Improving antibiotic prescribing for children in the resource-poor setting.

Antibiotics are a critically important part of paediatric medical care in low- and middle-income countries (LMICs), where infectious diseases are the leading cause of child mortality. The World Health Organization estimates that >50% of all medicines are prescribed, dispensed or sold inappropriately and that half of all patients do not take their medicines correctly. Given the rising prevalence of antimicrobial resistance globally, inappropriate antibiotic use is of international concern, and countries struggle to implement basic policies promoting rational antibiotic use. Many barriers to rational paediatric prescribing in LMICs persist. The World Health Organization initiatives, such as 'Make medicines child size', the Model List of Essential Medicines for Children and the Model Formulary for Children, have been significant steps forward. Continued strategies to improve access to appropriate drugs and formulations, in conjunction with improved evidence-based clinical guidelines and dosing recommendations, are essential to the success of such initiatives on both a national and an international level. This paper provides an overview of these issues and considers future developments that may improve LMIC antibiotic prescribing

What do I need to know about aminoglycoside antibiotics?

The aminoglycosides are broad-spectrum, bactericidal antibiotics that are commonly prescribed for children, primarily for infections caused by Gram-negative pathogens. The aminoglycosides include gentamicin, amikacin, tobramycin, neomycin, and streptomycin. Gentamicin is the most commonly used antibiotic in UK neonatal units. Aminoglycosides are polar drugs, with poor gastrointestinal absorption, so intravenous or intramuscular administration is needed. They are excreted renally. Aminoglycosides are concentration-dependent antibiotics, meaning that the ratio of the peak concentration to the minimum inhibitory concentration of the pathogen is the pharmacokinetic-pharmacodynamic index best linked to their antimicrobial activity and clinical efficacy. However, due to their narrow therapeutic index, the patient’s renal function should be monitored to avoid toxicity, and therapeutic drug monitoring is often required. Here we provide a review of aminoglycosides, with a particular focus on gentamicin, considering their pharmacokinetics and pharmacodynamics, and also practical issues associated with prescribing these drugs in a paediatric clinical setting

What do I need to know about penicillin antibiotics?

The penicillins remain the class of antibiotics most commonly prescribed to children worldwide. In an era when the risks posed by antimicrobial resistance are growing, an understanding of antibiotic pharmacology and how to apply these principles in clinical practice is increasingly important. This paper provides an overview of the pharmacology of penicillins, focusing on those aspects of pharmacokinetics, pharmacodynamics and toxicity that are clinically relevant in paediatric prescribing. Penicillin allergy is frequently reported but a detailed history of suspected adverse reactions is essential to identify whether a clinically relevant hypersensitivity reaction is likely or not. The importance of additional factors such as antibiotic palatability, concordance and stewardship are also discussed, highlighting their relevance to optimal prescribing of the penicillins for children

Global shortage of neonatal and paediatric antibiotic trials: rapid review.

OBJECTIVES: There have been few clinical trials (CTs) on antibiotics that inform neonatal and paediatric drug labelling. The rate of unlicensed and off-label prescribing in paediatrics remains high. It is unclear whether the current neonatal and paediatric antibiotic research pipeline is adequate to inform optimal drug dosing. Using the ClinicalTrials.gov registry, this review aims to establish the current global status of antibiotic CTs in children up to 18 years of age. METHODS: Studies were identified using key word searches of the ClinicalTrials.gov registry and were manually filtered using prespecified inclusion/exclusion criteria. RESULTS: 76 registered open CTs of antibiotics in children were identified globally; 23 (30%) were recruiting newborns (only 8 (11%) included preterm neonates), 52 (68%) infants and toddlers, 58 (76%) children and 54 (71%) adolescents. The majority of registered trials were late phase (10 (15%) phase 3 and 23 (35%) phase 4/pharmacovigilance). Two-thirds were sponsored by non-profit organisations, compared with pharmaceutical companies (50 (66%) vs 26 (34%), respectively). A greater proportion of non-profit funded trials were efficacy-based strategic trials (n=34, 68%), in comparison with industry-led trials, which were most often focused on safety or pharmacokinetic data (n=17, 65%). Only 2 of the 37 antibiotics listed on the May 2016 Pew Charitable Trusts antibiotic development pipeline, currently being studied in adults, appear to be currently recruiting in open paediatric CTs. CONCLUSIONS: This review highlights that very few paediatric antibiotic CTs are being conducted globally, especially in neonates. There is a striking disparity noted between antibiotic drug development programmes in adults and children

Variation in target attainment of β-lactam antibiotic dosing between international pediatric formularies

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. β-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dose recommendations from the major paediatric reference sources and tries to answer the question: does β-lactam dose heterogeneity matter? Does it impact on pharmacodynamic (PD) target attainment? For three important severe clinical infections - pneumonia, sepsis and meningitis - pharmacokinetic (PK) models were identified for common β-lactam antibiotics. Real-world demographics were derived from three multi-center point prevalence surveys. Simulation results were compared with minimum inhibitory concentration (MIC) distributions, to inform appropriateness of recommended doses in targeted and empiric treatment. Whilst cephalosporin dose regimens are largely adequate for target attainment, they also pose most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin and meropenem doses as potentially requiring review/optimisation in order to preserve the use of these agents in future

Did the accuracy of oral amoxicillin dosing of children improve after British National Formulary dose revisions in 2014? National cross-sectional survey in England.

OBJECTIVES: Inaccurate antibiotic dosing can lead to treatment failure, fuel antimicrobial resistance and increase side effects. The British National Formulary for Children (BNFC) guidance recommends oral antibiotic dosing according to age bands as a proxy for weight. Recommended doses of amoxicillin for children were increased in 2014 'after widespread concerns of under dosing'. However, the impact of dose changes on British children of different weights is unknown, particularly given the rising prevalence of childhood obesity in the UK. We aimed to estimate the accuracy of oral amoxicillin dosing in British children before and after the revised BNFC guidance in 2014. SETTING AND PARTICIPANTS: We used data on age and weights for 1556 British children (aged 2-18 years) from a nationally representative cross-sectional survey, the Health Survey for England 2013. INTERVENTIONS: We calculated the doses each child would receive using the BNFC age band guidance, before and after the 2014 changes, against the 'gold standard' weight-based dose of amoxicillin, as per its summary of product characteristics. PRIMARY OUTCOME MEASURE: Assuming children of different weights were equally likely to receive antibiotics, we calculated the percentage of the children who would be at risk of misdosing by the BNFC age bands. RESULTS: Before 2014, 54.6% of children receiving oral amoxicillin would have been underdosed and no child would have received more than the recommended dose. After the BNFC guidance changed in 2014, the number of children estimated as underdosed dropped to 5.8%, but 0.5% of the children would have received too high a dose. CONCLUSIONS: Changes to the BNFC age-banded amoxicillin doses in 2014 have significantly reduced the proportion of children who are likely to be underdosed, with only a minimal rise in the number of those above the recommended range

Pharmacokinetics of penicillin G in preterm and term neonates.

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but poorly for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We described PK of penicillin G in neonates with gestational age (GA) ≥32 weeks and postnatal age 90% for MICs ≤2 mg/L with doses of 25,000 IU/kg/q12h. In neonates, regardless of GA, PK parameters of penicillin G are similar. The dose of 25,000 IU/kg/q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 hours of life

A cascade of magmatic events during the assembly and eruption of a super-sized magma body

