Annals of Pharmacotherapy

Background: Optimizing vancomycin dosing may help eradicate bacteria while avoiding resistance. The guidelines recommend loading doses; however, there are no data to demonstrate that this may result in a more rapid achievement of therapeutic troughs. Objective: To evaluate the percentage of troughs reaching therapeutic levels at 12, 24, and 36 hours following an initial vancomycin dose of 30 mg/kg compared with 15 mg/kg. Methods: This prospective, randomized study was performed in a community academic medical center. Patients who were to receive vancomycin in the emergency department were randomized to an initial traditional dose of 15 mg/kg or a 30-mg/kg loading dose followed by 15 mg/kg every 12 hours for 3 doses. Patients weighing >120 kg or with creatinine clearances <50 mL/min were excluded. Results: In total, 99 patients were enrolled; 12 hours after the initial dose of vancomycin, there was a significantly greater proportion of patients reaching target trough levels of 15 mg/L among the patients who received a loading dose as compared with a traditional dose (34% vs 3%, P < 0.01). This trend continued at 24 hours but was not statistically significant. At 36 hours, there was no difference in the percentage of patients reaching target levels between the 2 groups. No statistically significant difference in nephrotoxicity or adverse events among the 2 groups was demonstrated. Conclusion: A loading dose of 30 mg/kg of vancomycin achieved a higher percentage of therapeutic levels at 12 hours when compared with the traditional dose of 15 mg/kg, without increased nephrotoxicity or adverse events.

Background: Adjunctive medications to manage alcohol withdrawal syndrome (AWS) in patients not adequately responding to escalating doses of benzodiazepines (BZDs) are limited. The use of the N-methyl-d-aspartate antagonist ketamine, may serve as an effective adjunct agent; however, no published data currently exist for this practice. Objective: To determine the safety and efficacy of adjunct ketamine for management of AWS. Methods: The study was a retrospective review of adult patients from April 2011 to March 2014 who were administered ketamine specifically for management of AWS. Outcomes included changes in BZD requirements and ketamine-related adverse reactions. Results: Of 235 patients screened, 23 patients met study eligibility. Ketamine was initiated primarily with toxicology consultation for significant BZD requirements or delirium tremens. The mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively. Mean initial infusion dose and median total infusion rate during therapy were 0.21 and 0.20 mg/kg/h, respectively. There was no change in sedation or alcohol withdrawal scores in patients within 6 hours of ketamine initiation. The median change in BZD requirements at 12 and 24 hours post–ketamine initiation were −40.0 and −13.3 mg, respectively. The mean time to AWS resolution was 5.6 days. There was one documented adverse reaction of oversedation, requiring dose reduction. Conclusions: Ketamine appears to reduce BZD requirements and is well tolerated at low doses. Prospective dose range evaluations in the management of AWS would be helpful in determining its place as an adjunctive agent.

Background: Nursing home patients with dementia may be more likely to suffer adverse drug events from suboptimal prescribing. Previous studies have not used national samples, nor have they examined multiple types of suboptimal prescribing by dementia severity. Objective: To examine the prevalence of and factors associated with potentially suboptimal prescribing in older veteran nursing home patients with dementia. Methods: This is a retrospective descriptive study of 1303 veterans 65 years or older admitted between January 1, 2004, and June 30, 2005, with dementia for long stays (90+ days) to 133 Veterans Affairs Community Living Centers. Dementia severity was determined by the Cognitive Performance Scale and functional status dependences. Results: Overall, 70.2% with mild-moderate dementia (n = 1076) had underuse because they did not receive an acetylcholinesterase inhibitor (AChEI), and 27.2% had evidence of inappropriate use because of a drug-disease or drug-drug-disease interaction. Of the 227 with severe dementia, 36.1% had overuse by receiving an AChEI or lipid-lowering or other agents, and 25.1% had evidence of inappropriate use as a result of a drug-disease or drug-drug interaction. Multinomial logistic regression analyses among those with mild to moderate dementia identified that living in the South versus other regions was the single factor associated with all 3 types of suboptimal prescribing. In those with severe dementia, antipsychotic use was associated with all 3 suboptimal prescribing types. Conclusions: Potentially suboptimal prescribing was common in older veteran nursing home patients with dementia. Clinicians should develop a heightened awareness of these problems. Future studies should examine associations between potentially suboptimal prescribing and health outcomes in patients with dementia.

