Cefotaxime/sulbactam plus gentamicin as a potential carbapenem- and amikacin-sparing first-line combination for neonatal sepsis in high ESBL prevalence settings.

BACKGROUND: Infection with ESBL-producing Enterobacteriaceae infection is ubiquitous in some neonatal ICUs and increasing levels of antibiotic resistance are a cause for urgent concern. Delineation of bacterial and viral sepsis can be challenging, often leading to patients receiving empirical antibiotics without or whilst waiting for a definitive causal diagnosis. Empirical therapy is often dependent on broad-spectrum 'Watch' antibiotics, contributing to further resistance. METHODS: ESBL-producing Enterobacteriaceae clinical isolates found to have caused neonatal sepsis and meningitis underwent a detailed in vitro screening including susceptibility testing, chequerboard combination analysis and hollow-fibre infection model dynamic analyses using combinations of cefotaxime, ampicillin and gentamicin in combination with ß-lactamase inhibitors. RESULTS: Additivity or synergy was found for all antibiotic combinations against seven Escherichia coli and three Klebsiella pneumoniae clinical isolates. Cefotaxime or ampicillin plus sulbactam combined with gentamicin was able to consistently inhibit the growth of ESBL-producing isolates at typical neonatal doses, and the combination cleared the hollow-fibre infection model system of organisms resistant to each agent alone. The combination of cefotaxime/sulbactam and gentamicin was consistently bactericidal at clinically achievable concentrations (Cmax of 180, 60 and 20 mg/L for cefotaxime, sulbactam and gentamicin, respectively). CONCLUSIONS: The addition of sulbactam to cefotaxime or ampicillin to the typical first-line empirical therapy could obviate the need for carbapenems and amikacin in settings with high ESBL-infection prevalence.

Correction to: Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review.

The original article [1] contains an error in Fig. 1 whereby the number of selected articles of the first box is incorrect.

Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review.

Background: Antibiotics are the most common medicines prescribed to children in hospitals and the community, with a high proportion of potentially inappropriate use. Antibiotic misuse increases the risk of toxicity, raises healthcare costs, and selection of resistance. The primary aim of this systematic review is to summarize the current state of evidence of the implementation and outcomes of pediatric antimicrobial stewardship programs (ASPs) globally. Methods: MEDLINE, Embase and Cochrane Library databases were systematically searched to identify studies reporting on ASP in children aged 0-18 years and conducted in outpatient or in-hospital settings. Three investigators independently reviewed identified articles for inclusion and extracted relevant data. Results: Of the 41,916 studies screened, 113 were eligible for inclusion in this study. Most of the studies originated in the USA (52.2%), while a minority were conducted in Europe (24.7%) or Asia (17.7%). Seventy-four (65.5%) studies used a before-and-after design, and sixteen (14.1%) were randomized trials. The majority (81.4%) described in-hospital ASPs with half of interventions in mixed pediatric wards and ten (8.8%) in emergency departments. Only sixteen (14.1%) studies focused on the costs of ASPs. Almost all the studies (79.6%) showed a significant reduction in inappropriate prescriptions. Compliance after ASP implementation increased. Sixteen of the included studies quantified cost savings related to the intervention with most of the decreases due to lower rates of drug administration. Seven studies showed an increased susceptibility of the bacteria analysed with a decrease in extended spectrum beta-lactamase producers E. coli and K. pneumoniae; a reduction in the rate of P. aeruginosa carbapenem resistance subsequent to an observed reduction in the rate of antimicrobial days of therapy; and, in two studies set in outpatient setting, an increase in erythromycin-sensitive S. pyogenes following a reduction in the use of macrolides. Conclusions: Pediatric ASPs have a significant impact on the reduction of targeted and empiric antibiotic use, healthcare costs, and antimicrobial resistance in both inpatient and outpatient settings. Pediatric ASPs are now widely implemented in the USA, but considerable further adaptation is required to facilitate their uptake in Europe, Asia, Latin America and Africa.

