Faculty Bibliography

Polymyxin B and fosfomycin are two 'old' antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, each antibiotic's use in monotherapy has been associated with high rates of treatment failure. Therefore, our objective was to investigate the combinatorial pharmacodynamics of polymyxin B and fosfomycin against KPC-producing K. pneumoniae. Polymyxin B front-loading (3.33 mg/kg for 1 dose followed by 1.43 mg/kg q12h starting 12h later) and burst (5.53 mg/kg for 1 dose followed by no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4g q8h) against KPC-2-producing K. pneumoniae ST258 in a hollow fibre infection model over 120h. Population analysis profiles were used to track the temporal polymyxin B and fosfomycin resistance profiles. Against isolate KPC-Kp 9A (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: ≤8mg/L), monotherapies resulted in >3 log₁₀CFU/mL killing within 3h, but regrowth and proliferation of resistant subpopulations within 48h. Polymyxin B combinations with fosfomycin demonstrated rapid bacterial killing (>6 log₁₀CFU/mL reductions) while preventing propagation of polymyxin and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: 32g/L), a polymyxin B burst and fosfomycin combination caused a >6 log₁₀CFU/mL reduction within 1 hour, although bacterial regrowth occurred with the amplification of fosfomycin-resistant subpopulations. Polymyxin B in combination with fosfomycin may provide a practicable treatment strategy against KPC-producing K. pneumoniae and warrants further investigation.

BACKGROUND:There exist racial and ethnic disparities in the prevalence of chronic medical illnesses. However, it is unclear if the disparities arise from patients' self-reported estimates on these diseases and whether there is an association between healthcare utilization and diagnosis. OBJECTIVE:To estimate national racial/ethnic prevalence of undiagnosed hypertension, diabetes, high cholesterol, and kidney disease and identify characteristics associated with undiagnosed diseases. DESIGN/METHODS:Retrospective analysis of multi-year survey data. PARTICIPANTS/METHODS:Adults 18 years and older who participated in the National Health and Nutrition Examination Survey during 2011-2014 (n = 10,403). MAIN OUTCOMES/RESULTS:Undiagnosed hypertension (SBP ≥ 140 or DBP ≥ 90 on physical examination with no history of hypertension), undiagnosed diabetes (hgba1c ≥ 6.5% with no history of diabetes), undiagnosed high cholesterol (LDL ≥ 160 mg/dL with no history of high cholesterol), and undiagnosed kidney disease (eGFR ≤ 30 with no history of kidney disease). RESULTS:The study sample was categorized into Whites, Blacks, Hispanics, Asians, and Other. After adjusting for sociodemographic characteristics, Asians had increased odds of undiagnosed hypertension (OR = 1.41 [1.06-1.86]) and diabetes (OR = 6.16 [3.76-10.08]) compared to Whites. Blacks (OR = 2.53 [1.71-3.73]) and Hispanics (OR = 1.88 [1.19-2.99]) had increased odds of undiagnosed diabetes compared to Whites. Multivariate logistic regression analysis indicated that not having any health insurance was associated with increased odds of undiagnosed diabetes and hyperlipidemia (OR = 1.56 [1.00-2.44] and OR = 2.08 [1.44-3.00], respectively). A recent healthcare visit was associated with a lower likelihood of having undiagnosed hypertension (OR = 0.58 [0.41-0.83]) and diabetes (OR = 0.35 [0.18-0.69]). CONCLUSIONS:In a nationally representative cohort, Asians had higher rates of undiagnosed hypertension and diabetes, and all minorities were more likely to have undiagnosed diabetes compared to Whites. Healthcare utilization was associated with undiagnosed medical conditions. Our study showed that reliance on self-reported data may systemically underestimate the prevalence of chronic illnesses among minorities and further research is needed to understand the significance of healthcare utilization in health outcomes.

The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3-month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3-months posttransplant. Among those with stable allograft function at 3 months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n = 71) and Group II: Subclinical Inflammation (SCI, n = 129). We evaluated differences in kidney function at 24-months and allograft histology score at 12-month biopsy. SCI patients had a higher serum creatinine (1.6 ± 0.7 vs 1.38 ± 0.45; P = .02) at 24-months posttransplant, and at last follow-up at a mean of 42.5 months (1.69 ± 0.9 vs 1.46 ± 0.5 mg/dL; P = .027). The allograft chronicity score (ci + ct + cg + cv) at 12-months posttransplant was higher in the SCI group (2.4 ± 1.35 vs 1.9 ± 1.2; P = .02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P = .015). De novo donor-specific antibody within 12 months was more prevalent in the SCI group (12/129 vs 1/71, P = .03). SCI is likely not a benign finding and may have long-term implications for kidney allograft function.

