Neglected Populations Not to Be Forgotten: Tackling Antimicrobial Resistance in Neonatal Infections.

Making further progress in reducing child mortality hinges on lowering the annual count of neonatal deaths; currently, this stands at 2 [...].

The Management of Neonates ≥34 Weeks' Gestation at Risk of Early Onset Sepsis: A Pilot Study.

Early onset sepsis (EOS) is a potentially fatal condition in neonates, and its correct management is still challenging for neonatologists. Early antibiotic administration in the neonatal period may carry short- and long-term risks. Neonatal EOS calculator has been recently introduced as a new strategy to manage infants at risk of sepsis, and has shown promising results. METHODS: In this single-center observational retrospective study, 1000 neonates ≥ 34 weeks' gestation were enrolled with the aim to evaluate our standard protocol for the management of suspected EOS compared to the EOS calculator. Outcome measures included the following: (1) incidence of EOS and (2) proportion of infants in need of sepsis evaluations and antibiotics using our standard protocol versus theoretical application of EOS calculator. RESULTS: A total of 223/1000 infants underwent blood investigations versus 35/1000 (3.5%) if EOS calculator had been applied (p < 0.0001; k = 0.18). Furthermore, 48/1000 infants received antibiotics with our protocol versus 35/1000 with EOS calculator (p = 0.12; k = 0.58). Three infants had a positive blood culture that EOS calculator would have missed. CONCLUSIONS: In our study, EOS calculator could have reduced investigations but not antibiotic therapy. EOS calculator is an effective and promising tool, but further studies are required to improve it.

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.

Effects of Perinatal Antibiotic Exposure and Neonatal Gut Microbiota.

Antibiotic therapy is one of the most important strategies to treat bacterial infections. The overuse of antibiotics, especially in the perinatal period, is associated with long-lasting negative consequences such as the spread of antibiotic resistance and alterations in the composition and function of the gut microbiota, both of which negatively affect human health. In this review, we summarize recent evidence about the influence of antibiotic treatment on the neonatal gut microbiota and the subsequent negative effects on the health of the infant. We also analyze the possible microbiome-based approaches for the re-establishment of healthy microbiota in neonates.

The Role of Virulence Factors in Neonatal Sepsis Caused by Enterobacterales: A Systematic Review.

Neonatal sepsis is a life-threatening condition with high mortality. Virulence determinants relevant in causing Gram-negative (GN) neonatal sepsis are still poorly characterized. A better understanding of virulence factors (VFs) associated with GN neonatal sepsis could offer new targets for therapeutic interventions. The aim of this review was to assess the role of GN VFs in neonatal sepsis. We primarily aimed to investigate the main VFs leading to adverse outcome and second to evaluate VFs associated with increased invasiveness/pathogenicity in neonates. MEDLINE, Embase, and Cochrane Library were systematically searched for studies reporting data on the role of virulome/VFs in bloodstream infections caused by Enterobacterales among neonates and infants aged 0-90 days. Twenty studies fulfilled the inclusion criteria. Only 4 studies reported data on the association between pathogen virulence determinants and neonatal mortality, whereas 16 studies were included in the secondary analyses. The quality of reporting was suboptimal in the great majority of the published studies. No consistent association between virulence determinants and GN strains causing neonatal sepsis was identified. Considerable heterogeneity was found in terms of VFs analysed and reported, included population and microbiological methods, with the included studies often showing conflicting data. This variability hampered the comparison of the results. In conclusions, pathogens responsible for neonatal sepsis are widely heterogenous and can use different pathways to develop invasive disease. The recent genome-wide approach needs to include multicentre studies with larger sample sizes, analyses of VF gene profiles instead of single VF genes, alongside a comprehensive collection of clinical information. A better understanding of the roles of virulence genes in neonatal GN bacteraemia may offer new vaccine targets and new markers of highly virulent strains. This information can potentially be used for screening and preventive interventions as well as for new targets for anti-virulence antibiotic-sparing therapies.

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.

Treatment and Outcomes of Children With Febrile Urinary Tract Infection Due to Extended Spectrum Beta-lactamase-producing Bacteria in Europe: TOO CUTE Study.

