Health Services Research findings (HSR) reported in scientific publications may become part of the decision-making process on healthcare. This study aimed to explore associations between researcher’s individual, institutional, and scientific environment factors and the occurrence of questionable research practices (QRPs) in the reporting of messages and conclusions in scientific HSR publications.p-value < .30 were included in four multivariate models tested through a multiple Poisson regression.We employed a mixed-methods study design. We identified factors possibly contributing to QRPs in the reporting of messages and conclusions through a literature review, 14 semi-structured interviews with HSR institutional leaders, and 13 focus-groups amongst researchers. A survey corresponding with these factors was developed and shared with 172 authors of 116 scientific HSR publications produced by Dutch research institutes in 2016. We assessed the included publications for the occurrence of QRPs. An exploratory factor analysis was conducted to identify factors within individual, institutional, and environmental domains. Next, we conducted bivariate analyses using simple Poisson regression to explore factors’ association with the number of QRPs in the assessed HSR publications. Factors related to QRPs with a In total, 78 (45%) participants completed the survey (51.3% first authors and 48.7% last authors). Twelve factors were included in the multivariate analyses. In all four multivariate models, a higher score of “pressure to create societal impact” , was associated with higher number of QRPs. Higher scores on “specific training”  and “co-author conflict of interest”  factors were associated with a lower number of QRPs. Stratification between first and last authors indicated different factors were related to the occurrence of QRPs for these groups.Experienced pressure to create societal impact is associated with more QRPs in the reporting of messages and conclusions in HSR publications. Specific training in reporting messages and conclusions and awareness of co-author conflict of interests are related to fewer QRPs. Our results should stimulate awareness within the field of HSR internationally on opportunities to better support reporting in scientific HSR publications. In 2009, it was estimated that 85% of research funding in biomedical sciences was avoidably wasted . In the In this study we focus on the field of Health Services Research (HSR). HSR has a direct link to policy and practice, where stakeholders and funders may contribute considerably to the interpretation of results , 7. AddiRecent work has suggested that scientific HSR publications may include a median of six QRPs in the reporting of messages and conclusions . QRPs weScientific journals have taken the lead in implementing control measures to provide structure to the review process and improve responsible reporting . These eHSR institutions in the Netherlands have varying organizational policies in fostering responsible conduct of research, including responsible reporting. This variety in institutional culture and organisation offers the opportunity to learn from each other’s reporting practices. Improving scientific publication of HSR requires an understanding of factors that influence authors in their writing, as well as those that impact the publication process itself (e.g. pressure and relationships with funders) –21. ReseConsequently, the aim of this study was to explore associations between individual, institutional, and scientific environment factors and the frequency of inadequacies in the reporting of messages and conclusions in scientific HSR publications.We employed a mixed-methods study design. First, we identified factors possibly contributing to the occurrence of QRPs in the reporting of messages and conclusions in scientific HSR publications through a literature review, 14 semi-structured interviews with leaders of HSR groups or institutions in the Netherlands, and 13 focus-groups amongst junior health services researchers. Factors were clustered into three domains: individual, institutional and scientific environmental domains . Second,The study involved publications and participants from 13 HSR groups, departments, or institutions including both academic and non-academic institutions (hereafter referred to as “HSR institutions”) in the Netherlands. These institutions agreed to participate in an effort to assure the overall quality of HSR publications in the Netherlands.Factors potentially associated with QRPs in HSR were identified through an exploratory literature review, 14 semi-structured interviews with 19 leaders/representatives of the 13 participating institutions, and 13 focus-groups comprised of 57 junior/PhD researchers at participating HSR institutions. An initial overview of factors was created through the literature review. This overview was then discussed in the semi-structured interviews with the leaders/representatives of participating institutions. Within the focus-groups, an open conversation was held with participants to identify additional factors overlooked in the literature and interviews  policy to produce a certain number of publications per year. The scientific environmental domain included factors that manifest outside of the direct control of the institution, including those characterizing scientific culture and systems in general.The framework of included factors is provided in Table The survey was designed based on the framework described above. For each identified factor in the preliminary framework, one or more survey questions were developed. Questions were evaluated on their face validity by the co-authors and two project advisors, both senior health services researchers. For this study, we developed a new questionnaire, as no validated questionnaires were tailored to the field of HSR or scientific reporting. One existing question from the publication pressure questionnaire was included in our newly developed questionnaire . The queA “think out loud” test was performed with two people from the target population. RG sat down with two researchers individually as they answered the survey questions and commented on their interpretation. The survey was designed in English and checked by a native speaker. After the final revision, the survey included 97 questions related to the factors within individual, institutional and scientific environment domains. Seven additional questions were included to assess personal and background characteristics. Answers to survey questions were provided on a Likert-scale .The survey is provided in supplementary material In a previous study we assessed QRPs in the reporting of messages and conclusions in 116 international peer-reviewed publications authored by researchers from the 13 participating institutions. QRPs were defined as “to report, either intentionally or unintentionally, conclusions or messages that may lead to incorrect inferences and do not accurately reflect the objectives, the methodology, or the results of the study.”  