Publications by authors named "Christine E MacBrayne"

26 Publications

  • Page 1 of 1

IVIG Compared to IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

Pediatrics 2021 Sep 22. Epub 2021 Sep 22.

Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2021-052702DOI Listing
September 2021

IVIG Compared to IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

Pediatrics 2021 Sep 21. Epub 2021 Sep 21.

Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO;

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2021-052702DOI Listing
September 2021

Pharmacological Management of Pediatric Clostridioides difficile Infection: Clarifying the Controversies.

J Pediatr Health Care 2021 Aug 17. Epub 2021 Aug 17.

Clostridioides difficile infection (CDI) is a major public health concern for pediatric and adult patients. The management of pediatric CDI poses a challenge to healthcare providers due to lack of strong randomized controlled trials to guide pharmacological management. Additionally, recent updates to CDI guidelines recommend oral vancomycin over metronidazole for the management of CDI in adults, leaving questions regarding how to best manage pediatric patients. This continuing education pharmacotherapy review describes available evidence for the safety and efficacy of medications used in the treatment and management of pediatric CDI and aims to clarify discrepancies between pediatric and adult recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pedhc.2021.06.005DOI Listing
August 2021

Time to Blood Culture Positivity by Pathogen and Primary Service.

Hosp Pediatr 2021 09;11(9):953-961

Department of Pediatric Infectious Diseases, Children's Hospital Colorado and School of Medicine, University of Colorado, Aurora, Colorado.

Objectives: Initiation and continuation of empirical antimicrobial agents for a 48-72-hour observation period is routine practice in the diagnosis and treatment of infants and children with concern for bacteremia. We examined blood cultures at a freestanding pediatric hospital over a 6-year period to determine the time to positivity.

Methods: Data were extracted for all patients who were hospitalized and had blood cultures drawn between January 2013 and December 2018. Time to positivity was calculated on the basis of date and time culture was collected compared with date and time growth was first reported.

Results: Over a 6-year period, 89 663 blood cultures were obtained, of which 6184 had positive results. After exclusions, a total of 2121 positive blood culture results remained, including 1454 (69%) pathogens and 667 contaminants (31%). For all positive blood culture results, the number and percentage positive at 24, 36, and 48 hours were 1441 of 2121 (68%), 1845 of 2121 (87%) and 1970 of 2121 (93%), respectively. One hundred twenty-five (66 pathogens, 59 contaminants) of the 89 663 cultures (0.14%) yielded positive results between 36 and 48 hours, indicating that 719 patients would need to be treated for 48 hours rather than 36 hours to prevent 1 case of antibiotic termination before positive result. Median times to positive result by pathogen and service line are presented.

Conclusions: This study reveals that ≤36 hours may be a sufficient period of observation for infants and children started on empirical antimicrobial agents for concern for bacteremia. These findings highlight opportunities for antimicrobial stewardship to limit antimicrobial .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/hpeds.2021-005873DOI Listing
September 2021

Impact of Antimicrobial Stewardship Bundle on Inpatient Use of Highly Bioavailable Antibacterials.

Hosp Pediatr 2021 05;11(5):509-514

Children's Hospital Colorado, Aurora, Colorado.

Objectives: Intravenous (IV) to enteral transition of highly bioavailable antibacterial drugs is associated with improved safety and lower cost. We evaluated the impact of a bundle of stewardship-driven interventions (including in-person stewardship rounding, clinical pathways, and clinical pharmacist-driven enteral transition workflows) on IV versus enteral administration of highly bioavailable antibacterials at a freestanding children's hospital.

Methods: We collected 2010-2018 inpatient usage data for clindamycin, levofloxacin, ciprofloxacin, metronidazole, rifampin, linezolid, and trimethoprim-sulfamethoxazole. We analyzed total use (in days of therapy [DOTs] per 1000 patient-days [PDs]) and the percentage of total use administered enterally, both hospital wide and stratified by unit subgrouping, specifically comparing use 1-year prestewardship implementation with year-5 postimplementation.

