Optimizing outcomes using vancomycin therapeutic drug monitoring in patients with MRSA bacteremia: trough concentrations or area under the curve?

BACKGROUND: Vancomycin therapeutic drug monitoring is routinely performed but the specific measure used in practice is variable. OBJECTIVE: To evaluate the relationship between the first measured vancomycin trough, area-under-the-curve (AUC), and failure in patients with MRSA bacteremia. METHODS: This retrospective, cohort study included adult non-neutropenic patients with MRSA bacteremia who received vancomycin. The primary outcome was treatment failure. Initial trough and AUC values were compared between the failure and success groups. Classification and regression tree analysis was used to identify thresholds associated with failure. Multivariate analysis was performed to control for identified confounders. RESULTS: There were 89 patients. Failure occurred in 23 (26%). Trough and AUC values associated with failure were < 10.6 mg/L (39% vs. 13%; P = 0.006) and AUC < 410mg*h/L (40% vs. 17%; P = 0.014). Both remained significant after controlling covariates (trough < 10.6 mg/L, OR [95% CI] = 4.91 [1.6-15]; AUC<410mg*h/L, OR [95% CI] = 3.13 [1.14-8.62]). Only AUC was predictive of nephrotoxicity. CONCLUSION: Failure was more common with troughs < 10.6 mg/L or AUC < 410 mg*h/L. Supratherapeutic AUCs, but not trough, were associated with nephrotoxicity.

Comparison of acute kidney injury risk associated with vancomycin and concomitant piperacillin/tazobactam or cefepime in the intensive care unit.

PURPOSE: The objective of this study was to evaluate AKI incidence with concomitant vancomycin and piperacillin/tazobactam (PTZ) compared to vancomycin and cefepime (FEP) in critically ill patients. MATERIALS AND METHODS: A retrospective, cohort study was conducted in adult critically ill patients from January 1, 2014 to December 31, 2017. The primary aim was to compare the incidence of AKI during concomitant therapy or until hospital discharge. Secondary analyses included AKI severity, time to AKI as well as recovery, and clinical outcomes. RESULTS: Overall, 333 patients were evaluated. The AKI rate in the vancomycin/PTZ group and vancomycin/FEP group were similar (19.5% vs. 17.3%, respectively, p = .612). Renal replacement therapy (RRT) was initiated in 10.0% and 3.8% administered vancomycin/PTZ and vancomycin/FEP groups, respectively (p = .04). Multivariate regression found vancomycin/PTZ was not associated with an increased risk of developing AKI although the presence of shock was identified as an independent risk factor (odds ratio, 3.22; 95% CI, 1.66-6.26). No significant differences in hospital or ICU length of stay or in-hospital mortality were observed between study groups. CONCLUSIONS: Concomitant PTZ and vancomycin in ICU patients was not associated with an increased risk of developing AKI compared to FEP and vancomycin combinations. More patients administered vancomycin/PTZ received RRT.

Trigger alerts associated with laboratory abnormalities on identifying potentially preventable adverse drug events in the intensive care unit and general ward.

BACKGROUND: Medication safety strategies involving trigger alerts have demonstrated potential in identifying drug-related hazardous conditions (DRHCs) and preventing adverse drug events in hospitalized patients. However, trigger alert effectiveness between intensive care unit (ICU) and general ward patients remains unknown. The objective was to investigate trigger alert performance in accurately identifying DRHCs associated with laboratory abnormalities in ICU and non-ICU settings. METHODS: This retrospective, observational study was conducted at a university hospital over a 1-year period involving 20 unique trigger alerts aimed at identifying possible drug-induced laboratory abnormalities. The primary outcome was to determine the positive predictive value (PPV) in distinguishing drug-induced abnormal laboratory values using trigger alerts in critically ill and general ward patients. Aberrant lab values attributed to medications without resulting in an actual adverse event ensuing were categorized as a DRHC. RESULTS: A total of 634 patients involving 870 trigger alerts were included. The distribution of trigger alerts generated occurred more commonly in general ward patients (59.8%) than those in the ICU (40.2%). The overall PPV in detecting a DRHC in all hospitalized patients was 0.29, while the PPV in non-ICU patients (0.31) was significantly higher than the critically ill (0.25) (p = 0.03). However, the rate of DRHCs was significantly higher in the ICU than the general ward (7.49 versus 0.87 events per 1000 patient days, respectively, p < 0.0001). Although most DRHCs were considered mild or moderate in severity, more serious and life-threatening DRHCs occurred in the ICU compared with the general ward (39.8% versus 12.4%, respectively, p < 0.001). CONCLUSIONS: Overall, most trigger alerts performed poorly in detecting DRHCs irrespective of patient care setting. Continuous process improvement practices should be applied to trigger alert performance to improve clinician time efficiency and minimize alert fatigue.

Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients.

BACKGROUND: Phenytoin is a common medication for seizure treatment and prophylaxis in the intensive care unit (ICU). The clinical utility of the Sheiner-Tozer equation for adjusting total phenytoin levels for hypoalbuminemia remains controversial. OBJECTIVE: The purpose of this study was to evaluate the correlation of this formula in predicting phenytoin serum concentrations. METHODS: A retrospective cohort study was conducted in the adult ICU between January 1, 2010, and June 21, 2013. Patients meeting the following study criteria were included: age ≥18 years, admission to the ICU, simultaneously drawn total and free serum phenytoin concentrations with albumin ≤48 hours of phenytoin draws. Study end points were the correlation as well as the level of agreement in the interpretation of the free and adjusted phenytoin concentrations using the Sheiner-Tozer formula in critically ill patients with hypoalbuminemia. RESULTS: A total of 238 patients were analyzed. Mean adjusted total phenytoin and free levels were 16.1 ± 8.1 and 1.5 ± 0.8 µg/mL, respectively (r = 0.817; P < 0.001). Absolute agreement with level interpretation between adjusted total phenytoin and free levels was 77% (κ = 0.633; P < 0.001). Adjusted phenytoin serum concentrations more frequently overestimated the free level. CONCLUSIONS: There is a significant correlation between free and adjusted total phenytoin levels using the Sheiner-Tozer equation in critically ill patients. However, disagreement was noted with interpretation, primarily because of the adjusted concentration overestimating the free level. This imprecision may lead to inaccurate decision making regarding the management of phenytoin in this patient population. Thus, free phenytoin levels should be utilized.

Impact of a clinical pharmacist stress ulcer prophylaxis management program on inappropriate use in hospitalized patients.

PURPOSE: Appropriate utilization of stress ulcer prophylaxis should be limited to high-risk, intensive care unit (ICU) patients. However, inappropriate stress ulcer prophylaxis use among all hospitalized patients remains a concern. The purpose of this study was to evaluate the clinical and economic impact of a novel pharmacist-managed stress ulcer prophylaxis program in ICU and general ward patients. METHODS: This retrospective, pre- and poststudy design was conducted in adult ICU and general ward patients at a large academic medical center between January 1, 2011 and January 31, 2012 to compare the rates of inappropriate stress ulcer prophylaxis before and after the implementation of a pharmacist-led stress ulcer prophylaxis management program. RESULTS: A total of 1134 unique patients consisting of 16,415 patient days were evaluated. The relative reduction in the rate of inappropriate stress ulcer prophylaxis days after program implementation in ICU and general ward patients was 58.3% and 83.5%, respectively (P < .001). The rates of ICU patients inappropriately continued on stress ulcer prophylaxis upon hospital discharge in the pre- and postimplementation groups were 29.9% and 3.6%, respectively (P < .001), whereas general ward patients significantly decreased from 36.2% to 5.4% in the pre- and postimplementation groups, respectively (P < .001). Total inpatient costs associated with all stress ulcer prophylaxis administered was $20,052.70 in the pre- and $3280.49 in the postimplementation group (P < .001), resulting in an estimated cost savings of > $200,000 annually. No differences in clinical outcomes were observed. CONCLUSIONS: The implementation of a pharmacist-managed stress ulcer prophylaxis program was associated with a decrease in inappropriate acid suppression rates during hospitalization and upon discharge, as well as significant cost savings.

