OBJECTIVE: To compare the efficacy of pitavastatin 1 mg once daily with that of atorvastatin 10 mg once daily on lipoprotein change, safety, and cost per percent LDL-C reduction.

METHODS: An 8-week, randomized, open-label, parallel trial was conducted in patients with hypercholesterolemia. One hundred patients were equally randomized to receive pitavastatin 1 mg once daily or atorvastatin 10 mg once daily; 98 completed the study. Outcomes were assessed at baseline and at the end of the study.

RESULTS: Pitavastatin lowered LDL-C levels from baseline by 37% compared with 46% in the atorvastatin group (p < 0.001). The reduction of total cholesterol (TC) levels from baseline was significantly different between the pitavastatin (28%) and atorvastatin (32%) groups (p = 0.005). There was no significant difference in the percentage of changes in triglyceride and high-density lipoprotein cholesterol levels between groups. The percentage of patients who achieved LDL-C goals according to National Cholesterol Education Program-Adult Treatment Panel III guidelines was not significantly different between the pitavastatin (74%) and atorvastatin (84%) groups (p = 0.220). In addition, both regimens were well tolerated, with no patient developing an elevation of more than 3 times the upper normal limit of alanine aminotransferase or 10 times that of creatine kinase. The monthly cost per percent LDL-C reduction in the pitavastatin group ($0.77) was about 50% lower than the cost in the atorvastatin ($1.56) group.

CONCLUSIONS: Although pitavastatin 1 mg daily was not as effective at lowering LDL-C and TC levels as atorvastatin 10 mg daily, the number of patients achieving their LDL-C goals with pitavastatin was comparable with the number using atorvastatin. Pitavastatin 1 mg once daily may be an alternative regimen with cost-saving benefits but without a significant decrease in therapeutic benefit or increase in adverse events in patients with hypercholesterolemia.

OBJECTIVE: To determine barriers to provision of MTMS perceived by pharmacists and factors associated with the likelihood of working in a pharmacy that provides MTMS.

METHODS: Surveys were mailed to 906 community pharmacists licensed in West Virginia using a stratified random sample. The instrument was constructed and finalized following a review by experts and pilot tested in a convenience sample of pharmacists. Principal components analysis was performed to determine the factors that describe perceived barriers to provision of MTMS. Discriminant analysis using factor scores and other demographic and practice variables was performed to predict respondents' likelihood to work in a pharmacy that provides MTMS.

RESULTS: A 3-factor model was extracted from the responses, which explained 53.3% of the total variance. The factors included perceived ability to respond to patient interest, pharmacy-related factors, and enabling factors. The discriminant function correctly classified 76.2% of cases and included comfort level with provision of services, perceived value of services to patients, perceived ability to respond to patient interest, and whether they currently offer MTMS. These variables were all positively correlated with pharmacists' likelihood of working in a pharmacy that provides MTMS.

CONCLUSIONS: Comfort level and ability are important factors that influence pharmacists' likelihood of working in a pharmacy that provides MTMS. These findings highlight the importance of advanced practice experiences, certificate programs, and residencies to build pharmacists' confidence, and the role of targeted recruitment to attract pharmacists to community pharmacies that provide MTMS.

OBJECTIVE: To determine the impact that pharmacy staffing configurations that include a tele-ICU pharmacist have on compliance with an intensive care unit (ICU) sedation guideline in critically ill mechanically ventilated patients requiring continuous-infusion sedative medications.

METHODS: Compliance with an established ICU sedation guideline, the performance of daily sedative interruptions, and the number of sedative medication-related interventions were evaluated before and after expansion of the ICU pharmacist staffing model to include comprehensive off-hours pharmacist coverage supported with established tele-ICU resources. In both groups, sedation was managed by the primary ICU team. In the intervention group, a pharmacist working in the tele-ICU center performed electronic record audits and made sedative medication recommendations to the primary team.

RESULTS: The addition of third shift tele-ICU pharmacist support was associated with a significant increase in the percentage of patients who received a daily sedative interruption (45% vs 54%; p < 0.0001). This occurred in the context of significant increases in the total number of ICU pharmacist interventions (36 vs 49.4 per 100 patient days, p < 0.0001), the number of therapeutic interventions (20.4 vs 26.1 per 100 patient days, p < 0.001), and the number of sedative-related interventions (0.9 vs 4.4 per 100 patient days, p < 0.0001).

