The US healthcare system has been widely criticized by many and praised by others for many reasons that are not mutually exclusive. There is no doubt that, compared with our peer industrialized countries, the US ranks near the bottom in many of the benchmark criteria such as life expectancy, infant mortality, and mortality of the population that is amenable to health care. Despite these shortcomings, the US has been a major innovator in healthcare technology including the development of biological and pharmacological drugs. The shortcomings of our system are often focused on the fact that a significant portion of the population lacks access to these cutting-edge resources and therapies. In this commentary, the healthcare reform proposals that have been introduced in 2008-2009, with a focus on the 3 leading plans that have been put forward by the House of Representatives and Senate, are reviewed. The inclusion of pharmacist-delivered medication therapy management (MTM) as well as medication reconciliation (MedRec) is specifically stated in 2 of the 3 plans. Integrated care delivery models (ie, community health teams, or "medical homes") are also directed to provide MedRec and MTM during transitions of care. Finally, in the Senate Health, Education, Labor, and Pensions language, there is a directive that health insurers implement a payment schedule for MTM and care compliance. The many other ways in which each of these evolving reform proposals may impact pharmacists and the care they deliver to their communities are also highlighted.

OBJECTIVE: To review the pathophysiology, pandemics/epidemics, transmissibility, clinical presentation, treatment, prevention/immunization, and resistance associated with seasonal, avian, and swine influenza.

DATA SOURCES: Literature was obtained from MEDLINE (1966-October 2009) and International Pharmaceutical Abstracts (1971-October 2009) using the search terms influenza, seasonal influenza, avian influenza, swine influenza, H1N1, novel H1N1, H3N2, and H5N1.

STUDY SELECTION AND DATA EXTRACTION: Available English-language articles were reviewed, along with information obtained from the Centers for Disease Control and Prevention, the Food and Drug Administration, and the World Health Organization.

DATA SYNTHESIS: The influenza virus has caused disease in birds, swine, and humans for many centuries. Pandemics and epidemics have occurred throughout history and reports of new strains continue to emerge. Two major surface antigenic glycoproteins, hemagglutinin and neuraminidase, have various subtypes, resulting in numerous combinations of these proteins. For example, combinations occur when an influenza strain from a bird "mixes" with a strain from a human. This mixing occurs in a host, often in pigs, resulting in a new strain. This new strain can cause pandemics since people have no immunity to the new strain. An H1N1 subtype pandemic occurred in 1918, causing millions of deaths. Simultaneously, veterinary reports of "influenza" in pigs also emerged. It is postulated that humans infected pigs with this H1N1 virus. H1N1 reappeared in humans in 1976, and more recently in 2009. Other pandemics have occurred with H2N2 and H3N2 strains. In 1997, strain H5N1, which usually causes disease in fowl, was able to infect humans.

CONCLUSIONS: Influenza subtypes continue to change, causing disease in animals and humans. Utilization of immunization and antiviral treatment options are available to prevent, treat, and contain the spread of this infection.

OBJECTIVE: To review the literature regarding statins and myotoxicity and evaluate these data to determine whether incidence rates are higher with simvastatin.

DATA SOURCES: Literature was identified from a search of MEDLINE (1966- August 2009) and International Pharmaceutical Abstracts (1970-August 2009), as well as references of selected articles. Key search terms included the names of individual statins, rhabdomyolysis, myopathy, myalgia, myotoxicity, statins, and drug interactions.

STUDY SELECTION AND DATA EXTRACTION: All English-language articles discussing statin-related myotoxicity and relevant drug interactions that involved human subjects were examined.

DATA SYNTHESIS: Simvastatin is a commonly prescribed, moderately potent statin. Recent evidence suggests that the risk of severe muscle toxicity with simvastatin may be higher than that with other statins, particularly when used in combination with cytochrome P450 isoenzyme inhibitors. However, the lack of direct comparative clinical trials assessing the risk of myotoxicity among the statins in equivalent doses precludes definitive conclusions. Data sources examining low-to-moderate doses of simvastatin suggest that myotoxicity with this agent is infrequent, with rates similar to those seen with other statins. Conversely, findings from clinical trials using the maximum daily dose (80 mg) and a clinical trials database of varying doses of simvastatin suggest a possible increase in rates of myotoxicity with the 80-mg dose compared with lower doses and a higher incidence rate when compared with maximum doses of other statins.

CONCLUSIONS: Overall, the rates of severe myotoxicity with all statins are low, especially with low-to-moderate doses. However, recent trials for those using simvastatin 80 mg daily suggest a higher incidence of myotoxicity compared with maximum approved doses of other statins. Practitioners should be aware of these possible risks and individualize therapy to limit myotoxicity.