For the First and last authors of the 116 scientific publications were included in our assessment.We identified a total of 202 authors (116 first authors and 86 unique last authors) as the sample for our study. Contact information  was obtained through the participating institutions. These institutions were asked to encourage their researchers to participate in the survey, however, participation was voluntary and participants could stop at any time. Participants of the survey were informed of the goal of the study and data handling procedures in the invitation e-mail and at the start of the survey. We excluded 30 authors who’s contact information was unknown, resulting in a final sample of 172 authors. The response rate was 45% (78 respondents).The main dependent variable of this study was the number of QRPs in the reporting of messages and conclusions in HSR publications. QRP’s were identified by RG, JM, and a third assessor. Two reviewers independently assed the HSR publications. Absence and presence of QRP’s was discussed for all publications and identified through mutual consensus. The data were obtained from one of our previous studies, that provides more details on the applied methodology for identifying QRPs .The items  included in the survey questionnaire derived from three major domains as described above . An exploratory factor analysis was conducted to identify factors underlying items within each domain. The factors identified in the exploratory analyses were named as much as possible in alignment with the factors in our theoretical framework.We used the factors identified from the factor analysis as independent variables in our analyses. The methods and results of the factor analysis are further described in supplementary material Considering the explorative nature of our study, no assumptions were made regarding the relative importance of factors within and between domains. Due to our explorative aim, we decided to include all factors resulting from the factor analyses.We collected several personal characteristics in the survey . We described sample characteristics based on these variables.The basic characteristics of study samples were described based on the measurement scale of the variables. Categorical variables  were presented as frequency and percentage, whereas numerical variables  were presented using mean and standard deviation.We conducted bivariate analysis using simple Poisson regression. Poisson regression was chosen considering the nature of the outcome (number of QRPs) as count data with a relatively small mean value. This analysis specifically assessed the association between each factor score and the number of QRPs in HSR publications. The analysis was also intended to reduce the number of factors which were included in the multivariate model.ps < .3). The last two models included number of years of work experience as scientific researcher, as well as the journal’s impact factor, to examine the influence of these variables’ influence on the quality of reporting. For easier interpretation, we provided the coefficient of each explanatory variable (B), exponential form of the coefficient (Exp B) and the 95% confidence interval (95% CI). The goodness of fit of all models was checked using the chi-square goodness of fit test as part of the Poisson regression procedure, with results suggesting all models demonstrated good fit.Following the bivariate analysis, we applied multiple Poisson regression to further assess the association between the factor domains and the number of QRPs in HSR publications. For the purpose of model development, we provided four models in our multivariate analysis to ensure the stability of our results. The first two models were crude models (unadjusted) and included 12 factors from the bivariate analyses that exhibited a significant association with QRPs (rs < 0.3). Hence, these findings suggested no multi-collinearity issues in our analysis.Considering that the factors we used as independent variables may be interrelated, we checked for collinearity in our regression model. Results from the correlation matrix in the exploratory factor analysis procedure showed 35 of 171 pairs between scales (20%) were significantly but not strongly correlated  and professors (29.5%) were the most frequent academic positions in our sample. First authors were predominantly PhD students (50.0%), whereas the last authors were predominately professors (57.9%). Both first (40%) and last (28.9%) authors primarily had an academic background in the social sciences (40%). Last authors were older, had longer working experience as a scientific researcher, and reported a larger number of publications co-authored as compared to first authors. The journal impact factor of the publications was similar between last and first authors. The number of QRPs per publication was slightly higher for the last authors than first authors. The basic characteristics of the study sample are provided in Table 5.6% and Table Results of multivariate analyses are presented in Table In the fully-adjusted model , a one-point increase on the “pressure to create societal impact” item was associated with a 28% increase in the number QRPs in an HSR publication . Conversely, a one-point increase on the “specific training in reporting messages and conclusions” was associated with a 15% decrease in the number QRPs of an HSR publication . A one-point increase on the “co-author conflict of interest” item was associated with a 15% decrease in the number of QRPs in an HSR publication  was associated with fewer QRPs. “Feedback culture” at their research institute  and “pressure to create societal impact”  contribute to a higher number of QRPs. For last authors no significant relationship was identified between factors and QRPs.The aim of this study was to explore the possible association between individual, institutional, and scientific environment factors and inadequacies in the reporting of messages and conclusions in scientific HSR publications.We identified three factors independently associated with QRPs in the reporting of messages and conclusions in scientific