Results: Across the 8-year study window, clindamycin, fluoroquinolones, and metronidazole, together, accounted for 96% of IV DOTs for highly bioavailable antibacterials. Overall, clindamycin use decreased from 44.4 to 20.2 DOTs per 1000 PDs ( < .001), with the enteral percentage of total use increasing from 23% to 43% ( < .001) hospital wide. Overall, fluoroquinolone use decreased from 33.7 to 19.3 DOTs per 1000 PDs ( < .001), with the enteral percentage increasing from 40.7% to 55.9% ( < .001). Overall, metronidazole use increased, and the enteral percentage decreased (42.0% to 33.7%; = .007). Low-IV-use antibacterials (rifampin, linezolid, and trimethoprim-sulfamethoxazole) showed no significant changes in total use or the enteral percentage of total use.

Conclusions: Stewardship interventions were associated with decreased overall use and an increased enteral percentage of total use for both clindamycin and fluoroquinolones, although not metronidazole. These data provide an easy-to-collect benchmark for pediatric hospitals to compare IV with enteral use of highly bioavailable antibacterials within the context of overall antibacterial use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/hpeds.2020-001016DOI Listing
May 2021

Primary Care Physicians' Perspective on Pharmacists Delivering Vaccines to Adults.

J Am Board Fam Med 2021 Mar-Apr;34(2):392-397

From the Department of Pharmacy, Children's Hospital Colorado, Aurora, (CEM); Adult and Child Consortium for Health Outcomes Research and Delivery Science, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora (LPH, STO, JRC, LAC, CG, MB, BLB, AK); Division of General Internal Medicine, Denver Health, Denver, CO (LPH); Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora (STO, JRC, MB, AK); Department of Community and Behavioral Health, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora (LAC).

Introduction: Since 2009, pharmacists in all 50 states have been authorized to provide vaccinations to adults. The objective of this study was to assess primary care physicians' (PCPs) experiences with and attitudes about pharmacists administering vaccinations.

Methods: Internet and mail survey of PCPs representative of American College of Physicians' and American Academy of Family Physicians' memberships.

Results: Response rate was 69% (642/926). Ninety-eight percent of respondents agreed (79% "Strongly," 19% "Somewhat") that it is their responsibility to assure their adult patients receive recommended vaccinations. Most respondents agreed that pharmacists either did not have access to patient medical information (33% "Strongly," 45% "Somewhat") or did not have adequate vaccination history (33% "Strongly," 41% "Somewhat"). The majority also agreed that pharmacists did not inform them when vaccinations were given (35% "Strongly," 39% "Somewhat") and did not enter vaccinations administered into immunization information systems (IISs) (20% "Strongly," 37% "Somewhat"). However, 83% agreed (31% "Strongly," 52% "Somewhat") that it is helpful to have pharmacists share the role of vaccinating adults.

Conclusions: PCPs have mixed feelings about pharmacists delivering vaccines. Universal use of IISs by pharmacists could partially address physicians' concerns by providing a systematic way for pharmacists and physicians to share patient vaccination histories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3122/jabfm.2021.02.200486DOI Listing
September 2021

Etravirine in treatment-experienced HIV-1-infected children 1 year to less than 6 years of age.

AIDS 2021 07;35(9):1413-1421

University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Objective: To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age.

Design: Phase I/II, open-label, multicenter, dose-finding study.

Methods: Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants with ETR AUC12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics.

Results: Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC12  h less than 2350 ng h/ml and underwent a dose increase. ETR AUC12  h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued.

Conclusion: ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000002902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270511PMC
July 2021

Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of Coronavirus Disease 2019 in Children and Adolescents.

J Pediatric Infect Dis Soc 2021 May;10(5):629-634

Department of Pediatrics, Division of Infectious Diseases, Children's Hospital at Montefiore, New York, New York, USA.

Background: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for 2 novel virus-neutralizing monoclonal antibody therapies, bamlanivimab and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products.

Methods: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion.

Results: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high-risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis.

Conclusions: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence and ensure the implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piaa175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799019PMC
May 2021

Management of an Immunocompromised Pediatric Patient With Multiple Hospitalizations for Symptomatic COVID-19.

J Pediatr Hematol Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Pediatrics, Section of Pediatric Infectious Diseases, University of Colorado School of Medicine, Aurora, CO.

Relapse of infection due to SARS-CoV-2 has been rarely described and there is little guidance regarding the management of such cases in immunocompromised hosts. We present a case of an adolescent female with B-cell acute lymphoblastic leukemia hospitalized multiple times for symptomatic SARS-CoV-2 infection who was safely treated with 2 courses of remdesivir (RDV) and has had no additional readmissions to date. Though additional studies are needed to confirm the safety and efficacy of an additional course of RDV in the setting of relapsed or prolonged severe COVID-19, our observations suggest that a second course of RDV may be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000002014DOI Listing
November 2020

Long-Term Impact of a Clinical Care Guideline for Pediatric Acute Musculoskeletal Infections: Are Improved Outcomes Sustainable?

Hosp Pediatr 2020 12 5;10(12):1107-1113. Epub 2020 Nov 5.

Hospital Medicine and Infectious Diseases, Department of Pediatrics and

Background: Acute hematogenous musculoskeletal infections are a common cause of hospitalization in children. A locally developed clinical care guideline (CCG) for acute musculoskeletal infections was implemented at our quaternary care pediatric hospital in July 2012. The purpose of this study was to evaluate the long-term sustainability of previously described improvements after CCG implementation.

Methods: Clinical outcomes for children hospitalized with musculoskeletal infections at Children's Hospital Colorado from June 2009 through September 2018 were retrospectively reviewed. Patients were included if they had an or discharge diagnosis of acute osteomyelitis, septic arthritis, or pyomyositis and were between 6 months and 18 years of age at admission. Patients with underlying medical complexity or nonhematogenous musculoskeletal infections were excluded. Patients were categorized by date of admission as either "pre-CCG" (June 2009 to June 2011) or "sustain-CCG" (July 2014 to September 2018). Primary outcomes were hospital length of stay and intravenous antimicrobial length of therapy.

Results: From pre-CCG to sustain-CCG, median length of stay decreased by 1.29 days (5.56 vs 4.27; < .004) and median length of therapy decreased by 5.04 days (8.33 vs 3.29; < .0001). Statistical process control charts support that these were sustained improvements many years after CCG implementation. Additional secondary clinical improvements were observed in the sustain-CCG group including faster fever resolution, more consistent blood and source culture acquisition, and decreased central line placement. There was no increase in related readmissions or therapeutic failures in the sustain-CCG group.

Conclusions: Implementation of a CCG to standardize care for musculoskeletal infections can be sustained many years after implementation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/hpeds.2020-0118DOI Listing
December 2020

Handshake antimicrobial stewardship as a model to recognize and prevent diagnostic errors.

Diagnosis (Berl) 2021 08 28;8(3):347-352. Epub 2020 Oct 28.

Division of Emergency Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado, Aurora, CO, USA.

Objectives: Few studies describe the impact of antimicrobial stewardship programs (ASPs) on recognizing and preventing diagnostic errors. Handshake stewardship (HS-ASP) is a novel ASP model that prospectively reviews hospital-wide antimicrobial usage with recommendations made in person to treatment teams. The purpose of this study was to determine if HS-ASP could identify and intervene on potential diagnostic errors for children hospitalized at a quaternary care children's hospital.

Methods: Previously self-identified "Great Catch" (GC) interventions by the Children's Hospital Colorado HS-ASP team from 10/2014 through 5/2018 were retrospectively reviewed. Each GC was categorized based on the types of recommendations from HS-ASP, including if any diagnostic recommendations were made to the treatment team. Each GC was independently scored using the "Safer Dx Instrument" to determine presence of diagnostic error based on a previously determined cut-off score of ≤1.50. Interrater reliability for the instrument was measured using a randomized subset of one third of GCs.

Results: During the study period, there were 162 GC interventions. Of these, 65 (40%) included diagnostic recommendations by HS-ASP and 19 (12%) had a Safer Dx Score of ≤1.50, (Κ=0.44; moderate agreement). Of those GCs associated with diagnostic errors, the HS-ASP team made a diagnostic recommendation to the primary treatment team 95% of the time.

Conclusions: Handshake stewardship has the potential to identify and intervene on diagnostic errors for hospitalized children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/dx-2020-0032DOI Listing
August 2021

Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

J Pediatric Infect Dis Soc 2021 Feb;10(1):34-48

Division of Infectious Diseases, Department of Pediatrics, Children's Hospital at Montefiore, New York, New York, USA.