BACKGROUND: The prevalence of extended-spectrum beta-lactamase producing Εnterobacteriaceae (ESBL-PE) is increasing globally. ESBL-PE are an important cause of urinary tract infections (UTIs) in children. We aimed to characterize the clinical presentation, treatment and outcomes of childhood UTI caused by ESBL-PE in Europe. METHODS: Multicenter retrospective cohort study. Children 0 to 18 years of age with fever, positive urinalysis and positive urine culture for an ESBL-PE uropathogen, seen in a participating hospital from January 2016 to July 2017, were included. MAIN OUTCOME MEASURES: Primary outcome measure: day of defervescence was compared between (1) initial microbiologically effective treatment (IET) versus initial microbiologically ineffective treatment (IIT) and (2) single initial antibiotic treatment versus combined initial antibiotic treatment. SECONDARY OUTCOME MEASURES: Clinical and microbiologic failure of initial treatment. RESULTS: We included 142 children from 14 hospitals in 8 countries. Sixty-one children had IET and 77 IIT. There was no statistical difference in time to defervescence for effective/ineffective groups (P = 0.722) and single/combination therapy groups (P = 0.574). Two of 59 (3.4%) and 4/66 (6.1%) patients exhibited clinical failure during treatment (P = 0.683) when receiving IET or IIT, respectively. Eight of 51 (15.7%) receiving IET and 6/58 (10.3%) receiving IIT patients (P = 0.568) had recurring symptoms/signs suggestive of a UTI. Recurrence of a UTI occurred 15.5 days (interquartile range, 9.0-19.0) after the end of treatment. CONCLUSIONS: Time to defervescence and clinical failure did not differ between IET/IIT groups. Non-carbapenem beta-lactam antibiotics may be used for the empiric treatment of ESBL febrile UTIs, until susceptibility testing results become available.

Gastrointestinal Symptoms in Severe COVID-19 Children.

There are growing evidence of clinical manifestations other than acute respiratory syndrome in severe acute respiratory syndrome associated with coronavirus 2-infected children. In our multicenter retrospective analysis, we observed among 127 severe acute respiratory syndrome associated with coronavirus 2 positive children that the presence of gastrointestinal symptoms was more frequently associated with severe and critical phenotype (P = 0.029). Moreover, having gastrointestinal symptoms was more frequently reported in patients who developed cardiac impairment.

Interventions to reduce occupational stress and burn out within neonatal intensive care units: a systematic review.

Occupational stress is an emerging problem among physician and nurses, and those working in intensive care settings are particularly exposed to the risk of developing burnout. To verify what types of interventions to manage occupational stress and burn out within neonatal intensive care units (NICUs) have been introduced so far and to verify their efficacy among caregivers. PsycINFO (PsycINFO 1967-July week 3 2019), Embase (Embase 1996-2019 week 29) e Medline (Ovid MEDLINE(R) without revisions 1996-July week 2 2019) were systematically searched combining MeSH and free text terms for "burn out" AND "healthcare provider" AND "NICU". Inclusion criteria were interventions directed to healthcare providers settled in NICUs. Only English language papers were included. Six articles were included in the final analysis. All the studies reported an overall efficacy of the interventions in reducing work-related stress, both when individual focused and organisation directed. The analysis revealed low quality of the studies and high heterogeneity in terms of study design, included populations, interventions and their evaluation assessment. There is currently very limited evidence regarding the management of occupational stress and burn out within NICUs. The quality of available studies was suboptimal. The peculiarities of the NICUs should be considered when developing strategies for occupational stress management. Training self-awareness of workers regarding their reactions to the NICU environment, also from the pre-employment stage, could be an additional approach to prevent and manage stress.

Rotavirus vaccines in clinical development: Current pipeline and state-of-the-art.

