Randolph E. Regal

Acid Suppressive Therapy Use on an Inpatient Internal Medicine Service

Background: Use of acid suppressant medications has increased in both frequency and breadth in recent years. Data have indicated that questionable use of acid suppressants for non-accepted indications is common. Objective: To assess the indications and prevalence of acid suppressants used by inpatients on admission and at discharge. Methods: A retrospective chart review of 213 patients admitted to the University of Michigan Hospital non-critical care general medical service was conducted. Relevant medical history, acid suppressant drug used, and indications were collected from both inpatient medical records and discharge medication lists. Results: Of the 213 patients reviewed, 29% were taking acid suppressants prior to admission, with 33% being proton pump inhibitors (PPIs). Once patients were admitted, acid suppressant use increased to 71% (152 of 213), with 84% PPIs, 11% histamine2-receptor antagonists, and 5% combination therapy. Based upon our criteria, only 10% (15 of 152) of those on acid suppressants were found to have an acceptable indication. In patients where any history of gastroesophageal reflux disorder (GERD) was deemed as an acceptable indication (32 other patients), 31% (47 of 152) had an acceptable indication. For the 137 patients with non-accepted indications, 29% had no discernable indication and 38% were prescribed acid suppressants for corticosteroid-associated or stress ulcer prophylaxis. A history of gastrointestinal bleeds or peptic ulcer disease of more than 3 months since initial diagnosis or documented exacerbation of symptoms comprised 8% of the population. The aforementioned group of GERD patients made up 23% of this group. Compared to the 29% of patients taking acid suppressants prior to admission, 54% (115 of 213) of patients were prescribed acid suppressants at discharge. If only recent exacerbations of GERD were deemed as long-term indications, 10% (12 of 115) of these patients were found to have accepted indications. If all GERDs were acceptable long-term indications, 27% (31 of 115) would have met criteria for acceptable outpatient use. Conclusions: There is considerable excess usage of acid suppressants in both the inpatient and outpatient settings.

Incidence of Carbapenem-Associated Allergic-Type Reactions among Patients with versus Patients without a Reported Penicillin Allergy

This retrospective analysis sought to determine the comparative incidence of cross-reactivity associated with carbapenem antibiotic treatment among patients with versus those without penicillin allergy. We sought to determine whether the incidence of cross-reactivity is different between imipenem-cilastatin and meropenem. A total of 211 patients were treated with a carbapenem antibiotic. Included were 100 patients with and 111 patients without a documented or reported penicillin allergy. Within each group, subgroups of penicillin-allergic and penicillin-nonallergic patients were balanced equally between imipenem-cilastatin and meropenem. The incidence of patients with a reported or documented penicillin allergy experiencing an allergic-type reaction to a carbapenem was 11%, which is 5.2 times greater than the risk in patients who were reportedly not allergic to penicillin (P=.024). No difference in the occurrence of allergic-type reactions was observed between the 2 carbapenems.

Indications for Dual Antiplatelet Therapy with Aspirin and Clopidogrel: Evidence-Based Recommendations for Use

OBJECTIVE: To review the literature assessing dual antiplatelet therapy with aspirin and clopidogrel and subsequently provide evidence-based recommendations for appropriate indications and length of therapy. DATA SYNTHESIS: An English-language MEDLINE search (1950–December 2007) was conducted using the search terms antiplatelet, aspirin, thienopyridine, and clopidogrel to identify articles assessing dual antiplatelet therapy. Evaluation of references from identified trials for possible inclusion was also conducted. STUDY SELECTION AND DATA EXTRACTION: All studies that assessed treatment with the combination of aspirin and clopidogrel for any indication were included. DATA SYNTHESIS: Aspirin and clopidogrel have complementary mechanisms of action to inhibit platelet function. Indications that have been studied include coronary artery disease (CAD), atherosclerotic ischemic stroke, and atrial fibrillation. This combination has been beneficial in patients with acute coronary syndrome (ACS) with or without percutaneous coronary intervention (PCI), and in PCI patients without an acute event. There is a small but significant risk for increased bleeding with dual antiplatelet therapy for these indications. When used in patients with a history of atherosclerotic ischemic stroke or for prevention of cardioembolic stroke in patients with atrial fibrillation, this combination has been shown to increase bleeding, providing no clinical benefit, and to increase outcomes including stroke, myocardial infarction, and death, respectively. CONCLUSIONS: There is evidence to support use of aspirin in combination with clopidogrel for patients presenting with all ACS types, as well as for patients presenting with PCI for any indication. The treatment duration varies, but patients who have received stenting should receive at least 1 year of combination therapy. There is no evidence to support this combination for primary prevention of CAD or atherosclerotic ischemic events, secondary prevention of stable CAD, or prevention of cardioembolic stroke in patients with atrial fibrillation. The possible benefits of dual antiplatelet therapy also must be weighed against the risk of bleeding.

The effect of an antimicrobial restriction program on Pseudomonas aeruginosa resistance to β-lactams in a large teaching hospital

Study Objectives. To compare the use of β‐lactams and subsequent Pseudomonas aeruginosa sensitivity patterns before and after implementation of a clinical pharmacist‐facilitated antimicrobial restriction program in August 1997.

Daclatasvir A NS5A Replication Complex Inhibitor for Hepatitis C Infection

OBJECTIVES To review the pharmacology, efficacy, and safety of daclatasvir in the treatment of patients with chronic hepatitis C virus (HCV) infection. DATA SOURCES A literature search through EMBASE and PubMed was conducted (January 1966 to August 2015) using the terms BMS-790052, daclatasvir, and hepatitis C. References from retrieved articles were reviewed for any additional material. Additionally, the new drug application and prescribing information were retrieved. STUDY SELECTION/DATA EXTRACTION The literature search was limited to human studies published in English. Phase 1, 2, and 3 studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daclatasvir for HCV were identified. DATA SYNTHESIS Daclatasvir, a nonstructural 5A protein inhibitor, combined with sofosbuvir, is indicated for adult patients with chronic HCV genotype 3 regardless of treatment or cirrhosis status. The phase III ALLY-3 trial (n = 152) demonstrated that daclatasvir taken once daily with sofosbuvir for 12 weeks was effective at achieving sustained virological response (SVR) rates in treatment-naïve (97%) and treatment-experienced (94%) patients without cirrhosis. Patients with cirrhosis had significantly lower SVR rates (58 and 69%, respectively). The most common adverse drug events associated with daclatasvir and sofosbuvir in ALLY-3 were headache (20%), fatigue (19%), and nausea (12%). CONCLUSIONS Daclatasvir, when combined with sofosbuvir, is an effective agent to treat HCV genotype 3, with SVR rates above 90% for patients without cirrhosis who are treatment naïve or experienced. SVR rates for treatment-naïve or -experienced patients with cirrhosis are not as robust (58%-69%).Objectives: To review the pharmacology, efficacy, and safety of daclatasvir in the treatment of patients with chronic hepatitis C virus (HCV) infection. Data Sources: A literature search through EMBASE and PubMed was conducted (January 1966 to August 2015) using the terms BMS-790052, daclatasvir, and hepatitis C. References from retrieved articles were reviewed for any additional material. Additionally, the new drug application and prescribing information were retrieved. Study Selection/Data Extraction: The literature search was limited to human studies published in English. Phase 1, 2, and 3 studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daclatasvir for HCV were identified. Data Synthesis: Daclatasvir, a nonstructural 5A protein inhibitor, combined with sofosbuvir, is indicated for adult patients with chronic HCV genotype 3 regardless of treatment or cirrhosis status. The phase III ALLY-3 trial (n = 152) demonstrated that daclatasvir taken once daily with sofosbuvir for 12 weeks was effective at achieving sustained virological response (SVR) rates in treatment-naïve (97%) and treatment-experienced (94%) patients without cirrhosis. Patients with cirrhosis had significantly lower SVR rates (58 and 69%, respectively). The most common adverse drug events associated with daclatasvir and sofosbuvir in ALLY-3 were headache (20%), fatigue (19%), and nausea (12%). Conclusions: Daclatasvir, when combined with sofosbuvir, is an effective agent to treat HCV genotype 3, with SVR rates above 90% for patients without cirrhosis who are treatment naïve or experienced. SVR rates for treatment-naïve or -experienced patients with cirrhosis are not as robust (58%-69%).

Combination Therapy for the Treatment and Prevention of Hepatic Encephalopathy

OBJECTIVE: To evaluate the efficacy and safety of combination therapy for the treatment and prevention of hepatic encephalopathy (HE). DATA SOURCES: A PubMed MEDLINE search was conducted (1947-June 2012) using the key terms lactulose, lactitol, nonabsorbable disaccharide, metronidazole, rifaximin, neomycin, probiotics, and hepatic encephalopathy. Searches were limited to include articles published in English. STUDY SELECTION AND DATA EXTRACTION: Study selection included published trials, case reports, and case series of humans with HE who were treated with combination therapy of rifaximin, lactulose, lactitol, metronidazole, neomycin, and/or probiotics. DATA SYNTHESIS: Only 6 studies that evaluated the benefits of combination drug therapy in the treatment or prevention of HE were available for review. Four studies addressed the treatment of HE, 2 found no significant difference between lactulose/neomycin versus placebo or rifaximin/lactulose, 1 assessed the use of rifaximin/lactulose without a control group, and the fourth found no significant difference between lactulose/probiotics versus either drug alone, although each group showed improvement from baseline. In the 2 prevention trials, both of which stemmed from the same data, the combination of rifaximin/lactulose was superior to lactulose alone, showing significant improvement in mental status, blood ammonia levels, and health-related quality of life and reductions in HE recurrence and hospitalization. Currently, there are no available clinical studies evaluating dual antibiotic therapy, metronidazole with nonabsorbable disaccharides, or antibiotics with probiotics. CONCLUSIONS: The evidence evaluating the use of combination therapy for the treatment of HE does not support its widespread use. The combination of rifaximin and lactulose may be considered in the treatment of HE and in patients refractory to monotherapy. The combination of rifaximin and lactulose should be considered for the prevention of HE, especially after the second episode of HE recurrence.

