Encefalopatía por cefepima en paciente renal: una reacción adversa a medicamento / Cefepime encephalopathy in a kidney patient: an adverse reaction to the drug

RESUMEN La reacción adversa a medicamentos es un problema importante para la salud de pacientes en manejo hospitalario, encontrado de manera regular durante la práctica médica y cuya asociación no identificamos de forma oportuna, pero que aumentan la morbimortalidad y la estancia hospitalaria; en este artículo presentamos el caso clínico de un paciente con encefalopatía severa asociada al uso de cefepima, el deterioro clínico evidenciado durante su proceso de hospitalización y el razonamiento a través del cual se identificó una reacción adversa tipo A como causa de encefalopatía.

SUMMARY The adverse reaction to medications represents a major problem for the health of patients in hospital management, which we encounter on a regular basis during medical practice and whose association we do not identify in a timely manner, but increase morbidity and mortality and hospital stay; In this article we present the clinical case of a patient with severe encephalopathy associated with the use of cefepima, the clinical deterioration evidenced during the hospitalization process and the reasoning through which an adverse type A reaction was identified as a cause of encephalopathy.

A meta-analysis of piperacillin/tazobactam versus cefepime treatment in cancer patients with febrile neutropenia / Uma meta análise de piperacilina/tazobactam versus tratamento com cefepima em pacientes oncológicos com neutropenia febril

Febrile neutropenia (FN) causes a major threat to cancer patients after chemotherapy. Broadspectrum antibiotic treatment is a well-established practice for febrile neutropenia. Piperacillin/Tazobactam (P/T) is the frequently used antibiotic in most of FN cases, whereas the use of cefepime remains unclear regarding its potential risk. However, little systematic analysis has been conducted about comparison between these two drugs. Thus, we undertook this meta-analysis to compare these two monotherapies for febrile neutropenia. Through searching Pubmed, Google scholar, Medline databases, EMBASE, OvidSP, ScienceDirect, Web of science, and China Journal Net (CJN) databases, we used the keywords "(Piperacillin/Tazobactam AND cefepime) AND (febrile neutropenia) AND (cancer or tumor)". Only studies with randomized controlled trials were included in the meta-analysis. We screened out a total number of seven clinical trials. This meta-analysis supported that P/T treatment was superior to cefepime treatment based on the average OR comparison, without statistical significance (OR = 1.27, 95% confidence interval = 0.98 to 1.64, p = 0.07). We further divided the seven studies into two subgroups based on age and treatment time. The young group (age <= 19) showed no significant difference (OR = 1.10, p = 0.65). While the old group (age > 19) showed that P/T treatment was better than cefepime with statistical difference (OR = 1.44, p = 0.05). The short-term group (time <= 3 ds) showed P/T treatment was better than cefepime with statistical difference (OR = 1.40, p = 0.05). While in the long-term group (time > 5 ds), there was no significant difference between P/T and cefepime therapy (OR = 1.06, p = 0.79) Asymmetry in Funnel plots indicated no publication bias (CHI2 = 1.47, I2=0%, and p-value = 0.96) in this meta-analysis. It would be a good clinical trial to use P/T treatment to cure FN in cancer patients compared with cefepime treatment, especially in adult patients or patients with a short-term treatment period. This meta-analysis is practically important during antibiotic treatment in FN management.

