Publications

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

Islands as Hotspots for Emerging Mosquito-Borne Viruses: A One-Health Perspective

 

Authors: Mavian C, Dulcey M, Munoz O, Salemi M, Vittor AY, Capua I.

Published in: JViruses. 2019; 11(1):11

Abstract During the past ten years, an increasing number of arbovirus outbreaks have affected tropical islands worldwide. We examined the available literature in peer-reviewed journals, from the second half of the 20th century until 2018, with the aim of gathering an overall picture of the emergence of arboviruses in these islands. In addition, we included information on environmental and social drivers specific to island setting that can facilitate the emergence of outbreaks. Within the context of the One Health approach, our review highlights how the emergence of arboviruses in tropical islands is linked to the complex interplay between their unique ecological settings and to the recent changes in local and global sociodemographic patterns. We also advocate for greater coordination between stakeholders in developing novel prevention and mitigation approaches for an intractable problem.

 

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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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29

Apr, 2019

Immunoglobulin-like Domain of HsFcμR as a Capture Molecule for Detection of Crimean-Congo Hemorrhagic Fever Virus- and Zika Virus-Specific IgM Antibodies

 

Authors: Rackow A, Ehmen C, von Possel R, et al.

Published in: Clin Chem. 2019;65(3):451-461.

Background The cellular surface molecule HsTOSO/FAIM3/HsFcμR has been identified as an IgM-specific Fc receptor expressed on lymphocytes. Here, we show that its extracellular immunoglobulin-like domain (HsFcμR-Igl) specifically binds to IgM/antigen immune complexes (ICs) and exploit this property for the development of novel detection systems for IgM antibodies directed against Crimean-Congo hemorrhagic fever virus (CCHFV) and Zika virus (ZIKV).

Methods His-tagged HsFcμR-Igl was expressed in Escherichia coli and purified by affinity chromatography, oxidative refolding, and size-exclusion chromatography. Specific binding of HsFcμR-Igl to IgM/antigen ICs was confirmed, and 2 prototypic ELISAs for the detection of anti-CCHFV and anti-ZIKV IgM antibodies were developed. Thereby, patient sera and virus-specific recombinant antigens directly labeled with horseradish peroxidase (HRP) were coincubated on HsFcμR-Igl-coated ELISA plates. Bound ICs were quantified by measuring turnover of a chromogenic HRP substrate.

Results Assay validation was performed using paired serum samples from 15 Kosovar patients with a PCR-confirmed CCHFV infection and 28 Brazilian patients with a PCR-confirmed ZIKV infection, along with a panel of a priori CCHFV/ZIKV-IgM-negative serum samples. Both ELISAs were highly reproducible. Sensitivity and specificity were comparable with or even exceeded in-house gold standard testing and commercial kits. Furthermore, latex beads coated with HsFcμR-Igl aggregated upon coincubation with an IgM-positive serum and HRP-labeled antigen but not with either component alone, revealing a potential for use of HsFcμR-Igl as a capture molecule in aggregation-based rapid tests.

Conclusions Recombinant HsFcμR-Igl is a versatile capture molecule for IgM/antigen ICs of human and animal origin and can be applied for the development of both plate- and bead-based serological tests.

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29

Apr, 2019

Incidence of switching to second-line antiretroviral therapy and associated factors in children with HIV: an international cohort collaboration

 

Authors: Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration.

Published in: Lancet HIV. 2019;6(2):e105-e115.

Background Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration.

Methods In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks.

Findings At the data cutoff of Sept 16, 2015, 182 747 children with HIV were included in the CIPHER dataset, of whom 93 351 were eligible, with 83 984 (90·0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3·9 years (IQR 1·6–6·9) and 82 885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9–52). 3883 (4·2%) patients switched to second-line ART after a median of 35 months (IQR 20–57) of ART. The cumulative incidence of switching at 3 years was 3·1% (95% CI 3·0–3·2), but this estimate varied widely depending on the cohort monitoring strategy, from 6·8% (6·5–7·2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0·8% (0·6–1·0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p<0·0001). Cohort-level factors that increased the likelihood of switching were higher-income country (p=0·0017) and routine or targeted monitoring of CD4 and viral load (p<0·0001), which was associated with a 166% increase in likelihood of switching compared with CD4 only monitoring (subdistributional hazard ratio 2·66, 95% CI 2·22–3·19).