HSR publications i.e., “pressure to create societal impact”, “specific training reporting messages and conclusions” and “co-author conflict of interest”. Stratification between first and last author indicated different factors related to the occurrence of QRPs.Our results indicated three factors are independently associated with QRPs in the reporting of messages and conclusions in HSR literature. The other factors in the assessed framework, however, are not irrelevant. All included factors may relate to multiple aspects of the publication process and are worth addressing in future studies on QRPs. Our study was explorative, and we therefore recommend further empirical research on the resulting factors.The association between a higher number of QRPs and the factor “pressure to create societal impact” facilitates important insights on the current research culture of HSR. HSR is often intended for practical intervention . To impr“Specific training in reporting messages and conclusions” was associated with a lower number of QRPs. The positive association between training and the improvement of reporting skills has been identified in previous studies , 27. The“Co-author conflict of interest” was associated with a lower number of reporting adequacies. This finding contradicts the assumption that research quality generally decreases when a conflict of interest arises. A possible explanation may be that awareness of a conflict of interest by co-authors may have stimulated a more nuanced or careful interpretation of the research findings. Policies in place at HSR institutions could assure that those conflicts of interests are positively mitigated and result in more attention to research conduct .One method used by research institutions to force a stimulating debate is to introduce structured peer-feedback . AlthougOur analyses further indicate that factors contributing to QRPs may be different for first and last authors. First authors may contribute to more QRPs when they experience more pressure to create societal impact and a positive feedback culture. They may contribute to fewer QRPs when they receive more specific training in reporting messages and conclusions. Additional research on the unique roles of first and last authors in the prevention of QRPs when reporting messages and conclusions in scientific HSR publications is recommended.The main strength of our approach was our mixed methods design. By constructing a framework from the experiences of a sample of health services researchers, we could tailor the survey to our study participants. Moreover, most research on research integrity is derived from self-report. Our assessment of QRPs provides a more impartial approach.Considering the large turnover of research staff and PhD students at each institution, a response of 45% may be optimal. The average number of QRPs is similar to that of all assessed HSR publications. Nevertheless, non-respondents might have rejected participation because of time pressures or a lack of communication with the HSR community. The relatively small sample size in the current study also presents as a limitation and necessitates replication in larger and more diverse samples. Further, due to our explorative aim, we decided to include factors with a lower threshold of reliability. In follow-up research we recommend to improve the factors’ reliability.We acknowledge the publications we analysed are nested in the thirteen participating Dutch institutions, which may influence the associations between institutional factors and QRPs. However, intraclass variation cannot be fully avoided. Institutions differ in structural conditions/resources, social conditions, role of supervisors, and cultural conditions. Consequently, associations may be attributed to an institutional factor although it is dependent on the context of a particular institution. A multilevel analysis including the institution in which the publication is nested would be the ideal option to address this issue. However, such an analysis would likely have required a larger dataset to provide a robust estimation of effects, particularly given the fact that publications are typically written by authors from multiple institutions. Considering the relatively small sample size and the explorative nature of our study, a single-level regression was a more appropriate choice. Further study with a larger data set and clearly distinguished institutions will allow for a more sophisticated analysis technique to confirm findings from our study.The assessed publications were published in 2016. Researchers might not have had a very vivid memory of their working experience 2 years prior. This would have made our connections between publication and person somewhat less reliable. Nevertheless, we do not expect institutional or scientific factors to have changed significantly in the course of 2 years. Risk for recall bias was likely minimal.The researchers and studies included in this study all originated from Dutch research institutions. Institutional structures and individual experiences of research culture will be different across countries. For instance, Dutch universities employ PhD students, who are often the primary authors of research papers, rather than provide scholarships. Moreover, they share supervisory structures requiring at least two supervising seniors. Nevertheless, HSR researchers and institutions often deal with similar challenges as those encountered in the Netherlands, including publication pressures and creating societal impact. Aspects of the results from the current study are thus likely to provide a helpful guide for HSR institutions internationally.In the field of HSR there is potential for a different set of guidelines for assessing QRPs as compared to the biomedical field. Due to the different research questions and methodologies applied, the research studies presented in HSR should adhere to the standards set by reporting guidelines and tools designed specifically for the field . Peer reOur study moreover identified factors that are best addressed through changes by research institutions. Results should stimulate awareness within the HSR community internationally. In support of a more responsible translation of findings to policy and practice, they should address the identified factors to contribute to better reporting in scientific HSR publications. We recommend the development of institutional interventions to encourage responsible reporting of messages and conclusions in HSR. Specialized writing courses and workshops may increase writing confidence . SpecifiExperienced pressure to create societal impact is associated with a higher number of QRPs in the reporting of messages and conclusions in HSR publications. Specific training in reporting messages and conclusions, and awareness of co-author conflict of interests are related to fewer QRPs in HSR publications. This study was exploratory and we therefore recommend further research on the identified factors. Our results should stimulate awareness within the field of HSR internationally on opportunities better support reporting in scientific HSR publications, and thus a more responsible translation of findings to policy and practice.Additional file 1.Additional file 2.Additional file 3.Additional file 4.Additional file 5.