Anticoagulation in Patients With Cirrhosis Caught Between a Rock-Liver and a Hard Place

Objective: To review current literature for anticoagulation in patients with cirrhosis and provide a summary of the effects of cirrhosis on the coagulation cascade, therapeutic monitoring through interpretation of antifactor Xa (anti-Xa), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) as well as current prophylaxis and treatment recommendations in cirrhotic patients. Methods: A systematic electronic literature search was conducted in PubMed using the key terms anticoagulation, warfarin, low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), target-specific oral anticoagulants, deep-vein thrombosis (DVT), pulmonary embolism (PE), portal vein thrombosis (PVT), venous thromboembolism, anti-Xa, activated partial thromboplastin time, anticoagulation therapeutic monitoring, coagulopathy, coagulation cascade, chronic liver disease, cirrhosis, and decompensated liver disease. Study Selection: Studies written in the English language from January 2000 to December 2015 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by authors independently. Conclusions: Patients with cirrhosis are at higher risk for both bleeding and thrombosis-related complications. Cirrhosis affects production of both procoagulant and anticoagulant factors, thus resulting in increased INR and aPTT levels and decreased anti-Xa levels. LMWH is the treatment of choice for the prevention and treatment of DVT/PE/PVT in patients with cirrhosis, and monitoring with anti-Xa levels for dose adjustment is not recommended. UFH is an alternative in cirrhotic patients for shorter-term use and in cases of severe renal dysfunction and/or hemodynamic instability. Cirrhotic patients on anticoagulation therapy should be monitored closely for signs and symptoms of bleeding and thrombosis.

“Triple Phase” Budesonide Capsules for the Treatment of Olmesartan-Induced Enteropathy

Objective: To describe the treatment of a case of olmesartan-induced enteropathy in a patient with inflammatory areas widely distributed along the gastrointestinal tract. Case Summary: A 75-year-old patient presented with a 5-month history of recurrent severe diarrhea, diagnosed as olmesartan-induced enteropathy. A modified regimen of oral enteric-coated budesonide (EC-BUD), in combination with other antidiarrheal and anti-inflammatory therapies, was prescribed. The patient experienced rapid improvement in symptoms and was able to titrate off all enteropathy medications, including budesonide within 4 months after hospital discharge. Discussion: Olmesartan-induced enteropathy is a recently identified adverse effect of this angiotensin II receptor blocker. Oral budesonide is indicated for use in Crohn’s disease to provide topical anti-inflammatory therapy without significant systemic steroid absorption. Budesonide, as enteric-coated oral 3-mg capsules, was chosen as therapy in this patient because of its localized effect and proven efficacy in gastrointestinal inflammatory disorders. The administration technique was modified to target areas of inflammation throughout the gastrointestinal tract. Conclusions: We postulate that this modified administration of EC-BUD may be an effective therapeutic modality for olmesartan-induced enteropathy. It may likewise be an appropriate adjunct to other conditions involving widespread gastrointestinal inflammation, including eosinophilic gastroenteritis and gastrointestinal graft versus host disease.

Evaluation of Vancomycin Dosing in Patients With Cirrhosis: Beginning De-Liver-ations about a New Nomogram

Background: Reduced hepatic production of creatinine precursors in patients with decompensated cirrhosis leads to falsely low serum creatinine values. Therefore, when performing empiric dosing of vancomycin, an overestimation of creatinine clearance may result in significantly supratherapeutic vancomycin levels and increased risks of nephrotoxicity. Objective: The objective of the study is to evaluate vancomycin dosing requirements in patients with cirrhosis stratified by Child-Pugh Score, with subsequent comparison with doses that are recommended in the previously published and validated Kullar nomogram. Methods: A retrospective evaluation of patients with cirrhosis who received vancomycin for at least 3 full days and had at least 1 serum concentration drawn. Vancomycin daily dose and corresponding serum concentration were collected with patients stratified by Child-Pugh Score for comparison. Each patient had their vancomycin dose compared with the dose suggested by a published nomogram. Results: A total of 201 courses of vancomycin were followed. There were no significant differences between the Child-Pugh cohorts with respect to initial vancomycin dosing. There was also no significant difference in the median initial vancomycin trough concentration between the 3 cohorts (Child-Pugh A: 13.7 µg/mL [interquartile range, IQR: 10.4-22.1]; Child-Pugh B: 20.2 µg/mL [IQR: 15.1-25.9]; Child-Pugh C: 19.3 µg/mL [IQR: 14.9-25.2, P = .08]. The median vancomycin dose using the Kullar nomogram would have been 3.0 g/day (IQR: 2.0-3.75, P < .001), but the median dose actually used in this patient population was significantly less at 2.0 g/day. Nonetheless, the median vancomycin trough concentration in the entire patient population was 19.8 µg/mL (IQR: 15.4-25.9). Conclusion: In patients with cirrhosis, there was a high incidence of supratherapeutic vancomycin serum concentrations despite the fact that dosing was significantly less than that suggested by the published Kullar nomogram.