The impact of levofloxacin prophylaxis on empiric intravenous antibiotic use in pediatric hematopoietic stem cell transplant recipients.

Levofloxacin prophylaxis during periods of neutropenia in pediatric hematopoietic stem cell transplant (HSCT) may reduce the number of febrile episodes and use of empiric intravenous antibiotics (EIA); however, the literature is conflicting. This retrospective review compared EIA use before and after implementation of levofloxacin prophylaxis at a children's hospital. Levofloxacin prophylaxis was associated with reduced use of certain EIA; however, did not reduce the number of positive blood cultures or clinical deteriorations. Therefore, levofloxacin prophylaxis may have implications for the stewardship of broad-spectrum intravenous antibiotics used in pediatric HSCT.

Improving inpatient paediatric de-labelling of allergies to beta-lactams: a quality improvement study.

OBJECTIVE: To evaluate the implementation of an antimicrobial stewardship programme-led inpatient beta-lactam allergy de-labelling programme using a direct oral provocation test (OPT). DESIGN: One-year quality improvement study using a before-after design. SETTING: Free-standing tertiary care paediatric hospital. PATIENTS: Patients with a reported beta-lactam allergy admitted to the paediatric medicine inpatient unit. INTERVENTIONS: Following standardised assessment and risk stratification of reported symptoms, patients with a low-risk history were offered an OPT. Beta-lactam allergy labels were removed if a reported history was considered non-allergic or after successful OPT. MAIN OUTCOME MEASURES: Removal of inappropriate beta-lactam allergy labels. RESULTS: 80 patients with 85 reported beta-lactam allergies were assessed. Median age was 8.1 years (IQR 4.8-12.9) and 34 (42%) were female. The majority (n=55, 69%) had an underlying medical condition. Amoxicillin was the most reported allergy (n=25, 29%). Reported reactions were primarily dermatological (n=65, 77%). Half of participants (n=40) were ineligible for OPT, with equal proportions due to clinical reasons or the nature of the reported reaction. Of the 40 eligible patients, 28 patients (70%) were de-labelled either by history alone (n=10) or OPT (n=18). All OPTs were successful. De-labelling allowed five additional patients (11% of those receiving antibiotics) to receive the preferred beta-lactam. Including patients who were subsequently assessed in the allergy clinic, almost half of all evaluated patients were de-labelled (n=37, 46%). CONCLUSIONS: An antimicrobial stewardship programme-led programme using a direct OPT was feasible and safe for expanding beta-lactam allergy de-labelling to paediatric patients admitted to the paediatric medicine inpatient unit.

Development of Quality Indicators to Evaluate the Appropriateness of Empiric Antimicrobial Use in Pediatric Patients.

Background: Use of quality indicators is one strategy recommended to assess antimicrobial prescribing for pediatric inpatients. Objective: To achieve consensus from infectious diseases clinicians on quality indicators that characterize appropriate empiric antimicrobial use for the management of infectious syndromes in pediatric inpatients. Methods: This study was completed using the Delphi technique. The research team developed an initial list of quality indicators, informed by a literature search. A multidisciplinary group of health care providers with expertise in infectious diseases was invited to participate. The list was disseminated to this panel of experts using Opinio survey software. The experts were asked to rate the indicators on a 9-point Likert scale in relation to the following criterion: "The importance of each item in determining appropriateness considering benefit or harm at the individual or population level". Consensus was defined as at least 75% agreement and a median score of 7 or higher. Results: Twelve of 31 invited experts completed at least 1 round of the survey, and 10 completed all rounds. Consensus was achieved on 28 of 31 proposed indicators after 3 rounds. Indicators with consensus were categorized under "empiric choice" (n = 12 indicators), "dose" (n = 5), "duration" (n = 2), "administration" (n = 4), "diagnosis" (n = 2), and "documentation" (n = 3). Six of the indicators for which consensus was achieved were rephrased by the experts. Conclusions: Consensus was achieved on quality indicators to assess the appropriateness of empiric antimicrobial use in pediatric patients. Clinicians and researchers can use these consensus-based indicators to assess adherence to best practice.

