Comparing reactogenicity of COVID-19 vaccine boosters: a systematic review and meta-analysis.

INTRODUCTION: Different COVID-19 vaccines are being utilized as boosters. This systematic review and meta-analysis aims to evaluate the reactogenicity of COVID-19 vaccines given as booster doses, according to vaccine type, dose, timing, participant characteristics and primary immunization regimen received. METHODS: Four databases (MEDLINE, Embase, Web of Science and CENTRAL) were searched for randomized controlled trials between 1 January 2020 and 1 January 2023 according to predetermined criteria. RESULTS: Twenty-eight studies describing 19 vaccines of four different types (viral vector, inactivated, mRNA and protein sub-unit) were identified. BNT162b2 vaccine (Pfizer-BioNTech) was selected as the control as it was most often compared with other vaccines. Fever, fatigue, headache, injection-site pain, redness, and swelling were the most frequently reported solicited events. mRNA vaccines were the most reactogenic, followed by viral vector vaccines and protein sub-unit vaccines, while inactivated vaccines were the least reactogenic. Full-dose vaccines were more reactogenic than half-dose vaccines. Heterologous BNT162b2 boosters were more reactogenic than boosters with the same vaccine used for primary immunization. CONCLUSIONS: COVID-19 vaccine booster schedules have distinct reactogenicity profiles, dependent on dose and vaccine type, which may allow targeted recommendations and provide choice for specific populations. Greater standardization of adverse event reporting will aid future studies.

The safety and immunogenicity of vaccines administered to pregnant women living with HIV: a systematic review and meta-analysis.

Background: Human Immunodeficiency Virus (HIV)-exposed uninfected (HEU) infants have a higher burden of infectious diseases related morbidity and mortality compared with HIV-unexposed uninfected (HUU). Immunization of pregnant women living with HIV (PWLWH) could reduce the severity and burden of infectious diseases for HEU in early infancy. Methods: We conducted a systematic review of safety and immunogenicity of vaccines administered to PWLWH and meta-analyses to test the overall effect of immunogenicity comparing pregnant women without HIV (PWWH) to PWLWH. We searched MEDLINE, Embase, Web of Science, Virtual Health Library and Cochrane databases in accordance with PRISMA guidelines for randomized controlled trials and observational studies. Review articles, case series, conference abstracts, and animal studies were excluded. Studies were included from inception to 6th September 2023, with no language restrictions. Random effects meta-analyses were performed for immunogenicity using Review manager (RevMan) analysis software version 5.4.1, Geometric Mean Titer (GMT) values were transformed to obtain the mean and standard deviation within RevMan, the effect size was computed and reported as mean difference with respective 95% confidence intervals. The review was registered with PROSPERO CRD42021289081. Findings: We included 12 articles, comprising 3744 pregnant women, 1714 were PWLWH given either influenza, pneumococcal or an investigational Group B streptococcal (GBS) vaccine. Five studies described safety outcomes, and no increase in adverse events was reported in PWLWH compared to PWWH. The GMT increase from baseline to 28-35 weeks post vaccination in HA units ranged from 12.4 (95% CI: 9.84-14.9) to 238.8 (95% CI: 0.35-477.9). Meta-analyses of influenza vaccines showed the pooled geometric mean difference in Hemagglutination Inhibition (HAI) titers post vaccination was 56.01 (95% CI: 45.01-67.01), p < 0.001. The increase was less in PWLWH when compared with PWWH: -141.76 (95% CI: -194.96, -88.55), p < 0.001. Interpretation: There are limited data on the safety and immunogenicity of vaccines given to PWLWH making policy consideration in this group difficult when new vaccines are introduced. With new vaccines on the horizon, PWLWH need to be included in studies to promote vaccine confidence for this special population. Funding: This work was funded by Medical Research Council Joint Clinical Trials Round 9 [MR/T004983/1].

Using the COM-B framework to elucidate facilitators and barriers to COVID-19 vaccine uptake in pregnant women: a qualitative study.

