Nitrofurantoin as an Add-On to Conventional Prophylaxis for the Treatment of Urinary Tract Infections in Kidney Recipients: A Prospective Cohort Study.

Urinary tract infections (UTIs) constitute one of the main complications in kidney recipients, increasing both morbidity and mortality. Due to the resurgence of antimicrobial resistance, new prophylactic approaches are being investigated. Nitrofurantoin is an antibiotic from the nitrofuran group that is effective against several Gram-negative and Gram-positive organisms; hence, there has been a resurgence in its prescription for treating MDR pathogens. Objectives: This study aims to assess the effectiveness of nitrofurantoin as an add-on to conventional therapy (amikacin + ceftriaxone or cefotaxime) for the treatment of urinary tract infections in kidney recipients. Methods: In a prospective cohort study, we included patients who received a kidney in a tertiary-care hospital. According to the intensive care specialist, group 1 patients were treated with the conventional prophylactic treatment plus nitrofurantoin as an add-on. Group 2 patients were treated only with the conventional prophylactic treatment. They were followed-up for 3 months, and the incidence of urinary tract infections was reported. Results: The UTI incidence for group 1 at 3 months was 20.6%, and for group 2, it was 20.0%; no statistical difference between treatments was observed (p = 0.9). The most commonly isolated pathogens were E. coli (28.5) and K. pneumonie (28.5%). The factor most associated with developing a UTI was female gender (aHR: 7.0; 95% IC 2.3-20.9, p < 0.001). Conclusions: In our cohort study, nitrofurantoin as an add-on in conventional therapy did not prove to be effective in preventing UTI development; therefore, other treatment options should be considered as a part of prophylactic treatment.

Ascorbate and Antibiotics, at Concentrations Attainable in Urine, Can Inhibit the Growth of Resistant Strains of Escherichia coli Cultured in Synthetic Human Urine.

There are conflicting reports on the antibacterial activity of ascorbate; all at concentrations much higher than the typical in human plasma, but that can be reached in urine. The effect of 10 mM ascorbate (in itself not inhibitory) along with antibiotics, was tested both in Mueller-Hinton broth (MHb) and in synthetic human urine (SHU), against resistant isolates of Escherichia coli from lower urinary infections. The activity of nitrofurantoin and sulfamethoxazole was higher in SHU than in MHb; minimal inhibitory concentrations (MICs) in SHU with ascorbate were below typical urinary concentrations. For other antibiotics, MICs were the same in MHb vs. SHU, with no effect of ascorbate in MHb; but in SHU with ascorbate, MICs of ciprofloxacin and gentamicin also went below reported urinary concentrations, with a lesser effect with norfloxacin and trimethoprim, and none with ampicillin. The effect of ascorbate was independent of oxygen and not related to the susceptibility of each strain to oxidative stress. Ascorbate oxidizes during incubation in SHU, and bacterial growth partially prevented oxidation. These results suggest that 10 mM ascorbate can enhance the inhibitory activity of antibiotics upon resistant strains in urine. Clinical experimentation with ascorbate-antibiotic combinations against urinary infections caused by resistant bacteria is warranted.

Mecanismos de resistencia a la colistina, la nitrofurantoína y la fosfomicina en Enterobacterales / Mechanisms of resistance to colistin, nitrofurantoin and fosfomycin in Enterobacteriaceae

Resumen Las enterobacterias son un grupo amplio y heterogéneo de bacilos Gram negativos que se aíslan de forma rutinaria en el laboratorio clínico y se asocian a una gran cantidad de cuadros clínicos. Aquellas resistentes a antibióticos de última línea, como a los carbapenémicos, representan un gran reto en los centros de salud. Ante la dificultad para tratar infecciones causadas por este tipo de bacterias, se ha retomado el uso de antimicrobianos clásicos como la colistina, la nitrofurantoína y la fosfomicina. El objetivo de este trabajo es detallar los principales mecanismos de resistencia para estos tres fármacos descritos en enterobacterias. Para ello, se efectuó una revisión bibliográfica de artículos científicos publicados entre los años 1999 y 2022, utilizando las bases de datos PubMed (NCBI), PLOS, Redalyc, Google Scholar y Science Direct. En este proceso, se usaron las palabras clave "Carbapenem-Resistant Enterobacteriaceae", "colistin", nitrofurantoin", "fosfomycin", "resistance" y "plasmids". Se encontró que los mecanismos de resistencia son variados y abarcan fenómenos como modificación del sitio blanco, inactivación enzimática, impermeabilidad y eflujo. Además, los determinantes genéticos de resistencia se encuentran en cromosomas o en plásmidos. Conocer este tipo de información permite mejorar la vigilancia basada en el laboratorio, combatir el problema de resistencia a los antimicrobianos y optimizar el uso de estos antibióticos que forman parte del escaso arsenal para el tratamiento de ciertas infecciones causadas por microorganismos multidrogorresistentes.

