Consideration of Aggressive and Strategic Approaches to Address Declining Enrollment in US Pharmacy Schools.

Members from Cohort 13 of the Academic Leadership Fellows Program (ALFP) 2016-2017 were challenged to present a debate on the topic: "In Turbulent Times, Pharmacy Education Leaders Must Take Aggressive Action to Prevent Further Declines in Enrollment" at the American Association of Colleges of Pharmacy INfluence 2017 meeting in Rio Grande, Puerto Rico. This paper is the result of thoughtful insights emerging from this debate. We present a discussion of the question of whether pharmacy education leaders must take aggressive action or strategic approaches to prevent further declines in enrollment. There are many thoughts regarding current declines in enrollment. Some educators contend that a more aggressive approach is needed while others argue that, while aggressive actions might lead to short-term gains, a more viable approach involves strategic actions targeting the underlying causes for decreasing enrollment. This paper explores themes of enrollment challenges, current and future workforce needs, and financial issues for both pharmacy programs and students. In summation, both aggressive actions and a strategic, sustainable approach are urgently needed to address declining enrollment.

Transitioning from pharmacy practice into administration.

Transitioning from a pharmacy practice faculty member into an administrator will offer new challenges you have never faced in your career. Whether you are currently considering a transition in your career or have recently made such a transition, many questions will come up along the way. Through this commentary, I offer some advice from my own personal trials and errors as I continue on my administrative journey, and I hope this will help you in yours.

Transgender students in pharmacy school, part 1: What academic administrators need to know.

While gender transition is a very exciting time for most students embarking upon this personal journey, it is not without its stressors as well. For students choosing to further their education and become pharmacists, the complexity and demands of pharmacy education during the transition period can be one such additive stressor. As pharmacy educators and administrators, we have the ability to help shape this professional journey and alleviate stress by maintaining our obligation to provide a safe and non-discriminatory learning environment for all students. Therefore, this two-part commentary will serve as a means to provide information and insights to administrators and faculty advisors in order to ensure transgender students, including those actively undergoing gender transition, achieve both a successful transition and pharmacy school career.

Transgender students in pharmacy school part 2: How faculty advisors can support their advisees.

Faculty advisors serve a critical role in the success of pharmacy students during their academic careers, frequently serving as a problem-solver or sounding board during times of both triumph and struggle. Additionally, faculty advisors help students overcome barriers along their journey to ensure a successful progression through pharmacy school. This role is particularly important to transgender students, given the additional barriers they may face, which were highlighted in Part One of the commentary on transgender students in pharmacy school. To help faculty serve as a successful mentor to transgender advisees, Part Two of the commentary provides resources and insights into advising transgender students, including those actively undergoing gender transition.

The 2016 ACCP Pharmacotherapy Didactic Curriculum Toolkit.

The 2016 American College of Clinical Pharmacy (ACCP) Educational Affairs Committee was charged with updating and contemporizing ACCP's 2009 Pharmacotherapy Didactic Curriculum Toolkit. The toolkit has been designed to guide schools and colleges of pharmacy in developing, maintaining, and modifying their curricula. The 2016 committee reviewed the recent medical literature and other documents to identify disease states that are responsive to drug therapy. Diseases and content topics were organized by organ system, when feasible, and grouped into tiers as defined by practice competency. Tier 1 topics should be taught in a manner that prepares all students to provide collaborative, patient-centered care upon graduation and licensure. Tier 2 topics are generally taught in the professional curriculum, but students may require additional knowledge or skills after graduation (e.g., residency training) to achieve competency in providing direct patient care. Tier 3 topics may not be taught in the professional curriculum; thus, graduates will be required to obtain the necessary knowledge and skills on their own to provide direct patient care, if required in their practice. The 2016 toolkit contains 276 diseases and content topics, of which 87 (32%) are categorized as tier 1, 133 (48%) as tier 2, and 56 (20%) as tier 3. The large number of tier 1 topics will require schools and colleges to use creative pedagogical strategies to achieve the necessary practice competencies. Almost half of the topics (48%) are tier 2, highlighting the importance of postgraduate residency training or equivalent practice experience to competently care for patients with these disorders. The Pharmacotherapy Didactic Curriculum Toolkit will continue to be updated to provide guidance to faculty at schools and colleges of pharmacy as these academic pharmacy institutions regularly evaluate and modify their curricula to keep abreast of scientific advances and associated practice changes. Access the current Pharmacotherapy Didactic Curriculum Toolkit at http://www.accp.com/docs/positions/misc/Toolkit_final.pdf.

Successful Use of Ceftolozane-Tazobactam to Treat a Pulmonary Exacerbation of Cystic Fibrosis Caused by Multidrug-Resistant Pseudomonas aeruginosa.

Ceftolozane-tazobactam, a novel ß-lactam/ß-lactamase inhibitor, was recently approved for the treatment of complicated urinary tract and intraabdominal infections, as monotherapy and in combination with metronidazole, respectively. Ceftolozane-tazobactam exhibits a wide spectrum of activity against both gram-positive bacteria, gram-negative bacteria including multidrug-resistant (MDR) Pseudomonas aeruginosa, and some anaerobic bacteria. Although not currently approved for any pulmonary indication, studies have demonstrated excellent distribution to epithelial lining fluid, indicating that it may be an alternative agent to use in the treatment of respiratory tract infections caused by MDRP. aeruginosa. Unfortunately, data are lacking regarding the use of ceftolozane-tazobactam in the treatment of respiratory tract infections including patients with cystic fibrosis (CF). We describe the first case report, to our knowledge, of a 25-year-old white man successfully treated with ceftolozane-tazobactam for a pulmonary exacerbation of his CF caused by MDRP. aeruginosa. He was admitted for his fourth hospitalization in 7 months for a pulmonary exacerbation of his CF. After blood and sputum were cultured, prednisone, cefepime, inhaled tobramycin, and intravenous ciprofloxacin were started. On day 4, after no signs of clinical improvement, respiratory cultures revealed nonmucoid MDRP. aeruginosa, susceptible only to colistin. ß-Lactam therapy was subsequently changed to ceftolozane-tazobactam 3 g intravenously every 8 hours while continuing ciprofloxacin and inhaled tobramycin. Ceftolozane-tazobactam susceptibility was determined by the Etest method (minimum inhibitory concentration 1.5 µg/ml). By day 3 of therapy, the patient showed signs of clinical improvement and was discharged after completion of a 12-day course of antibiotics. Until additional research is available, we hope this evidence will provide consideration of ceftolozane-tazobactam for this novel off-label indication.

5-Day versus 10-Day Course of Fluoroquinolones in Outpatient Males with a Urinary Tract Infection (UTI).

INTRODUCTION: Current guidelines classify urinary tract infections (UTIs) in males as complicated and recommend longer treatment than for UTIs in females. The objective of this study is to demonstrate that males with UTIs may be successfully treated with an outpatient 5-day course of levofloxacin. METHODS: Data were obtained from a previously conducted clinical trial (www.clinicaltrials.gov identifier NCT00210886), a multicenter, double-blind, randomized, noninferiority study comparing levofloxacin 750 mg intravenously/by mouth once daily for 5 days and ciprofloxacin 400/500 mg intravenously/by mouth twice daily for 10 days in complicated UTI (cUTI). The current study was a post hoc, subgroup analysis of male and female subjects with cUTI. Subjects were stratified into groups based on sex and antibiotic received. The subjects were analyzed at the end of therapy (EOT) and post therapy (PT) for clinical success rates, defined as no further need for antimicrobial treatment. RESULTS: Totals of 427 patients (224 male, 203 female) and 350 patients (189 male, 161 female) were included in the modified intent-to-treat (mITT) population and microbiologically evaluable (ME) populations, respectively. Clinical success rates between males and females were not statistically different between antibiotic groups in either the mITT or ME populations at EOT or PT. CONCLUSION: This study demonstrates that males with UTI may be treated with a shorter course of antimicrobial therapy for UTI than previously recommended.

Researchers' Experience with Clinical Data Sharing.

The topic of transparency in industry-sponsored clinical trials has gathered the attention of researchers in medicine. Patient-level data from recently completed clinical trials is now available for investigators to reanalyze or perform new analyses. In this Special Communication, the authors discuss their experience using this type of research and provide recommendations for success.

Vancomycin Combined With Clindamycin for the Treatment of Acute Bacterial Skin and Skin-Structure Infections.

BACKGROUND: Acute bacterial skin and skin-structure infections (ABSSSIs) are common causes of hospital admissions. These infections are often caused by methicillin-resistant Staphylococcus aureus; therefore, vancomycin remains a commonly used therapy. The purpose of this study was to compare hospital length of stay (LOS) in patients treated with vancomycin monotherapy vs combination therapy with clindamycin for ABSSSIs. METHODS: This was a retrospective analysis of 269 patients admitted with ABSSSIs to a 941-bed hospital in northern Alabama. Patients who received either vancomycin monotherapy or vancomycin in combination with clindamycin were included. The primary outcome was hospital LOS; secondary outcomes included 90-day readmission rate and the impact of the following on the primary outcome: organisms cultured, presence of abscess, incision and debridement (I&D), failure of a trial of outpatient antibiotics, and presence of diabetes. RESULTS: Hospital LOS was similar between groups when evaluating all ABSSSIs (3.7 ± 1.5 days vs 4.0 ± 2.0 days, P = .192, combination and monotherapy, respectively). In patients with abscesses, combination therapy was significantly associated with decreased LOS by 18.2% compared with monotherapy (95% confidence interval [CI], 0.818 [.679 to .985]; P = .034). Among the entire population, significantly fewer patients in the combination group were readmitted within 90 days (5.3% vs 15.3%; P = .006; odds ratio [OR], 3.2; 95% CI [1.35 to 7.66]). The 90-day readmission rates were significantly lower among patients with abscesses as well (2.0% vs 24.3%; P = .0001; OR, 14.6; 95% CI [2.98 to 71.37]). CONCLUSIONS: Combination therapy with vancomycin and clindamycin was associated with decreased hospital LOS for patients with an abscess. The 90-day hospital readmission rates for those with ABSSSIs may be reduced when combination therapy is utilized. A larger, prospective, multicentered study is needed to validate these findings.

Aminoglycoside-induced nephrotoxicity.

Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral agents in this class include gentamicin, tobramycin and amikacin. Aminoglycosides are concentration-dependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30S subunit of the bacterial ribosome. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. When other, safer, antimicrobial agents became available, the use of aminoglycosides sharply declined. The development of multi-drug resistance among bacteria has now lead clinicians to reexamine the role of the aminoglycosides in the treatment of serious infections. This review will revisit the mechanism and risk factors for the development of aminoglycoside-induced nephrotoxicity, as well as strategies to prevent patients from developing nephrotoxicity.

Mitiglinide for type 2 diabetes treatment.

INTRODUCTION: Mitiglinide , a rapid-acting insulin secretion-stimulating agent, is approved in Japan for the treatment of type 2 diabetes (T2DM). Rapid-acting insulin secretion-stimulating agents, also known as meglitinides, are not recommended as monotherapy, however, may be added to metformin therapy for those patients with continued postprandial hyperglycemia. Currently, repaglinide (Prandin®) and nateglinide (Starlix®) are the only US Food and Drug Administration-approved agents in this class of drugs. AREAS COVERED: This review describes the pharmacology, pharmacokinetics, efficacy, safety, and potential role in therapy of mitiglinide therapy. Phase II and III clinical studies have demonstrated that A1C levels should be expected to decrease by 0.17 - 1.1% with mitiglinide therapy. The most common adverse effects in these studies were hypoglycemia related. EXPERT OPINION: Meglitinides are limited by their cost, frequency of administration, and minimal available data assessing clinical impact; however, mitiglinide shows selective action on the pancreatic ß-cells, has greater affinity for ß-cells, and limited metabolism when compared to other meglitinides. These properties may allow more utility in patients with chronic kidney disease or at high risk of hypoglycemia. The primary role in therapy for mitiglinide is the treatment of elevated postprandial glucose in patients with T2DM.

Rivoglitazone: a new thiazolidinedione for the treatment of type 2 diabetes mellitus.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of the thiazolidinedione rivoglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, to determine its potential role in the treatment of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-February 2013) was conducted for English-language studies in humans, using the terms rivoglitazone and CS011. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings from 2007 to 2012 were also evaluated for relevant data. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of rivoglitazone were reviewed. DATA SYNTHESIS: Rivoglitazone has been shown, through small clinical studies, to decrease hemoglobin A(1c) (A1C) by 0.11-1.1% when compared with placebo and may provide greater A1C reduction than pioglitazone. Rivoglitazone reduces hyperglycemia, hyperinsulinemia, and hypertriglyceridemia by acting as an agonist of PPAR-γ. Rivoglitazone is the most potent PPAR-γ agonist; the initial recommended dose is 1 mg daily, with adjustment as needed to a maximum dose of 2 mg daily. Additionally, rivoglitazone has a longer half-life than other PPAR-γ agonists. Similar to those of the other PPAR-γ agonists, rivoglitazone's adverse effects include peripheral edema and weight gain. CONCLUSIONS: Rivoglitazone is the fourth agent in the thiazolidinedione class of antidiabetes drugs. Although rivoglitazone appears to be more potent in its ability to lower A1C levels compared with other thiazolidinediones, further studies of longer duration are needed to fully assess the risks associated with this drug. Until these can be completed, we cannot recommend rivoglitazone over currently approved drugs in this class.

Prazosin for the treatment of nightmares related to posttraumatic stress disorder: a review of the literature.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disorder with symptoms that include insomnia due to hyperarousal and recurring nightmares. These symptoms are believed to be due to a conditioned response that is regulated by norepinephrine. Prazosin, an α(1) antagonist, can decrease levels of norepinephrine in the central nervous system, thereby reducing nightmares related to PTSD. DATA SOURCES: A literature search was conducted for all studies evaluating the effectiveness of prazosin as therapy for nightmare symptoms of PTSD. MEDLINE was utilized to identify all English-language studies published between 1966 and March 2011. Keywords searched included prazosin, PTSD, and nightmares. RESULTS: Eleven studies were identified, including 4 open-label trials, 4 retrospective chart reviews, and 3 placebo-controlled trials. Prazosin demonstrated favorable clinical efficacy and was found to be safe for relieving PTSD-associated nightmares. CONCLUSIONS: Current data indicate that prazosin is an effective agent for the treatment of nightmares associated with PTSD. However, the data are limited by small study sizes, lack of diversified investigators, and lack of regional diversity.

Development of an antibiogram in a long-term care facility.

OBJECTIVE: To create an antibiogram-a profile of an organism's susceptibility/resistance to a panel of antibiotics- for a long-term care facility to assess the prevalence of resistance of bacteria present at the facility. DESIGN: Retrospective analysis of culture and sensitivity data from July 1, 2009, through June 30, 2010. SETTING: A long-term care facility in Huntsville, Alabama. PATIENTS AND PARTICIPANTS: Residents of the long-term care facility that had one or more culture and sensitivity test performed. MAIN OUTCOME MEASURE: Susceptibility of bacteria to each antimicrobial tested. RESULTS: Results were compiled and reported according to the Clinical and Laboratory Standards Institute Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data. The most commonly seen bacteria in our long-term care facility were Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis. Resistance rates for these bacteria were high and included the presence of methicillinresistant S. aureus and extended-spectrum beta-lactamase-producing bacteria. CONCLUSION: Resistance rates were high among all organisms reported. This poses a serious threat to the health care team's ability to effectively treat residents of this facility. Development of an antibiogram to assist physicians in antimicrobial selection will be beneficial in helping evaluate trends in drug resistance to current available treatments. Implementing clinical pathways for empiric treatment of infections could improve the ability to provide consistent treatment for all residents in the facility.

Mitiglinide: a novel agent for the treatment of type 2 diabetes mellitus.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of mitiglinide, a rapid-acting insulin secretion-stimulating agent to determine its potential role in therapy for the treatment of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-May 2010) was conducted for English-language, human studies using the terms mitiglinide, KAD 1229, S 21403, and meglitinide analogs. Abstracts presented at the American Association and European Association for the Study of Diabetes annual meetings from 2005 to 2009 were also evaluated for relevant data. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of mitiglinide were reviewed. DATA SYNTHESIS: Mitiglinide has been shown through small clinical studies (N <400) to modestly decrease hemoglobin A(1c), postprandial hyperglycemia, and oxidative stress and inflammatory markers associated with postprandial hyperglycemia. Mitiglinide exerts its hypoglycemic activity by closing adenosine triphosphate (ATP)-sensitive potassium channels in the ß-islet cells of the pancreas. This agent has a rapid onset and short duration of action, mimicking a physiologic pattern of insulin release in nondiabetic people. Studies suggest a starting dose of 5 mg 3 times daily with meals and a maximum dose of 20 mg 3 times daily. Overall, mitiglinide is well tolerated, with the most common adverse effect being hypoglycemia. CONCLUSIONS: Mitiglinide is the third agent in the class of meglitinides that targets postprandial hyperglycemia. Because of a more intensive dosing regimen, potential cost, and lack of studies assessing the clinical impact of mitiglinide therapy on oxidative stress and inflammatory markers secondary to postprandial hyperglycemia, we cannot recommend this therapy over currently approved therapies.

Alternate-day statin therapy for the treatment of hyperlipidemia.

OBJECTIVE: To evaluate the safety, efficacy, and cost of alternate-day statin therapy in the treatment of hyperlipidemia. DATA SOURCES: Systematic searches were conducted for primary literature sources involving alternative statin regimens using PubMed, EMBASE, Google Scholar, and International Pharmaceutical Abstracts (January 1966-March 2010). Articles selected were limited to those published in the English language. Reference citations from relevant publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified were reviewed and 17 trials (14 prospective and 3 retrospective) involving alternate-day statin dosing were included. Studies involving alternative statin dosing regimens other than alternating days were excluded from this review. DATA SYNTHESIS: Daily administration of statins is the standard of therapy used to reduce low-density lipoprotein cholesterol (LDL-C) levels as well as atherosclerosis that may lead to coronary events. Through LDL-C lowering and pleiotropic effects, statins decrease cardiovascular morbidity and mortality. Unfortunately, due to cost and adverse effects of statins, some patients are nonadherent to statin therapy. Several small studies have found alternate-day statin therapy to be as effective at reducing LDL-C as daily administration, while also lowering the incidence of adverse reactions and potentially lowering cost. CONCLUSIONS: Alternate-day statin therapy may decrease cost and therapy-limiting adverse reactions while potentially increasing regimen adherence and positively affecting the lipid panel. Further research is needed to determine whether this alternative regimen produces similar cardiovascular outcomes as those with daily statin therapy.

A possible case of saw palmetto-induced pancreatitis.