Contexte: L'utilisation d'indicateurs de qualité est l'une des stratégies recommandées pour évaluer la prescription d'antimicrobiens aux patients pédiatriques hospitalisés. Objectif: Parvenir à un consensus, entre les cliniciens des maladies infectieuses, portant sur les indicateurs de qualité qui caractérisent l'utilisation empirique appropriée des antimicrobiens pour la prise en charge des syndromes infectieux chez les patients pédiatriques hospitalisés. Méthodes: Cette étude a été réalisée à l'aide de la technique Delphi. L'équipe de recherche a dressé une liste initiale d'indicateurs de qualité éclairée par une recherche documentaire. Un groupe multidisciplinaire de prestataires de soins de santé ayant une expertise dans le domaine des maladies infectieuses a été invité à participer. La liste a été diffusée à ce panel d'experts à l'aide du logiciel d'enquête Opinio. Les experts ont été invités à noter les indicateurs sur une échelle de Likert de 9 points par rapport au critère suivant : « L'importance de chaque élément pour déterminer la pertinence compte tenu du bienfait ou du dommage à l'échelle individuelle ou de la population ¼. Le consensus était défini comme « Un accord d'au moins 75 % et un score médian d'au moins 7 ¼. Résultats: Douze des 31 experts invités ont terminé au moins 1 cycle de l'enquête et 10 les ont tous terminés. Un consensus a été atteint pour 28 des 31 indicateurs proposés après 3 cycles. Les indicateurs qui ont atteint le consensus ont été classés en « choix empirique ¼ (n = 12 indicateurs), « dose ¼ (n = 5), « durée ¼ (n = 2), « administration ¼ (n = 4), « diagnostic ¼ (n = 2) et « documentation ¼ (n = 3). Six indicateurs faisant consensus ont été reformulés par les experts. Conclusions: Un consensus a été atteint pour les indicateurs de qualité visant à évaluer l'utilisation empirique appropriée des antimicrobiens chez les patients pédiatriques. Les cliniciens et les chercheurs peuvent utiliser ces indicateurs basés sur le consensus pour évaluer le respect des meilleures pratiques.

Multinational consensus antimicrobial stewardship recommendations for children managed in hospital settings.

Children are entitled to receive antibiotic therapy that is based on evidence and best practice, but might be overlooked in hospital programmes designed to achieve antimicrobial stewardship [AMS]. This failure to include children could be because children make up small proportion of patients in most hospitals, and are cared for by specialised paediatric staff. We reviewed the evidence and consulted experts in three global regions to develop ten recommendations for good-practice in hospital AMS programmes for children. We performed a review of scientific research, published between Jan 1, 2007, and Oct 17, 2019, concerning AMS, and formed a multinational expert group comprising members from the USA, Canada, the UK, Belgium, Switzerland, Australia, and Aotearoa New Zealand to develop the recommendations. These recommendations aim to help health-care workers who care for children in these regions to deliver best-practice care. We surveyed health-care workers with expertise in antibiotic therapy for children across these regions, and found that the recommendations were considered both very important and generally feasible. These recommendations should be implemented in hospitals to improve antibiotic therapy for children and to stimulate research into future improvements in care.

AUCs and 123s: a critical appraisal of vancomycin therapeutic drug monitoring in paediatrics.