Abstract Enterobacteriaceae is a large and heterogeneous group of Gram-negative bacilli that are routinely isolated in the clinical laboratory and are associated with a large number of clinical conditions. Those resistant to last-line antibiotics, such as carbapenems, represent a great challenge in health-care centers. Given the difficulty in treating this type of infections, the use of old drugs such as colistin, nitrofurantoin and fosfomycin has been studied. The objective of this work is to detail the main resistance mechanisms described in Enterobacteriaceae for these three antibiotics. To do this, a survey of scientific articles from the years 1999 to 2022 was carried out using databases such as PubMed (NCBI), Google Scholar, PLOS, Redalyc and Science Direct. In this process, keywords "Carbapenem- Resistant Enterobacteriaceae", "colistin", nitrofurantoin", "fosfomycin", "resistance" and "plasmids" were used. Resistance mechanisms were found to be varied and involve phenomena such as target site modification, enzyme inactivation, impermeability, and efflux. In addition, the genetic determinants of resistance are found at the chromosomal level or in plasmids. Knowing this type of information makes it possible to improve laboratory-based surveillance, fight the problem of resistance to antibiotics and take care of these antibiotics, which are part of the scarce arsenal for the treatment of certain infections caused by multidrug-resistant microorganisms.

Prevalence Estimation, Antimicrobial Susceptibility, and Serotyping of Salmonella enterica Recovered from New World Non-Human Primates (Platyrrhini), Feed, and Environmental Surfaces from Wildlife Centers in Costa Rica.

Concern about zoonoses and wildlife has increased. Few studies described the role of wild mammals and environments in the epidemiology of Salmonella. Antimicrobial resistance is a growing problem associated with Salmonella that threatens global health, food security, the economy, and development in the 21st century. The aim of this study is to estimate the prevalence and identify antibiotic susceptibility profiles and serotypes of non-typhoidal Salmonella enterica recovered from non-human primate feces, feed offered, and surfaces in wildlife centers in Costa Rica. A total of 180 fecal samples, 133 environmental, and 43 feed samples from 10 wildlife centers were evaluated. We recovered Salmonella from 13.9% of feces samples, 11.3% of environmental, and 2.3% of feed samples. Non-susceptibility profiles included six isolates from feces (14.6%): four non-susceptible isolates (9.8%) to ciprofloxacin, one (2.4%) to nitrofurantoin, and one to both ciprofloxacin and nitrofurantoin (2.4%). Regarding the environmental samples, one profile was non-susceptible to ciprofloxacin (2.4%) and two to nitrofurantoin (4.8%). The serotypes identified included Typhimurium/I4,[5],12:i:-, S. Braenderup/Ohio, S. Newport, S. Anatum/Saintpaul, and S. Westhampton. The epidemiological surveillance of Salmonella and antimicrobial resistance can serve in the creation of strategies for the prevention of the disease and its dissemination throughout the One Health approach.

Nitrofurantoin removal by the photo-Fenton process: degradation, mineralization, and biological inactivation.

Antibiotics may induce super-resistant bacteria if they are available in the environment. Therefore, the removal of aqueous nitrofurantoin (NFT), and more importantly, the removal of the remaining antimicrobial activity after treatment, by the photo-Fenton process, was herein studied. Degradation experiments were performed according to an experimental design (0.5% error; factors: concentrations of NFT, Fe3+, and H2O2). Degradation conditions were: 20 mg NFT L-1, 10 mg Fe3+ L-1, and 170 mg H2O2 L-1. Fixed parameters were: 100 mL of the NFT solution, pH 2.5, 15-min stirring, and 25.0 ± 0.5°C. The initial rate constant (k0) and the maximum oxidation capacity (MOC) of the system were 0.61 min-1 and 100%, respectively (R2 = 0.986). 97% of the NFT and 93% of the organic carbon initially present were removed. Five degradation products (DPs) were detected by HPLC-MS and their endpoints estimated by the ECOSAR (ECOlogical Structure-Activity Relationships) 2.0 software. NFT and its DPs presented no toxicity towards Lactuca sativa. The antimicrobial activity (Escherichia coli) of NFT and/or DPs was completely removed in 15 min. Structures were proposed for the detected DPs. In short, the tested advanced oxidation technology (AOP), besides being capable of removing and mineralizing aqueous NFT in a short time, 15 min, also rendered the treated water biologically inactive (no ecotoxicity, no antimicrobial activity).

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.