Interpretation Our global paediatric analysis found wide variations in the incidence of switching to second-line ART across monitoring strategies. These findings suggest the scale-up of viral load monitoring would probably increase demand for paediatric second-line ART formulations.

29

Apr, 2019

Severe haematologic toxicity is rare in high risk HIV-exposed infants receiving combination neonatal prophylaxis.

 

Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord

Published in: HIV Med. 2019;20(5):291-307

Objectives Combination neonatal prophylaxis (CNP) is recommended in high‐risk situations for the prevention of mother‐to‐child HIV transmission, although data on its safety are limited. The aim of the study was to identify whether neonatal prophylaxis (NP) type is associated with the risk of severe anaemia or neutropaenia.

Methods An individual patient data meta‐analysis was conducted within six European cohorts, in infants at high risk for acquiring HIV infection. Adjusted logistic regression models were used to assess the risk of National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) grade 3–4 anaemia/neutropaenia at ages 0–6 months. Mixture models of haemoglobin (Hb) level and log10‐transformed neutrophil count (NC) were used to explore associations with NP type at ages 0–18 months.

Results Of 1836 infants, 25% were preterm, 1149 (63%) had antenatal combination antiretroviral therapy (cART) exposure and 395 (22%) received NP (125 received CNP with three drugs). Overall, 117 (6.7%) infants had grade 3–4 anaemia at age 0–6 months and 140 (9.1%) had grade 3–4 neutropaenia. The presence of grade 3–4 anaemia or neutropaenia was not associated with NP type [adjusted odds ratio (aOR) 1.04 for one‐drug NP and 1.60 for three‐drug NP versus two‐drug NP (P = 0.879 and P = 0.277, respectively) for anaemia; aOR 1.33 for one‐drug NP and 1.98 for three‐drug NP versus two‐drug NP (=0.330 and =0.113, respectively) for neutropaenia], but was associated with preterm delivery. Overall, 7746 Hb and NC results were available for 1836 infants up to age 18 months; no significant differences in predicted Hb level or NC were apparent by NP type.

Conclusions A small proportion of infants experienced grade 3–4 haematological adverse events; risk of anaemia or netropenia was not associated with type of NP.

29

Apr, 2019

Prevalence and clinical outcomes of poor immune response despite virologically suppressive antiretroviral therapy among children and adolescents with HIV in Europe and Thailand: cohort study

 

Authors: Collins IJ; European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord

Published in: Clin Infect Dis. 2019; 28. pii: ciz253. doi: 10.1093/cid/ciz253. [Epub ahead of print]

Background In HIV-positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children on suppressive ART.

Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children aged<18 years at ART initiation, with sustained viral suppression (VS) (≤400copies/mL) for ≥1 year were included. The prevalence of PIR (defined as WHO advanced/severe immunosuppression for age: CD4%<30% in children aged<12 months, CD4%<25% in 12-35 months, CD4%<20% in 36-59 months; CD4%<15%/CD4<350 cells/mm3 in ≥5-years) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of AIDS or death on suppressive ART were calculated by PIR status.

Results Of 2318 children included, median age was 6.4 [IQR, 2.1, 10.4] years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis-B coinfection and residing in Thailand (all p≤0.03). Rates of AIDS/death (95% CI) per 100,000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92), p<0.001.

Conclusions One in eight children in our cohort experienced PIR despite sustained viral suppression. While the overall rate of AIDS/death was low, children with PIR had four-fold increase in risk of event as compared to immune responders.

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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