CONCLUSIONS: Tele-ICU resources can be utilized to increase compliance with an established ICU sedation guideline and extend the benefits that daytime ICU clinical pharmacy services provide. Increased ICU pharmacist availability may have additional benefits not measured in this study.

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.

OBJECTIVE: To describe an evidence-based, multidisciplinary approach that was taken to ensure optimal, safe, and cost-effective treatment of patients with FabAV.

METHODS: Following an analysis of the available literature, a multidisciplinary committee was formed to construct a protocol for use of FabAV. This group included clinical pharmacists, pharmacy administrators, emergency medicine physicians who specialized in wilderness medicine and pharmacy residents.

RESULTS: A multidisciplinary FabAV usage protocol was constructed and implemented to ensure appropriate patient evaluation, FabAV use and preparation, monitoring, and follow-up. This protocol was based on the available literature and the expert opinion of the committee. Through the use of a 24-hour in-house pharmacy resident on-call system, clinical pharmacy services were provided to ensure a multidisciplinary approach to the care of these patients emergently. Although limited, initial data show that this approach is effective and may result in substantial cost savings.

CONCLUSIONS:. Initial results from implementation of a protocol for use of FabAV have limited inappropriate use, reduced medication wastage, and decreased costs.

OBJECTIVE: To identify the references that emergency medicine (EM) clinicians use for prescribing in pregnant patients, the prescribing trends when clinicians are given the pregnancy category information, and clinician awareness of access to drug information references.

METHODS: This cross-sectional survey was administered to EM clinicians. In part I, clinicians listed the top 3 drug information references that they routinely use in clinical practice. In part II, clinicians ranked their willingness to prescribe a Category A, B, C, D, or X drug using a 5-point Likert scale. In part III, clinicians selected from a list of electronic and print resources those that they consider available to them in the ED to find pregnancy-related drug prescribing information. Statistical analyses included frequency distribution and bivariate analysis.

RESULTS: Fifty-five clinicians with an average of 5.71 ± 7.95 years (± SD) in the profession completed the survey. The most commonly used references included Micromedex, Tarascon Pocket Pharmacopoeia, and Epocrates (29%, 18%, and 14%, respectively). Ten (18%) respondents stated that they would be willing to prescribe Category C drugs. Among the 5 pregnancy-specific drug information references that are available in our ED, only 20% of EM clinicians stated that these references were available to them.

CONCLUSIONS: EM clinicians rely on general references to make prescribing decisions for pregnant patients and are willing to prescribe medications that have data to support safe use in pregnancy. A minority of EM clinicians acknowledged the availability of pregnancy-specific references in the ED. Increased awareness of references that incorporate human data into their pharmacotherapy recommendations is warranted to assist EM clinicians in achieving their goal of prescribing safely in the pregnant patient.

OBJECTIVE: To determine the stability of both sugar-containing and sugar-free rufinamide suspensions over a 90-day period.

METHODS: A suspension of rufinamide 40 mg/mL was prepared by grinding twelve 400-mg tablets of rufinamide tablets in a glass mortar. Sixty milliliters of Ora-Plus and 60 mL of either Ora-Sweet or Ora-Sweet SF (sugar free) were mixed and added to the powder to make a final volume of 120 mL. Three identical samples of each formulation were prepared and placed in 60-mL amber plastic bottles and were stored at room temperature. A 1-mL sample was withdrawn from each of the 6 bottles with a micropipette immediately after preparation and at 7, 14, 28, 56, and 90 days. After further dilution to an expected concentration of 0.4 mg/mL, the samples were assayed using high-performance liquid chromatography. Stability was defined as the retention of at least 90% of the initial concentration.

RESULTS: At least 90% of the initial rufinamide concentration remained throughout the 90-day study period in both preparations. There were no detectable changes in color, odor, taste, and pH and no visible microbial growth.

CONCLUSIONS: Extemporaneously compounded suspensions of rufinamide 40 mg/mL in a 1:1 mixture of Ora-Plus and Ora-Sweet or Ora-Sweet SF were stable for at least 90 days when stored in 59-mL amber polypropylene plastic bottles at room temperature.

OBJECTIVE: To characterize the incidence of electrolyte disturbances following PEGBPs administered prior to colonoscopy among elderly inpatients and hypothesize that PEGBP would be associated with hypokalemia in this setting.

