Candace Smith

Effects of intravitreal dexamethasone on concentration of intravitreal vancomycin in experimental methicillin-resistant Staphylococcus epidermidis endophthalmitis.

Intravitreal corticosteroids in the treatment of bacterial endophthalmitis remain controversial. We utilized an experimental rabbit model of methicillin-resistant Staphylococcus epidermidis endophthalmitis (i) to calculate the intravitreal vancomycin concentration in rabbit eyes receiving intravitreal vancomycin alone or in combination with intravitreal dexamethasone and (ii) to determine whether an intravitreal steroid has any effect on intravitreal vancomycin levels. All right eyes were infected and all left eyes were uninfected. The rabbits were divided into two treatment groups: (i) 32 eyes (group I) were injected with intravitreal vancomycin, 1.0 mg (0.1 ml); (ii) 32 additional eyes (group II) were injected with intravitreal dexamethasone, 400 micrograms (0.1 ml), in addition to vancomycin. Measurement of intravitreal vancomycin concentration was performed following sacrifice, utilizing a microbiologic agar diffusion assay. Analyses of intravitreal vancomycin concentrations were performed by using model-independent parameters, with area under the concentration-time curves derived by trapezoidal approximation. The intravitreal vancomycin concentration was significantly lower in both uninfected and infected group II eyes (P less than 0.002). Analysis of intravitreal vancomycin concentration-time relationships was performed by using a nonlinear least-squares regression program; data best fit a one-compartment model. In addition, no vancomycin-dexamethasone interaction could be demonstrated. The reduced level of intravitreal vancomycin in the presence of intravitreal dexamethasone may have important clinical implications.

Fluorescence polarization immunoassay: can it result in an overestimation of vancomycin in patients not suffering from renal failure?

It has been reported in scientific data that fluorescence polarization immunoassay (FPIA) results in overestimation of vancomycin in patients with renal failure. This overestimation is caused by interference of the degradation product, CDP-1, in this assay. Increases in vancomycin levels have also been reported in patients not suffering from renal failure (nonrenal failure patients) who are receiving vancomycin therapy for approximately 10 days or more. The authors tested whether this increase in vancomycin in nonrenal failure patients is a result of CDP-1 interfering with FPIA or a change in the pharmacokinetics of the drug. Serum vancomycin peak and trough samples were obtained from 10 adult (mean age ± SD: 55.9 years ± 17.5) nonrenal failure patients (mean ClCr ± SD: 76.2 mL/min ± 29.20) receiving vancomycin therapy for at least 10 days. These peaks and troughs were obtained at steady state and again at approximately 10 days of therapy. All serum samples were analyzed initially by fluorescence polarization immunoassay (FPIA, TDx®) (Abbot Diagnostics; Irving, TX) and again by enzyme multiplied immunoassay (EMIT Vancomycin Assay) (Dade Behring; San Jose, CA). Statistical analysis (Wilcoxon signed-rank test) determined that there was no difference between the values obtained from the two assays. This demonstrates that the increase in vancomycin levels is not caused by the accumulation of CDP-1 and may be the result of a change in the pharmacokinetics of the drug.

A Pharmacodynamic Study of Morphine and Its Glucuronide Metabolites After Single Morphine Dosing in Cancer Patients with Pain

Eleven morphine naïve patients with cancer-related pain were given a single dose of either intravenous morphine (n = 5) or oral morphine (n = 6). Blood sampling was performed over a 24-hr period and serial pain assessments were made using a categorical scale. Plasma samples were analyzed for morphine, morphine-6-glucuronide (M-6-G), morphine-3-glucuronide (M-3-G), and normorphine using high-performance liquid chromatography. In neither the intravenous nor oral group was there a correlation between analgesia duration and the half-lives of morphine and M-6-G. There was no correlation between the time to peak analgesia and time to peak concentration for morphine or M-6-G. There was no significant difference in absolute concentrations of M-6-G or M-3-6 nor in the ratio of M-3-G to M-6-G at peak analgesia versus relapse.