A 65-year-old male with a history of diabetes, hypertension, hyperlipidemia, gout, Barrett esophagitis, and chronic gastritis developed acute pancreatitis after taking one week of the herbal medicine, saw palmetto, for symptoms related to benign prostatic hyperplasia (BPH). Ultrasound and computed tomography ruled out cholelithiasis and obstruction, triglycerides were normal, and he had no recent infection or trauma. He had a history of occasional alcohol consumption, though there was no recent increased intake. The most likely cause of pancreatitis in this case was saw palmetto. Saw palmetto (Serenoa repens) is an herbal medication used primarily in the treatment of symptoms related to BPH. It has a high content of fatty acids and phytosterols which are thought to exert their effects by inhibiting the enzyme 5-alpha-reductase, thereby preventing the conversion of testosterone into dihydrotestosterone (DHT). It has been postulated that saw palmetto directly stimulates estrogenic receptors and inhibits progesterone receptors in the prostate tissue. A previous report implicated the estrogen/antiandrogen properties of saw palmetto as inducing hepatotoxicity in a patient. Additionally, it has also been postulated that stimulation of the estrogenic receptors may lead to increased triglyceride levels or induction of a hypercoagulable state that leads to pancreatic necrosis. Finally, inhibition of cyclooxygenase, a property of saw palmetto, may be linked to acute pancreatitis. Acute pancreatitis, a serious and sometimes fatal disorder may occur secondary to medications. Although the mechanism is not fully known, this is the second case of acute pancreatitis that has been documented secondary to the herbal medication saw palmetto. It is important for clinicians to obtain detailed medication histories, including over-the-counter and herbal medications, in order to prevent further complications from occurring.

Evaluation of the chronic kidney disease epidemiology collaboration equation for dosing antimicrobials.

BACKGROUND: Since the derivation of the Modification of Diet in Renal Disease (MDRD) equation for estimating glomerular filtration rate (GFR), investigators determined that it cannot be used for drug dosing. In 2009, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) derived an equation that was more accurate than the MDRD estimation of GFR. Therefore, questions exist about which method should be preferred in making dosage adjustments for renally eliminated antimicrobials. OBJECTIVE: To determine whether a difference exists when making antimicrobial dosage adjustments in patients with CKD based on estimation of GFR using the CKD-EPI and Cockcroft-Gault equations. METHODS: A database of 409 patients with CKD admitted to a tertiary care facility was used. GFR was calculated using both the CKD-EPI equation(s) and the Cockcroft-Gault equation and compared using correlation and Bland-Altman methodology. Dosage discordance rates of antimicrobials were determined. RESULTS: Average GFRs for all patients using the Cockcroft-Gault and CKD-EPI equations were 34.8 +/- 12 mL/min and 39.9 +/- 13 mL/min, respectively (5.09 [95% CI 4.60 to 5.59]; p < 0.001). The correlation coefficient between the 2 estimations was high (r = 0.91). The Bland-Altman plot yielded limits of agreement of 15.3 and -5.1; thus, the CKD-EPI estimation may range from 5.1 mL/min below to 15.3 mL/min above the Cockcroft-Gault estimation for 95% of the cases. A discordance rate of 15-25% existed among the recommended dosing adjustments of the selected antimicrobials when comparing the Cockcroft-Gault and CKD-EPI estimations. CONCLUSIONS: Though this study did not determine which equation should be selected to dose adjust antimicrobials, it demonstrated statistically significant differences between the Cockcroft-Gault and CKD-EPI equations. The clinical significance of these differences is uncertain in the absence of data assessing clinical outcomes that result from the use of the discordant doses. Clinical judgment should be employed when making renal dosage adjustments of antimicrobials.

A comprehensive review of the loop diuretics: should furosemide be first line?

