Publications

12

May, 2020

Differences in inducibility of the latent HIV reservoir in perinatal and adult infection

 

Authors: Dhummakupt A, Rubens JH, Andeson T, et al.

Published in: JCI Insight. 2020;5(4)

Abstract The HIV latent reservoir in resting memory CD4+ T cells precludes cure. Therapeutics to reactivate and eliminate this reservoir are in clinical trials in adults, but not yet in pediatric populations. We determined, ex vivo, the inducibility of the latent reservoir in perinatal infection as compared with adult infections using the Tat/rev induced limiting dilution assay (TILDA), in which a single round (12 hours) of CD4+ T cell stimulation with PMA/ionomycin maximally activates T cells and leads to proviral expression with multiply spliced HIV RNA production. Markers of immune activation and exhaustion were measured to assess interactions with inducibility. Although rates of T cell activation with PMA/ionomycin were similar, the latent reservoir in perinatal infection was slower to reactivate and of lower magnitude compared with adult infection, independent of proviral load. An enhanced TILDA with the addition of phytohemagglutin and a duration of 18 hours augmented proviral expression in perinatal but not adult infection. The baseline HLA-DR+CD4+ T cell level was significantly lower in perinatal compared with adult infections, but not correlated with induced reservoir size. These data support the hypothesis that there are differences in kinetics of latency reversal and baseline immune activation in perinatal compared with adult infections, with implications for latency reversal strategies toward reservoir clearance and remission.

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28

Apr, 2020

A comparison of five paediatric dosing guidelines for antibiotics

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Authors: Mathur S, Jackson C, Urus H, Ziarko I, Goodbun M, Hsia Y, Ellis S, Sharland M.

Published in: Bulletin of the World Health Organization, April 2020

Objective To compare dosing guidance in the paediatric formularies of high-income countries and emerging economies for 32 commonly prescribed antibiotics on the World Health Organization’s (WHO’s) 2017 Model List of Essential Medicines for Children.

Methods We identified paediatric antibiotic guidelines that were either widely used internationally or originated in countries in which antibiotic use has increased markedly in recent years (i.e. Brazil, China, India, the Russian Federation and South Africa).

Findings The study analysis considered five leading antibiotic guidelines: (i) the Manual of childhood infections: the blue book; (ii) the BNF (British national formulary) for children; (iii) the Red book®: 2018–2021 report of the committee on infectious diseases; (iv)WHO’s Pocket book of hospital care for children; and (v) Indian national treatment guidelines for antimicrobial use in infectious diseases. There was marked heterogeneity in the recommended dosing (i.e. daily dose, age dosing bands and dose frequency) for most commonly used antibiotics. The rationale for dosing recommendations was generally unclear.

Conclusion The pharmacokinetic, pharmacodynamic and clinical evidence supporting paediatric antibiotic dosing, particularly on total doses and on age or weight dosing bands, needs to be improved. Future research should consider whether the variations in guidance identified stem from different clinical disease patterns, varying levels of antibiotic resistance or drug availability rather than historical preferences. Interested global parties could collaborate with WHO’s Model list of essential medicines antibiotic working group to develop an evidence-based consensus and identify research priorities.

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26

Apr, 2020

Interim pharmacokinetic analysis of a multi-centre randomised open label phase IIb study in neonates to validate the meta-analysis population pharmacokinetic model used to simulate an optimised dosing regimen in neonates and infants aged < 90 days: the NeoVanc trial

 

Authors: L. Hill, E. Jacqz-Aigrain, V. Elie, W. Zhao, M. Clements, M. Turner, I. Lutsar, P. Heath, E. Roilides, S. Walker, M. Sharland

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Vancomycin remains one of the most widely prescribed antibiotics for Gram-positive neonatal late onset sepsis (LOS), however, a consensus on optimal vancomycin dosing and duration is lacking. Robust neonatal clinical pharmacokinetic (PK) data comparing different vancomycin dosing regimens remain sparse. NeoVanc (NCT02790996) is a European, randomised controlled, non-inferiority trial comparing an optimised and standard vancomycin regimen in infants aged ≤90 days with suspected/proven Gram-positive LOS. The optimised regimen was determined through pre-clinical studies including a population PK meta-analysis of individual data from >1600 babies.

Materials/methods: Babies with clinical sepsis (≥3 clinical/laboratory criteria) or confirmed sepsis (Gram-positive blood culture and ≥1 clinical/laboratory criterion) were recruited. Participants were randomised 1:1 to the optimised regimen (vancomycin loading dose (25 mg/kg) followed by 5±1 day course) or a standard regimen (no loading dose;10±2 day vancomycin course). An interim PK analysis was performed; the validation dataset was collected from 8 centres in 5 European countries. Data collected included demographic variables (gestational and postnatal age, birth and current weight), vancomycin admin- istration (dose, time of start and end of infusion, exact sampling time), creatinine concentrations (Jaffe, enzymatic), vancomycin concentrations (ultraperformance liquid chromatography-tandem mass spectrometry).

Results: 68 babies recruited between March 2017 and April 2018 were included in the interim analysis. Gestational age was <29 (n=16), 29–36 (n=22), >35 (n=30) weeks. Median (IQR) birthweight was 1258 (455–4040)g with median weight at randomisation being 1525 (590–4156)g. Median post-menstrual age at randomisation was 33.8(25.1–47) weeks. Median se- rum creatinine was 41.5(8.84–96.36) μmol/L. 240/255 PK and scavenged PK samples were evaluable. Vancomycin concen- trations were used to confirm the reliability of the meta-analysis model where clearance (CL) was dependant on current weight, method used to quantify creatininaemia, renal maturation (RM) and renal function (RF) according to CL= θ6×(CW/1350) θ7×RM×RF×FJaffé-Enzymatic × Frace

Conclusions: External validation with NeoVanc trial PK data confirmed the predictive performance of the model developed fromthe PK meta-analysis.

26

Apr, 2020

An optimised dosing regimen vs. a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in infants less than 90 days: the NeoVanc trial

 

Authors: L. Hill, M. Clements, M. Turner, I. Lutsar, E. Jacqz-Aigrain, P. Heath, E. Roilides, S. Walker, M. Sharland

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Vancomycin remains one of the most widely prescribed antibiotics for Gram-positive neonatal late onset sep- sis (LOS). Robust neonatal clinical outcome data comparing different vancomycin dosing regimens is lacking. NeoVanc (NCT02790996) is a European, multicentre, phase IIb, randomised controlled, non-inferiority trial comparing an optimised and standard vancomycin regimen in infants aged ≤90 days with known/suspected Gram-positive LOS.

Materials/methods: Infants with clinical sepsis (≥3 clinical/laboratory criteria) or confirmed sepsis (Gram-positive blood culture and ≥1 clinical/laboratory criterion) were included. Participants were randomised 1:1 to an optimised regimen (loading dose [25 mg/kg] followed by 5±1 days of 15 mg/kg q12h or q8h dependent on postmenstrual age [PMA] or a standard regimen [10±2 day course at 15 mg/kg q24h, q12h, or q8h dependent on PMA]). The primary endpoint was successful outcome at end of vancomycin therapy and no clinically/microbiologically significant relapse/new infection requiring treatment with anti-staphylococcal antibiotics within 10 days of stopping vancomycin.

Secondary endpoints included safety and pharmacokinetics. ‘Per protocol’ was all participants receiving/not receiving the loading dose as randomised and ≥48h of study vancomycin.

Results: 242 infants were randomised between March 2017 and July 2019 from 22 neonatal intensive care units in 5 European countries. Per-protocol population is presented (183 participants): 55% were male, with a median (IQR) postmenstrual age of 32(29–37) weeks and postnatal age at onset of LOS of 14(8–25) days. Mean weight was 1663g(924g SD) and central lines were present in 115/183(63%) participants at randomisation. 133/183(73%) received antibiotics in the 7 days before randomi- sation. 25/183(14%) had positive blood culture for Gram-positive organisms of interest at randomisation, and 179/183(98%) had ≥3 clinical/laboratory signs on randomisation. 141/183(77%) received vancomycin according to the randomised duration. There were 4 deaths and 4 withdrawals/loss to follow-up prior to TOC.

There were 40 post-randomisation exclusions.

128/179(72%) had a successful primary outcome. 2/165(1%) of all randomised infants had abnormal renal function at short- term follow-up.

Conclusions: NeoVanc is the largest LOS vancomycin trial to provide clinical efficacy and safety outcome data associated with alternative dosing strategies. Preliminary results are included (some events not yet adjudicated): final results comparing randomised groups and outcomes will be presented.

26

Apr, 2020

Respiratory pathogens detected in children with community-acquired sepsis-like syndrome in 6 European countries

 

Authors: V. Matheeussen, K. Loens, K. Jacobs, P. Horby, H. Goossens, M. Kohns Vasconcelos, M. Sharland, M. De Jong, M. P. G. Koopmans, P. Fraaij, M. Ieven

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: The management of infants admitted to hospital with sepsis-like syndrome (SLS) without apparent focus remains challenging. There is growing evidence indicating that this clinical picture is triggered by viral pathogens, like adenovirus, enterovirus or parechovirus with a possible respiratory point of entry. We aimed to identify an association in the presence of respiratory pathogens in nasopharyngeal swabs between children with SLS and controls.

Materials/methods: A total of 102 children (≤ 6 months old) admitted to hospital with community-acquired SLS and 308 asymptomatic controls (0-6 years old) were enrolled in a prospective case-control study as part of the MERMAIDS Trial (Multi-centre EuRopean study of MAjor Infectious Disease Syndromes, www.prepare-europe.eu) in 12 hospitals in 6 European countries. The Fast Track Diagnostics Respiratory pathogens 21 plus real-time PCR assay was used to determine the presence of respira- tory pathogens in nasopharyngeal swabs

Results: The most prevalent respiratory viral targets detected in the nasopharyngeal swabs of SLS patients were rhinovirus (28%), RSV A/B (9%), enterovirus (8%) and parainfluenzavirus (5%). All other viruses (influenzavirus, coronavirus, parechovirus, human metapneumovirus, adenovirus and bocavirus) were detected in <5%. Also bacterial targets like Staphylococcus aureus and Streptococcus pneumoniae, possibly colonizers, were often detected, both in 30% of the samples. Neither Myco- plasma pneumoniae, Chlamydophila pneumoniae nor Haemophilus influenzae type B were present. Compared to the control group, enterovirus and RSV A/B were detected more frequently in the SLS patients (8 versus 2% for enterovirus, p=0.01 and 9 versus 2% for RSV A/B, p=0.01). Adeno- and bocavirus were found more often in the control group (7 versus 1% for both viruses, p=0.02). No respiratory target was detected in 25% of the SLS samples.

Conclusions: Most (75%) of the nasopharyngeal samples from SLS patients contained one or more viral or bacterial respiratory targets. In our study, the role of influenza viruses was relatively limited. The possible role of enterovirus and RSV A/B in the pathophysiology of SLS should be further elucidated.

26

Apr, 2020

Aetiology and outcome of children hospitalised for acute respiratory tract infections in Europe: findings from a multi-country combined case-control and cohort study

 

Authors: M. Kohns Vasconcelos; on behalf of the PED-MERMAIDS Study Group

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Recently, major aetiology and outcome studies on paediatric acute respiratory tract infections (ARI) have been reported from LMICs. In contrast, studies using standardised protocols across Europe are lacking.

Materials/methods: The EU-funded Paediatric Multi-centre EuRopean study of MAjor Infectious Disease Syndromes (PED-MER- MAIDS) enrolled children under 5 years hospitalised for ARI and well controls across 11 EU countries. Information on symptoms, course of disease and clinical management was collected prospectively. Admission day nasopharyngeal swabs were analysed for influenza, parainfluenza, rhinovirus, coronavirus, metapneumovirus, bocavirus, respiratory syncytial virus (RSV), parechovirus, enterovirus and adenovirus and Streptococcus pneumoniae (Sp), Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae and Staphyloccous aureus.

