Antimicrobials

10

Jan, 2020

Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review

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Authors: Donà D, Barbieri E, Daverio M, Lundin R, Giaquinto C, Zaoutis T, Sharland M

Published in: Antimicrob Resist Infect Control.2020;9:3

Background Antibiotics are the most common medicines prescribed to children in hospitals and the community, with a high proportion of potentially inappropriate use. Antibiotic misuse increases the risk of toxicity, raises healthcare costs, and selection of resistance. The primary aim of this systematic review is to summarize the current state of evidence of the implementation and outcomes of pediatric antimicrobial stewardship programs (ASPs) globally.

Methods MEDLINE, Embase and Cochrane Library databases were systematically searched to identify studies reporting on ASP in children aged 0-18 years and conducted in outpatient or in-hospital settings. Three investigators independently reviewed identified articles for inclusion and extracted relevant data.

Results Of the 41,916 studies screened, 113 were eligible for inclusion in this study. Most of the studies originated in the USA (52.2%), while a minority were conducted in Europe (24.7%) or Asia (17.7%). Seventy-four (65.5%) studies used a before-and-after design, and sixteen (14.1%) were randomized trials. The majority (81.4%) described in-hospital ASPs with half of interventions in mixed pediatric wards and ten (8.8%) in emergency departments. Only sixteen (14.1%) studies focused on the costs of ASPs. Almost all the studies (79.6%) showed a significant reduction in inappropriate prescriptions. Compliance after ASP implementation increased. Sixteen of the included studies quantified cost savings related to the intervention with most of the decreases due to lower rates of drug administration. Seven studies showed an increased susceptibility of the bacteria analysed with a decrease in extended spectrum beta-lactamase producers E. coli and K. pneumoniae; a reduction in the rate of P. aeruginosa carbapenem resistance subsequent to an observed reduction in the rate of antimicrobial days of therapy; and, in two studies set in outpatient setting, an increase in erythromycin-sensitive S. pyogenes following a reduction in the use of macrolides.

Conclusions Pediatric ASPs have a significant impact on the reduction of targeted and empiric antibiotic use, healthcare costs, and antimicrobial resistance in both inpatient and outpatient settings. Pediatric ASPs are now widely implemented in the USA, but considerable further adaptation is required to facilitate their uptake in Europe, Asia, Latin America and Africa.

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30

Dec, 2019

Standardising neonatal and pediatric anitibiotic clinical trial design and conduct: the PENTA-ID network review

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Authors: Folgori L, Lutsar I, Standing JF, et al.

Published in: BMJ Open. 2019; 9:e032592

Abstract: Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators.
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16

Oct, 2019

Towards understanding global patterns of antimicrobial use and resistance in neonatal sepsis: insights from the NeoAMR network

 

Authors: Li G, Bielicki JA, Ahmed ASMNU, et al.

Published in: Arch Dis Child.2091;0:1-6

Objective To gain an understanding of the variation in available resources and clinical practices between neonatal units (NNUs) in the low-income and middleincome country (LMIC) setting to inform the design of an observational study on the burden of unit-level antimicrobial resistance (AMR).Design A web-based survey using a REDCap database was circulated to NNUs participating in the Neonatal AMR research network. The survey included questions about NNU funding structure, size, admission rates, access to supportive therapies, empirical antimicrobial guidelines and period prevalence of neonatal blood culture isolates and their resistance patterns.Setting 39 NNUs from 12 countries.Patients Any neonate admitted to one of the participating NNUs.

Interventions This was an observational cohort study.

Results The number of live births per unit ranged from 513 to 27 700 over the 12-month study period, with the number of neonatal cots ranging from 12 to 110. The proportion of preterm admissions <32 weeks ranged from 0% to 19%, and the majority of units (26/39, 66%) use Essential Medicines List ’Access’ antimicrobials as their first-line treatment in neonatal sepsis. Cephalosporin resistance rates in Gram-negative isolates ranged from 26% to 84%, and carbapenem resistance rates ranged from 0% to 81%. Glycopeptide resistance rates among Gram-positive isolates ranged from 0% to 45%.

Conclusion AMR is already a significant issue in NNUs worldwide. The apparent burden of AMR in a given NNU in the LMIC setting can be influenced by a range of factors which will vary substantially between NNUs. These variations must be considered when designing interventions to improve neonatal mortality globally

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15

Oct, 2019

Differential susceptibility of Staphylococcus epidermidis biofilms to vancomycin, daptomycin and linezolid between clinical Isolates from neonates and adults

 

Authors:Simitsopoulou M, Kadiltzoglou P, Kyrpitzi D, Roilides E.