Since April 2021, COVID-19 vaccines have been recommended for pregnant women. Despite this, COVID-19 vaccine uptake in this group is low compared to the non-pregnant population of childbearing age. Our aim was to understand barriers and facilitators to COVID-19 vaccine uptake among pregnant women in Northern Ireland using the COM-B framework, and so to make recommendations for public health interventions. The COM-B proposes that human behaviour is influenced by the extent to which a person has the capability, opportunity, and motivation to enact that behaviour. Understanding the factors underpinning behaviour through this lens helps discern what needs to change to change behaviour, therefore supporting the development of targeted interventions.This study consisted of eight semi-structured interviews with new/expectant mothers who did not receive a COVID-19 vaccine dose while pregnant since April 2021, and a focus group with five participants who received at least one COVID-19 vaccine dose while pregnant. Interview and focus group data were analysed using semi-deductive reflexive thematic analysis framed by a subtle realist approach. The COM-B was used to categorise codes and subthemes were developed within each COM-B construct.Within Psychological Capability, subthemes captured the need for consistent and reliable COVID-19 vaccine information and access to balanced and jargon-free, risk-benefit information that is tailored to the pregnant individual. The behaviour/opinions of family, friends, and local healthcare providers had a powerful influence on COVID-19 vaccine decisions (Social Opportunity). Integrating the COVID-19 vaccine as part of routine antenatal pathways was believed to support access and sense of familiarity (Physical Opportunity). Participants valued health autonomy, however experienced internal conflict driven by concerns about long-term side effects for their baby (Reflective Motivation). Feelings of fear, lack of empathy from healthcare providers, and anticipated guilt commonly underpinned indecision as to whether to get the vaccine (Automatic Motivation).Our study highlighted that the choice to accept a vaccine during pregnancy generates internal conflict and worry. Several participants cited their concern was primarily around the safety for their baby. Healthcare professionals (HCPs) play a significant part when it comes to decision making about COVID-19 vaccines among pregnant women. HCPs and pregnant women should be involved in the development of interventions to improve the delivery and communication of information.

Gabapentinoid consumption in 65 countries and regions from 2008 to 2018: a longitudinal trend study.

Recent studies raised concerns about the increasing use of gabapentinoids in different countries. With their potential for misuse and addiction, understanding the global consumption of gabapentinoids will offer us a platform to examine the need for any interventional policies. This longitudinal trend study utilised pharmaceutical sales data from 65 countries and regions across the world to evaluate the global trends in gabapentinoid consumption between 2008-2018. The multinational average annual percentage change of gabapentinoid consumption was +17.20%, increased from 4.17 defined daily dose per ten thousand inhabitants per day (DDD/TID) in 2008 to 18.26 DDD/TID in 2018. High-income countries had the highest pooled gabapentinoid consumption rate (39.92 DDD/TID) in 2018, which was more than six times higher than the lower-middle income countries (6.11 DDD/TID). The study shows that despite differences in healthcare system and culture, a consistent increase in gabapentinoid consumption is observed worldwide, with high-income countries remaining the largest consumers.

Quality indicators for appropriate antibiotic prescribing in urinary tract infections in children.

BACKGROUND: The aim of this study was to define a set of urinary tract infections (UTIs)-specific quality indicators for appropriate prescribing in children and evaluate clinical practices in a district general hospital in Greece. METHODS: The UTIs-specific quality indicators were informed by a review of the existing literature. Quality indicators were selected to describe the overall antibiotics use, prescribing patterns and UTIs clinical management regarding treatment and prophylaxis in a cohort of children admitted with a UTI. Microbiological, clinical and prescribing data about dosing, duration and route of administration were collected from the patients' electronic health records. RESULTS: Twelve quality indicators were adapted or developed for prescribing in childhood UTIs. A broad variety of antibiotics were prescribed for UTIs, with a drug utilization (DU) 90% rate of 6 and 9 different antibiotics for febrile and afebrile UTIs, respectively. Despite the low incidence of multi-drug resistant UTIs in the study period (9/261, 3.4%), broad-spectrum antibiotics were prescribed in 33.5% (164/490) of prescriptions. A total of 62.8% (164/261) of patients were started on empiric combined therapies, while opportunities to de-escalate were missed in 37.8% (62/164) of them. One quarter (67/261, 25.7%) of patients did not fulfil the criteria for receiving treatment, while nearly half of those prescribed prophylaxis (82/175, 46.9%) could have avoided having a prophylaxis prescription. CONCLUSIONS: Our study identified substantial gaps for improvement in antimicrobial prescribing for UTIs in children. The application of the proposed quality indicators could help to limit unnecessary antibiotics use in children with UTI.

Machine learning applications on neonatal sepsis treatment: a scoping review.