OBJECTIVE: To review the literature regarding the pharmacokinetic profiles, comparative safety and efficacy, and comparative costs of loop diuretics to evaluate the current clinical usefulness of furosemide. DATA SOURCES: A search of MEDLINE (1966-June 2009) was conducted using the terms furosemide, torsemide, bumetanide, ethacrynic acid, and loop diuretics. Articles were limited to those written in English. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. Studies were eligible if they encompassed pharmacokinetics, comparative safety and efficacy, or comparative costs of the loop diuretics. DATA SYNTHESIS: In patients with heart failure (HF), torsemide demonstrated decreased mortality compared with furosemide in 1 study (2.2% vs 4.5% in the furosemide group; p < 0.05), decreased hospitalizations in 1 study (23 in the torsemide group vs 61 in the furosemide group; p < 0.01), and improved New York Heart Association functional classifications in 2 studies. In the first, 45.8% with torsemide versus 37.2% with furosemide demonstrated improvement in at least one functional class (p = 0.00017). In the second, 40.2% with torsemide and 30.7% with furosemide demonstrated improvement in at least one functional class (p = 0.014). In 2 of 3 studies of patients with cirrhosis, torsemide increased natriuresis and total volume diuresed compared with furosemide in patients with cirrhosis; however, no significant difference between the agents with respect to plasma renin and aldosterone concentrations was demonstrated. In patients with pulmonary hypertension, central venous pressure, capillary wedge pressure, and stroke volume significantly improved from baseline among patients who received torsemide, but not in those who received furosemide, although the intergroup analysis failed to reach statistical significance. Among patients with chronic kidney disease, no significant differences were noted with respect to natriuresis and blood pressure control between the 2 agents; however, in patients with acute kidney injury, patients who received furosemide had a significant improvement in urine output versus the torsemide group. Additionally, 2 trials comparing bumetanide with furosemide were identified, although the results were conflicting. In patients with nephrotic syndrome, bumetanide significantly improved weight loss in the first 4 weeks and in week 20, compared with furosemide. In patients with HF, significant improvement in dyspnea at rest and on exertion was exhibited in the bumetanide group, but not in the furosemide group; no significant difference was noted between the 2 groups when evaluating global assessment. CONCLUSIONS: Growing evidence demonstrates more favorable pharmacokinetic profiles of torsemide and bumetanide compared with furosemide. Furthermore, torsemide may be more efficacious and safer than furosemide in patients with HF. A trial comparing all 3 drugs would be required to confirm torsemide as the primary loop diuretic in patients with HF, but based upon limited current evidence, we recommend torsemide over furosemide. Currently, little evidence exists to support either torsemide or bumetanide as first-line treatment over furosemide in patients with other edematous disease states.

Efungumab: a novel agent in the treatment of invasive candidiasis.

OBJECTIVE: To review the use of efungumab as an adjunctive agent in the treatment of invasive candidiasis (IC) and to provide guidance on formulary placement. DATA SOURCES: Searches of MEDLINE (1966-June 2009) and EMBASE (1974-June 2009) were conducted using the terms efungumab, Mycograb, heat shock protein 90, and invasive candidiasis. Other resources included www.clinicaltrials.gov and article bibliographies. STUDY SELECTION AND DATA EXTRACTION: All studies and case reports evaluating efungumab use in IC were included. Literature review was limited to the English language. DATA SYNTHESIS: Efungumab is a monoclonal antibody targeted against heat shock protein 90 (HSP 90). It binds to HSP 90, preventing a conformational change needed for fungal viability. In vitro data show that HSP 90 inhibition may decrease resistance against antifungal agents and increase antifungal activity. Efungumab shows activity against Candida spp. when used alone and synergism when combined with fluconazole, caspofungin, and amphotericin B. A randomized controlled trial evaluated combination therapy of efungumab 1 mg/kg twice daily and liposomal amphotericin B versus amphotericin B therapy alone. At day 10, a favorable response was seen in 84% of patients in the efungumab group compared with 48% of patients in the placebo group (OR 5.76; 95% CI 2.4 to 13.8). Mortality at day 33 was also lower in the efungumab group, 4% versus 18%, respectively (OR 0.168; 95% CI 0.036 to 0.797). Although adverse effects were similar in this trial (10% vs 7%), case reports revealed an increased incidence of blood pressure fluctuations. Cytokine release syndrome has also been linked to efungumab use, warranting further exploration of its safety. CONCLUSIONS: Efungumab is a new antifungal agent with a novel mechanism of action. Available clinical data and synergy studies support the use of efungumab in combination with other antifungal agents for the treatment of IC. Further safety data are needed before formulary recommendations can be made.