Bacteriuria asintomática en el embarazo. Serie de casos en una clínica privada de Uruapan, Michoacán / Asymptomatic bacteriuria in pregnancy. Cases series in a private clinic in Uruapan Michoacán

Resumen OBJETIVO: Determinar la prevalencia de bacteriuria asintomática, su adecuado tratamiento con base en el reporte del antibiograma de pacientes embarazadas que acudieron a control prenatal en una clínica privada. MATERIALES Y MÉTODOS: Estudio retrospectivo de una serie de casos, descriptivo y transversal efectuado en mujeres embarazadas que acudieron a control prenatal en la consulta externa del Hospital Fray Juan de San Miguel de Uruapan, Michoacán, entre el 1 de enero de 2019 y el 31 de diciembre de 2021. Variables de estudio: edad de las madres, semanas de embarazo, embarazos, bacteriuria, agente causal, antibiótico indicado y respuesta al tratamiento. Para interpretar los resultados obtenidos se aplicaron estadística descriptiva, medidas de tendencia central y de frecuencias simples. RESULTADOS: Se estudiaron 227 embarazadas; de ellas, 49 tuvieron un urocultivo positivo. La prevalencia de bacteriuria asintomática fue de 21.59. Escherichia coli fue el agente causal más reportado. De los urocultivos de control 36 de 37 resultaron negativos y solo 1 de 37 fue positivo. CONCLUSIÓN: La prevalencia de bacteriuria asintomática de este estudio fue de 21.59% y el principal agente etiológico asilado E. coli en la mayoría de los casos, con sensibilidad a nitrofurantoína en la mayoría de los casos.

Abstract OBJECTIVE: To determine the prevalence of asymptomatic bacteriuria, its adequate treatment based on the antibiogram report of pregnant patients who attended prenatal control in a private clinic. MATERIALS AND METHODS: Retrospective study of a case series, descriptive and cross-sectional carried out in pregnant women who attended prenatal control in the outpatient clinic of the Hospital Fray Juan de San Miguel de Uruapan, Michoacán, between January 1, 2019 and December 31, 2021. Study variables: mothers' age, weeks of pregnancy, pregnancies, bacteriuria, causative agent, indicated antibiotic and response to treatment. Descriptive statistics, measures of central tendency and simple frequencies were used to interpret the results obtained. RESULTS: A total of 227 pregnant women were studied; 49 of them had a positive urine culture. The prevalence of asymptomatic bacteriuria was 21.59. Escherichia coli was the most reported causative agent. Of the control urine cultures 36 of 37 were negative and only 1 of 37 was positive. CONCLUSION: The prevalence of asymptomatic bacteriuria in this study was 21.59% and the main etiologic agent was E. coli in most cases, with sensitivity to nitrofurantoin in most cases.

Hipertensión intracraneal idiopática asociada a nitrofurantoína. Caso clínico / Idiopathic intracranial hypertension associated with nitrofurantoin. Case report

Resumen Introducción: La Hipertensión Intracraneal Idiopática (HICI) es un síndrome neurológico caracterizado por un aumento de la presión intracraneal en ausencia de lesión estructural o hidrocefalia. Los síntomas incluyen cefalea, tinnitus pulsátil, oscurecimientos visuales transitorios y pérdida visual. Dentro de los signos destacan diplopía por parálisis del VI par, edema de papila y disminución de la agudeza visual. Los pacientes no tienen compromiso de conciencia ni signos neurológicos focales. La principal complicación es la pérdida visual que puede ser irreversible. La asociación entre HICI y nitrofurantoína (NTF) se reportó en 1974. Caso clínico: Mujer de 42 años, con sobrepeso, que desarrolló una HICI aproximadamente 18 meses posterior al inicio de nitrofurantoína profiláctica. Consultó por cefalea frontal, opresiva que aumentaba con la maniobra de Valsalva, asociada a disminución fluctuante de la agudeza visual y episodios de oscurecimiento. Al examen destacó edema de papila bilateral, sin déficit neurológico focal. La presión del líquido cefalorraquídeo (LCR) fue de 25,5 cm de agua. La resonancia magnética mostró signos de aumento de la presión del LCR, sin lesiones estructurales ni hidrocefalia. El cuadro se recuperó concomitantemente a la suspensión de la NTF y el uso de topiramato. No se constató daño visual permanente. Conclusiones: Se debe sospechar la HICI en mujeres en edad fértil con sobrepeso. Dentro de los gatillantes del síndrome destacan varios fármacos, entre ellos la NTF. El principal objetivo del tratamiento de la HICI es preservar la función visual.

Abstract Introduction: Idiopathic intracranial hypertension (IIH) is a syndrome characterized by increased intracranial pressure without a space occupying lesion or hydrocephalus. The symptoms are headache, pulsatile tinnitus, transient visual obscurations, and visual loss. Signs are diplopia caused by sixth cranial nerve paresis and papilledema with its associated loss of sensory visual function. The patient maintains an alert and oriented mental state, but has no localizing neurologic findings. The only major morbidity with IIH is visual loss. The association between IIH and nitrofurantoin was reported in 1974. Case: A 42 years old female, overweighed, who developed IIH 18 months after the start of prophylactic nitrofurantoin. She had frontal oppressive headache that increased with the Valsalva maneuver, fluctuant visual loss and transient visual obscurations. She had bilateral papilledema without localizing neurologic findings. The cerebrospinal fluid (CSF) pressure was 25.5 cm H2O. Magnetic resonance imaging showed signs of increased CSF pressure without structural lesions or hydrocephalus. IIH recovered with the withdrawal of nitrofurantoin and the use of topiramate. There was not permanent visual loss. Conclusions: It is recommendable to suspect IIH in obese women in the childbearing years. There are several drugs associated with IIH including nitrofurantoin. The main objective of treatment is to prevent visual loss.

