehydrogenase. Further, the aerobic metabolism of the nitro drug was also affected by SOD, suggesting the existence of a previously unreported metabolic pathway for nitrofurantoin. These studies support the growing body of evidence which suggests that nitrofurantoin toxicity is mediated, at least in part, by the metabolic activation of oxygen by the nitro aromatic anion radical. Further, these data suggest that superoxide may be involved in the oxidative metabolism of the aromatic nitro compounds.