The revised vancomycin guidelines recommend implementing AUC24-based therapeutic drug monitoring (TDM) using Bayesian methods in both adults and paediatrics. The motivation for this change was accumulating evidence showing aggressive dosing to achieve high troughs, as recommended in the first guidelines for adults and extrapolated to paediatrics, is associated with increased nephrotoxicity without improving clinical outcomes. AUC24-based TDM requires substantial resources that may need to be diverted from other valuable interventions. It can therefore be justified only after certain assumptions are shown to be true: (i) there is a clear relationship between vancomycin efficacy and/or toxicity and the proposed therapeutic range; and (ii) maintaining exposure within the target range with AUC24-based TDM improves clinical outcomes and/or decreases toxicity. In this review, we critically appraise the scientific basis for these assumptions. We find studies evaluating the relationship between vancomycin AUC24/MIC and efficacy in adults and children do not offer strong support for the recommended lower limit of the proposed therapeutic range (i.e. AUC24/MIC ≥400). Nephrotoxicity in children increases in a stepwise manner along the vancomycin exposure continuum but it is unclear if one parameter (AUC24 versus trough) is a superior predictor. Overall, evidence in children suggests good-to-excellent correlation between AUC24 and trough. Most importantly, there is no convincing evidence that the method of vancomycin TDM has a causal role in improving efficacy or reducing toxicity. These findings question the need to transition to resource-intensive AUC24-based TDM over retaining trough-based TDM with lower targets to minimize nephrotoxicity in paediatrics.

Solid organ transplant-specific antibiogram in a tertiary pediatric hospital in Canada.

SOT recipients are more vulnerable to infections with antimicrobial-resistant organisms, and therefore, it may be useful for transplant centers to create transplant-specific antibiograms to direct empirical antimicrobial regimens and monitor trends in antimicrobial resistance. SOT-specific antibiograms were created using antimicrobial susceptibility data on isolates from 2012 to 2018 at The Hospital for Sick Children, Toronto, Ontario, Canada. The CLSI guidelines were followed to generate the antibiograms except that results from 2 years of data were pooled on a rolling basis to achieve larger sample sizes. The 3 most frequent organisms in one analysis period of the SOT antibiogram were Escherichia coli (average sample size ±standard deviation; n = 28.7 ± 3.8), Staphylococcus aureus (n = 27.8 ± 5.0), and Pseudomonas aeruginosa (non-CF) (n = 19.8 ± 8.8). For E.coli, susceptibilities in the SOT antibiogram were significantly lower than those in the hospital-wide antibiogram in 2017-2018 for ampicillin (27% vs 47%; p = .014), piperacillin/tazobactam (55% vs 88%; p < .001), cefotaxime (59% vs 89%; p < .001), ciprofloxacin (71% vs 88%; p = .007), and trimethoprim-sulfamethoxazole (41% vs 69%; p = .001), but not significantly different for aminoglycosides and meropenem. In the SOT antibiogram of E. coli, decreased susceptibility trend was confirmed in some antibiotics, including piperacillin/tazobactam (83% in 2012-2013 vs 55% in 2017-2018). At our center, the solid organ transplant-specific antibiogram revealed important differences in E. coli susceptibilities and trends in antimicrobial resistance. Developing a SOT antibiogram will assist in revising and improving empiric treatment guidelines as well as monitoring antimicrobial resistance in this population.

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

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.

Antibiotic Prescription Practice for Pediatric Urinary Tract Infection in a Tertiary Center.

OBJECTIVES: Prescribing antibiotics for suspected urinary tract infection (UTI) is common practice and may lead to unnecessary antibiotic exposure. We aimed to review UTI diagnosis and management in the emergency department and to identify targets for antimicrobial stewardship. METHODS: Single-center, retrospective cohort study of children aged 12 weeks to younger than 18 years discharged from the emergency department with a diagnosis of UTI between October and December 2016. Children with genitourinary malformations were excluded. Clinical information, urine collection method, laboratory findings, and urine culture results were gathered. The sensitivity and specificity of nitrite and leukocyte esterase for UTI diagnosis were calculated. The relationship between urinalysis characteristics and confirmed UTI was examined using logistic regression. RESULTS: A total of 183 children with a median (interquartile range) age of 4.2 (1.1-7.5) years were included; 82.5% were female. Almost all children were discharged home on antibiotics (n = 180, 98%) for a median (interquartile range) duration of 7 (7-10) days. A total of 85 patients (46.4%) received antibiotics despite negative urine cultures leading to 525 unnecessary antibiotic days. The presence of nitrites was the strongest predictor of UTI (odds ratio = 20.22, P < 0.001) and was highly specific. CONCLUSIONS: Current practice in managing suspected pediatric UTIs in our ED resulted in significant and unnecessary antibiotic exposure. We identified targets to reduce unnecessary antibiotic exposure including improving the diagnostic accuracy of UTIs, a process to discontinue antibiotics for negative cultures and standardizing antimicrobial duration.

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

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.

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

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.

Each Additional Day of Antibiotics Is Associated With Lower Gut Anaerobes in Neonatal Intensive Care Unit Patients.

BACKGROUND: Discontinuation of inappropriate antimicrobial therapy is an important target for stewardship intervention. The drug and duration-dependent effects of antibiotics on the developing neonatal gut microbiota needs to be precisely quantified. METHODS: In this retrospective, cross-sectional study, we performed 16S rRNA sequencing on stool swab samples collected from neonatal intensive care unit patients within 7 days of discontinuation of therapy who received ampicillin and tobramycin (AT), ampicillin and cefotaxime (AC), or ampicillin, tobramycin, and metronidazole (ATM). We compared taxonomic composition within term and preterm infant groups between treatment regimens. We calculated adjusted effect estimates for antibiotic type and duration of therapy on the richness of obligate anaerobes and known butyrate-producers in all infants. RESULTS: A total of 72 infants were included in the study. Term infants received AT (20/28; 71%) or AC (8/28; 29%) with median durations of 3 and 3.5 days, respectively. Preterm infants received AT (32/44; 73%) or ATM (12/44; 27%) with median durations of 4 and 7 days, respectively. Compositional analyses of 67 stool swab samples demonstrated low diversity and dominance by potential pathogens. Within 1 week of discontinuation of therapy, each additional day of antibiotics was associated with lower richness of obligate anaerobes (adjusted risk ratio [aRR], 0.84; 95% confidence interval [CI], .73-.95) and butyrate-producers (aRR, 0.82; 95% CI, .67-.97). CONCLUSIONS: Each additional day of antibiotics was associated with lower richness of anaerobes and butyrate-producers within 1 week after therapy. A longitudinally sampled cohort with preexposure sampling is needed to validate our results.

Quality Metrics for Antimicrobial Stewardship Programs.

BACKGROUND: Antimicrobial stewardship programs (ASPs) are targeted to optimize antimicrobial use. However, pediatric metrics used to measure outcomes of ASPs are not well established. Our aim for this project was to identify, refine, and develop consensus on standard metrics for pediatric ASPs. METHODS: By using a modified Delphi process, 2 surveys were sent to experts and stakeholders to establish consensus on the utility of metrics. These were subdivided into 4 ASP domains: (1) antimicrobial consumption, (2) microbiologic outcomes, (3) clinical outcomes, and (4) process measures. Respondents were asked to rank the scientific merit, impact, feasibility, and accountability of each metric. Metrics with ≥75% agreement for scientific merit were included and metrics with ≤25% agreement were discarded. Consensus was finalized with a face-to-face meeting and final survey. RESULTS: Thirty-eight participants from 15 pediatric hospitals across Canada completed all 3 rounds of the Delphi survey. In the domain of antimicrobial consumption, the 2 selected metrics were (1) days of therapy per 1000 patient-days and (2) total antimicrobial days. The clinical and process outcomes chosen were (1) 30-day readmission rate and (2) adherence to ASP recommendations, respectively. A microbiologic outcome was felt to be important and feasible, but consensus could not be obtained on a measure. Several barriers to implementation of the metrics were identified, including information technology limitations at various centers. CONCLUSIONS: We obtained consensus on 4 metrics to evaluate pediatric antimicrobial stewardship activities in Canada. Adoption of these metrics by pediatric ASPs will facilitate measurement of outcomes nationally and internationally.

Canadian Pediatric Antimicrobial Stewardship Programs: Current Resources and Implementation Characteristics.

