Annals of Pharmacotherapy

Background: Previous meta-analyses suggest that users of proton pump inhibitors (PPIs) have a higher risk of developing enteric infections compared with nonusers. These previous meta-analyses have considerable heterogeneity, and it is not clear whether the effect of PPIs is different for different types of microorganisms. Objective: The aim of this study is to update previous meta-analyses, concentrating on enteric infection in community settings and exploring potential sources of heterogeneity. Methods: A systematic search was conducted on electronic databases (all available years until November 2017). PubMed, EMBASE, Cochrane, and Web of Science were searched using specific keywords related to PPI therapy and community-acquired enteric infection. Eligible studies were selected based on prespecified criteria. Results: A total of 9 observational studies evaluating community-acquired enteric infection were eligible, including 12 separate analyses. The meta-analysis showed that PPI users have an increased risk of developing community-acquired enteric infection (pooled odds ratio [OR] = 4.28; 95% CI = 3.01-6.08). There was significant heterogeneity between the studies (I² = 85%; P < 0.001), which was partly explained by type of microorganism. The strength of the association was similar for Salmonella (pooled OR = 4.84; 95% CI = 2.75-8.54; I² = 58.7%; P = 0.064) and Campylobacter (pooled OR = 5.09; 95% CI = 3-8.64; I² = 81%; P < 0.001) but lower for studies that combined all bacteria (pooled OR = 2.42; 95% CI = 0.96-6.14; I² = 94.3%; P < 0.001). Conclusion: PPI users have an increased risk of developing community-acquired enteric infections compared with nonusers. The heterogeneity was partially explained by type of microorganism; the association is stronger for Salmonella and Campylobacter than for all bacteria combined.

Background: The role of nutrients and dietary factors in attention-deficit hyperactivity disorder (ADHD) remains unclear. Objectives: The primary objective was to evaluate the serum vitamin D level in children with a diagnosis of ADHD. The secondary objective was to detect the effect of vitamin D supplementation on cognitive function in those with vitamin D deficiency. Methods: A total of 50 children with ADHD and 40 healthy controls were included in the study. We measured the serum level of vitamin D. Patients with vitamin D deficiency were subdivided into 2 groups: one with vitamin D supplementation and the other without vitamin D supplementation. Further assessment and follow-up of children with ADHD was done. The Wisconsin Card Sorting Test, Conners’ Parent Rating Scale, and Wechsler Intelligence Scale for Children were performed at baseline and follow-up in all cohorts with an ADHD diagnosis. Results: The diagnosis of vitamin D deficiency was significantly greater in children with ADHD compared with the control group (P < 0.05). Children with ADHD had significantly (P = 0.0009) lower values of serum vitamin D (17.23 ± 8.98) than the control group(31.47 ± 14.42). The group receiving vitamin D supplementation demonstrated improvement in cognitive function in the conceptual level, inattention, opposition, hyperactivity, and impulsivity domains. Conclusion: Vitamin D supplementation in children with ADHD may improve cognitive function.

Background: Randomized clinical trials with the aim of evaluating the cardiovascular risks associated with glucagon-like peptide 1 (GLP-1) receptor agonists, lixisenatide, liraglutide, semaglutide, and exenatide, have been conducted. They showed different results among the agents, but the reason has not been explained. Objective: To evaluate the cardiovascular risks associated with GLP-1 receptor agonists by using an alternative measure to the hazard ratio. Methods: We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Four randomized clinical trials with cardiovascular events as a primary endpoint, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide), were reevaluated by estimating the RMSTs for each of the agents and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. Results: The differences of RMSTs (GLP-1 receptor agonist minus placebo: point estimate and 95% CI) for primary composite endpoint of cardiovascular events were 0 days [−14, 14] in ELIXA (1080 days follow-up), 20 days [6, 34] in LEADER (1620 days follow-up), 8 days [1, 15] in SUSTAIN-6 (672 days follow-up), and 11 days [−3, 26] in EXSCEL (1825 days follow-up). As for the risk of other cardiovascular outcomes, there were no substantial differences between GLP-1 receptor agonists and placebo. Conclusions: Liraglutide and semaglutide decrease the risk of major adverse cardiovascular events compared with placebo when using the difference in RMST. The previously reported result that GLP-1 receptor agonists do not increase the risk of cardiovascular outcomes compared with placebo is also confirmed.