Background: Although coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children.

Methods: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.

Results: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.

Conclusions: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543452PMC
February 2021

Anti-infective Waste in a Pediatric Institution: Pinpointing Problems in the Process.

Hosp Pharm 2020 Aug 4;55(4):220-223. Epub 2019 May 4.

Children's Hospital Colorado, Aurora, CO, USA.

At Children's Hospital Colorado (CHCO), there are approximately 40 000 inpatient anti-infective orders every year resulting over 100 000 dispenses. Significant quantities of anti-infectives are wasted, incurring roughly $100 000 in waste annually. Identifying areas for improvement will result in cost savings and ameliorate the impact of drug shortages. This descriptive report discusses the reasons for anti-infective waste at a free-standing, quaternary-care, pediatric hospital. The anti-infectives with the highest cost in waste ($) included meropenem ($38 084), micafungin ($21 690), amphotericin B liposome ($15 913). An internal audit of CHCO anti-infective waste revealed that drugs are wasted for the following reasons: patient discharge, medication order discontinuation or change, and misplaced doses. The CHCO Antimicrobial Stewardship Program and the Pharmacy have proposed 4 process improvement measures that will target anti-infective waste to reduce pharmaceutical waste and hospital costs. These measures may be applicable to other drug classes that likely suffer from a similar proportion of waste.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0018578719844164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370351PMC
August 2020

Inpatient Treatment of Acute Otitis Media at a Pediatric Hospital: A Missed Teaching Opportunity for Antimicrobial Stewardship.

Hosp Pediatr 2020 07 17;10(7):615-619. Epub 2020 Jun 17.

Departments of Pediatric Infectious Diseases.

Background: Acute otitis media (AOM) is a common pediatric condition known to contribute to excessive antibiotic use in the outpatient setting. Treatment of AOM in the inpatient setting has not been described. The objective was to describe the clinical features and inpatient management of AOM to harness this entity to teach learners about judicious antibiotic prescribing in all settings.

Methods: This is a single-center retrospective cohort study of inpatients treated for AOM from January 2015 to December 2018. Patients were included if they had an antibiotic ordered and either a provider-selected order indication of otitis media or an billing code of AOM. A chart review was performed to identify primary diagnoses, examination features, and treatment, including excess days of therapy.

Results: We included 840 hospitalized patients treated for AOM in this study. At least 71% of patients had a concurrent viral respiratory illness. Examinations were frequently discordant (34%), and 47% lacked documentation of a physical examination finding of a bulging tympanic membrane, contributing to 3417 potential excess days of therapy. Of the total patients treated for AOM, 40% were given excess duration of therapy. The vast majority (97%) of patients who qualified for a wait-and-watch approach were treated.

Conclusions: AOM is not being rigorously diagnosed or treated in a guideline-adherent manner in the inpatient setting. This is a lost opportunity for teaching antibiotic stewardship. Interventions, such as promoting the wait-and-watch approach and deferring treatment decisions to inpatient providers, could help promote the judicious use of antibiotics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/hpeds.2020-0090DOI Listing
July 2020

Vancomycin-Nonsusceptible Enterococci Mediated by at a Large Children's Hospital: Prevalence, Susceptibility, and Impact on Care of Enterococcal Bacteremia.

Open Forum Infect Dis 2020 May 6;7(5):ofaa160. Epub 2020 May 6.

Section of Infectious Diseases, Children's Hospital Colorado, Aurora, Colorado, USA.

and have inherent vancomycin resistance and, though known as pathogens, have not been well characterized in pediatric patients. We identified a significant prevalence of these enterococcal species among immunocompromised patients at a large pediatric institution and describe the impact on patient care, antibiotic stewardship, and infection control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246344PMC
May 2020

Multicenter Initial Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

J Pediatric Infect Dis Soc 2020 Dec;9(6):701-715

Department of Pediatrics, Division of Infectious Diseases, Hospital for Sick Children, Toronto, Canada.

Background: Although coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics.

Methods: A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion.

Results: Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available.

Conclusions: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piaa045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188128PMC
December 2020

Sustainability of Handshake Stewardship: Extending a Hand Is Effective Years Later.