METHODS: This retrospective chart review, conducted at 3 tertiary care teaching hospitals in Toronto, Canada, from 2005 to 2007, included 96 consecutive patients aged 65 or older who were admitted to the hospital and given PEGBP prior to their first inpatient colonoscopy. Patients were excluded if they received additional cathartics, underwent colonoscopy while admitted to a critical care unit, or were admitted for a complication arising from an outpatient colonoscopy. The primary outcome was hypokalemia (serum potassium ≤3.2 mEq/L) within 48 hours of PEGBP.

RESULTS: Of 96 patients, 73 had serum electrolytes measured at baseline and within 48 hours following PEGBP administration. Hypokalemia was identified in 4 patients (5.5%) prior to PEGBP and in 15 patients (20.5%) after PEGBP (p < 0.001). The incidence of significant hypokalemia, defined as serum potassium ≤3.0 mEq/L, in this group was 9.6% (p = 0.008). We found consistent results among patients with and without concomitant diuretic treatment.

CONCLUSIONS: Among older patients, administration of PEGBP is commonly complicated by the development of hypokalemia, which is occasionally severe. Monitoring of electrolytes may be necessary following colonoscopy, particularly in patients with cardiac or renal disease.

OBJECTIVE: To evaluate via meta-analysis the comparative efficacy of amoxicillin or amoxicillin/clavulanate to that of macrolide antibiotics in the treatment of children with AOM.

METHODS: A systematic literature search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts was conducted from the earliest available date through September 2008. We used the following MeSH and key words: amoxicillin, amoxicillin/clavulanate, Augmentin, azithromycin, ceftriaxone, clarithromycin, macrolides, AND media, otitis media, and effusion. Included studies were randomized, blinded, and controlled trials evaluating guideline-recommended antibiotics (amoxicillin or amoxicillin/clavulanate) compared to macrolide antibiotics (azithromycin or clarithromycin) in AOM in children. The primary outcome assessed was clinical failure measured between days 10 and 16 after starting antibiotic therapy. Results are reported as relative risks (RRs) with 95% confidence intervals and were calculated using a random-effects model.

RESULTS: A total of 10 trials (N = 2766) evaluating children 6 months-15 years old were included in the meta-analysis. Upon meta-analysis, the use of macrolide antibiotics was associated with an increased risk of clinical failure (RR 1.31 [95% CI 1.07 to 1.60]; p = 0.008) corresponding to a number needed to harm of 32. Upon safety analysis, rates of any adverse reaction (RR 0.74 [95% CI 0.60 to 0.90]; p = 0.003) and diarrhea (RR 0.41 [95% CI 0.32 to 0.52]; p < 0.0001) were significantly lower in the macrolide group.

CONCLUSIONS: The meta-analysis suggests that patients treated with macrolides for AOM may be more likely to have clinical failures. As such, it supports the current AAP AOM recommendation that macrolides be reserved for patients who can not receive amoxicillin or amoxicillin/clavulanate.

OBJECTIVE: To estimate patients' benefit-risk preferences for treatments for ITP.

METHODS: Patients' adverse event risk tolerance and the levels of benefit required to offset possible risks were evaluated using choice-format conjoint analysis. Subjects chose between pairs of hypothetical treatment alternatives defined by probability of achieving safe platelet levels, need for corticosteroids, mode of administration, risk of rebound, risk of elevated liver enzyme levels, and risk of thromboembolism.

RESULTS: In this study, we demonstrate that patients have clear and measurable benefit-risk preferences that physicians should consider when discussing treatment options with their patients. Patients were willing to accept significant risks of adverse events in return for an increase in the probability of achieving safe platelet levels, to avoid corticosteroids, and for more convenient administration. Patients were willing to accept significant risks of rebound and elevated liver enzymes for improvements in outcomes.

CONCLUSIONS: These results demonstrate that patients with ITP are willing to accept treatment-related risks in exchange for improvements in treatment efficacy and administration attributes and suggest the importance of considering a patient's benefit-risk preferences during discussions of therapeutic options.

DATA SOURCES: Literature searches were performed using PubMed/MEDLINE (through August 2009) and EMBASE (through January 2008) and were restricted to the English language. In PubMed/MEDLINE, search terms used were ibuprofen, acetaminophen, paracetamol, clinical trials, and randomized controlled trials. EMBASE search terms included ibuprofen and acetaminophen, restricted to human and clinical trials.

STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. Multiple review articles were studied for any pertinent references and this yielded additional articles. Only articles that directly compared ibuprofen and acetaminophen were eligible for this review.

DATA SYNTHESIS: Eighty-five studies that directly compared ibuprofen to acetaminophen were identified; 54 contained analgesic efficacy data, 35 contained antipyretic/temperature reduction data, and 66 contained safety data (some articles contained more than 1 type of data). Qualitative review of the literature revealed that, for the most part, ibuprofen was more efficacious than acetaminophen for the treatment of pain and fever in both pediatric and adult populations, and that these 2 drugs were equally safe. Meta-analyses on the subset of randomized clinical trial articles that reported sufficient quantitative information to calculate either an odds ratio (adverse event [AE]) or standardized mean difference (pain and fever) confirmed the qualitative results for adult (standardized mean difference [SMD] 0.69; 95% CI 0.57 to 0.81) and pediatric (SMD 0.28; 95% CI 0.10 to 0.46) pain at 2 hours postdose and pediatric fever (SMD 0.26; 95% CI 0.10 to 0.41) at 4 hours postdose. Conclusions regarding adult fever/temperature reduction could not be made due to a lack of evaluable data. The combined odds ratio for the proportion of adult subjects experiencing at least 1 AE slightly favored ibuprofen; however, the difference was not statistically significant (1.12; 95% CI 1.00 to 1.25). No significant difference between drugs in AE incidence was found for pediatric patients (0.82; 95% CI 0.60 to 1.12).

CONCLUSIONS: Ibuprofen is as or more efficacious than acetaminophen for the treatment of pain and fever in adult and pediatric populations and is equally safe.

DATA SOURCES: Literature was accessed through PubMed (1948-December 2009). Pitavastatin, itavastatin, nisvastatin, NK 104, and NKS 104 were used as search terms. Results were limited to articles written in the English language.

STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data source were reviewed for inclusion. Articles included were those pertaining to the pharmacology and pharmacokinetic properties of pitavastatin, in addition to original research evaluating the clinical efficacy of pitavastatin for hypercholesterolemia.

DATA SYNTHESIS: Pitavastatin is an oral HMG-CoA reductase inhibitor recently approved by the Food and Drug Administration for the treatment of primary hyperlipidemia and mixed dyslipidemia. Pitavastatin 2 mg has been shown to be noninferior to atorvastatin 10 mg and simvastatin 20 mg with respect to low-density lipoprotein cholesterol (LDL-C)-lowering ability. Additionally, pitavastatin 2 mg was shown in one study to lower LDL-C significantly more than pravastatin 10 mg. As with other HMG-CoA reductase inhibitors, primary safety concerns are related to myopathies and alterations in liver enzyme levels. While efficacy regarding beneficial effects on lipid parameters is comparable to that of other agents, a potential advantage of pitavastatin is its cytochrome P450 (CYP450) independent elimination, thereby reducing the likelihood of clinically significant drug-drug interactions. However, this is not a unique property, as pravastatin and rosuvastatin also possess this property.

CONCLUSIONS: In light of the lack of outcome data, pitavastatin offers no clear advantage over other drugs in this class.

DATA SOURCES: PubMed was searched (1966-April 2009) using the key words Kinrix and Pentacel. Subject headings included vaccines, combined; diphtheria-tetanus-pertussis vaccine; diphtheria-tetanus-acellular pertussis vaccines; poliovirus vaccine, inactivated; and Haemophilus influenzae type b polysaccharide vaccine-tetanus toxin conjugate. The search was limited to English-language publications involving humans. Product labeling was obtained from GlaxoSmithKline and Sanofi Pasteur. The Centers for Disease Control and Prevention (CDC) Web site was searched for relevant recommendations published June 2008-October 2009.

STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 clinical trials evaluating immunogenicity and safety of DTaP-IPV and DTaP-IPV/Hib were reviewed. Published trials were supplemented with abstracts, review articles, manufacturer product labeling, and CDC recommendations.

