Exantema intertriginoso y flexural simétrico por fármacos: presentación de un caso / Symmetrical drug-related intertriginous and flexural exanthema: a case report

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a benign, self-limited, immune-mediated, symmetric erythematous rash involving the buttocks and other intertriginous/flexural areas, observed after systemic exposure to a drug in an individual with or without prior sensitization. We present a 70-year old patient, who presented SDRIFE after the administration of piperacillin-tazobactam which improved rapidly after its suspension.

El exantema intertriginoso y flexural simétrico relacionado con fármacos (SDRIFE, por su sigla en inglés) es una erupción eritematosa simétrica, inmunomediada, benigna y autolimitada, que compromete glúteos y otras áreas intertriginosas, flexurales o ambas, y que se observa luego de la exposición sistémica a un fármaco en un individuo con sensibilización previa o sin ella. Se comenta el caso clínico de un paciente de 70 años de edad, que presentó SDRIFE posterior a la administración de piperacilina-tazobactam y que mejoró rápidamente luego de su suspensión.

Efetividade da infusão estendida de Piperacilina-tazobactana - Meropenem no tratamento de pacientes sépticos adultos queimados através da modelagem farmacocinética farmacodinâmica, PK/P / Meropenem and piperacillin/tazobactam by extended infusion and PK/PD approach for drug effectiveness

Introdução: Meropenem (MER) e Piperacilina/Tazobactana (PTZ) são agentes antimicrobianos largamente prescritos para pacientes grandes queimados internados em Unidade de Terapia Intensiva (UTI) com infecções nosocomiais causadas por Gram-negativos sensíveis CIM 2 mg/L, Enterobacteriaceae, EB e Non-enterobacteriaceae, NEB. A síndrome da resposta inflamatória sistêmica (SRIS) que ocorre durante o choque séptico no grande queimado pode causar alteração na farmacocinética do paciente em terapia intensiva, de modo que a dose recomendada pode não atingir o alvo desejado contra Gram-negativos de sensibilidade intermediária CIM >2 mg/L. Objetivo: Investigar a efetividade dos beta-lactâmicos piperacilina e meropenem na infusão estendida comparada à infusão intermitente recomendada, para os pacientes sépticos grandes queimados através da abordagem farmacocinética-farmacodinâmica (PK/PD). Ética, casuística e procedimentos: Autor e co-autores declararam não haver conflito de interesse. O protocolo foi aprovado, registro CAAE 07525118.3.0000.0068. No presente protocolo de estudo investigaram-se 36 pacientes sépticos grandes queimados, ambos os gêneros (12F/24M) em terapia intensiva do choque séptico com piperacilina-tazobactana 4,5g q6h ou meropenem 1g q8h. Os pacientes incluídos foram estratificados em dois grupos com base na administração através da infusão intermitente, 0,5 h (G1) ou da infusão estendida, 3 h (G2), ambos com 16 pacientes cada. Duas amostras sanguíneas (1,5mL/cada) foram coletadas no estado de equilíbrio (Steady State), 3ª e 5ª hora do início da infusão. Os níveis séricos de PTZ e MER foram mensurados através de cromatografia líquida, e a farmacocinética (PK) dos dois grupos de pacientes foi comparada aos dados reportados em voluntários sadios. A abordagem PK/PD foi aplicada para avaliação da cobertura do antimicrobiano a partir da estimativa do índice de predição de efetividade (% fΔT>CIM) e da probabilidade de alcançar o alvo terapêutico (PTA) com base no alvo PK/PD recomendado, 100%fΔT>CIM. Resultados e discussão: As características de admissão dos pacientes G1/G2 foram expressas através de mediana e interquartil: Clcr 115 (90-148) / 127 (90-170) ml/min; 30 (24-31) / 27 (24- 33,5) anos, 70 (61-75) / 71 (65-75) kg, 30 (20-42) / 33,9 (18-38,4)% área total de superfície queimada, SAPS3 53 (45-57) / 48 (37,8-59,5). Na admissão dos pacientes na UTI registrou-se G1/G2: trauma térmico (17/16), trauma elétrico (1/2), lesão inalatória (11/11), ventilação mecânica (16/9) e vasopressores foram necessários em 15/8 pacientes, G1/G2. Ocorreram diferentes alterações na farmacocinética dos dois beta-lactâmicos após a infusão estendida versus a infusão intermitente quando comparadas com dados relatados em voluntários sadios. Evidenciou-se prolongamento da meia vida decorrente do aumento do volume de distribuição. Estes resultados impactaram diferentemente a cobertura. O monitoramento de biomarcadores inflamatórios expressos em medianas (G1/G2) evidenciou aumento do PCR: 232/183mg/L e leucocitose (leucócitos 11/14 mil cel/mm3, neutrófilos 9/10 mil cel/mm3) na fase precoce do choque séptico. Relativamente à microbiologia dos isolados, a erradicação dos patógenos ocorreu para todos os pacientes após a infusão estendida contra Gram-negativos sensíveis (CIM: 2 mg/L), e de sensibilidade intermediária (CIM 4mg/L) como a K. pneumoniae e P. aeruginosa, enquanto a infusão intermitente garantiu erradicação de patógenos apenas até CIM 2 mg/L. Conclusão: Evidenciou-se a superioridade da infusão estendida frente à infusão intermitente na cobertura dos dois antimicrobianos, no alvo terapêutico considerado 100%fΔT>CIM. Registraram-se alterações na farmacocinética destes agentes nos pacientes frente aos dados reportados para voluntários sadios. Diferença significativa entre grupos (G1/G2) foi encontrada com relação meia vida biológica, e ao volume de distribuição tanto pata a piperacilina quanto para o meropenem

Background: Meropenem (MER) and Piperacillin/Tazobactam (PTZ), antimicrobial betalactam agents are widely prescribed to burn patients from the Intensive Care Unit (ICU) with nosocomial infections caused by Gram-negative strains. Change in the pharmacokinetics of critically ill patient occurs during the systemic inflammatory response syndrome (SIRS) at the course of septic shock. Then, the recommended dose administered by intermittent infusion, 0.5 hr cannot reach the target against gram-negative strains MIC > 2 mg/L. Subject: To investigate drug effectiveness of the beta-lactams piperacilin and meropenem in extended infusion compared to the recommended intermittent infusion in critically ill septic burn patients using pharmacokinetic-pharmacodynamic (PK/PD) approach. Ethics, Casuistry and Methods: All authors declared there is no conflict of interests. Ethical approval CAAE, register 07525118.3.0000.0068. It was investigated in the study protocol 36 septic burn patients of both genders (12M / 24F), undergoing antimicrobial therapy with PTZ 4.5 g q6h or MER 1g q8h. Based on the chosen antimicrobial therapy and drug infusion prescribed by the physician, patients were stratified in groups with intermittent 0.5h infusion (G1) or with the extended 3h infusion (G2), both groups with 16 patients each. Two blood samples were collected at the steady state (1.5mL / each), at the 3rd and 5th hrs of starting the infusion. Serum levels were measured by liquid chromatography. Pharmacokinetics (PK) of MER or PTZ was compared to data reported in healthy volunteers for both groups of patients. PK/PD approach was applied to estimate the drug effectiveness index (fΔT> MIC) and to assess the probability of target attained (PTA) based on the recommended PK/PD target, 100% fΔT> MIC. Results and discussion: Characteristics of patients admission G1/G2 were: Clcr 115(90- 148)/127(90-170) ml/min; 30(24-31)/27(24-34) yrs, 70(61-75)/71(65-75) kg, 30(20- 42)/33.9(18-38.4)% total burn surface area, SAPS3 53(45-57)/48(37.8-59.5), medians (interquartile): thermal trauma occurred (17/16), electric trauma (1/2), inhalation injury (11/11), mechanical ventilation (9/16) and vasopressors required in 15/8 patients. It was demonstrated that different PK changes occurred for both beta-lactam agents after the extended or intermittent infusion by comparison with data reported in healthy volunteers. PK changes were related to the prolongation of biological half-life and increases on volume of distribution with impact on pharmacodynamics. On the other hand, meropenem total body clearance reduced by 50% at the earlier period of septic shock could be explained by the reduction of MER-transporters expression in the tubular renal secretion, once only patients with renal function preserved were included in the study protocol. Inflammatory biomarkers increased at the earlier period of septic shock: C-rp 232/183mg/L; leukocytes 11/14*103cel/mm3, neutrophils 9/10*103cel/mm3, medians, G1/G2. Clinical and microbiological cure was obtained for all patients of G1 against MIC < 2mg/L after intermittent 0.5 h infusion; while PK/PD target was attained for G2 patients undergoing antimicrobial therapy with MER or PTZ by extended infusion against gram negative strains K. pneumoniae, P. aeruginosa up to MIC 4mg L. Conclusion: Superiority of the extended infusion over intermitent infusion was obtained for the two antimicrobials was evidenced, in the therapeutic target considered 100%fΔT>CIM. Changes in the pharmacokinetics of these agents were recorded in patients compared to data reported for healthy volunteers. A significant difference between groups (G1/G2) was found in relation to biological half-life and volume of distribution for both piperacillin and meropenem

Eficacia y seguridad del tratamiento empírico con piperacilina/tazobactan como monoterapia en episodios de neutropenia y fiebre en niños con cáncer: revisión sistemática y meta-análisis / Efficacy and safety of empirical treatment with piperacillin/tazobactan as monotherapy in episodes of neutropenia and fever in children with cancer: systematic review and meta-analysis

INTRODUCCIÓN: La neutropenia febril en niños con patología oncohematològica requiere un tratamiento empírico precoz y adecuado. Esta revisión sistemática se realizó para evaluar si piperacilina/tazobactam (PTZ) monoterapia es más efectiva y segura que los comparadores, en niños con episodios de neutropenia febril de causa oncológica. MATERIAL Y MÉTODOS: Se realizó una búsqueda bibliográfica en Embase, MEDLINE utilizando los términos de búsqueda (('febrile neutropenia' OR hemato oncology OR haemato oncology OR 'immunocompromised host' OR 'immunocompromised patient' OR 'chemotherapy-induced febrile neutropenia') AND (piperacillin OR tazobactam OR 'piperacillin plus tazobactam' OR 'piperacillin/tazobactam' OR 'piperacillin-tazobactam' OR tazocin OR 'piperacillin-tazobactam drug combination')). El criterio de valoración de eficacia fue la incidencia de fracaso terapéutico. El punto final de seguridad fue la ausencia de cualquier efecto adverso (EA). RESULTADOS: Se identificaron 1.388 estudios, de los cuales se incluyeron 11 que cumplían los criterios de elegibilidad. Los estudios presentaron notable homogeneidad ( I 2 0%) y no se detectó sesgo de publicación (p 0,36). El riesgo de fracaso terapéutico de PTZ no fue mayor que en los comparadores (RR global: 0,94; IC95% 0,83 a 1,07) como tampoco lo fue, la incidencia de EA. CONCLUSIONES: El riesgo de fracaso terapéutico no fue superior para la PTZ como monoterapia frente a los comparadores

BACKGROUND: Febrile neutropenia in children with onco-hematological diseases is an important cause of morbidity and mortality and requires early and adequate empirical treatment. This systematic review was conducted to evaluate if piperacillin/ tazobactan (PTZ) monotherapy leads to a lower incidence of therapeutic failures than comparators. METHODS: A literature search was carried out in Embase, and MEDLINE databases using the search terms ('febrile neutropenia' OR hemato oncology OR haemato oncology OR 'immunocompromised host' OR 'immunocompromised patient' OR 'chemotherapy-induced febrile neutropenia') AND (piperacillin OR tazobactam OR 'piperacillin plus tazobactam' OR 'piperacillin/tazobactam' OR 'piperacillin-tazobactam' OR tazocin OR 'piperacillin-tazobactam drug combination')), Efficacy endpoint was treatment failure rate. The safety end-point was absence of any adverse effects (AE). RESULTS: Eleven studies were included. No heterogeneity was detected ( I 2 0%). The risk of failure was not superior for piperacillin/tazobactan to comparators (Global RR: 0.94; IC95% 0.83 a 1.07). Rates of adverse events were similar among studies. No publication bias was detected (p 0.36). CONCLUSIONS: This systematic review and meta-analysis showed that treating episodes of febrile neutropenia in oncology pediatric patients, the risk of failure for PTZ was not superior to comparators. Adverse events were similar to the comparators.

Concentraciones plasmáticas de piperacilina/tazobactam en pacientes pediátricos críticos sometidos a ECMO: análisis preliminar / Plasmatic concentracion of piperacillin/tazobactam in pediatric patients on ECMO support: preliminary analysis

Resumen Introducción: Se desconocen las alteraciones farmacocinéticas de piperacilina/tazobactam (PT) en pacientes pediátricos que requieren de membrana de oxigenación extracorpórea (ECMO) y cómo dosificar adecuadamente dicho antimicrobiano. Objetivo: Describir las concentraciones plasmáticas (CP)y evaluar el cumplimiento del objetivo farmacocinético/famacodinámico de piperacilina en pacientes pediátricos en soporte con ECMO. Métodos: Presentamos tres pacientes pediátricos en tratamiento con PT que requirieran de ECMO en los que se midieron CP de piperacilina en la mitad del intervalo de dosificación mediante cromatografía liquida de alta resolución. Resultados: Las CP fueron 51,7-14,1 y 6,5 μg/mL para los pacientes A, B y C, respectivamente. Sólo se alcanzaron CP adecuadas en un paciente. Conclusión: Estos resultados preliminares sugieren que la disponibilidad de CP de piperacilina podría optimizar el cumplimiento de los objetivos farmacocinéticos/farmacodinámicos en pacientes pediátricos en soporte con ECMO.

Abstract Background: Pharmacokinetics and optimal dosing of piperacillin tazobactam (PT) have not been well studied in pediatric patients undergoing extracorporeal oxygenation membrane (ECMO). Aim: To describe piperacillin plasmatic concentration and evaluate achievement of pharmaccokinetic/pharmacodinamic objective in patients on ECMO support. Method: We report three pediatric patients admitted to the Pediatric Intensive Care Unit, treated with PT undergoing ECMO. Plasmatic concentrations of piperacillin were obtained in the middle of the dosing interval using high performance liquid chromatography. Results: Plasmatic concentrations were 51,7-14,1 and 6,5 μg/mL for patient A, B and C respectively. Only one patient reached adequate concentrations. Conclusion: These preliminary results suggest that availability of plasmatic concentrations of piperacillin could optimize the achievement of pharmacokinetic/pharmacodynamic objectives in pediatric patients on ECMO support.

