Mark G. Weiner

The U.S. Food and Drug Administration's Mini‐Sentinel program: status and direction

The Mini‐Sentinel is a pilot program that is developing methods, tools, resources, policies, and procedures to facilitate the use of routinely collected electronic healthcare data to perform active surveillance of the safety of marketed medical products, including drugs, biologics, and medical devices. The U.S. Food and Drug Administration (FDA) initiated the program in 2009 as part of its Sentinel Initiative, in response to a Congressional mandate in the FDA Amendments Act of 2007.

Impact of a Hospital-Based Antimicrobial Management Program on Clinical and Economic Outcomes

Inappropriate use of antimicrobial agents results in unnecessary exposure to medication, persistent or progressive infection, emergence of resistance, and increased costs. We implemented a program to control use of restricted agents while improving care. This study compared 2 major mechanisms for improving use of antimicrobial agents: (1) recommendations made by the Antimicrobial Management Team (AMT), which included a clinical pharmacist backed up by a physician from the Division of Infectious Diseases (ID), and (2) recommendations made by ID fellows. Outcome measures included appropriateness of recommendations, cure rate, number of treatment failures, and cost of care, which were assessed for 180 patients. The AMT outperformed the ID fellows in all outcomes examined by the study (including appropriateness [87% vs. 47%; P<.001], cure rate [64% vs. 42%; P=.007], and treatment failures [15% vs. 28%; P=.03]), although the differences in economic outcomes between cases managed by the AMT and those managed by the ID fellows were not statistically significant. In an academic setting with a restricted formulary, the AMT demonstrated better antimicrobial prescribing than ID fellows.

Design considerations, architecture, and use of the Mini-Sentinel distributed data system

We describe the design, implementation, and use of a large, multiorganizational distributed database developed to support the Mini‐Sentinel Pilot Program of the US Food and Drug Administration (FDA). As envisioned by the US FDA, this implementation will inform and facilitate the development of an active surveillance system for monitoring the safety of medical products (drugs, biologics, and devices) in the USA.

Imipenem resistance among pseudomonas aeruginosa isolates: risk factors for infection and impact of resistance on clinical and economic outcomes.

OBJECTIVES To identify risk factors for infection with imipenem-resistant Pseudomonas aeruginosa and determine the impact of imipenem resistance on clinical and economic outcomes among patients infected with P. aeruginosa. DESIGNS An ecologic study, a case-control study, and a retrospective cohort study. SETTING A 625-bed tertiary care medical center. PATIENTS All patients who had an inpatient clinical culture positive for P. aeruginosa between January 1, 1999, and December 31, 2000. RESULTS From 1991 through 2000, the annual prevalence of imipenem resistance among P. aeruginosa isolates increased significantly (P<.001 by the chi (2) test for trend). Among 879 patients infected with P. aeruginosa during 1999-2000, a total of 142 had imipenem-resistant P. aeruginosa infection (the case group), whereas 737 had imipenem-susceptible P. aeruginosa infection (the control group). The only independent risk factor for imipenem-resistant P. aeruginosa infection was prior fluoroquinolone use (adjusted odds ratio, 2.52 [95% confidence interval {CI}, 1.61-3.92]; P<.001). Compared with patients infected with imipenem-susceptible P. aeruginosa, patients infected with imipenem-resistant P. aeruginosa had longer subsequent hospitalization durations (15.5 days vs 9 days; P=.02) and greater hospital costs (81,330 dollars vs 48,381dollars ; P<.001). The mortality rate among patients infected with imipenem-resistant P. aeruginosa was 31.1%, compared with 16.7% for patients infected with imipenem-susceptible P. aeruginosa (relative risk, 1.86 [95% CI, 1.38-2.51]; P<.001). In multivariable analyses, there remained an independent association between infection with imipenem-resistant P. aeruginosa and mortality. CONCLUSIONS The prevalence of imipenem resistance among P. aeruginosa strains has increased markedly in recent years and has had a significant impact on both clinical and economic outcomes. Our results suggest that curtailing use of other antibiotics (particularly fluoroquinolones) may be important in attempts to curb further emergence of imipenem resistance.

Use of primary care electronic medical record database in drug efficacy research on cardiovascular outcomes: comparison of database and randomised controlled trial findings

Objectives To determine whether observational studies that use an electronic medical record database can provide valid results of therapeutic effectiveness and to develop new methods to enhance validity. Design Data from the UK general practice research database (GPRD) were used to replicate previously performed randomised controlled trials, to the extent that was feasible aside from randomisation. Studies Six published randomised controlled trials. Main outcome measure Cardiovascular outcomes analysed by hazard ratios calculated with standard biostatistical methods and a new analytical technique, prior event rate ratio (PERR) adjustment. Results In nine of 17 outcome comparisons, there were no significant differences between results of randomised controlled trials and database studies analysed using standard biostatistical methods or PERR analysis. In eight comparisons, Cox adjusted hazard ratios in the database differed significantly from the results of the randomised controlled trials, suggesting unmeasured confounding. In seven of these eight, PERR adjusted hazard ratios differed significantly from Cox adjusted hazard ratios, whereas in five they didn’t differ significantly, and in three were more similar to the hazard ratio from the randomised controlled trial, yielding PERR results more similar to the randomised controlled trial than Cox (P<0.05). Conclusions Although observational studies using databases are subject to unmeasured confounding, our new analytical technique (PERR), applied here to cardiovascular outcomes, worked well to identify and reduce the effects of such confounding. These results suggest that electronic medical record databases can be useful to investigate therapeutic effectiveness.

