Publications

16

Oct, 2019

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

 

Authors: Li GBielicki JAAhmed 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.

1

Oct, 2019

Experimental infection of pregnant female sheep with Zika Virus during early gestation

 

Authors: Schwarz ER, Pozor MA, Pu R, et al.

Published in: Viruses. 2019;11(9)

Abstract Zika virus (ZIKV) is a vertically and sexually transmissible virus resulting in severe congenital malformation. The goal of this study was to develop an ovine model of ZIKV infection. Between 28–35 days gestation (DG), four pregnant animals were infected with two doses of 6 × 106 PFU of ZIKV; four control animals received PBS. Animals were evaluated for 45 days (D) post-infection (PI) and necropsies were performed. Viral RNA was detected in infected ewe peripheral blood mononuclear cells (PBMC) during the first week PI; however, all fluids and tissues were negative upon culture. Anti-ZIKV IgM (1:400) and neutralizing antibodies were detected in all infected animals. Clinical disease, virus, or ZIKV antibodies were not detected in control ewes. After two weeks PI, fetal loss occurred in two infected animals, and at necropsy, three infected animals had placental petechiation and ecchymosis and one had hydramnion. Fetal morphometrics revealed smaller cranial circumference to crown-rump length ratios (p < 0.001) and relative brain weights (p = 0.038) in fetuses of infected animals compared with control fetuses. Immunophenotyping indicated an increase in B cells (p = 0.012) in infected sheep. Additionally, in vitro experiments using both adult and fetal cell lines demonstrated that ovine cells are highly permissive to ZIKV infection. In conclusion, ZIKV infection of pregnant sheep results in a change in fetal growth and gestational outcomes.

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1

Oct, 2019

Pregnancy outcomes after maternal Zika virus infection in a non-endemic region: prospective cohort study

 

Authors: Sulleiro E, Rando A, Alejo I, et al.

Published in: Clin Microbiol Infect. 2019;25(5):633.e5-633.e9

Objectives The aim was to describe pregnancy outcomes after Zika virus (ZIKV) infection in a non-endemic region.

Methods According to the Spanish protocol issued after the ZIKV outbreak in Brazil in 2015, all pregnant women who had travelled to high-burden countries were screened for ZIKV. Serological and molecular tests were used to identify ZIKV-infected pregnant women. They were classified as confirmed ZIKV infection when reverse transcription (RT) PCR tested positive, or probable ZIKV infection when ZIKV immunoglobulin M and/or immunoglobulin G and ZIKV plaque reduction neutralization tests were positive. Women found positive using molecular or serological tests were prospectively followed-up with ultrasound scans and neurosonograms on a monthly basis until delivery; magnetic resonance imaging and amniotic fluid testing were performed after signed informed consent. Samples of placenta, and fetal and neonatal tissues were obtained.

Results Seventy-two pregnant women tested positive for ZIKV infection: ten were confirmed by RT-PCR, and 62 were probable cases based on serological tests. The prevalence of adverse perinatal outcomes was 33.3% (three out of nine, 95% CI 12.1-64.6%): two cases of congenital ZIKV syndrome (CZS) and one miscarriage, all born to women infected in the first trimester of gestation. All ZIKV-confirmed women had persistent viraemias beyond 2 weeks (median 61.50 days; IQR 35.50-80.75). Amniotic fluid testing was only positive in the two fetuses with anomalies.

Conclusions The prevalence of perinatal adverse outcomes for women with ZIKV-confirmed infection was 33.3%. Amniocentesis for ZIKV RT-PCR is recommended when fetal abnormalities are found. Intensive prenatal and postnatal follow-up of ZIKV-infected pregnancies is advised in confirmed cases.

1

Oct, 2019

Screening for Zika virus infection in 1057 potentially exposed pregnant women, Catalonia (northeastern Spain)

 

Authors: Sulleiro E, Rando A, Alejo I, et al.

Published in: Travel Med Infect Dis. 2019;29:69-71

No abstract available

1

Oct, 2019

Development of secondary microcephaly after delivery: possible consequence of mother-baby transmission of Zika Virus in breast milk

 

Authors: Siqueira Mello A, Pascalicchio Bertozzi APA, Rodrigues MMD, et al.

Published in: Am J Case Rep. 2019 May 21;20:723-725

Background The Zika virus is an arbovirus that has as main source of transmission the bite of infected insects of the genus Aedes and has been associated with cases of congenital malformation and microcephaly in neonates. However, other sources of transmission have been identified since the emergence of this virus in the world population, such as vertical transmission by semen and possibly other body fluids such as vaginal secretion and breast milk.
Case Report An infant, born to a mother whose previous delivery was a baby with severe microcephaly, was normal and was negative for Zika virus at birth but developed secondary microcephaly 1 month later, that persisted. The baby was exclusively breast-fed and Zika virus was present in the mother’s milk.
Conclusions We report the detection of Zika virus exclusively in the breast milk of a woman after her second delivery of an infant, who later developed microcephaly. This case is consistent with possible vertical transmission.

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1

Oct, 2019

Detection of Zika virus in paired urine and amniotic fluid samples from symptomatic and asymptomatic women and their babies during a disease outbreak: association with neurological symptoms in newborns

 

Authors: Vedovello D, Witkin SS, Silva ACB, et al.