INTRODUCTION: Neonatal sepsis is a major cause of health loss and mortality worldwide. Without proper treatment, neonatal sepsis can quickly develop into multisystem organ failure. However, the signs of neonatal sepsis are non-specific, and treatment is labour-intensive and expensive. Moreover, antimicrobial resistance is a significant threat globally, and it has been reported that over 70% of neonatal bloodstream infections are resistant to first-line antibiotic treatment. Machine learning is a potential tool to aid clinicians in diagnosing infections and in determining the most appropriate empiric antibiotic treatment, as has been demonstrated for adult populations. This review aimed to present the application of machine learning on neonatal sepsis treatment. METHODS: PubMed, Embase, and Scopus were searched for studies published in English focusing on neonatal sepsis, antibiotics, and machine learning. RESULTS: There were 18 studies included in this scoping review. Three studies focused on using machine learning in antibiotic treatment for bloodstream infections, one focused on predicting in-hospital mortality associated with neonatal sepsis, and the remaining studies focused on developing machine learning prediction models to diagnose possible sepsis cases. Gestational age, C-reactive protein levels, and white blood cell count were important predictors to diagnose neonatal sepsis. Age, weight, and days from hospital admission to blood sample taken were important to predict antibiotic-resistant infections. The best-performing machine learning models were random forest and neural networks. CONCLUSION: Despite the threat antimicrobial resistance poses, there was a lack of studies focusing on the use of machine learning for aiding empirical antibiotic treatment for neonatal sepsis.

Attention-deficit/hyperactivity disorder medication consumption in 64 countries and regions from 2015 to 2019: a longitudinal study.

Background: Timely recognition and appropriate treatment of attention-deficit/hyperactivity disorder (ADHD) are essential to enhance long-term outcomes of individuals with ADHD. This study aimed to evaluate the multinational trends and patterns of ADHD medication consumption. Methods: In this longitudinal trend study, we used pharmaceutical sales data of ADHD medication from the IQVIA-Multinational Integrated Data Analysis System between 2015 and 2019, covering 64 countries across the world. Consumption rates of ADHD medication were expressed as defined daily dose per 1000 child and adolescent inhabitants (aged 5-19) per day (DDD/TID). Linear mixed models were used to estimate the multinational, regional, and income level trend changes. Findings: The results showed that multinational ADHD medication consumption increased by +9.72% (95% confidence interval [CI], +6.25%, +13.31%) per year, from 1.19 DDD/TID in 2015 to 1.43 DDD/TID in 2019 across the 64 countries with marked differences between geographical locations. When stratified by countries' income levels, increases in ADHD medication consumption were observed in high-income countries but not in middle-income countries. In 2019, the pooled consumption rates of ADHD medication were 6.39 DDD/TID (95% CI, 4.63, 8.84) in high-income countries, 0.37 DDD/TID (95% CI, 0.23, 0.58) in upper-middle-income countries and 0.02 DDD/TID (95% CI, 0.01, 0.05) in lower-middle-income countries. Interpretation: Current ADHD prevalence estimates and rates of ADHD medication consumption in most middle-income countries are lower than the global epidemiological prevalence. It is therefore imperative to evaluate the potential barriers to diagnosis and treatment in these countries to minimise the risk of negative outcomes from undiagnosed and untreated ADHD. Funding: This project was funded by a grant from the Hong Kong Research Grants Council Collaborative Research Fund (project number C7009-19G).

Incidence of Group B Streptococcus Disease in Infants in China: An Updated Systematic Review and Meta-analysis.

New studies of Group B Streptococcus (GBS) in infants <3 months of age in China have been published since our previous systematic review and meta-analysis. Using the same methodology, we updated these estimates and determined a total incidence of 0.41 (95% CI, 0.32-0.51) cases/1000 live births, lower than previously (0.55/1000). New intrapartum antibiotic prophylaxis policies may have played an important role in this reduction.

Comparing reactogenicity of COVID-19 vaccines: a systematic review and meta-analysis.