Drug absorption in celiac disease

PURPOSE Published evidence on established and theorized effects of celiac disease on drug absorption and pharmacokinetics is reviewed. SUMMARY Patients with celiac disease develop a variety of gastric disorders requiring oral medications, but the impact of damage to intestinal villi and other celiac disease sequelae on drug absorption remains poorly understood. A review of the pertinent literature (English-language articles on research in adults published during the period 1970-August 2012) identified several reports of altered drug absorption mechanisms in patients with celiac disease, including accelerated or delayed gastric emptying, increased permeability of jejunal mucosa, changes in intraluminal pH, decreased intestinal surface area, and reduced intestinal cytochrome P-450 enzymes. A small number of published studies suggest that celiac disease may be associated with altered drug absorption, resulting in higher serum concentrations of propranolol, lower peak concentrations of acetaminophen and practolol, higher dosing requirements with levothyroxine, impaired or delayed absorption of certain antibiotics, and other pharmacokinetic effects with a potential impact on medication efficacy and toxicity. However, these studies involved very small patient samples and were poorly controlled, with some yielding contradictory results. More and larger pharmacokinetic studies in patients with celiac disease-especially studies of drugs that are dosed empirically or are not amenable to dosage adjustment according to vital signs or laboratory values-are needed. CONCLUSION Given the sometimes conflicting data on drug absorption in the context of celiac disease, cautious medication selection, dosage adjustment, and monitoring for efficacy and potential adverse effects are advised.

Incidence of Sepsis and Mortality With Prior Exposure of HMG-COA Reductase Inhibitors in a Surgical Intensive Care Population.

ABSTRACT The anti-inflammatory properties of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may reduce the risk of developing sepsis in surgical intensive care patients and improve outcomes in those who do become septic. The objective of this study was to assess whether surgical intensive care unit (SICU) patients with prior exposure to HMG-CoA reductase inhibitors had a lower incidence of developing sepsis and improved outcomes. A retrospective cohort study was conducted. Patient demographic data, statin use, sequential organ failure assessment (SOFA) scores, vasopressor requirements, ventilator days, length of SICU stay, and mortality in septic patients were collected. Incidence of development of sepsis was determined using systemic inflammatory response syndrome criteria. Patients were grouped into cohorts based on whether they met the sepsis criteria and if they had previously received statins. Cohorts of patients who did and did not become septic with prior statin exposure were compared and an odds ratio was calculated to determine a protective effect. The setting was a SICU. The study comprised of 455 SICU patients and had no interventions. Among the 455 SICU patients, 427 patients were included for the final results. Patients receiving statins verses not receiving statins were similar in demographics. Previous statin exposure had a protective effect in the development of sepsis (9.77% on statins vs. 33.6% without statins; odds ratio 0.203, confidence interval 0.118–0.351). Of those patients who developed sepsis, there was a statistically significant decrease in 28-day mortality in patients with prior statin exposure (P = 0.0341). No statistical difference was noted in length of stay, vasopressor requirements, or days on mechanical ventilation. Prior exposure to statins may have a protective effect on the development of sepsis and decrease mortality in critically ill surgical patients.

Once-daily memantine: pharmacokinetic and clinical considerations.

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Modification of a Pharmacokinetics Course Design to Improve Student Performance

Objective. To determine if the addition of weekly quizzes or reducing the number of faculty members teaching improved third-year (P3) pharmacy students’ final grades in a clinical pharmacokinetics course. Design. Four sections of a pharmacokinetics and pharmacodynamics course were divided according to the number of faculty members teaching the course and the administration of weekly quizzes. Two sections were taught by 6 faculty members and 2 were taught by 3 faculty members. Also, 1 section in each group received weekly quizzes, creating a 2-by-2 design. Assessment. The performance of the 201 P3 students enrolled in the course was assessed by comparing the average of 3 examination grades while excluding quiz grades. The mean final grade of classes in which quizzes were not administered was lower than that for classes in which quizzes were administered (p=0.019). The mean final grade in classes taught by 3 faculty members vs 6 faculty members was higher, but not significantly. A positive significant correlation existed between performance in a prerequisite biopharmaceutics class and this advanced class. Conclusion. Making minor modifications to the delivery of a course, such as number of quizzes administered and number of faculty members teaching the course, had a positive impact on student performance. Grades in a prerequisite course may enable earlier identification of students at risk of poor performance in advanced courses.