Published in: J Neurovirol 2019 Sep 9. doi: 10.1007/s13365-019-00797-0

Abstract Paired maternal and newborn urine and amniotic fluid from 138 subjects collected during a Zika virus (ZIKV) outbreak was analyzed for ZIKV by gene amplification (RT-qPCR), and the findings were correlated with clinical symptoms and neurological anomalies in the babies. ZIKV was detected in 1 of 9 symptomatic women (11.1%) and in 19 of 129 asymptomatic women (14.7%). Neurological manifestations were present in 19 babies (13.7%), 10 of 20 (50%) positive and 9 of 119 (7.6%) negative (p < 0.001) for ZIKV. Twelve (8.6%) urines collected during gestation were ZIKV-positive; only 2 remained positive for ZIKV postpartum. Six (4.1%) newborn urines collected within 1 day of delivery were ZIKV-positive cases. In 3 of these cases, ZIKV was detected in mother’s urine pre- and postpartum and in both mother’s urine and babies’ urine. Four of the amniotic fluid samples (2.9%) were ZIKV-positive. Among ZIKV-negative babies with neurological sequel, 87.5% were female; in contrast, 72.7% ZIKV-positive babies with neurological abnormalities were male (p = 0.019). We conclude that during a ZIKV outbreak, clinical symptoms and ZIKV detection in biological fluids are poor predictors of infection and adverse neurologic sequel in newborns.

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27

Sep, 2019

The challenge of the laboratory diagnosis in a confirmed congenital Zika virus syndrome in utero: a case report

 

Authors: Sulleiro E, Frick MA, Rodó C, et al.

Published in: Medicine (Baltimore). 2019;98(20):e15532

Introduction Zika virus (ZIKV) has caused one of the most challenging global infectious epidemics in recent years because of its causal association with severe microcephaly and other congenital malformations. The diagnosis of viral infections usually relies on the detection of virus proteins or genetic material in clinical samples as well as on the infected host immune responses. Serial serologic testing is required for the diagnosis of congenital infection when diagnostic molecular biology is not possible.

Patient concerns A 2-year-old girl, born to a mother with confirmed ZIKV infection during pregnancy, with a confirmed ZIKV infection in utero, showed at birth a severe microcephaly and clinical characteristics of fetal brain disruption sequence compatible with a congenital ZIKV syndrome (CZS).

Diagnosis ZIKV-RNA and ZIKV-IgM serological response performed at birth and during the follow-up time tested always negative. Serial serologic ZIKV-IgG tests were performed to assess the laboratory ZIKV diagnosis, ZIKV-IgG seroreversion was observed at 21 months of age. ZIKV diagnosis of this baby had to be relied on her clinical and radiological characteristics that were compatible with a CZS.

Interventions The patient was followed-up as per protocol at approximately 1, 4, 9, 12, 18-21, and 24 months of age. Neurological, radiological, audiological, and ophthalmological assessment were performed during this period of time. Prompt rehabilitation was initiated to prevent potential adverse long-term neurological outcomes.

Outcomes The growth of this girl showed a great restriction at 24 months of age with a weight of 8.5 kg (-2.5 z-score) and a head circumference of 40.5 cm (-4.8 z-score). She also had a great neurodevelopmental delay at the time of this report.

Conclusions We presume that as a consequence of prenatal ZIKV infection, the fetal brain and other organs are damaged before birth through direct injury. Following this, active infection ends during intrauterine life, and as a consequence the immune system of the infant is unable to build up a consistent immune response thereafter. Further understanding of the mechanisms taking part in the pathogenesis of ZIKV congenital infection is needed. This finding might change our paradigm regarding serological response in the ZIKV congenital infection.

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24

Sep, 2019

Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: the GABA-1 trial-a study protocol

 

Authors: Kaguelidou F, Le Roux E, Mangiarini L, et al.; GAPP consortium

Published in: BMJ Open. 2019;9(2):e023296

Introduction Gabapentin is currently used ‘off-label’ in children and adolescents with chronic neuropathic pain, and reliable evidence of its effects and optimal dosing are lacking.

Objectives The GABA-1 trial aims to compare the efficacy and safety of gabapentin liquid formulation relative to tramadol and to explore the pharmacokinetics of both drugs in the treatment of chronic, neuropathic or mixed pain in the paediatric population.

Methods and analysis The trial is a multicentre, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial. Participants aged from 3 months to <18 years of age with moderate to severe (≥4/10 in age-appropriate pain scales) chronic neuropathic or mixed pain will be recruited in 14 clinical sites in eight European countries. A total of 94 subjects will be randomised to receive gabapentin and tramadol placebo or tramadol and gabapentin placebo throughout 16–19 weeks (including 3 weeks of titration [optimisation period], 12 weeks of treatment at a stable dose [maintenance period] and 1–4 weeks of tapering [discontinuation period]). The primary objective is to assess the efficacy of gabapentin relative to tramadol for the treatment of moderate to severe chronic neuropathic or mixed pain by comparing the difference in average pain scores (assessed by age-appropriate pain scales) between intervention arms after 15 weeks of treatment. Secondary objectives include the assessment of the safety, quality of life and global satisfaction with treatment and the description of the pharmacokinetic–pharmacodynamic relationship of gabapentin liquid formulation and tramadol oral drops to validate the recommended paediatric doses. Only rescue pain medication by paracetamol and/or ibuprofen is allowed during the trial.

Ethics and dissemination Ethic approval was obtained in the eight participating countries. Results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.

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