Prolonged Acetaminophen-Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration, and Urinary Adduct Concentrations After Acetaminophen Overdose.

Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 ± 2.2 h versus 26.8 ± 1.1 h [mean ± SEM], respectively, p < 0.001). CVVHDF failed to remove detectable amounts of APAP-CYS in any of the nine subjects studied. Sixty-eight percent of 557 urine samples from 168 subjects contained no detectable APAP-CYS, despite levels in serum up to 16.99 µM. Terminal elimination half-life of serum APAP-CYS was prolonged in patients with renal failure for reasons unrelated to renal urinary adduct elimination, and consideration of prolonged elimination needs to be considered if attempting back-extrapolation of adduct concentrations. CVVHDF did not remove detectable APAP-CYS, suggesting approximate APAP-protein adduct molecular weights ≥ 50,000 Da. The presence of urinary APAP-CYS in the minority of instances was most compatible with renal adduct production and protein shedding into urine rather than elimination of serum adducts.

Ethylene glycol elimination kinetics and outcomes in patients managed without hemodialysis.

STUDY OBJECTIVE: Ethylene glycol remains an important toxic cause of metabolic acidosis and acute renal failure. Traditionally, inhibition of alcohol dehydrogenase along with hemodialysis has been used for treatment. Because of reported long elimination half-life of ethylene glycol during alcohol dehydrogenase inhibition, hemodialysis has been used in patients who are otherwise doing well to clear ethylene glycol. We study ethylene glycol elimination kinetics in patients treated with fomepizole, but without hemodialysis. METHODS: This was a retrospective, multicenter cohort study of patients older than 15 years who were treated at one of 3 medical centers during an 8-year period. Inclusion criteria were peak serum ethylene glycol concentration greater than 20 mg/dL, lack of renal failure on admission, treatment with fomepizole but without hemodialysis, and availability of serial serum ethylene glycol concentrations, allowing calculation of elimination half-life. The primary outcome variable was ethylene glycol elimination half-life; mortality and onset of renal failure were secondary outcome variables. RESULTS: During the study period, 85 patients were treated for ethylene glycol toxicity, of whom 40 met inclusion criteria. The mean serum ethylene glycol elimination half-life was 14.2 hours (SD=3.7 hours; 95% confidence interval 13.1 to 15.3 hours). One patient presented with metabolic acidosis on admission and developed mild transient renal insufficiency but did not require hemodialysis. No patient died. CONCLUSION: The mean elimination half-life of ethylene glycol in this population was shorter than previously reported without hemodialysis, and this select group of patients did well without enhanced elimination by hemodialysis.

The clinical significance of variations in ethanol toxicokinetics.

INTRODUCTION: Many variables affect the interpretation of an isolated ethanol level in an acutely intoxicated patient. This review demonstrates the significant variability in metabolism and elimination of ethanol, how it can differ between individuals, and the clinical importance of these variables. DISCUSSION: Isolated ethanol values in a clinical scenario are only a snapshot of a dynamic process. The individual pharmacokinetic differences of people make it extremely difficult to estimate ethanol elimination rates or calculate previous ethanol concentrations at the time of an accident because of medical-legal reasons. Not only are the techniques used in measuring ethanol concentrations in bodily fluids (blood, serum, breath, and urine) not equivalent, but also the units used to report ethanol concentrations are often misinterpreted. Acute and chronic tolerance and social adaptive changes make interpreting this isolated ethanol level extremely difficult. The purpose of this review is to enable the clinician to appropriately interpret ethanol concentrations. CONCLUSION: The clinical evaluation of a patient's inebriation is always more reliable than an isolated ethanol level for determining disposition. Only an estimation of a current serum ethanol level can be made if the blood draw was performed hours earlier. This review is clinically important because it shows the clinically significant variability in metabolism and elimination of ethanol and how it can differ between individuals. It will also describe different ways to measure ethanol concentrations and how to compare them. Finally, the interpretation of isolated ethanol levels will be discussed.

