Flucloxacillin-Induced Hepatotoxicity - Association with HLA-B*5701

SUMMARY Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

RESUMO A hepatotoxicidade à flucloxacilina é rara e classifica-se como idiossincrática, uma vez que é dependente da suscetibilidade individual, não expectável e independente da dose. Apresentamos o caso de um homem, 74 anos, antecedentes de gamapatia monoclonal e hábitos alcoólicos de 24 g/dia, com quadro de astenia, anorexia, náuseas, desconforto abdominal e febrícula com três dias de evolução. Referência a dois ciclos de antibioterapia com flucloxacilina por erisipela (três meses e duas semanas antes da admissão). Analiticamente com AST 349 U/L, ALT 646 U/L, FA 302 U/L, GGT 652 U/L, bilirrubina total 3,3 mg/dL, bilirrubina direta 2,72 mg/dL. Excluídas etiologias infecciosa, autoimune, metabólica, bem como patologia das vias biliares por colangio-RM. Biópsia hepática mostrou esteatose multifocal ligeira (predominantemente microvesicular); alterações acentuadas nas áreas centrolobulares (dilatação sinusoidal, congestão acentuada, hemorragia e colapso multifocal de hepatócitos); expansão das áreas portais com constituição de pontes; ductos biliares proliferados e infiltrado inflamatório de densidade variável, predominantemente de tipo mononucleado. Tipagem de HLA-B*5701 positiva. Agravamento analítico atingindo bilirrubina total 24,1 mg/dL, com desenvolvimento de icterícia, prurido e colúria. Admitida a hepatotoxicidade, iniciou terapêutica com ácido ursodesoxicólico. Verificou-se evolução favorável, sem evidência de coagulopatia ou encefalopatia. A normalização analítica foi, no entanto, lenta, com evolução para cronicidade. Os autores apresentam este caso para alertar para a possibilidade de hepatotoxicidade moderada a grave à flucloxacilina, antibiótico de uso comum na prática clínica e associação com o alelo HLA-B*5701 relatada na literatura.

Valor do ecocardiograma na Endocardite Infecciosa associada aos dispositivos cardíacos implantáveis / Use of echocardiography in Infectious Endocarditis associated with implantable cardiac devices

Nas últimas décadas, o aumento das indicações para dispositivos cardíacos eletrônicos implantáveis tem sido acompanhado pela elevação dos casos de complicações relacionadas ao seu uso, dentre elas a endocardite infecciosa. Apesar dos avanços diagnósticos e terapêuticos da doença, esta mantém elevada morbimortalidade. Os casos relacionados aos dispositivos apresentam importantes limitações referentes aos critérios e aos métodos diagnósticos que implicam na tomada de decisão terapêutica sobre retirada do dispositivo, com risco de morte e outras complicações. Ainda assim, o ecocardiograma mantém um grande valor no diagnóstico da endocardite infecciosa relacionada a dispositivos cardíacos e de suas complicações. O entendimento das limitações e dos desafios acerca do diagnóstico reforça a necessidade de mais estudos sobre do tema. O presente artigo visa descrever a epidemiologia, a microbiologia, os fatores de risco, a patogenia, o diagnóstico e o tratamento da endocardite infecciosa associada aos dispositivos cardíacos eletrônicos implantáveis, visando demonstrar, principalmente, o valor dos exames de imagem na abordagem dessa condição clínica, com ênfase nos achados ao ecocardiograma.

In recent decades, the increase in indications for implantable electronic cardiac devices has been accompanied by an increase in cases of complications related to their use, including infectious endocarditis. Despite the diagnostic and therapeutic advances of the disease, it maintains high morbidity and mortality. The cases related to the devices have important limitations regarding the criteria and diagnostic methods that imply in making a therapeutic decision about removing the device, with risk of death and other complications. Still, echocardiography remains of great value in the diagnosis of infective endocarditis related to cardiac devices and their complications. Understanding the limitations and challenges regarding diagnosis reinforces the need for further studies on the topic. This article aims to describe the epidemiology, microbiology, risk factors, pathogenesis, diagnosis and treatment of infective endocarditis associated with implantable electronic cardiac devices, aiming to demonstrate, mainly, the value of imaging tests in addressing this clinical condition , with emphasis on echocardiogram findings.