We use comprehensive geochemical and petrological records from whole-rock samples, crystals, matrix glasses and melt inclusions to derive an integrated picture of the generation, accumulation and evacuation of 530 km3 of crystal-poor rhyolite in the 25.4 ka Oruanui supereruption (New Zealand). New data from plagioclase, orthopyroxene, amphibole, quartz, Fe-Ti oxides, matrix glasses, and plagioclase- and quartz-hosted melt inclusions, in samples spanning different phases of the eruption, are integrated with existing data to build a history of the magma system prior to and during eruption. A thermally and compositionally zoned, parental crystal-rich (mush) body was developed during two periods of intensive crystallisation, 70 and 10-15 kyr before the eruption. The mush top was quartz-bearing and as shallow as ~3.5 km deep, and the roots quartz-free and extending to >10 km depth. Less than 600 yr prior to the eruption, extraction of large volumes of ~840 °C low-silica rhyolite melt with some crystal cargo (between 1 and 10%), began from this mush to form a melt-dominant (eruptible) body that eventually extended from 3.5-6 km depth. Crystals from all levels of the mush were entrained into the eruptible magma, as seen in mineral zonation and amphibole model pressures. Rapid translation of crystals from the mush to the eruptible magma is reflected in textural and compositional diversity in crystal cores and melt inclusion compositions, versus uniformity in the outermost rims. Prior to eruption the assembled eruptible magma body was not thermally or compositionally zoned and at temperatures of ~790°C, reflecting rapid cooling from the ~840 °C low-silica rhyolite feedstock magma. A subordinate but significant volume (3-5 km3) of contrasting tholeiitic and calc-alkaline mafic material was co-erupted with the dominant rhyolite. These mafic clasts host crystals with compositions which demonstrate that there was some limited pre-eruptive physical interaction of mafic magmas with the mush and melt-dominant body. However, the mafic magmas do not appear to have triggered the eruption or controlled magmatic temperatures in the erupted rhyolite. Integration of textural and compositional data from all available crystal types, across all dominant and subordinate magmatic components, allows the history of the Oruanui magma body to be reconstructed over a wide range of temporal scales using multiple techniques. This history spans the tens of millennia required to grow the parental magma system (U-Th disequilibrium dating in zircon), through the centuries and decades required to assemble the eruptible magma body (textural and diffusion modelling in orthopyroxene), to the months, days, hours and minutes over which individual phases of the eruption occurred, identified through field observations tied to diffusion modelling in magnetite, olivine, quartz and feldspar. Tectonic processes, rather than 57 any inherent characteristics of the magmatic system, were a principal factor acting to drive the rapid accumulation of magma and control its release episodically during the eruption. This work highlights the richness of information that can be gained by integrating multiple lines of petrologic evidence into a holistic timeline of field-verifiable processes

The effects of socioeconomic status and indices of physical environment on reduced birth weight and preterm births in Eastern Massachusetts

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Air pollution and social characteristics have been shown to affect indicators of health. While use of spatial methods to estimate exposure to air pollution has increased the power to detect effects, questions have been raised about potential for confounding by social factors.Methods: A study of singleton births in Eastern Massachusetts was conducted between 1996 and 2002 to examine the association between indicators of traffic, land use, individual and area-based socioeconomic measures (SEM), and birth outcomes ( birth weight, small for gestational age and preterm births), in a two-level hierarchical model.Results: We found effects of both individual ( education, race, prenatal care index) and area-based ( median household income) SEM with all birth outcomes. The associations for traffic and land use variables were mainly seen with birth weight, with an exception for an effect of cumulative traffic density on small for gestational age. Race/ethnicity of mother was an important predictor of birth outcomes and a strong confounder for both area-based SEM and indices of physical environment. The effects of traffic and land use differed by level of education and median household income.Conclusion: Overall, the findings of the study suggested greater likelihood of reduced birth weight and preterm births among the more socially disadvantaged, and a greater risk of reduced birth weight associated with traffic exposures. Results revealed the importance of controlling simultaneously for SEM and environmental exposures as the way to better understand determinants of health.This work is supported by the Harvard Environmental Protection Agency (EPA) Center, Grants R827353 and R-832416, and National Institute for Environmental Health Science (NIEHS) ES-0002

Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid.

Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5-20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection