A targeted likelihood estimation comparing cefepime and piperacillin/tazobactam in critically ill patients with community-acquired pneumonia (CAP).

Cefepime and piperacillin/tazobactam are antimicrobials recommended by IDSA/ATS guidelines for the empirical management of patients admitted to the intensive care unit (ICU) with community-acquired pneumonia (CAP). Concerns have been raised about which should be used in clinical practice. This study aims to compare the effect of cefepime and piperacillin/tazobactam in critically ill CAP patients through a targeted maximum likelihood estimation (TMLE). A total of 2026 ICU-admitted patients with CAP were included. Among them, (47%) presented respiratory failure, and (27%) developed septic shock. A total of (68%) received cefepime and (32%) piperacillin/tazobactam-based treatment. After running the TMLE, we found that cefepime and piperacillin/tazobactam-based treatments have comparable 28-day, hospital, and ICU mortality. Additionally, age, PTT, serum potassium and temperature were associated with preferring cefepime over piperacillin/tazobactam (OR 1.14 95% CI [1.01-1.27], p = 0.03), (OR 1.14 95% CI [1.03-1.26], p = 0.009), (OR 1.1 95% CI [1.01-1.22], p = 0.039) and (OR 1.13 95% CI [1.03-1.24], p = 0.014)]. Our study found a similar mortality rate among ICU-admitted CAP patients treated with cefepime and piperacillin/tazobactam. Clinicians may consider factors such as availability and safety profiles when making treatment decisions.

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

Evaluation of the effect of antibiotics used during parenteral nutrition treatment on Candidemia

SUMMARY OBJECTIVE: Parenteral nutrition is an important risk factor for candidemia. In this risk analysis study, the effect of previous antibiotic administration apart from the length of hospital stay, duration of Parenteral nutrition treatment, and Candida score parameters on developing candidemia was evaluated in the non-neutropenic patients receiving Parenteral nutrition treatment. METHODS: In this double center, retrospective, and cross-sectional study, the data of patients who received Parenteral nutrition treatment were collected. Patients with or without candidemia after the initiation of Parenteral nutrition treatment were compared in terms of demographic features, Candida score, length of hospital stay, duration of Parenteral nutrition treatment, and previous use of antibiotics. Then, predictor factors affecting the probability of candidemia during Candida growth time were determined by the Cox regression analysis. RESULTS: A total of 148 patients (59.5% males) were included and 16 (10.81%) of these had candidemia after initiation of parenteral nutrition treatment. The median (min-max) duration of parenteral nutrition treatment was 11 (4-72) days and the Candida growth time was 13 (7-29) days. Statistically significant differences were found between patients with or without candidemia groups in terms of length of hospital stay (p<0.001), duration of parenteral nutrition treatment (p<0.001), and Candida score (p<0.001). To determine the effect of these variables and antibiotics on candidemia, length of hospital stay [Hazard Ratio 1.030; p=0.021] and piperacillin-tazobactam (Hazard Ratio 5.626; p=0.030) were found significant and independent risk factors on the development of candidemia. CONCLUSION: There are some well-known risk factors including length of hospital stay, duration of Parenteral nutrition treatment, and Candida score; the potential impact of piperacillin-tazobactam administration should also be considered since they may be effective on the development of candidemia.

Risk Factors of Death in Bloodstream Infections Caused by AmpC ß-Lactamase-Producing Enterobacterales in Patients with Neoplasia.

PURPOSE: The infections caused by ESCPM Enterobacterales (Enterobacter spp., Serratia spp., Citrobacter spp., Providencia spp. and Morganella spp.) have limited therapeutic options. Patients with neoplastic diseases are particularly vulnerable to bloodstream infections (BSIs). OBJECTIVE: To analyze determinant factors of death in patients with neoplasia complicated with BSI caused by ESCPM Enterobacterales. PATIENTS AND METHODS: A cohort study of patients aged 18 years or older with neoplasia and BSI due to ESCPM group was conducted at the Cancer Hospital I of the National Cancer Institute, Brazil, from September 2012 to December 2017. The variables associated with death were analyzed using multivariate logistic regression. RESULTS: Of the 103 patients included in the cohort, 67.0% were male, the median age was 63 years and 67.0% had solid tumors. Of the 107 BSI episodes evaluated, 70.1% were hospital-acquired infections, 54.2% were secondary to extravascular focus of infection, gastrointestinal tract (19.6%), mainly. Enterobacter spp. (n: 49, 45.4%) was the most frequent agent isolated followed by Serratia spp. (n: 34, 31.5%), Morganella morganii (n: 16, 14.9%), Citrobacter freundii. (n: 7, 6.5%) and Providencia spp. (n: 2, 1.8%). Ten (9.3%) BSI episodes were caused by multidrug-resistant ESCPM Enterobacterales (MDR-ESCPM). The 7-day and 30-day mortality were 9.3% and 21.5%, respectively. The BSIs caused by MDR-ESCPM were independently associated with 7-day death (OR = 21.62 95% CI: 1.81-258.51 P = 0.01). Monotherapy with piperacillin-tazobactam tended to be associated with 7-day death (OR = 10.46 95% CI: 0.97-112.91 P = 0.05) and 30-day death (OR = 2.73 95% CI: 0.96-7.70 P = 0.05). CONCLUSION: BSIs due to ESCPM group have high mortality and when caused by MDR-ESCPM are independently associated with 7-day death. The possible association of piperacillin-tazobactam monotherapy for BSI-ESCPM with death needs to be better studied.

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.

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.

PIPERACILLIN/TAZOBACTAM IN CONTINUOUS INFUSION VERSUS INTERMITTENT INFUSION IN CHILDREN WITH FEBRILE NEUTROPENIA.

Background: Febrile neutropenia (FN) is a common complication in children who receive chemotherapy for cancer. Objective: The objective of this study was to evaluate the clinical efficacy of the continuous versus intermittent infusion of piperacillin/tazobactam (TZP) in febrile neutropenic pediatric patients. Methods: This is a non-blinded randomized controlled clinical trial. Eligible group consisted of hemato-oncological patients with FN who were candidates to receive TZP. Patients were randomized to one of two groups: Group 1 received antibiotic treatment through intravenous intermittent infusion of TZP 300 mg/kg/day based on piperacillin, divided into four doses, not exceeding 16 g/day; Group 2 received an initial TZP loading dose of 75 mg/kg infusion over 30 min, and then a continuous infusion of TZP 300 mg/kg/day through central line with pump over 24 h. Results: There were 176 episodes that could be assessed, 100 in Group 1 and 76 in Group 2. There was no statistically significant difference in treatment failure in the experimental group (continuous infusion) compared with the intermittent group, 21% versus 13% (p = 0.15). The increase in the absolute risk reduction was 0.08% (95% confidence interval 0.12-0.30), and the number needed to treat was 12.4. One patient in each group died. Conclusions: There were no differences in fever resolution, clinical cure rate, or mortality when comparing the continuous with the intermittent TZP infusion.

Piperacillin/tazobactam in continuous infusion versus intermittent infusion in children with febrile neutropenia

Abstract Background Febrile neutropenia (FN) is a common complication in children who receive chemotherapy for cancer. Objective The objective of this study was to evaluate the clinical efficacy of the continuous versus intermittent infusion of piperacillin/tazobactam (TZP) in febrile neutropenic pediatric patients. Methods This is a non-blinded randomized controlled clinical trial. Eligible group consisted of hemato-oncological patients with FN who were candidates to receive TZP. Patients were randomized to one of two groups: Group 1 received antibiotic treatment through intravenous intermittent infusion of TZP 300 mg/kg/day based on piperacillin, divided into four doses, not exceeding 16 g/day; Group 2 received an initial TZP loading dose of 75 mg/kg infusion over 30 min, and then a continuous infusion of TZP 300 mg/kg/day through central line with pump over 24 h. Results There were 176 episodes that could be assessed, 100 in Group 1 and 76 in Group 2. There was no statistically significant difference in treatment failure in the experimental group (continuous infusion) compared with the intermittent group, 21% versus 13% (p = 0.15). The increase in the absolute risk reduction was 0.08% (95% confidence interval 0.12-0.30), and the number needed to treat was 12.4. One patient in each group died. Conclusions There were no differences in fever resolution, clinical cure rate, or mortality when comparing the continuous with the intermittent TZP infusion.

Delftia acidovorans pneumonia with lung cavities formation.

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.

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.

In vivo pharmacodynamics of piperacillin/tazobactam: implications for antimicrobial efficacy and resistance suppression with innovator and generic products.

Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of ß-lactam/ß-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT>threshold). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT>threshold and TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 ß-lactamase. We also explored the dynamics of resistance selection with the innovator and a non-equivalent generic, extrapolated the results to the clinic by Monte Carlo simulation of standard TZP doses, and estimated the economic impact of generic-selected resistance. The fT>threshold index described well the efficacy of TZP versus E. coli, with threshold values from 0.5 mg/L to 2 mg/L and mean exposures of 42% for stasis and 56% for 1 log10 kill. The non-equivalent generic required a longer exposure (fT>threshold 33%) to suppress resistance compared with the innovator (fT>threshold 22%), leading to a higher frequency of resistance selection in the clinical simulation (16% of patients with the generic vs. 1% with the innovator). Finally, we estimated that use of TZP generics in a scenario of 25% therapeutic non-equivalence would result in extra expenses approaching US$1 billion per year in the USA owing to selection of resistant micro-organisms, greatly offsetting the savings gained from generic substitution and further emphasising the need for demonstrated and not assumed therapeutic equivalence.

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

Piperacillin/tazobactam-induced neurotoxicity in a hemodialysis patient: a case report.

Antibiotics are potentially a cause of neurotoxicity in dialysis patients, the most common are the beta-lactams as ceftazidime and cefepime, and few cases have been reported after piperacillin/tazobactam use. This report presents a case of a hypertensive and diabetic 67-year-old woman in regular hemodialysis, which previously had a stroke. She was hospitalized presenting pneumonia, which was initially treated with cefepime. Two days after treatment, she presented dysarthria, left hemiparesis, ataxia, and IX and X cranial nerves paresis. Computed tomography showed no acute lesions and cefepime neurotoxicity was hypothesized, and the antibiotic was replaced by piperacillin/tazobactam. The neurologic signs disappeared; however, 4 days after with piperacillin/tazobactam treatment, the neurological manifestations returned. A new computed tomography showed no new lesions, and the second antibiotic regimen withdrawn. After two hemodialysis sessions, the patient completely recovered from neurological manifestations. The patient presented sequentially neurotoxicity caused by two beta-lactams antibiotics. This report meant to alert clinicians that these antibiotics have dangerous neurological effects in chronic kidney disease patients.

Drug-laboratory interaction between beta-lactam antibiotics and the galactomannan antigen test used to detect mould infections.

Several studies have demonstrated that piperacillin/tazobactam produces a false-positive result for the galactomannan antigen test. However, the most recent literature has demonstrated that this interaction is no longer a concern. There is little information regarding the drug-laboratory interaction with the generics of piperacillin/tazobactam or other broad-spectrum beta-lactams, such as ceftaroline, doripenem, imipenem/cilastatin, and meropenem. The purpose of this study was to determine if a drug-laboratory interaction exists with these antibiotics. Tests showed that one lot of imipenem/cilastatin by Hospira Healthcare India Private Limited produced a false-positive result for the galactomannan antigen test. All other medications tested, including piperacillin/tazobactam from seven manufacturers and imipenem/cilastatin by Hospira Inc., did not produce positive results. Since the reason for this drug-laboratory interaction with imipenem/cilastatin is unknown, more studies are needed to further investigate this interaction. Providers also should be educated of these findings: no drug-laboratory interaction with piperacillin/tazobactam and a possible drug-laboratory interaction with imipenem/cilastatin (Hospira Healthcare India Private Limited).

Proteomic changes in Bacteroides fragilis exposed to subinhibitory concentration of piperacillin/tazobactam.

Bacteroides fragilis is the anaerobe most frequently isolated from clinical specimens and piperacillin/tazobactam is among the drugs that can be used to treat polymicrobial infections in which this bacteria is often involved. During antibiotic therapy, inhibitory concentrations of antibiotics are always followed by subinhibitory concentrations which can generate phenotypic changes in bacteria. So, in this study we aimed to evaluate changes in the proteomic profile of B. fragilis grown in a sub-MIC of PTZ, using 2-D electrophoresis followed by matrix-assisted laser desorption/ionization time-of-flight/time of-flight. Analysis of the 2-DE gels showed 18 spots with significantly different volume percentages between experimental conditions and 12 were successfully identified by MS/MS. Two proteins with decreased abundance in sub-MIC condition were involved in the glycolysis (glyceraldehyde-3-phosphate dehydrogenase and triose phosphate isomerase), others two involved in amino acid metabolism (Oxoacyl-(acyl-carrier protein) synthase II and dihydrodipicolinate reductase), and finally, one protein involved in fatty acid metabolism (UDP-N-acetylglucosamine acyltransferase). Among the proteins with increased abundance, we founded three ATP synthase (alpha, beta, and alpha type V), which could be involved in antibiotic bacterial resistance by efflux pump, one protein involved in glycolysis (enolase), and one involved in protein degradation (aminoacyl-histidine dipeptidase). In conclusion, our data show overall changes in the proteome of B. fragilis conducted by sub-MIC of PTZ, whose consequences on bacterial physiology deserve further investigation.

Galactomannan detection from piperacillin-tazobactam brands available in the Brazilian market

Piperacillin-tazobactam is a broad spectrum antimicrobial agent that can cause false-positive results in the commercial Platelia Aspergillus EIA test. So far, no study has been performed in Latin America to evaluate the clinical implication of this finding. Here we studied the potential for galactomannan detection in piperacillin-tazobactam batches commercialized in the Brazilian market. Five batches from distinct laboratories were tested in duplicate in the Platelia Aspergillus EIA according to the manufacturer's instructions. Only one drug showed crossreaction at a cut-off of 0.5. Human serum was spiked with this particular drug aiming to mimic achievable piperacillin-tazobactam concentrations in the serum. Results were all negative for galactomannan detection, even at high drug concentrations. Results from this pilot study suggest that piperacillin-tazobactam might not be a clinically significant cause of false-positive results in the Platelia Aspergillus EIA test in Brazil.