Published in: Int J Biol Med Res.2019;10(1):6591-6596

Abstract This study aimed to compare the effects of vancomycin, linezolid and daptomycin against planktonic cells and biofilms of 32 bloodstream isolates derived from neonates and adults of three hospitals. Staphylococcus epidermidis biofilm formation was spectrophotometrically assessed following safranin staining. Susceptibility testing of planktonic and biofilm cells was performed by XTT reduction assay. MICs of vancomycin and daptomycin were 1mg/L and that of linezolid 0.5 mg/L. At concentrations >0.5 mg/L, complete eradication of planktonic cells was effected by all three antibiotics. The biofilm MICs for the three antibiotics were 3-7 twofold dilutions higher than the corresponding planktonic MICs (P<0.05). Vancomycin and linezolid exhibited similar median MICs against biofilms of neonatal isolates ranging from 16 to 32mg/L with comparable damage (44%-84% for vancomycin vs 56%-77% for linezolid). Their MICs against biofilms of isolates from adults were 128 mg/L and 4 mg/L, respectively (P<0.001). Vancomycin showed lower MIC than daptomycin against biofilms of neonatal isolates (16 mg/L vs 64 mg/L, respectively; P<0.05). Biofilm MIC of linezolid was lower than the corresponding daptomycin MIC for both age groups (neonatal isolates: 16 mg/L vs 64 mg/L; adult isolates: 4 mg/L vs 64 mg/L, P<0.05). Vancomycin and linezolid are equally effective against biofilms of neonatal blood isolates and both exhibit superior activity to daptomycin. In the adult group, linezolid is more efficacious than both vancomycin and daptomycin against biofilms, while vancomycin and daptomycin exhibit similar anti-biofilm activities. Our results suggest that vancomycin and linezolid show better anti-biofilm activity than daptomycin against biofilms of neonates and linezolid have increased activity against biofilms of adults.

14

Oct, 2019

Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

 

Authors: Jacqz-Aigrain E, Leroux S, Thomson AH, et al.

Published in: J Antimicrob Ther 2019; 74(8):2128-2138

Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.
Methods 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.
Results 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.
Conclusions 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.

18

Jun, 2019

Use of the WHO Access, Watch, and Reserve classification to define patterns of hospital antibiotic use (AWaRe): an analysis of paediatric survey data from 56 countries.

 

Authors: Hsia Y, Lee BR, Versporten A, et al; GARPEC and Global-PPS networks.

Published in: Lancet Glob Health. 2019;7(7):e861-e871

Background Improving the quality of hospital antibiotic use is a major goal of WHO’s global action plan to combat antimicrobial resistance. The WHO Essential Medicines List Access, Watch, and Reserve (AWaRe) classification could facilitate simple stewardship interventions that are widely applicable globally. We aimed to present data on patterns of paediatric AWaRe antibiotic use that could be used for local and national stewardship interventions.

Methods 1-day point prevalence survey antibiotic prescription data were combined from two independent global networks: the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children and the Global Point Prevalence Survey on Antimicrobial Consumption and Resistance networks. We included hospital inpatients aged younger than 19 years receiving at least one antibiotic on the day of the survey. The WHO AWaRe classification was used to describe overall antibiotic use as assessed by the variation between use of Access, Watch, and Reserve antibiotics, for neonates and children and for the commonest clinical indications.

Findings Of the 23 572 patients included from 56 countries, 18 305 were children (77·7%) and 5267 were neonates (22·3%). Accessantibiotic use in children ranged from 7·8% (China) to 61·2% (Slovenia) of all antibiotic prescriptions. The use of Watch antibiotics in children was highest in Iran (77·3%) and lowest in Finland (23·0%). In neonates, Access antibiotic use was highest in Singapore (100·0%) and lowest in China (24·2%). Reserve antibiotic use was low in all countries. Major differences in clinical syndrome-specific patterns of AWaRe antibioticuse in lower respiratory tract infection and neonatal sepsis were observed between WHO regions and countries.

Interpretation There is substantial global variation in the proportion of AWaRe antibiotics used in hospitalised neonates and children. The AWaRe classification could potentially be used as a simple traffic light metric of appropriate antibiotic use. Future efforts should focus on developing and evaluating paediatric antibiotic stewardship programmes on the basis of the AWaRe index.

