Association between antimicrobial stewardship programs and antibiotic use globally: a systematic review and meta-analysis

IMPORTANCE: Antimicrobial resistance continues to spread rapidly at a global scale. Little evidence exists on the association of antimicrobial stewardship programs (ASPs) with the consumption of antibiotics across health care and income settings. OBJECTIVE: To synthesize current evidence regarding the association between antimicrobial stewardship programs and the consumption of antibiotics globally. DATA SOURCES: PubMed, Web of Science, and Scopus databases were searched from August 1, 2010, to Aug 1, 2020. Additional studies from the bibliography sections of previous systematic reviews were included. STUDY SELECTION: Original studies of the association of ASPs with antimicrobial consumption across health care and income settings. Animal and environmental studies were excluded. DATA EXTRACTION AND SYNTHESIS: Following the Preferred Reporting Items in Systematic Reviews and Meta-Analyses guideline, the pooled association of targeted ASPs with antimicrobial consumption was measured using multilevel random-effects models. The Effective Public Health Practice Project quality assessment tool was used to assess study quality. MAIN OUTCOMES AND MEASURES: The main outcome measures were proportion of patients receiving an antibiotic prescription and defined daily doses per 100 patient-days. RESULTS: Overall, 52 studies (with 1 794 889 participants) measured the association between ASPs and antimicrobial consumption and were included, with 40 studies conducted in high-income countries and 12 in low- and middle-income countries (LMICs). ASPs were associated with a 10% (95% CI, 4%-15%) reduction in antibiotic prescriptions and a 28% reduction in antibiotic consumption (rate ratio, 0.72; 95% CI, 0.56-0.92). ASPs were also associated with a 21% (95% CI, 5%-36%) reduction in antibiotic consumption in pediatric hospitals and a 28% reduction in World Health Organization watch groups antibiotics (rate ratio, 0.72; 95% CI, 0.56-0.92). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, ASPs appeared to be effective in reducing antibiotic consumption in both hospital and nonhospital settings. Impact assessment of ASPs in resource-limited settings remains scarce; further research is needed on how to best achieve reductions in antibiotic use in LMICs

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations.

Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations

High tea consumption diminishes salivary 17beta-estradiol concetration in Polish women

Artykuł recenzowany / peer-reviewed articleWe hypothesized that among reproductive-age women consuming large quantities of tea, the production of estradiol would be suppressed. It has been shown that catechins and theaflavines, the major constituents of tea, inhibit aromatase, an enzyme which catalyses the conversion of androgens to estrogens. Our study included Polish women living in urban (N=61) and rural (N=48) areas. Women collected daily saliva samples for one complete menstrual cycle and filled out dietary questionnaires. Saliva samples were analyzed by radioimmunoassay for concentration of 17-β estradiol (E2). Women with high (above the median) average daily consumption of black tea had reduced levels of salivary E2, in comparison with women who drank less black tea (below median). This effect was observed within the whole study group, as well as separately within urban (p = 0.0006) and rural (p = 0.013) groups. High intake of the sum of subclasses of tea catechins and epigallocatechin gallate, assessed using the USDA database [http://www.nal.usda.gov], was also associated with lower concentrations of E2 within all women (p = 0.01 and p = 0.0001, respectively) and within the urban group (p = 0.0001 and p = 0.004, respectively). Similar relationships were observed between the sum of subclasses of theaflavines and thearubigines and E2 levels for the whole group (p = 0.002) and for urban women (p = 0.02). Women with high consumption of tea had lower levels of E2 concentration throughout the entire menstrual cycle. These results may have implications for reducing hormone-related cancer risk by a relatively easy dietary intervention.the State Committee for Scientific Research, Warsaw, Poland, project No. 3 P05E 016 25 and 6 P05D 112 20, the Radcliffe Institute of Advanced Study, Harvard University and the Norwegian Cancer Society

Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity.

INTRODUCTION: Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets. OBJECTIVE: The aim of this study was to model efficacious and safe exposure for current neonatal amoxicillin dosing regimens, given a range of assumptions for minimal inhibitory concentration (MIC), targeted %fT > MIC, and potential for aminopenicillin-related neurotoxicity. METHODS: Individual intravenous amoxicillin exposures based on 6 international and 9 Swiss neonatal dosing recommendations, reflecting the range of current dosing approaches, were assessed by a previously developed population pharmacokinetic model informed by neonatal data from an international cohort. Exposure was simulated by attributing each dosing regimen to each patient cohort. End points of interest were %fT > MIC and potential neurotoxicity using Cmax > 140 mg/L as threshold. RESULTS: None of the dosing regimens achieved targets of ≥100%fT > MIC at any of the relevant MICs for a desired probability of target attainment (PTA) of ≥90%. All regimens achieved a PTA ≥90% for Streptococcus agalactiae (MIC 0.25 mg/L) and Listeria monocytogenes (MIC 1 mg/L) when targeting ≤70%fT > MIC. In contrast, none of the regimens resulted in a PTA ≥90% targeting ≥70%fT > MIC for enterococci (MIC 4 mg/L). The maximum amoxicillin concentration associated with potential neurotoxicity was exceeded using 4 dosing regimens (100 mg/kg q12, 60/30 mg/kg q12/8, 50 mg/kg q12/8/6, and 50 mg/kg q12/8/4) for ≥10% of neonates. CONCLUSIONS: The acceptability of regimens is highly influenced by efficacy and toxicity targets, the selection of which is challenging. Novel randomized trial designs combined with pharmacometric modeling and simulation could assist in selecting optimal dosing regimens in this understudied population

Surveillance of Gram-negative bacteria: impact of variation in current European laboratory reporting practice on apparent multidrug resistance prevalence in paediatric bloodstream isolates.