Clin Infect Dis 2020 05;70(11):2325-2332

Department of Pediatrics, Section of Pediatric Infectious Diseases and Department of Infection Prevention and Control, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.

Background: Children's Hospital Colorado created a unique method of antimicrobial stewardship, called handshake stewardship, that effectively decreased hospital anti-infective use and costs in its pilot year (2013). Handshake stewardship is distinguished by: (1) the lack of prior authorization; (2) a review of all prescribed anti-infectives; (3) a shared review by the physician and the pharmacist; and (4) a daily, rounding-based, in-person approach to supporting providers. We sought to reevaluate the outcomes of the program after 5 years of experience, totaling 8 years of data.

Methods: We retrospectively measured anti-infective (antibiotic, antiviral, antifungal) use hospital-wide by unit and by drug for an 8-year period spanning October 2010 to October 2018. Aggregated monthly use was measured in days of therapy per thousand patient days (DOT/1000 PD). The percentage of children admitted ever receiving an anti-infective was also measured, as well as severity-adjusted mortality, readmissions, and lengths of stay.

Results: Hospital-wide mean anti-infective use significantly decreased, from 891 (95% confidence interval [CI] 859-923) in the pre-implementation phase to 655 (95% CI 637-694) DOT/1000 PD in post-implementation Year 5; in a segmented regression time series analysis, this was a rate of -2.6 DOT/1000 PD (95% CI -4.8 to -0.4). This is largely attributable to decreased antibacterial use, from 704 (95% CI 686-722) to 544 (95% CI 525 -562) DOT/1000 PD. The percentage of children ever receiving an anti-infective during admission likewise declined, from 65% to 52% (95% CI 49-54). There were no detrimental effects on severity adjusted mortality, readmissions, or lengths of stay.

Conclusions: The handshake method is an effective and sustainable approach to stewardship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciz650DOI Listing
May 2020

Hospital-wide Description of Clinical Indications for Pediatric Anti-infective Use.

Clin Ther 2019 08 11;41(8):1605-1611.e0. Epub 2019 Jun 11.

Department of Pediatrics, Section of Pediatric Infectious Diseases, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA; Department of Infection Prevention and Control, Children's Hospital Colorado, Aurora, CO, USA. Electronic address:

Purpose: This study is the first description of hospital-wide anti-infective use according to clinical indication for a pediatric hospital. Children's Hospital Colorado (CHCO) is uniquely poised to examine its anti-infective use after the implementation of provider-selected order indications (PSOIs), which are distinct from Diagnosis Related Group classifications in that they are used for clinical treatment as opposed to final diagnosis codes for billing and thus are more granular.

Methods: This study used our institution's mandatory PSOIs to describe overall clinical indications for anti-infective use. For 2016, all anti-infective orders were extracted from the electronic medical record (Epic), including drug name, route, prescribing unit, and PSOI. We calculated the number of times each drug was associated with each indication and the number of times an indication was attributed to each drug, and then analyzed these data in Excel.

Findings: There were 29,258 orders at CHCO in 2016 with at least 1 indication. The most common clinical indication was "prophylaxis-medical/surgical," accounting for 23% of all orders and commonly associated with cefazolin (42% of prophylaxis-medical/surgical orders). This was followed by the indications of "sepsis/bacteremia" and "pneumonia/sinusitis." The most commonly prescribed anti-infectives for nonprophylactic clinical indications were IV vancomycin (14%), ceftriaxone (11%), and ampicillin (6%).

Implications: Knowledge of the clinical reasons for hospital-wide anti-infective use enables hospitals to identify targets for improved use through education and guideline and policy development. This description provides better details than billing codes about the clinical reasons anti-infectives are used and offers a useful template for implementation at other hospitals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinthera.2019.05.008DOI Listing
August 2019

Increased tenofovir monoester concentrations in patients receiving tenofovir disoproxil fumarate with ledipasvir/sofosbuvir.

J Antimicrob Chemother 2019 08;74(8):2360-2364

Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus (AMC), Aurora, CO, USA.

Background: Intracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir.

Methods: HIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests.

Results: Ten participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0-287.5) and 0.74 ng/mL (0.27-2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40-18.05; P = 0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25-11.78; P = 0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71-4.57; P = 0.001) and 7.31-fold (95% CI 4.47-11.95; P < 0.0001), respectively, after 4 weeks of ledipasvir/sofosbuvir.