Exposure to sub-inhibitory ciprofloxacin and nitrofurantoin concentrations increases recA gene expression in uropathogenic Escherichia coli: The role of RecA protein as a drug target.

Sub-inhibitory concentrations (sub-MIC) of antimicrobial agents can lead to genetic changes in bacteria, modulating the expression of genes related to bacterial stress and leading to drug resistance. Herein we describe the impact of sub-MIC of ciprofloxacin and nitrofurantoin on three uropathogenic Escherichia coli strains. Disk-diffusion assays with different antimicrobial agents were tested to detect phenotype alterations, and quantitative real-time PCR (qRT-PCR) was performed to analyze the expression of ompF and recA genes. Significant reduction on the susceptibility to ciprofloxacin and nitrofurantoin was detected on disk diffusion test. The qRT-PCR results revealed a 1.2-4.7 increase in recA expression in all E. coli studied, while the ompF expression varied. Because RecA was pointed as an important component to the development of drug resistance, molecular docking studies were performed with three experimentally known inhibitors of this enzyme. These studies aimed to understand the inhibitory binding mode of such compounds. The results confirmed the ADP/ATP binding site as a potential site of inhibitor recognition and a binding mode based on π-stacking interactions with Tyr103 and hydrogen bonds with Tyr264. These findings can be useful for guiding the search and design of new antimicrobial agents, mainly concerning the treatment of infections with resistant bacterial strains.

Interaction of nitrofurantoin with lipid langmuir monolayers as cellular membrane models distinguished with tensiometry and infrared spectroscopy.

Knowing how a drug interacts with cell membranes is important to understand and predict its effects at the molecular level. Therefore, we aimed to study the interaction of nitrofurantoin (NFT), a compound with potential antibiotic and antitumor properties, with lipidic biological interfaces using Langmuir monolayers. We employed the phospholipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS), which were spread on the surface of water to form Langmuir films, to investigate the membrane-drug interactions. The interaction of the drug with the lipid monolayers was evaluated by using surface pressure-area isotherms, surface pressure-time kinetic curves, Brewster angle microscopy (BAM), and polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). Nitrofurantoin shifted the isotherms to lower DPPC molecular areas, indicating monolayer condensation, and to higher DPPS molecular areas, indicating monolayer expansion. Meanwhile, BAM images showed the appearance of interfacial aggregates for DPPS, but not for DPPC, in the presence of NFT. PM-IRRAS spectra showed that bands related to methylene stretches changed their relative intensities and maximum position related to their asymmetric and symmetric modes for both lipids. This suggested an alteration of the monolayer packing degree and the conformational order of the lipid alkyl chains, which were related to an increase in configurational order for DPPS, but disorder for DPPC. In conclusion, NFT caused distinctive changes in the thermodynamic, morphological, and structural properties of DPPC and DPPS monolayers, which may be associated with its bioactivity in cellular membranes and other lipidic interfaces of pharmaceutical interest.

El tratamiento de la cistitis aguda no complicada de la mujer en la comunidad ¿es un problema resuelto en el país?

RESUMEN Introducción: la práctica de la Medicina enfrenta frecuentemente al manejo de pacientes del sexo femenino con infección de vías urinarias no complicada, en las que se necesita iniciar un tratamiento empírico para Escherichia coli, basado en la identificación de los llamados antibióticos de primera línea para dicho germen y en el conocimiento de la resistencia local a los mismos. Objetivos: analizar los textos de Medicina Interna, Nefrología, Microbiología, guías internacionales y otras publicaciones recientes para identificar los antibióticos como los de primera línea para el tratamiento de la cistitis aguda no complicada en la mujer: nitrofurantoína, fosfomicina, cotrimoxazol (trimetoprim-sulfametoxazol) y pivmecillinam. Resultados: de los antibióticos mencionados sólo están disponibles en el país la nitrofurantoína y el cotrimoxazol. En un estudio que hemos publicado recientemente se encontró que la resistencia de Escherichia coli a la nitrofurantoína fue 4% y al cotrimoxazol fue del 35%. Conclusión: de los antibióticos considerados de primera línea para el tratamiento empírico de la cistitis aguda no complicada en la mujer, solo tenemos disponible en el país la nitrofurantoína y el cotrimoxazol, siendo baja (4%) la resistencia local de Escherichia coli a la nitrofurantoina y elevada (35%) al cotrimoxazol.