Auditing use of antibiotics in Zimbabwean neonates.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality in low-income settings. As signs of sepsis are non-specific and deterioration precipitous, antibiotics are often used profusely in these settings where diagnostics may not be readily available. Harare Central Hospital, Zimbabwe, delivers 12000 babies per annum admitting ∼4800 to the neonatal unit. Overcrowding, understaffing and rapid staff turnover are consistent problems. Suspected sepsis is highly prevalent, and antibiotics widely used. We audited the impact of training and benchmarking intervention on rationalizing antibiotic prescription using local, World Health Organization-derived, guidelines as the standard. METHODS: An initial audit of admission diagnosis and antibiotic use was performed between 8th May - 6th June 2018 as per the audit cycle. An intern training programme, focusing on antimicrobial stewardship and differentiating between babies 'at risk of' versus 'with' clinically-suspected sepsis was instituted post-primary audit. Re-audit was conducted after 5 months. RESULTS: Sepsis was the most common admitting diagnosis by interns at both time points but reduced at repeat audit (81% versus 59%, P<0.0001). Re-audit after 5 months demonstrated a decrease in antibiotic prescribing at admission and discharge. Babies prescribed antibiotics at admission decreased from 449 (98%) to 96 (51%), P<0.0001. Inpatient days of therapy (DOT) reduced from 1243 to 1110/1000 patient-days. Oral amoxicillin prescription at discharge reduced from 349/354 (99%) to 1% 1/161 (P<0.0001). CONCLUSION: A substantial decrease in antibiotic use was achieved by performance feedback, training and leadership, although ongoing performance review will be key to ensuring safety and sustainability.

Interventions to prevent urinary catheter-associated infections in children and neonates: a systematic review.

INTRODUCTION: Few data are available to inform strategies for the prevention of catheter-associated urinary tract infection (CAUTI) in children and neonates. Many recommendations are derived from studies in adults and cannot be applied to the paediatric population. OBJECTIVE: This study was aimed to identify all studies that measured the efficacy of an intervention for the prevention of CAUTI in children and neonates. METHODS: A systematic review using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) was conducted. Eligible studies published between January 1st, 1995 and December 31st, 2017, were identified in PubMed, the Cochrane Database of Systematic Reviews, LILACS, SciELO and DOAJ if applying an intervention with the aim of CAUTI prevention in inpatient children, infants or neonates. The following study designs were included: controlled and non-controlled before-and-after studies, (controlled) interrupted time series analyses and randomized controlled trials. Quantitative or qualitative studies on interventions in both adults and children were eligible if data on children could be extracted. Reviews, case series, letters, notes, conference abstracts and opinion articles were excluded. RESULTS: Of 99 articles identified, six were included in the final analysis, after consensus from three independent investigators. Four studies used a multimodal strategy (using at least four or more different components at the same time) as follows: aseptic rules during catheter insertion and removal; cleaning the urethral meatus with sterile water; use of a new silicone catheter per insertion with a closed sterile drainage system by a sterile technique; daily evaluation of catheter requirement; placement of indwelling urinary catheters only for approved indications; reducing of urinary catheter days and positioning of the patient and collection device to assist in urine drainage. One study tested periurethral cleaning intervention to reduce CAUTI. One study described the association of the presence of a physician safety champion with urinary catheter device utilization ratios. Catheter-associated UTI reduction rates were reported in four studies; three achieved statistically significant decreases in CAUTI rates. Positive results were achieved only when a multimodal strategy was used with at least four or more components. This strategy could be adopted for paediatric healthcare institutions to reduce CAUTI rates in children and neonates. CONCLUSION: Evidence exists to support the use of a multimodal strategy for CAUTI reduction in hospitalized children and neonates.

Role of antimicrobial stewardship programmes in children: a systematic review.

