Drug-induced Liver Injury Following Prolonged use of Nitrofurantoin.

Nitrofurantoin is the antibiotic of choice for treatment and prophylaxis of recurrent episodes of lower urinary tract infections. Although adverse effects such as anorexia, vomiting, and pulmonary hypersensitivity are commonly reported with nitrofurantoin use, studies have demonstrated that rarely nitrofurantoin can also induce diverse forms of liver injury, spanning from mild hepatitis to severe and potentially fatal fulminant liver failure. These occur especially in elderly females with preexisting liver or renal impairment. Here, we present a case of a 62-year-old female in good health who exhibited symptoms of fatigue, abdominal pain, and dark-colored urine. Through investigation, she was diagnosed with a case of drug-induced liver injury associated with the prolonged use of nitrofurantoin.

RésuméLa nitrofurantoïne est l'antibiotique de choix pour le traitement de la prophylaxie d'épisodes récurrents d'infections des voies urinaires intérieures. Bien que des effets indésirables tels que l'anorexie, des vomissements et une hypersensibilité pulmonaire soient fréquemments rapportés lors de l'utilisation de la nitrofuratoïne, des études ont demontré que dans de rares cas, la nitrofurantoïne peut également induire diverses formes de lésions hépatiques, allant d'une hépatite légère à une incapacité hépatique fulminante grave et potentiellement mortelle. Celle-ci surviennent particulièrement chez des femmes âgées ayant une insuffisance hépatique ou rénale préexistante.Nous présentons ici l'étude d'une femme de 62 ans en bonne santé qui manifestait des symptômes de fatigue, de douleurs abdominales et d'urine de couleur foncée. À travers une enquête, on lui a diagnostiquée un cas de lésion hépatique d'origine médicamenteuse associée à l'utilisation prolongée de la nitrofurantoïne.

Aplastic anaemia following antibiotic use for urinary tract infection.

Aplastic anaemia is often associated with recent viral illnesses to include EBV and parvovirus along with certain medications such as anticonvulsants and sulfa containing antibiotics. We describe a case report of a female patient in her 70s who presented with pancytopenia after being treated with nitrofurantoin and ciprofloxacin for suspected urinary tract infection. She underwent an extensive workup to rule out alternative aetiologies of her pancytopenia to include a broad viral, autoimmune and malignancy evaluation which were unrevealing. Given her recent exposure to ciprofloxacin and nitrofurantoin and marrow recovery following removal of these agents, it was presumed that antibiotic exposure was the underlying cause of her aplastic anaemia.

Nitrofurantoin: properties and potential in treatment of urinary tract infection: a narrative review.

Nitrofurantoin (NF), a wide-spectrum antibiotic accessible since 1953, is utilized widely to treat urinary tract infections as it usually stays active against drug-resistant uropathogen. The use of Nitrofurantoin has increased exponentially since new guidelines have repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). To, although fluoroquinolones are usually used to re-evaluate the first- and second-line therapies for treating uncomplicated UTI, their level of utilization is thought to be inappropriately excessive and will eventually have a detrimental impact; thus, we hypothesize that NF might be the best choice for this condition, because of its low frequency of utilization and its high susceptibility in common UTI pathogens. It can be concluded from this review that NF can be considered as the most effective drug in the treatment of acute urinary infection, but due to the long-term side effects of this drug, especially in elderly patients, it is essential to introduce some criteria for prescribing NF in cases of chronic UTI.

Nitrofurantoin for the treatment of uncomplicated urinary tract infection in female patients: the impact of dosing regimen, age, and renal function on drug exposure.

PURPOSE: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied. METHODS: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated. RESULTS: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively). CONCLUSION: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Safety and efficacy of nightly nitrofurantoin as prophylaxis in dogs with recurrent urinary tract infections: 13 cases (2015-2021).

OBJECTIVES: To report the protocol, efficacy and adverse events in dogs receiving nightly nitrofurantoin therapy as antimicrobial prophylaxis for recurrent urinary tract infections. MATERIALS AND METHODS: Retrospective case series of dogs prescribed nitrofurantoin as prophylaxis for recurrent urinary tract infections. Data on urological history, diagnostic investigation, protocol, adverse events and efficacy (through serial urine cultures) were extracted from medical records. RESULTS: Thirteen dogs were included. Before therapy, dogs had a median of 3 (range 3 to 7) positive urine cultures in the past year. In all but one dog, standard antimicrobial therapy was given before starting the nightly nitrofurantoin. The nightly nitrofurantoin was then prescribed at a median dose of 4.1 mg/kg orally every 24 hours for a median of 166 days (range 44 to 1740). The median infection-free interval on therapy was 268 days (95% confidence interval: 165 to undefined). Eight dogs had no positive urine cultures while on therapy. Of these, five (three which discontinued and two which remained on nitrofurantoin) had no return of clinical signs or bacteriuria at time of last follow-up evaluation or death, and three had suspected or confirmed bacteriuria 10 to 70 days after discontinuation. Five dogs developed bacteriuria on therapy, four of which were nitrofurantoin-resistant Proteus spp. Most other adverse events were minor; none were considered likely caused by the drug on causality assessment. CLINICAL SIGNIFICANCE: Based on this small study group, nightly nitrofurantoin appears well tolerated and might be efficacious prophylaxis for recurrent urinary tract infections in dogs. Infection with nitrofurantoin-resistant Proteus spp. was a common reason for treatment failure.

Drug-induced haemolysis: another reason to be cautious with nitrofurantoin.

We report the case of a previously healthy woman in her 60s who presented to the emergency department with acute confusion, vomiting and fever. She was recently diagnosed with a urinary tract infection as an outpatient and had completed the fifth day of a 7-day course of treatment with nitrofurantoin. We maintained a wide differential diagnosis including infectious, metabolic, autoimmune and medication-related causes. She developed an acute normocytic anaemia in hospital with a haemoglobin drop from 121 g/L to 89 g/L. Further investigation revealed evidence of haemolysis with an elevated bilirubin, lactate dehydrogenase, reticulocyte count and decreased haptoglobin. She was worked up for both inherited and acquired causes of haemolysis and found to have glucose-6-phosphate dehydrogenase deficiency. Her presentation was thought to be secondary to nitrofurantoin-induced haemolysis and she recovered completely with conservative management through intravenous fluids and discontinuation of nitrofurantoin.

First trimester pregnancy exposure to fosfomycin and risk of major congenital anomaly: a comparative study in the EFEMERIS database.

PURPOSE: Fosfomycin trometamol has been recommended as first-line bactericidal antibiotic for urinary tract infections in pregnant women since 2015 in France. However, studies assessing fosfomycin safety in pregnancy are sparse. This study aimed to assess the risk of major Congenital Anomaly (CA) after fosfomycin exposure during the first trimester of pregnancy. METHODS: We performed a comparative study in EFEMERIS, the French database including expecting mothers covered by the French Health Insurance System of Haute-Garonne from July 1st, 2004 to December 31th, 2018. EFEMERIS contains prescribed and dispensed reimbursed medications during pregnancy and pregnancy outcomes. Logistic regressions have been conducted to compare three groups: (1) pregnancies exposed at least once to fosfomycin; (2) pregnancies exposed at least once to nitrofurantoin; and (3) pregnancies exposed neither to fosfomycin nor to nitrofurantoin, another antibiotic prescribed for urinary infections, before and during pregnancy. RESULTS: A total of 2724 (2.0%) pregnant women received at least one fosfomycin prescription during the first trimester, 650 (0.5%) received nitrofurantoin during the first trimester, and 133,502 (97.5%) pregnant women were not exposed to fosfomycin nor to nitrofurantoin. First trimester pregnancy exposure to fosfomycin was not associated with an increased risk of major CA, compared to first trimester exposure to nitrofurantoin (2.0% versus 2.5%; ORa = 0.80 [0.44-1.47]), or to pregnancies unexposed to fosfomycin and nitrofurantoin (2.0% versus 2.1%; ORa = 0.97 [0.73-1.30]). CONCLUSION: This is the first large comparative study assessing fosfomycin safety in pregnancy. It does not exhibit an increased risk of major CA after fosfomycin exposure during the first trimester of pregnancy.

Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries.

Nitrofurantoin is a synthetic antibiotic that is recommended as first-choice treatment for uncomplicated urinary tract infections. The prescription of this drug has increased dramatically, especially in Latin American countries. We described the demographics, clinical characteristics, biochemical features, and outcome of nitrofurantoin-induced liver injury. We analyzed 23 cases from the Latin American DILI Network (LATINDILI) and the Spanish DILI Registry. Causality was assessed with the RUCAM and RECAM scale. Of the 23 DILI cases included in our series, 96% patients were women, and the mean age of the whole cohort was 61 years. The median time of drug exposure was 175 days (interquartile range [IQR] 96-760), with 11 patients who were prescribed nitrofurantoin for more than six months. Hepatocellular damage was the most frequent pattern of liver injury (83%), and nearly half of the patients had an asymptomatic presentation (52%). Neither death nor liver transplantation was documented in this series. Overall, 65% of the patients (n = 15) presented with positive autoantibody titres. The median time to resolution was 81 days (IQR 57-141), and 15 patients (83%) recovered within six months. Five patients (22%) developed nitrofurantoin-induced autoimmune-like hepatitis (NI-AILH), of whom two were characterized by a persistent increase in transaminases that required immunosuppressive treatment to achieve normalization of liver enzymes. Clinicians who prescribe nitrofurantoin should be aware that patients who had taken nitrofurantoin for a long term may be at risk of developing nitrofurantoin-induced autoimmune-like hepatitis.

Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.

BACKGROUND & AIMS: Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN). METHODS: Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661). RESULTS: Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10-4), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10-5), and non-NTF DILI (OR 3.34, p = 0.003). CONCLUSION: NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies. IMPACT AND IMPLICATIONS: Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.

Nitrofurantoin and Minocycline-Associated Vasculitic Neuropathy: Case Reports and Literature Review.

BACKGROUND: Vasculitic neuropathies usually present acutely to subacutely, with an asymmetric pattern, involving multiple peripheral nerve territories. Drug-induced vasculitis is an often overlooked etiology of vasculitic neuropathy. METHODS: We present the first reported case of nitrofurantoin-associated and an illustrative case of minocycline-associated vasculitic neuropathy, with a review of the literature. RESULTS: The first patient is a 60-year-old woman who developed axonal sensorimotor peripheral neuropathy after nitrofurantoin use, with a superficial radial nerve biopsy confirming vasculitis. The second patient is a 23-year-old woman, with a history of acne vulgaris treated with minocycline, who presented with a subacute right common peroneal mononeuropathy followed by a left deep peroneal mononeuropathy, with elevated antinuclear, perinuclear-antineutrophil cytoplasmic, and myleoperoxidase antibodies, and MPO titers, and a sural nerve biopsy showing large arteriole vasculitis. Finally, we provide a comprehensive review of previously published cases. CONCLUSIONS: Medications should be considered as a trigger for medication-induced vasculitic neuropathy. Accurate diagnosis would ensure timely treatment.

Nitrofurantoin plasma- and urine exposure in eight healthy beagle dogs following standard nitrofurantoin dosing regimen.

Bacterial cystitis is common in dogs and is usually treated with antibiotics. Nitrofurantoin is used for treatment of bacterial cystitis in humans and might provide a feasible treatment option in dogs. The aim of this study was to investigate the nitrofurantoin plasma concentration-time course and potential adverse effects in dogs. Nitrofurantoin (4.4-5.0 mg/kg) was administered orally to eight healthy beagles every 8 h for five days before repeated plasma and urine samples were collected. An additional four beagles served as untreated controls. The nitrofurantoin plasma and urine concentrations were measured using ultra high precision liquid chromatography coupled to tandem mass-spectrometry and further analysed using a non-compartmental pharmacokinetic model. In plasma, the median Cmax was 2.1 µg/mL, tmax was 2 h, the terminal rate constant was 0.9 per h and the terminal half-life was 0.8 h. In urine, median Cmax was 56 µg/mL, tmax was 1 h and the terminal half-life was 4.3 h. No adverse effects were observed clinically or in haematology or biochemistry. The data presented in this study combined with in vitro sensitivity data from common urine pathogens and the lack of observed adverse effects suggest that nitrofurantoin in a standard dosing regimen could be effective in sporadic bacterial cystitis treatment in dogs. Further clinical studies are highly warranted to verify the effectiveness in clinical cases.

Systemic Inflammatory Response Syndrome from Nitrofurantoin: A Case Report.

BACKGROUND Nitrofurantoin is an antibiotic that is commonly used and preferred to treat lower urinary tract infections due to its relatively safe adverse effects profile. However, with the increased emphasis on antibiotic stewardship, it is important to recognize the rare, yet serious adverse effects profile of this medication. One of the rare adverse reactions is the development of systemic inflammatory response syndrome from nitrofurantoin. CASE REPORT We present a case of a 66-year-old woman who developed a classic systemic inflammatory response syndrome, including leukocytosis and fevers, after 2 repeated exposures to nitrofurantoin after a urological procedure. The patient had an initial infectious workup which was negative. A suspected adverse reaction to nitrofurantoin was suspected and the patient was found to have complete resolution of symptoms with discontinuation of the drug and with supportive treatment. CONCLUSIONS This case demonstrates that although nitrofurantoin is known to be relatively well tolerated, clinicians should still be aware of the adverse reactions, including a potential systemic inflammatory response, from nitrofurantoin use. This information should be used to educate patients going forward on potential adverse effects to be aware of.

Awareness of long-term nitrofurantoin adverse effects.

Overview of: Speirs TP, Tuffin N, Mundy-Baird F, et al Long-term nitrofurantoin: an analysis of complication awareness, monitoring, and pulmonary injury cases. BJGP Open 2021;5:BJGPO.2021.0083.

Nitrofurantoin 100 mg versus 50 mg prophylaxis for urinary tract infections, a cohort study.

OBJECTIVES: Guidelines do not distinguish between 50 mg or 100 mg nitrofurantoin as daily prophylaxis for recurrent urinary tract infection (UTI), although 50 mg might have a better safety profile. Our objective was to compare the effectiveness and safety of both regimens. METHODS: Data were retrospectively collected from 84 Dutch GP practices between 2013 and 2020. Nitrofurantoin prescriptions of 100 mg and 50 mg every 24 hours in women were included. Cox proportional hazard regression analysis was used to calculate hazard ratios on first episode of UTI, pyelonephritis and (adverse) events. Patients were followed for the duration of consecutive repeated prescriptions, assuming non-informative right censoring, up to 1 year. RESULTS: Nitrofurantoin prophylaxis was prescribed in 1893 patients. Median lengths of follow up were 90 days (interquartile range (IQR) 37-179 days) for 100 mg (n = 551) and 90 days (IQR 30-146 days) for 50 mg (n = 1342) with few differences in baseline characteristics between populations. Under 100 mg and 50 mg, 82/551 (14.9%) and 199/1342 (14.8%) developed UTI and 46/551 (8.3%) and 81/1342 (6.0%) developed pyelonephritis, respectively. Adjusted HRs of 100 mg versus 50 mg were 1.01 (95% CI 0.78-1.30) on first UTI, 1.37 (95% CI 0.95-1.98) on first pyelonephritis episode, 1.82 (95% CI 1.20-2.74) on first consultation for cough, 2.68 for dyspnoea (95% CI 1.11-6.45) and 2.43 for nausea (95% CI 1.03-5.74). CONCLUSION: Daily prophylaxis for recurrent UTI with 100 mg instead of 50 mg nitrofurantoin was associated with an equivalent hazard on UTI or pyelonephritis, and a higher hazard on cough, dyspnoea and nausea. We recommend 50 mg nitrofurantoin as daily prophylaxis.