Dec, 2021

Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial


Authors: Hill L.F, Clements M.N, Turner M.A, Donà D, Lutsar I, Jacqz-Aigrain E, Heath P.T, Roilides E, Rawcliffe L, Alonso-Diaz C, Baraldi E, Dotta A, Ilmoja M, Mahaveer A, Metsvaht T, Mitsiakos G,  Papaevangelou V, Sarafidis K, Walker A.S, Sharland M, on behalf of the NeoVanc Consortium

Published in: The Lancet


Jul, 2021

Global estimates of the relative pediatric consumption and cost of oral amoxicillin and amoxicillin plus clavulanic acid


Authors: G. A. Levine, M. Sharland, S. Ellis, Y. Ferrisse, C. Loze, Y. Hsia, G. Fink, J. Bielicki; for the PediCAP project

Published in: ECCMID 2021



Background: Amoxicillin and co-amoxiclav are commonly used antibiotics for community-acquired infections in young children. Both are classified as Access antibiotics for pediatric respiratory infections in the WHO EMLc. Despite higher cost, robust data to support the additional clinical benefit of co-amoxiclav in primary care settings are lacking. Relative consumption and their economic implications globally are unknown.

Materials/Methods: We estimated consumption and costs of oral amoxicillin and co-amoxiclav for young children and identified variations across countries. 2015 IQVIA-MIDAS antibiotic wholesale data for 75 low-, lower-middle-, upper-middle- and high-income countries/regions were used to determine sales volume of all child-appropriate formulations (CAF). Value was estimated by applying 2015 median global buyer prices from the International Medical Products Price Guide. We estimated value and consumption in standard units (SU) (single tablet/capsule solid or 5 mL liquid preparation) per child-year for each country using United Nations Population data annual population estimates. Cost and consumption estimates for each World Bank income group were applied to the size of the pediatric population not represented in IQVIA to estimate total global consumption and costs. We modelled cost savings compared with 2015 observed estimates under different plausible scenarios.

Results: CAFs of amoxicillin and co-amoxiclav had estimated global sales values of 171 million and 540 million USD in 2015, respectively. Co-amoxiclav accounted for 45.8% of consumption and 75.5% of sales value. Co-amoxiclav consumption ranged from 3.3% (Norway) to 99.7% (Kuwait) of the two antibiotics. The median consumption was 11.6 SUs of amoxicillin (IQR 3.5- 20.5) and 8.2 SUs of co-amoxiclav per child-year (IQR: 3.2, 16.0). 71 million USD (10% reduction) could be saved if all amoxicillin consumption was in solid rather than liquid formulations. Targeting co-amoxiclav use to a maximum of 10% of combined use would save approximately 219 million USD (38% reduction).

Conclusions: Co-amoxiclav use is very common in some countries and accounts for a disproportionate fraction of cost, relative to consumption. Estimates represent wholesale purchases specifically and are only a fraction of total cost and consumption. Large efficiency gains seem feasible by encouraging amoxicillin for treating non-severe infections and limiting co-amoxiclav use to target severe infections.

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Jan, 2021

Harmonising regulatory approval for antibiotics in children


Authors: Phoebe C M Williams, John Bradley, Emmanuel Roilides, Linus Olson, Sheldon Kaplan, Irja Lutsar, Carlo Giaquinto, Daniel K Benjamin, Mike Sharland

Published in: The Lancet

Introduction: Antimicrobial resistance represents a substantial threat to the Sustainable Development Goals (SDGs), with a large impact on the health of children worldwide. However, very few paediatric trials for new antibiotics have been done to inform the optimal treatment of multidrug-resistant infections in children.

The current drug regulatory framework has evolved from a system that rightly aimed to protect children, yet remains governed by interpretation of laws established in response to historical incidents involving agents that caused harm. This approach, particularly for medicines from well established classes with a long experience of safe use in children (such as β-lactam penicillins), now unnecessarily complicates the process of paediatric antibiotic development, and is one of the many barriers to children with multidrug-resistant infections being appropriately treated with licensed drugs.




Jul, 2020

Global sales of oral antibiotics formulated for children

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Authors: Li G, Jackson C, Bielicki J, Ellis S, Hsiac Y, Sharland M

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

Objective To investigate international consumption patterns of child-appropriate oral formulations of antibiotics by formulation type, with a focus on dispersible tablets, using data from a global sales database.

Methods Antibiotic sales data for 2015 covering 74 countries and regional country groups were obtained from the MIDAS® pharmaceutical sales database, which includes samples of pharmacy wholesalers and retailers. The focus was on sales of child-appropriate oral formulations of Access antibiotics in the 2017 World Health Organization’s WHO Model list of essential medicines for children. Sales volumes are expressed using a standard unit (i.e. one tablet, capsule, ampoule or vial or 5 mL of liquid). Sales were analysed by antibiotic, WHO region and antibiotic formulation.

Findings Globally, 17.7 billion standard units of child-appropriate oral antibiotic formulations were sold in 2015, representing 24% of total antibiotic sales of 74.4 billion units (both oral and parenteral) in the database. The top five child-appropriate Access antibiotics by sales volume were amoxicillin, amoxicillin with clavulanic acid, trimethoprim–sulfamethoxazole, cefalexin and ampicillin. The proportion of the top five sold for use as a syrup varied between 42% and 99%. Dispersible tablets represented only 22% of all child-appropriate oral formulation sales and made up only 15% of sales of 10 selected Access antibiotics on the model list for children.

Conclusion Globally most child-appropriate oral antibiotics were not sold as dispersible tablets in 2015, as recommended by WHO. There is a clear need for novel solid forms of antibiotics suitable for use in children.



Apr, 2020

A comparison of five paediatric dosing guidelines for antibiotics


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.



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.


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.


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.


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 ( 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.


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