Browsing by Author "Kotloff, Karen L."

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    Associations between Household-Level Exposures and All-Cause Diarrhea and Pathogen-Specific Enteric Infections in Children Enrolled in Five Sentinel Surveillance Studies
    (MDPI, 2020-11) Colston, Josh M.; Faruque, Abu S. G.; Hossain, M. Jahangir; Saha, Debasish; Kanungo, Suman; Mandomando, Inácio; Nisar, M. Imran; Zaidi, Anita K. M.; Omore, Richard; Breiman, Robert F.; Sow, Samba O.; Roose, Anna; Levine, Myron M.; Kotloff, Karen L.; Ahmed, Tahmeed; Bessong, Pascal; Bhutta, Zulfiqar; Mduma, Estomih; Penatero Yori, Pablo; Sunder Shrestha, Prakash; Olortegui, Maribel P.; Kang, Gagandeep; Lima, Aldo A. M.; Humphrey, Jean; Prendergast, Andrew; Schiaffino, Francesca; Zaitchik, Benjamin F.; Kosek, Margaret N.; Medicine, School of Medicine
    Diarrheal disease remains a major cause of childhood mortality and morbidity causing poor health and economic outcomes. In low-resource settings, young children are exposed to numerous risk factors for enteric pathogen transmission within their dwellings, though the relative importance of different transmission pathways varies by pathogen species. The objective of this analysis was to model associations between five household-level risk factors—water, sanitation, flooring, caregiver education, and crowding—and infection status for endemic enteric pathogens in children in five surveillance studies. Data were combined from 22 sites in which a total of 58,000 stool samples were tested for 16 specific enteropathogens using qPCR. Risk ratios for pathogen- and taxon-specific infection status were modeled using generalized linear models along with hazard ratios for all-cause diarrhea in proportional hazard models, with the five household-level variables as primary exposures adjusting for covariates. Improved drinking water sources conferred a 17% reduction in diarrhea risk; however, the direction of its association with particular pathogens was inconsistent. Improved sanitation was associated with a 9% reduction in diarrhea risk with protective effects across pathogen species and taxa of around 10–20% risk reduction. A 9% reduction in diarrhea risk was observed in subjects with covered floors, which were also associated with decreases in risk for zoonotic enteropathogens. Caregiver education and household crowding showed more modest, inconclusive results. Combining data from diverse sites, this analysis quantified associations between five household-level exposures on risk of specific enteric infections, effects which differed by pathogen species but were broadly consistent with hypothesized transmission mechanisms. Such estimates may be used within expanded water, sanitation, and hygiene (WASH) programs to target interventions to the particular pathogen profiles of individual communities and prioritize resources.
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    Evaluation of Vancomycin Dose Needed to Achieve 24-Hour Area Under the Concentration-Time Curve to Minimum Inhibitory Concentration Ratio Greater Than or Equal to 400 Using Pharmacometric Approaches in Pediatric Intensive Care Patients
    (Wolters Kluwer, 2024-10-01) Jung, Dawoon; Kishk, Omayma A.; Bhutta, Adnan T.; Cummings, Ginny E.; El Sahly, Hana M.; Virk, Manpreet K.; Moffett, Brady S.; Morris Daniel, Jennifer L.; Watanabe, Amy; Fishbane, Nicholas; Kotloff, Karen L.; Gu, Kenan; Ghazaryan, Varduhi; Gobburu, Jogarao V. S.; Akcan-Arikan, Ayse; Campbell, James D.; Pediatrics, School of Medicine
    Objectives: To investigate which independent factor(s) have an impact on the pharmacokinetics of vancomycin in critically ill children, develop an equation to predict the 24-hour area under the concentration-time curve from a trough concentration, and evaluate dosing regimens likely to achieve a 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC24/MIC) greater than or equal to 400. Design: Prospective population pharmacokinetic study of vancomycin. Setting: Critically ill patients in quaternary care PICUs. Patients: Children 90 days old or older to younger than 18 years who received IV vancomycin treatment, irrespective of the indication for use, in the ICUs at the University of Maryland Children's Hospital and Texas Children's Hospital were enrolled. Interventions: Vancomycin was prescribed at doses and intervals chosen by the treating clinicians. Measurements and main results: A median of four serum levels of vancomycin per patient were collected along with other variables for up to 7 days following the first administration. These data were used to characterize vancomycin pharmacokinetics and evaluate the factors affecting the variability in achieving AUC24/MIC ratio greater than or equal to 400 in PICU patients who are not on extracorporeal therapy. A total of 302 children with a median age of 6.0 years were enrolled. A two-compartment model described the pharmacokinetics of vancomycin with the clearance of 2.76 L/hr for a typical patient weighing 20 kg. The glomerular filtration rate estimated using either the bedside Schwartz equation or the chronic kidney disease in children equation was the only statistically significant predictor of clearance among the variables evaluated, exhibiting equal predictive performance. The trough levels achieving AUC24/MIC = 400 were 5.6-10.0 μg/mL when MIC = 1 μg/mL. The target of AUC24/MIC greater than or equal to 400 was achieved in 60.4% and 36.5% with the typical dosing regimens of 15 mg/kg every 6 and 8 hours (q6h and q8h), respectively. Conclusions: The pharmacokinetics of vancomycin in critically ill children were dependent on the estimated glomerular filtration rate only. Trough concentrations accurately predict AUC24. Typical pediatric vancomycin dosing regimens of 15 mg/kg q6h and q8h will often lead to AUC24/MIC under 400.