ABSTRACT Introduction: The practice of medicine frequently faces the management of female patients with uncomplicated urinary tract infection, in which an empirical treatment for Escherichia coli is needed, based on the identification of the so-called first-line antibiotics for this germ and in the knowledge of local resistance to them. Objectives: To analyze the texts of Internal Medicine, Nephrology, Microbiology, international guidelines and other recent publications to identify the following antibiotics as those of first line for the treatment of uncomplicated acute cystitis in women: nitrofurantoin, fosfomycin, cotrimoxazole (trimethoprim -sulfamethoxazole) and pivmecillinam. Results: Of the above mentioned antibiotics, only nitrofurantoin and cotrimoxazole are available in Paraguay. In a study we recently published it was found that the resistance of E. coli to nitrofurantoin was 4% and to cotrimoxazole 35%. Conclusion: Of the antibiotics considered as of first line for the empirical treatment of uncomplicated acute cystitis in women, only nitrofurantoin and cotrimoxazole are available in the country, being low (4%) the local resistance of E. coli to nitrofurantoin and high (35%) to cotrimoxazole.

Prevalencia de infección de la vía urinaria y perfil microbiológico en mujeres que finalizaron el embarazo en una clínica privada de Lima, Perú / Prevalence of urinary tract infection and microbiological profile in women who end their pregnancy in a private clinic in Lima, Peru

Resumen Objetivo: Describir la prevalencia de infección de la vía urinaria en mujeres que finalizaron el embarazo en una clínica privada (nivel II-2) de Lima, Perú, además de conocer el perfil microbiológico e identificar la resistencia a los antibióticos. Materiales y métodos: Estudio retrospectivo, observacional y transversal efectuado en pacientes que finalizaron el embarazo en la Clínica Jesús del Norte del distrito de Independencia de Lima, Perú, entre enero de 2016 y diciembre del 2017. Criterio de inclusión: pacientes con al menos seis citas médicas de control prenatal en la clínica. Se obtuvo el resultado de los urocultivos y el de resistencia a los antibióticos. Se buscaron medidas de tendencia central como promedios, desviación estándar y frecuencias. Resultados: Se registraron 1455 pacientes que cumplieron con el criterio de inclusión; de éstas 108 (7.4%) tuvieron infección de la vía urinaria con urocultivo positivo. El microorganismo aislado con más frecuencia fue Escherichia coli en 70 (63.6%) casos, con resistencia a ampicilina (60.8%), ciprofloxacina (34.7%) y norfloxacina (34.7%), y sensibilidad a amikacina, nitrofurantoína y cefuroxima. En 13 (11.8%) pacientes también se identificó Escherichia coli y enterobacterias productoras de betalactamasas de espectro extendido resistentes a cefalosporinas. Conclusión: La prevalencia de infección de la vía urinaria estuvo dentro del valor de referencia expresado en los reportes internacionales (7.4%). Los microorganismos aislados con mayor frecuencia fueron E. coli y E. coli productora de betalactamasas de espectro extendido.

Abstract Objective: To describe the prevalence of urinary tract infections (UTI) and their microbiological profile in pregnant women attended in a private clinic of level II-2 of Lima, Peru. Materials and methods: An analytical cross-sectional observational study was conducted, in women they had their delivery in a private clinic during January 2016 to December 2017. Inclusion criteria were those who had at least 06 prenatal care. Results of urocultures and their respective antibiotic resistance were obtained. In the statistical analysis, central tendency measures such as averages, standard deviation and frequencies were found. Results: 1455 met the selection criteria. We found 108 patients (7.4%) with UTI with a positive urine culture. The 70 cases (63.6%) were Escherichia coli resistant to antibiotics such as: ampicillin (57.6%), ciprofloxacin (30.7%) and norfloxacin (30.7%), and sensitive to: amikacin, nitrofurantoin and cefuroxime. However, was is found that 13 (11.8%) had Escherichia coli BLEE resistant to cephalosporins. Conclusion: The prevalence of urinary infection was within what was expected in relation to international reports. The most commonly isolated uropathogen was Escherichia coli, followed by Escherichia coli BLEE.

Susceptibilidad in vitro a los antibióticos de bacterias productoras de infecciones urinarias en la mujer: evaluación retrospectiva de 5 años / In vitro susceptibility testing to antimicrobial agents of urinary tract infection bacteria in women: a 5-year retrospective study

INTRODUCCIÓN: Las crecientes tasas de resistencia que muestran los patógenos urinarios representan un grave problema. El objetivo de este estudio ha sido realizar un seguimiento de la etiología de las infecciones urinarias, de adquisición comunitaria, de la resistencia a los antimicrobianos de primera línea y la presencia de Betalactamasas de Espectro Extendido en bacilos gram negativos (BLEE). MATERIAL Y MÉTODOS: El estudio fue realizado entre enero de 2011 y diciembre de 2015 con datos del Laboratorio Microbiología del Hospital de Clínicas de la Universidad Nacional de Asunción. RESULTADOS: Se obtuvieron 1957 uropatógenos en mujeres. Escherichia coli fue el gérmen más frecuentemente aislado (57%), seguido de Klebsiella pneumoniae (11%) y Streptococcus agalactiae, Staphylococcus saprophyticus y Proteus mirabilis (2%). El promedio de resistencia de Escherichia coli fue para trimetoprim-sulfametoxazol 43 %, ciprofloxacina 32%, ampicilina-sulbactam 32%, cefotaxima 13%, piperacilina tazobactam 8%, nitrofurantoína 2% y meropenem no presentaba resistencia alguna en este lapso. El 11% de las cepas de Escherichia coli y el 30 % de Klebsiella pneumoniae produjo betalactamasas de espectro extendido. CONCLUSIONES: Las tasas de resistencia y de resistencias cruzadas que se evidencian en este estudio representan un grave problema que obliga a evaluar permanentemente el tratamiento empírico de las infecciones urinarias en nuestro hospital

