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.

Sensibilidad a nitrofurantoína en el uropatógeno intrahospitalario E. Coli procedente de pacientes gerontes hospitalizados / Snsitivity to nitrofurantoin of urocultures from hospitalized gerontes with E. Coli from urinary tract infections

En la presente investigación se determinó la sensibilidad a nitrofurantoína (NTF) mediante un análisis observacional retrospectivo de informes de antibiogramas, por disco de difusión, de urocultivos provenientes de gerontes hospitalizados. En la serie observada (N=90) el desarrollo más frecuente fue E. Coli que presentó una sensibilidad a NTF de 100%. Al considerar la sensibilidad total (es decir de todos las bacterias uropatógenas Gram negativas, (BGN) la resistencia para NTF fue de 26%. Se debate además sus limitaciones médicas y algunos de los potenciales usos de NTF en pacientes hospitalizados

In the present investigation, sensitivity to nitrofurantoin (NTF) was determined through a retrospective observations analysis of reports of antibiograms, by diffusion disc, of urocultures from hospitalized gerontes. In the series observed (N=90), the most frequent development was E. coli, which showed a sensitivity to NTF of 100%. When considering the total sensitivity (ie of all Gram-negative uropathogenic bacteria, BGN) the resistance for NTF was 26%. It also discusses its medical limitations and some of the potential uses of NTF in hospitalized patients

Impact of Allergy and Resistance on Antibiotic Selection for Recurrent Urinary Tract Infections in Older Women.

OBJECTIVES: To review the impact of antibiotic allergy and resistance in older women with recurrent urinary tract infections (RUTIs) as determinants for a suitable oral antibiotic treatment choice. METHODS: A prospectively maintained database of women 65 years old and older with documented RUTIs (≥3 UTI/y) and trigonitis on cystoscopy was reviewed. Demographic data, known drug allergies, renal function, antibiotic susceptibility of most recent urine culture, allergy, or resistance to trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, and nitrofurantoin were obtained. RESULTS: From 2006 to 2014, 86 women with RUTIs met study criteria. Mean age was 77.9 ± 7.8, with 94% being Caucasian. An estimated glomerular filtration rate >30 mL/min was noted in 94%. The percentage of women allergic, resistant, or both allergic and resistant to TMP-SMX was 33%, 29%, and 15%, to fluoroquinolones was 14%, 34%, and 8.1%, or nitrofurantoin was 16%, 14%, and 5%, respectively. Twenty-eight percent (24 of 86) of women who were allergic and/or resistant to TMP-SMX and fluoroquinolones were sensitive to nitrofurantoin. Twenty percent (17 of 86) were allergic and/or resistant to all 3 antibiotics. Women who were allergic or resistant to TMP-SMX had a significantly higher number of other antibiotic resistances compared with women sensitive to TMP-SMX (4.9 ± 3.6 vs 2.1 ± 2.3; P < .0001). Similarly, women with fluoroquinolone allergy or resistance had significantly more antibiotic resistances than those who were fluoroquinolone sensitive (5.8 ± 3.5 vs 2.3 ± 2.5; P < .0001). CONCLUSION: Because of allergy and/or antibiotic resistance, several first-line antibiotics are not available for many older women with RUTIs. In nearly a third of women, nitrofurantoin was the only viable alternative.

Herbal extracts differentially inhibit oxidative effects caused by the biotransformation of nifurtimox, nitrofurantoin and acetaminophen on rat liver microsomes / Extractos herbales inhiben diferencialmente los efectos oxidativos causados por la biotransformación de nifurtimox, nitrofurantoína y acetaminofeno en microsomas hepáticos de rata]

Inflammation is a cellular defensive mechanism associated to oxidative stress. The administration of nitrofurantoin, nifurtimox and acetaminophen generates oxidative stress by their biotransformation through CYP450 system. The main adverse effect described for the first two drugs is gastrointestinal inflammation and that of the last, hepatitis. Therefore, standardised dry extracts from Rosmarinus officinalis, Buddleja globosa Hope, Cynara scolymus L., Echinacea purpurea and Hedera helix were tested to evaluate their capacity to decrease drug-induced oxidative stress. For that, rat liver microsomes were incubated with drugs in the presence of NADPH (specific CYP450 system cofactor) to test oxidative damage on microsomal lipids, thiols, and GST activity. All drugs tested induced oxidation of microsomal lipids and thiols, and inhibition of GST activity. Herbal extracts prevented these phenomena in different extension. These results show that antioxidant phytodrugs previously evaluated could alleviate drugs adverse effects associated to oxidative stress.