Validated microbiological and HPLC methods for the determination of moxifloxacin in pharmaceutical preparations and human plasma

The article presents a comparison between microbiological and high performance liquid chromatographic (HPLC) assays for quantification of moxifloxacin in tablets, ophthalmic solutions and human plasma. The microbiological method employed a cylinder-plate agar diffusion assay using a strain of Esherichia coli ATCC 25922 as the test organism and phosphate buffer (pH8) as the diluent. The calibration curves were linear (R²> 0.98) over a concentration range of 0.125 to 16 µgml-1. The within day and between days precisions were < 4.47% and < 6.39% respectively. Recovery values were between 89.4 and 110.2%. The HPLC assay used Hypersil® BDS C18 reversed phase column (250×4.6 mm, 5µm) with a mobile phase comprising 20 mM ammonium dihydrogen orthophosphate (pH3) and acetonitrile (75:25) and flowing at 1.5 ml/min. The detection was at 295nm. The calibration curves were linear (R²> 0.999) over the range of 0.125 to 16 µg ml-1. The within day and between days precisions were < 4.07% and < 5.09% respectively. Recovery values were between 97.7 and 107.6%. Similar potencies were obtained after the analysis of moxifloxacin tablets and ophthalmic solutions by both methods. Also pharmacokinetic parameters were calculated after the analysis of plasma samples of six male healthhy volunteers by both validated methods.

Spectrophotometric determination of ampicillin, dicloxacillin, flucloxacillin and amoxicillin in pharmaceutical preparations using potassium periodate

Different Spectrophotometric methods were used for the determination of beta-lactam antibiotics using complex formation with Cu [II][1-6] and nickel [II][7]ions or titration against Cu [II] ions using ion-selective electrode [8,9]. Modified Spectrophotometric methods were developed for the determination of some important antibiotics including amoxicillin and ampicillin through charge transfer complexation reaction with chloranil [10,11] Amoxicillin and ampicillin were determined spectrophotometrically in pharmaceutical preparations using potassium iodate [12] picric and picramic acids [13] some nitro compounds [14] certain pi-acceptors[15] or with ammonium molybdite [16]. A Spectrophotometric method based on coupling of amoxicillin with different diazotized primary aromatic amines was developed [17]. Amoxicillin was determined spectrophotometrically in a binary mixture with dicloxacillin[18] or in the presence of dicloxacillin or flucloxacillin[19] Dicloxacillin [in urine] and flucloxacillin [in some pencillin derivatives] were determined using TLC spectrophotometry [20,21]. Two Spectrophotometric methods [22] [using N-bromos- uccinimide and N-chtorosuccinimide] or two colourimetric methods [23] [using sodium hypochlorite and 1-chlorobenzotriazole] were described for the determination of amoxicillin. Ampicillin was determined spectrophotometrically in tablets, capsules, powder and granules with the use of Na 3, 4 -naphthaquinone -1- sulphonate [24]or with l-fluoro-2,4-dinitrobenzene[22] reagents. HPLC methods [26,27] were used for the determination of amoxicillin in different pharmaceutical preparations

Antibióticos I: betalactámicos: penicilinas o penames / Antibiotics I: betalactamics: penicillins or penames

Entre los 53 años transcurridos desde la introducción de la penicilina al campo de la terapéutica, se ha modificado substancialmente la patología infecciosa; han aparecido cepas microbianas resistentes a algunos antibióticos y se han descubierto nuevos antimicrobianos de espectros más amplios; de efectos más potentes y de mejor tolerancia. Uno de los grupo de antibióticos de mayor utilidad es el de las penicilinas o penames que tienen todas un núcleo 6 aminopenicilánico común y que forman parte de los betalactámicos. En esta revisión se presentan esquemáticamente los espectros de acción, las principales indicaciones clínicas y las dosis habituales de los diversos tipos de penicilinas disponibles

Kinetics of degradation of flucloxacillin in different solutions and in the presence of some intravenous components

The kinetics of degradation of flucloxacillin in solution was investigated at 37C, 70C, and constant ionic strength of O.5 over a pH range of 2-7. The decomposition followed a pseudo first order kinetics under the experimental conditions studied and the rates were found to be influenced by general acid base-catalysis. The apparent heats of activation were determined to be 20.72 kCal and 21.64 kCal at pH 4 and 6, respectively. The pH rate profile in buffer solutions showed a minimum at pH 6. The shelf life at this pH was 75 hours compared with 26.6 hours at pH 4 and 37C. Dextrose solution was found to exert a tremendous catalytic effect on the degradation of flucloxacillin

