Piperacillin-tazobactam dosing in anuric acute kidney injury patients receiving continuous renal replacement therapy.

INTRODUCTION: To determine appropriate dosing of piperacillin-tazobactam in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: The databases of PubMed, Embase, and ScienceDirect were searched. We used the Medical Subject Headings of "piperacillin-tazobactam," "CRRT," and "pharmacokinetics" or related terms or synonym to identify the studies for reviews. A one-compartment pharmacokinetic model was conducted to predict piperacillin levels for the initial 48 h of therapy. The pharmacodynamic target was 50% of free drug level above the minimum inhibitory concentration (MIC) and 4 times of the MIC. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. RESULTS: Our simulation study reveals that the dosing regimen of piperacillin-tazobactam 12 g/day is appropriate for treating Pseudomonal infection with KDIGO recommended effluent rate of 25-35 mL/kg/h. The MIC values of each setting were an important factor to design piperacillin-tazobactam dosing regimens. CONCLUSION: The Monte Carlo simulation can be a useful tool to evaluate drug dosing in critically ill acute kidney injury patients receiving CRRT when limited pharmacokinetic data are a concern. Clinical validation of these results is needed.

Acute kidney injury in the tropics.

The tropics are a region consisting of more than 125 countries, accounting for 40% of the world's population. The region's population is expected to increase up to 60% in the coming decades. Many tropical countries continue to experience public health problems such as high rates of infectious diseases, lack of sanitation, climate change impacts, poor regulation of herbal medicines and low access to healthcare. These conditions produce the unique problem of tropical acute kidney injury (AKI), which is associated with high morbidity and mortality. Tropical infections such as leptospirosis, dengue and malaria have varied mechanisms of AKI, including both direct kidney invasion and indirect effects, depending on the disease characteristics. Animal toxins from snakebites and arthropods along with plant toxins, such as djenkol beans, starfruit and herbal medicine, are characterized by a harmful renal effect from each toxic substance. Environmental factors such as heat stress, natural disasters and chemical compounds also lead to AKI and have a systemic effect from their own pathogenesis. The long-term kidney prognosis varies among these etiologies depending on the cause and severity of disease. However, all these conditions are potentially preventable and treatable. Prompt management and good preventive approaches are needed. This article will focus on the epidemiology, pathogenesis and management of AKI associated with tropical infections, toxins and environment impacts.

Comprehensive versus standard care in post-severe acute kidney injury survivors, a randomized controlled trial.

BACKGROUND: Currently, there is a lack of evidence to guide optimal care for acute kidney injury (AKI) survivors. Therefore, post-discharge care by a multidisciplinary care team (MDCT) may improve these outcomes. This study aimed to demonstrate the outcomes of implementing comprehensive care by a MDCT in severe AKI survivors. METHODS: This study was a randomized controlled trial conducted between August 2018 to January 2021. Patients who survived severe AKI stage 2-3 were enrolled and randomized to be followed up with either comprehensive or standard care for 12 months. The comprehensive post-AKI care involved an MDCT (nephrologists, nurses, nutritionists, and pharmacists). The primary outcome was the feasibility outcomes; comprising of the rates of loss to follow up, 3-d dietary record, drug reconciliation, and drug alert rates at 12 months. Secondary outcomes included major adverse kidney events, estimated glomerular filtration rate (eGFR), and the amount of albuminuria at 12 months. RESULTS: Ninety-eight AKI stage 3 survivors were enrolled and randomized into comprehensive care and standard care groups (49 patients in each group). Compared to the standard care group, the comprehensive care group had significantly better feasibility outcomes; 3-d dietary record, drug reconciliation, and drug alerts (p < 0.001). The mean eGFR at 12 months were comparable between the two groups (66.74 vs. 61.12 mL/min/1.73 m2, p = 0.54). The urine albumin: creatinine ratio (UACR) was significantly lower in the comprehensive care group (36.83 vs. 177.70 mg/g, p = 0.036), while the blood pressure control was also better in the comprehensive care group (87.9% vs. 57.5%, p = 0.006). There were no differences in the other renal outcomes between the two groups. CONCLUSIONS: Comprehensive care by an MDCT is feasible and could be implemented for severe AKI survivors. MDCT involvement also yields better reduction of the UACR and better blood pressure control. Trial registration Clinicaltrial.gov: NCT04012008 (First registered July 9, 2019).