DATA SYNTHESIS: DTaP-IPV is immunogenic compared to its component vaccines, with no effect of concomitantly administered measles, mumps, and rubella vaccine. Although injection site pain has occurred more with the combination vaccine, its use would reduce by 1 the number of injections given when a child is 4-6 years old. DTaP-IPV/Hib is immunogenic and safe compared to separate vaccines. Immunogenicity to 7-valent pneumococcal conjugate vaccine and hepatitis B (HepB) vaccine is not affected by concomitant administration. DTaP-IPV/Hib decreases injections by up to 7 when given at 2, 4, 6, and 15-18 months of age. It fits into the schedule more easily than DTaP-HepB-IPV (Pediarix), the other DTaP-containing combination vaccine indicated for the primary infant series.

CONCLUSIONS: DTaP-IPV and DTaP-IPV/Hib combination vaccines are immunogenic and safe when given to infants and children. They reduce the number of required injections. Combination vaccines are encouraged to promote timely vaccination and complete immunization schedules.

DATA SOURCES: A literature search was conducted in MEDLINE (1966-November 2009), International Pharmaceutical Abstracts (1970-November 2009), and EMBASE (1990-November 2009) using the MeSH terms and key words AZD6140, ticagrelor, P2Y12 receptor antagonist, cardiovascular disease, ACS, atherothrombosis, and platelets.

STUDY SELECTION AND DATA EXTRACTION: Selected studies evaluated the pharmacology, pharmacokinetics, pharmacodynamics, safety, and efficacy of ticagrelor for the treatment of ACS.

DATA SYNTHESIS: Ticagrelor selectively and reversibly blocks the P2Y12 receptor, inhibiting platelet aggregation and preventing amplification of platelet activation. Optimal dosing strategy as determined by ticagrelor's pharmacokinetic and pharmacodynamic profile is a loading dose of 180 mg followed by 90 mg by mouth twice daily. At these doses, greater platelet inhibition is observed with ticagrelor as compared to clopidogrel 75 mg once daily in both clopidogrel-experienced and -naïve patients. Studies in patients experiencing ACS concluded that ticagrelor reduced the rate of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and overall mortality compared to clopidogrel without increasing major bleeding when administered with standard therapy for ACS. There was no significant difference in the risk of stroke with ticagrelor compared to clopidogrel; however, intracranial bleeding was more common with ticagrelor. Ticagrelor is well tolerated; however, minor bleeding, dyspnea, hypotension, nausea, and ventricular pauses were reported more frequently than with clopidogrel. Reversible inhibition with ticagrelor may allow for more rapid surgical intervention after discontinuation, suggesting greater flexibility in treatment of ACS.

CONCLUSIONS: Ticagrelor's improved pharmacokinetic and pharmacodynamic profile builds upon the limitations of currently available P2Y12 receptor antagonists. Ticagrelor represents a promising approach for the prevention of cardiovascular events in patients with ACS.

DATA SOURCES: A literature search was conducted in MEDLINE (1950-October week 4, 2009), International Pharmaceutical Abstracts (1970-October 2009), and Evidence Based Medicine Database (1991-2009 week 44) to identify relevant publications. Key words searched included pramlintide, weight loss, obesity, and overweight. Additional data sources were obtained through a bibliographic review of selected articles.

STUDY SELECTION/DATA EXTRACTION: All studies conducted on humans and published in English that examined the effects of pramlintide on body weight as a primary or secondary endpoint were selected for analysis.

DATA SYNTHESIS: Pramlintide is a human amylin analog approved by the Food and Drug Administration for use in conjunction with insulin therapy in patients with type 1 or 2 diabetes. In addition to its glucoregulatory actions, pramlintide has been shown to increase satiety and, therefore, decrease caloric intake via a central mechanism. Several studies show that this translates into statistically significant weight loss in overweight or obese patients with type 1 or 2 diabetes; patients with type 1 diabetes lost up to 1.7 kg over 1 year with pramlintide 60 µg 3 times daily, while patients with type 2 diabetes experienced a placebo-subtracted weight loss of up to 3.7 kg after 16 weeks of pramlintide 120-240 µg administered 3 times daily. Preliminary trials assessing the use of pramlintide for weight loss in obese patients without diabetes have demonstrated weight loss of up to 8 kg after 1 year. In all studies, the drug was generally well tolerated, with nausea being the most commonly reported adverse effect.

CONCLUSIONS: Based on preliminary evidence, pramlintide facilitates modest weight loss in obese or overweight patients with and without diabetes. However, current trials were limited by inconsistent study design, dosing, and patient population.

DATA SOURCES: Literature retrieval was accessed through MEDLINE (1950 through October 2009) and United Network for Organ Sharing online database (available data through October 2009), using the terms lung transplantation, prophylaxis, and fungal infection. In addition, reference citations from publications identified were reviewed.

