Gordon Choi

Principles of antibacterial dosing in continuous renal replacement therapy

Objectives: To outline the concepts involved in optimizing antibacterial dosing in critically ill patients with acute renal failure undergoing continuous renal replacement therapy (CRRT), provide a strategy for optimizing dosing, and summarize the data required to implement the strategy. Data Sources: MEDLINE search from February 1986 to 2008. Data Extraction and Synthesis: Optimal dosing of antibacterials is dependent on achieving pharmacokinetic targets associated with maximal killing of bacteria and improved outcomes. The initial dose is dependent on the volume of distribution. Maintenance doses are dependent on clearance. Both should be adjusted according to the pharmacokinetic target associated with optimal bacterial killing, when known. The volume of distribution of some antibacterials is altered by critical illness or acute renal failure or both. Clearance by CRRT is dependent on the dose and mode of CRRT and the sieving or saturation coefficient of the drug. Both sieving and saturation coefficient are related to the plasma protein binding and thus may be altered in renal failure. Conclusions: Appropriate dose calculation requires knowledge of the pharmacokinetic target and the usual minimum inhibitory concentration of the suspected organism in the patients locality (or if unavailable, the break point for the organism), published pharmacokinetic data (volume of distribution, non-CRRT clearance) on critically ill patients receiving CRRT (which may differ substantially from noncritically ill patients or those without renal failure), the sieving or saturation coefficient of the relevant drug in critically ill patients, the dose and mode of CRRT being used, and the actual dose of CRRT that is delivered. This large number of variables results in considerable inter- and intrapatient heterogeneity in dose requirements. This article provides basic principles and relevant data to guide the clinician in prescribing individualized dosing regimes.

A systematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: do current studies supply sufficient data?

BACKGROUND Drug dosing for septic patients with acute renal failure receiving continuous renal replacement therapy (CRRT) is complicated, and failure to correctly dose may result in either drug toxicity or treatment failure and development of antibiotic resistance. The aim of this study was to establish an ideal dataset that needs to be reported when presenting pharmacokinetic data for these patients and review current literature for completeness of this dataset. METHODS An ideal dataset was established of the parameters that should be reported when calculating a drug dosing regimen from first principles. A Medline search was performed of relevant literature producing 64 citations from which completeness of the specified criteria was examined. RESULTS None of the studies analysed presented the full dataset that we established as necessary. Of concern, basic pharmacokinetic parameters such as volume of distribution (V(d)) and clearance (CL) were specified in only 79% and 81% of studies, respectively. CONCLUSIONS A large proportion of current studies do not report key information necessary to devise a rational dosing regimen for patients with acute renal failure receiving CRRT, and we hope this dataset will be a useful guide when reporting future pharmacokinetic data.

Principles of Antibacterial Dosing in Continuous Renal Replacement Therapy

Background: Appropriate antibacterial therapy is important to maximize patient survival in sepsis. Acute renal failure complicates optimal antibiotic administration. Methods: MEDLINE search from 1986 to 2010 using the terms ‘acute renal failure’, ‘pharmacokinetics’, ‘clearance’, ‘dosage’, ‘h(a)emofiltration’, ‘h(a)emodialysis’, ‘h(a)emodiafiltration’, ‘continuous renal replacement therapy’, ‘antibiotics’, ‘intensive care’ and ‘critically ill’. Results: Maximal bacterial killing and minimization of side effects depend on achieving pharmacokinetic targets appropriate to the selected antibacterial agent. Volume of distribution and clearance may be altered by critical illness and/or acute kidney injury. Clearance is determined by nonrenal clearance, residual renal clearance and continuous renal replacement therapy dose. Sieving and saturation coefficients are membrane specific, but may be altered by changes in protein binding induced by critical illness. A significant proportion of studies failed to report the essential dataset required for adequate antibacterial dosage calculation. Conclusions: Individualized dosing based on first principles may be the most appropriate method of dosing, particularly when enhanced by therapeutic drug monitoring.