Linguistic and cultural adaptation to the Portuguese language of antimicrobial dose adjustment software / Adaptação linguística e cultural para a língua portuguesa de um software para ajuste de dose de antimicrobianos

ABSTRACT Objective To adapt an antibiotic dose adjustment software initially developed in English, to Portuguese and to the Brazilian context. Methods This was an observational, descriptive study in which the Delphi method was used to establish consensus among specialists from different health areas, with questions addressing the visual and operational aspects of the software. In a second stage, a pilot experimental study was performed with the random comparison of patients for evaluation and adaptation of the software in the real environment of an intensive care unit, where it was compared between patients who used the standardized dose of piperacillin/tazobactam, and those who used an individualized dose adjusted through the software Individually Designed and Optimized Dosing Strategies. Results Twelve professionals participated in the first round, whose suggestions were forwarded to the software developer for adjustments, and subsequently submitted to the second round. Eight specialists participated in the second round. Indexes of 80% and 90% of concordance were obtained between the judges, characterizing uniformity in the suggestions. Thus, there was modification in the layout of the software for linguistic and cultural adequacy, minimizing errors of understanding and contradictions. In the second stage, 21 patients were included, and there were no differences between doses of piperacillin in the standard dose and adjusted dose Groups. Conclusion The adapted version of the software is safe and reliable for its use in Brazil.

RESUMO Objetivo Adaptar um software de ajuste de dose de antibióticos inicialmente elaborado em língua inglesa para o português e a conjuntura brasileira. Métodos Trata-se de estudo observacional, descritivo, em que foi utilizado o método Delphi para estabelecer consenso entre especialistas de diferentes áreas da saúde, com perguntas que abordaram os aspectos visuais e operacionais do software. Em uma segunda etapa, foi realizado um estudo piloto, experimental, com alocação aleatória dos pacientes, para avaliação e adaptação do software em ambiente real de uma unidade de tratamento intensivo, onde foram comparadas diferenças entre pacientes que utilizaram dose padronizada usual de piperacilina/tazobactam, e os que utilizaram a dose individualizada ajustada por meio do software Individually Designed Optimum Dosing Strategies. Resultados Participaram da primeira rodada 12 profissionais cujas sugestões foram encaminhadas ao desenvolvedor do software para adequação e ajustes, e posteriormente submetidas à segunda rodada. Oito especialistas participaram da segunda rodada. Foram obtidos índices de 80% e 90% de concordância entre os juízes, caracterizando uniformidade nas sugestões. Dessa forma, houve modificação no layout do software para adequação linguística e cultural, minimizando erros de entendimento e contradições. Na segunda etapa, foram incluídos 21 pacientes, e não houve diferenças entre doses de piperacilina nos grupos dose padronizada e dose ajustada. Conclusão A versão adaptada do software é segura e confiável para seu uso no Brasil.

Delftia acidovorans pneumonia with lung cavities formation / Neumonia con formación de cavidades pulmonares causada por Delftia acidovorans

Abstract Case Description: A 52-year-old female patient was admitted to our clinic with complaints of cough, sputum, fever and fatigue. The patient has been receiving immunosuppressive therapy for thrombocytopenic purpura for 5 years. Clinical Finding: Inspiratory crackles were heard on both hemithorax. Oxygen saturation measured with the pulse oximeter was 97%. Chest X-ray showed diffuse reticular opacities that were more prominent in the upper zones of both lungs. WBC counts were 17,600 mm3 and Platelet counts were 29,000 mm3. Thorax CT showed that there were many thin-walled cavities and millimetric nodules accompanied by ground-glass infiltrates in the upper and middle lobes. Gram staining of bronchial fluid, taken by bronchoscopy, revealed Gram-negative bacilli and intense polymorphonuclear leukocytes. The bacteria were defined as Delftia acidovorans by BD Phoenix automated system. Treatment and outcomes: The patient was hospitalized with suspicion of opportunistic pulmonary infections and cavitary lung disease. After the empirical treatment of intravenous piperacillin-tazobactam and oral clarithromycin, her clinical and radiological findings significantly regressed, and she was discharged with outpatient follow-up. Clinical Relevance: This is the first example of cavitary pneumonia due to Delftia acidovorans in an immunocompromised patient. We would like to emphasize that Delftia pneumonia should be considered in the differential diagnosis of pulmonary cavitary involvement in such patients.