A Neutropenia Febril (NF) apresenta-se como uma grande ameaça aos pacientes oncológicos após a quimioterapia. O tratamento antibiótico de amplo espectro é uma prática bem estabelecida para a neutropenia febril. Piperacilina/tazobactam (P/T) é o antibiótico frequentemente na maioria dos casos de NF, enquanto que o uso de cefepima permanece pouco claro em relação ao seu potencial risco. No entanto, pouca análise sistemática foi feita sobre a comparação entre esses dois fármacos. Assim, nós realizamos esta meta-análise para comparar estas duas monoterapias para a neutropenia febril. Através da pesquisa na Pubmed, Google Scholar, nas bases de dados da Medline, EMBASE, OvidSP, ScienceDirect, Web of science e nas bases de dados do China Journal Net (CJN), nós usamos as palavras-chave "(Piperacillin/Tazobactam AND cefepime) AND (febrile neutropenia) AND (cancer or tumor)". Apenas estudos com ensaios clínicos randomizados foram incluídos na meta-análise. Nós selecionamos um número total de sete ensaios clínicos. Esta meta-análise suportou que o tratamento com P/T foi superior ao tratamento com cefepima baseado na média da comparação OU (average OR comparision, em inglês), sem significância estatística (OR = 1.27, 95% confidence interval = 0.98 to 1.64, p = 0.07). Posteriormente, nós dividimos os sete estudos em dois subgrupos baseados na idade e no tempo de tratamento. O grupo jovem (idade <= 19) não mostrou uma diferença significativa (OR = 1.10, p = 0.65). Enquanto que o grupo mais velho (idade > 19) mostrou que o tratamento com P/T foi melhor do que o com cefepima com diferença estatística (OR = 1.44, p = 0.05). O grupo de curto prazo (tempo <= 3 ds*) mostrou que o tratamento com P/T foi melhor do que o com cefepima com diferença estatística (OR = 1.40, p = 0.05). Enquanto isso, no grupo de longo termo (tempo > 5 ds) não houve diferença significativa entre as terapias com P/T e Cefepima (OR = 1.06, p = 0.79). A assimetria nos gráficos de funil (funnel plots, em inglês) não indicaram viés de publicação (CHI2 = 1.47, I2=0%, and pvalue = 0.96) nesta meta-análise. Seria um bom ensaio clínico utilizar o tratamento P/T para curar NF em pacientes oncológicos comparados com o tratamento com cefepima, especialmente em pacientes adultos ou pacientes submetidos a um tratamento de curto prazo. Esta meta-análise é importante na prática durante o tratamento com antibióticos na administração de NF.

Quantification and stress degradation studies of cefepime/tazobactam in dry injection form by an RP-HPLC method

A simple, specific, precise, accurate, linear, rapid, economic and validated stability indicating an RP-HPLC method for the simultaneous quantification of cefepime and tazobactam in a dry injection dosage form has been developed. Separation was performed on a 5 µm ACE C18 column with phosphate buffer, pH adjusted to 4.5 with phosphoric acid: methanol (70:30) at a flow rate of 1 mL/min and at a temperature of 25 °C. Regression analysis showed linearity at a detector wavelength of 290 nm in the range of 200-600 μg/mL for cefepime and 25-75 μg/mL for tazobactam. All of the analytes were adequately resolved with acceptable tailing. The percentage content found for cefepime was 99.98% and of tazobactam was 99.49% in the parenteral formulation. The method was validated in terms of linearity, precision, accuracy, specificity, robustness and system suitability according to ICH guidelines. Stress degradation studies were performed on the placebo and drug products, drugs of interest were well resolved from the degradation products. The developed method was effectively applied for the simultaneous quantification of cefepime and tazobactam in a dry injection formulation.

Desenvolveu-se método específico, preciso, exato, linear, rápido e econômico, de validação de estabilidade, indicando o método de CLAE-FR para a quantificação simultânea de cefepima e tazobactam na forma de dosagem injetável seca. A separação foi realizada em coluna C18 de ACE 5 mM com tampão fosfato, pH ajustado para 4,5 com ácido fosfórico:metanol (70:30), em fluxo de 1 mL/min e temperatura de 25 °C. A análise de regressão mostrou linearidade no detector de comprimento de onda de 290 nm, na faixa de 200-600 μg/mL, para cefepima, e 25-75 μg/mL, para tazobactam. Todos os analitos foram, adequadamente, resolvidos com cauda aceitável. O teor percentual encontrado na formulação parenteral foi de 99,98%, para cefepima, e de 99,49%, para o tazobactam. O método foi validado em termos de linearidade, precisão, exatidão, especificidade, robustez e adequação do sistema de acordo com as diretrizes ICH. Estudos de degradação por estresse foram realizados no grupo placebo e nos medicamentos e os fármacos de interesse foram bem resolvidos a partir dos produtos de degradação. O método desenvolvido foi efetivamente aplicado para quantificação simultânea de cefepima e tazobactam na formulação injetável seca.

