Comparison of vancomycin area under the concentration-time curve (AUC) using two-point pharmacokinetics versus two open-access online single-concentration vancomycin calculators.

WHAT IS KNOWN AND OBJECTIVE: Current vancomycin monitoring guidelines recommend the use of area under the concentration-time curve (AUC24 ) monitoring in patients with serious Methicillin-Resistant Staphylococcus aureus (MRSA) infections by utilizing either a Bayesian approach or first-order analytic equations. Several open-access websites exist that allow estimation of vancomycin AUC24 with the use of a single steady-state concentration. It is uncertain how these open-access calculators perform against guideline-recommended methods. The objective was to compare AUC24 estimates from two online, open-access, single-concentration vancomycin calculators compared with the two-point pharmacokinetic (2PK) method. METHODS: AUC24 estimates were made using the 2PK reference method and the single-concentration vancomycin calculators, ClinCalc and VancoPK. The AUC24 estimates from the 2PK reference method were compared to the online calculators by assessing bias (median AUC24 difference) and precision (AUC24 difference ± 100 mg*h/L). Clinical precision was also assessed by characterizing the frequency that the 2PK reference method and the online calculators showed clinical disagreement based on the following AUC24 categories: (1) AUC24 < 400 mg*h/L; (2) AUC24 400-600 mg*h/L and (3) AUC24 > 600 mg*h/L. RESULTS AND DISCUSSION: A total of 253 patients were included in the study. The AUC24 estimates from the ClinCalc and VancoPK single-concentration vancomycin calculators showed some bias and imprecision, though VancoPK appeared to have less. Clinical disagreement versus the 2PK reference method occurred in 31.2% and 19.4% of AUC24 estimates from the ClinCalc and VancoPK single-concentration vancomycin calculators, suggesting clinical imprecision. WHAT IS NEW AND CONCLUSION: The AUC24 estimates from single-concentration, online vancomycin calculators showed some bias and imprecision in comparison to the 2PK method. Institutions should validate these online, trough-only calculators relative to a 2PK method in their patient populations prior to adoption as standard-of-care.

A single-center cost analysis assessing a change in vasopressin formulation.

PURPOSE: Cost savings achieved at an academic medical center by reformulating the institution's standard vasopressin infusions to reduce waste are described. SUMMARY: After a retrospective review of vasopressin utilization over a 4-month period revealed that only approximately 40% of dispensed vasopressin units were actually administered to patients, pharmacy leaders determined that the institution's standard vasopressin concentration for continuous infusions (100 units in 100 mL of sodium chloride 0.9% injection) was resulting in substantial waste, as many infusion preparations were not needed within the 18- to 24-hour expiration window. A concentration of 20 units/100 mL was adopted as the new standard formulation for vasopressin continuous infusions, with use of alternative concentrations allowed on a restricted basis. A pre-post study to assess the impact of the formulation change indicated a 38.7% decrease in vasopressin utilization (from 21,900 to 8,480 units) relative to utilization in a retrospective sample of patients who received vasopressin infusions prior to the formulation change. This reduced utilization equated to a cost decrease of $55,656.20 (as calculated on the basis of 2017 cost estimates) or $77,214.23 (as calculated on the basis of 2019 cost estimates) for the time period collected. It was estimated that the new formulations could yield annual cost savings ranging from $222,625 to $308,857. CONCLUSION: To our knowledge, this is the first description of cost savings following a change in formulation of vasopressin for continuous infusions. Other institutions could consider employing a similar approach in addition to the previously reported cost-saving interventions, such as lower vasopressin starting doses and vasopressin restriction policies.

Cost comparison of AUC:MIC- versus trough-based vancomycin monitoring for MRSA bacteremia.

OBJECTIVES: It is anticipated that the updated vancomycin monitoring guidelines will reconsider area under the concentration-time curve to minimum inhibitory concentration ratio (AUC:MIC)-based monitoring instead of trough-based monitoring for methicillin-resistant Staphylococcus aureus (MRSA) infections. The AUC:MIC can be estimated using 2 steady-state serum concentrations and first-order pharmacokinetic equations or Bayesian modeling. The cost of AUC:MIC-based monitoring compared with trough-based monitoring is unknown and has been cited as a potential barrier to implementing this monitoring method. The objective of this study was to compare the total vancomycin drug and monitoring cost for patients with MRSA bacteremia who received AUC:MIC- or trough-based monitoring. DESIGN: This was a single-center, retrospective cohort study. SETTING AND PARTICIPANTS: This study included patients who were treated for MRSA bacteremia between May 1, 2013 and December 31, 2018, with an 8-month washout period between trough and AUC:MIC-based monitoring at our institution. OUTCOME MEASURES: The primary outcome was the aggregate cost of vancomycin therapy, which included the cost associated with sample collection (i.e., supply cost and nursing time), sample analysis (i.e., assay cost and laboratory technician time), result interpretation (i.e., pharmacist time), and drug cost (i.e., cost of total administered vancomycin dose) during the hospital stay. RESULTS: A total of 52 patients met inclusion criteria with 26 patients in each group. The median (interquartile range) total vancomycin drug and monitoring cost was $338.14 ($235.07-$601.05) for the AUC:MIC-based group compared with $316.79 ($253.36-$520.96) for the trough-based group (P = 0.687). CONCLUSION: Vancomycin monitoring using 2 steady-state serum concentrations and first-order pharmacokinetic equations to calculate AUC:MIC was no more costly than a trough-based approach in patients with MRSA bacteremia at our institution.