INTRODUCTION: The growing resistance rates of urinary pathogens represent a serious problem. The aim of this study was to analyze the etiology of community-acquired urinary tract infections, their first-line antimicrobial resistance and the presence of extended-spectrum beta-lactamases (ESBL) in gram negative bacilli. METHODS: The study was conducted between January 2011 and December 2015 using data from the Microbiology Laboratory at the teaching hospital Hospital de Clínicas, which belongs to the National University of Asunción. RESULTS: A total of 1957 urinary pathogens were found in women. Escherichia coli was the most commonly isolated bacterium (57%), followed by Klebsiella pneumoniae (11%) and Streptococcus agalactiae (2%), Staphylococcus saprophyticus (2%) and Proteus mirabilis (2%). The resistance rates of Escherichia coliwere the following: to trimetoprim-sulfametoxazol, 43%; to ciprofloxacin, 32%; to ampicilin/sulbactam, 32%; to cefotaxime, 13 %; to piperacillin/tazobactam, 8%; nitrofurantoin, 2%, whereas it did not show resistance to meropenem during this period. Extended-spectrum beta-lactamases were produced by 11% of the E. coliisolates and 30% of the Klebsiella pneumoniae isolates. CONCLUSIONS: The resistance and cross-resistance rates found in this study pose a serious problem which compels the continuous assessment of the empirical therapy for urinary tract infections at this hospital

N-pentyl-nitrofurantoin induces apoptosis in HL-60 leukemia cell line by upregulating BAX and downregulating BCL-xL gene expression.

BACKGROUND: Nitrofurantoin is a nitroderivative antibiotic that has bactericidal activity against pathogens causing urinary tract infection. A few studies have reported that nitrofurantoin has cytotoxic activity against cancer cells; however, nitrofurans remain a poorly explored class of compounds with respect to their anticancer potential. The aim of this study was to investigate the anticancer effects of a nitrofurantoin derivative, n-pentyl-nitrofurantoin (NFP), on HL-60 leukemia cells. METHODS: Cytotoxicity was assayed by the MTT assay. Cell morphology and phosphatidylserine externalization were visualized after Giemsa-May-Grunwald and annexin V staining, respectively. DNA content and mitochondrial depolarization were measured by flow cytometry. BAX and BCL-xL expression was examined by RT-PCR. RESULTS: NFP was 3.8-fold more cytotoxic against HL-60 leukemia cells than against normal cells. NFP reduced the number of viable cells 24h after the treatment with a concomitant increase in the number of apoptotic cells indicated by the externalization of phosphatidylserine, DNA fragmentation, and mitochondrial depolarization. The mRNA levels of BAX increased, whereas the mRNA levels of BCL-xL decreased. CONCLUSION: The results indicate that NFP induces apoptosis in HL-60 cells by upregulating BAX and downregulating BCL-xL.

Aspectos morfológicos de la enfermedad hepática inducida por drogas / Morphological Issues of Drug Induced Liver Disease

La enfermedad hepática inducida por drogas es un fenómeno multifacético y su espectro morfológico es muy variado imitando cualquier patrón de daño hepático, tanto en pacientes expuestos en forma aguda o crónica, en aquellos susceptibles en forma idiosincrática a una dosis terapéutica o por toxicidad intrínseca, a su vez puede estar afectada por otros factores como son los genéticos, la edad o el sexo, el estado nutricional, la exposición a otros fármacos o la existencia de una enfermedad de base; puede ser la única manifestación clínica del efecto adverso de una droga o estar acompañado de manifestaciones sistémicas o de otros órganos, e incluso puede llegar a ser fatal (1). Su incidencia no está bien definida, algunos estudios afirman que la incidencia global es variable encontrándose entre 1-15 x 100.000 personas/año, en USA ocurren 20 nuevos casos x 100.000 habitantes/año. Se han descrito como causantes de lesión hepática más de 900 drogas, productos herbales, homeopáticos, suplementos dietéticos o toxinas, sean productos naturales o de la industria farmacéutica, utilizados o no en dosis terapéuticas, que son las responsables de aproximadamente 15% de consultas y hospitalizaciones por ictericia, hepatitis aguda o crónica; en la población adulta, por encima de los 50 años, llega a 40% de todos los casos de hepatitis. Es también la causante de 11-50% de casos de falla hepática aguda. Los datos publicados indican que los antibióticos son responsables entre un 27-46% de los casos, seguidos por medicamentos para enfermedades del sistema nervioso central entre 13-17%, antiinflamatorios y analgésicos de 5-17% y los productos herbales 9%. Nuevos biomarcadores y el uso de microRNA se están estudiando y serán prometedores en un futuro cercano para identificar pacientes que puedan presentar hepatotoxicidad inducida por medicamentos. Son tantos los tipos de lesión hepática atribuidos a estos agentes que solo podremos dar algunos ejemplos en este artículo, basados en los patrones de daño hepático y enfatizando la importancia de una adecuada y profunda correlación clínica (2, 3).

