Optimizing Piperacillin Dosing in Pediatric Liver Transplant Recipients: A Case Series.

BACKGROUND: Pathophysiological changes post-liver transplantation impact the pharmacokinetics and pharmacodynamics of antibiotics. Piperacillin, often used in combination with tazobactam, is a key antibiotic after transplantation to its broad-spectrum activity, but there is a lack of specific pharmacokinetic data in this population. This study aims to describe the pharmacokinetic parameters and target attainment of piperacillin in pediatric liver transplant recipients. METHODS: Patients with preserved renal function (estimated glomerular filtration rate > 50 mL/min/1.73 m2) receiving intravenous piperacillin-tazobactam at 112.5 mg/kg every 8 h (100 mg piperacillin/12.5 mg tazobactam), with a rapid infusion (0.5-1 h), were included. Two blood samples per child were collected during the same interval within 48 h of starting therapy. A Bayesian approach was applied to estimate individual pharmacokinetic parameters and perform dosing recommendations against Enterococcus spp., Enterobacterales and Pseudomonas aeruginosa. RESULTS: Eight patients with median age of 8 months were included. Median piperacillin clearance and central volume of distribution for the cohort were 11.11 L/h/70 kg and 9.80 L/70 kg, respectively. Seven patients (87.5%) presented with concentrations below the target of 100% fT > MIC. Simulations suggested that these patients required more frequent dosing and extended duration of infusion to ensure target attainment. One patient (12.5%) had trough concentrations that exceed 16 mg/L and could receive a lower daily dose. CONCLUSIONS: This case series highlights the importance of personalized therapy in pediatric liver transplant recipients due to the unpredictable and highly variable piperacillin pharmacokinetics in this population.

Itraconazole Serum Trough Concentrations Using Oral Capsules for the Treatment of Chronic Pulmonary Aspergillosis: What is the Target?

BACKGROUND: In regions where there is only itraconazole capsule as a therapeutic option for treatment of chronic pulmonary aspergillosis (CPA), measuring the serum concentrations becomes even more important for therapeutic success. OBJECTIVE: Evaluate the initial itraconazole serum trough concentrations after the administration of oral capsule of itraconazole for the treatment of CPA. METHODS: The measurement was performed at least 7-days after initiation of therapy. The standard treatment at our institution was a 200 mg capsule every 12 h. We defined that an adequate serum trough concentration of itraconazole during treatment was 1-4 mg/L. RESULTS: This study recruited 28 patients. The median value was 0.30 mg/L (IQR 0.01-0.70). Only 11% (n = 3) had adequate serum concentrations based on guideline recommendation. All patients with clinical deterioration had itraconazole serum levels ≤ 0.8 mg/L. CONCLUSION: The initial serum concentrations of itraconazole after capsule formulation administration were low. Increasing the dose should be considered when the itraconazole concentration is low, especially if it is ≤ 0.8 mg/L, and the patient presents with clinical deterioration. Larger studies are needed to evaluate the adequate concentrations recommended for CPA.

Analysis of chlorhexidine, antibiotics and bacterial community composition in water environments from Brazil, Cameroon and Madagascar during the COVID-19 pandemic.