The effect of single-dose tramadol on oxycodone clearance.

We have noticed increased prescribing of tramadol by emergency physicians for breakthrough pain in patients chronically taking oxycodone. Both oxycodone and tramadol undergo oxidative metabolism by CYP2D6 and CYP3A4, suggesting the possibility that tramadol may compete with oxycodone for metabolism. A randomized controlled trial in 10 human volunteers was performed to determine if single-dose tramadol therapy would impair oxycodone clearance. Subjects were randomized whether to enter the control or experimental arm of the study first, with each subject serving as his or her own control. In the control arm, each subject received 10 mg immediate-release oxycodone orally and had serial plasma oxycodone and oxymorphone concentrations measured over 8 h. The experimental arm was identical except that 100 mg tramadol was ingested 1.5 h before oxycodone. Clearance divided by fraction absorbed (CL/f) was calculated using the dose and the area under the 8-h time-plasma oxycodone concentration curve. Peak plasma oxycodone concentrations (C(max)) and time until peak oxycodone concentrations (T(max)) were secondary outcome parameters. Group size was chosen to produce a power of 0.8 to detect a 20% difference in CL/f between study arms. Values for CL/f, C(max), and T(max) were compared between study arms using two-tailed, paired t-tests. No statistically significant difference between groups was demonstrated for any parameter. We failed to demonstrate that single doses of tramadol impaired oxycodone clearance.

Effect of intravenous albumin infusion on brain salicylate concentration.

BACKGROUND: Salicylate poisoning appears to result in death, despite supportive care, once a critical brain salicylate concentration is reached. The binding of salicylate to albumin is saturable; free plasma salicylate concentrations rise disproportionately to total drug levels. Because unbound salicylate distributes into the brain, the authors questioned whether an intravenous (i.v.) infusion of albumin would cause a redistribution of salicylate from the brain back into the plasma, which might allow enough time for hemodialysis to be instituted. OBJECTIVES: To determine if i.v. albumin infusion would lower brain salicylate concentrations through redistribution in a porcine model of acute salicylate poisoning. METHODS: In a randomized controlled trial, 17 swine under anesthesia and controlled ventilation received 400 mg/kg of sodium salicylate i.v. over 15 minutes. At 60 minutes, nine animals received 1.25 g/kg albumin (25% solution) i.v. over 15 minutes, while eight control animals received an equal volume of normal saline (5 mL/kg). Arterial pH was maintained between 7.45 and 7.55. Serial measurements of serum albumin as well as free and total salicylate concentrations were obtained, and urine was collected for measurement of total salicylate excretion. At 180 minutes, animals were killed and brains harvested for measurement of brain salicylate concentrations. RESULTS: Average peak serum total salicylate concentrations of 105.5 and 109 mg/dL were achieved in control and albumin-treated animals, respectively. Albumin infusion was accompanied by statistically significant increases in serum total salicylate concentrations (median from 79.5 to 86.9 mg/dL at 75 minutes), while levels decreased slightly in control animals. Serum free salicylate concentrations decreased slightly in albumin-treated animals, but the difference was not statistically significant. Median brain salicylate concentrations were about 14% lower in the albumin treatment group (17.8 mg/100 g brain) compared with controls (20.5 mg/100 g brain); this approached statistical significance (p = 0.075). Median urinary salicylate excretion was higher in the albumin-treated group (0.83 vs. 0.48 g; p = 0.072), with similar urinary pH and volumes in both groups. CONCLUSIONS: In this animal model of salicylate poisoning, i.v. infusion of 1.25 g/kg albumin was accompanied by a 14% decline in median brain salicylate concentrations, which approached statistical significance.