Background: Patients often receive broad-spectrum antibiotics for nosocomial infections commonly with activity against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Previous retrospective and/or single-center studies have suggested that the combination of vancomycin and piperacillin/tazobactam might be associated with an increased risk of acute kidney injury. Objectives: To compare the incidence of nephrotoxicity in patients receiving intravenous vancomycin in combination with cefepime, meropenem, or piperacillin/tazobactam. Methods: This was a prospective, multicenter observational study of patients receiving vancomycin in combination with piperacillin/tazobactam versus cefepime or meropenem. Adult patients 18 years of age or older who were hospitalized and received 72 or more hours of intravenous vancomycin and 72 hours or more of cefepime, meropenem, or piperacillin/tazobactam were eligible. Patient and medication characteristics were examined for the 242 patients included. Results: The incidence of acute kidney injury for patients treated with vancomycin and piperacillin/tazobactam was significantly higher than for those treated with vancomycin and cefepime or meropenem, 29.8% versus 8.8%, respectively, P < 0.001. Binary logistic regression demonstrated that patients receiving vancomycin and piperacillin/tazobactam were 6.7 times more likely to develop acute kidney injury compared with the other cohort. Conclusions: The combination of vancomycin with piperacillin/tazobactam significantly increases the risk of acute kidney injury compared with other broad-spectrum antibiotic combinations. Clinicians should be vigilant when employing this regimen.

Background: Few studies on adult and pediatric patients have shown pyridoxine efficacy as additional therapy for those receiving levetiracetam (LEV) to prevent and mitigate behavioral adverse effects (BAEs). Objective: The aim of our study was to analyze the safety and efficacy of pyridoxine supplementation in the prevention of LEV adverse effects, including suicidal ideation. Methods: This randomized, case-control trial included patients receiving LEV as monotherapy treatment. Patients were subdivided into 2 groups, according to whether they were treated with LEV only (group 1) or LEV with supplemental pyridoxine (group 2). Results: In both cohorts, the most frequent BAEs were irritability/aggression followed by depression and confusion. Those patients (92%) who initiated pyridoxine after 1 month of LEV treatment did not need to change or suspend LEV (P < 0.001), and BAE improved after 9.06 ± 3.05 days of pyridoxine supplementation. None of the patients complained of symptoms of pyridoxine toxicity, and no new adverse effects of LEV off-label were reported. Conclusions: In our study, we found pyridoxine to be safe and effective in controlling LEV-induced BAEs in children.

Background: Ganciclovir-resistant cytomegalovirus (GR-CMV) is a serious complication of transplantation. Recurrence after primary infection is common. Little is known about CMV drug resistance and latency. Objective: Review CMV genotype during episodes of recurrent CMV viremia after prior documentation of ganciclovir resistance to evaluate if resistance is redemonstrated. Methods: All adult transplant recipients with history of GR-CMV viremia from January 1, 2011, to December 31, 2015, were screened; those with subsequent laboratory evidence of recurrent CMV viremia and genotyping were included. Results: A total of 23 patients had genetically confirmed GR-CMV within the study time period; 14 were excluded due to lack of repeat resistance testing at recurrence and 4 due to of lack of negativity between testing, leaving 5 patients with 7 episodes of recurrent viremia to evaluate. At first recurrent viremia, 4 patients (80%) demonstrated resistant genotype; 1 patient had wild type. Two patients went on to have a second viremia recurrence; both demonstrated wild-type genotype, despite the fact that the first recurrence in these patients was resistant genotype. Conclusion: In transplant recipients with history of GR-CMV, it appears that there is strain variability in latency: repeat genetic testing in patients with recurrent viremia after GR-CMV should be conducted. In the setting of wild-type repopulation, use of GCV should be considered.