Resumen Descripción del caso: Una mujer de 52 años llegó a la clínica con tos, esputo, fiebre y fatiga. El paciente estuvo recibiendo terapia inmunosupresora durante 5 años para el tratamiento de la púrpura trombocitopénica. Hallazgo clínico: se escucharon crepitaciones inspiratorias en ambos hemitórax. La saturación de oxígeno fue del 97%. La radiografía de tórax mostró opacidades reticulares difusas que eran más prominentes en las zonas superiores de ambos pulmones. Los recuentos de leucocitos fueron de 17,600 mm3 y los recuentos de plaquetas fueron de 29,000 mm3. La TC de tórax mostró muchas cavidades de pared delgada y nódulos milimétricos acompañados de infiltrados vitrales en los lóbulos superior y medio. La tinción de Gram del líquido bronquial reveló bacilos gramnegativos y leucocitos polimorfonucleares. Las bacterias fueron identificadas como Delftia acidovorans. Tratamiento y resultados: La paciente fue hospitalizado con una sospecha de infección oportunista pulmonar y enfermedad pulmonar cavitaria. Después del tratamiento empírico de piperacilina-tazobactam intravenosa y claritromicina oral, los síntomas y signos retrocedieron significativamente, y fue dada de alta con seguimiento ambulatorio. Relevancia clínica: este es el primer registro de neumonía cavitaria causado por Delftia acidovorans en una paciente inmunocomprometida. Enfatizamos que la neumonía por Delftia debe considerarse en el diagnóstico diferencial de la afectación de la cavidad pulmonar en tales pacientes.

Evaluación de susceptibilidad y respuesta al tratamiento con piperacilina/tazobactam en pacientes con infecciones por Escherichia coli productoras de β -lactamasas de espectro extendido (BLEE) CTX-M / Evaluation of susceptibility and response to therapy with piperacillin-tazobactam in patients with infections caused by Escherichia coli with extended-spectrum β -lactamase (ESBL) CTX-M

Resumen Introducción: En las infecciones por enterobacterias productoras de β-lactamasas de espectro extendido (BLEE), los β-lactámicos preferidos para tratamiento son los carbapenémicos. Sin embargo, estudios clínicos muestran eficacia de piperacilina/tazobactam en ciertas infecciones por Escherichia coli productoras de BLEE. Objetivo: Determinar la cura clínica y microbiológica con piperacilina/tazobactam en pacientes con infecciones por E. coli productoras de BLEE, tipo CTX-M. Materiales/Métodos: Estudio descriptivo, retrospectivo, con adultos internados en un hospital universitario. Incluimos infecciones del tracto urinario (ITU), intra-abdominales (IIA) e infecciones de tejidos blandos (ITB). Resultados: Estudiamos 40 pacientes, donde 65% correspondían a ITU, 25% IIA y 10 % ITB. La cura clínica global se logró en 89,4%, con mejores resultados en las ITU (100%), seguidas de ITB (80%) e IIA (70%). El 85% de las cepas tenía concentraciones inhibitorias mínimas (CIM) ≤ 8 μg/mL y 70% con CIM ≤ 4 μg/mL. La tasa de fracaso fue mayor en las infecciones con inóculos altos intraabdominales. La BLEE del tipo CTX-M-15 se encontró en 62,5%. Conclusiones: Piperacilina/tazobactam logró cura clínica y microbiológica, en pacientes con infecciones por E. coli productoras de BLEE susceptibles, especialmente en ITU e IPB y en menor medida en IIA.

Background: Carbapenems are the preferred β-lactamics for treatment for infections caused by enterobacteria producing extended-spectrum β-lactamases (ESBL); however, clinical studies show effectiveness of piperacillin/tazobactam in certain infections by Escherichia coli ESBL producers. Aim: To determine the clinical and micro-biological cure with piperacillin/tazobactam in patients with infections caused by E. coli ESBL producers, CTXM type. Methods: Retrospective descriptive study with adults hospitalized in a university hospital. We included urinary tract infections (UTI), intra-abdominal infections (IAI), soft tissue infections (STI) and/or bacteremia. Results: We studied 40 patients, where 65% corresponded to UTI, 25% to IAI and 10% were STI. The overall clinical cure was achieved in 89.4%, with the best results in the ITU (100%), followed by STI (80%) and 70% in IAI. The 85% of the strains had minimum inhibitory concentrations (MIC) ≤8 μg/ml and 70% with MIC ≤4 μg/mL, however the rate of failure were high in intra-abdominal infections with high inocula or not controlled; CTX-M-15 was found in the 62.5%. Conclusions: Piperacillin/tazobactam was efficient to obtain clinical and microbiological cure in patients with infections caused by ESBL producers but susceptible E. coli, especially in UTI and STI and to a lesser extent in IAI.

Susceptibilidad de enterobacterias a piperacilina/tazobactam en un hospital pediátrico de Chile / Enterobacteriaceae susceptibility to piperacillin/tazobactam in a Chilean pediatric hospital