STUDY SELECTION AND DATA EXTRACTION: All articles or related abstracts in English identified from the data sources above were evaluated. Literature including adult lung transplant recipients who received systemic antifungal prophylaxis to prevent invasive fungal infections (IFIs) was included in the review.

DATA SYNTHESIS: IFIs after lung transplantation remain a common postoperative problem and are associated with high mortality. The lung is the most vulnerable solid organ to be transplanted, as it is the main organ responsible for gas exchange and therefore the high risk for pulmonary-related IFIs. It is most susceptible to developing an IFI, as it serves as a medium for organisms traveling from air to human tissue, potentially causing life-threatening infections. Such infections typically involve Candida and Aspergillus spp. and tend to occur within the first 12 months after transplant. Although there has been an increase in lung transplants performed over the past decade, no standard antifungal prophylactic regimen exists. Literature describing antifungals used to prevent IFI after transplant is scarce, which may be due to a lack of consistency in regimens used between transplant centers. Several regimens have been described utilizing different antifungal agents as both monotherapy and combination therapy. The majority of the literature reviewed here describes aerosolized amphotericin B formulations and azole antifungals demonstrating an overall decreased risk of fungal infection after lung transplantation. It has become the standard of practice to initiate some form of antifungal prophylaxis in these patients.

CONCLUSIONS: The risk of fungal infection after lung transplant is multifactorial and optimal prophylactic regimens should include agents with adequate activity against the most pathogenic fungi.

DATA SOURCES: MEDLINE (1950-September 2009), EMBASE (1980-September 2009), and International Pharmaceutical Abstracts (1970-September 2009) were searched, using the terms meropenem, carbapenems, pharmacodynamics, and pharmacokinetics. Reference citations from publications identified were reviewed.

STUDY SELECTION AND DATA EXTRACTION: Articles discussing administration of meropenem to adults with normal renal function and comparing at least 2 regimens, 1 of which included the manufacturer-recommended regimen of 0.5 g or 1 g every 8 hours infused over 30 minutes, with clinical, pharmacodynamic, or pharmacoeconomic endpoints, were included. The pharmacodynamic endpoint of interest was percent time that the unbound drug concentration exceeded the minimal inhibitory concentration for a bacterial pathogen.

DATA SYNTHESIS: Sixteen studies were reviewed, which included 13 pharmacokinetic and dynamic assessments using Monte Carlo simulations, 5 clinical evaluations, and 3 pharmacoeconomic appraisals. Data on clinical and economic outcomes are largely nonrandomized retrospective analyses and case reports. Meropenem via intermittent prolonged infusion potentially increases the likelihood of achieving pharmacodynamic targets. However, a strong link with improved clinical outcomes is lacking. Smaller doses with shorter intervals appear to provide pharmacodynamic target attainment rates and clinical outcomes similar to those with traditional dosing, with potential pharmacoeconomic benefits. Meropenem via continuous infusion appears to increase the likelihood of achieving pharmacodynamic targets, compared with intermittent infusions. The sparsity of clinical evidence supporting this practice limits its broad application to practice. No studies have formally examined adverse effects with alternative dosing regimens.

CONCLUSIONS: Meropenem alternative dosing strategies provide similar pharmacodynamic target attainment rates compared with traditional dosing strategies. Small doses with shorter interval dosing provide additional pharmacoeconomic benefits and similar clinical outcomes. Alternative dosing strategies for meropenem were largely studied in healthy subjects; individuals with pharmacokinetic parameters that differ significantly may be ideal subjects for empiric dose modification.

DATA SOURCES: A MEDLINE search (1948-November 2009) was conducted using ulcerative colitis and probiotics as terms for identifying pertinent studies. Search limits included English language and humans. Additional information was obtained from bibliographies.

STUDY SELECTION AND DATA EXTRACTION: Prospective trials published in English and conducted in adults were included. Two open-label and 3 double-blind randomized trials evaluated probiotic efficacy for maintaining remission of UC. Clinical and surrogate markers for maintaining remission of UC were assessed.