Donepezil Dosing Strategies: Pharmacokinetic Considerations

Donepezil (Aricept) is a cholinesterase inhibitor approved for the treatment of Alzheimers disease. Immediate release formulations of 5- and 10-mg tablets were approved by the Food and Drug Administration in the United States in 1996. In July 2010, the Food and Drug Administration approved a 23-mg sustained release (SR) formulation. The SR formulation may provide additional benefit to patients receiving 10 mg daily but the incidence of adverse reactions is increased. We derived plasma concentration profiles for higher dose immediate-release formulations (15 mg once daily, 10 mg twice daily, and 20 mg once daily) and for the profile anticipated to result from the 23-mg SR formulation. Our model predicts similar steady-state concentration profiles for 10 mg twice daily, 20 mg once daily, and 23 mg SR once daily. This provides the theoretical basis for incremental immediate release dose escalation to minimize the emergence of adverse reactions and the potential to offer a cost-effective alternative to the SR formulation with currently approved generic immediate release formulations.

Cholinesterase Inhibitors: Applying Pharmacokinetics to Clinical Decision Making

BACKGROUND Cholinesterase inhibitors are indicated for the treatment of Alzheimer-type dementia. There are few direct comparative studies of adverse effects or studies to suggest clinical superiority of one inhibitor over the others. OBJECTIVE The objective of this study was to relate pharmacokinetic differences among the agents to potential clinical considerations. METHODS Population pharmacokinetics were obtained from US Food and Drug Administration-approved label information and published literature. Plasma concentration-time profiles were derived from these parameters using noncompartmental pharmacokinetic modeling. RESULTS Plasma concentration profiles differed significantly among different agents and between different formulations of the same agent. CONCLUSIONS The initial choice among the various cholinesterase inhibitors requires consideration to adherence and cost. Consideration to differences in pharmacokinetics among these drugs provides a better understanding for the clinical practice of dose titration, identification and management of drug-related side effects, and lapses in therapy. Pharmacokinetic considerations among the various agents and formulations provide the clinician with options to enhance therapy when these agents are chosen for treatment of patients with Alzheimer-type dementia.

1399: PHENYLEPHRINE VS. NOREPINEPHRINE EFFECT ON 28-DAY MORTALITY AND SICU LENGTH OF STAY IN SEPTIC SHOCK

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: Patients with refractory septic shock often require high dose vasopressors to augment mean arterial pressure (MAP). However, in patients with a concomitant acidemia, adrenergic receptor activity may be diminished with a need for alternative agents to maintain MAP. Vasopressin (AVP) is often utilized in these patients as an alternative vasoactive agent and to reduce catecholamine (CA) requirements. This evaluation attempted to determine the effect of pH on AVP response in patients with refractory septic shock. Methods: This was a single center, retrospective cohort of patients who received adjunctive, fixeddose AVP for septic shock for at least 6 hours in the Medical, Surgical or NeuroSciences ICU. Patients were classified based on pH at AVP initiation (< 7.3 or ≥7.3); AVP response and clinical outcomes were compared between groups. Additionally, a multivariable logistic regression for AVP response was created. Response was defined as a decrease in CA requirements and achievement of MAP ≥65 mmHg 6 hours after AVP initiation. Results: There were 815 patients included: 349 with pH < 7.3, 466 with pH ≥7.3. There were significant differences in characteristics at AVP initiation when comparing those with pH < 7.3 vs. pH ≥7.3, including APACHE III score (111.7 ± 37.6 vs. 102.7 ± 31.3; p < 0.01), lactate concentration (6.3 ± 5.5 vs. 3.6 ± 2.5; p < 0.01) and CA dose (31.6 ± 23.9 vs. 26.7 ± 17.5; p < 0.01). Patients with pH < 7.3 had a lower incidence of AVP response (35.5% vs. 51.1%; p < 0.01), higher rates of ICU mortality (69.3% vs. 54.5%; P < 0.01), and fewer ICU free days (1.4 ± 3.2 vs. 2.2 ± 3.7; p < 0.01). Additionally, patients with pH < 7.3 also had significantly higher CA doses at 2, 6 and 12 hours after AVP initiation (p < 0.01 for each time point). After adjustment for baseline characteristics, pH < 7.3 was independently associated with a lower odds of AVP response (OR 0.57 [95%CI 0.470.83]; p = 0.016). Conclusions: Having a pH < 7.3 was found to be independently associated with a decreased odds of AVP response in patients with septic shock. Based on these findings, caution should be warranted when utilizing the presence of acidemia as an indication for initiation of AVP.