Funding GARPEC was funded by the PENTA Foundation. GARPEC-China data collection was funded by the Sanming Project of Medicine in Shenzhen (SZSM2015120330). bioMérieux provided unrestricted funding support for the Global-PPS.

5

Jun, 2019

Hard to study, hard to treat: putting children at the centre of antibiotic research and development

 

Authors: Balasegaram M, Pécoul B, Gray G, Sharland M, Swaminathan S.

Published in: Lancet Infect Dis. 2019;19(6):573-574

Abstract Newborn babies, infants, and children are substantially affected by antimicrobial resistance. Globally, infectious diseases remain a major cause of morbidity and mortality in children, and an estimated 214 000 newborn babies died from drug-resistant bacterial infections in 2015

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28

May, 2019

R&D for children’s antibiotics – a wake-up call

 

Authors: O’Brien S, Sharland M, Zaoutis T

Published in: AMR CONTROL 2019-2020; online edition

Abstract It is time to prioritize children’s needs in the context of antimicrobial resistance (AMR). Children, especially babies and young infants, are particularly vulnerable to the rise in drug-resistant infection and need treatments that are adapted to their specific needs. Yet, there are almost no clinical trials looking into children’s antibiotics. This lack of prioritization threatens the attainment of the UN Sustainable Development Goals. The Global Antibiotic Research & Development Partnership (GARDP), Penta, St George’s, University of London and global partners are working together to tackle AMR in children. They call on governments, researchers, industry and more – to join them.

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26

Apr, 2019

The use of polymyxins to treat carbapenem resistant infections in neonates and children

 

Authors: Thomas R, Velaphi S, Ellis S, et al.

Published in: Expert Opin Pharmacother. 2019;20(4):415-422. 

Introduction The incidence of healthcare-associated multidrug resistant bacterial infections, particularly due to carbapenem resistant organisms, has been on the rise globally. Among these are the carbapenem resistant Acinetobacter baumannii and Enterobacteriaceae, which have been responsible for numerous outbreaks in neonatal units. The polymyxins (colistin and polymyxin B) are considered to be the last resort antibiotics for treating such infections. However, pharmacokinetic and pharmacodynamic data on the use of polymyxins in neonates and children are very limited, and there are safety concerns.

Areas Covered In this review, the authors summarize the global burden of multidrug resistance, particularly carbapenem resistance, in the neonatal and paediatric population, and the potential wider use of polymyxins in treating these infections.

Expert Opinion Both colistin and polymyxin B have similar efficacy in treating multidrug resistant infections but have safety concerns. However, polymyxin B appears to be a better therapeutic option, with more rapid and higher steady state concentrations achieved compared to colistin and less reported nephrotoxicity. There is virtually no data in neonates and children currently; there is therefore an urgent need for pharmacokinetic and safety trials in these populations to determine the optimal drug and dosing regimens and provide recommendations for their use against carbapenem resistant infections.

26

Apr, 2019

Effects of an antimicrobial stewardship intervention on perioperative antibiotic prophylaxis in pediatrics

 

Authors: Donà D, Luise D, La Pergola E, et al.

Published in: Antimicrob Resist Infect Control. 2019;8:13. 

Purpose This study aims to determine the effectiveness of anAntimicrobial Stewardship Program based on a Clinical Pathway (CP) to improve appropriateness in perioperative antibiotic prophylaxis (PAP).

Materials and Methods This pre-post quasi-experimental study was conducted in a 12 month period (six months before and six months after CP implementation), in a tertiary Pediatric Surgical Centre. All patients from 1 month to 15 years of age receiving one or more surgical procedures were eligible for inclusion. PAP was defined appropriate according to clinical practice guidelines.

Results Seven hundred sixty-six children were included in the study, 394 in pre-intervention and 372 in post-intervention. After CP implementation, there was an increase in appropriate PAP administration, as well as in the selection of the appropriate antibiotic for prophylaxis, both for monotherapy (p = 0.02) and combination therapy (p = 0.004). Even the duration of prophylaxis decreased during the post-intervention period, with an increase of correct PAP discontinuation from 45.1 to 66.7% (p < 0.001). Despite the greater use of narrow-spectrum antibiotic for fewer days, there was no increase in treatment failures (10/394 (2.5%) pre vs 7/372 (1.9%) post, p = 0.54).

Conclusions CPs can be a useful tool to improve the choice of antibiotic and the duration of PAP in pediatric patients.

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