Adsorption of Amikacin, a Significant Mechanism of Elimination by Hemofiltration

ABSTRACT We used an in vitro model of continuous venovenous hemofiltration (CVVH) to characterize amikacin adsorption by polyacrylonitrile (PAN) and polyamide filters. A blood-crystalloid mixture dosed with amikacin was pumped from a reservoir through a hemofiltration circuit and back to the reservoir. All ultrafiltrate was also returned to the reservoir. The level of adsorption was calculated from the fall in the amikacin concentration. The dose and the initial concentration of amikacin were varied, as were the pH, the type of hemofilter, and the hemofilter surface area. The reversibility of adsorption and the effect of repeated dosing were also studied. The level of adsorption by 0.6-m2 PAN filters was significantly greater than that by 0.6-m2 polyamide filters. Adsorption was increased by increasing the dose of amikacin even when the initial concentration was unchanged. It was unaffected by the pH (pH 6.8 or 7.4) or the hemofilter surface area (0.6 m2 or 0.9 m2). Repeated doses of amikacin resulted in further adsorption. In a saturation experiment, the maximum adsorptive capacity of 0.6-m2 PAN hemofilters was at least 546.9 mg (range, 427.6 to 577.5 mg). The adsorption of amikacin by hemofilters is irreversible and was associated with the dose and the hemofilter material but not the hemofilter surface area. Close monitoring of peak amikacin levels should be considered for patients receiving CVVH with PAN hemofilters.

How to optimise antimicrobial prescriptions in the Intensive Care Unit: principles of individualised dosing using pharmacokinetics and pharmacodynamics

Optimising antimicrobial dosing for critically ill patients is highly challenging and when it is not achieved can lead to worse patient outcomes. To this end, use of dosing regimens recommended in package inserts from drug manufacturers is frequently insufficient to guide dosing in these patients appropriately. Whilst the effect of critical illness pathophysiology on the pharmacokinetic (PK) behaviour of antimicrobials can be profound, the variability of these changes between patients is still being quantified. The PK effects of hypoproteinaemia, organ dysfunction and the presence of augmented renal clearance may lead to plasma antimicrobial concentrations that are difficult to predict at the bedside, which may result in excess toxicity or suboptimal bacterial killing. This paper outlines the factors that affect pharmacokinetics in critically ill patients and how knowledge of these factors can increase the likelihood of achieving optimal antimicrobial plasma concentrations. In selected settings, we advocate individualised dosing of renally cleared antimicrobials using physiological data such as measured creatinine clearance and published non-renal clearance data. Where such data do not exist, therapeutic drug monitoring may be a useful alternative and has been associated with significant clinical benefits, although it is not currently widely available.

The Adsorption of Vancomycin by Polyacrylonitrile, Polyamide, and Polysulfone Hemofilters

The aim of this study was to characterize vancomycin adsorption by polyacrylonitrile (PAN), polyamide, and polysulfone hemofilters using an in vitro model of hemofiltration. Vancomycin (36 mg) was added to a blood-crystalloid mixture of known volume (target concentration of 50 mg/L) and pumped around a closed circuit. Adsorption, which was calculated from the fall in concentration over 120 min, was significantly greater by 0.6-m(2) PAN filters (10.08 +/- 2.26 mg) than by 0.6-m(2) polyamide (5.20 +/- 1.82 mg) or 0.7-m(2) polysulfone (4.80 +/- 2.40 mg) filters (P < 0.05). Cumulative adsorption was not changed by the addition of 500-mL lactated Ringers solution (to reduce the circulating vancomycin concentration). These data show that although adsorption of vancomycin by PAN, polyamide, and polysulfone hemofilters occurs, the absolute adsorption is small. Adsorption is dependent on filter material and is not reversed by a decrease in circulating concentration.

The involvement of regulatory non-coding RNAs in sepsis: a systematic review

BackgroundSepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis.MethodsWe searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words (“microRNA”, “long non-coding RNA”, “circular RNA”, “sepsis” and/or “septic shock”) from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool.ResultsObservational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common.ConclusionsAlthough non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful.

Autophagy in sepsis: Degradation into exhaustion?

ABSTRACT Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro- and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.

SaMpling Antibiotics in Renal Replacement Therapy (SMARRT): an observational pharmacokinetic study in critically ill patients

BackgroundOptimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality.Methods/DesignWe designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient’s blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients’ demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics.DiscussionUsing the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT.Trial registrationAustralian New Zealand Clinical Trial Registry (ACTRN12613000241730) registered 28 February 2013

Systemic inflammation in the elderly

Inflammation is an adaptive response to surgery. When the pro-inflammatory responses are unregulated and become over reactive, systemic inflammatory response syndrome may occur. Postoperative systemic inflammation is more common than is generally acknowledged and is observed in about 10-15% of elderly patients undergoing major surgery. Although the vast majority of systemic inflammation is related to infections, other important predisposing risk factors, such as extent of trauma and haemorrhage, should not be overlooked. Increased awareness, modification of risk factors and early recognition are the key elements in the management of systemic inflammation. Prompt resuscitation aiming to correct hypotension, hypovolaemia and tissue hypoxia may improve outcome. Future large prospective observational studies are needed to define the incidence, risk factors and impact of systemic inflammatory syndrome in the elderly surgical patients. A better understanding of the molecular events during the systemic inflammatory response syndrome is required for future development of specific immunotherapy.