Results: 353 ARI children, median age 1.13 years (IQR:0.44-2.56) and 352 controls, median age 1.76 years (IQR:0.96-3.73) were enrolled over 21⁄2 years. Swabs were analysed from 327 ARI children and 302 controls. No potential pathogen was detect- ed in 4.6% of ARI, only bacteria in 10.9%, only viruses in 33.9% and both bacterial and viral potential pathogens in 51.4%. Codetection of multiple (up to 4) viruses occurred in 31.2% of ARI and codetection of multiple bacteria in 16.9%. The most commonly detected pathogens are listed in table 1. Respiratory pathogens were detected in 62.8% of controls. Of the frequently detected pathogens, only RSV and influenza were strongly associated with hospitalisation for ARI (table 1). The population attributable fractions (PAF) were 33.6% for RSV and 18.0% for Sp. 209 ARI children (60.6%) received antibiotics, but this was not associated with detection of bacterial pathogens in study samples (OR=0.78, 95%-CI:0.48-1.28). Length of stay in hospital ranged between 0 and 49 days (median 3, IQR:2-5) and no child in the study died after admission for ARI.

Conclusions: Similarly to LMIC studies, RSV had the highest PAF for ARI hospitalisation in Europe, but with considerably lower mortality.

26

Apr, 2020

Application of WISCA (Weighted Incidence Syndromic Combination Antibiogram) to guide empiric therapy in oncological paediatric patients with febrile neutropenia

 

Authors: E. Barbieri, D. Bottigliengo, P. Costenaro, A. Marzollo, M. Petris, M. Pierobon, G. Biddeci, C. Giaquinto, A. Biffi, D. Donà

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Febrile neutropenia (FN) is an acute potentially life-threatening oncological complication which should be treated promptly with antibiotics. With the spread of antibiotic resistance, the choice of an empiric therapy is driven by local epidemiology usually described by cumulative pathogens susceptibilities antibiograms. The WISCA attempts to address the unmet need for syndRome-specific local susceptibility data to guide empirical prescribing, providing estimates for different treatment reg- imens as a weighted average of pathogens susceptibilities. Our aim was to create a WISCA model to inform empirical antibiotic regimens selection for FN in children.

Materials/methods: We included all non-duplicate blood cultures from patients aged 0-17 years with FN admitted to the paediatric oncology/hematology wards in Padua from January 2016 to August 2019. WISCA was developed by estimating the sensibility of 29 antibiotic regimens with a Bayesian probabilities distribution. Moreover, we created a second model with 57 blood cultures excluding potentially contaminant bacteria.

Results: We collected 69 blood cultures, 41 Gram- and 28 Gram+ bacteria. Considering most used combinations such as piperacillin-tazobactam + amikacin the median sensibility was 58% (BUI 33-84%) that increased to 70% (BUI 42-85%) in the second model. When adding a glycopeptide to this combination the median sensibility increased dramatically (Figure 1). The highest median sensibility for a beta-lactam + aminoglycoside combination was 66% (BUI 37-86%; meropenem + amikacin) in the first model and 75% (BUI 46-85%) in the second model; the lowest was 42% (BUI 26-75%; ceftriaxone + amikacin) and 50% (BUI 32- 76%) respectively. Overall mono-treatments had median sensibility lower than 50%, exept meropenem (65%; BUI 35-85) and gentamycin (60%; BUI 33-84%), but in the second model most median sensibilities increased above 50%. WISCA model with median sensibilities and uncertainty intervals is shown in Figure 1.

Conclusions: WISCAs represent a valid tool to maximize the clinical utility of microbiological surveillance data supporting appropriate empirical antibiotic treatment selection, while contributing to conservation of broad-spectrum antibiotics.