The widespread of chlorhexidine and antibiotics in the water bodies, which grew during the global COVID-19 pandemic, can increase the dispersion of antibiotic resistance. We assessed the occurrence of these pharmaceutical compounds as well as SARS-CoV-2 and analysed the bacterial community structure of hospital and urban wastewaters from Brazil, Cameroon, and Madagascar. Water and wastewater samples (n = 59) were collected between January-June 2022. Chlorhexidine, azithromycin, levofloxacin, ceftriaxone, gentamicin and meropenem were screened by Ultra-High-Performance Liquid Chromatography coupled with mass spectrometer. SARS-CoV-2 was detected based on the nucleocapsid gene (in Cameroon and Madagascar), and envelope and spike protein-encoding genes (in Brazil). The total community-DNA was extracted and used for bacterial community analysis based on the 16S rRNA gene. To unravel likely interaction between pharmaceutical compounds and/or SARS-CoV-2 with the water bacterial community, multivariate statistics were performed. Chlorhexidine was found in hospital wastewater effluent from Brazil with a maximum concentration value of 89.28 µg/L. Additionally, antibiotic residues such as azithromycin and levofloxacin were also present at concentrations between 0.32-7.37 µg/L and 0.11-118.91 µg/L, respectively. In Cameroon, azithromycin was the most found antibiotic present at concentrations from 1.14 to 1.21 µg/L. In Madagascar instead, ceftriaxone (0.68-11.53 µg/L) and levofloxacin (0.15-0.30 µg/L) were commonly found. The bacterial phyla statistically significant different (P < 0,05) among participating countries were Proteobacteria, Patescibacteria and Dependentiae which were mainly abundant in waters sampled in Africa and, other phyla such as Firmicutes, Campylobacterota and Fusobacteriota were more abundant in Brazil. The phylum Caldisericota was only found in raw hospital wastewater samples from Madagascar. The canonical correspondence analysis results suggest significant correlation of azithromycin, meropenem and levofloxacin with bacteria families such as Enterococcaceae, Flavobacteriaceae, Deinococcaceae, Thermacetogeniaceae and Desulfomonilaceae, Spirochaetaceae, Methanosaetaceae, Synergistaceae, respectively. Water samples were also positive for SARS-CoV-2 with the lowest number of hospitalized COVID-19 patients in Madagascar (n = 7) and Brazil (n = 30). Our work provides new data about the bacterial community profile and the presence of pharmaceutical compounds in the hospital effluents from Brazil, Cameroon, and Madagascar, whose limited information is available. These compounds can exacerbate the spreading of antibiotic resistance and therefore pose a risk to public health.

Pharmacokinetics and Therapeutic Target Attainment of Meropenem in Pediatric Post-Liver Transplant Patients: Extended vs Intermittent Infusion.

PURPOSE: The aim of this study is to characterize the concentration-time profile, pharmacokinetics parameters, and therapeutic target attainment of meropenem in pediatric post-liver transplant patients according to the duration of infusion. METHODS: This is a prospective cohort of pediatric transplant recipients with preserved renal function receiving meropenem 40 mg/kg every 8 hours. The patients were stratified into 2 groups based on infusion duration: G1 (15 minutes of intermittent infusion) and G1 (3 hours of extended infusion). Two blood samples per child were collected during the same interval within 48 hours of starting the antimicrobial. Meropenem concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were assessed using a noncompartmental analysis. The therapeutic target was defined as 100% of the time above the minimum inhibitory concentration. FINDINGS: Fourteen patients with 28 measured meropenem concentrations were included. Lower values of volume of distribution and meropenem clearance compared with other critically ill pediatric populations were found. All patients achieved the therapeutic target against gram-negative pathogens with a minimum inhibitory concentration of ≤8 mg/L. Patients receiving a 15-minute infusion had higher values of peak and trough concentrations, resulting in unnecessary increased total drug exposure when compared to patients receiving a 3-hour infusion (P < .05). CONCLUSIONS: Meropenem at 120 mg/kg/d attained the therapeutic target against sensitive microorganisms in pediatric liver transplant recipients. The extended infusion should be preferred for patient safety. Because of the pharmacokinetic changes resulting from liver transplantation, individualized meropenem dosing regimens may be necessary.

A rare association between factor H deficiency and lupus: Case report and experimental treatment with curcumin.

Factor H (FH) is one of the most important regulatory proteins of the alternative pathway of the complement system. FH deficiency is a rare condition that causes unregulated C3 consumption, leading to an increased susceptibility to infections and glomerulopathies. Our previous studies have demonstrated a FH deficient patient carrying a c.452G > A, p.R127H FH mutation which leads to a misfolded protein and its retention in the endoplasmic reticulum. In his cultured fibroblasts, FH-delayed secretion was partially rescued when treated with curcumin, and once secreted, exhibited normal regulatory function. Here, we report a childhood-onset systemic lupus erythematosus (cSLE) in this FH deficient patient and the results of experimental treatment with curcumin aiming to rescue FH secretion and regulatory activity.

Neoplastic ascites in osteosarcoma: a case report.