The United Nations and the World Health Organization have designated antimicrobial resistance (AMR) as a major health priority and developed action plans to reduce AMR in all healthcare settings. Establishment of institutional antimicrobial stewardship programmes (ASPs) is advocated as a key intervention to reduce antibiotic consumption in hospitals and address high rates of multi-drug-resistant (MDR) bacteria. PUBMED and the Cochrane Database of Systematic Reviews (January 2007-March 2017) were searched to identify studies reporting the effectiveness of ASPs in general paediatric wards and paediatric intensive care units (PICUs) for reducing antibiotic consumption, use of broad-spectrum/restricted antibiotics, and antibiotic resistance and healthcare-associated infections (HAIs). Neonatal units and antifungal agents were excluded. Of 2509 titles and abstracts, nine articles were eligible for inclusion in the final analysis. All studies reported a reduction in the use of broad-spectrum/restricted antibiotics or antibiotic consumption. One study reported a reduction in HAIs in a PICU, and another study evaluated bacterial resistance, showing no effect following ASP implementation. Prospective audit on antibiotic use was the most common ASP core component (eight of nine studies). Antibiotic pre-authorization was described in two studies. Other described interventions were the provision of guidelines or written information (five of nine studies), and training of healthcare professionals (one study). There is limited evidence for a reduction in antibiotic consumption and use of broad-spectrum/restricted agents following ASP implementation specifically in PICUs. Data evaluating the impact of ASPs on HAIs and AMR in PICUs are lacking. In addition, there is limited information on effective components of a successful ASP in PICUs.

The methodology of surveillance for antimicrobial resistance and healthcare-associated infections in Europe (SUSPIRE): a systematic review of publicly available information.

OBJECTIVES: Surveillance is a key component of any control strategy for healthcare-associated infections (HAIs) and antimicrobial resistance (AMR), and public availability of methodologic aspects is crucial for the interpretation of the data. We sought to systematically review publicly available information for HAIs and/or AMR surveillance systems organized by public institutions or scientific societies in European countries. METHODS: A systematic review of scientific and grey literature following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was performed. Information on HAIs and/or AMR surveillance systems published until 31 October 2016 were included. RESULTS: A total of 112 surveillance systems were detected; 56 from 20 countries were finally included. Most exclusions were due to lack of publicly available information. Regarding AMR, the most frequent indicator was the proportion of resistant isolates (27 of 34 providing information, 79.42%); only 18 (52.9%) included incidence rates; the data were only laboratory based in 33 (78.5%) of the 42 providing this information. Regarding HAIs in intensive care units, all 22 of the systems providing data included central line-associated bloodstream infections, and 19 (86.3%) included ventilator-associated pneumonia and catheter-associated urinary tract infections; incidence density was the most frequent indicator. Regarding surgical site infections, the most frequent procedures included were hip prosthesis, colon surgery and caesarean section (21/22, 95.5%). CONCLUSIONS: Publicly available information about the methods and indicators of the surveillance system is frequently lacking. Despite the efforts of European Centre for Disease Control and Prevention (ECDC) and other organizations, wide heterogeneity in procedures and indicators still exists.

The relationship between Gram-negative colonization and bloodstream infections in neonates: a systematic review and meta-analysis.

OBJECTIVES: Neonates admitted to neonatal intensive care units (NICU) are at significant risk of developing bloodstream infections (BSIs). Gram-negative bacteria (GNB) both colonize and infect, but the association between these entities is unclear. By conducting a systematic literature review, we aimed to explore the impact of factors on the association between GN colonization and GN-BSI at both baby-level and unit-level. METHODS: We searched Medline, Embase, and Cochrane Library. Observational cohort studies published after 2000 up to June 2016 reporting data on the total number of neonates (0-28 days) colonized with GNB assessed by rectal/skin swab culture and the total number of neonates with GN-BSI (same bacteria) were included. Studies were excluded if data on skin/rectal colonization, neonates, and GNB could not be identified separately. Meta-analyses along with multivariate meta-regression with a random-effect model were performed to investigate factors associated with the GN colonization and GN-BSI at baby-level and unit-level. RESULTS: Twenty-seven studies fulfilled our inclusion criteria, 15 for the baby-level and 12 for the unit-level analysis. Study heterogeneity was high, with suboptimal overall quality of reporting assessed by the STROBE-NI statement (44.8% of items adequately reported). In 1984 colonized neonates, 157 (7.9%) developed GN-BSI compared with 85 of 3583 (2.4%) non-colonized neonates. Considerable heterogeneity was observed across studies. Four factors were included in the meta-regression model: gross domestic product (GDP), pathogen, outbreak, and frequency of screening. There was no statistically significant impact of these factors on GN colonization and GN-BSI in baby-level. We were unable to perform the multivariate meta-regression because of insufficient reported data for unit-level. CONCLUSIONS: Study limitations include the small number and the high heterogeneity of the included studies. While this report shows a correlation between colonization and BSI risk, these data currently do not support routine screening for GNB. Analysis of large cohorts of colonized neonates with clinical outcomes is still needed to define the major determinants leading from colonization to infection.