Características demográficas, morbilidad y mortalidad de los pacientes adultos con neutropenia febril tratados con cefepima / Demographics, morbidity, and mortality febrile neutropenic adult patients treated with cefepime

Introduction: Cefepime efficacy for treatment of febrile neutropenia (FN) in cancer adult patients is a controversial issue. Objective: To describe the demographic characteristics and general mortality of patients suffering from febrile neutropenia treated with cefepime in a fourth-level Latin American hospital. Patients and Methods: A cross-sectional observational study was performed. Study settled at San Ignacio of Bogotá, Colombia. University Hospital from January 2004 to December 2008. Results: A total of 333 patients were treated with cefepime, of whom 125 had suffered FN and met pre established inclusion and exclusion criteria. The general mortality was 14.4%, which was similar to the overall mortality in FN in other reports. Conclusions: Although there is still no clarity regarding the efficacy of cefepime in FN, its use has not been restricted. This study did not identify an excess risk of mortality in patients treated with cefepime.

Introducción: La eficacia de cefepima en pacientes adultos con cáncer y neutropenia febril (NF) es objeto de controversia en las publicaciones científicas. Objetivo: Describir las características demográficas y la mortalidad general de los pacientes adultos con NF tratados con cefepima en un hospital latinoamericano de cuarto nivel. Pacientes y Métodos. Estudio observacional descriptivo, de corte transversal en el que se incluyeron todos los pacientes tratados con cefepima en el Hospital Universitario San Ignacio de Bogotá, Colombia entre enero de 2004 y diciembre de 2008. Resultados: Recibieron cefepime un total 333 pacientes, de los cuales 125 tenían diagnóstico de NF y cumplían criterios pre-establecidos de inclusión y exclusión. Como desenlace final se encontró una mortalidad de 14,4%, un porcentaje similar a la mortalidad general en NF reportada en la literatura médica. Conclusiones: Aún no hay claridad sobre la eficacia del uso de cefepima en NF; sin embargo, tampoco se ha proscrito su uso y los datos del presente estudio no encontraron un riesgo adicional de mortalidad.

Effect of a cholesterol rich diet, recurrent infection and possible treatment modalities on the pulmonary vascular system: an experimental study / Efecto de la dieta rica en colesterol, la infección recurrente, y las posibles modalidades de tratamiento sobre el sistema vascular pulmonar: un estudio experimental

OBJECTIVE: Infection may lead to inflammation, atherosclerosis and thrombotic vascular events. The atherosclerotic effect of hypercholesterolaemia on the vascular system is well-known. However, limited studies were done on the therapeutic and preventative agents. The aim of this study was to investigate the effects of infection and cholesterol rich diet combined with an antibiotic, anti-inflammatory agent and red wine on the pulmonary vascular system. METHODS: Fifty-nine rats were evaluated. Six groups were created: Control-Group I (n = 10); infection - Group II (n = 9), infection-cholesterol rich diet - Group III (n = 12), infection-cholesterol rich dietcefepime - Group IV (n = 11); infection-cholesterol rich diet-diclofenac potassium - Group V (n = 9); infection-cholesterol rich diet and red wine - Group VI (n = 8). Blood samples of rats were collected for cholesterol analysis every month. Sections of central pulmonary arteries were examined for thickness of the intima and medial wall by computerised image analysis. RESULTS: There was a statistically significant difference in serum cholesterol levels and in thickness of the intima between the groups (p = 0.000). The rest of the groups had more intimal thickening than Group I (p = 0.000). Group III had thicker intima than Groups IV and V (p = 0.009, p = 0.011 respectively). There was no significant difference between the groups in thickness of media (p = 0.432). CONCLUSION: Infection and cholesterol rich diet have a synergistic effect on atherosclerosis in pulmonary arteries. However, antibiotics and anti-inflammatory agents could be useful in prevention.

OBJETIVO: La infección puede conducir a inflamación, ateroesclerosis y eventos vasculares trombóticos. El efecto aterosclerótico de la hipercolesterolemia en el sistema vascular es bien conocido. Sin embargo, se hicieron estudios limitados sobre los agentes preventivos y terapéuticos. El objetivo de este estudio fue investigar los efectos de la infección y la dieta rica en colesterol, combinados con agentes antibióticos, anti-inflamatorios, y vino tinto, sobre el sistema vascular pulmonar. MÉTODOS: Cincuenta y nueve ratas fueron evaluadas. Se hicieron seis grupos: grupo-control I (n = 10), grupo-infección II (n = 9), grupo infección-dieta rica en colesterol III (n = 12), grupo-infección-dieta rica en colesterol-cefepima IV (n = 11), grupo-infección-dieta rica en colesterol-diclofenaco potásico V (n = 9), grupo-infección-dieta rica en -vino tinto VI (n = 8). Se tomaron muestras de sangre de ratas para analizar el colesterol cada mes. Se examinaron secciones de las arterias pulmonares centrales para determinar el grosor de la pared íntima y media mediante análisis computarizado de imágenes. RESULTADOS: Hubo una diferencia estadísticamente significativa en los niveles de colesterol en suero y el grosor de la íntima entre los grupos (p = 0.000). El resto de los grupos tenía más engrosamiento de la íntima que el grupo I (p = 0.000). El grupo III tenía una íntima más gruesa que los grupos IV y V (p = 0,009, p = 0.011 respectivamente). No hubo ninguna diferencia significativa entre los grupos en cuanto al espesor de la media (p = 0.432). CONCLUSIÓN: La infección y la dieta rica en colesterol tienen un efecto sinérgico sobre la aterosclerosis en las arterias pulmonares. Sin embargo, los antibióticos y los agentes antiinflamatorios podrían ser útiles para la prevención.

