Christopher D. Miller

Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End‐Stage Renal Disease Requiring Chronic Hemodialysis

Despite prescribing guidance, limited data exist to describe the use of apixaban in patients with end‐stage renal disease (ESRD) requiring hemodialysis (HD). Current apixaban dosing recommendations for this patient population are based largely on a single‐dose pharmacokinetic study of eight patients. We describe the clinical application and pharmacodynamic monitoring of apixaban in a 62‐year‐old 156‐kg African‐American woman with nonvalvular atrial fibrillation and ESRD requiring hemodialysis who developed calciphylaxis while receiving warfarin therapy. Based on a multidisciplinary clinical judgment decision due to concern for drug accumulation after multiple doses in patients with ESRD receiving HD, she was anticoagulated with apixaban 2.5 mg twice/day, as opposed to 5 mg twice/day as recommended by the package insert. Antifactor Xa monitoring was used, and resultant peak and trough apixaban concentrations were above the upper limit of detection for our clinical laboratory (more than 2.00 IU/ml). On day 7 of her hospitalization, the patient developed gastrointestinal bleeding, and apixaban was discontinued; no further clinical signs of bleeding occurred during her subsequent hospitalization course. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between apixaban exposure and the manifestation of gastrointestinal bleeding. The patient ultimately died 44 days after the acute bleeding event; however, coagulation concerns were not implicated in the patients death. To our knowledge, this is the first case report that describes apixaban use and associated antifactor Xa monitoring in a patient with ESRD receiving HD, and it provides concern for current apixaban dosing recommendations in this patient population. Further pharmacokinetic and clinical data are likely necessary to better characterize apixaban use in these patients to optimize safety and efficacy.

Are Vancomycin Trough Concentrations of 15 to 20 mg/L Associated With Increased Attainment of an AUC/MIC ≥ 400 in Patients With Presumed MRSA Infection?

Purpose: To determine whether there is an association between higher vancomycin trough concentrations and attainment of a calculated area under the concentration–time curve (AUC)/minimum inhibitory concentration (MIC) ≥400. Methods: A retrospective analysis was conducted among vancomycin-treated adult patients with a positive methicillin-resistant Staphylococcus aureus (MRSA) culture. Attainment of a calculated AUC/MIC ≥400 was compared between patients with troughs in the reference range of 15 to 20 mg/L and those with troughs in the following ranges: <10, 10 to 14.9, and >20 mg/L. Nephrotoxicity was assessed as a secondary outcome based on corrected average vancomycin troughs over 10 days of treatment. Results: Overall, 226 patients were reviewed and 100 included. Relative to troughs ≥10, patients with vancomycin troughs <10 mg/L were 73% less likely to attain an AUC/MIC ≥400 (odds ratio [OR] 0.27, 95% confidence interval [CI]: 0.01-0.75). No difference was found in the attainment of an AUC/MIC ≥400 in patients with troughs of 10 to 14.9 mg/L and >20 mg/L when compared to patients with troughs of 15 to 20 mg/L. The mean corrected average vancomycin trough was higher in patients developing nephrotoxicity compared to those who did not (19.5 vs 14.5 mg/L, P < .001). Conclusion: Achieving vancomycin serum trough concentrations of 15 to 20 mg/L did not result in an increased attainment of the AUC/MIC target relative to troughs of 10 to 14.9 mg/L but may increase nephrotoxicity risk.