Background: For people with dementia, burdensome transitions may indicate poorer-quality end-of-life care. Little is known regarding the association between home healthcare (HHC) and these burdensome transitions. We aimed to investigate the impact of HHC on transitions and hospital/intensive care unit (ICU) utilisation nearing the end-of-life for people with dementia at a national level. Methods: A nested case-control analysis was applied in a retrospective cohort study using a nationwide electronic records database. We included people with new dementia diagnoses who died during 2002–2013 in whole population data from the universal healthcare system in Taiwan. Burdensome transitions were defined as multiple hospitalisations in the last 90 days  or any hospitalisation or emergency room visit in the last three days of life . People with (cases) and without (controls) burdensome transitions were matched on a ratio of 1:2. We performed conditional logistic regression with stratified analyses to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI) of the risks of transitions. Results: Among 150,125 people with new dementia diagnoses, 61,399 died during follow-up, and 31.1% had burdensome transitions (50% were early and 50% late). People with ET had the highest frequency of admissions and longer stays in hospital/ICU during their last year of life, while people with LT had fewer hospital/ICU utilisation than people without end-of-life transitions. Receiving HHC was associated with an increased risk of ET  but a decreased risk of LT . In the people receiving HHC, however, those who received longer duration  or more frequent HHC or HHC delivered closer to the time of death were associated with a remarkably lower risk of ET. Conclusions: HHC has differential effects on early and late transitions. Characteristics of HHC such as better continuity or interdisciplinary coordination may reduce the risk of transitions at the end-of-life. We need further studies to understand the longitudinal effects of HHC and its synergy with palliative care, as well as the key components of HHC that achieve better end-of-life outcomes. Dementia is currently one of the commonest causes of death in Western countries and will be one of the major and increasing global causes of serious health-related suffering ,2,3. PeoBurdensome end-of-life transitions for people with dementia, mainly investigated in the US and Europe ,9,10, arPrevious observational studies have shown that palliative care was associated with fewer referrals to the emergency room (ER) and reduced use of life-sustaining treatments at the end-of-life for people with dementia ,12,13. HHome healthcare (HHC) is increasingly recognised as important in supporting people with dementia living in the community . HHC mosn = 290) had fewer end-of-life hospitalisations than those that died within one year of admission to nursing homes (n = 2730) [Previous studies that investigated HHC interventions for similar end-of-life outcomes in people with dementia were mostly in small samples or followed a short period before death ,22. JennOur population-based cohort study aimed to investigate the patterns and characteristics of HHC utilisation, burdensome transitions, and hospital/ICU use at the end-of-life for people with dementia following from the point of their dementia diagnosis. We examined the association between HHC and burdensome end-of-life transitions and the impact of characteristics of HHC on these transitions at a national level in Taiwan.Our hypothesis was that more continuous or more interdisciplinary collaboration in HHC may be associated with a lower risk of burdensome transitions in people with dementia at the end-of-life.The NHI in Taiwan, initiated in 1995, provides single-payer healthcare services and covers 99.9% of Taiwan’s legal residents . Almost HHC in Taiwan covers nurses’ and physicians’ visits, drug injections, respiratory therapy, and laboratory tests (before 2015), with extended services provided by more disciplines added after 2015 . HHC is This is a nationwide cohort study using Taiwan’s National Health Insurance Research Database (NHIRD), which is a routinely collected, claim-based, and anonymised electronic record database, including the entire inpatient and ambulatory healthcare services between 2000 and 2013. In the NHIRD, information about any utilisation of NHI-reimbursed healthcare services or drug prescriptions for an individual is obtained by tracing specific administrative codes and is linked by an encrypted identification code. Disease diagnoses are based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes before 2016. The study protocol was approved by the institutional review board of Chi-Mei Medical Center in Taiwan  and informed consent waived due to the anonymous nature of NHIRD analysis.The study cohort included people aged 40 years and older who had a new dementia diagnosis from the whole country from 2002 to 2013. Individuals with dementia were identified by the ICD-9-CM codes for dementia , followeNext, people with dementia who died by the end of 2013 were selected as the study focus. Death was determined when a patient was coded as “in-hospital death” or “sudden death” at the ER or withdrew from the NHI programme without any other healthcare visits in the following 6 months, as is a common working criteria for the NHIRD .A nested case-control analysis in cohort decedents was applied to minimise the bias of identifying end-of-life outcomes. We identified people with dementia who experienced end-of-life burdensome transitions before death, including ET or LT. ET was defined as three or more hospitalisations in the last 90 days of life, while LT was defined as any ER visit or hospitalisation in the last three days of life [We examined all records of HHC received by people with dementia during the follow-up period before death , comorbidities, and age-adjusted Charlson Comorbidity Index (aCCI) at baseline . The aCCThe mean and standard deviation (SD) or median and interquartile range was estimated for continuous variables. Discrete variables were described as the frequency with percentage. People with (cases) and without (controls) burdensome end-of-life transitions were matched on a ratio of 1:2 by year of death to diminish the influence of changes to policy or end-of-life care practice over time. Conditional logistic regression was then used to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI) of risks of transitions between cases and controls. Stratified analyses for potential factors of interest were estimated and presented as forest plots. In addition, characteristics of HHC among people who received HHC were estimated using unconditional logistic regression analysis. All regression analyses were adjusted for age, gender, socioeconomic status, aCCI, and listed comorbidities. SAS 9.4  was used for all statistical analyses.Among 150,125 people with a new dementia diagnosis, a total of 61,399 decedents were identified. The mean age of decedents was 83.2 years at death, and the mean survival period was 1030.7 days after the diagnosis of dementia, 48.2% of whom were female . The perMost characteristics at the time of dementia diagnosis were significantly different in proportions between cases and controls, and the group with ET had a much higher proportion of males . For theThe risk of burdensome end-of-life transitions between those with and without HHC and the stratified group analysis are shown in We used a large database to conduct the first national-level cohort study on the impact of HHC on burdensome end-of-life transitions in people with dementia, following from dementia diagnosis to death. HHC, in general, is not specifically targeted at end-of-life care needs and, thus, is seldom investigated for its effect on end-of-life outcomes. Our findings have important implications for focusing interventions on those who experience ET and have the highest acute healthcare needs at the end of life. We need to understand further the differential effects of routine HHC on ET and LT and the specific components of HHC that reduced the risk of end-of-life transitions.Overall, in Taiwan, 31.1% of decedents with dementia experienced end-of-life transitions, a much higher proportion than the counterparts reported in US Medicare 19%) or Finish nursing home residents (9.9%), as well as in the UK (16%) ,9,10. Th% or FiniA tendency towards aggressive healthcare at the end of life for people with dementia in Taiwan is associated with cultural norms of avoiding the discussion on end-of-life issues in advance, lack of recognition of dementia as a terminal illness, and the fee-for-service predominant design of the healthcare system, which we illustrated in our previous publications ,11. The Much research on burdensome transitions or acute healthcare utilisation at the end of life has focused on residents living in long-term care facilities ,9,29. SlThe percentage of ET and LT in the group who received HHC in our study were 34.5% and 31.2%, respectively. In comparison with previous studies, Mitchell et al. included only those people with advanced dementia who died within 12 months after admissions to either the HHC programme or nursing home care and found that the ratio of hospitalisation within the 90 days prior to their last minimum dataset assessment was 31.5% in the HHC group, which was lower than the ratio of 43.7% in the nursing home group . JenningIn our study, the HHC intervention had an opposite effect on ET and LT in people with dementia. The slightly higher risk of ET in the HHC group compared to those who did not have HHC may have occurred because people who received HHC may have had more multi-morbidities, more complex care needs, or have been at increased risk of using acute healthcare services before the HHC service ,31. For p = 0.04) than those who received HHC but did not complete the POLST; however, the former group were also more likely to have had a discussion about hospice care , die with hospice care , and die at home .This interesting phenomenon of divergence between HHC and end-of-life transitions in different periods prior to death (early or late) may reflect the results of Jennings’ research . This stOur key finding is that the characteristics of HHC impacts on burdensome end-of-life transitions for people with dementia. HHC with longer duration, higher frequency, or that was provided continuously closer to the time of death may be factors indicating a better continuity of care (CoC) , and CoCAlthough HBPLC showed increased odds of home death and had a heterogeneous effect on reduced hospitalisations at the end of life for people with different diseases ,41, the Considering the low coverage and late referral to specialist palliative care in people with dementia ,14,42, eOur study has several limitations. With the fundamental weaknesses of an administrative database, we were unable to obtain information about the severity of cognitive impairment or comorbidities, lifestyle and social support factors, or functional status, which may lead to confounding. We were unable to define the place of residence of participants, which means an analysis of transitions between home and care home and the influence of place of care is not possible. A lack of detailed clinical information on the reasons for acute healthcare utilisation made the judgment of avoidable admissions or transitions difficult. There were no records of patients’ preferences and advance directives, nor the process of surrogate decision-making. It may be difficult to compare the results to other countries due to differences in healthcare delivery, reimbursement, or resources allocation. Finally, using old claims data for this study could lead to an incomplete depiction of the current situation. Future research will include more updated datasets. Despite these limitations, the association between routine HHC and the risk of end-of-life transition from a 12-year nationwide population-based cohort in Taiwan is novel and provides a key step for further investigation.For people with dementia, HHC has contrasting effects on early and late burdensome end-of-life transitions prior to death. Characteristics of HHC such as intensity, continuity, or interdisciplinary coordination may reduce the risk of transitions at the end of life. We suggest that researchers and policymakers explore the synergy between routine HHC and specialist palliative care, and how they interact, to impact on acute healthcare utilisation in longitudinal studies through the trajectory from dementia diagnosis to death.


Optimizing the use of antibiotics has become mandatory, particularly for the pediatric population where limited options are currently available. Selecting the dosing strategy may improve overall outcomes and limit the further development of antimicrobial resistance. Time-dependent antibiotics optimize their free concentration above the minimal inhibitory concentration (MIC) when administered by continuous infusion, however evidences from literature are still insufficient to recommend its widespread adoption. The aim of this review is to assess the state-of-the-art of intermittent versus prolonged intravenous administration of antibiotics in children and neonates with bacterial infections. We identified and reviewed relevant literature by searching PubMed, from 1 January 1 2000 to 15 April 2020. We included studies comparing intermittent versus prolonged/continuous antibiotic infusion, among the pediatric population. Nine relevant articles were selected, including RCTs, prospective and retrospective studies focusing on different infusion strategies of vancomycin, piperacillin/tazobactam, ceftazidime, cefepime and meropenem in the pediatric population. Prolonged and continuous infusions of antibiotics showed a greater probability of target attainment as compared to intermittent infusion regimens, with generally good clinical outcomes and safety profiles, however its impact in terms on efficacy, feasibility and toxicity is still open, with few studies led on children and adult data not being fully extendable. Infections acquired during hospitalization (HAIs) are particularly challenging among vulnerable populations, particularly neonates and children affected by chronic conditions such as immune deficiency or when admitted to the intensive care unit. The emergency of multidrug resistant bacteria as a common cause of HAIs, with very limited treatment options available for pediatric use, increases the need of optimizing the use of currently employed antibiotics, focusing on the best dosing strategy to improve overall outcomes as well as to limit the further development of antimicrobial resistance. Pseudomonas aeruginosa and/or bacteria with high minimal inhibitory concentration (MIC) [Prolonged and continuous infusion of time-dependent antibiotics aimed at increasing the probability of attaining pharmacokinetic/pharmacodynamic (PK/PD) targets may be considered to address challenges related to difficult-to-treat pathogens and improve efficacy . Althougon (MIC) ,6,7,8. Several aspects have to be taken into account in selecting the most appropriate antimicrobial treatment for patients with suspected or confirmed infection. Several aspects have to be considered in the decisional approach, including pathogens’ characteristics and their sensitivity/resistance pattern to common antibiotics, the drugs’ intrinsic pharmacodynamic features, the infection site and the patient’s pathophysiology . ComposiAmong all antibiotics, it has been shown that the bactericidal activity of time-dependent antibiotics, such as beta-lactams and oxazolidinones, is related to the duration of the maintenance of their free concentration above the minimal inhibitory concentration (MIC) during each dosing interval  while thIn 2012, Walker and colleagues examined intermittent versus continuous administration of such antibiotics in children , reportiThe aim of this narrative review is to evaluate the state-of-the-art in the literature on the intravenous use of systemic antibiotic treatment for both children and neonates with infections due to either Gram-positive and Gram-negative bacteria, particularly focusing on intermittent versus prolonged infusion.We identified and reviewed relevant literature by searching PubMed, from 1 January 2000 to 15 April 2020. Within the research strategy used for PubMed, combinations of the following search terms were used: “antibiotic”, “antimicrobials”, “children”, “paediatric”, “pediatric”, “neonate”, “infusion”, “extended infusion,” “prolonged infusion,” “continuous infusion,” “continuous administration,” “dosing regimen,” “dosing regimens,” “continuous vs. intermittent,” “extended vs. intermittent,” “standard vs. prolonged,” “extended vs. standard,” or “intermittent vs. prolonged,” “piperacillin/tazobactam”, “meropenem”, ceftazidime”, “cefepime”, “vancomycin”, with a filter of “text availability: abstract, free full text and full text”. Moreover, a reference list from eligible articles was reviewed to identify other potentially relevant studies. The last search was conducted on 15 April 2020. In the current review, we included studies comparing the outcomes of different infusion regimens in the pediatric population, focusing on intermittent versus prolonged/continuous infusion rates. Randomized controlled trials, pharmacokinetic/pharmacodynamic studies, observational studies, and case series were included if involving pediatric patients (age 0–18 years) and if comparing prolonged or extended versus intermittent infusion of time-dependent antibiotics. Manuscript comments, letters, editorials, conference abstracts and opinion articles were excluded. Data were extracted using a standardized data collection form, which summarized information about authors, year of publication, study design, country, study period, setting, multicentric involvement, type of intervention, and main results.Of 38,906 titles and abstracts, 114 were eligible for inclusion in this review, and ten studies were included, nine published in English and one in Spanish. Staphylococcus aureus (MRSA) and Enterococcus species; oral administration of glycopeptides is also recommended for the management of Clostridium difficile infection [This class of antibiotics exhibits time-dependent bactericidal activity against most gram-positive bacteria, including methicillin-resistant nfection .d-Ala-d-Ala terminal of the growing peptide chain during Gram positive cell wall synthesis. Details about spectrum of activity, adverse effects and hints to antibiotic resistance can be found in Table 2. Its volume of distribution is 0.4–1 L/kg [Vancomycin inhibits cell wall synthesis by binding to the 4–1 L/kg  and prot4–1 L/kg . Vancomy4–1 L/kg  while in4–1 L/kg .Serum levels of vancomycin should be monitored and a target trough concentration goal of 15–20 μg/mL is recommended for serious, complicated infections, including methicillin-resistant staphylococcal-related infections ,25.The most useful target parameters to evaluate vancomycin PK/PD