This study evaluates whether estimated multidrug resistance (MDR) levels are dependent on the design of the surveillance system when using routine microbiological data. We used antimicrobial resistance data from the Antibiotic Resistance and Prescribing in European Children (ARPEC) project. The MDR status of bloodstream isolates of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was defined using European Centre for Disease Prevention and Control (ECDC)-endorsed standardised algorithms (non-susceptible to at least one agent in three or more antibiotic classes). Assessment of MDR status was based on specified combinations of antibiotic classes reportable as part of routine surveillance activities. The agreement between MDR status and resistance to specific pathogen-antibiotic class combinations (PACCs) was assessed. Based on all available antibiotic susceptibility testing, the proportion of MDR isolates was 31% for E. coli, 30% for K. pneumoniae and 28% for P. aeruginosa isolates. These proportions fell to 9, 14 and 25%, respectively, when based only on classes collected by current ECDC surveillance methods. Resistance percentages for specific PACCs were lower compared with MDR percentages, except for P. aeruginosa. Accordingly, MDR detection based on these had low sensitivity for E. coli (2-41%) and K. pneumoniae (21-85%). Estimates of MDR percentages for Gram-negative bacteria are strongly influenced by the antibiotic classes reported. When a complete set of results requested by the algorithm is not available, inclusion of classes frequently tested as part of routine clinical care greatly improves the detection of MDR. Resistance to individual PACCs should not be considered reflective of MDR percentages in Enterobacteriaceae

The Biological Standard of Living in the two Germanies.

Physical stature is used as a proxy for the biological standard of living in the two Germanies before and after unification in an analysis of a cross-sectional sample (1998) of adult heights, as well as among military recruits of the 1990s. West Germans tended to be taller than East Germans throughout the period under consideration. Contrary to official proclamations of a classless society, there were substantial social differences in physical stature in East-Germany. Social differences in height were greater in the East among females, and less among males than in the West. The difficulties experienced by the East-German population after 1961 is evident in the increase in social inequality of physical stature thereafter, as well as in the increasing gap relative to the height of the West-German population. After unification, however, there is a tendency for East-German males, but not of females, to catch up with their West-German counterparts

Implementation of infection prevention and control for hospitalized neonates: A narrative review.

BACKGROUND: The most prevalent infections encountered in neonatal care are healthcare-associated infections. The majority of healthcare-associated infections are considered preventable with evidence-based infection prevention and control (IPC) practices. However, substantial knowledge gaps exist in IPC implementation in neonatal care. Furthermore, the knowledge of factors which facilitate or challenge the uptake and sustainment of IPC programmes in neonatal units is limited. The integration of implementation science approaches in IPC programmes in neonatal care aims to address these problems. OBJECTIVES: The aim of this narrative review was to identify determinants which have been reported to influence the implementation of IPC programmes and best practices in inpatient neonatal care settings. SOURCES: A literature search was conducted in PubMed, MEDLINE (Medical Literature Analysis and Retrieval System Online) and CINAHL (Cumulative Index to Nursing and Allied Health Literature) in May 2022. Primary study reports published in English, French, German, Spanish, Portuguese, Italian, Danish, Swedish or Norwegian since 2000 were eligible for inclusion. Included studies focused on IPC practices in inpatient neonatal care settings and reported determinants which influenced implementation processes. CONTENT: The Consolidated Framework for Implementation Research was used to identify and cluster reported determinants to the implementation of IPC practices and programmes in neonatal care. Most studies reported challenges and facilitators at the organizational level as particularly relevant to implementation processes. The commonly reported determinants included staffing levels, work- and caseloads, as well as aspects of organizational culture such as communication and leadership. IMPLICATIONS: The presented knowledge about factors influencing neonatal IPC can support the design, implementation, and evaluation of IPC practices

Prevalence of overweight and obesity in children aged 6–13 years—alarming increase in obesity in Cracow, Poland