Evaluation of Dabigatran Utilization and Risk Among Hospitalized Patients

Background: Few data exist to evaluate the use of dabigatran among hospitalized patients and this population that may be at increased risk for toxicity or reduced efficacy. As such, the objectives of this study were to describe the characteristics of hospitalized patients prescribed dabigatran and to compare select characteristics with patients included in the Randomized Evaluation of Long-Term Anticoagulation (RE-LY) phase III clinical trial. Methods: A cross-sectional study was performed at Upstate University Hospital. Select patient characteristics, including age, renal function, and drug interaction exposure, were compared with those for patients in the RE-LY trial. Results: The study included 140 patients. Mean age was 69.7 years (SD = 13.8) and 72 (51.4%) were male. The mean CHADS2 score was 2.48 as compared with 2.2 in RE-LY. Significantly more patients in our study had moderate to severe renal dysfunction (creatinine clearance [CrCl] < 50 mL/min) as compared with the RE-LY trial (27.5% vs 19.4%, P = .0207) when analyzing our study patients’ worst recorded CrCl. Among the 29 patients prescribed dose-adjusted dabigatran, 3 were correctly dose adjusted, 2 were overdosed, and 26 were underdosed. At least 1 pharmacokinetic drug interaction with dabigatran occurred in 110 study patients (78.6%). Use of proton pump inhibitors was more predominant in our study population when compared with RE-LY (64.3% vs 13.9%, P < .0001). Conclusions: Hospitalized patients exhibit multiple characteristics that place them at heightened risk for altered dabigatran drug concentrations and may have a heightened risk for clinical sequelae related to dabigatran use.

Y-site Incompatibility between Premix Concentrations of Vancomycin and Piperacillin-Tazobactam: Do Current Compatibility Testing Methodologies Tell the Whole Story?:

Background Published literature has demonstrated commercially available premix vancomycin (5 mg/mL) and piperacillin-tazobactam (67.5 mg/mL) as physically compatible via simulated Y-site methodology. Compatibility via actual Y-site infusion has yet to be established. Objective To assess and compare the compatibility of commercially available premix concentrations of vancomycin and piperacillin-tazobactam via simulated and actual Y-site evaluation. Methods Vancomycin and piperacillin-tazobactam were tested using simulated and actual Y-site infusion methodologies. Simulated Y-site compatibility was performed using previously published methods via visual inspection, turbidity evaluation, and pH evaluation. Evaluation occurred immediately, 60 minutes, 120 minutes, and 240 minutes following mixing for each mixture and control. Mixtures were considered physically incompatible if there was visual evidence of precipitation or haze, an absorbance value was greater than 0.01 A, or an absolute change of 1.0 pH unit occurred. Actual Y-site infusion was simulated to mirror antibiotic infusion in the clinical setting by nursing personnel using smart pumps and intravenous tubing. Results No evidence of physical incompatibility was observed during simulated Y-site testing via visual inspection, turbidity assessment, and pH evaluation. Conversely, physical incompatibility was observed to the unaided eye within 2 minutes during actual Y-site infusion. Conclusions Despite observed compatibility between vancomycin and piperacillin-tazobactam via simulated Y-site testing, visual evidence of physical incompatibility was observed during actual Y-site infusion. This poses a potential compromise to patient safety if these antibiotics are administered simultaneously in the clinical setting. Actual Y-site testing should be performed prior to clinical adoption of compatibility studies that are based solely on simulated methodologies.

Characterization of Drug-Related Problems Occurring in Patients Receiving Outpatient Antimicrobial Therapy:

Background: Despite the numerous benefits of outpatient parenteral antimicrobial therapy (OPAT), appreciable risks of drug-related problems (DRPs) exist. No studies to date comprehensively assess DRPs in this population. Objectives: Objectives of this study were to (1) characterize the frequency and types of DRPs experienced by patients discharged on OPAT and (2) determine the fraction of adverse drug reactions (ADRs) resulting in hospital readmission or emergency department (ED) presentation and changes in therapy. Methods: This was a retrospective chart analysis evaluating consecutive adult patients discharged on OPAT between May 2015 and October 2015. Patients were assessed for the presence of DRPs until the cessation of antimicrobial treatment, including oral step-down therapy. The outcome of each ADR was recorded, including those resulting in hospital readmissions, presentation to the ED, or changes in antimicrobials. Results: Among 144 patients discharged on OPAT, 199 DRPs occurred in 91 (63.2%) patients. Harm and potential impaired efficacy occurred in 76.9% and 23.1%, respectively. The ADRs comprised 59% of DRPs, occurring in 44.4% of patients. The second most common DRP type was drug interactions (DIs), accounting for 22.6% of DRPs. Rifampin, fluoroquinolones, and daptomycin had the highest frequencies of preventable DRPs in the form of DIs, whereas cephalosporins had the fewest DRPs. Approximately 26% of ADRs caused changes in therapy and 9% resulted in hospital readmission or ED utilization. Conclusion: DRPs with the potential to cause patient harm or impair treatment efficacy often occur with OPAT, most commonly ADRs and DIs. Enhanced monitoring and transitions of care management may reduce the incidence of these DRPs.