Background: Infants younger than 6 months of age are at high risk for contracting pertussis because of not being fully vaccinated. The Advisory Committee on Immunization Practices (ACIP) recommends vaccinating all pregnant women with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) between 27 and 36 weeks to offer passive immunity to the infant to help protect them until they are able to receive the full pertussis series. Objective: To assess and compare compliance with the 2013 ACIP recommendation of vaccinating pregnant women with Tdap at 27 to 36 weeks’ gestation in 2 obstetric clinics. Methods: This cross-sectional, retrospective chart review evaluated Tdap vaccine compliance in a random sample of obstetric patients from October 2013 to September 2014. The primary outcome evaluated the proportion of patients who received Tdap between 27 and 36 weeks’ gestation. Secondary outcomes included the proportion of patients who received Tdap at any point in pregnancy and within 30 days postpartum. Results: The charts of 573 patients were reviewed, and 237 met inclusion criteria. For the primary outcome, 142 patients (59.9%) received the Tdap vaccine. Overall, 156 patients (65.8%) received Tdap at some point during the pregnancy. Factors associated with receiving the Tdap vaccination were insurance status, prenatal care risk level and site of prenatal care, receipt of the influenza vaccine, and preterm labor in the current pregnancy. Conclusion: The Tdap vaccine rate was 65.8%, with 59.9% of patients receiving the vaccine within the recommended ACIP timeframe. Further education, improvements in documentation, and chart reminders are needed to enhance administration.

Objective: To review the literature on drug-induced restless legs syndrome (DI-RLS). Data Sources: The review included a search for English-language literature from 1966 to December 2017 in the MEDLINE, PubMed, and Ovid databases using the following search terms: restless legs syndrome (RLS), periodic limb movement, adverse effects, and drug-induced. In addition, background articles on the pathophysiology, etiology, and epidemiology of RLS were retrieved. Bibliographies of relevant articles were reviewed for additional citations. Study Selection and Data Extraction: All case reports, case series, and review articles of DI-RLS were identified and analyzed. There were only a small number of controlled clinical trials, and most data were from case reports and case series. Results: Several drugs and drug classes have been implicated in DI-RLS, with antidepressants, antipsychotics, and antiepileptics having the most evidence. In addition, RLS may be linked with a number of disorders or underlying predisposing factors as well. Conclusions: The prevalence of RLS is variable and ranges from 3% to 19% in the general population. There are many predisposing factors to RLS, but an emerging body of evidence suggests that there is an association between numerous drugs and RLS.

Objectives: To review the immunogenicity, efficacy, and safety of the herpes zoster subunit vaccine (HZ/su) for use in adult patients for the prevention of shingles. Data Sources: A literature search through PubMed was conducted (June 2008 to October 2017) using the terms shingles vaccine and varicella zoster virus. References from retrieved articles and the prescribing information were also reviewed for any additional material. Study Selection/Data Extraction: The literature search was limited to human studies published in English. Randomized controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of HZ/su. Literature on the epidemiology and pathology of herpes zoster virus infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. Data Synthesis: HZ/su is a new adjuvanted recombinant vaccine approved by the Food and Drug Administration for the prevention of herpes zoster in adults 50 years of age and older. HZ/su significantly reduced the risk of developing herpes zoster by more than 90% as compared with placebo and displayed a comparable adverse effect profile. The most common local adverse events were injection site pain, redness, and swelling, and the most common systemic adverse events were myalgia, fatigue, and headache. The ACIP recommends the routine use of HZ/su as the preferred vaccine for the prevention of herpes zoster in immunocompetent adults 50 years of age and older. Conclusions: Based on published immunogenicity, efficacy, and safety data, as well as the recent recommendations by the ACIP, HZ/su should be included on both hospital and community pharmacy formularies and recommended to all immunocompetent patients older than 50 years to prevent herpes zoster.