Inflamación es un mecanismo de defensa el cual está asociado a estrés oxidativo. La administración de nitrofurantoína, nifurtimox y paracetamol genera estrés oxidativo al metabolizarse a través del sistema CYP450. El principal efecto adverso de los dos primeros fármacos es inflamación gastrointestinal y del tercero, hepatitis. Por lo tanto, utilizamos diversos extractos herbales para disminuir el estrés oxidativo inducido por estos fármacos. Para esto se incubaron microsomas hepáticos de rata con dichos fármacos en presencia de NADPH (cofactor específico del sistema CYP450) y se evaluó el daño oxidativo generado sobre los lípidos, los tioles y la actividad GST microsómica. Todos los fármacos indujeron oxidación de los lípidos y los tioles microsómicos e inhibieron la actividad GST. Los extractos herbales previnieron estos fenómenos oxidativos en diferente extensión. Estos resultados indican que fitofármacos antioxidantes previamente evaluados, podrían aliviar los efectos adversos asociados a estrés oxidativo de los fármacos.

Evaluation of the Risk of Nitrofurantoin Lung Injury and Its Efficacy in Diminished Kidney Function in Older Adults in a Large Integrated Healthcare System: A Matched Cohort Study.

OBJECTIVES: To determine the risk to older adults of lung injury associated with treatment of cystitis using nitrofurantoin and the risk of treatment failure in the presence of diminished creatinine clearance (CrCl). DESIGN: Retrospective, matched cohort. SETTING: Integrated healthcare system. PARTICIPANTS: Individuals aged 65 and older with a diagnosis of cystitis between 2007 and 2012 who were given nitrofurantoin (N = 13,421) were matched 1:3 on age, sex, race and ethnicity, and prescription date with individuals who were given other antibiotics for cystitis. MEASUREMENTS: Conditional logistic regression determined the association between nitrofurantoin and lung injury in the matched cohort. In participants exposed to nitrofurantoin, chronic treatment was compared with acute treatment using multivariable logistic regression. Treatment failure was compared in three CrCl groups. RESULTS: Nitrofurantoin exposure was not statistically significantly associated with lung injury (adjusted risk ratio (aRR) = 0.90, 95% confidence interval (CI) = 0.80-1.00), but chronic nitrofurantoin therapy was associated with greater risk of lung injury than acute exposure (aRR = 1.53, 95% CI = 1.04, 2.24). Treatment failure rates did not differ according to CrCl. CONCLUSION: This large, retrospective, matched-cohort study conducted in older adults supports the 2012 American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommendations against the use nitrofurantoin for long-term suppressive treatment of cystitis but not the recommendation against its use in poor renal function because of the risk of treatment failure.

Mitigación de efectos adversos de nitrofurantoína administrada por vía oral utilizando un extracto seco estandarizado de Buddleja globosa Hope (matico) / Mitigation of adverse effects of nitrofurantoin administered orally using a standardized dry extract of Buddleja globosa Hope (matico)

La nitrofurantoína es un antibiótico derivado del nitrofurano utilizado como fármaco de primera elección para el tratamiento de infecciones del tracto urinario. Sin embargo, este fármaco produce serios efectos adversos principalmente de origen gastrointestinal. Se postula que las reacciones adversas se deberían al estrés oxidativo provocado por la nitroreducción de la nitrofurantoína que genera especies reactivas del oxígeno. Por lo tanto, BG126®, preparado herbal a base de hojas de Buddleja globosa Hope, podría mitigar los efectos adversos de nitrofurantoína; este fitofármaco se ha caracterizado por su alta actividad antioxidante (datos aún no publicados). Los resultados de este estudio clínico doble ciego y randomizado, mostraron que el tratamiento asociado de nitrofurantoína (200mg/día) y BG126® (2 cápsulas/día), efectivamente disminuyó los efectos adversos gastrointestinales de pacientes mujeres con infección bacteriana del tracto urinario (ITU). Entre estas reacciones adversas se cuantificó nausea, dolor abdominal y diarrea. Más aún, este tratamiento conjunto potenció la actividad antibacteriana de la nitrofurantoína; al final del tratamiento, todos los pacientes que recibieron nitrofurantoína y BG126® presentaron urocultivos negativos, mientras que el 19% de los pacientes que recibieron sólo nitrofurantoína mostraron urocultivos positivos, lo cual indica la presencia de cepas bacterianas resistentes a nitrofurantoína. Cabe destacar que a capacidad antioxidante plasmática de ambos grupos de pacientes no fue significativamente diferente. Así, no se observaron diferencias significativas en la capacidad reductora de hierro, ni en los niveles de MDA de ambos grupos de pacientes, el que recibió sólo nitrofurantoína y aquel que recibió en forma conjunta nitrofurantoína y BG126®. Estos resultados parecen indicar que la absorción de BG126® es baja y por tanto, el efecto observado es mayoritario a nivel de la pared gastrointestinal. El aumento de la resistencia a antibióticos de las diferentes cepas bacterianas que infectan al hombre, es un problema de salud pública a nivel mundial. Si sumamos a lo anterior, las reacciones adversas de los fármacos antibacterianos, como son los derivados de nitrofuranos, las estrategias terapéuticas contra las diversas infecciones bacterianas se ven muy limitadas. Interesantemente, BG126® no sólo disminuyó la severidad de las reacciones adversas provocadas por la nitrofurantoína, sino que al parecer potenció su efecto antibacteriano. Nuevos experimentos están en proceso con el objeto de dilucidar los mecanismos que permitan explicar el comportamiento antibacteriano de nitrofurantoína comparada con la mezcla nitrofurantoína-BG126®