Rotavirus (RV) disease is a leading cause of mortality and morbidity, especially in children under 5 years of age. The introduction of the two oral rotavirus vaccines Rotarix® and RotaTeq® has shown significant reductions in RV-related mortality, severe RV disease, and hospitalizations. However, some barriers, including a reduced efficacy in low-income countries, safety issues regarding the intussusception risk, age restrictions on vaccine use, the live-attenuated nature itself, and the substantial vaccine costs, currently restrict the full potential of RV disease prevention. Therefore, research is now focusing on the implementation of new oral vaccines and the development of parenteral vaccines to overcome these limits. This review provides an overview of the new rotavirus vaccines in clinical development and the ongoing clinical trials on new RV vaccines in the pediatric age.

Strategic Trials to Define the Best Available Treatment for Neonatal and Pediatric Sepsis Caused by Carbapenem-resistant Organisms.

The optimal standard of care for carbapenem-resistant bloodstream infections in children is currently unknown. This systematic review, aiming to define the best available treatments to be compared with new antibiotics in clinical trials, clearly points out the paucity of available data. The simplification and a wider harmonization of study design are a global priority to inform the best strategies to treat these life-threatening infections in children.

Future Challenges in Pediatric and Neonatal Sepsis: Emerging Pathogens and Antimicrobial Resistance.

The incidence of severe infections caused by multidrug-resistant (MDR) pathogens is currently rising worldwide, and increasing numbers of neonates and children with serious bloodstream infections due to resistant bacteria are being reported. Severe sepsis and septic shock due to gram-negative bacteria represent a significant cause of morbidity and mortality, and contribute to high health care costs. Antimicrobial resistance among Enterobacteriaceae represents a major problem in both health care-associated and community-acquired infections, with extended-spectrum ß-lactamases (ESBLs) and carbapenem-resistant Enterobacteriaceae (CRE) now presenting the main threat. These infections in adult populations have been associated with poor clinical outcomes, but very limited data have been published so far about risk factors and clinical outcome of ESBL-associated and CRE sepsis in the pediatric population. The treatment of these infections in neonates and children is particularly challenging due to the limited number of available effective antimicrobials. Evidence-based use of new and older antibiotics based on both strategic and regulatory clinical trials is paramount to improve management of these severe infections in neonates and children.

Standardising neonatal and paediatric antibiotic clinical trial design and conduct: the PENTA-ID network view.

Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators.

Antibiotics and Cure Rates in Childhood Febrile Urinary Tract Infections in Clinical Trials: A Systematic Review and Meta-analysis.

PURPOSE: Urinary tract infections (UTIs) are common bacterial infections among children. OBJECTIVE: To systematically review the antimicrobials used for febrile UTIs in paediatric clinical trials and meta-analyse the observed cure rates and reasons for treatment failure. MATERIALS AND METHODS: We searched Medline, Embase and Cochrane central databases between January 1, 1990, and November 24, 2016, combining MeSH and free-text terms for: "urinary tract infections", AND "therapeutics", AND "clinical trials" in children (age range 0-18 years). Two independent reviewers assessed study quality and performed data extraction. The major outcome measures were clinical and microbiological cure rates according to different antibiotics. RESULTS: We identified 2762 published studies and included 30 clinical trials investigating 3913 cases of paediatric febrile urinary tract infections. Children with no underlying condition were the main population included in the trials (n = 2602; 66.5%). Cephalosporins were the most frequent antibiotics studied in trials (22/30, 73.3%). Only a few antibiotics active against resistant UTIs have been tested in randomised clinical trials, mainly aminoglycosides. The average point cure rate of all investigational drugs was estimated to 95.3% (95% CI 93.5-96.9%). Among 3002 patients for whom cure and failure rates were reported, only 3.9% (3.9%; 118/3002) were considered clinically to have treatment failure, while 135 (4.5%; 135/3002) had microbiological failure. CONCLUSIONS: We observed high treatment cure rates, regardless of the investigational drug chosen, the route of administration, duration and dosing. This suggests that future research should prioritise observational studies and clinical trials on children with multi-drug-resistant infections.

Evaluating Safety Reporting in Paediatric Antibiotic Trials, 2000-2016: A Systematic Review and Meta-Analysis.