Resumen Introducción: Las enterobacterias son bacilos gram-negativos responsables de infecciones graves en el ser humano. Se reporta una susceptibilidad en Klebsiella pneumoniae de 79,4% a piperacilina/tazobactam (PIP/TAZO) en hospitales pediátricos de Chile, pero según nuestro conocimiento, no existen datos publicados a la fecha respecto a la susceptibilidad de otras enterobacterias a PIP/TAZO en la población pediátrica chilena. Objetivo: Determinar la susceptibilidad in vitro a PIP/TAZO en cepas obtenidas de infecciones por Enterobacteriaceae en un hospital pediátrico de Chile. Material y Método: Estudio descriptivo y prospectivo de cepas de Enterobacteriaceae en Hospital de Niños Roberto del Río (HRRIO) entre 1 de enero de 2013 y el 27 de agosto de 2014. Se definió la susceptibilidad a PIP/TAZO por método de gradiente (E-test®) según puntos de corte CLSI 2014. Resultados: Se incluyeron 163 casos. El promedio de edad fue de 4 años 15 días. 70,6% de sexo femenino. El 79,7% de las cepas fueron aisladas en urocultivos. La susceptibilidad de Enterobacteriaceae a PIP/TAZO fue 95,1% (n = 155). La susceptibilidad intermedia fue 1,8% (n = 3). Discusión: Los aislados estudiados presentan alta susceptibilidad a PIP/TAZO. Este hallazgo puede explicarse por la baja circulación de microrganismos productores de BLEE y el limitado uso de PIP/TAZO en esta población pediátrica.

Introduction: Enterobacteriaceae are a group of gram-negative rods that can cause serious infections in humans. A susceptibility in Klebsiella pneumoniae of 79.4% to piperacillin/tazobactam (PIP/TAZO) is reported in pediatric hospitals in Chile. There is no published data published to date regarding PIP/TAZO susceptibility to other Enterobacteriaceae species in this population. Aim: To measure the in vitro PIP/TAZO susceptibility in Enterobacteriaceae isolates from patients in a pediatric hospital in Chile. Methods: Descriptive and prospective study of Enterobacteriaceae positive cultures from patients assisting to the "Hospital de niños Roberto del Río" (HRRIO) between January 2013 and August 2014. PIP/TAZO susceptibility was established by gradient diffusion method (E-test®) according to the 2014 CLSI standards. Results: 163 cases were included. The average age was 4 years and 15 days. 70.6% were female. 79.7% of samples were urine cultures. PIP/TAZO susceptibility in Enterobacteriaceae was 95.1% (n = 155). The intermediate susceptibility was 1.8% (n = 3). Discussion: The isolates studied present high susceptibility to PIP/TAZO. This finding could be explained by the fact that this population has not been exposed to this antimicrobial therapy and also the low rates for ESBL in pediatric infections.

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.

Comparación del esquema antibiótico entre la Piperacilina-Tazobactam y Amikacina vs Metronidazol y Gentamicina en el tratamiento de la apendicitis complicada en niños / Comparison between two antibiotic schemes gentamycin-metronidazole vs. piperacillin-tazobactam and amikacin in treating complicated appendectomies in children

Introducción. Los pacientes que tuvieron complicaciones infecciosas post cirugía de apendicitis siguen usualmente un esquema de tratamiento establecido de antibióticos en el Hospital San Juan de Dios (HSJD). Se realizó un análisis retrospectivo de 60 pacientes pediátricos con apendicitis complicada a quienes se les efectuó una apendicectomía abierta y se utilizó el esquema antibiótico de metronidazol y gentamicina. Objetivo. Evaluar la eficacia del esquema de antibióticos usados. Metodología. El estudio se efectuó en la Unidad de Cirugía Pediátrica del HGSJD en el período de tiempo de enero a diciembre de 2013. Se evaluaron las complicaciones infecciosas en los pacientes que requirieron la omisión de los antibióticos mencionados y el inicio de la combinación de piperacilina tazobactam ­ amikacina. Resultados. Hubo 56 (93%) pacientes en quienes el esquema inicial de metronidazol ­ gentamicina fue el único empleado sin que presentaran complicación infecciosa alguna, mientras que 4 (7%) pacientes presentaron colecciones abdominales que requirieron el cambio a piperacilina tazobactam-amikacina con lo que resolvieron la sepsis abdominal. Conclusiones. La utilización de la combinación antibiótica de metronidazol-gentamicina continúa siendo eficiente en la población pediátrica con apendicitis aguda complicada que consulta a nuestro hospital dejando el empleo de la piperacilina tazobactam y amikacina como una alternativa terapéutica útil. Palabras clave: Apendicetomía, metronidazol-gentamicina, piperacilina-tazobactam, amikacina

Introduction: A retrospective study was conducted with 60 pediatric patients with diagnosis of complicated appendicitis, in which open appendectomy was performed and treated with metronidazole and gentamycin. Objective: To evaluate efficacy between the combination of a routinely stablished treatment of metronidazole and gentamycin and piperacillin-tazobactam with amikacin in the treatment of complicated appendectomies. Methodology: This retrospective study was conducted in the Pediatric Surgery Unit of the General Hospital San Juan de Dios from January to December 2013. The postoperative complications were assessed of patients who needed a change in antibiotic therapy to piperacillin tazobactam-amikacin. Results: Fifty-six patients (93%) in which the initial antibiotic combination was used recovered without any complications. Four (7%) patients developed intraabdominal collections and needed therapy with piperacillin tazobactam­amikacin with which they resolved the abdominal sepsis. The antibiotic combination gentamycin and metronidazole is still effective in the pediatric population with complicated acute appendicitis in our hospital, leaving the use of piperacillin tazobactam ­ amikacin as a useful alternative. Keywords: Appendectomy, metronidazole-gentamycin, piperacillin tazobactam-amikacyn