The Culture of Carbapenem Overconsumption: Where Does It Begin? Results of a Single-Center Survey.

Purpose: The United States has seen an increased consumption of carbapenem antibiotics in recent years. The increased utilization of these agents has potential negative consequences, including the increasing incidence of carbapenem-resistant Enterobacteriaceae. Reasons for the rise in carbapenem use among providers in acute care hospitals are not well elucidated in literature. The objectives of this study were to identify factors that influence empiric carbapenem use among providers in a single academic medical center, and to assess therapeutic knowledge pertaining to carbapenem use. Methods: A cross-sectional, single-center, 9-item electronic research survey was developed independently and validated by an infectious diseases pharmacist and infectious diseases physician. The survey was distributed to email accounts of providers at a single academic medical center. Demographic data, factors affecting carbapenem prescription, and baseline therapeutic knowledge were assessed. Results: Ninety-five of 416 providers responded to the survey (response rate of 22.8%). Respondents were well distributed across all levels of training with primary roles in internal medicine and surgery. The most important factors influencing empiric carbapenem use were suspected pathogens at the site of infection, drug allergies, history of multidrug resistant organisms, severity of illness, type of infection, and local resistance rates. A recommendation from a pharmacist was selected as the most likely factor for deterring carbapenem use. Misconceptions pertaining to penicillin drug allergy and beta-lactam cross reactivity, knowledge of local resistance rates according to the institutional antibiogram, and comparative efficacy data for carbapenems were apparent across all levels of training. Conclusions: Provider misconceptions regarding several factors appear to contribute to unnecessary use of carbapenems. An opportunity exists for hospital pharmacists to improve the prescribing patterns of carbapenems by correcting provider misconceptions through education.

Readiness to implement vancomycin monitoring based on area under the concentration-time curve: A cross-sectional survey of a national health consortium.

PURPOSE: The purpose of this study was to (1) determine whether academic medical centers implemented area under the concentration-time curve (AUC)-based monitoring for vancomycin and (2) characterize perceived barriers to implementation and challenges experienced during the implementation process. METHODS: A multicenter, cross-sectional electronic survey was distributed to pharmacy representatives from 124 academic medical centers within the Vizient University Health System Consortium Pharmacy Network. RESULTS: Seventy-eight institutions completed the survey, representing a 62.9% response rate. Most institutions were approximately 500-1,000 beds (68/78, 87.2%), and pharmacists were primarily responsible for vancomycin therapeutic drug monitoring (66/78, 84.6%) using pharmacist-driven protocols (57/78, 73.1%). Less than one fourth (18/78, 23.1%) of responding academic medical centers performed AUC-based vancomycin monitoring, and the majority (12/18, 66.7%) used 2-point pharmacokinetics, with a smaller fraction using either Bayesian software or population-based pharmacokinetics. Of the responding institutions that only perform trough-based therapeutic drug monitoring (60/78, 76.9%), most (53/60, 88.3%) did not plan to or were unsure about transitioning to AUC-based monitoring within the next year. Both the most common challenge encountered (13/18, 72.2%) for institutions performing AUC-based monitoring and the most common barrier (44/60, 73.3%) to implementation of this monitoring strategy were pharmacist and/or provider unfamiliarity. CONCLUSION: The majority of surveyed academic medical centers have not yet implemented AUC-based vancomycin monitoring, and most institutions did not plan to adopt or were unsure about adopting this monitoring strategy within the next year.

Ibalizumab, a Novel Monoclonal Antibody for the Management of Multidrug-Resistant HIV-1 Infection.

Limited antiretrovirals are currently available for the management of multidrug-resistant (MDR) HIV-1 infection. Ibalizumab, a recombinant humanized monoclonal antibody, represents the first novel agent for HIV-1 management in over a decade and is the first monoclonal antibody for the treatment of MDR HIV-1 infection in combination with other forms of antiretroviral therapy in heavily treatment-experienced adults who are failing their current antiretroviral regimen. Ibalizumab demonstrates a novel mechanism of action as a CD4-directed postattachment inhibitor and has a favorable pharmacokinetic profile that allows for a dosing interval of every 14 days after an initial loading dose. Clinical studies have demonstrated reasonably substantial antiretroviral activity with ibalizumab among a complex patient population with advanced HIV-1 infection who are receiving an optimized background regimen, where limited therapeutic options exist. Ibalizumab was well tolerated in clinical trials, and the most common adverse effects included diarrhea, nausea, dizziness, fatigue, pyrexia, and rash. Resistance to ibalizumab has also been observed via reduced expression or loss of the potential N-linked glycosylation sites in the V5 loop of the envelope glycoprotein 120. The mechanism of action, pharmacokinetic parameters, efficacy, and safety of ibalizumab present an advance in the management of MDR HIV-1 infection. Future studies and postmarketing experience will further determine longer-term clinical efficacy, safety, and resistance data for ibalizumab.