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.

Compartmentalized dynamics of cytomegalovirus replication in treated congenital infection.

BACKGROUND: Cytomegalovirus (CMV) is the most prevalent congenital infection in developed countries. A significant number of infected infants develop long-term neurodevelopmental and hearing impairment irrespective of whether disease is detectable at birth. Studies of viral load and replication dynamics have informed the treatment of CMV in adult populations but no similar data exist in neonates. OBJECTIVES: To study CMV virus kinetics in different body fluids of babies treated for congenital infection. STUDY DESIGN: CMV virus load was sequentially analyzed in blood, urine and saliva in 17 babies treated for symptomatic congenital CMV infection. RESULTS: Virus was detectable in the urine and saliva of all babies at baseline but in only 15/17 in blood. At the end of 6 weeks of antiviral treatment CMV remained detectable in 9/14 blood samples, 9/12 urine samples and 4/7 salivary swabs. Median half-life (T1/2) of virus decline in blood was 2.4 days (IQR 1.9-3.3) and basic reproductive number (Ro) was 2.3. Although T1/2 values were similar in urine and saliva to those observed in blood, virus dynamics differed both during and after treatment. CONCLUSIONS: T1/2 and Ro in blood in this group of neonates were similar to values derived from studies of immunocompromised adults. The persistent viremia observed in treated neonates cannot therefore be adequately explained by the virus dynamics early in treatment. The different dynamics exhibited in blood and urine suggests that studying changes in distinct body compartments may assist in further understanding long-term manifestations of disease.

Most international guidelines on prevention of healthcare-associated infection lack comprehensive recommendations for neonates and children.

International infection prevention and control (IPC) guidelines provide standardized recommendations for healthcare-associated infection (HCAI) prevention in adults, but often lack specific information about neonates and children. We reviewed ten international IPC/HCAI guidelines to identify paediatric-specific recommendations for HCAI prevention. Hand hygiene, bloodstream infection, ventilator-associated pneumonia, environmental control and outbreak management were frequently reported with recommendations applicable to children and newborns, but documents on catheter-associated urinary tract infection and surgical site infection were lacking.

Lack of evidence for the efficacy of enhanced surveillance compared to other specific interventions to control neonatal healthcare-associated infection outbreaks.

BACKGROUND: Despite current prevention efforts, outbreaks of healthcare-associated infections in neonatal units remain high globally, with a considerable burden of mortality and morbidity. METHODS: We searched Medline, Cochrane Library and Outbreak database to identify studies of neonatal healthcare-associated outbreaks between 2005 and 2015 that described interventions to control outbreaks. All studies were evaluated using the ORION guidance. RESULTS: Thirty studies were identified including 17 102 infants of whom 664 (3.9%) became infected. No single intervention was identified that reduced duration or mortality. Studies that introduced multiple interventions had significantly reduced case fatality ratio and outbreak duration compared to those that used basic surveillance only. Low and low-middle income countries reported the fewest interventions to control outbreaks and these studies were also associated with higher mortality than that found in middle and high income countries. CONCLUSIONS: Systematic reporting and formal evaluation of interventions used to reduce healthcare-associated neonatal infection outbreaks is key to identifying containment strategies worldwide.

Supporting decisions to increase the safe discharge of children with febrile illness from the emergency department: a systematic review and meta-analysis.

BACKGROUND: Despite fewer serious infections presenting to the children's emergency department (ED), hospital admissions of children with febrile illness have increased. We review evidence for the use of decision rules to increase the safe discharge of these children from the ED. METHODS: A systematic review of prospective studies of decision rules for the discharge of children with febrile illness, and prediction rules for the diagnosis of serious infections in children presenting to ED. We reviewed the MEDLINE database, Cochrane Library and hand searched the bibliographies of related studies. The search was limited to the English language. RESULTS: Thirty-three studies were identified. Fourteen reported low-risk criteria to rule out serious bacterial infection (SBI) in infants less than 3 months of age. In this group, clinical tools such as the Rochester and Philadelphia criteria support the safe discharge of low-risk infants without empirical antibiotics. Seventeen studies reported prediction rules in older children, though only four included children over 3 years. Two impact studies based upon multivariable prediction models failed to demonstrate any impact on rates of discharge from ED. CONCLUSIONS: The use of clinical prediction models can improve discrimination between serious and self-limiting infections in children. The application of low-risk thresholds may help to rule out serious infections and discharge children from the ED without empirical antibiotics. A growing evidence base for prediction rules has so far failed to translate into validated rules to aid decision-making. Future work should evaluate decision rules in well designed impact studies, focusing on the need for hospital admission and antibiotic therapy.

Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates.

OBJECTIVES: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens. METHODS: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations. RESULTS: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg ·â€Šh/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups. CONCLUSIONS: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.

Variation in paediatric hospital antibiotic guidelines in Europe.

OBJECTIVE: To assess the availability and source of guidelines for common infections in European paediatric hospitals and determine their content and characteristics. DESIGN: Participating hospitals completed an online questionnaire on the availability and characteristics of antibiotic prescribing guidelines and on empirical antibiotic treatment including duration of therapy for 5 common infection syndromes: respiratory tract, urinary tract, skin and soft tissue, osteoarticular and sepsis in neonates and children. RESULTS: 84 hospitals from 19 European countries participated in the survey of which 74 confirmed the existence of guidelines. Complete guidelines (existing guidelines for all requested infection syndromes) were reported by 20% of hospitals and the majority (71%) used a range of different sources. Guidelines most commonly available were those for urinary tract infection (UTI) (74%), neonatal sepsis (71%) and sepsis in children (65%). Penicillin and amoxicillin were the antibiotics most commonly recommended for respiratory tract infections (RTIs) (up to 76%), cephalosporin for UTI (up to 50%) and for skin and soft tissue infection (SSTI) and bone infection (20% and 30%, respectively). Antistaphylococcal penicillins were recommended for SSTIs and bone infections in 43% and 36%, respectively. Recommendations for neonatal sepsis included 20 different antibiotic combinations. Duration of therapy guidelines was mostly available for RTI and UTI (82%). A third of hospitals with guidelines for sepsis provided recommendations for length of therapy. CONCLUSIONS: Comprehensive antibiotic guideline recommendations are generally lacking from European paediatric hospitals. We documented multiple antibiotics and combinations for most infections. Considerable improvement in the quality of guidelines and their evidence base is required, linking empirical therapy to resistance rates.

Quantifying the Burden of Hospital-Acquired Bloodstream Infection in Children in England by Estimating Excess Length of Hospital Stay and Mortality Using a Multistate Analysis of Linked, Routinely Collected Data.

BACKGROUND: Hospital-acquired bloodstream infection (HA-BSI) is associated with substantial morbidity, mortality, and healthcare costs in all patient populations. Young children have been shown to have a high rate of healthcare-associated infections compared with the adult population. We aimed to quantify the excess mortality and length of stay in pediatric patients from HA-BSI. METHODS: We analyzed data collected retrospectively from a probabilistically linked national database of pediatric (aged 1 month-18 years) in-patients with a microbiologically confirmed HA-BSI in England between January and March 2009. A time-dependent Cox regression model was fit to determine the presence of any effect. Furthermore, a multistate model, adjusted for the time to onset of HA-BSI, was used to compare outcomes in patients with HA-BSI to those without HA-BSI. We further adjusted for patients' characteristics as recorded in hospital admission data. RESULTS: The dataset comprised 333 605 patients, with 214 cases of HA-BSI. After adjustment for time to HA-BSI and comorbidities, the hazard for discharge (dead or alive) from hospital for patients with HA-BSI was 0.9 times (95% confidence interval [CI], .8-1.1) that of noninfected patients. Excess length of stay associated with all-cause HA-BSI was 1.6 days (95% CI, .2-3.0), although this duration varied by pathogen. Patients with HA-BSI had a 3.6 (95% CI, 1.3-10.4) times higher hazard for in-hospital death than noninfected patients. CONCLUSIONS: Hospital-acquired bloodstream infection increased the length of stay and mortality of pediatric inpatients. The results of this study provide an evidence base to judge the health and economic impact of programs to prevent and control HA-BSI in children.