26

Apr, 2020

Antibiotic treatment for paediatric outpatients with community-acquired pneumonia: findings from 10 years of prescribing habits in Italy

 

Authors: P. Costenaro, A. Cantarutti, E. Barbieri, A. Scamarcia, A. Oletto, P. Sacerdoti, R. Lundin, L. Cantarutti, C. Giaquinto, D. Dona’

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Despite national and international efforts to promote appropriate antibiotic prescribing, Italian paediatric antimicrobial prescription rates are among the highest in Europe, with an overuse of broad-spectrum antibiotics. Community-acquired pneumonia (CAP) is one of the most common infections in pediatrics, and a main cause of antibiotic prescriptions. Aim of this study is to describe the first-line treatment approach for CAP at primary care level in Italian children.

Materials/methods: Retrospective observational study conducted among children with CAP enrolled in Pedianet, a network of community-based paediatricians from 12 Italian regions (http://www.pedianet.it). Children (3 months-14 years of age) with at least one reported CAP from 01/01/2009 to 31/12/2018 were included, if treated with antibiotics (ABT). CAP was defined according to ICD-9-CM (codes 485, 486, 482.9, 481), a new episode was recorded if occurring >=30 days after previous CAP. We defined “narrow-spectrum” (NS) ABT if treatment was amoxicillin and “broad-spectrum” (BS) if amoxicillin/clavulanic acid, cephalosporins or any combination ABT. Chi-squared and Fisher’s test were used for categorical or continuous variables. Crude and adjusted logistic regression for the ODDS of receiving a NS-ABT were conducted (all episodes of CAP and per patient). A p-value <0,05 was considered statistically significant.

Results: Among 9691 CAP, 7260 episodes from 6409 children followed by 147 pediatricians were included. The 16.7% of CAP (95% C.I.15,9%-17,6%) received a narrow-spectrum ABT while 53.3% (95% C.I.52%-54,4%) received a broad-spectrum ABT and 30% (95% C.I. 28,9%-31,1%) a macrolide. Within 10 years, an increasing trend of NS-ABT prescription was observed (p<0.001, Chi-square test for linear trend). Factors independently associated with reduced ODDS of receiving a NS-ABT compared to BS- ABT including macrolides were being older than 5 years (OR 0.45, 95% C.I.0.39 – 0.52), living in Center/South of Italy (OR 0.13, 95% C.I.0.10 – 0.16) and being exposed to ABT 3 months before (OR 0.61, 95% C.I. 0.53 – 0.70). These findings were confirmed comparing NS-ABT versus BS-ABT excluding macrolides (n=5079) and when adjusted analysis was limited to index CAP.

Conclusions: Our findings provide an alarming overview of the Italian prescribing habits, reporting a very limited use of NS-ABT for children with CAP.

21

Apr, 2020

An optimised dosing regimen versus a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in neonates and infants aged less than 90 days (NeoVanc): study protocol for a randomised controlled trial

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Authors: Hill LF, Turner MA, Lutsar I, et al; NeoVanc Consortium.

Published in: Trials. 2020;21(1):329

Background Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late–onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin‘s continued efficacy.

Methods NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy.

Discussion Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS.

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17

Apr, 2020

Genomic and epidemiological surveillance of Zika virus in the Amazon region

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Authors: Giovanetti M, Faria NR, Lourenco J, et al.

Published in:  Cell Rep. 2020;30(7):2275-2283

Abstract Zika virus (ZIKV) has caused an explosive epidemic linked to severe clinical outcomes in the Americas. As of June 2018, 4,929 ZIKV suspected infections and 46 congenital syndrome cases had been reported in Manaus, Amazonas, Brazil. Although Manaus is a key demographic hub in the Amazon region, little is known about the ZIKV epidemic there, in terms of both transmission and viral genetic diversity. Using portable virus genome sequencing, we generated 59 ZIKV genomes in Manaus. Phylogenetic analyses indi- cated multiple introductions of ZIKV from northeastern Brazil to Manaus. Spatial genomic analysis of virus movement among six areas in Manaus suggested that populous northern neighborhoods acted as sources of virus transmission to other neighborhoods. Our study revealed how the ZIKV epidemic was ignited and maintained within the largest urban metropolis in the Amazon. These results might contribute to improving the public health response to outbreaks in Brazil.

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