Efecto de un extracto seco de matico (BG126) sobre el daño oxidativo inducido por biorreducción de nitrofurantoína / Effect of a dry matico extract (BG126) on oxidative damage induced by nitrofurantoin biorreduction

La nitrofurantoína es el antimicrobiano de elección para el tratamiento de infecciones del tracto urinario bajo en Chile, debido a su alta eficacia y bajo desarrollo de resistencia. Sin embargo, el tratamiento oral con este fármaco provoca efectos adversos, principalmente gastrointestinales, los que conllevan al abandono del tratamiento por un porcentaje significativo de los pacientes. Este fármaco es nitrorreducido en una reacción catalizada por reductasas, generando especies reactivas del oxígeno, lo que conduce a estrés oxidativo. Por lo tanto, se postula que los efectos adversos gastrointestinales provocados por nitrofurantoína, podrían ser la consecuencia de este estrés oxidativo. Asimismo, se postula que la coadministración de nitrofurantoína y el preparado herbal BG126, extracto seco estandarizado de hojas de Buddleja globosa Hope (matico), podría minimizar los efectos adversos producidos por nitrofurantoína. Los resultados obtenidos indican que la administración oral de nitrofurantoína en ratas machos Sprague Dawley, produce daño gastrointestinal observado macroscópicamente y a través de cambios de los parámetros del perfil bioquímico y el hemograma. Estos parámetros fueron normalizados a los valores control por la coadministración de nitrofurantoína y BG126. Más aún, esta combinación también normalizó las alteraciones de la capacidad antioxidante plasmática (FRAP) producidas por el tratamiento oral con nitrofurantoína. Además, BG126 inhibió la lipoperoxidación y la oxidación de los tioles microsómicos hepáticos de estas ratas, producidas por nitrofurantoína en condiciones de nitrorredución. Los resultados obtenidos demuestran que los efectos adversos producidos por la administración oral de nitrofurantoína se deben, al menos en parte, a la generación de estrés oxidativo a través de su nitrorredución. Dado que BG126 es un extracto de matico, planta de reconocida actividad antioxidante, la coadministración con nitrofurantoína podría ser una buena estrategia para disminuir los efectos adversos producidos por este fármaco y evitar así, el abandono de la terapia.

Women's quality of life is decreased by acute cystitis and antibiotic adverse effects associated with treatment.

BACKGROUND: Although acute cystitis is a common infection in women, the impact of this infection and its treatment on women's quality of life (QOL) has not been previously described. OBJECTIVES: To evaluate QOL in women treated for acute cystitis, and describe the relationship between QOL, clinical outcome and adverse events of each of the interventions used in the study. DESIGN: Randomized, open-label, multicenter, treatment study. SETTING: Two family medicine outpatient clinics in Iowa. PATIENTS: One-hundred-fifty-seven women with clinical signs and symptoms of acute uncomplicated cystitis. INTERVENTION: Fifty-two patients received trimethoprim/sulfamethoxazole 1 double-strength tablet twice daily for 3 days, 54 patients received ciprofloxacin 250 mg twice daily for 3 days and 51 patients received nitrofurantoin 100 mg twice daily for 7 days. MEASUREMENTS: QOL was assessed at the time of enrollment and at 3, 7, 14 and 28 days after the initial visit. QOL was measured using a modified Quality of Well-Being scale, a validated, multi-attribute health scale. Clinical outcome was assessed by telephone interview on days 3, 7, 14 and 28 using a standardized questionnaire to assess resolution of symptoms, compliance with the prescribed regimen, and occurrence of adverse events. RESULTS: Patients experiencing a clinical cure had significantly better QOL at days 3 (p = 0.03), 7 (p < 0.001), and 14 (p = 0.02) compared to patients who failed treatment. While there was no difference in QOL by treatment assignment, patients experiencing an adverse event had lower QOL throughout the study period. Patients treated with ciprofloxacin appeared to experience adverse events at a higher rate (62%) compared to those treated with TMP/SMX (45%) and nitrofurantoin (49%), however the difference was not statistically significant (p = 0.2). CONCLUSION: Patients experiencing cystitis have an increase in their QOL with treatment. Those experiencing clinical cure have greater improvement in QOL compared to patients fail therapy. While QOL is improved by treatment, those reporting adverse events have lower overall QOL compared to those who do not experience adverse events. This study is important in that it suggests that both cystitis and antibiotic treatment can affect QOL in a measurable way.

Foetal rat lung epithelial (FRLE) cells: partial characterisation and response to pneumotoxins.

Cultured cell lines are routinely used for in vitro toxicity screens, reducing the requirement for animal studies during the development of new pharmaceutical, agrochemical and cosmetic products. The foetal rat lung epithelial (FRLE) cell line was originally derived from alveolar type II cells (ATII) of the lung. The aims of this study were to further characterise FRLE cells and investigate their potential for screening for pneumotoxins. The cells were found to have retained some of the features of their progenitor cells, namely the expression of cytokeratin proteins, specifically cytokeratin 18, and the ability to actively accumulate the non-selective contact herbicide paraquat. However, the cells have lost the ability to synthesise surfactant protein mRNA and no longer contain multiple lamellar bodies. Toxins that damage ATII cells in vivo (cadmium chloride, cobalt chloride and paraquat) were found to induce cytotoxicity in FRLE cells, as did the non-specific pneumotoxin nitrofurantoin, and hydrogen peroxide. However, the cells were less sensitive to the effects of compounds that require metabolic activation (1-nitronaphthalene, coumarin and butylated hydroxytoluene) and the hepatotoxin bromobenzene. Thus, FRLE cells appear to be a good in vitro model for monitoring the potential toxicity to ATII cells and could be used as an initial screen for pneumotoxicity.

A trial comparing low-dose, short-course ciprofloxacin and standard 7 day therapy with co-trimoxazole or nitrofurantoin in the treatment of uncomplicated urinary tract infection.

The study was undertaken to compare the safety and efficacy of twice-daily ciprofloxacin for 3 days with standard 7 day therapy with either co-trimoxazole or nitrofurantoin in the treatment of women with acute, uncomplicated urinary tract infections (UTI). This multicentre, prospective, randomized, double-blind trial compared oral ciprofloxacin (100 mg bd) for 3 days with co-trimoxazole (160/800 mg bd) or nitrofurantoin (100 mg bd) for 7 days. Bacteriological and clinical evaluations were performed at study entry, during therapy and 4-10 days and 4-6 weeks after the completion of therapy. The primary efficacy parameter was eradication of the causative organism 4-10 days following treatment. Of 713 women enrolled and evaluable for safety, 521 were evaluable for efficacy (168 ciprofloxacin, 174 co-trimoxazole, 179 nitrofurantoin). Escherichia coli (83%) was the most frequently isolated pathogen in all treatment groups. Bacteriological eradication was reported in 88% of ciprofloxacin patients, 93% of co-trimoxazole patients and 86% of nitrofurantoin patients. At the 4-6 week follow-up, ciprofloxacin had statistically significantly higher eradication rates (91%) than co-trimoxazole (79%; 95% confidence limit (CL) = -20.6%, -3.9%) and nitrofurantoin (82%; 95% CL = -17.1%, -0.9%). Clinical resolution 4-10 days after therapy and at the 4-6 week follow-up was similar among the three treatment groups. The overall incidence of treatment-emergent adverse events was not significantly different (P = 0.093) among the three drug regimens, although co-trimoxazole was associated with a greater number of adverse events than ciprofloxacin (P < or = 0.05). Ciprofloxacin also caused fewer episodes of nausea than either of the other agents (P < or = 0.01).

Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice.

A total of 538 patients from 45 different general practice centres across the UK was admitted to an open study and randomized to one of the following treatment groups: nitrofurantoin modified release (MR) 100 mg bd, trimethoprim 200 mg bd or co-trimoxazole 960 mg bd. Each patient received seven days of medication. Clinical cure, defined as relief from symptoms at visit 2, occurred in 87.2% of the patients treated with nitrofurantoin MR, 84.5% of the co-trimoxazole group and 86.5% of the trimethoprim group. The bacteriological cure rate for nitrofurantoin MR was comparable to co-trimoxazole at 82.3% and 83.2%, respectively, with trimethoprim the lowest at 76.8%. Whilst the cure rate for Escherichia coli infection was similar, 81.5% cured with nitrofurantoin MR, 82.5% with co-trimoxazole and 78.4% by trimethoprim, for non-E. coli pathogens nitrofurantoin MR was equivalent to co-trimoxazole with 86.7% cure but higher than trimethoprim at 72.0%. In-vitro sensitivity to all pathogens isolated at baseline was very high for nitrofurantoin at 96.1%, significantly higher than either co-trimoxazole or trimethoprim at 87.5% (P < 0.01). The test drugs were equally well tolerated with 28 patients (15.7%) reporting adverse events with nitrofurantoin MR, 28 (15.5%) with co-trimoxazole and 28 (15.6%) with trimethoprim. However, nitrofurantoin MR showed fewer patients with drug-related adverse events (5.6%) as judged by the investigator, compared to co-trimoxazole (8.8%) or trimethoprim (7.3%). (ABSTRACT TRUNCATED AT 250 WORDS)

Clinical experience with ofloxacin in upper and lower urinary tract infections. A comparison with co-trimoxazole and nitrofurantoin.

The efficacy and tolerance of ofloxacin were compared with those of co-trimoxazole in upper urinary tract infections (UTIs) and nitrofurantoin in lower UTIs in a prospective, controlled, randomised, observer-blind study. Ofloxacin proved to be an effective and well-tolerated substance. The clinical cure rate was more pronounced than that of both comparative drugs and ofloxacin was also superior to co-trimoxazole and nitrofurantoin in terms of bacterial elimination. A second, controlled study showed that single doses of ofloxacin 100mg were clinically and bacteriologically as effective as a 3-day course of ofloxacin 100mg twice daily in women with uncomplicated lower UTIs.

[Drug-induced changes in the lungs]. / Medikamentös bedingte Lungenveränderungen.

The author reviews changes in the lung induced by pharmacotherapy. Attention is drawn to the differences in mode of reaction of the individual drug noxae. Roentgenological changes are demonstrated by means of x-ray film examples and the various roentgenological signs are pointed out. In accordance with the classification by v. Wichert, the drugs are tabulated according to the pathogenetic mechanisms triggered by them at the lung parenchyma, the tabulation being arranged in groups. Wrong interpretations of the changes in the lung can be avoided by means of intensive co-operation between the clinician and the radiologist and by including the possibility of lung damage caused by drugs in the diagnostic deliberations.

Excretion studies of nitrofurantoin and nitrofurantoin with deglycyrrhizinated liquorice.

Nitrofurantoin and nitrofurantoin with liquorice were given to healthy volunteers and patients suffering from urinary tract infections. The excretion rates of the drug, colony counts and side effects were studied in patients and excretion rates in the volunteers. The excretion rates of the drug were significantly higher in patients receiving the drug with liquorice and also side effects were minimal. There was no significant difference in the excretion rates of the drug with addition of liquorice in healthy volunteers.

Drug therapy reviews: nitrofurantoin.

Mechanism of action, antimicrobial spectrum, pharmacology, adverse reactions and therapeutic uses of nitrofurantoin, a broad-spectrum antimicrobial agent, are discussed. The frequency and potential severity of reactions attributed to nitrofurantoin, plus its inability to achieve therapeutic blood concentrations, relegate this drug to a position of secondary importance. Nitrofurantoin compares favorably with other standard agents for the therapy of acute and recurrent urinary tract infections in women which may be caused by susceptible organisms, and it is an effective chemoprophylactic agent for patients with recurrent urinary tract infections. The compound has no apparent adverse effects on the developing fetus and can be used in pregnant women. This is not sanctioned by the package insert, however. Nitrofurantoin should not be administered when the possibility of bacteremia exists, as the drug does not achieve therapeutic serum levels when administered orally. Nitrofurantoin is contraindicated for patients with renal insufficiency. The value of this compound for men with acute urinary tract infection, recurrent urinary tract infection, acute bacterial prostatitis or chronic bacterial prostatitis has not been established. There are no indications for prescribing parenteral nitrofurantoin.