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.

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.

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.

Systemic antifungal prescribing in neonates and children: outcomes from the Antibiotic Resistance and Prescribing in European Children (ARPEC) Study.

The appropriate use of systemic antifungals is vital in the prevention and treatment of invasive fungal infection (IFI) in immunosuppressed children and neonates. This multicenter observational study describes the inpatient prescribing practice of antifungal drugs for children and neonates and identifies factors associated with prescribing variability. A single-day point prevalence study of antimicrobial use in hospitalized neonates and children was performed between October and December 2012. The data were entered through a study-specific Web-based portal using a standardized data entry protocol. Data were recorded from 17,693 patients from 226 centers. A total of 136 centers recorded data from 1,092 children and 380 neonates receiving at least one antifungal agent. The most frequently prescribed systemic antifungals were fluconazole (n=355) and amphotericin B deoxycholate (n=195). The most common indications for antifungal administration in children were medical prophylaxis (n=325), empirical treatment of febrile neutropenia (n=122), and treatment of confirmed or suspected IFI (n=100 [14%]). The treatment of suspected IFI in low-birthweight neonates accounted for the majority of prescriptions in the neonatal units (n=103). An analysis of variance (ANOVA) demonstrated no significant effect of clinical indication (prophylaxis or treatment of systemic or localized infection) on the total daily dose (TDD). Fewer than one-half of the patients (n=371) received a TDD within the dosing range recommended in the current guidelines. Subtherapeutic doses were prescribed in 416 cases (47%). The predominance of fluconazole and high incidence of subtherapeutic doses in participating hospitals may contribute to suboptimal clinical outcomes and an increased predominance of resistant pathogenic fungi. A global consensus on antifungal dosing and coordinated stewardship programs are needed to promote the consistent and appropriate use of antifungal drugs in neonates and children.

Timing of positive blood samples does not differentiate pathogens causing healthcare-associated from community-acquired bloodstream infections in children in England: a linked retrospective cohort study.

Paediatricians recognize that using the time-dependent community-acquired vs. hospital-acquired bloodstream infection (BSI) dichotomy to guide empirical treatment no longer distinguishes between causative pathogens due to the emergence of healthcare-associated BSIs. However, paediatric epidemiological evidence of the aetiology of BSIs in relation to hospital admission in England is lacking. For 12 common BSI-causing pathogens in England, timing of laboratory reports of positive paediatric (3 months to 5 years) bacterial blood isolates were linked to in-patient hospital data and plotted in relation to hospital admission. The majority (88·6%) of linked pathogens were isolated <2 days after hospital admission, including pathogens widely regarded as hospital acquired: Enterococcus spp. (67·2%) and Klebsiella spp. (88·9%). Neisseria meningitidis, Streptococcus pneumoniae, group A streptococcus and Salmonella spp. were unlikely to cause hospital-acquired BSI. Pathogens commonly associated with hospital-acquired BSI are being isolated <2 days after hospital admission alongside pathogens commonly associated with community-acquired BSI. We confirm that timing of blood samples alone does not differentiate between bacterial pathogens. Additional factors including clinical patient characteristics and healthcare contact should be considered to help predict the causative pathogen and guide empirical antibiotic therapy.

Antibacterial usage in English NHS hospitals as part of a national Antimicrobial Stewardship Programme.

Antimicrobial resistance (AMR) has become a global problem for health care services, with fewer antimicrobials entering the market and some pathogenic organisms becoming resistant to commonly used antimicrobials. Antimicrobial stewardship (AS), including evidence-based standard setting, education and communication, and audits of practice, has become a key method of preventing the rise in the rise in AMR. Data on antibiotic consumption are often obtained through prospective and retrospective point prevalence audits of antibiotic usage, but such studies are very resource intensive and only provide a snapshot of consumption. The objective of the study reported here was to examine longitudinal total antibacterial usage at a national level and cross-sectional usage at an individual hospital trust level using a commercial database that captures antimicrobial prescribing from at least 99% of English hospital Trusts.

The Chennai Declaration: India's landmark national commitment to antibiotic stewardship demonstrates that 'truth alone triumphs'.

A joint meeting of the medical societies in India took place in Chennai in August 2012, giving rise to national recommendations and an action plan to address the challenge of antimicrobial resistance in India. The 'Chennai Declaration', published in November 2012, has a pragmatic achievable plan and represents a bold national commitment to antibiotic stewardship and infection control across India. The global importance of implementing such an antibiotic policy as a national strategy needs to be recognized and supported internationally.

Clinically targeted screening for congenital CMV - potential for integration into the National Hearing Screening Programme.

UNLABELLED: Screening for a condition should only be undertaken if certain strict criteria are met. Congenital CMV (cCMV) is a leading cause of sensorineuronal hearing loss (SNHL) and meets many of these criteria, but is not currently screened for in the UK. Ganciclovir reduces CMV-induced progressive SNHL if treatment is begun in the first month of life. The Newborn Hearing Screening Programme (NHSP) has been shown to identify SNHL at the earliest possible age. The potential of integrating screening for cCMV into the NHSP is discussed to consolidate the link between screening, early diagnosis and management. CONCLUSION: The early diagnosis and treatment of cCMV may prevent a small proportion of late SNHL. In the absence of any screening programme, we provide evidence that clinically targeted screening through the NHSP is a potential option in the UK, enhancing the diagnostic pathway and enabling appropriate early treatment to reduce long-term morbidity.

Variation in gentamicin and vancomycin dosage and monitoring in UK neonatal units.

BACKGROUND: Gentamicin and vancomycin are commonly used in neonatal units for the treatment of life-threatening infections. This study aimed to describe the dosage regimen and the approach to therapeutic drug monitoring (TDM) for both antibiotics in units that participate in a UK neonatal network. METHODS: Questionnaires were sent to all units across the Extended Neonatal Network, requesting details of each unit's dosing regimen and TDM practice. RESULTS: A total of 43 (of 114) units replied to the gentamicin questionnaire and 29 to the vancomycin questionnaire. Ten different gentamicin dosing regimens were used, depending on gestational age and weight. Most units (79%) followed British National Formulary for Children dosing guidance regarding vancomycin, but there were nine variations in TDM practice. CONCLUSIONS: There is significant variation in gentamicin and vancomycin dosing regimens and TDM guidance across a UK network of neonatal units. The development of standardized, evidence-based protocols should be prioritized.

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.

An evaluation of the completeness of reporting of childhood tuberculosis.

The sensitivity of the Enhanced Tuberculosis Surveillance (ETS) scheme for monitoring tuberculosis in children is unknown. We used the British Paediatric Surveillance Unit (BPSU) reporting scheme to conduct a prospective observational study of tuberculosis in children aged <16 yrs in the UK. Reported cases were then matched with records from the ETS database. A total of 320 cases were reported to the BPSU between January and December 2004. We estimated that there were 557 paediatric cases in England, Wales and Northern Ireland in 2004: 222 (40%) cases reported to both BPSU and ETS, 98 (18%) reported to BPSU but not ETS and 237 (42%) reported to ETS but not BPSU. Children aged <5 yrs were significantly less likely to be reported to ETS compared with older children (p<0.01). There is substantial under-reporting of childhood tuberculosis, especially of children aged <5 yrs. ETS provides a representative picture of the demographics but may miss approximately 20% of cases. This should be taken into account when planning training and resource requirements for tuberculosis. Increased efforts are needed to ensure that all paediatric cases are reported to ETS.

Has UK guidance affected general practitioner antibiotic prescribing for otitis media in children?

BACKGROUND: Since 1997, UK guidance has advocated limiting antibiotic prescribing for otitis media. It is not known whether this has influenced general practitioner prescribing practice. Aims and objectives To investigate the trends in diagnoses and antibiotic prescribing for otitis media in children in relation to guidance. METHODS: We used the General Practice Research Database to conduct time-trend analyses of diagnoses and antibiotic prescribing for otitis media in 3 months to 15 years old, between 1990 and 2006. RESULTS: A total of 1 210 237 otitis media episodes were identified in 464 845 children; two-thirds (68%; 818 006) received antibiotics. Twenty-two percent (267 335) were classified as acute, 85% (227 335) of which received antibiotics. Overall, antibiotic prescribing for otitis media declined by 51% between 1995 and 2000. Much of this reduction predated guidance. During this period, prescribing for otitis media coded as acute increased by 22%. Children diagnosed with acute otitis media were more likely to receive antibiotics than otitis media not coded as acute (P < 0.05). From 2000 prescribing plateaued, despite publication of further guidance. Otitis media diagnoses consistently paralleled prescribing. CONCLUSIONS: The reduction in antibiotic prescribing for otitis media predated guidance. The simultaneous decrease in prescribing for non-acute otitis media and increase for acute otitis media suggest diagnostic transfer, possibly to justify the decision to treat.

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.

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.