Research Spotlight

Posted November 15th 2016

Coronary Artery Bypass Graft Versus Percutaneous Coronary Intervention: Meds Matter: Impact of Adherence to Medical Therapy on Comparative Outcomes.

Michael J. Mack M.D.

Michael J. Mack M.D.

Kurlansky, P., M. Herbert, S. Prince and M. Mack (2016). “Coronary artery bypass graft versus percutaneous coronary intervention: Meds matter: Impact of adherence to medical therapy on comparative outcomes.” Circulation 134(17): 1238-1246.

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BACKGROUND: Multiple studies have compared coronary artery bypass graft (CABG) with percutaneous coronary interventions (PCI) for coronary revascularization. There is considerable evidence that adherence to medical therapy can affect the outcomes of therapeutic interventions. However, the long-term influence of compliance with recommended medical therapy on the comparative outcomes of CABG versus PCI remains to be defined. METHODS: All non-ST-segment-elevation myocardial infarction patients undergoing coronary revascularization in an 8-hospital network were followed for up to 8 years to determine medication history and major adverse cardiac events: all-cause mortality, nonfatal myocardial infarction, and reintervention. All mortalities were checked against the Social Security Death Index. Survival curves were derived with Kaplan-Meier methods; hazard ratios were calculated with the Cox proportional hazard model; and propensity score matching was used to account for differences in patient selection. RESULTS: Among the 973 CABG and 2255 PCI patients, Kaplan-Meier major adverse cardiac event-free survival curves demonstrated a significant benefit for antiplatelet, lipid-lowering, and beta-blocker therapy in both the CABG and PCI groups (P=0.001 for all 3 medications). Cox regression identified compliance with optimal medical therapy as a more powerful predictor of major adverse cardiac event-free survival than choice of therapy (hazard ratio for noncompliance=2.79; 95% confidence limits, 2.19-3.54; P<0.001; hazard ratio for PCI versus CABG=1.68, 95% confidence limits, 138-2.04; P<0.001). In propensity-matched patients, CABG outcomes were superior to PCI outcomes in patients nonadherent to optimal medical therapy (P=0.001) but were not different in patients adherent to optimal medical therapy (P=0.574). CONCLUSIONS: Regardless of coronary revascularization strategy, medication adherence has a dramatic effect on long-term outcome. Among comparable patients who adhere to optimal medical therapy, outcomes of PCI and CABG may not differ; however, among nonadherent patients, CABG affords better major adverse cardiac event-free survival. Therefore, patient compliance with medical therapy may inform clinical decision making and should be incorporated into all future comparative studies of comparative coronary revascularization strategies.


Posted November 15th 2016

A Karnofsky performance status-based score predicts death after hospital discharge in patients with cirrhosis.

Jacqueline O'Leary M.D.

Jacqueline O’Leary M.D.

Tandon, P., K. R. Reddy, J. G. O’Leary, G. Garcia-Tsao, J. G. Abraldes, F. Wong, S. W. Biggins, B. Maliakkal, M. B. Fallon, R. M. Subramanian, P. Thuluvath, P. S. Kamath, L. R. Thacker and J. S. Bajaj (2016). “A karnofsky performance status-based score predicts death after hospital discharge in patients with cirrhosis.” Hepatology: 2016 Oct [Epub ahead of print].

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BACKGROUND AND AIMS: Identification of patients with cirrhosis at risk for death within 3 months of discharge from the hospital is essential to individualize post-discharge plans. The objective of the study was to identify an easy-to-use prognostic model based on the Karnofsky Performance Status (KPS). METHODS: NACSELD consists of 16 tertiary-care hepatology centers that prospectively enroll non-electively admitted cirrhotic patients. Patients enrolled had KPS assessed one week post-discharge. KPS was categorized into low (score 10-40), intermediate (50-70) and high (80-100). RESULTS: Of 954 middle aged patients, (57+/-10 years, men: 63% median MELD: 17 (IQR 13 to 21), the mortality for the low, intermediate and high performance status groups were 23% (36/159), 11% (55/489) and 5% (15/306), respectively. Low, intermediate and high performance status was seen in 17%, 51% and 32% of the cohort. Low performance status was associated with older age, dialysis, hepatic encephalopathy, longer length of stay and higher white blood cell count or MELD score at discharge. A model was derived using the three independent predictors of 3-month mortality: KPS, Age and MELD score (termed the KAM model). KAM had better discrimination (AUC=0.74) than a model using MELD (AUC=0.62) or MELD and age (AUC=0.67) to predict 3 month mortality. CONCLUSIONS: Cirrhotic patients at risk for 3 month post discharge mortality can be identified using a novel KPS-based (KAM) score. This score may be adopted in practice to guide post-discharge early interventions, including the integrated provision of active and palliative management strategies.