Drug-induced liver disease is a multifaceted phenomenon which has a varied morphological spectrum that mimics other patterns of liver damage both in cases of acute drug exposure and in cases of chronic exposure to drugs. Those patients who are idiosyncratically susceptible at the therapeutic dose or to intrinsic toxicity may also be affected by other factors including genetic factors, age, sex, nutritional status, exposure to other drugs and the existence of an underlying disease. The only clinical manifestation of the disease may be the adverse effect of a drug, but it can also be accompanied by systemic manifestations and manifestations in other organs, and it can even be fatal (1). The incidence of drug-induced liver disease is not well defined, but some studies claim that its overall annual incidence varies between 1/100,000 people and 15/100,000 people. In the United States, twenty new cases per 100,000 inhabitants occur every year. More than 900 natural and pharmaceutical drugs, herbal medicines, homeopathic products, dietary supplements and toxins have been reported to cause liver damage. This can occur whether or not they are used at normal therapeutic doses. These cases are responsible for about 15% of consultations and hospitalizations for jaundice, acute hepatitis, and chronic hepatitis in adults above the age of 50, and in up to 40% of all cases of hepatitis. Drug-induced liver disease also accounts for 11% to 50% of all cases of acute liver failure. Published data indicate that antibiotics are responsible for between 27% and 46% of cases, that drugs for diseases of the central nervous system are responsible for between 13% and 17%, anti-inflammatory and analgesic agents are responsible for between 5% and 17%, and herbal products are responsible for 9%. New biomarkers and the use of microRNA are being studied and may become promising alternatives in the near future for identifying patients susceptible to drug-induced hepatotoxicity. There are so many types of liver damage attributed to these agents that only give some examples can be provided in this article. These examples have been chosen on the basis ofn the patterns of liver damage with emphasis on the importance of proper and thorough clinical correlation (2, 3).

Antimicrobial Effect and Transdentinal Diffusion of New Intracanal Formulations Containing Nitrofurantoin or Doxycycline

The aim of this study was to investigate in vitro the antimicrobial effect and diffusion against E. faecalis of new intracanal medications on the external root surface. The medications tested were a placebo gel (PC); the new formulations with either 3% nitrofurantoin (NIT) or 3% doxycycline hydrochloride (DX) and 2% chlorhexidine (CHX) gel as positive control. The new formulations were tested using the traditional agar diffusion test (ADT) and an adapted agar diffusion method (AADM), where the teeth were filled with the medications and left to diffuse on agar surface seeded with E. faecalis. In the ADT, the larger zones of microbial growth inhibition were seen in DX, followed by CHX and NIT. In the AADM test only DX and CHX showed antimicrobial effect. Statistically significant differences between groups were observed by the Kruskal-Wallis test (2=47.126; p<0.001). The new intracanal formulations with DX and NIT have demonstrated antimicrobial effect against E. faecalis, but only DX was able to diffuse through the dentinal tubules and exert antimicrobial effect outside the roots.

O objetivo deste estudo foi investigar, in vitro, o efeito antibacteriano e a difusão frente ao E. faecalis, de novas medicações intracanal na superfície externa da raiz. As medicações testadas foram um gel placebo (PC), as novas formulações quer com nitrofurantoína a 3% (NIT) ou hidrocloridrato de doxiciclina a 3%(DX) e um gel de clorexidina a 2% (CHX) como controle positive. As novas formulações foram testadas usando o tradicional teste de difusão em agar (ADT) e um método de difusão adaptado (AADM), onde os dentes foram preenchidos com as medicações e deixados a difundir numa superfície de agar semeada com E. faecalis. No ADT, a maior área de inibição foi registada para DX, seguida por CHX e NIT. No teste AADM, apenas DX e CHX demonstraram ação antimicrobiana. Foram observadas diferenças significativas entre os grupos através do teste Kruskal-Wallis (X2=47.126; p<0.001). As novas formulações intracanais contendo DX e NIT demonstraram ação antimicrobiana quando em contacto com E. faecalis, mas apenas DX teve capacidade de difundir através dos túbulos dentinários e exercer ação antimicrobiana fora das raízes.