BACKGROUND: There are very few options to treat multidrug-resistant bacterial infections in children. A major barrier is the duration and complexity of regulatory trials of new antibiotics. Extrapolation of safety data from adult trials could facilitate drug development for children. OBJECTIVE: We performed a systematic review on the safety of antibiotic clinical trials (CTs) in children (0-18 years) to evaluate the overall quality of safety trials conducted in children and to determine if age-specific adverse events (AEs) could be identified for specific antibiotic classes. DATA SOURCES: We searched the MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov electronic databases for trials conducted between 2000 and 2016. STUDY SELECTION: All trials in which safety was declared a primary or secondary endpoint were included. Exclusion criteria were (1) topical or inhalational route of administration; (2) non-infectious conditions; (3) administration for prophylaxis rather than treatment; (4) selected population (i.e. cystic fibrosis, malignancies, HIV and tuberculosis); and (5) design other than randomized controlled trials. Trials reporting data on both adults and children were included only if paediatric results were reported separately. DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted the data. To assess the quality of published trials, the Extension for harms for Consolidated Standards of Reporting Trials (CONSORT) Statement 2004 was used. MAIN OUTCOME AND MEASURE: In order to quantitatively assess the rate of developing AEs by drug class, the numbers of overall and body-system-specific AEs were collected for each study arm, and then calculated per single drug class as median and interquartile range (IQR) of the proportions across CTs. The AEs most frequently reported were compared in the meta-analysis by selecting the CTs on the most represented drug classes. RESULTS: Eighty-three CTs were included, accounting for 27,693 children. Overall, 69.7% of CONSORT items were fully reported. The median proportion of children with any AE was 22.5%, but did not exceed 8% in any single body system. Serious drug-related AEs and drug-related discontinuations were very rare (median 0.3 and 0.9%, respectively). Limitations included the inability to stratify by age group, particularly neonates. CONCLUSIONS AND RELEVANCE: Overall, AEs in paediatric antibiotic CTs were predictable and class-specific, and no unexpected (age-specific) side effects were identified. Smaller, open-label, dose-finding, high-quality, single-arm pharmacokinetic trials seem potentially sufficient for certain common antibiotic classes, extrapolating well-established safety profiles determined from large adult efficacy trials. This approach could reduce duration and enhance subsequent registration of urgently needed new antibiotics. This will need to be combined with enhanced methods of pharmacovigilance for monitoring of emerging AEs in routine clinical practice.

Urinary Tract Infection Antibiotic Trial Study Design: A Systematic Review.

CONTEXT: Urinary tract infections (UTIs) represent common bacterial infections in children. No guidance on the conduct of pediatric febrile UTI clinical trials (CTs) exist. OBJECTIVE: To assess the criteria used for patient selection and the efficacy end points in febrile pediatric UTI CTs. DATA SOURCES: Medline, Embase, Cochrane central databases, and clinicaltrials.gov were searched between January 1, 1990, and November 24, 2016. STUDY SELECTION: We combined Medical Subject Headings terms and free-text terms for "urinary tract infections" and "therapeutics" and "clinical trials" in children (0-18 years), identifying 3086 articles. DATA EXTRACTION: Two independent reviewers assessed study quality and performed data extraction. RESULTS: We included 40 CTs in which a total of 4381 cases of pediatric UTIs were investigated. Positive urine culture results and fever were the most common inclusion criteria (93% and 78%, respectively). Urine sampling method, pyuria, and colony thresholds were highly variable. Clinical and microbiological end points were assessed in 88% and 93% of the studies, respectively. Timing for end point assessment was highly variable, and only 3 studies (17%) out of the 18 performed after the Food and Drug Administration 1998 guidance publication assessed primary and secondary end points consistently with this guidance. LIMITATIONS: Our limitations included a mixed population of healthy children and children with an underlying condition. In 6 trials, researchers studied a subgroup of patients with afebrile UTI. CONCLUSIONS: We observed a wide variability in the microbiological inclusion criteria and the timing for end point assessment. The available guidance for adults appear not to be used by pediatricians and do not seem applicable to the childhood UTI. A harmonized design for pediatric UTIs CT is necessary.