BACKGROUND: Multiple medicine use among elderly persons is likely to be the result of treatment regimens developed over a long period of time. By learning more about how multiple medication use develops, the quality of prescribing may be improved across the adult lifespan.

OBJECTIVE: To describe patterns of multiple medicine use in the general Swedish population and its association with sociodemographic, lifestyle, and health status factors.

METHODS: Data from a cross-sectional population health survey collected during 2001-2005 from 2816 randomly selected Swedish residents (age 30-75 y; response rate 76%) were analyzed. Multiple medicine use was restricted to prescription drugs and defined as the 75th percentile; that is, the 25% of the study group using the highest number of drugs per individual.

RESULTS: Seventy-one percent of the respondents used some kind of drug, 51.5% used one or more prescription drug, 38.4% used one or more over-the-counter (OTC) medication, and 8.3% used one or more herbal preparation. The cutoff amounts defining multiple medicine use were: 2 or more medications for 30- to 49-year-olds, 3 or more for 50- to 64-year-olds, and 5 or more for 65- to 75- year-olds. No association between use of multiple medicines and use of OTC drugs or herbal preparations was found. When drugs were classified into therapeutic subgroups, 76.3% of those aged 30-49 years, 97.9% of those aged 50-64 years, and 100% of those aged 65-75 years were taking a unique combination of drugs. Multivariate analyses showed that diabetes and poor self-rated health were associated with multiple medicine use in all age cohorts. Female sex and hypertension were associated with multiple medicine use among those aged 30-49 and 50-64 years, current smoking among those aged 50-64 years, and obesity among those aged 65-75 years.

CONCLUSIONS: Multiple medicine use was associated with morbidity and poor self-rated health across all age groups. The vast majority of users of multiple drugs are taking a unique combination of medications.

BACKGROUND: Lorazepam is recommended by the Society of Critical Care Medicine as the preferred agent for sedation of critically ill patients. Intravenous lorazepam contains propylene glycol, which has been associated with toxicity when high doses of lorazepam are administered.

OBJECTIVE: To evaluate the accumulation of propylene glycol in critically ill patients receiving lorazepam by continuous infusion and determine factors associated with propylene glycol concentration.

METHODS: A 6-month, retrospective, safety assessment was conducted of adults admitted to the medical intensive care unit who were receiving lorazepam by continuous infusion for 12 hours or more. Propylene glycol serum concentrations were obtained 24-48 hours after continuous-infusion lorazepam was initiated and every 3-5 days thereafter. Propylene glycol accumulation was defined as concentrations of 25 mg/dL or more. Groups with and without propylene glycol accumulation were compared and factors associated with propylene glycol concentration were determined using multivariate correlation regression analyses.

RESULTS: Forty-eight propylene glycol serum samples were obtained from 33 patients. Fourteen (42%) patients had propylene glycol accumulation, representing 23 (48%) serum samples. Univariate analyses showed the following factors were related to propylene glycol accumulation: baseline renal dysfunction, presence of alcohol withdrawal, sex, age, Acute Physiology and Chronic Health Evaluation (APACHE II) score, rate of lorazepam continuous infusion, and 24-hour lorazepam dose. Multivariate linear regression modeling demonstrated that propylene glycol concentration was strongly associated with the continuous infusion rate and 24-hour dose (adjusted r² ≥0.77; p < 0.001). Independent correlation analyses showed that these 2 variables were so strongly associated with propylene glycol concentration (r² ≥0.71; p < 0.001) that they alone predicted propylene glycol concentration. Seven (21%) patients developed renal dysfunction after continuous-infusion lorazepam was initiated, but associated causes were indeterminable. Other possible propylene glycol-associated adverse effects were not observed.

CONCLUSIONS: The continuous infusion rate and cumulative 24-hour lorazepam dose are strongly associated with and independently predict propylene glycol concentrations. Despite the absence of confirmed propylene glycol-associated adverse effects, clinicians should be aware that propylene glycol accumulation may occur with continuous-infusion lorazepam.

OBJECTIVE: To review pharmacologic, pharmacokinetic, efficacy, and safety data for fesoterodine and determine its role in the treatment of overactive bladder.

DATA SOURCES: A MEDLINE search (1966-July 2009) was conducted using the key words fesoterodine, tolterodine, muscarinic receptor antagonist, anticholinergic, overactive bladder, urge incontinence, efficacy, safety, adverse effect, pharmacology, pharmacokinetic, and receptor binding.