OBJECTIVES: A number of vaccines have now been developed against COVID-19. Differences in reactogenicity and safety profiles according to the vaccine technologies employed are becoming apparent from clinical trials. METHODS: Five databases (Medline, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, London School of Hygiene and Tropical Medicine COVID-19 vaccine tracker) were searched for relevant randomized controlled trials between 1 January 2020 and 12 January 2022 according to predetermined criteria with no language limitations. RESULTS: Forty-two datasets were identified, with 20 vaccines using four different technologies (viral vector, inactivated, mRNA and protein sub-unit). Adults and adolescents over 12 years were included. Control groups used saline placebos, adjuvants, and comparator vaccines. The most consistently reported solicited adverse events were fever, fatigue, headache, pain at injection site, redness, and swelling. Both doses of mRNA vaccines, the second dose of protein subunit and the first dose of adenovirus vectored vaccines were the most reactogenic, while the inactivated vaccines were the least reactogenic. CONCLUSIONS: The different COVID-19 vaccines currently available appear to have distinct reactogenicity profiles, dependent on the vaccine technology employed. Awareness of these differences may allow targeted recommendations for specific populations. Greater standardization of methods for adverse event reporting will aid future research in this field.

Antibiotic Prescription Patterns in the Paediatric Primary Care Setting before and after the COVID-19 Pandemic in Italy: An Analysis Using the AWaRe Metrics.

The containment measures following COVID-19 pandemic drastically reduced airway infections, but they also limited the access of patients to healthcare services. We aimed to assess the antibiotic prescription patterns in the Italian paediatric primary care setting before and after the containment measures implementation. For this retrospective analysis, we used a population database, Pedianet, collecting data of patients aged 0-14 years enrolled with family paediatricians (FP) from March 2019 to March 2021. Antibiotic prescriptions were classified according to WHO AWaRe classification. An interrupted time series evaluating the impact of the containment measures implementation on the monthly antibiotic index, on the access to watch index, and on the amoxicillin to co-amoxiclav index stratified by diagnosis was performed. Overall, 121,304 antibiotic prescriptions were retrieved from 134 FP, for a total of 162,260 children. From March 2020, the antibiotic index dropped by more than 80% for respiratory infections. The Access to Watch trend did not change after the containment measures, reflecting the propensity to prescribe more broad-spectrum antibiotics for respiratory infections even during the pandemic. Similarly, co-amoxiclav was prescribed more often than amoxicillin alone for all the diagnoses, with a significant variation in the trend slope for upper respiratory tract infections prescriptions.

A paediatric hospital care AMC report for Northern Ireland.

BACKGROUND: Antimicrobial stewardship (AMS) is high on the agenda of healthcare policymakers and measurement of its impact is reliant on antimicrobial consumption (AMC) and antimicrobial resistance (AMR) data. Recent AMC reports have identified high antimicrobial prescribing rates in Northern Ireland (NI), compared with UK and European countries, but no separate paediatric data were reported. OBJECTIVES: To describe AMC trends in paediatric and neonatal inpatient care in NI between September 2015 and September 2020, in order to: (i) create a paediatric-specific AMC report and benchmark for future AMS interventions; and (ii) develop an action plan for establishing paediatric AMC/AMR surveillance in NI. METHODS: AMC data, measured in monthly DDD, as well as hospital bed occupancy and admissions statistics were analysed. Hospital AMC was measured using several metrics and subdivided by level of paediatric and neonatal care, and by proportion of antibiotic use according to the WHO AWaRe classification. RESULTS: Paediatric-specific consumption in hospital care was 0.3-0.42 DDD per 1000 inhabitants per day, representing approximately 10% of total AMC. There was variation in AMC rates between similar units. In some areas, an increasing proportion of Watch and Reserve antibiotic consumption was observed. CONCLUSIONS: A baseline AMC dataset for paediatric and neonatal units across NI has been created. Continuous prospective collection and analysis of these data, along with AMR surveillance, would strengthen paediatric AMS programmes and provide crucial information for their resourcing. It is hoped that this report will act as a catalyst to galvanize paediatric AMS efforts regionally.

Global, regional, and national trends in opioid analgesic consumption from 2015 to 2019: a longitudinal study.