OBJECTIVES/OBJECTIVE:The National Patient-Centered Clinical Research Network (PCORnet) supports observational and clinical research using healthcare data. The PCORnet Antibiotics and Childhood Growth Study is one of PCORnet's inaugural observational studies. The objectives of this manuscript are to describe (1) the processes used to integrate and analyze data from children across 36 participating institutions and (2) the cohort characteristics and prevalence of antibiotic use. METHODS:percentile. RESULTS:681,739 children met the cohort inclusion criteria and were racially/ethnically diverse (24.9% black, 17.5% Hispanic). Before 24 months, 55.2% of children received at least one antibiotic prescription; 21.3% received a single antibiotic prescription, 14.3% received four or more, and 33.3% received a broad spectrum antibiotic. Overweight and obesity prevalence was 27.6% at 4 to <6 years of age (n=362,044) and 36.2% at 9 to <11 years (n=58,344). CONCLUSION/CONCLUSIONS:The PCORnet Antibiotics study is a large, national longitudinal observational study in a diverse population that will examine the relationship between early antibiotic use and subsequent growth patterns in children.

BACKGROUND:Hepatocellular carcinoma (HCC) is a complication of chronic hepatitis B and C virus (HBV and HCV) infection. New York City (NYC) has a high prevalence of HBV and HCV, and infected persons likely face increased mortality from HCC and other causes. We describe the mortality profile of NYC residents with HBV or HCV, emphasizing the contributions of HCC and HIV coinfection. METHODS: Two existing data sets were combined to examine all individuals diagnosed with HBV or HCV in NYC first reported to the Health Department during 2001-2012 and their HCC, HIV, and vital status. Logistic regression was used to calculate the odds of HCC diagnosis by viral hepatitis status, whereas Cox proportional hazard regression was used to estimate the hazard of death by HCC/HIV status. RESULTS:In total, 120 952 and 127 933 individuals were diagnosed with HBV or HCV, respectively. HCV-infected individuals had 17% higher odds of HCC diagnosis than HBV-infected individuals and 3.2 times higher odds of HIV coinfection. Those with HCV were twice as likely to die during the study period (adjusted hazard ratio, 2.04; 95% confidence interval, 1.96-2.12). The risk of death increased for those with HIV or HCC and was highest for those with both conditions. CONCLUSIONS:HCC and HIV represent substantial risks to survival for both HBV- and HCV-infected individuals. Individuals with HBV need close monitoring and treatment, when indicated, and routine HCC screening. Those with HCV need increased, timely access to curative medications before developing liver disease.

Obstructive sleep apnea (OSA) is common, and many cross-sectional and longitudinal studies have established OSA as an independent risk factor for the development of a variety of adverse metabolic disease states, including hypertension, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, dyslipidemia, and atherosclerosis. Nasal continuous positive airway pressure (CPAP) has long been the mainstay of therapy for OSA, but definitive studies demonstrating the efficacy of CPAP in improving metabolic outcomes, or in reducing incident disease burden, are lacking; moreover, CPAP has variable rates of adherence. Therefore, the future of OSA management, particularly with respect to limiting OSA-related metabolic dysfunction, likely lies in a coming wave of alternative approaches to endophenotyping OSA patients, personalized care, and defining and targeting mechanisms of OSA-induced adverse health outcomes.

Background/UNASSIGNED:Primary care models that offer comprehensive, accessible care to all patients may provide insufficient resources to meet the needs of patients with complex conditions who have the greatest risk for hospitalization. Objective/UNASSIGNED:To assess whether augmenting usual primary care with team-based intensive management lowers utilization and costs for high-risk patients. Design/UNASSIGNED:Randomized quality improvement trial. (ClinicalTrials.gov: NCT03100526). Setting/UNASSIGNED:5 U.S. Department of Veterans Affairs (VA) medical centers. Patients/UNASSIGNED:Primary care patients at high risk for hospitalization who had a recent acute care episode. Intervention/UNASSIGNED:Locally tailored intensive management programs providing care coordination, goals assessment, health coaching, medication reconciliation, and home visits through an interdisciplinary team, including a physician or nurse practitioner, a nurse, and psychosocial experts. Measurements/UNASSIGNED:Utilization and costs (including intensive management program expenses) 12 months before and after randomization. Results/UNASSIGNED:2210 patients were randomly assigned, 1105 to intensive management and 1105 to usual care. Patients had a mean age of 63 years and an average of 7 chronic conditions; 90% were men. Of the patients assigned to intensive management, 487 (44%) received intensive outpatient care (that is, ≥3 encounters in person or by telephone) and 204 (18%) received limited intervention. From the pre- to postrandomization periods, mean inpatient costs decreased more for the intensive management than the usual care group (-$2164 [95% CI, -$7916 to $3587]). Outpatient costs increased more for the intensive management than the usual care group ($2636 [CI, $524 to $4748]), driven by greater use of primary care, home care, telephone care, and telehealth. Mean total costs were similar in the 2 groups before and after randomization. Limitations/UNASSIGNED:Sites took up to several months to contact eligible patients, limiting the time between treatment and outcome assessment. Only VA costs were assessed. Conclusion/UNASSIGNED:High-risk patients with access to an intensive management program received more outpatient care with no increase in total costs. Primary Funding Source/UNASSIGNED:Veterans Health Administration Primary Care Services.