STUDY SELECTION AND DATA EXTRACTION: All articles written in English that were identified from the data sources were evaluated, prioritizing randomized, controlled trials with human data. The references of published articles that we identified were examined for any additional studies appropriate for the review.

DATA SYNTHESIS: Fesoterodine, a competitive muscarinic receptor antagonist, is converted to its active metabolite, 5-hydroxymethyltolterodine, by nonspecific esterases, bypassing the cytochrome P450 system. Two randomized controlled Phase 3 trials examined the safety and efficacy of fesoterodine in the treatment of overactive bladder. Fesoterodine was found to produce significant improvements in the treatment of overactive bladder symptoms compared with placebo. Post hoc analysis of these trials demonstrated significant improvements in health-related quality of life in patients with overactive bladder. Only one study included tolterodine, and direct comparisons between fesoterodine and tolterodine were not conducted. The most common treatment-emergent adverse effects associated with fesoterodine included dry mouth, constipation, urinary tract infection, and headache.

CONCLUSIONS: Fesoterodine appears to be effective and generally safe for the treatment of overactive bladder. The efficacy and safety of fesoterodine in overactive bladder treatment seem to be at least similar to that of tolterodine. Although additional comparative trials are needed, based on available data, it does not appear that fesoterodine provides a substantial advantage over extended-release tolterodine in either efficacy or safety.

OBJECTIVE: To review the published literature characterizing the impact of ezetimibe-containing lipid-lowering regimens on endothelial function and other markers of cardiovascular risk and discuss the potential relevance of these effects to the clinical benefit of ezetimibe.

DATA SOURCES: A MEDLINE search (2000-August 2009) was completed using the key words ezetimibe, statins, endothelial function, flow-mediated dilation, pleiotropic, and inflammation to identify relevant literature. Bibliographies of identified literature were reviewed for additional references.

STUDY SELECTION AND DATA EXTRACTION: All clinical studies published in English that evaluated the effect of ezetimibe on ancillary endpoints of cardiovascular disease risk, including endothelial function, inflammation, thrombosis, and oxidative stress, were evaluated.

DATA SYNTHESIS: Recent studies in patients with coronary artery disease (CAD), heart failure, and hypercholesterolemia have demonstrated that treatment with ezetimibe for 4-12 weeks elicits no improvement of endothelial function or other measures of cardiovascular disease risk. In contrast, other studies have reported that ezetimibe improves endothelial function in certain patient populations, including those with rheumatoid arthritis, CAD with type 2 diabetes, and metabolic syndrome. However, the statin monotherapy comparator groups in these studies that yielded equivalent reductions in cholesterol were superior, or at least equivalent to, ezetimibe-containing regimens in the improvement of these ancillary endpoints.

CONCLUSIONS: Overall, the evidence to date suggests that administration of ezetimibe, either as monotherapy or in combination with a statin, exerts minimal beneficial effects on endothelial function and other ancillary measures of cardiovascular disease risk beyond those conferred by its cholesterol-lowering effects. Studies with larger sample sizes and follow-up beyond 12 weeks remain necessary to further define the impact of ezetimibe on the processes integral to the pathogenesis and progression of cardiovascular disease.

OBJECTIVE: To evaluate the utility of therapeutic drug monitoring (TDM) for ribavirin in chronic hepatitis C.

DATA SOURCES: Literature searches were conducted through PubMed (1949-June 2009), EMBASE (1980-June 2009), BIOSIS Previews (1969-June 2009), International Pharmaceutical Abstracts (1970-June 2009), Google, and www.clinicaltrials.gov using the terms ribavirin, therapeutic monitoring, hepatitis C, and drug levels. In addition, pertinent reference citations from identified publications were reviewed. Studies were limited to English language, adult age, and human subjects.

STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated. Studies that measured ribavirin concentrations or dose and treatment response were included in the review.

DATA SYNTHESIS: While monitoring of ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C has been described in the literature, the utility of TDM for ribavirin in this group of patients has not been systematically studied. Thus, a previously published 9-step decision-making algorithm was employed to help determine whether TDM is warranted, based on currently available evidence. Thirty articles involving patients with chronic hepatitis C mono-infection, 12 for hepatitis C-HIV coinfection, 5 for renal dysfunction, and 5 for post-liver transplant patients were reviewed. In all subpopulations, studies exist that either support or refute the usefulness of ribavirin TDM. Additionally, the majority of the included studies had methodologic limitations, such as small sample size, retrospective analyses, and lack of p value adjustment for multiple analyses. Large randomized controlled trials would help to definitively answer this question.

CONCLUSIONS: There is conflicting evidence about the existence of a correlation between ribavirin concentrations and virologic response or development of toxicity. This inconsistent evidence, coupled with the currently employed effective strategies that maximize sustained virologic response and minimize development of anemia, precludes the utility of TDM for ribavirin.

BACKGROUND: The Food and Drug Administration has issued a public health advisory regarding cancer risk from topical calcineurin inhibitors.

OBJECTIVE: To compare the rates of cancer among patients with common dermatologic conditions who were exposed or not exposed to topical calcineurin inhibitors.

METHODS: A retrospective cohort observational study used data from an integrated healthcare delivery system on 953,064 subjects with diagnoses of atopic dermatitis or eczema between 2001 and December 2004. The main endpoint was initial cancer diagnosis. Chart review was performed to confirm cancer diagnosis in the subjects exposed to topical calcineurin inhibitors when any particular cancer rate was at least 3 times higher than that in unexposed subjects. Data were analyzed using the Cox proportional hazards model.

RESULTS: Age- and sex-adjusted hazard ratios for all cancers were 0.93 (95% CI 0.81 to 1.07; p = 0.306) for tacrolimus-exposed versus -unexposed subjects and 1.15 (95% CI 0.99 to 1.31; p = 0.054) for pimecrolimus-exposed versus -unexposed subjects. T-cell lymphoma was the only cancer associated with a significantly increased risk among subjects exposed to tacrolimus (HR = 5.04, 95% CI 2.39 to 10.63; p < 0.001) or pimecrolimus (HR = 3.76, 95% CI 1.71 to 8.28; p = 0.010). Subsequent chart review of subjects in the exposed group with T-cell lymphoma found that 4 of 16 had skin lesions that were suspected to be the early lesions of T-cell lymphoma prior to exposure to tacrolimus or pimecrolimus. After these 4 cases were excluded, the age and sex hazard ratio for T-cell lymphoma was 5.44 (95% CI 2.51 to 11.79; p < 0.001) for tacrolimus and 2.32 (95% CI 0.89 to 6.07; p = 0.086) for pimecrolimus. There was no statistically significantly increased risk for other subgroups of cancer, including melanoma.

CONCLUSIONS: Exposure to topical tacrolimus or pimecrolimus was not associated with an increase in the overall cancer rate. Use of topical tacrolimus may be associated with an increased risk of T-cell lymphoma.

OBJECTIVE: To review the efficacy and safety of colchicine as primary and secondary prophylaxis for pericarditis.

DATA SOURCES: We searched MEDLINE, EMBASE, PubMed, BIOSIS Previews, International Pharmaceutical Abstracts, Web of Science, and CENTRAL for controlled studies from database inception date to July 2009. Search terms included colchicine, pericarditis, and postpericardiotomy syndrome (PPS).

STUDY SELECTION AND DATA EXTRACTION: Prospective, randomized, controlled trials investigating the use of colchicine in preventing pericarditis were included. Data extracted included design, inclusion criteria, demographics, interventions, background therapy, and pericarditis-related clinical outcomes.

DATA SYNTHESIS: Data were synthesized qualitatively, given variable study designs. Three trials were identified. A single trial examining primary prevention evaluated the use of colchicine versus placebo for preventing PPS in patients undergoing cardiopulmonary bypass grafting. No significant reduction in PPS was found. Two studies examined secondary prevention of pericarditis, comparing colchicine plus aspirin versus aspirin alone. One study examined using these comparators to treat a first episode of pericarditis. After 3 months, there was a significant reduction in recurrent pericarditis with colchicine plus aspirin (11.7% vs 33%; p = 0.009). Another study examined this same regimen in recurrent pericarditis, finding a significant reduction in recurrence after 6 months (21% vs 45%; p = 0.02).

CONCLUSIONS: Despite limitations in study designs, current evidence suggests a role for colchicine in the secondary prophylaxis for recurrent pericarditis. The evidence for use of colchicine as primary prophylaxis in PPS is indeterminate; therefore, colchicine cannot be recommended routinely. While colchicine should be recommended for the prevention of recurrent pericarditis, questions regarding the optimal regimen and long-term safety profile need to be further elucidated.

OBJECTIVE: To report a case of multidrug-resistant Enterococcus faecium requiring combination antibacterial therapy.

CASE SUMMARY: A 39-year-old female presented with chest pain and a history of endocarditis 3 years prior to admission. Blood cultures were positive for E. faecium. She was treated initially with daptomycin 6 mg/kg daily, which was later increased to 8 mg/kg daily despite poor gentamicin clearance. A variety of antibiotics were used in combination with daptomycin, but the patient remained febrile, with positive blood cultures revealing vancomycin minimum inhibitory concentration (MIC) greater than 256 µg/mL and daptomycin MIC 3 µg/mL (and later, 4 µg/mL). Following the addition of tigecycline, the patient experienced rapid clinical and microbiologic improvement, and blood cultures remained negative 9 weeks after discharge.

DISCUSSION: Limited clinical data support the use of daptomycin for the treatment of E. faecium endocarditis, and information regarding the effects of escalating doses and combination therapy is scant. After failing multiple combination regimens, this patient responded to a combination of tigecycline and daptomycin. Daptomycin 8 mg/kg daily did not result in creatine kinase elevation in the face of evidence of possible renal dysfunction.

CONCLUSIONS: Increasing doses of daptomycin may enhance efficacy without compromising safety, even in patients with some renal dysfunction. The combination of daptomycin and tigecycline may be useful for the treatment of multi-drug- resistant E. faecium.

BACKGROUND: The main adverse effect of polymyxin B is nephrotoxicity. There are few data on polymyxin-associated renal injury.

OBJECTIVE: To assess the prevalence of and risk factors for acute kidney injury (AKI) in patients treated with polymyxin B.

METHODS: The studied population included 114 patients who received at least 3 consecutive days of intravenous polymyxin B and had baseline serum creatinine (SCr) and at least one further SCr measurement during treatment. AKI was defined as an SCr increase to 1.8 mg/dL or greater in patients with baseline SCr less than 1.5 mg/dL, or an increase greater than or equal to 50% in baseline SCr when it was already greater than or equal to 1.5 mg/dL, or need for dialysis.

RESULTS: AKI developed in 22% of the patients. They were older, had a higher baseline SCr, had a higher frequency of baseline SCr greater than or equal to 1.5 mg/dL, used other nephrotoxic drugs and furosemide more often, and required vasoactive drugs and mechanical ventilation more frequently. Progression to renal failure was significantly more probable when the bacteria were isolated in the abdomen, catheter, or blood. AKI patients had a higher mortality rate (92% vs 53%; p < 0.001). Logistic regression identified abnormal baseline SCr (odds ratio [OR] 3.51); need for vasoactive drugs (OR 3.03); and abdomen, blood, or catheter as the infection site (OR 3.82) as independent risk factors for AKI.

CONCLUSIONS: Patients who developed AKI had a strikingly elevated mortality rate. Polymyxin B should be used with extreme caution in patients who have an abnormal baseline SCr; use vasoactive drugs; or have abdomen, blood, or catheter as the infection site.

OBJECTIVE: To report the successful use of topical voriconazole 1% given alone as primary therapy against a case of Candida albicans keratitis.

CASE SUMMARY: A 48-year-old previously well man presented to the emergency department with pain and foreign body sensation in the left eye following exposure to dust while driving a forklift. He wore weekly disposable soft contact lenses. Anterior stromal scar and dense infiltrate were detected in the left eye. The anterior chamber remained deep, with flare and copious white cells. Intraocular pressure was 12 mm Hg and visual acuity was 20/200. The epithelial defect persisted, with progressive thinning despite topical fluorometholone and ofloxacin 0.3% therapy for 2 days. Microbiology testing revealed C. albicans as the affecting pathogen. Hourly administration of voriconazole 1% eye drops was initiated as antifungal therapy. The corneal infiltrate began to resolve and the epithelial defect decreased in size within 2 days. Visual acuity improved to 20/120. After 4 days of voriconazole use, the epithelial defect was completely healed and visual acuity was 20/30 in the affected eye. No fungi were isolated from a second eye scrape.

DISCUSSION: Topical voriconazole as salvage monotherapy to manage fungal keratitis has been previously reported. It can be argued, however, that the primary therapy has facilitated the positive response to subsequent topical voriconazole. To date, there has been no solid evidence to suggest that topical voriconazole is effective when used as primary therapy. The current report provides evidence of topical voriconazole demonstrating clinical success when used as first-line therapy to treat C. albicans keratitis. The use of topical voriconazole can reduce the costs, toxicity, and drug interactions associated with common antifungal therapies.

CONCLUSIONS: Topical voriconazole 1% eye drops administered alone demonstrated success as first-line therapy against the most common fungal keratitis, C. albicans keratitis.