DATA SYNTHESIS: A relationship between immune response and gastrointestinal microbials appears to be involved in the mechanism of UC. Trial results comparing the probiotic Escherichia coli Nissle 1917 to mesalazine have reported equivalent rates of UC relapse. Treatment with Lactobacillus rhamnosus GG strain alone or in combination with mesalazine resulted in a nonsignificant odds ratio decrease for relapse and a significant increase in time to relapse compared to treatment with mesalazine alone. Additionally, bifidobacteria-fermented milk-supplemented patients had significant reductions in UC exacerbations when compared to nonsupplemented patients. Probiotics were well tolerated, with adverse event rates similar between treatments.

CONCLUSIONS: Studies evaluating probiotics for maintaining remission of UC are limited by trial design and use of different probiotics with variable bacterial contents. Thus, questions remain regarding optimal probiotic, dosing, specific patient populations, and placement in therapy. To answer these questions, large, randomized, controlled trials need to be conducted before probiotics can be routinely recommended for maintaining remission of UC.

DATA SOURCES: A literature search was conducted through PubMed (up to December 2009), International Pharmaceutical Abstracts (1970-December 2009), and The Cochrane Library (up to December 2009) using combinations of the following key search terms: proton pump inhibitor, GERD, infant, children, pediatric, omeprazole, rabeprazole, lansoprazole, esomeprazole, and pantoprazole. Reference citations from identified articles were also reviewed.

STUDY SELECTION AND DATA EXTRACTION: All double-blind, placebo-controlled trials published in English that evaluated the safety and efficacy of PPIs in infants with GERD were included in this review. Trials involving children older than 12 months were not included.

DATA SYNTHESIS: GERD is a source of pain and discomfort in adults; yet, in infants, symptoms that are thought to be indicative of painful stimuli have no clear cause-and-effect relationship with infant GERD. PPIs are beneficial in relieving symptoms of GERD in the adult population, but their usefulness in decreasing GERD-associated behaviors in infants is still questionable, despite a large increase in PPI prescribing for children <1 year of age. In all studies reviewed, infants treated with PPIs did not experience a significant decrease in behaviors perceived to be caused by GERD. The largest placebo-controlled trial to date found that rates of adverse events were increased in the PPI group compared with the placebo group, whereas the other trials reviewed reported no difference in adverse effects with the use of PPIs.

CONCLUSIONS: Clinical trials reveal that PPI therapy is not an effective treatment for common infant GERD-associated symptoms. Evidence supporting safety of PPI use in infants is conflicting, and more large-scale, randomized, placebo-controlled trials are necessary to better establish the role of PPIs in infant GERD.

CASE SUMMARY: This case series describes the use of lubiprostone for the treatment of constipation in 3 adults with CF (mean ± SD length of therapy 17.3 ± 1.5 mo). All 3 patients were prescribed lubiprostone 24 µg twice daily after hospitalization for treatment of intestinal obstruction. Patient 1 continues on chronic polyethylene glycol (PEG) 3350 and lubiprostone and has not had a recurrence of obstruction. Patient 2 requires aggressive chronic therapy with PEG 3350, lubiprostone, and methylnaltrexone. She has had 1 recurrence of obstruction. Patient 3 continues with lubiprostone taken several times per week with good control of constipation and no recurrence of obstruction to date. The adverse effect profile has been tolerable in all 3 patients.

DISCUSSION: CF is caused by a genetic mutation resulting in a dysfunctional or absent CF transmembrane conductance regulator that normally functions as a chloride channel. This results in viscous secretions in multiple organ systems including the lungs and intestinal tract. Accumulation of viscous intestinal contents contributes to constipation, which is common among adults with CF and can sometimes lead to intestinal obstruction. Lubiprostone is indicated for chronic constipation and works by activating type 2 chloride channels (ClC-2) in the intestinal tract. Because it utilizes an alternate chloride channel, lubiprostone may be especially effective for constipation in patients with CF.

CONCLUSIONS: Lubiprostone provides an additional option for the treatment of constipation in adults with CF. Its use in the CF population deserves further study.

CASE SUMMARY: A 38-year-old woman experienced a right internal carotid artery dissection and right anterior and middle cerebral artery strokes due to unknown causes and subsequently developed vasogenic edema requiring right hemi-craniectomy. Her postoperative course was complicated by multiple infections, and she developed multidrug, carbapenem-resistant Acinetobacter baumannii cerebritis. She was treated with a prolonged course of multiple antibiotics, including 18 days of therapy with tigecycline. Time-paired serum and CSF samples were obtained, and tigecycline concentrations were analyzed by high-performance liquid chromatography. We report serial, steady-state, serum, and CSF concentrations of tigecycline when administered in the Food and Drug Administration-approved dose of 50 mg every 12 hours. CSF concentrations remained relatively stable, suggesting that tigecycline did not accumulate in the CSF, at least in our patient. Tigecycline concentrations in the CSF were between 0.035 and 0.048 mg/L, while corresponding serum concentrations were 0.097-0.566 mg/L. The calculated tigecycline penetration ratio in this patient ranged from 0% to 52%, depending on the calculation methodology utilized.

DISCUSSION: Concentrations, regardless of sample timing relative to dose, remained relatively stable in the CSF of our patient. The pharmacodynamic profile of tigecycline is not completely elucidated; however, it is presumed that the drug must be at the site of infection for efficacy. Our patient never obtained tigecycline concentrations in excess of the minimum inhibitory concentration for A. baumannii in either the serum or the CSF.

CONCLUSIONS: Our patient experienced low CSF tigecycline concentrations and failed to achieve a clinical response while on therapy. CSF drug disposition of tigecycline requires further systematic study to fully elucidate the pharmacokinetic profile. Reduced CSF concentrations urge caution in the treatment of cerebritis with standard dosing of tigecycline.

CASE SUMMARY: A 65-year-old female with relapsed multiple myeloma developed fluid retention, ascites, and general anasarca following bortezomib administration (1.3 mg/m² on days 1, 4, 8, and 11). Aggressive albumin infusion and loop diuretics did not lead to improvement and the patient received 2 sessions of hemodialysis for pulmonary edema. Although the bortezomib dose was reduced (0.7 mg/m² on days 1, 4, and 11) for the second cycle, CLS recurred after treatment. Dexamethasone was given along with bortezomib in the third cycle and subsequent CLS was prevented. The patient's multiple myeloma responded partially to the treatment, but the patient later died from cardiac amyloidosis.

DISCUSSION: Bortezomib is associated with several well-known adverse effects, such as peripheral neuropathy, thrombocytopenia, and gastrointestinal complications. CLS has not previously been reported to be associated with bortezomib. In this case, CLS developed twice after the patient received bortezomib treatment. The severity of CLS was dose-dependent and this adverse effect was preventable by concomitant use of steroids; this clearly demonstrated the close relationship between CLS and bortezomib in this patient. Using the Naranjo probability scale, the occurrence of CLS related to bortezomib treatment was probable.

CONCLUSIONS: Our report demonstrates CLS as an unusual adverse effect of bortezomib. As bortezomib use may become more common, clinicians should be aware of this novel but potentially life-threatening adverse effect. Based on our experience, timely management with steroids is important in dealing with this complication.

CASE SUMMARY: A 68-year-old female with a history of hypertension, hyperlipidemia, and anxiety presented with symptoms that mimicked acute coronary syndrome (ACS); the chief symptom was chest tightness. An electrocardiogram showed normal sinus rhythm, with minimal ST elevation in the anterior leads. The patient was initially treated for ST-segment elevation myocardial infarction and symptoms resolved. Coronary angiography ruled out ACS and confirmed a diagnosis of takotsubo cardiomyopathy.

DISCUSSION: Takotsubo cardiomyopathy is commonly triggered by severe emotional or psychological stress and occurs primarily in postmenopausal women. A reversible contractility abnormality of the left ventricle causes the ventricle to take on a balloon-like appearance; hence the name of tako-tsubo, a Japanese octopus fishing pot that has a narrow neck and a wide midsection. Signs and symptoms of takotsubo cardiomyopathy mimic those of ACS. Takotsubo cardiomyopathy is best diagnosed with coronary angiography, which can rule out blockage. Treatment usually consists of carvedilol and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocking agent if left ventricular ejection fraction is less than 40%. The syndrome is usually spontaneously reversible and cardiovascular function returns to normal after a few weeks.

CONCLUSIONS: Takotsubo cardiomyopathy causes a reversible left ventricle dysfunction which occurs most commonly in postmenopausal women with or without cardiovascular disease. Recognition is detected with coronary angiography. It is thought to primarily be due to an abnormally high sympathetic stimulation after emotional or psychological stress. Treatment consists of an angiotensin-converting enzyme inhibitor and/or beta blocker if needed for left ventricular dysfunction and possibly an anxiolytic agent.