Flucloxacillin induced neutropenia during treatment of osteomyelitis

The neutropenia was associated with a characteristic clinical sequence starting with fever, followed by generalised maculopapular rash. We report on 11 patients with Flucloxacillin induced neutropenia during treatment of acute and chronic osteomyelitis. The time of onset ranged from 10 to 14 days after beginning of treatment. The thrombo-cytopenia occurred in 8 patients. Discontinuation of the drugs resulted in recovery from the neutropenia within 2 to 4 days. Neutropenia and concomitant symptoms should be kept in mind when treating osteomyelitis with flucloxacillin. Complete blood count and differential leukocyte count should be checked regularly during the treatment

pH-Induced difference spectrophotometric assay of amoxicillin in the presence of dicloxacillin or flucloxacillin

A method is presented for the direct determination of amoxacillin in the presence of dicloxacillin or flucloxacillin without prior separation using first and second derivative spectra [AD 1 and AD 2] at the zero contribution of flucloxacillin or dicloxacillin. The method was proved using laboratory prepared mixtures of amoxacillin with flucloxacillin or dicloxacillin

Valoración de la eficacia y seguridad de flucloxacilina en amigdalitis, faringitis y faringoamigdalitis: primera-parte; pacientes pediátricos / Evaluation of efficiency and safety of flucloxacyllin in tonsillitis, pharyngitis and pharingotonsillitis: part I; pediatric patients

En la primera parte de este estudio multicéntrico, 112 pacientes pediátricos con amigdalitis, faringitis o faringoamigdalitis, de 10 ciudades de la República Mexicana, fueron tratados con flucloxacilina en dosis bucales de 250 mg cada ocho horas. El diagnóstico y valoración de los resultados fueron realizados en base a los datos clínicos. De los 112 pacientes, 110 fueron incluidos para la valoración final, ya que dos pacientes fueron excluidos, uno (curado) ya que recibió penicilina G y el otro (mejorado) debido a que recibió gentamicina. De los 110, 55 eran mujeres y 55 varones, con edades entre dos meses y 11 años (promedio 4.7 años). Los diagnósticos fueron: faringitis 31%, amigdalitis 40% y faringoamigdalitis 29%. Los parámetros clínicos valorados fueron: temperatura, pulso, estado de la orofaringe, dolor, deglución y estado general. La valoración se realizó al inicio, quinto día y al final. La temperatura se normalizó al quinto día en 97.3% y al final 99.1%, resolución de la condición de orofaringe en 97.3%, en dolor 99.1% y en cuanto a la deglución 98.2%. La respuesta final al tratamiento fue satisfactoria en 98.2% de los pacientes, con 1.8% de fracasos (dos pacientes). La duración promedio de la terapéutica fue de cinco días. La tolerancia al tratamiento fue excelente, con 7.3% de pacientes quienes presentaron efectos indeseables, los cuales no obligaron a abandonar el tratamiento. Los resultados obtenidos en este estudio confirmaron que flucloxacilina representa una terapéutica eficaz y segura en este tipo de infecciones

Valoración de la eficacia y seguridad de flucloxacilina en amigdalitis, faringitis y faringoamigdalitis: segunda parte; pacientes adolescentes y adultos / Evaluation of efficiency and safety of flucloxacyllin in tonsillitis, pharyngitis and pharyngotonsillitis: part II; adolescent and adult patients

En este estudio multicéntrico (parte II), se estudiaron 103 pacientes adolescentes y adultos con diagnóstico clínico de amigdalitis, faringitis o fariongoamigdalitis en 10 ciudades de la República Mexicana, los cuales fueron tratados con flucloxacilina en dosis bucales de 500 mg cada ocho horas. El diagnóstico y valoración de los resultados se realizó en base a datos clínicos. De los 103 pacientes, 99 fueron incluidos para la valoración final ya que cuatro fueron excluidos, uno (curado) debido a que recibió penicilina G, los otros tres, porque no acudieron a control al quinto día. De los 99 que fueron incluidos, 50 eran mujeres y 45 varones, con edades entre 12 y 50 años (promedio 18.2). Los diagnósticos fueron: faringitis 24.3%. amigdalitis 52.5% y faringoamigdalitis 23.2%. Los parámetros clínicos valorados fueron: temperatura, pulso, estado de la orofaringe, dolor, deglución y estado general. Las valoraciones se realizaron al inicio, quinto día y al final. La normalización de la temperatura en el quinto día fue en 96% y al final 99% de pacientes. Resolución en las condiciones de la orofaringe en 98%, dolor en 99% y deglución en 98%. La respuesta final al tratamiento fue satisfactoria en 99% de casos, con 1% de fracasos. La duración promedio de la terapéutica fue de cinco días. La tolerancia al tratamiento fue excelente en 3% de pacientes informando efectos indeseables, los cuales no impidieron continuar con el tratamiento. Los resultados obtenidos en este estudio confirman que flucloxacilina representa una terapéutica eficaz y segura en este tipo de infecciones