Monitoramento plasmático e análise PK/PD dos antimicrobianos vancomicina e piperacilina no controle das infecções em pacientes queimados / Serum monitoring and PK/PD analysis of vancomycin and piperacillin for sepsis control in burn patients

Introdução: Reportam-se modificações metabólicas e hemodinâmicas em pacientes críticos em sepse e incluem-se neste grupo, os grandes queimados. Nesses pacientes ocorrem profundas alterações na farmacocinética de agentes antimicrobianos hidrofílicos prescritos no tratamento empírico das infecções bacterianas graves. Então, o alvo terapêutico não é alcançado em decorrência das concentrações plasmáticas desses antimicrobianos serem inferiores às requeridas para o controle das infecções. Na suspeita de sepse, a terapia antimicrobiana de primeira escolha prevê administração sistêmica dos antimicrobianos a vancomicina e a piperacilina, sendo esta última associada à tazobactana, um inibidor da beta-lactamase. Objetivo: Propôs-se nesse projeto a investigação da farmacocinética da vancomicina e da piperacilina através do monitoramento plasmático. Propôs-se ainda a avaliação da efetividade dos dois antimicrobianos na dose empírica recomendada com base na função renal aos pacientes críticos grandes queimados em sepse por patógeno hospitalar. Métodos: Investigaram-se 42 pacientes grandes queimados em terapia intensiva com lesões de 2° grau profundo e de 3° grau com suspeita de sepse por patógeno hospitalar. A prescrição constou de terapia combinada de vancomicina e piperacilina nas doses empíricas recomendadas com base na função renal de cada paciente. Seguem as características dos pacientes investigados: adultos de ambos os sexos (33M/9F), médias/ DP: 40,9±17,5 anos, 70,1±11,5 Kg, 33,6±20,7% de superfície corpórea total queimada (SCTQ), sendo 37/42 pacientes apresentaram função renal normal, e 5/42 pacientes com insuficiência renal, sem necessidade de prescrição de diálise pelo nefrologista. Registrou-se trauma térmico/ elétrico em 39/3; a lesão inalatória ocorreu em 25 pacientes. Efetuou-se coleta seriada de 2-3 amostras sanguíneas (Vacutainer/EDTA sódico); após separação do sangue por centrifugação a 2800g para obtenção do plasma, realizou-se o processamento laboratorial para os dois analitos pelo monitoramento plasmático da vancomicina e da piperacilina através da cromatografia líquida de alta eficiência. Realizou-se o estudo farmacocinético com base no modelo aberto monocompartimental. Através da análise PK/PD foi possível determinar os índices de efetividade para a vancomicina a partir da razão da área sob a curva no intervalo de 24 horas e a concentração inibitória mínima ASCss 0-24/CIM > 400, e para a piperacilina 70%fΔT>CIM; o significado desse último índice determinado para o derivado ß-lactâmico está relacionado a fração do intervalo de dose em que a concentração plasmática livre da piperacilina permanece acima da CIM. Resultados: Registrou-se alteração da farmacocinética da vancomicina e da piperacilina nos pacientes queimados com função renal normal pela comparação entre cada paciente e o valor de referência reportado para voluntários sadios. Nos pacientes com insuficiência renal registrou-se o prolongamento da meia vida biológica pela alteração na depuração e/ou no volume de distribuição. Registrou-se farmacocinética alterada em diferentes proporções tanto nos pacientes queimados com função renal preservada, como naqueles com disfunção renal. Após a análise PK/PD, a dose empírica de vancomicina administrada aos pacientes com função renal normal, registrou-se cobertura em 37/37 pacientes contra patógenos sensíveis (CIM 1mg/L), caindo para 18/37 (49%) pacientes para patógenos, CIM 2 mg/L. Não se registrou cobertura contra patógenos CIM>2 mg/L (CIM 4mg/L) independente da função renal dos pacientes. Após a dose empírica prescrita na função renal preservada, a cobertura da piperacilina ocorreu até CIM 4mg/L, para os patógenos sensíveis, caindo para 34/37 (92%) CIM 8 mg/L. Apenas 22/37 (60%) pacientes se encontraram protegidos contra patógenos sensíveis mais agressivos CIM 16 mg/L Pseudomonas aeruginosa e Enterococcus spp. Conclusão: O monitoramento plasmático da vancomicina e da piperacilina indica que a dose empírica recomendada para os dois agentes não alcança efetividade no controle das infecções causadas por patógenos hospitalares sensíveis à vancomicina (CIM>1mg/L) e à piperacilina (CIM >4 mg/L) em consequência de níveis plasmáticos inferiores aos requeridos no controle das infecções, devido a profundas alterações na farmacocinética desses antimicrobianos

Introduction: Metabolic and hemodynamic changes were reported in critically ill patients including burn patients in sepsis. Then, pharmacokinetics is altered in those patients mainly for hydrophilic antimicrobial agents prescribed for the control of severe bacterial infections; consequently, the therapeutic target wasn't reached based on drug plasma concentrations lower than expected. Antimicrobial therapy recommended in sepsis suspicious is based in a combination of two antimicrobials; vancomycin, a glycopeptides derivative and a beta-lactam agent piperacillin-tazobactam, a beta-lactamase inhibitor. Objective: It was proposed a pharmacokinetic investigation for vancomycin and piperacillin based on drug plasma monitoring followed by drug effectiveness measurements by PK/PD analysis after the empiric dose regimen recommended to normal renal function or renal failure burn patients in sepsis. Methods: 42 adult burn patients of both gender (33M/9F) with deep 2nd and 3rd injuries in septic shock by nosocomial pathogens under intensive care were investigated. A combined antimicrobial therapy at the recommended empirical dose regimen vancomycin-piperacillin was prescribed on the basis of renal function. Characteristics of population of patients investigated, means/SD were: 40.9±17.5 yrs, 70.1±11.5 kg, 33.6±20.7% total burn surface area (TBSA). Normal renal function was registered in 37/42 patients against 5/42 of them with renal failure. Thermal/electrical injuries occur in 39/3, and inhalation injury were in 25 of them. A serial of 2-3 blood samples were obtained from venous catheter into vacuum tubes (sodium EDTA); after centrifugation (2800g) plasma samples were obtained for drug plasma monitoring; both analytes, vancomycin and piperacillin were quantified by high performance liquid chromatography. Pharmacokinetics investigation based on one compartment open model was performed. PK/PD analysis was done to determine antimicrobial effectiveness against nosocomial pathogens isolated. Recommended drug effectiveness index was AUCss 0-24/MIC > 400 for vancomycin and 70%fΔT>MIC for piperacillin. Results: Pharmacokinetics for both antimicrobials investigated showed to be altered in a different extension for vancomycin and piperacillin in burn patients with normal renal function by comparison with reference data reported in healthy adult volunteers. PK/PD analysis indicated that after the initial dose regimen 2g daily for patients with normal renal function, the vancomycin effectiveness occurs only for susceptible pathogens MIC 1mg/L, once drug effectiveness falls to 49% (18/37) against pathogens (MIC 2mg/L). Similarly, piperacillin effectiveness occurs just for susceptible pathogens MIC ≤ 4 mg/L in patients with normal renal function, once only 22/37 (60%) of patients reached the target MIC 16mg/L for Pseudomonas aeruginosa and Enterococcus spp. Conclusion: Vancomycin and piperacillin plasma monitoring indicated that the therapeutic target wasn´t reached with the empiric dose regimen recommended against nosocomial pathogens vancomycin susceptible (MIC>1mg/L) and piperacillin susceptible (MIC >4 mg/L) due to plasma levels lower than expected as a consequence of kinetic disposition altered for both antimicrobials

Desarrollo y validación de una metodología por cromatografía líquida de alta eficiencia para la determinación simultánea de piperacilina sódica y tazobactam sódico en inyectables para uso humano / Validation of a high performance liquid chromatography method for the simultaneous determination of sodium piperacillin and sodium tazobactam in human injections

Se presentan en este artículo los resultados obtenidos en desarrollo y validación de una metodología analítica para la cuantificación simultánea de piperacilina sódica y tazobactam sódico en inyectables para uso humano. El procedimiento consiste en una separación por cromatografía líquida de alta eficiencia (HPLC) en fase inversa empleando como fase móvil una mezcla de acetonitrilo e hidróxido de tetrabutilamonio 0,005M de pH 5,0 (31:69), una columna C18 a 38°C y detección a una longitud de onda de 220 nm. Se encontró que el método es selectivo, lineal y preciso. Estas características junto con su sencillez permiten que el método sea adecuado y conveniente para el objetivo propuesto. La robustez de la metodología fue también investigada. El método validado se aplicó para la determinación de las dos sustancias en un producto inyectable del mercado colombiano con registro sanitario del Instituto Nacional de Vigilancia y Control de Medicamentos y Alimentos (Invima).

A reverse phase high performance liquid chromatographic method was developed for the simultaneous quantitative assay of sodium piperaciline and sodium tazobactam. The method was validated and then applied to the quantitative determination assay of each of two substances A C18 column stabilized at 38 °C was used and the detection was performed at 220 nm. A mixture of acetonitrile and tetrabutylammonium hydroxide 0,005M pH 5,0 (31:69) was used as mobile phase. The method is selective, linear and shows a good repeatibility. The robustness was also verified. These properties besides their simplicities make it convenient for the objective proposed. The validated method was applied for the simultaneous assay of piperaciline and tazobactam in one market products with sanitary register at Instituto Nacional de Vigilancia y Control de Medicamentos y Alimentos (INVIMA).