BACKGROUND: Previous studies have reported an extremely unbalanced global access to opioid analgesics. We aimed to determine contemporary trends and patterns of opioid analgesic consumption at the global, regional, and national levels. METHODS: We analysed the global pharmaceutical sales data of 66 countries or regions from the IQVIA-Multinational Integrated Data Analysis System database on opioid analgesics between 2015 and 2019. Opioid analgesic consumption was measured in milligram morphine equivalent per 1000 inhabitants per day (MME per 1000/day). The global, regional, and national trend changes were estimated using linear regressions. Factors associated with consumption patterns and trend changes were explored in multivariable linear regression analyses. FINDINGS: Overall opioid analgesic sales in the 66 countries or regions increased from 27·52 MME per 1000/day (16·63-45·54) in 2015 to 29·51 MME per 1000/day (17·85-48·79) in 2019 (difference per year 3·96%, 95% CI 0·26 to 7·80). Sales reduced yearly in North America (-12·84%; 95% CI -15·34 to -10·27) and Oceania (-2·96%; -4·20 to -1·70); increased in South America (28·69%; 7·18 to 54·53), eastern Europe (7·68%; 3·99 to 11·49), Asia (5·74%; 0·61 to 11·14), and western and central Europe (1·64%; 0·52 to 2·78); and did not differ in Africa or central America and the Caribbean. The global opioid consumption patterns were associated with country-level Human Development Index (p=0·040), cancer death rate excluding leukaemia (p=0·0072), and geographical location (p<0·0001). In 2019, opioid analgesic consumption ranged from 0·01 MME per 1000/day to 5·40 MME per 1000/day in the 17 countries and regions in the lowest consumption quartile, despite high income levels and cancer death rates in some of them. INTERPRETATION: Global opioid analgesic consumption increased from 2015 to 2019. The trend changes were distinctive across regions, which could reflect the different actions in response to known issues of opioid use and misuse. Disparities in opioid analgesic consumption remained, indicating potential inadequate access to essential pain relief in countries with low consumption. FUNDING: None.

Antibiotic Susceptibility, Virulome, and Clinical Outcomes in European Infants with Bloodstream Infections Caused by Enterobacterales.

Mortality in neonates with Gram-negative bloodstream infections has remained unacceptably high. Very few data are available on the impact of resistance profiles, virulence factors, appropriateness of empirical treatment and clinical characteristics on patients' mortality. A survival analysis to investigate 28-day mortality probability and predictors was performed including (I) infants <90 days (II) with an available Enterobacterales blood isolate with (III) clinical, treatment and 28-day outcome data. Eighty-seven patients were included. Overall, 299 virulence genes were identified among all the pathogens. Escherichia coli had significantly more virulence genes identified compared with other species. A strong positive correlation between the number of resistance and virulence genes carried by each isolate was found. The cumulative probability of death obtained by the Kaplan-Meier survival analysis was 19.5%. In the descriptive analysis, early age at onset, gestational age at onset, culture positive for E. coli and number of classes of virulence genes carried by each isolate were significantly associated with mortality. By Cox multivariate regression, none of the investigated variables was significant. This pilot study has demonstrated the feasibility of investigating the association between neonatal sepsis mortality and the causative Enterobacterales isolates virulome. This relationship needs further exploration in larger studies, ideally including host immunopathological response, in order to develop a tailor-made therapeutic strategy.

Global antibiotic dosing strategies in hospitalised children: Characterising variation and implications for harmonisation of international guidelines.

BACKGROUND: Paediatric global antibiotic guidelines are inconsistent, most likely due to the limited pharmacokinetic and efficacy data in this population. We investigated factors underlying variation in antibiotic dosing using data from five global point prevalence surveys. METHODS & FINDINGS: Data from 3,367 doses of the 16 most frequent intravenous antibiotics administered to children 1 month-12 years across 23 countries were analysed. For each antibiotic, we identified standard doses given as either weight-based doses (in mg/kg/day) or fixed daily doses (in mg/day), and investigated the pattern of dosing using each strategy. Factors underlying observed variation in weight-based doses were investigated using linear mixed effects models. Weight-based dosing (in mg/kg/day) clustered around a small number of peaks, and all antibiotics had 1-3 standard weight-based doses used in 5%-48% of doses. Dosing strategy was more often weight-based than fixed daily dosing for all antibiotics apart from teicoplanin, which had approximately equal proportions of dosing attributable to each strategy. No strong consistent patterns emerged to explain the historical variation in actual weight-based doses used apart from higher dosing seen in central nervous system infections, and lower in skin and soft tissue infections compared to lower respiratory tract infections. Higher dosing was noted in the Americas compared to the European region. CONCLUSIONS: Antibiotic dosing in children clusters around a small number of doses, although variation remains. There is a clear opportunity for the clinical, scientific and public health communities to consolidate behind a consistent set of global antibiotic dosing guidelines to harmonise current practice and prioritise future research.

Reliability of dried blood spot (DBS) cards in antibody measurement: A systematic review.

BACKGROUND: Increasingly, vaccine efficacy studies are being recommended in low-and-middle-income countries (LMIC), yet often facilities are unavailable to take and store infant blood samples correctly. Dried blood spots (DBS), are useful for collecting blood from infants for diagnostic purposes, especially in low-income settings, as the amount of blood required is miniscule and no refrigeration is required. Little is known about their utility for antibody studies in children. This systematic review aims to investigate the correlation of antibody concentrations against infectious diseases in DBS in comparison to serum or plasma samples that might inform their use in vaccine clinical trials. METHODS AND FINDINGS: We searched MEDLINE, Embase and the Cochrane library for relevant studies between January 1990 to October 2020 with no language restriction, using PRISMA guidelines, investigating the correlation between antibody concentrations in DBS and serum or plasma samples, and the effect of storage temperature on DBS diagnostic performance. We included 40 studies in this systematic review. The antibody concentration in DBS and serum/plasma samples reported a good pooled correlation, (r2 = 0.86 (ranged 0.43 to 1.00)). Ten studies described a decline of antibody after 28 days at room temperature compared to optimal storage at -20°C, where antibodies were stable for up to 200 days. There were only five studies of anti-bacterial antibodies. CONCLUSIONS: There is a good correlation between antibody concentrations in DBS and serum/plasma samples, supporting the wider use of DBS in vaccine and sero-epidemiological studies, but there is limited data on anti-bacterial antibodies. The correct storage of DBS is critical and may be a consideration for longer term storage.

Global Divergence of Antifungal Prescribing Patterns: Data From the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children Surveys.

BACKGROUND: Globally, invasive fungal diseases (IFDs) have a significant impact in human health. With an increasing pediatric population at risk of IFD, effective antifungal drugs access and affordability should be ensured universally. The aim of our study was to characterize the global antifungal drug use in neonates and children and its variability between countries in different income groups. METHODS: Data were extracted from the Global Antimicrobial Resistance, Prescribing and Efficacy in Neonates and Children Point Prevalence Survey project, consisting in 1 pilot and four 1-day Point Prevalence Survey between 2015 and 2017. The data had been entered through a study-specific web-based data collection tool. RESULTS: From a total of 13,410 children included, 7.8% (1048/13,410) received at least 1 systemic antifungal drug: 9.5% (95% confidence interval: 8.9%-10.1%) in high income countries (HIC) versus 5.0% (95% confidence interval: 4.4%-5.6%) in low-middle income countries (LMIC) (P < 0.01). A significant proportion of patients on antifungals belonged to high-risk group for IFD (67.4%; 706/1048); most of these were managed in HIC (72.8%, P < 0.01). The likelihood of receiving antifungals being in high-risk group was higher in HIC compared with LMIC (ratio of 5.8 vs. 3.4, P < 0.01). Antifungal prophylaxis was more likely prescribed in HIC (67.2% vs. 30.4%, P < 0.01). Fluconazole was the most frequently prescribed drug. The proportional use of fluconazole was higher in LMIC compared with HIC. CONCLUSIONS: A significant variability of antifungal prescribing patterns was observed. The proportional use of systemic antifungals was twice as high in HIC compared with LMIC. More detailed data on access and antifungal use in limited-resource settings should be explored.

Variation in Target Attainment of Beta-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. Beta-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 dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta-lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections-pneumonia, sepsis, and meningitis-pharmacokinetic models were identified for common for beta-lactam antibiotics. Real-world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.

High global consumption of potentially inappropriate fixed dose combination antibiotics: Analysis of data from 75 countries.

Antibiotic fixed dose combinations (FDCs) can have clinical advantages such as improving effectiveness and adherence to therapy. However, high use of potentially inappropriate FDCs has been reported, with implications for antimicrobial resistance (AMR) and toxicity. We used a pharmaceutical database, IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS®), to estimate sales of antibiotic FDCs from 75 countries in 2015. Antibiotic consumption was estimated using standard units (SU), defined by IQVIA as a single tablet, capsule, ampoule, vial or 5ml oral suspension. For each FDC antibiotic, the approval status was assessed by either registration with the United States Food and Drug Administration (US FDA) or inclusion on the World Health Organization (WHO) Essential Medicines List (EML). A total of 119 antibiotic FDCs were identified, contributing 16.7 x 109 SU, equalling 22% of total antibiotic consumption in 2015. The most sold antibiotic FDCs were amoxicillin-clavulanic acid followed by trimethoprim/sulfamethoxazole and ampicillin/cloxacillin. The category with the highest consumption volume was aminopenicillin/ß-lactamase inhibitor +/- other agents. The majority of antibiotic FDCs (92%; 110/119) were not approved by the US FDA. Of these, the most sold were ampicillin/cloxacillin, cefixime/ofloxacin and metronidazole/spiramycin. More than 80% (98/119) of FDC antibiotics were not compatible with the 2017 WHO EML. The countries with the highest numbers of FDC antibiotics were India (80/119), China (25/119) and Vietnam (19/119). There is high consumption of FDC antibiotics globally, particularly in middle-income countries. The majority of FDC antibiotic were not approved by either US FDA or WHO EML. International initiatives such as clear guidance from the WHO EML on which FDCs are not appropriate may help to regulate the manufacturing and sales of these antibiotics.

Association of Empiric Antibiotic Regimen Discordance With 30-Day Mortality in Neonatal and Pediatric Bloodstream Infection-A Global Retrospective Cohort Study.

BACKGROUND: While there have been studies in adults reporting discordant empiric antibiotic treatment associated with poor outcomes, this area is relatively unexplored in children and neonates despite evidence of increasing resistance to recommended first-line treatment regimens. METHODS: Patient characteristics, antibiotic treatment, microbiology, and 30-day all-cause outcome from children <18 years with blood-culture-confirmed bacterial bloodstream infections (BSI) were collected anonymously using REDCap™ through the Global Antibiotic Prescribing and Resistance in Neonates and Children network from February 2016 to February 2017. Concordance of early empiric antibiotic treatment was determined using European Committee on Antimicrobial Susceptibility Testing interpretive guidelines. The relationship between concordance of empiric regimen and 30-day mortality was investigated using multivariable regression. RESULTS: Four hundred fifty-two children with blood-culture-positive BSI receiving early empiric antibiotics were reported by 25 hospitals in 19 countries. Sixty percent (273/452) were under the age of 2 years. S. aureus, E. coli, and Klebsiella spp. were the most common isolates, and there were 158 unique empiric regimens prescribed. Fifteen percent (69/452) of patients received a discordant regimen, and 7.7% (35/452) died. Six percent (23/383) of patients with concordant regimen died compared with 17.4% (12/69) of patients with discordant regimen. Adjusting for age, sex, presence of comorbidity, unit type, hospital-acquired infections, and Gram stain, the odds of 30-day mortality were 2.9 (95% confidence interval: 1.2-7.0; P = 0.015) for patients receiving discordant early empiric antibiotics. CONCLUSIONS: Odds of mortality in confirmed pediatric BSI are nearly 3-fold higher for patients receiving a discordant early empiric antibiotic regimen. The impact of improved concordance of early empiric treatment on mortality, particularly in critically ill patients, needs further evaluation.

Antibiotic Prescribing Patterns in Paediatric Primary Care in Italy: Findings from 2012-2018.

Comprehensive data are needed to monitor antibiotic prescribing and inform stewardship. We aimed to evaluate the current antibiotic prescribing patterns, including treatment switching and prolongation, in the paediatric primary care setting in Italy. This database study assessed antibiotic prescriptions retrieved from Pedianet, a paediatric primary care database, from 1 January 2012 to 31 December 2018. Descriptive analyses were stratified by diagnosis class, calendar year, and children's age. Generalized linear Poisson regression was used to assess variation in the prescriptions. In total, 505,927 antibiotic prescriptions were included. From 2012 to 2018, the number of antibiotics per child decreased significantly by 4% yearly from 0.79 in 2012 to 0.62 in 2018. Amoxicillin prescriptions decreased with increasing children's age, while macrolides and third-generation cephalosporins had the opposite trend. Prescriptions were associated with a diagnosis of upper respiratory infection in 23% of cases, followed by pharyngitis (21%), bronchitis and bronchiolitis (12%), and acute otitis media (12%). Eight percent of treatment episodes were prolonged or switched class, mostly represented by co-amoxiclav, macrolides, and third-generation cephalosporins. Our findings report an overall decrease in antibiotic prescriptions, but pre-schoolers are still receiving more than one antibiotic yearly, and broad-spectrum antibiotics prescription rates remain the highest.