Epidemiology and impact of imipenem resistance in Acinetobacter baumannii.

BACKGROUND Acinetobacter baumannii is an emerging gram-negative pathogen that can cause healthcare-acquired infections among patients. Treatment is complicated for cases of healthcare-acquired infection with A. baumannii resistant to imipenem. OBJECTIVE To elucidate the risk factors for imipenem-resistant A. baumannii (IRAB) infection or colonization and to identify the effect of resistance on clinical and economic outcomes. METHODS We analyzed data from 2 medical centers of the University of Pennsylvania. Longitudinal trends in the prevalence of IRAB clinical isolates were characterized during the period from 1989 through 2004. For A. baumannii isolates obtained from 2001 through 2006, a case-control study was conducted to investigate the association between prior carbapenem use and IRAB infection or colonization, and a cohort study was performed to identify the effect of IRAB infection or colonization on mortality, length of stay after culture, and hospital cost after culture. RESULTS From 1989 through 2004, the annual prevalence of IRAB isolates ranged from 0% to 21%. During the period from 2001 through 2006, there were 386 unique patients with A. baumannii isolates, and 89 (23.1%) had IRAB isolates. Prior carbapenem use was independently associated with IRAB infection or colonization (adjusted odds ratio, 3.04 [95% confidence interval, 1.07-8.65]). There was a borderline significant association between IRAB infection or colonization and mortality, although this association was limited to isolates recovered from blood samples (adjusted odds ratio, 5.30 [95% confidence interval, 0.81-34.59]). Compared with patients with imipenem-susceptible A. baumannii infection or colonization, patients with IRAB infection or colonization had a longer hospital stay after culture (median, 21 vs 16 days; P = .07) and greater hospital charges after culture (mean,

Imipenem Resistance in Pseudomonas aeruginosa: Emergence, Epidemiology, and Impact on Clinical and Economic Outcomes

334,516 vs

Barriers to adherence and hypertension control in a racially diverse representative sample of elderly primary care patients

276,059; P = .03). After controlling for patient location in an intensive care unit, transfer from another facility, and length of hospital stay before culture, there was no longer an independent association between IRAB infection or colonization and higher cost after culture and length of stay after positive culture result. CONCLUSIONS Many A. baumannii isolates exhibit imipenem resistance, which is strongly associated with prior use of carbapenems. Given the high mortality rate associated with A. baumannii infection or colonization, interventions to curb further emergence of cases of IRAB infection and strategies to optimize therapy are needed.

Risk Factors for Fluconazole-Resistant Candida glabrata Bloodstream Infections

BACKGROUND Pseudomonas aeruginosa is one of the most common gram-negative hospital-acquired pathogens. Resistance of this organism to imipenem complicates treatment. OBJECTIVE To elucidate the risk factors for imipenem-resistant P. aeruginosa (IRPA) infection or colonization and to identify the effect of resistance on clinical and economic outcomes. METHODS Longitudinal trends in prevalence of IRPA from 2 centers were characterized during the period from 1989 through 2006. For P. aeruginosa isolates obtained during the period from 2001 through 2006, a case-control study was conducted to investigate the association between prior carbapenem use and IRPA infection or colonization, and a cohort study was performed to identify the effect of IRPA infection or colonization on mortality, length of stay after culture, and hospital cost after culture. RESULTS From 1989 through 2006, the proportion of P. aeruginosa isolates demonstrating resistance to imipenem increased from 13% to 20% (P < .001, trend). During the period from 2001 through 2006, there were 2,542 unique patients with P. aeruginosa isolates, and 253 (10.0%) had IRPA isolates. Prior carbapenem use was independently associated with IRPA infection or colonization (adjusted odds ratio [OR], 7.92 [95% confidence interval {CI}, 4.78-13.11]). Patients with an IRPA isolate recovered had higher in-hospital mortality than did patients with an imipenem-susceptible P. aeruginosa isolate (17.4% vs 13.4%; P = .01). IRPA infection or colonization was an independent risk factor for mortality among patients with isolates recovered from blood (adjusted OR, 5.43 [95% CI, 1.72-17.10]; P = .004) but not among patients with isolates recovered from other anatomic sites (adjusted OR, 0.78 [95% CI, 0.51-1.21]; P = .27). Isolation of IRPA was associated with longer hospital stay after culture (p < .001) and greater hospital cost after culture (P < .001) than was isolation of an imipenem-susceptible strain. In multivariable analysis, IRPA infection or colonization remained an independent risk factor for both longer hospital stay after culture (coefficient, 0.20 [95% CI, 0.04-0.36]; P = .02) and greater hospital cost after culture (coefficient, 0.30 [95% CI, 0.06-0.54]; P = .02). CONCLUSIONS The prevalence of IRPA infection or colonization has increased significantly, with important implications for both clinical and economic outcomes. Interventions to curb this continued increase and strategies to optimize therapy are urgently needed.

Toward Reuse of Clinical Data for Research and Quality Improvement: The End of the Beginning?

To examine the effect of antihypertensive adherence on blood pressure and barriers to adherence in racially diverse elderly patients.