Paediatric global antibiotic guidelines are inconsistent, most likely due to the limited pharmacokinetic and efficacy data in this population. We investigated factors underlying variation in ...antibiotic dosing using data from five global point prevalence surveys.
Data from 3,367 doses of the 16 most frequent intravenous antibiotics administered to children 1 month-12 years across 23 countries were analysed. For each antibiotic, we identified standard doses given as either weight-based doses (in mg/kg/day) or fixed daily doses (in mg/day), and investigated the pattern of dosing using each strategy. Factors underlying observed variation in weight-based doses were investigated using linear mixed effects models. Weight-based dosing (in mg/kg/day) clustered around a small number of peaks, and all antibiotics had 1-3 standard weight-based doses used in 5%-48% of doses. Dosing strategy was more often weight-based than fixed daily dosing for all antibiotics apart from teicoplanin, which had approximately equal proportions of dosing attributable to each strategy. No strong consistent patterns emerged to explain the historical variation in actual weight-based doses used apart from higher dosing seen in central nervous system infections, and lower in skin and soft tissue infections compared to lower respiratory tract infections. Higher dosing was noted in the Americas compared to the European region.
Antibiotic dosing in children clusters around a small number of doses, although variation remains. There is a clear opportunity for the clinical, scientific and public health communities to consolidate behind a consistent set of global antibiotic dosing guidelines to harmonise current practice and prioritise future research.
In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.
A 'meta-model' with 4894 concentrations from 1631 neonates was ...built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates.
A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients.
The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.
Background. Recent evidence suggests that decreases in morbidity and mortality in cohorts of adults infected with human immunodeficiency virus (HIV) are showing signs of reversal. We describe changes ...over time in these characteristics and in the response to treatment among children in the United Kingdom and Ireland with perinatally acquired HIV infection, many of whom are now adolescents. Methods. We analyzed prospective cohort data reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) and the Collaborative HIV Paediatric Study. Results. By mid 2006, 1441 HIV-infected children were reported to NSHPC; 40% were ⩾10 years old at their most recent follow-up visit, and 34% were receiving care outside London. The proportion of children born abroad increased from 24% during 1994–1996 to 64% during 2003–2006. The percentage of total child time during which children received highly active antiretroviral therapy (HAART) increased from 36% during 1997–1999 to 61% during 2000–2002 and 63% during 2003–2006. Of children who were naive to antiretroviral therapy at the start of HAART, the percentage with an HIV-1 RNA load of <400 copies/mL after 12 months increased from 52% during 1997–1999 to 79% during 2003–2006. In multivariate analysis, only calendar time predicted virological response, whereas both younger age and lower CD4 cell percentage at HAART initiation predicted increases of >10% in the CD4 cell percentage. A total of 31% of children aged 5–14 years and 38% aged ⩾15 years at their most recent follow-up visit had been exposed to drugs from each of the 3 main HAART classes. The rate of AIDS and mortality combined decreased from 13.3 cases per 100 person-years before 1997 to 3.1 and 2.5 cases per 100 person-years, respectively, during 2000–2002 and 2003–2006; rates of hospital admission also declined during this interval. Of 18 children known to have died since 2003, 9 died within 1 month after presentation. Conclusions. Morbidity and mortality rates among HIV-infected children continue to decrease over time. Because these children are increasingly dispersed outside London, specialist care is now provided in national clinical networks. Transition pathways to adolescent and adult services and long-term observation to monitor the effects of prolonged exposure to both HIV and HAART are required.
Tackling antimicrobial resistance in neonatal sepsis Folgori, Laura; Ellis, Sally J; Bielicki, Julia A ...
The Lancet global health,
November 2017, 2017-11-00, 20171101, 2017-11-01, Letnik:
5, Številka:
11
Journal Article
Abstract Purpose We aimed to assess the impact of UK primary care policy reforms implemented in April 2004 on potentially avoidable unplanned short-stay hospital admissions for children with primary ...care–sensitive conditions. Methods We conducted an interrupted time series analysis of hospital admissions for all children aged younger than 15 years in England between April 2000 and March 2012 using data from National Health Service public hospitals in England. The main outcomes were annual short-stay (<2-day) unplanned hospital admission rates for primary care–sensitive infectious and chronic conditions. Results There were 7.8 million unplanned admissions over the study period. More than one-half (4,144,729 of 7,831,633) were short-stay admissions for potentially avoidable infectious and chronic conditions. The primary care policy reforms of April 2004 were associated with an 8% increase in short-stay admission rates for chronic conditions, equivalent to 8,500 additional admissions, above the 3% annual increasing trend. Policy reforms were not associated with an increase in short-stay admission rates for infectious illness, which were increasing by 5% annually before April 2004. The proportion of primary care–referred admissions was falling before the reforms, and there were further sharp reductions in 2004. Conclusions The introduction of primary care policy reforms coincided with an increase in short-stay admission rates for children with primary care–sensitive chronic conditions, and with more children being admitted through emergency departments. Short-stay admission rates for primary care–sensitive infectious illness increased more steadily and could be related to lowered thresholds for hospital admission.
Assessment of regional pediatric last-resort antibiotic utilization patterns is hampered by potential confounding from population differences. We developed a risk-adjustment model from readily ...available, internationally used survey data and a simple patient classification to aid such comparisons.
We investigated the association between pediatric conserve antibiotic (pCA) exposure and patient / treatment characteristics derived from global point prevalence surveys of antibiotic prescribing, and developed a risk-adjustment model using multivariable logistic regression. The performance of a simple patient classification of groups with different expected pCA exposure levels was compared to the risk model.
226 centers in 41 countries across 5 continents.
Neonatal and pediatric inpatient antibiotic prescriptions for sepsis/bloodstream infection for 1281 patients.
Overall pCA exposure was high (35%), strongly associated with each variable (patient age, ward, underlying disease, community acquisition or nosocomial infection and empiric or targeted treatment), and all were included in the final risk-adjustment model. The model demonstrated good discrimination (c-statistic = 0.83) and calibration (p = 0.38). The simple classification model demonstrated similar discrimination and calibration to the risk model. The crude regional pCA exposure rates ranged from 10.3% (Africa) to 67.4% (Latin America). Risk adjustment substantially reduced the regional variation, the adjusted rates ranging from 17.1% (Africa) to 42.8% (Latin America).
Greater comparability of pCA exposure rates can be achieved by using a few easily collected variables to produce risk-adjusted rates.
Antibiotics remain the cornerstone of modern medicine. Yet there exists an inherent dilemma in their use: we are able to prevent harm by administering antibiotic treatment as necessary to both humans ...and animals, but we must be mindful of limiting the spread of resistance and safeguarding the efficacy of antibiotics for current and future generations. Policies that strike the right balance must be informed by a transparent rationale that relies on a robust evidence base.
One way to generate the evidence base needed to inform policies for managing antibiotic resistance is by using mathematical models. These models can distil the key drivers of the dynamics of resistance transmission from complex infection and evolutionary processes, as well as predict likely responses to policy change in silico. Here, we ask whether we know enough about antibiotic resistance for mathematical modelling to robustly and effectively inform policy. We consider in turn the challenges associated with capturing antibiotic resistance evolution using mathematical models, and with translating mathematical modelling evidence into policy.
We suggest that in spite of promising advances, we lack a complete understanding of key principles. From this we advocate for priority areas of future empirical and theoretical research.
Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children.
To determine the efficacy, safety and impact on antimicrobial ...resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia.
A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland.
Paediatric emergency departments, paediatric assessment/observation units and inpatient wards.
Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge.
Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio.
The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication.
A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants median age 2.5 (interquartile range 1.6-2.7) years; 52% male were randomised to either 3 (
= 413) or 7 days (
= 401) of trial medication at either lower (
= 410) or higher (
= 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (
= 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms.
End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children.
Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms.
Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing.
Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 25, No. 60. See the NIHR Journals Library website for further project information.
OBJECTIVES To describe trends in the epidemiology of healthcare-associated Infections (HAIs) in pediatric/neonatal intensive care units (ICUs) and to evaluate risk factors and impact of multidrug ...resistance in children admitted to ICUs. DESIGN Multicenter, retrospective, cohort study with a nested case-control study conducted from January 1, 2010, through December 31, 2014. SETTING Three tertiary care pediatric hospitals in Italy and Brazil with a total of 103 ICU beds. PATIENTS Inclusion criteria were admission to ICU during the study period, age at onset less than 18 years, and microbiologically confirmed HAI. RESULTS A total of 538 HAIs in 454 children were included; 93.3% of patients had comorbidities. Bloodstream infections were the leading pattern (45.4%). The cumulative incidence of HAI was 3.6/100 ICU admissions and the crude 30-day fatality rate was 5.7/1,000 admissions. The most frequently isolated pathogens were Enterobacteriaceae, followed by Pseudomonas aeruginosa and Staphylococcus aureus. Forty-four percent of isolates were multidrug-resistant (MDR). Two multivariate logistic regressions were performed. Factors independently associated with an MDR-HAI were country, previous antibiotics, transplantation, major surgery, and colonization by an MDR strain. Factors independently associated with 30-day case fatality were country, previous transplantation, fungal infection, bloodstream infection, lower respiratory tract infection, and infection caused by MDR strains. CONCLUSIONS Infection control and prevention can limit the spread of MDR strains and improve outcomes. Targeted surveillance programs collecting neonatal and pediatric HAI/bloodstream infection data and outcomes would allow global benchmarking. The next step is to identify methods to monitor key HAIs and integrate these into affordable intervention programs. Infect Control Hosp Epidemiol 2016;1-8.
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