Encefalopatia por cefepima / Cefepime-induced encephalopathy

A cefepima é um antimicrobiano da classe das cefalosporinas de quarta geração, prescritapara muitas infecções consideradas graves. Os efeitos adversos que mais chamam a atençãosão os que envolvem o sistema nervoso central, relatados como encefalopatia por cefepima. Odiagnóstico dessa enfermidade deve ser rápido, e a interrupção da droga, imediata.

Cefepime is a fourth-generation cephalosporin antibiotic commonly prescribed for severeinfections. Its most serious adverse effects, known as cefepime-induced encephalopathy, involvethe central nervous system. This disorder must be quickly diagnosed and the drug suspendedimmediately.

Caracterización fenotípica y genotípica de la resistencia enzimática a las cefalosporinas de tercera generación en Enterobacter spp. / Phenotypic and genotypic characterization of resistance to third-generation cephalosporins in Enterobacter spp.

Enterobacter spp. es un patógeno intrahospitalario que presenta múltiples mecanismos de resistencia a los antibióticos b-lactámicos. Se caracterizaron fenotípica y genotípicamente las diferentes b-lactamasas presentes en 27 aislamientos consecutivos e ininterrumpidos de Enterobacter spp. (25 Enterobacter cloacae y 2 Enterobacter aerogenes). También se evaluó la habilidad de diferentes métodos fenotípicos para detectar b-lactamasas de espectro extendido (BLEE) en estos microorganismos. En 15/27 aislamientos (63%) se observó resistencia a las cefalosporinas de tercera generación. En 12 de los aislamientos resistentes se detectó un alto nivel de producción de cefalosporinasa cromosómica, siendo 6 de ellos también productores de PER-2. Dicha resistencia en los 3 aislamientos restantes se debió exclusivamente a la presencia de BLEE, PER-2 en 2 de ellos y CTX-M-2 en un caso. Sólo CTX-M-2 se detectó con todas las cefalosporinas probadas en los ensayos de sinergia, utilizando el método de difusión, mientras que cefepima mejoró la detección de PER-2 en 7/8 aislamientos productores de esta BLEE, 4/8 utilizando la prueba de doble disco y 7/8 comparando discos de cefepima con y sin el agregado de ácido clavulánico. El método de dilución empleado solo detectó 1/9 BLEE al comparar las cefalosporinas con y sin el agregado de inhibidor.

Enterobacter spp. are becoming increasingly frequent nosocomial pathogens with multiple resistance mechanism to b-lactam antibiotics. We carried out the phenotypic and genotypic characterization of beta-lactamases in 27 Enterobacter spp. (25 Enterobacter cloacae y 2 Enterobacter aerogenes), as well as the ability of different extended spectrum b-lactamase (ESBL) screening methods. Resistance to third generation cephalosporins was observed in 15/27 (63%) isolates. Twelve resistant isolates produced high level chromosomal encoded AmpC b-lactamase; 6 of them were also producers of PER-2. Resistance to third generation cephalosporins in the remaining 3 isolates was due to the presence of ESBLs, PER-2 in 2 cases, and CTX-M-2 in the other. Only CTX-M-2 production was detected with all tested cephalosporins using difusion synergy tests, while cefepime improved ESBLs detection in 7/8 PER-2 producers, 4/8 in the inhibitor aproximation test and 7/8 with double disk test using cefepime containing disk with and without clavulanic acid. Dilution method, including cephalosporins with and without the inhibitor detected 1/9 ESBLs producers.