This study in children aged 6–13 years (n = 1,499) was performed between October 2008 and March 2009. Height and weight measurements were taken to calculate BMI. The prevalence of overweight and obesity was determined by means of IOTF cut-offs with respect to age. Alarming is the fact that the percentage of obese children in Cracow increased dramatically from 1.04% in boys and 0.20% in girls in 1971 to 7% in boys and 3.6% in girls in 2009. In this report, a higher percentage of overweight boys was observed in rural boys (28.14%) than in urban ones (27.31%). Obesity was identified in an almost twice as high percentage of urban boys (7.78%) as in rural ones (3.52%). A higher percentage of overweight girls was registered in rural areas (16.49%) than in urban ones (16.09%). Obesity was prevailing in rural girls (4.12%) relative to their urban counterparts (3.44%). The highest number of overweight urban boys was diagnosed in the group of 12-year-olds (n = 48) and rural boys in the group of 10-year-olds (n = 39), as well as in urban girls aged 11 (n = 17) and rural girls aged 9 (n = 9). The highest number of obesity was observed in rural boys aged 12 (n = 3) and in urban boys aged 9 and 10 (n = 9 in both groups). In the group of girls, obesity prevailed in urban 9-year-olds (n = 5) and in rural 7-year-olds (n = 5). Conclusions: Overweight and obesity affect boys almost twice as frequently as girls. Obesity is twice as frequent in urban boys as in their rural peers

Swissped-RECOVERY: masked independent adjudication for the interpretation of non-randomised treatment in a two-arm open-label randomised controlled trial (methylprednisolone vs immunoglobulins) in Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) involving 10 secondary and tertiary paediatric hospitals in Switzerland.

OBJECTIVES: In trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of trial findings. Swissped-RECOVERY was set up as one of the first randomised controlled trials worldwide, investigating the comparative effectiveness of anti-inflammatory treatment with intravenous methylprednisolone or intravenous immunoglobulins in children and adolescents with Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). We present one approach towards improving the interpretation of non-randomised treatment in a randomised controlled trial. DESIGN: This is a pre-planned ancillary analysis of the Swissped-RECOVERY trial, a randomised multicentre open-label two-arm trial. SETTING: 10 Swiss paediatric hospitals (secondary and tertiary care) participated. PARTICIPANTS: Paediatric patients hospitalised with PIMS-TS. INTERVENTIONS: All patient-first intercurrent events, if applicable, were presented to an independent adjudication committee consisting of four international paediatric COVID-19 experts to provide independent clinical adjudication to a set of standardised questions relating to whether additional non-randomised treatments were clinically indicated and disease classification at the time of the intercurrent event. RESULTS: Of 41 treatments in 75 participants (24/41 (59%) and 17/41 (41%) in the intravenous methylprednisolone and immunoglobulin arms of the trial, respectively), two-thirds were considered indicated. The most common treatment (oral glucocorticoids, 14/41, 35%) was mostly considered not indicated (11/14, 79%), although in line with local guidelines. Intercurrent events among patients with Shock-like PIMS-TS at baseline were mostly considered indicated. A significant proportion of patients with undifferentiated PIMS-TS at baseline were not attributed to the same group at the time of the intercurrent event (6/12 unchanged, 4/12 Kawasaki disease-like, 2/12 Shock-like). CONCLUSION: The masked adjudication of intercurrent events contributes to the interpretation of results in open-label trials and should be incorporated in the future. TRIAL REGISTRATION NUMBERS: SNCTP000004720 and NCT04826588

Validity of mobile electronic data capture in clinical studies: a pilot study in a pediatric population.

BACKGROUND: Clinical studies in children are necessary yet conducting multiple visits at study centers remains challenging. The success of "care-at-home" initiatives and remote clinical trials suggests their potential to facilitate conduct of pediatric studies. This pilot aimed to study the feasibility of remotely collecting valid (i.e. complete and correct) saliva samples and clinical data utilizing mobile technology. METHODS: Single-center, prospective pilot study in children undergoing elective tonsillectomy at the University of Basel Children's Hospital. Data on pain scores and concomitant medication and saliva samples were collected by caregivers on two to four inpatient study days and on three consecutive study days at home. A tailored mobile application developed for this study supported data collection. The primary endpoint was the proportion of complete and correct caregiver-collected data (pain scale) and saliva samples in the at-home setting. Secondary endpoints included the proportion of complete and correct saliva samples in the inpatient setting, subjective feasibility for caregivers, and study cost. RESULTS: A total number of 23 children were included in the study of which 17 children, median age 6.0 years (IQR 5.0, 7.4), completed the study. During the at-home phase, 71.9% [CI = 64.4, 78.6] of all caregiver-collected pain assessments and 53.9% [CI = 44.2, 63.4] of all saliva samples were complete and correct. Overall, 64.7% [CI = 58.7, 70.4] of all data collected by caregivers at home was complete and correct. The predominant reason for incorrectness of data was adherence to the timing of predefined patient actions. Participating caregivers reported high levels of satisfaction and willingness to participate in similar trials in the future. Study costs for a potential sample size of 100 patients were calculated to be 20% lower for the at-home than for a traditional in-patient study setting. CONCLUSIONS: Mobile device supported studies conducted at home may provide a cost-effective approach to facilitate conduct of clinical studies in children. Given findings in this pilot study, data collection at home may focus on electronic data capture rather than biological sampling