Background: Proton pump inhibitors (PPIs) are inappropriately prescribed in up to 50% of users. Systematic medication review and cessation of inappropriate medications or deprescribing may improve patient outcomes and reduce costs. Objective: The aim of this study was to assess the feasibility of a patient-centered deprescribing process in a population of adults with complex polypharmacy. Methods: This was a prospective feasibility study. Participants were recruited from hospital outpatient clinics. The patient-centered deprescribing process consisted of 5 steps: comprehensive medication history, identification of potentially inappropriate medications, determining if the medication can be ceased, planning the withdrawal regimen (eg, tapering where necessary), and provision of monitoring, support, and documentation. Feasibility was determined by assessing time taken to complete the different steps of the deprescribing process and participant feedback. Results: In all, 57 PPI users were recruited; participants were 70 ± 14 years old and took 14 ± 6 medications. The indication for PPI use was verified in 43 participants and judged as potentially inappropriate in 19 (44%); 8 were suitable for trial withdrawal, and 6 consented. All 6 successfully ceased (n = 3) or reduced (n = 3) their PPI use, and this was sustained at 6 months postintervention in 4 participants. Conclusions: The patient-centered deprescribing process can safely reduce inappropriate PPI prescribing in a small proportion of people. Although the process was acceptable to participants, difficulties in accessing complete medical histories, time limitations, and minimal evidence to support effectiveness in certain indications were barriers to implementation of the process in clinical practice.

Background: Radiopharmaceuticals are regarded as safe by the nuclear medicine community, but up to now, no survey has been conducted with from the perspective of pharmacovigilance. Objective: To describe the adverse reactions to radiopharmaceuticals (ARRPs) reported to the French Pharmacovigilance Database (FPVD). Methods: We selected and described all reports encompassing at least one radiopharmaceutical in the FPVD. The annual incidence of reported ARRPs used in diagnosis was also estimated. Results: From 1989 to 2013, 304 reports of ARRPs were identified (43.0% serious, 12 deaths) in 54.6% women and 45.4% men; the median age was 58 years. Five therapeutic radiopharmaceuticals (¹³¹I-sodium iodide, ¹³¹I-lipiodol, ⁸⁹Sr-chloride, ¹⁵³Sm-lexidronam, and ⁹⁰Y-ibritumomab-tiuxetan) were involved in 48 reports (97 adverse reactions: 86.6% serious, 9 deaths). Pulmonary disorders represented 44.3% of ARRPs used for therapy, mainly related to ¹³¹I-lipiodol. There were 34 diagnostic radiopharmaceuticals involved in 256 reports (451 adverse reactions: 38.1% serious, 3 deaths); 8 diagnostic products (^99mTc-oxidronate, ¹⁸F-fluorodeoxyglucose, ^99mTc-tin pyrophosphate, ^99mTc-tetrofosmin, ^99mTc-dimercaptosuccinic acid, ²⁰¹Tl-chloride, ^99mTc-sestamibi, and ¹¹¹In-pentetate) accounted for two-thirds of ARRPs. The most frequent adverse reactions were skin (34.4%), general (18.2%), nervous (9.0%), and gastrointestinal disorders (7.0%). There were 25 cases of altered images and 10 medication errors. The annual incidence of reported adverse reactions ranged from 1.2 × 10⁻⁵ to 3.4 × 10⁻⁵ diagnostic administrations. Conclusions: Reported ARRPs occurred rarely and were more serious in the therapeutic than in the diagnostic field. The notification of ARRPs was able to provide new guidance for safe use, as was the case for ¹³¹I-lipiodol. Therefore, it is important to report ARRPs to a pharmacovigilance system.

Objectives: Systematically review the literature assessing outcomes of acute myeloid leukemia (AML) treatment during pregnancy. Data Sources: A Pubmed literature search (January 1969 to June 2014) for articles written about AML and pregnancy, and bibliographies/citations of previously published reviews. Study Selection and Data Extraction: Articles written in the English language that administered active AML chemotherapy during pregnancy were included. Data Synthesis: Eighty-five fetuses were exposed to chemotherapy from 83 mothers: 8 mothers began induction chemotherapy in the first trimester, 61 mothers in the second trimester, and 14 mothers in the third trimester. Chemotherapy resulted in more fetal deaths and spontaneous abortions during the first trimester (37.5%) compared with the second (9.7%) and third trimesters (0%). All cases included cytarabine; 47 fetuses were exposed to daunorubicin and 8 fetuses to idarubicin. The percentages of fetal defects and death for cytarabine and daunorubicin combinations were 8.5% and 6.4%, respectively. With cytarabine and idarubicin combinations, the percentages of fetal defects and death were 28.6% and 12.5%, respectively. Complete remission (CR) rates were 100%, 81%, and 67% in the first, second, and third trimesters. Conclusions: Treatment during the second and third trimesters resulted in fewer fetal complications than the first trimester. However, delaying AML treatment may adversely affect the mother’s outcomes. In the reported cases, induction during pregnancy resulted in CR rates comparable to that in nonpregnant patients. The choice of anthracycline is still unclear, but the decision should be made with careful consideration, weighing the outcomes for the mother and fetus.

Objective: To review the literature on the pharmacotherapy of bloodstream infections (BSI) caused by vancomycin-resistant enterococci (VRE). Data Sources: A MEDLINE literature search was performed for the period 1946 to May 2014 using the search terms Enterococcus, enterococci, vancomycin-resistant, VRE, bacteremia, and bloodstream infection. References were also identified from selected review articles. Study Selection and Data Extraction: English-language case series, cohort studies, and meta-analyses assessing the options in the pharmacotherapy of VRE BSIs in adult patients were evaluated. Data Synthesis: Studies were identified that utilized linezolid, quinupristin/dalfopristin (Q/D), and daptomycin. In all, 8 comparative retrospective cohort studies, 2 meta-analyses of daptomycin and linezolid, and 3 retrospective comparisons of linezolid and Q/D were included for review. Mortality associated with VRE BSIs was high across studies, and the ability to determine differences in outcomes between agents was confounded by the complex nature of the patients included. Two meta-analyses comparing daptomycin with linezolid for VRE BSIs found modest advantages for linezolid, but these conclusions may be hampered by heterogeneity within the included studies. Conclusions: VRE BSIs remain a difficult-to-treat clinical situation. Differences in toxicity between the agents used to treat it are clear, but therapeutic differences are more difficult to discern. Meta-analyses suggest that a moderate advantage for linezolid over daptomycin may exist, but problems with the nature of studies that they included make definitive conclusions difficult.

Objective: To review the available evidence regarding the utility of the currently available β-lactam/β-lactamase inhibitor combinations (BLICs) as well as the emerging body of data for the novel agents in the pipeline. Data Sources: A MEDLINE literature search (1960-August 2014) was performed using the search terms β-lactamase, β-lactamase inhibitor, clavulanate, sulbactam, tazobactam, avibactam, NXL104, MK-7655, and RPX7009. Current studies focusing on new agents were obtained from clinicaltrials.gov. Additional references were identified from a review of literature citations and meeting abstracts. Study Selection and Data Extraction: All English-language studies pertaining to BLICs were evaluated. Data Synthesis: Historical clinical and in vitro data focusing on the characteristics of the conventional BLICs are reviewed. Avibactam, relebactam (formerly MK-7655), and RPX7009 are new β-lactamase inhibitors that are being studied in combination with β-lactams. Clinical and in vitro data that provide support for their use for multidrug-resistant organisms are reviewed. β-Lactam antibiotics are a mainstay for the treatment of many infections. The addition of β-lactamase inhibitors enhances their activity against organisms that produce β-lactamases; however, organisms that produce extended-spectrum β-lactamases, AmpC β-lactamases, and carbapenemases are proliferating. The BLICs (amoxicillin/clavulanate, ticarcillin/clavulanate, ampicillin/sulbactam, and piperacillin/tazobactam) lack activity against some of these enzymes, presenting a critical need for new antibiotics. Conclusions: The historical BLICs are useful for many infections; however, evolving resistance limits their use. The new BLICs (combinations with avibactam, relebactam, and RPX7009) may be valuable options for patients infected with multidrug-resistant organisms.