Objective: To review available evidence for dolutegravir-based dual therapy as maintenance treatment in HIV-1 infected patients. Data Sources: A literature search was conducted using PubMed, MEDLINE, and Google Scholar to the end of January 2018. Conference abstracts and article bibliographies were also reviewed. Study Selection and Data Extraction: All English-language, randomized, and observational studies were included. Data Synthesis: In all, 12 studies were identified: 10 were observational, and 2 were randomized trials. Rilpivirine or lamivudine were the most common second agent used in combination with dolutegravir. Virological suppression seen in observational studies appear promising; however, the most compelling evidence to date is the 48-week results from 2 large open-label randomized trials (SWORD 1 and 2). These studies found that dual therapy with rilpivirine and dolutegravir was noninferior to 3- or 4-drug combination antiretroviral therapy (cART). The long-term efficacy, safety, and tolerability of dual therapy, as compared with usual cART, are less clear and require further data. Conclusions: Regimen switching in virally suppressed HIV-1–infected patients may be considered to reduce pill burden or dosing frequency, decrease short- or long-term toxicity, prevent or manage drug-drug interactions, and/or decrease cost. Based on available evidence, a switch to dual therapy with dolutegravir and rilpivirine appears viable for virologically suppressed patients without prior resistance mutations to these agents. Randomized studies of other dual-therapy regimens that include dolutegravir and longer-term follow-up as well as cost-effectiveness analyses are needed to provide confirmation that this strategy offers advantages to traditional cART regimens.

Objective: To review the pharmacology, efficacy, and safety of lesinurad and determine its role relative to other agents in the management of chronic gout. Data Sources: A PubMed search (1946 to February 2018) using the terms lesinurad and RDEA594 was conducted to identify relevant articles. Study Selection and Data Extraction: In vitro or in vivo evaluations of lesinurad published in the English language were eligible for inclusion. Phase II and III trials were selected for review of efficacy and safety. Data Synthesis: Five clinical trials were evaluated. In 4 trials in which lesinurad was used in combination with a xanthine oxidase inhibitor (XOI), a greater percentage of patients receiving lesinurad 200 mg (54.0%-63.0%) compared with placebo (23.3%-46.8%) achieved a serum uric acid (sUA) level of <6 mg/dL at 1 to 6 months. In one trial involving lesinurad used as monotherapy, a sUA level of <6 mg/dL was achieved by a significantly greater percentage of patients receiving lesinurad 400 mg (29.9%) compared with placebo (1.9%) at 6 months. When used as combination therapy, the drug had an acceptable safety profile, with upper-respiratory-tract infection, nasopharyngitis, and hypertension occurring most commonly and transient renal-related events detected less frequently. Conclusions: Lesinurad has a novel mechanism of action and is safe and effective for the treatment of chronic gout. At this time, lesinurad may be considered as an add-on therapy for patients who have an inadequate response to maximum tolerated doses of a XOI.

The scope of practice for pharmacists in the United States increasingly includes elements of prescribing under collaborative practice agreements and statewide protocols. However, as a result of continued health care access concerns, we believe that pharmacists will be called on to serve as independent prescribers in the future. For this anticipated practice expansion to become a successful reality, the assurance of pharmacist preparedness and continuous professional development through profession-wide standards will be imperative.

“Prescription adaptation services” refers to the ability of a pharmacist to autonomously “adapt” an existing prescription when the action is intended to optimize the therapeutic outcome. Adaptation services typically fall into 2 categories: (1) renewals and (2) changes. Renewals ensure continuity of care for patients and may be emergency renewals (typically 72 hours) or continuation-of-therapy renewals (typically 90 or more days). Changes include therapeutic substitutions or changes to quantity, formulation, route of administration, dose/interval, and completing missing information. With an appropriate framework in place, adaptation services can safely optimize medication therapy outcomes while promoting efficiencies.