Prevalence and Predictors of Important Telaprevir Drug Interactions Among Patients Coinfected With Hepatitis C and Human Immunodeficiency Virus

Background: Among patients with HIV and hepatitis C (HCV) coinfection, drug–drug interactions involving nonstructural protein 3/4 (NS3/4A) serine protease inhibitors for HCV infection are an important concern because these drugs affect cytochrome P450 metabolism and p-glycoprotein transporters. Objectives: The primary objective was to determine the prevalence of clinically significant drug–drug interactions (CSDDIs) in HIV/HCV coinfected patients if telaprevir-based HCV therapy is added to patients’ medication regimens. Secondary objectives were to identify antiretroviral therapy (ART) regimens associated with the lowest risk of CSDDI and determine the clinical risk factors. Methods: A cross-sectional study was performed among adult HIV/HCV coinfected patients. Demographics, comorbidities, social history, and medication lists were extracted from medical records. For each patient, CSDDIs were identified by entering all medications and pegylated interferon, ribavirin, and telaprevir into Lexi-Interact drug interaction software. The number and nature of CSDDIs were recorded before and after addition of telaprevir-based therapy. Results: There were 335 patients included. Prior to the addition of telaprevir-based HCV therapy, there was a high frequency (82.1%) of any CSDDI. After the addition of telaprevir-based HCV therapy, the frequency of any CSDDI increased to 97% (P < .001). Contraindicated interactions rose from 20.0% to 38.2% of patients after addition of telaprevir-based therapy. Use of ≥10 non-HIV medications, dyslipidemia, and HIV protease inhibitors were independently associated with the occurrence of a contraindicated interaction. Conclusions: Clinicians considering initiating telaprevir in HIV/HCV coinfected patients should be vigilant of drug–drug interactions, particularly among patients with dyslipidemia, those using ≥10 non-HIV medications, and those using HIV protease inhibitors.

Changes in Pharmacy Residency Training Design Between 2012 and 2017: A Perspective of Academic Medical Centers

Purpose:The role of health-system pharmacists continues to expand, and this area of pharmacy practice increasingly requires augmented baseline training. It is unclear how Post Graduate Year 1 (PGY-1) pharmacy residencies may be changing to meet these needs.The objectives of our survey were to describe PGY-1 pharmacy residency program design among academic medical centers, characterize program changes enacted over 5-year period, and describe career paths among PGY-1 pharmacy residency graduates. Methods: A 32-item questionnaire was developed independently, which was reviewed and validated by 4 residency program directors. The survey was uploaded to an online survey tool and sent electronically to residency program directors of 109 Vizient academic medical centers with PGY-1 pharmacy residency programs. Residency program directors were identified from a list of Vizient-participating hospitals. The survey was re-sent at 2-week intervals on 4 occasions to improve response rates. SPSS version 23.0 was used to analyze the data. Results: Overall, 49 (45%) of hospitals responded to the survey. Survey responses showed statistically significant increases over the 5-year survey period in the following areas: the number of PGY-1 resident positions offered (P = .001), percent of time spent on teaching experiences (P = .001), and percentage of PGY-1 residents pursuing PGY-2 or fellowship training (P = .026). Conclusion: We found that PGY-1 pharmacy residency programs at Vizient academic medical centers have undergone limited changes over the 5-year survey period and substantial variation exists between program designs. The most common change to program design was an increase in the percentage of time residents spend on teaching experiences. There was an increase in residents pursuing PGY-2 or fellowship training, which may suggest a shift toward increased specialization in clinical pharmacy practice or may reflect changes in the availability of job opportunities.