Espectro clínico de la hepatotoxicidad por nitrofurantoína en serie clínica de 12 pacientes / Clinical spectrum of nitrofurantoin hepatotoxicity in a series of 12 patients

Nitrofurantoin, commonly used for prolonged periods, can produce different patterns of liver damage. Patients: 12 women, mean age 55 years (range 17-72), with recurrent urinary infections, treated with nitrofurantoin for long periods of time (2 months to 15 years), who presented with secondary liver disease. Results: 7 had acute hepatitis (3 fulminant), 3 chronic hepatitis, and 2 cirrhosis. All acute cases had consistent liver biopsies, and 2 were treated with steroids and azathioprine for 2 and 7 months, with liver tests normalization. Two fulminant cases were transplanted (submassive hepatic necrosis on explanted livers) and 1 was successfully treated with steroids and mycofenolate. The 3 cases of chronic hepatitis also had confirmatory biopsies and 1 received steroids and azathioprine, with full recovery. The other 2 responded to the drug withdrawal and the 2 cirrhotic patients had only symptomatic treatment. All patients were negative for hepatitis virus, 7 (58 percent had positive anti-nuclear and/or anti-smooth muscle antibodies and 4 (33 percent) had elevated IgG levels. Conclusions: Nitrofurantoin may cause severe acute liver disease, even requiring liver transplantation. Nitrofurantoin can also cause chronic liver disease, have markers of autoimmunity and respond to immunosuppressive therapy. These data confirmed that nitrofurantoin can induce liver diseases, probably due to immunological mechanisms.

La nitrofurantoína, comúnmente utilizada por períodos prolongados, puede producir daño hepático, con diferentes formas de presentación y evolución. Pacientes: 12 mujeres, edad promedio 55 años (rango 17 a 72), con infecciones urinarias recurrentes, usuarias de nitrofurantoína por períodos prolongados (2 meses a 15 años), que presentaron daño hepático asociado a la droga. Resultados: 7 casos de hepatitis aguda (3 fulminantes), 3 casos de hepatitis crónica y 2 casos de cirrosis. Todos los casos de hepatitis agudas tenían biopsia hepática compatible y 2 fueron tratadas con corticoides y azatioprina por 2 y 7 meses, con normalización de los exámenes. De las 3 pacientes con hepatitis fulminante, 2 fueron trasplantadas (necrosis submasiva en el hígado explantado) y 1 fue tratada con corticoides y micofenolato, con buena respuesta. Los 3 casos de hepatitis crónica tenían confirmación histológica y 1 se trató con corticoides y azatioprina, con excelente evolución. Las otras pacientes respondieron favorablemente sólo a la suspensión del fármaco. Los 2 casos con cirrosis han recibido tratamiento sintomático. Todas las pacientes fueron negativas para los virus hepatitis, 7/12 (58 por ciento) tenían anticuerpos antinucleares y/o antimúsculo liso positivos y 4/12 (33 por ciento) IgG elevada. Conclusión: La nitrofurantoína puede provocar una severa enfermedad hepática aguda, requiriendo incluso trasplante hepático. Además, puede producir hepatitis crónica y cirrosis, tener marcadores de autoinmunidad y buena respuesta a la terapia inmunosupresora habitual. Lo anterior confirma su capacidad de inducir un daño hepático, probablemente por mecanismos inmunológicos.

Pneumonia eosinofílica crônica secundária ao uso prolongado de nitrofurantoína: achados da tomografia computadorizada de alta resolução do tórax / Chronic eosinophilic pneumonia secondary to long-term use of nitrofurantoin: high-resolution computed tomography findings

Os autores relatam o caso de uma paciente com estenose de uretra que desenvolveu pneumonia eosinofílica crônica secundária ao uso prolongado de nitrofurantoína como profilaxia para infecção urinária de repetição. A paciente havia sido submetida a uma biópsia pulmonar a céu aberto. É dada ênfase aos achados da tomografia computadorizada de alta resolução do tórax, já que, embora as alterações pulmonares associadas à toxicidade da nitrofurantoína geralmente sejam basais e bilaterais, no caso aqui descrito, as lesões de natureza interstício-alveolares situaram-se nas regiões subpleurais dos lobos superiores. Esses achados, por si só, são muito sugestivos de pneumonia eosinofílica crônica. O diagnóstico foi confirmado por meio da revisão da biópsia.

The authors report the case of a female patient who developed chronic eosinophilic pneumonia secondary to long-term use of nitrofurantoin for prophylaxis of recurrent urinary tract infections due to urethral stenosis. On high-resolution computed tomography scans, the pulmonary reaction to nitrofurantoin most commonly manifests as an interstitial-alveolar pattern in both lung bases. However, in this case, the alterations were most pronounced in the periphery of the upper lobes. In itself, this tomographic profile is strongly indicative of chronic eosinophilic pneumonia. The patient had previously been submitted to an open lung biopsy. The diagnosis of chronic eosinophilic pneumonia was confirmed through a review of the biopsy.