correlation are the area under the curve (AUC) and MIC. According to Rybak et al., an AUC/MIC ratio higher than 400 is related to a plasma trough level above 15 μg/mL, assuming 1 mg/L MIC or less .S. aureus (MRSA) with MIC of 1.0 μg/mL or greater, suggesting that dose should be increased to 60/mg/kg/die [In the pediatric population, PK/PD data on vancomycin are limited. A model study reports that the current empiric recommended vancomycin dose in children of 40 mg/kg/day is unlikely to achieve the recommended pharmacodynamic target of AUC 24/MIC > 400 in case of methicillin-resistant g/kg/die . Similarg/kg/die ,28,29. Ig/kg/die .Although evidence from adults showed that continuous infusion of vancomycin (CIV) decreases the risk of nephrotoxicity and the incidence of infusion-related reactions while also decreasing time to therapeutic concentrations and drug cost at the same time, compared to IIV ,32,33, lZylbersztajn et al. published a case series of six children between two months and seven years of age, being initially treated for MRSA sepsis with vancomycin 40 and 60 mg/kg/day every 8–6 h. Because of poor outcome, they were all shifted to continuous infusion at 50 mg/kg/day, for 9 to 18 days. They reached blood levels between 10 and 25 ug/mL, with a favorable outcome and negativization of cultures, with no signs of nephrotoxicity .A randomized trial conducted by Gwee et al. compared the treatment outcome of continuous infusion of vancomycin (20–50 mg/kg/day) with the intermittent administration of 15 mg/kg/dose every 24, 12, 8 or 6 h according to gestational age in 111 infants admitted in NICU and PICU with suspected sepsis. Both administration regimens were related to clinical improvement and no significant side-effects were reported. However, only 41% (21 out of 51) of children of the intermittent intravenous (IIV) group achieved a target concentration of 15 to 25 mg/L at first steady-state level, compared to the 85% (45/53) of continuous intravenous (CIV) group . The same outcome was evaluated in a retrospective study of 77 preterm infants  with suspected late-onset sepsis , treated with 20 mg/kg/day of vancomycin: 48 h after treatment initiation, 52.8% of infants of CIV achieved therapeutic levels, compared to 34.1% of patients of the IIV group. Microbiological outcomes and clinical responses did not differ significantly between the two groups .Hurst and colleagues retrospectively evaluated the achievement of serum vancomycin goal concentration at different age range and the associated safety and tolerability among a cohort of 240 pediatric patients who were shifted from IIV to CIV. In their cohort, the average final total daily dose of CIV required to attain a therapeutic serum vancomycin concentrations (SVCs) was 54% to 64% of the final IIV dosing, suggesting that CIV has the potential to result in goal SVCs with much lower dosing than IIV . As for As for compliance outcomes and availability for outpatients, there are to date no available data in the pediatric population, but evidence from studies involving adults seem to confirm a good tolerance, efficacy and safety profile for CIV with elastomeric pumps in home settings ,39. Beta lactams are a family of time-dependent pharmacodynamic antibiotics that include penicillins, cephalosporins, carbapenems and monobactams, acting as inhibitors of bacterial cell wall synthesis . SeveralPseudomonas aeruginosa (details in Table 2). Few pharmacokinetic data are available for piperacillin alone or piperacillin-tazobactam in children less than the age of two years, thus limiting its use in this population. Piperacillin/tazobactam (TZP) is a broad spectrum beta-lactam/beta-lactamase inhibitor combination widely used in hospitalized children with either suspected or documented severe infections, due to its wide spectrum of activity against Gram-positive/Gram-negative aerobic and anaerobic pathogens ,46,47,48This drug is routinely administered with a 30-min or 1-h infusion time, as recommended for any other beta-lactams. However, recent studies challenge currently used dosing regimens and way of administration. According to De Cock et al., a Monte Carlo simulation conducted in a population of critically ill children receiving 75–100 mg/kg piperacillin every 6–8 h as a short infusion lead to very low probability of target attainment (PTA), estimated between 5.9% and 34% for piperacillin, potentially leading to subtherapeutic treatment. On the other side, continuous or prolonged (every 4 h) infusions met the PTA criterion for piperacillin , definedTo date, few pieces of evidence evaluate the clinical impact of prolonged or continuous administration of piperacillin/tazobactam in children. Only one non-blinded RCT, published in 2019 by Solórzano-Santos et al., evaluated the clinical efficacy of TZP administered through continuous rather than intermittent infusion in onco-hematological children with febrile neutropenia. Continuous infusion included a loading dose of 75 mg/kg over 30 min, followed by a 24 h continuous infusion of 300 mg/kg/day. Among 176 episodes assessed, no statistically significant difference was found in fever resolution, clinical cure rate or mortality between the continuous Infusion group and the intermittent administration group, with respectively 16 and 13 cases of treatment failure; one patient in each group died . E. coli and K. pneumoniae) invasive infection and treated with prolonged TZP infusion achieved clinical cure at 21 days after treatment initiation. Although 38.5% (n = 15) of patients had a readmission after 30 days, no deaths were reported in this cohort. Indeed, adverse effects related to extended infusion TZP were not experienced [A retrospective case series published in 2017 showed that 29 (74%) out of 39 children of five years (IQR 2–9) median age affected by an Enterobacteriaceae , while severe infections 200 mg/kg/day divided every 8 h  being recommended for cystic fibrosis patients) .P. aeruginosa, Monte Carlo simulations showed that continuous-infusion ceftazidime doses of 4–6 g/day attained optimal PTAs (>90%) across most of 16 different clinical scenarios based on four classes of eGFR and body surface area [Ceftazidime has an almost complete renal excretion (80–90%) and has a low protein binding profile (10%) . It is uace area . Dalle eace area . Few studies evaluated the clinical impact of continuous rather than intermittent administration of ceftazidime in the pediatric population. P. aeruginosa) while the continuous infusion regimen ensured higher serum ceftazidime levels with no values below the MIC [In their prospective