Posted November 15th 2016

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Dahdah, M. N., S. Barnes, A. Buros, R. Dubiel, C. Dunklin, L. Callender, C. Harper, A. Wilson, R. Diaz-Arrastia, T. Bergquist, M. Sherer, G. Whiteneck, C. Pretz, R. D. Vanderploeg and S. Shafi (2016). “Variations in inpatient rehabilitation functional outcomes across centers in the traumatic brain injury model systems study and the influence of demographics and injury severity on patient outcomes.” Arch Phys Med Rehabil 97(11): 1821-1831.

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OBJECTIVE: To compare patient functional outcomes across Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers using an enhanced statistical model and to determine factors that influence those outcomes. DESIGN: Multicenter observational cohort study. SETTING: TBIMS centers. PARTICIPANTS: Patients with traumatic brain injury (TBI) admitted to 19 TBIMS rehabilitation centers from 2003-2012 (N=5505). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional outcomes of patients with TBI. RESULTS: Individuals with lower functional status at the time of admission, longer duration of posttraumatic amnesia, and higher burden of medical comorbidities continued to have worse functional outcomes at discharge from inpatient rehabilitation and at the 1-year follow-up, whereas those who were employed at the time of injury had better outcomes at both time periods. Risk-adjusted patient functional outcomes for patients in most TBIMS centers were consistent with previous research. However, there were wide performance differences for a few centers even after using more recently collected data, improving on the regression models by adding predictors known to influence functional outcomes, and using bootstrapping to eliminate confounds. CONCLUSIONS: Specific patient, injury, and clinical factors are associated with differences in functional outcomes within and across TBIMS rehabilitation centers. However, these factors did not explain all the variance in patient outcomes, suggesting a role of some other predictors that remain unknown.


Posted November 15th 2016

Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Deshpande, D., S. Srivastava, E. Nuermberger, J. G. Pasipanodya, S. Swaminathan and T. Gumbo (2016). “Concentration-dependent synergy and antagonism of linezolid and moxifloxacin in the treatment of childhood tuberculosis: The dynamic duo.” Clin Infect Dis 63(suppl 3): S88-s94.

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BACKGROUND: No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. METHODS: We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression. RESULTS: The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 +/- 0.66 for linezolid and 3.80 +/- 1.34 hours for moxifloxacin. The kill rate constant was 0.060 +/- 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 +/- 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively. CONCLUSIONS: We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children.


Posted November 15th 2016

Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Deshpande, D., S. Srivastava, J. G. Pasipanodya, S. J. Bush, E. Nuermberger, S. Swaminathan and T. Gumbo (2016). “Linezolid for infants and toddlers with disseminated tuberculosis: First steps.” Clin Infect Dis 63(suppl 3): S80-s87.

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BACKGROUND: Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC0-24). METHODS: To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days. RESULTS: The linezolid extracellular half-life was 2.64 +/- 0.38 hours, whereas intracellular half-life was 8.93 +/- 1.30 hours (r2 = 0.89). Linezolid efficacy was linked to the AUC0-24 to minimum inhibitory concentration (MIC) ratio (r2 = 0.98). The exposure associated with maximal Mtb kill was an AUC0-24/MIC of 23.37 +/- 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC0-24 best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg x hour/L (highest r2 = 0.98). CONCLUSIONS: We identified the linezolid AUC0-24/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC0-24 threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis.