Publications

INTRODUCTION: Based on Infectious Diseases Society of America (IDSA) guidelines, inappropriate fluconazole therapy in patients with candidemia is defined as an empiric dose <6 mg/kg/d, <12 mg/kg/d after Candida glabrata identification, or continued fluconazole use after identification of Candida krusei. However, the extent to which inappropriate antifungal therapy is due to improper dosing or drug selection has not been well investigated. The objectives of this study were to assess the incidence of inappropriate fluconazole therapy in patients with candidemia and to identify variables associated with inappropriate therapy.

METHODS: Retrospective cohort study from four medical centers of hospitalized patients with candidemia prescribed fluconazole. Appropriateness of fluconazole dosages (adjusted for renal dysfunction) was assessed at the time of symptom onset and after Candida identification.

RESULTS: Patients (206) were identified. Sixty-one of 112 (55%) patients who were given empiric therapy received an initial dose of fluconazole <6 mg/kg. After identification of the Candida species, 97 of 206 (47%) patients received inadequate fluconazole therapy based on IDSA guideline recommendations due to a fluconazole dose <12 mg/kg after isolation of C. glabrata (12%), continued use of fluconazole after isolation of C. krusei (3%), or a dose <6 mg/kg for all other Candida species (32%). Using multivariate logistic regression, increased weight in 1-kg increments (OR: 1.02; p = 0.0142) and a creatinine clearance (CRCL) >50 ml/minute (OR: 3.17; p = 0.0003) were associated with increased risk of inadequate fluconazole therapy.

CONCLUSION: A high prevalence of suboptimal dosing of fluconazole given empirically or after Candida species identification was documented. Increased weight and CRCL were significant predictors of inadequate fluconazole doses.

BACKGROUND: High-dose fluconazole is an alternative for patients with candidemia caused by Candida glabrata or other Candida species with decreased fluconazole susceptibility. However, empiric high-dose fluconazole is not currently recommended and may result in higher drug costs and toxicity.

OBJECTIVE: To determine the cost-effectiveness of using empiric high-dose fluconazole in intensive care unit (ICU) with suspected invasive candidiasis.

DESIGN: Decision analytic model.

TARGET POPULATION: ICU patients with suspected invasive candidiasis.

TIME HORIZON: Lifetime.

PERSPECTIVE: Societal.

INTERVENTIONS: Low-dose fluconazole (loading dose of 800 mg followed by 400 mg daily) vs. high-dose fluconazole (loading dose of 1600 mg followed by 800 mg daily). Generic fluconazole costs were used for the analysis.

OUTCOME MEASURES: Incremental life expectancy and incremental cost per discounted life year (DLY) saved. RESULT OF BASE-CASE ANALYSIS: Based on current national levels of fluconazole resistance and ability to correctly identify patients with candidemia, high-dose fluconazole was the more effective but more expensive treatment strategy. Empiric high-dose fluconazole therapy decreased the mortality rate by 0.15% compared to low-dose strategy with a cost-effectiveness rate of $55,526 per DLY saved.

RESULTS OF SENSITIVITY ANALYSIS: Empirical high-dose fluconazole was an acceptable treatment strategy (using $100,000 per DLY saved as threshold) unless the physical age of an ICU survivor was 66 years or older. Empirical high-dose fluconazole was an acceptable treatment strategy using $50,000 per DLY saved with minor changes in parameters estimates.

LIMITATIONS: The estimates of our model may not be applicable to all ICU patients. Other hospitals with differences in fluconazole resistance, prevalence of invasive candidiasis, or duration of fluconazole therapy may produce different results.

CONCLUSION: These results suggest that empiric high-dose fluconazole therapy should reduce the mortality associated with invasive candidiasis at an acceptable cost.

Mortality significantly increases in patients with candidaemia who receive inappropriate fluconazole therapy. The goals of this study were to compare hospital length of stay and costs for non-neutropenic patients with candidaemia treated with fluconazole based on the empirical dose and time until initiation of therapy. A retrospective cohort study was conducted of patients with candidaemia who were prescribed fluconazole at the onset of candidaemia or later. Hospital-related costs were compared based on time to initiation of fluconazole therapy and empirical fluconazole dose. A total of 192 non-neutropenic patients (55% male; mean age+/-standard deviation, 56+/-17 years) were identified. Isolated Candida species included C. albicans (59%), C. glabrata (15%), C. parapsilosis (11%), C. tropicalis (6%), C. krusei (3%) or other Candida spp. (6%). Time to initiation of fluconazole was Day 0 (35.4%), Day 1 (14.1%), Day 2 (26.6%) or Day >or=3 (23.9%). Thirty-two patients (17%) received a dose of fluconazole >or=6 mg/kg on Day 0. Total costs were lowest for patients started on fluconazole on the culture day with adequate doses ($35,459+/-25,988) compared with all other patients ($52,158+/-53,492) (P=0.0088). After controlling for covariates, each 1-day delay in fluconazole therapy was associated with increased total hospital costs of $6392+/-3000 (P=0.0344), and an adequate fluconazole dose was associated with decreased total hospital costs of $18,744+/-7173 (P=0.0097). A delay or an inadequate dose or fluconazole in patients with candidaemia was associated with increased hospital costs. Improved methods to diagnose patients with candidaemia quickly are needed.

BACKGROUND: The presence of angiotensin receptor blockers (ARBs) on the formularies of Medicare Part D prescription drug plans (PDPs) is vitally important to the health of seniors who cannot tolerate angiotensin-converting enzyme (ACE) inhibitors.

OBJECTIVE: To determine whether ARBs are present on the formularies of PDPs and how the prescription cost-sharing for ARBs under Part D compares to cost-sharing before Part D.

DESIGN/PARTICIPANTS: Cross-sectional analyses of March 2006 Medicare Part D formularies (n = 1,446) and of ARB utilization and cost-sharing for adults over the age of 64 included in the nationally representative Medical Expenditure Panel Survey.

MAIN OUTCOME MEASURES: (1) Presence of ARBs on Part D formularies. (2) Average out-of-pocket costs for 30-day supply of ARBs before and after Part D (both in 2006 dollars).

RESULTS: All PDP formularies included at least 1 ARB. Most plans covered 2 ARBs (41%) and 35% covered all 7. The average monthly copay for the most commonly used ARB, valsartan, is $28 under part D, $14 before Part D for individuals with prescription coverage, and $53 before Part D for individuals without coverage.

CONCLUSIONS: Whereas ARBs are present on all Part D formularies, many seniors will pay more for these drugs under Part D. Any savings in copayments under Part D may be erased by the monthly premium and by more expensive cost-sharing when seniors reach the 'donut hole'.

BACKGROUND: Nonadherence to prescription drugs results in poorer control of chronic health conditions. Because of significant racial/ethnic disparities in the control of many chronic diseases, differences in the rates of and reasons for medication nonadherence should be studied.

OBJECTIVES: 1) To determine whether rates of and reasons for medication nonadherence vary by race/ethnicity among seniors; and 2) to evaluate whether any association between race/ethnicity and nonadherence is moderated by prescription coverage and income.

DESIGN/SETTING: Cross-sectional national survey, 2003.

PATIENTS: Medicare beneficiaries > or = 65 years of age, who reported their race/ethnicity as white, black, or Hispanic, and who reported taking at least 1 medication (n = 14,829).

MAIN OUTCOME MEASURES: Self-reported nonadherence (caused by cost, self-assessed need, or experiences/side effects) during the last 12 months.

RESULTS: Blacks and Hispanics were more likely than whites to report cost-related nonadherence (35.1%, 36.5%, and 26.7%, respectively, p < .001). There were no racial/ethnic differences in nonadherence caused by experiences or self-assessed need. In analyses controlling for age, gender, number of chronic conditions and medications, education, and presence and type of prescription drug coverage, blacks (odds ratio [OR] 1.38; 95% confidence interval [CI] 1.08-1.78) and Hispanics (1.35; 1.02-1.78) remained more likely to report cost-related nonadherence compared to whites. When income was added to the model, the relationship between cost-related nonadherence and race/ethnicity was no longer statistically significant (p = .12).

CONCLUSIONS: Racial/ethnic disparities in medication nonadherence exist among seniors, and are related to cost concerns, and not to differences in experiences or self-assessed need. Considering the importance of medication adherence in controlling chronic diseases, affordability of prescriptions should be explicitly addressed to reduce racial/ethnic disparities.

BACKGROUND: There is a paucity of reports evaluating the perioperative risk of noncardiac surgery in patients with hypertrophic cardiomyopathy (HCM).

HYPOTHESIS: The study was undertaken to evaluate the incidence of acute myocardial infarction (MI) and all-cause inhospital mortality following noncardiac surgery in patients with HCM.

METHODS: We searched the National Hospital Discharge Survey database for patients with a diagnosis of HCM who had undergone noncardiac surgery. Cases were matched by age, gender, and year of surgery. Death or acute MI were used as endpoints for analysis.

RESULTS: From 1996 to 2002, 227 patients with HCM were matched with 554 controls (representing national estimates of 25,874 HCM and 50,326 controls patients). Patients with HCM were more likely than controls to have a history of atrial fibrillation (22.7 vs. 10.6%, p < 0.001) and of congestive heart failure (CHF) (24.2 vs. 14.1%, p < 0.001). The in-hospital incidence of death or MI was higher in patients with HCM than in controls (6.7 vs. 2.5%, p < 0.001 for death and 2.2 vs. 0.3%, p < 0.001 for MI). After correcting for age, gender, race, presence of hypertension, diabetes mellitus, history of coronary artery-disease, history of CHF, atrial fibrillation, and ventricular arrhythmias in a multivariate binary logistic regression model, the presence of HCM increased the odds of death by 61% (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.46-1.77, p < 0.001), and almost tripled the odds of the combined endpoint of death or MI (OR = 2.82, 95% CI 2.59-3.07, p < 0.001).

CONCLUSION: The presence of HCM significantly increases the risk of death and MI associated with noncardiac surgery. Patients with HCM undergoing elective procedures may require more careful preoperative assessment and perioperative monitoring. The impact of the severity of HCM on outcomes of noncardiac surgery needs further study.

Primary and metastatic bone cancers are difficult to eradicate and novel approaches are needed to improve treatment and extend life. As bone cancer grows, osteoclasts, the principal bone-resorbing cells of the body, are recruited to and activated at sites of cancer. In this investigation, we determined if osteoclast lineage cells could function as a cell-based gene delivery system to bone cancers. We used the cytosine deaminase (CD) 5-fluorocytosine (5-FC) enzyme/prodrug system and studied bone marrow and bones from transgenic mice expressing a novel CD gene regulated by the osteoclast tartrate-resistant acid phosphatase (TRAP) gene promoter (Tg/NCD). DsRed2-labeled 2472 sarcoma cells were placed in Tg/NCD osteoclastogenic cultures and treated with 5-FC. 5-FC treatment resulted in profound bystander killing (90%; P < 0.05). The effect of 5-FC treatment on osteoclast lineage cells was most dramatic when administered at the beginning of the 7-day cultures, suggesting that mature osteoclasts are less sensitive to 5-FC. Evaluation of osteoclast-directed bystander killing in vivo revealed dramatic killing of bone cancer with only a modest effect on osteoclast number. Specifically, 5-FC treatment of tumor-bearing Tg/NCD mice or Tg/NCD bone marrow transplanted C3H mice (Tg/NCD-C3H) resulted in 92% and 44% reductions in tumor area, respectively (P < 0.05). Eight of ten 5-FC-treated Tg/NCD mice had complete bone tumor killing and five of six 5-FC-treated Tg/NCD-C3H mice had reduced tumor compared with controls. In addition, Tg/NCD osteoclasts were resistant to 5-FC treatment in vivo, a very important feature, as it identifies osteoclasts as an ideal CD gene delivery system.

BACKGROUND: An increased prevalence of bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) with a vancomycin hydrochloride MIC of 2 microg/mL was noted in a population of inpatients undergoing hemodialysis at Baptist Memorial Health Care, Memphis, Tennessee.

OBJECTIVES: The aims of this study were to determine risk factors for infection with MRSA and to assess the differences in clinical and economic outcomes in patients undergoing hemodialysis with MRSA bacteremia with vancomycin MIC 2 microg/mL versus those with MRSA bacteremia with vancomycin MIC < or =0.5 microg/mL and uninfected controls.

METHODS: This retrospective case-control study was conducted at Baptist Memorial Health Care. The study population (inpatients undergoing hemodialysis for MRSA bacteremia with vancomycin MIC 2 microg/mL [high-MIC group], MIC < or = 0.5 microg/mL [low-MIC group], and uninfected controls) was identified. Risk factors and clinical and economic outcomes (costs of hospitalization, nursing, and pharmacy) were determined and compared using univariate and multivariate statistics.

RESULTS: Fifty patients with MRSA bacteremia undergoing hemodialysis were identified during the study period (high-MIC group, 17 [11 women, 6 men; mean (SD) age, 60 (17) years]; low-MIC group, 33 [23 women, 10 men; mean (SD) age, 62 (14) years]) and matched with 100 uninfected controls (57 men, 43 women; mean [SD] age, 63 [15] years). Risk factors for MRSA bacteremia found to be associated with high MIC included female sex, higher body mass index (1-point increments), recent surgery, and a history of cardiovascular disease (P < 0.05, P < 0.046, P = 0.04, and P = 0.028, respectively) (multivariate analysis). In the outcomes analysis, mortality was significantly higher in the high-MIC group compared with those in the low-MIC and control groups (35% vs 24% and 15%, respectively; P = 0.022). Total mean (SD) hospitalization costs were significantly higher in the high-MIC group compared with those in the low-MIC group and controls (US $47,624 [$80,534] vs $26,792 [$25,167] and $13,185 [$15,568], respectively; P < 0.001). Nursing costs were almost 6-fold higher in both infected groups compared with those in controls. Pharmacy costs in the low- and high-MIC groups were 3- to 6-fold higher, respectively, compared with those in controls.

CONCLUSIONS: Surgery within the previous 6 months and intensive care unit admission were identified as significant risk factors for patients with MRSA bacteremia with a vancomycin MIC 2 microg/mL undergoing hemodialysis. These patients experienced a longer mean hospital length of stay and increased hospital costs compared with patients with MRSA bacteremia with a vancomycin MIC < or =0.5 microg/mL and uninfected controls.

BACKGROUND: Inadequate antimicrobial treatment is an independent determinant of hospital mortality, and fungal bloodstream infections are among the types of infection with the highest rates of inappropriate initial treatment. Because of significant potential for reducing high mortality rates, we sought to assess the impact of delayed treatment across multiple study sites. The goals our analyses were to establish the frequency and duration of delayed antifungal treatment and to evaluate the relationship between treatment delay and mortality.

METHODS: We conducted a retrospective cohort study of patients with candidemia from 4 medical centers who were prescribed fluconazole. Time to initiation of fluconazole therapy was calculated by subtracting the date on which fluconazole therapy was initiated from the culture date of the first blood sample positive for yeast.

RESULTS: A total of 230 patients (51% male; mean age +/- standard deviation, 56 +/- 17 years) were identified; 192 of these had not been given prior treatment with fluconazole. Patients most commonly had nonsurgical hospital admission (162 patients [70%]) with a central line catheter (193 [84%]), diabetes (68 [30%]), or cancer (54 [24%]). Candida species causing infection included Candida albicans (129 patients [56%]), Candida glabrata (38 [16%]), Candida parapsilosis (25 [11%]), or Candida tropicalis (15 [7%]). The number of days to the initiation of antifungal treatment was 0 (92 patients [40%]), 1 (38 [17%]), 2 (33 [14%]) or > or = 3 (29 [12%]). Mortality rates were lowest for patients who began therapy on day 0 (14 patients [15%]) followed by patients who began on day 1 (9 [24%]), day 2 (12 [37%]), or day > or = 3 (12 [41%]) (P = .0009 for trend). Multivariate logistic regression was used to calculate independent predictors of mortality, which include increased time until fluconazole initiation (odds ratio, 1.42; P < .05) and Acute Physiology and Chronic Health Evaluation II score (1-point increments; odds ratio, 1.13; P < .05).

CONCLUSION: A delay in the initiation of fluconazole therapy in hospitalized patients with candidemia significantly impacted mortality. New methods to avoid delays in appropriate antifungal therapy, such as rapid diagnostic tests or identification of unique risk factors, are needed.