Antimicrobial stewardship programs (ASPs) became an accreditation requirement for Canadian hospitals in 2013. Pediatric programs are in various stages of program development and implementation, with 93% of surveyed Canadian academic pediatric hospitals having established ASPs. The programs varied in their team composition, implementation of stewardship strategies, and measured metrics. Infect Control Hosp Epidemiol 2018;39:350-354.

Levofloxacin Use in the Neonate: A Case Series.

We report 6 cases of intravenous levofloxacin use to treat multidrug-resistant nosocomial respiratory infections in neonates with a postmenstrual age ranging from 27 to 42 weeks. Because of a lack of neonatal-specific information for levofloxacin, the usual pediatric dosage (10 mg/kg per dose every 12 hours) was used in these patients. Clinical cure occurred in 5 of the 6 patients. Only minimal short-term adverse effects were noted.

Angiotensin-Converting Enzyme Inhibitor Initiation and Dose Uptitration in Children With Cardiovascular Disease: A Retrospective Review of Standard Clinical Practice and a Prospective Randomized Clinical Trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are a mainstay of medical management in pediatric cardiology. However, there are no data defining how best to initiate and uptitrate the dose of these medications in children. METHODS AND RESULTS: Retrospective chart review revealed only 24% of our pediatric cardiology inpatients were discharged on predefined optimal doses of ACEIs and few underwent further dose uptitration in the 8 weeks after hospital discharge. Therefore, 2 alternative protocols for initiation of captopril were compared in a prospective randomized clinical trial. A "rapid uptitration" protocol reached an optimal dose on day 3, whereas the alternative, "prolonged uptitration" protocol, reached an optimal dose on day 9. Forty-6 patients (54% male) were recruited to the trial, with a median age of 0.7 year (IQR 0.5-2.3 years). Captopril was initiated while in intensive care in 39% of patients and on the cardiology ward in 61%. There were no differences between the protocols in episodes of hypotension, symptomatic hypotension, or indices of renal function. Patients following the rapid protocol reached higher doses of captopril (0.93±0.24 versus 0.57±0.38 mg/kg per dose, P<0.0001) and were more likely to have achieved the predefined target (88% versus 43%, P=0.002) and optimal ACEI doses (80% versus 29%, P=0.001) before discharge. CONCLUSIONS: A protocol of rapid ACEI dose uptitration for infants and children with cardiovascular disease can be introduced safely, even in patients receiving intensive care therapy. Compared with standard clinical practice or with a more prolonged protocol, rapid ACEI dose uptitration achieves a higher dosage in this population with no evident disadvantages. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00742040.

Association of blood type and patient characteristics with ovarian reserve.

OBJECTIVE: To assess whether blood type was associated with diminished ovarian reserve (DOR) (day-3 follicle-stimulating hormone level >10 IU/L), controlling for history of tobacco smoking, body mass index (BMI), history of endometriosis, ovarian surgery, previous pregnancy, and maternal age. DESIGN: Cross-sectional study. SETTING: Academic medical center, Division of Reproductive Endocrinology and Infertility. PATIENT(S): Women undergoing in vitro fertilization (IVF) from 2006-2011 (n = 305). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Presence of DOR in relation to a patient's blood type. RESULT(S): Other investigators have reported an increased risk for DOR in patients with blood type O and a protective effect on ovarian reserve for blood type A. We observed no association between a woman's blood type and DOR. We found an increased risk for DOR in patients aged 35 and older. Obesity (BMI ≥ 30 vs. BMI <25) was associated with lower odds of DOR. CONCLUSION(S): In comparison with blood type A, blood type O is not associated with an increase in DOR. We found no clinical implications for using blood type as a risk factor for DOR.

Pharmacologic therapy of heart failure in children: part of a special series on paediatric pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.

Paediatric cardiomyopathy and heart failure are distinct but frequently associated conditions, which have a high mortality. Traditional medical therapy has evolved to incorporate newer classes of heart failure drugs, although the evidence to support efficacy in children is limited. This perspective article discusses the rationale, benefits and limitations of the various classes of drug therapy used in paediatric heart failure due to cardiomyopathy or congenital heart disease. Controversies in management and challenges for future development are highlighted.