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of Technosphere insulin (TI), a new inhaled insulin product. Data Sources: Searches were conducted in PubMed/MEDLINE, Scientific Citation Index, and abstracts from both the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) meetings from 2005 to August 2014, utilizing the search terms Afrezza, Technosphere, Afresa, and inhaled insulin. References were reviewed to identify additional sources. Study Selection and Data Extraction: Studies with adequate sample sizes, evaluating clinically relevant end points were included. Data Synthesis: TI is approved by the Food and Drug Administration as a bolus insulin to treat patients with type 1 and type 2 diabetes. Its glucose-lowering properties are less than that of rapid-acting insulins, but it does demonstrate less hypoglycemia. TI’s kinetics make it the fastest absorbed of any insulin available, although its overall onset of action appears similar to insulin lispro. It represents an alternative to bolus injections but would likely be used concomitantly with injected basal insulin. Major adverse effects are respiratory in nature, with cough being the most prominent. There is a small decrease in the forced expiratory volume in 1 s (FEV₁) with TI; this appears to be consistent, nonprogressive, and reversible. Patients using TI must receive pulmonary function tests periodically throughout therapy. TI is contraindicated in patients with chronic lung disease and should be used with caution in patients who smoke. Conclusion: TI is a novel inhaled insulin that provides prandial coverage to patients with diabetes, representing an alternative to bolus insulin injections.

Objective: To review ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non–small-cell lung cancer (NSCLC). Data Sources: Literature searches were conducted in PubMed, EMBASE (1974 to July week 5, 2014), and Google Scholar using the terms ceritinib, LDK378, and non–small-cell lung cancer. Study Selection and Data Extraction: One phase 1 trial and 2 abstracts were identified. Data Synthesis: Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC in patients who are intolerant to or have progressed despite therapy with crizotinib. In the phase 1 clinical trial, the maximum tolerated dose was determined to be 750 mg once daily. The overall response rate (ORR) was 58% (95% CI = 48-67) in patients who received ≥400 mg daily (n = 114). In this group, the ORR was 56% (95% CI = 41-67) and 62% (95% CI = 44-78) among crizotinib-exposed and -naïve patients, respectively. The ORR was 59% (95% CI = 47-70) in patients who received 750 mg daily (n = 78). The ORR was 56% (95% CI = 41-70) in crizotinib-treated patients and 64% (95% CI = 44-81) in crizotinib-naïve patients, respectively, in this subset. The median duration of response was 8.2 months. Median progression-free survival was 7.0 months. The most common adverse reactions included diarrhea, nausea, vomiting, abdominal pain, anorexia, constipation, fatigue, and elevated transaminases. Conclusions: Ceritinib has activity in crizotinib-resistant and crizotinib-naïve patients and appears to be a viable alternative for ALK-positive NSCLC. Long-term data are needed to further define the role of ceritinib in the treatment of NSCLC.