Pharmacy impact on medication reconciliation in the medical intensive care unit

Objective: Pharmacy-driven medication history (MH) programs have been shown to reduce the number of serious or potentially life-threatening (S/PLT) medication discrepancies (MDs) in many settings, but not Intensive Care Units (ICUs). Methods: MHs were repeated over a 6-week period. Demographics, number, and nature of MDs were documented. Discrepancy severity was graded using a previously published method. Primary outcome was the proportion of MHs containing >1 S/PLT MDs. Findings: Sixty-three MHs were repeated. Pharmacy MHs were less likely to contain ≥1 S/PLT MDs (0% vs. 50%, P < 0.001). Conclusion: Pharmacy MHs contained fewer S/PLT MDs in this small sample. S/PLT MDs on admission and home medication lists were common in patients admitted to the medical ICU. Pharmacy-driven medication reconciliation (MR) reduced the number and frequency of these discrepancies. Further research is required to improve current MR procedures.

Significant Hyperbilirubinemia and Acute Hepatocellular Jaundice in a Pediatric Patient Receiving Deferasirox: A Case Report

Despite a boxed warning, postmarketing reports of deferasirox-associated hepatic injury in patients with chronic transfusions are not well described. Hepatic impairment, including failure, has been reported to occur more frequently in patients older than 55 years and in those with significant comorbidities, including liver cirrhosis and multiorgan failure. In this case report, we describe significant hyperbilirubinemia and acute hepatocellular jaundice related to deferasirox in a 7-year-old female being treated for iron overload secondary to chronic transfusions. This report outlines a unique case without preexisting risk factors in which other causes of liver injury are excluded as defined by the Roussel Uclaf Causality Assessment Method, which indicates a probable score of deferasirox causing the injury.

The Impact of AUC-Based Monitoring on Pharmacist-Directed Vancomycin Dose Adjustments in Complicated Methicillin-Resistant Staphylococcus aureus Infection

Objective: This study aimed to assess the impact of area under the curve (AUC)-based vancomycin monitoring on pharmacist-initiated dose adjustments after transitioning from a trough-only to an AUC-based monitoring method at our institution. Methods: A retrospective cohort study of patients treated with vancomycin for complicated methicillin-resistant Staphylococcus aureus (MRSA) infection between November 2013 and December 2016 was conducted. The frequency of pharmacist-initiated dose adjustments was assessed for patients monitored via trough-only and AUC-based approaches for trough ranges: 10 to 14.9 mg/L and 15 to 20 mg/L. Results: Fifty patients were included: 36 in the trough-based monitoring and 14 in the AUC-based-monitoring group. The vancomycin dose was increased in 71.4% of patients when troughs were 10 to 14.9 mg/L when a trough-only approach was used and in only 25% of patients when using AUC estimation (P = .048). In the AUC group, the dose was increased only when AUC/minimum inhibitory concentration (MIC) <400; unchanged regimens had an estimated AUC/MIC ≥400. The AUC-based monitoring did not significantly increase the frequency of dose reductions when trough concentrations were 15 to 20 mg/L (AUC: 33.3% vs trough: 4.6%; P = .107). Conclusions: The AUC-based monitoring resulted in fewer patients with dose adjustments when trough levels were 10 to 14.9 mg/L. The AUC-based monitoring has the potential to reduce unnecessary vancomycin exposure and warrants further investigation.