BACKGROUND: Osteosarcoma is a malignant tumor of connective tissue whose tumor cells produce bone tissue. It can be classified as osteoblastic, chondroblastic, or fibroblastic, according to the predominant histologic type of cells. Its dissemination is hematogenous, and the lungs are the most frequent site of clinically evident metastasis. Extrapulmonary metastases are rare and more frequently diagnosed at necropsy. We present a case of osteosarcoma with peritoneal dissemination that developed neoplastic ascites. CASE: A 46-year-old patient came to the hospital with a 4-month history of lumbar pain and weakness in the lower limbs. Computed tomography showed blastic lesions in the L3 vertebral body. Surgical resection and histologic analysis revealed a mixed osteoblastic and chondroblastic osteosarcoma. After only one session of chemotherapy, the patient presented a marked clinical worsening with extensive metastatic dissemination and occurrence of voluminous ascites. The cytologic examination of the ascitic fluid demonstrated frequent poorly differentiated tumor cells. The patient died a little more than 2 months after the diagnosis. CONCLUSION: This case is the only report of osteosarcoma primarily focused on the vertebral column affected by peritoneal metastasis shown by cytologic examination of ascitic fluid.

Does vancomycin administered at an empirical dose ensure coverage of pediatric patients against gram-positive pathogens? / A vancomicina administrada na dose empírica garante a cobertura de pacientes pediátricos contra patógenos Gram-positivos?

OBJECTIVE: To investigate the vancomycin effectiveness against gram-positive pathogens with the minimum inhibitory concentration of 1mg/L in pediatric patients based on the area under the curve and the minimum inhibitory concentration ratio > 400. METHODS: A population of 22 pediatric patients (13 boys) admitted to the pediatric intensive care unit with preserved renal function was stratified in two groups (G1 < 7 years and G2 ≥ 7 years). After the fourth dose administered of vancomycin (10 - 15mg/kg every 6 hours) was administered, two blood samples were collected (third and fifth hours), followed by serum measurement by immunoassays to investigate the pharmacokinetics and antimicrobial coverage. RESULTS: There was no difference between the groups regarding dose, trough level or area under the curve. Coverage against gram-positive pathogens with a minimum inhibitory concentration of 1mg/L occurred in only 46% of patients in both groups. The pharmacokinetics in both groups were altered relative to the reference values, and the groups differed in regard to increased total body clearance and shortening of the biological half-life, which were more pronounced in younger patients. CONCLUSION: A minimum empirical dose of 60mg/kg per day should be prescribed for pediatric patients in intensive care units with preserved renal function. The use of the ratio between the area under the curve and minimum inhibitory concentration in the evaluation of vancomycin coverage is recommended to achieve the desired outcome, since the pharmacokinetics are altered in these patients, which may impact the effectiveness of the antimicrobial.

OBJETIVO: Investigar a efetividade da vancomicina contra Gram-positivos com concentração inibitória mínima de 1mg/L em pacientes pediátricos com base na razão entre área sob a curva e concentração inibitória mínima > 400. MÉTODOS: População de 22 pacientes pediátricos (13 meninos) internados no centro de terapia intensiva pediátrica, com função renal preservada, que foram distribuídos em dois grupos (G1 < 7 anos e G2 ≥ 7 anos). Após a quarta dose de vancomicina (10 - 15mg/kg a cada 6 horas), duas amostras de sangue foram colhidas (terceira e quinta horas), seguidas da dosagem sérica por imunoensaios para investigação da farmacocinética e da cobertura do antimicrobiano. RESULTADOS: Não se registrou diferença entre os grupos com relação à dose, ao nível de vale ou ainda na área sob a curva. A cobertura contra Gram-positivos com concentração inibitória mínima de 1mg/L ocorreu em apenas 46% dos pacientes em ambos os grupos. A farmacocinética se mostrou alterada nos dois grupos diante dos valores de referência, mas a diferença entre grupos foi registrada pelo aumento da depuração total corporal e pelo encurtamento da meia-vida biológica, mais pronunciados nos pacientes mais novos. CONCLUSÃO: A dose empírica mínima de 60mg/kg ao dia deve ser prescrita ao paciente pediátrico de unidade de terapia intensiva com função renal preservada. A utilização da razão entre área sob a curva e concentração inibitória mínima na avaliação da cobertura da vancomicina é recomendada para se atingir o desfecho desejado, uma vez que a farmacocinética está alterada nesses pacientes, podendo impactar na efetividade do antimicrobiano.