study, Rappaz et al. compared the treatment outcome of continuous and intermittent infusion of ceftazidime, both administered in different times at the same cohort of 14 children affected by cystic fibrosis. In the intermittent administration regimen group, the mean drug trough level concentration in serum was highly variable and 32% of samples had values below the MIC of pathogen isolated in sputum . The parenteral administration of 50 mg/kg every 8 h (maximum dose: 6 g per day) is currently recommended for children and adolescents, traditionally administered as an intravenous infusion over 30 min. Neonates should receive 30 mg/kg/dose every 12 h, increasing the dose up to 50 mg/kg/dose every 12 h in case of meningitis or severe infections due to P. aeruginosa [Cefepime is a semi-synthetic, broad spectrum fourth-generation cephalosporin active against aerobic Gram-positive and Gram-negative pathogens including ruginosa . Enterobacteriaceae with elevated MIC (8 mcg/mL) [Previous studies confirmed that in children aged 2 months to 16 years cefepime has a shorter half-life (1.26–1.93 h), compared to adults. In addition, a larger volume of distribution of cefepime was observed in the pediatric population . For the mcg/mL) .To date, no studies evaluated the impact of administering cefepime as prolonged infusion, among the pediatric population. Descriptive evidence published by Nichols et al., suggests that implementing extended-infusion of cefepime as standard of care is feasible and not related to major complications, in children with a median age of six years admitted to several pediatric departments, excluding intensive care units . HoweverNo studies evaluated the tolerability and compliance of outpatients’ continuous infusion of ceftazidime with once-daily changes of infusion device. Voumard and colleagues described adult outpatients’ treatment with continuous infusion cefepime, demonstrating a good compliance profile with an effective and safe approach .Meropenem is a broad-spectrum beta-lactam antibiotic of the carbapenem class active against several Gram-positive and Gram-negative aerobic and anaerobic microorganisms, including extended-spectrum betha-lactamase (ESBL) producing bacteria (details in Table 2). It has a favorable penetration profile of tissues and body fluids alike, and it is well tolerated in preterm infants, neonates and children ,74,75. TEnterobacteriaceae (CPE), which have now become endemic worldwide, including in Europe and particularly in Italy and Greece [The inappropriate use of meropenem has led to an increasing incidence of carbapenemase-producing d Greece . To faced Greece . P. aeruginosa [P. aeruginosa infection received extended infusion  of 40 mg/kg meropenem every 8 h. At Monte Carlo simulation, meropenem administered with prolonged (3 h) infusion had a greater likelihood of obtaining 40% fT > MIC against pathogens with meropenem MICs of 1–8 mg/L, compared to intermittent (30 min) infusion [Meropenem is usually administered through infusion over 30 min, as some evidences indicated that this drug may undergo a degradation, few hours after reconstitution ,81. Noneruginosa ,85. Accoinfusion , with a Similar findings were reported by Cies et al.  that exaIn their recent population pK study, Rapp et al. simulated dosing regimens of meropenem in critically ill paediatric patients with differences in renal function. Their results showed that the best regimen was continuous infusion (60 and 120 mg/kg/day), which allowed attainment of the target of 50% fT > MIC and 100% fT > MIC in patients with normal and increased creatinine clearance, with infection by germs with high MIC values (>4 mg/L), with no risks of accumulation. However, this was not demonstrated in children with a decreased creatinine clearance and severe renal failure . Pseudomonas aeruginosa infection. The impact of extended infusion of meropenem in terms of clinical outcomes, such as mortality or clinical improvement, among the pediatric population is still unknown, as very few studies were conducted on this field. Recent evidence seems to confirm a better clinical outcome for neonates with Gram-negative late-onset sepsis (GN-LOS) treated with prolonged infusion of meropenem, if compared to conventional intermittent dosing . In factPettit et al. also confirmed that meropenem administered as prolonged infusion was well tolerated, as only one patient stopped therapy due to an unspecified adverse event . Lastly, Padari et al., in their study reported no cases of toxicity for meropenem given with continuous infusion to seriously ill premature neonates. As for mortality, there was 1/9 patient reported in the standard-infusion group and 1/10 in the prolonged-infusion group, both deaths occurred more than seven days after completion of therapy, with no relation to meropenem administration . All studies including patient data are summarized in Pediatric patients represent a challenging population, showing variations in pharmacokinetics throughout the different ages. The question whether time-dependent antibiotics should be administered in continuous or intermittent infusion is still open, with few studies led on children and adult data not being fully extendable. Indeed, prolonged and continuous infusions of antibiotics seem to have a greater probability of target attainment as compared to intermittent infusion regimens, with generally good clinical outcomes and tolerability and safety profile, and therefore should be considered in the pediatric population on a case-to-case basis. This way of administration also has the advantage of being cost-effective on a hospital basis and may be considered to reduce the length of hospitalization in stable children, as continuous infusion treatments can be administered at home with home-based or out clinic-based once-daily changes of infusion device . HoweverOur narrative review has some limitations: well-designed included studies were scarce and with different designs, therefore comparison between studies was not possible. Furthermore, we only considered studies in English, leading to the possibility of missing further data published in other languages. In light of results from pK/pD studies and considering the reported safety and tolerability of prolonged or continuous antibiotic infusion, our review highlights the need of conducting randomized-controlled trials aimed at exploring the clinical impact, tolerability and patient’s acceptability of continuous administration of time-dependent antibiotic administration, compared to intermittent infusion, in the neonatal and paediatric population.