Optimal levofloxacin dosing regimens in critically ill patients with acute kidney injury receiving continuous renal replacement therapy.

PURPOSES: To determine appropriate dosing of levofloxacin in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: All necessary pharmacokinetic and pharmacodynamic parameters from critically ill patients were obtained to develop mathematical models with first order elimination. Levofloxacin concentration-time profiles were calculated to determine the efficacy based on the probability of target attainment (PTA) of AUC24h/MIC ≥50 for Gram-positive and AUC24h/MIC ≥125 for Gram-negative infections. A group of 5000 virtual patients was simulated and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the dose achieved target PTA at least 90% of the virtual patients. RESULTS: No conventional, FDA approved regimens achieved at least 90% of PTA for Gram-negative infection with Pseudomonas aeruginosa at MIC of 2 mg/L. The successful dose (1750 mg on day 1, then 1500 mg q 24 h) was far exceeded the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg q 24 h was sufficient to attain PTA target of ~90% at the MIC of 2 mg/L for Streptococcus pneumoniae. CONCLUSIONS: Levofloxacin cannot be recommended as an empiric monotherapy for serious Gram-negative infections in patients receiving CRRT due to suboptimal efficacy.

Meropenem dosing recommendations for critically ill patients receiving continuous renal replacement therapy.

PURPOSES: To gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT. METHODS: All necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT>4MIC. A group of 5000 virtual patients was created and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the doses achieved at least 90% of the PTA. RESULTS: The recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20-25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population. CONCLUSIONS: A meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.

A double-blind, randomized, placebo-controlled trial of combined calcitriol and ergocalciferol versus ergocalciferol alone in chronic kidney disease with proteinuria.

BACKGROUND: KDOQI guideline suggests that nutritional vitamin D should be supplemented in chronic kidney disease (CKD) patients who have vitamin D insufficiency/deficiency. However, there are scarce data regarding the additional benefit of active vitamin D supplement in CKD patients who were receiving nutritional vitamin D supplement. This study was conducted to explore the effect of adding active vitamin D to nutritional vitamin D supplement on proteinuria and kidney function in CKD with vitamin D insufficiency/deficiency. METHODS: This double-blind, randomized placebo-controlled trial was performed to answer the above question. Sixty-eight patients with CKD stage 3-4, urine protein to creatinine ratio (UPCR) > 1 g/g, and serum 25OH-D level < 30 ng/mL were enrolled. Patients were randomly assigned to receive 12-week treatment with oral ergocalciferol plus placebo (n = 36) or oral ergocalciferol plus calcitriol (n = 32). RESULTS: The mean baseline values of UPCR of both groups were comparable (3.6 ± 3.8 g/g in combined group and 3.5 ± 3.0 g/g in ergocalciferol group). Following 12-week treatment, there were significant reductions in UPCR from baseline in both groups (2.3 ± 2.1 g/g in combined group and 2.4 ± 2.0 g/g in ergocalciferol group). The percentage reductions in UPCR of both groups were not significantly different. The mean eGFR and blood pressure did not differ between baseline and 12-week follow-up and between both groups. No severe hypercalcemia or serious side effects were noted in both groups. CONCLUSIONS: The proteinuria lowering effect of ergocalciferol in CKD patients with vitamin D deficiency was demonstrated. Additional calcitriol supplement did not have more effects on proteinuria. TRIAL REGISTRATION: (Thai Clinical Trials Registry (TCTR) 20140929002 ). Date of registration: September 27, 2014.

High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse.

Amphotericin B (Ampho B) isa fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically.W e tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression inpatients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with < 11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage,liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.