Background: Oral anticoagulants are prescribed to millions of Americans, and consequently are among the medications most likely to contribute to emergency department visits and hospitalizations. Although guidelines and consensus statements promote systematic approaches to therapy, anticoagulation (AC) management is often suboptimal. Electronic health records (EHRs) have the potential to improve safety and quality but have not yet incorporated specialized features necessary to optimize therapy. Objective: To generate a comprehensive, consensus-based list of EHR features clinically necessary to deliver optimized AC management, provide a “language bridge” to accelerate incorporation of features into EHR systems, and suggest mechanisms for the objective evaluation of available EHRs. Methods: A multidisciplinary panel of AC specialists utilized the framework of a previously published consensus statement to map outpatient AC management and developed a comprehensive array of sequential computer logic steps using a restricted language scheme. Logic steps were then translated into narrative descriptions of potential EHR features, which were refined through multiple group evaluations. A finalized list of proposed features was ranked according to perceived clinical necessity by physician, pharmacist, and nurse panelists in a blinded manner using a 5-point Likert scale. Features receiving no more than 1 dissenting opinion were included in a finalized list of clinically necessary features. Results: The task force generated 78 recommended EHR features across 20 key discrete areas and 425 individual logic steps. All recommended features received Strongly Agree or Agree rankings regarding their perceived clinical necessity, and no feature received more than a single Disagree response. Conclusion: The incorporation of key AC-related features into existing EHRs or specialized AC management systems has the potential to systematize the delivery of optimal AC care by health care professionals at the point of care. Optimized AC management has the potential to reduce adverse drug events associated with anticoagulant therapy in the outpatient setting.

Integration of accepted practice standards into electronic health record systems can facilitate standardization of anticoagulation care delivery and result in improved anticoagulation safety. However, the majority of commonly used electronic health record systems are lacking the specialized features necessary for optimal anticoagulation management. The Task Force on Electronic Health Records of the New York State Anticoagulation Coalition provides such a Consensus Statement in this issue of the journal. The Anticoagulation Forum endorses these recommendations and advises the electronic health record industry and health information technology programmers at the institutional level to adopt these recommendations in a comprehensive and timely manner.

In response to this growing movement of allied health “doctors,” the American Medical Association (AMA) launched its “Truth in Advertising” campaign in 2011, which aims to pass legislation regarding use of the “doctor” title. As a result of this initiative, several states have enacted laws that require any nonphysician practitioners who evoke the “doctor” salutation with patients to immediately identify their profession. Although designed to prevent confusion among patients, this initiative is misguided, and we as pharmacists need to use our professional organizations to open a dialog with the AMA and address this issue.

Objective: To describe the successful use of high-dose enoxaparin therapy (1.5 mg/kg subcutaneously twice daily) to attain a therapeutic anti–factor Xa (anti-Xa) level in a cancer patient with heparin resistance. Case Summary: A proven heparin-resistant patient with venous thromboembolism (VTE) and lung cancer who required approximately 66 000 units of unfractionated heparin daily was successfully transitioned to an off-label high-dose enoxaparin (OLHDE) 1.5 mg/kg subcutaneously twice daily. The patient was maintained on this same dose, and therapeutic levels were confirmed via use of the anti-Xa monitoring test. The patient was able to be discharged from the medical floor on this same dose with no further complications of VTE noted. No adverse events from this dosing were observed during the duration of therapy. Discussion: Options for overcoming heparin resistance are limited to case reports and small studies. The best course of treatment in the cancer patient is unclear. OLHDE allowed for the transition from intravenous to subcutaneous medication and transition off the medical floor. This case supports the use of OLHDE as a therapeutic option in heparin-resistant patients with cancer. Further study is needed to confirm the efficacy of OLHDE in this patient population. Conclusion: High-dose enoxaparin may be an option to treat cancer patients with confirmed heparin resistance and venous thromboembolism.

Objective: To report the occurrence of hepatotoxicity in a patient initiated on amlodipine. A review of other reports of amlodipine hepatotoxicity is also provided. Case Summary: A 34-year-old patient was admitted for worsening gastrointestinal graft versus host disease 100 days after an allogeneic stem cell transplant and treated with high-dose systemic steroids. Amlodipine was started for steroid-induced hypertension; 11 days after its initiation, alanine aminotransferase and aspartate aminotransferase peaked at 630 and 421 IU/L, respectively. Total bilirubin and alkaline phosphatase remained normal. A liver biopsy interpreted the liver injury as being possibly drug induced. Amlodipine, the most recently added medication, was discontinued, and transaminases trended down to normal within 2 weeks. Discussion: Allogeneic stem cell transplant patients are often prescribed many medications that carry the risk of hepatotoxicity. Amlodipine, ondansetron, and tacrolimus all have literature support for hepatotoxicity. Amlodipine, however, was the only agent for which initiation and discontinuation followed the acute rise and fall of liver transaminases. An objective causality assessment for liver toxicity, the RUCAM, revealed that the elevation in transaminases was “possible” drug toxicity caused by amlodipine. The package insert and other case reports of amlodipine hepatotoxicity suggest that it can occur both in the acute and chronic setting, and the injury is characterized as either cholestatic or hepatocellular. Conclusion: Amlodipine is a commonly used agent in allogeneic stem cell transplant patients. As the first published case in a hematopoietic stem cell transplantation patient, it brings to light a rare, yet important, event of which clinicians should be aware when caring for patients on this agent.

Objective: To report a case of severe rebound thrombocytopenia after temporary discontinuation of romiplostim during splenectomy in the context of refractory immune (idiopathic) thrombocytopenic purpura (ITP). Case Summary: A 65-year-old man with a history of severe refractory ITP failing multiple treatments was considered for romiplostim therapy. He was initiated on 1 µg/kg and titrated upward to 4 µg/kg to elevate and stabilize his platelet levels prior to splenectomy. On day 74 of his clinical course, his platelets increased to 434 × 10⁹/L, and his scheduled dose of romiplostim was withheld on day 75 for fear of romiplostim-induced postsplenectomy rebound thrombocytosis. On day 78, his platelets dropped precipitously to 9 × 10⁹/L, and he experienced multiple episodes of epistaxis. He was reinitiated at 5 µg/kg and soon recovered. He later missed a scheduled dose of romiplostim, and his platelets fell to 23 × 10⁹/L. After resuming romiplostim at 8 µg/kg, his platelets continued to recover. Discussion: Romiplostim, a thrombopoietin mimetic is directly regulated by megakaryocytes and existing circulating platelets via a negative feedback mechanism. This explains the theoretical risk of rapid clearance of romiplostim caused by an increased platelet pool. Clinically, alternative causes of his severe postoperative thrombocytopenia were considered and deemed unlikely. The rebound effect was observed after romiplostim was withdrawn on 2 occasions, and platelet counts improved after restarting romiplostim. The Naranjo Adverse Drug Reaction Probability Score of 7 suggests a probable adverse drug reaction. Conclusion: Physicians using romiplostim as a bridge to splenectomy should be cautious about withholding a scheduled dose around the time of surgery.

Objective: To present the case of a severe anaphylactic/anaphylactoid reaction to Crotalidae Polyvalent Immune Fab (Ovine) in a patient bitten by a copperhead snake. Case Summary: A 68-year-old man presented with progressive envenomation after receiving a copperhead snakebite on each hand. Crotalinae Fab antivenom was administered. While the initial and only dose was partially infusing, the patient developed an adverse drug reaction (ADR) of urticaria and hypotension, which resolved with cessation of the infusion, recurred with resumption of the infusion, and ultimately was completed with supportive care. An additional episode of hypotension, urticaria, and angioedema occurred shortly after antivenom therapy completion. Epinephrine was administered, resolving the reaction with complete patient recovery. The event received a Naranjo score of 10, indicating a definite ADR. Discussion: Treating copperhead snakebites with antivenom is a matter of debate. Concern over adverse events and cost induce some physicians to manage copperhead bites without antivenom because they are generally milder in severity. Conclusion: As demonstrated in this case, severe ADR can occur with Crotalinae Fab antivenom, and its efficacy for copperhead envenoming needs to be better established via placebo-controlled, randomized trials.