Conclusions: Tenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dkz184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640288PMC
August 2019

Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate.

J Antimicrob Chemother 2018 08;73(8):2112-2119

University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.

Background: The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions.

Objectives: To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate.

Methods: HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS.

Results: Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment.

Conclusions: These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dky146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054189PMC
August 2018

Experience with Continuous Infusion Vancomycin Dosing in a Large Pediatric Hospital.

J Pediatric Infect Dis Soc 2019 May;8(2):174-179

Department of Pharmacy, Children's Hospital Colorado, Aurora.

Background: There is a paucity of data on dosing of continuous infusion of vancomycin (CIV) in pediatric patients, despite it being an attractive treatment option for limiting escalating doses of intermittent infusion of vancomycin. The purpose of this study was to determine the total daily dose of CIV required to attain therapeutic serum vancomycin concentrations (SVCs) in pediatric patients according to age (≥31 days to <2 years, 2 to <8 years, and 8 to <18 years).

Methods: We retrospectively evaluated patients who were transitioned from intermittent infusion of vancomycin to CIV between January 2013 and December 2016. Demographic data, vancomycin data (indication, dosing, steady-state SVCs, and time to reach goal SVC), and adverse-effect data (infusion reactions and serum creatinine level) were collected.

Results: Of the 240 patients included, 76 had a goal SVC of 10 to 15 µg/mL and 164 had a goal of 15 to 20 µg/mL. The dose of CIV required to reach an SVC of 10 to 15 µg/mL in the youngest age group was 48.4 mg/kg per day versus 45.6 and 39.4 mg/kg per day in the older age groups (P < .005). The 2 younger age groups of patients with a goal SVC of 15 to 20 µg/mL required 50.2 and 50.6 mg/kg per day, respectively, whereas patients aged ≥8 years required 44.7 mg/kg per day (P = .008). One patient experienced renal injury, and 1 experienced renal failure.

Conclusions: CIV is an effective method for attaining a therapeutic SVC in pediatric patients. Patients <8 years of age require higher dosing than older pediatric patients to reach the goal SVCs of 10 to 15 and 15 to 20 µg/mL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piy032DOI Listing
May 2019

Small increase in dolutegravir trough, but equivalent total dolutegravir exposure with simeprevir in HIV/HCV seronegative volunteers.

J Antimicrob Chemother 2018 Jan;73(1):156-159

University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.

Background: Dolutegravir, an HIV integrase strand-transfer inhibitor, and simeprevir, an HCV NS3/4A PI, have the potential to interact as dolutegravir is a P-glycoprotein, uridine glucuronosyl transferase 1A1 and cytochrome P4503A substrate and simeprevir has been shown to mildly inhibit these.

Objectives: To compare dolutegravir and simeprevir pharmacokinetics (PK) when given separately versus in combination.

Methods: Healthy volunteers received: (i) 150 mg of simeprevir once daily for 7 days; (ii) 50 mg of dolutegravir once daily for 7 days; and (iii) 150 mg of simeprevir once daily plus 50 mg of dolutegravir once daily for 7 days, with randomization to treatment sequence. Twenty-four hour intensive PK sampling was performed on day 7 of each sequence following observed dosing and a standardized meal. PK parameters were determined using non-compartmental methods and compared using paired t-tests. Bioequivalence for area under the curve (AUCtau) and maximum concentration (Cmax) were also assessed. NCT02404805.

Results: Twenty-four subjects completed all three sequences. Dolutegravir trough was increased 24% (P = 0.0003) with simeprevir. Dolutegravir AUCtau was increased 15% (P = 0.002), but was deemed bioequivalent as the 90% CI for the geometric mean ratio was 107%-123%. Dolutegravir Cmax was bioequivalent. Simeprevir PK was unaffected by dolutegravir. There were no discontinuations due to adverse events and all adverse events were mild to moderate in severity.

Conclusions: Dolutegravir trough was increased slightly with simeprevir, but AUCtau was bioequivalent. Despite the increase in trough, dolutegravir concentrations were well within the range with established safety data. Suggesting that simeprevir and dolutegravir can be safely co-administered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dkx344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890669PMC
January 2018

Pharmacologic Considerations in the Treatment of Hepatitis C Virus in Persons With HIV.