Implementation of a two-point pharmacokinetic AUC-based vancomycin therapeutic drug monitoring approach in patients with methicillin-resistant Staphylococcus aureus bacteraemia.

Limited evidence exists evaluating pharmacokinetic thresholds for vancomycin efficacy and nephrotoxicity using non-Bayesian methods. The objective of this study was to evaluate the 24-h steady-state vancomycin area under the concentration-time curve (AUC24) thresholds for efficacy and nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus bacteraemia (MRSA-B) after implementing two-point pharmacokinetic therapeutic drug monitoring. A single-centre, retrospective cohort study was performed including adult patients admitted between 1 June 2016 and 1 January 2018 with MRSA-B treated with vancomycin for ≥72 h. The AUC24 was calculated using peak and trough vancomycin serum concentrations. Clinical success was defined as defervescence and blood culture sterilisation by Day 7. Nephrotoxicity was defined as an increase in serum creatinine of >0.5 mg/dL (or ≥50%) from baseline. Classification and regression tree (CART) analyses were performed to identify AUC24 thresholds for efficacy and nephrotoxicity. Forty-six patients were included in the study. Clinical success and nephrotoxicity were observed in 81.8% and 13.0%, respectively. The CART-derived vancomycin AUC24 thresholds for clinical success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L, respectively. Patients with an AUC24 ≥297 mg·h/L had a >2.7-fold increase in clinical success compared with those who did not (89.5% vs. 33.3%, respectively; P = 0.01), and patients with an AUC24 ≥710 mg·h/L had a >7-fold increase in nephrotoxicity compared with those with an AUC24 <710 mg·h/L (66.7% vs. 9.3%, respectively; P = 0.04). This study supports current recommendations to target vancomycin AUC24 values of 400-600 mg·h/L when calculated using two-point pharmacokinetics, although a wider range may exist.

Association between prothrombin time and bleeding in hospitalized patients receiving rivaroxaban.

PURPOSE: Results of an investigation of the pharmacodynamic effect of rivaroxaban anticoagulation, as measured by prothrombin time (PT), on bleeding risk and other outcomes in hospitalized patients are reported. METHODS: In a single-center retrospective cohort study, adult inpatients who had a PT measured within 24 hours after rivaroxaban administration during a designated 23-month period were identified. Patients who experienced in-hospital bleeding events were compared with those who did not. A multivariable logistic regression model was used to quantify the association between PT and bleeding events while adjusting for albumin levels and use of nonsteroidal antiinflammatory drugs and/or antiplatelet agents. Thromboembolic events were assessed as a secondary outcome. RESULTS: A total of 199 patients met the criteria for inclusion in the analysis; 41 experienced a bleeding event. Among patients with a PT of ≥30 seconds versus a PT of <30 seconds, the overall rate of bleeding events was significantly higher (38.7% versus 17.3%, p = 0.0067). Results of multivariable regression modeling showed that a PT of ≥30 seconds correlated with an approximately 3-fold higher bleeding risk (odds ratio, 3.25; 95% confidence interval, 1.09-9.66). Hypoalbuminemia was also a positive predictor of bleeding risk. There was no significant between-group difference in thromboembolic events. CONCLUSION: In hospitalized patients receiving rivaroxaban who had coagulation tests performed, a PT of ≥30 seconds was associated with a higher risk of bleeding. Hypoalbuminemia was also associated with bleeding in this population.

Clinical review of delafloxacin: a novel anionic fluoroquinolone.

Delafloxacin is a novel anionic fluoroquinolone (FQ) approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by a number of Gram-positive and Gram-negative organisms including MRSA and Pseudomonas aeruginosa. The unique chemical structure of delafloxacin renders it a weak acid and results in increased potency in acidic environments. In Phase III studies, delafloxacin had similar outcomes to comparator regimens for treatment of ABSSSIs, and was well tolerated overall. Similar to other FQs, delafloxacin is available in both intravenous and oral formulations, but differs in that delafloxacin exerts a minimal effect on cytochrome P450 enzymes and on the corrected QT interval. This novel FQ has the potential to be utilized across a wide variety of clinical settings; however, post-marketing surveillance and long-term safety and resistance data will be essential to identify optimal use scenarios.