Clin Infect Dis 2016 07;63 Suppl 1:S12-23

Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora.

Roughly one-third of individuals living with the human immunodeficiency virus (HIV) are coinfected with the hepatitis C virus (HCV) due to shared routes of transmission. HIV accelerates the progression of HCV disease; thus, coinfected individuals are at high priority for HCV treatment. Several new HCV therapies, called direct-acting antiviral agents (DAAs), are available that achieve cure rates of >90% in many patient populations including individuals with HIV. The primary consideration in treating HCV in HIV-infected persons is the potential for drug interactions. We describe the clinical pharmacology and drug interaction potential of the DAAs, review the interaction data with DAAs and antiretroviral agents, and identify the knowledge gaps in the pharmacologic aspects of treating HCV in individuals with HIV coinfection. This review will focus on DAAs that have received regulatory approval in the United States and Europe and agents in late stages of clinical development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciw220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928451PMC
July 2016

Tenofovir, emtricitabine, and darunavir/ritonavir pharmacokinetics in an HIV-infected patient after Roux-en-Y gastric bypass surgery.

Ann Pharmacother 2014 Jun 10;48(6):816-9. Epub 2014 Mar 10.

University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Objective: To determine antiretroviral (ARV) pharmacokinetics in a patient who previously underwent Roux-en-Y gastric bypass (RYGB) surgery.

Case Summary: We describe a 38-year-old Hispanic man who tested positive for human immunodeficiency virus (HIV) 11 months following RYGB surgery. When the patient presented for care of his HIV, his HIV-1 RNA was 146 138 copies/mL (5.20 log) and his CD4 T cell count was 320 cells/mm(3) (25%). He was initiated on tenofovir disoproxil fumarate (TDF) 300 mg once daily, emtricitabine (FTC) 200 mg once daily, and darunavir/ritonavir (DRV/r) 600/100 mg twice daily. ARV concentrations were similar to historical data. Six months following ARV initiation, HIV-1 RNA was <48 copies/mL and CD4 count had increased to 562 cells/mm(3) (39%).

Discussion: Bariatric surgery has been successfully performed in obese persons infected with the HIV, but data are limited on ARV drug selection and pharmacokinetics in this group. Optimal suppression of HIV replication requires appropriate concentrations of ARV drugs, and in a patient who has undergone RYGB, this can be challenging not only because of a decreased absorptive surface area but also because of an increased intragastric pH.

Conclusion: We found that once daily TDF/FTC and twice daily DRV/r produced trough concentrations similar to historic data in a patient who previously underwent RYGB with virologic suppression and immunologic recovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1060028014525034DOI Listing
June 2014

Development and validation of a dried blood spot assay for the quantification of ribavirin using liquid chromatography coupled to mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2014 Jan 31;944:18-24. Epub 2013 Oct 31.

Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, 12850 East Montview Blvd, C-238 V20, Aurora, CO 80045, USA. Electronic address:

Efficient, inexpensive and sensitive assays for the measurement of drugs are of interest for pharmacokinetic and pharmacodynamics (PK-PD) analysis. Dried blood spots (DBS) are a unique bioanaltyical matrix with the potential to fulfill this interest for the measurement of numerous analytes. Here we describe the development and validation of a reversed-phase high performance liquid chromatographic (LC), tandem mass spectrometry (MS/MS) assay for the determination of ribavirin (RBV) in DBS. A 3mm punch from spotted and dried whole blood was extracted in methanol utilizing isotopically labeled internal standard for LC-MS/MS analysis. Validation was performed over a range of 0.05μg/mL to 10.0μg/mL and the method was shown to be precise (coefficient of variation ≤15%) and accurate (within ±15% of control). These acceptance criteria were met for hematocrit ranges of 20-54%, for center versus edge punches and for spot volumes from 10 to 60μL. RBV was stable for up to 140 days at room temperature and -20°C as well as for three freeze/thaw cycles. Correlation of RBV in DBS versus in plasma yielded r(2)≥0.98 demonstrating that DBS can be used as an alternative to plasma for PK-PD studies in human subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2013.10.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950646PMC
January 2014
-->