Association of Empiric Antibiotic Regimen Discordance With 30-Day Mortality in Neonatal and Pediatric Bloodstream Infection-A Global Retrospective Cohort Study.

2020

2020 Dec 21

1532-0987

<p><strong>BACKGROUND: </strong>While there have been studies in adults reporting discordant empiric antibiotic treatment associated with poor outcomes, this area is relatively unexplored in children and neonates despite evidence of increasing resistance to recommended first-line treatment regimens.</p>

<p><strong>METHODS: </strong>Patient characteristics, antibiotic treatment, microbiology, and 30-day all-cause outcome from children &lt;18 years with blood-culture-confirmed bacterial bloodstream infections (BSI) were collected anonymously using REDCap™ through the Global Antibiotic Prescribing and Resistance in Neonates and Children network from February 2016 to February 2017. Concordance of early empiric antibiotic treatment was determined using European Committee on Antimicrobial Susceptibility Testing interpretive guidelines. The relationship between concordance of empiric regimen and 30-day mortality was investigated using multivariable regression.</p>

<p><strong>RESULTS: </strong>Four hundred fifty-two children with blood-culture-positive BSI receiving early empiric antibiotics were reported by 25 hospitals in 19 countries. Sixty percent (273/452) were under the age of 2 years. S. aureus, E. coli, and Klebsiella spp. were the most common isolates, and there were 158 unique empiric regimens prescribed. Fifteen percent (69/452) of patients received a discordant regimen, and 7.7% (35/452) died. Six percent (23/383) of patients with concordant regimen died compared with 17.4% (12/69) of patients with discordant regimen. Adjusting for age, sex, presence of comorbidity, unit type, hospital-acquired infections, and Gram stain, the odds of 30-day mortality were 2.9 (95% confidence interval: 1.2-7.0; P = 0.015) for patients receiving discordant early empiric antibiotics.</p>

<p><strong>CONCLUSIONS: </strong>Odds of mortality in confirmed pediatric BSI are nearly 3-fold higher for patients receiving a discordant early empiric antibiotic regimen. The impact of improved concordance of early empiric treatment on mortality, particularly in critically ill patients, needs further evaluation.</p>

10.1097/INF.0000000000002910

Pediatr Infect Dis J

33395208

Use of Antimicrobial Agents in Hospitalized Children for Noninfectious Indications.

2019

2019 Jul 31

2048-7207

<p>In this point-prevalence study of 32 US children's hospitals, we determined that 1.7% of hospitalized children received at least 1 antimicrobial agent for a non-infection-related reason; macrolides were used most commonly. Antimicrobial stewardship efforts to understand and affect use for these reasons is an unmet need; additional research considering the individual and societal effects of these antimicrobial-prescribing practices should be undertaken.</p>

10.1093/jpids/piz053

J Pediatric Infect Dis Soc

32677678

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

2020

3

2020

2047-2994

<p><strong>Background: </strong>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.</p>

<p><strong>Methods: </strong>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.</p>

<p><strong>Results: </strong>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 and a reduction in the rate of 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 following a reduction in the use of macrolides.</p>

<p><strong>Conclusions: </strong>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.</p>

10.1186/s13756-019-0659-3

Antimicrob Resist Infect Control

31911831

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

2020

3

2020 Jan 03

2047-2994

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.

10.1186/s13756-019-0659-3

Antimicrob Resist Infect Control

32381119

Appropriateness of Antibiotic Prescribing in U.S. Children's Hospitals: A National Point Prevalence Survey.

2020

2020 Jan 16

1537-6591

<p><strong>BACKGROUND: </strong>Studies estimate that 30-50% of antibiotics prescribed for hospitalized patients are inappropriate, but pediatric data are limited. Characterization of inappropriate prescribing practices for children are needed to guide pediatric antimicrobial stewardship.</p>

<p><strong>METHODS: </strong>Cross-sectional analysis of antibiotic prescribing at 32 US children's hospitals. Subjects included hospitalized children with ≥1 antibiotic order at 0800 on one day per calendar quarter, over six quarters (Quarter 3 2016 - Quarter 4 2017). Antimicrobial stewardship program (ASP) physicians and/or pharmacists used a standardized survey to collect data on antibiotic orders and evaluate appropriateness. The primary outcome was the percentage of antibiotics prescribed for infectious use that were classified as suboptimal, defined as inappropriate or needing modification.</p>

<p><strong>RESULTS: </strong>Of 34 927 children hospitalized on survey days, 12 213 (35.0%) had ≥1 active antibiotic order. Among 11 784 patients receiving antibiotics for infectious use, 25.9% were prescribed ≥1 suboptimal antibiotic. Of the 17 110 antibiotic orders prescribed for infectious use, 21.0% were considered suboptimal. Most common reasons for inappropriate use were bug-drug mismatch (27.7%), surgical prophylaxis &gt;24 hours (17.7%), overly broad empiric therapy (11.2%), and unnecessary treatment (11.0%). The majority of recommended modifications were to stop (44.7%) or narrow (19.7%) the drug. ASPs would not have routinely reviewed 46.1% of suboptimal orders.</p>

<p><strong>CONCLUSIONS: </strong>Across 32 children's hospitals, approximately 1 in 3 hospitalized children are receiving one or more antibiotics at any given time. One quarter of these children are receiving suboptimal therapy, and nearly half of suboptimal use is not captured by current ASP practices.</p>

10.1093/cid/ciaa036

Clin. Infect. Dis.

31942952

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

2019

e032592

2019 Dec 31

2044-6055

<p>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.</p>

10.1136/bmjopen-2019-032592

BMJ Open

31892658

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

2018

2018 Oct 11

1179-1950

<p><strong>PURPOSE: </strong>Urinary tract infections (UTIs) are common bacterial infections among children.</p>

<p><strong>OBJECTIVE: </strong>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.</p>

<p><strong>MATERIALS AND METHODS: </strong>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&nbsp;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.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

10.1007/s40265-018-0988-1

Drugs

30311096

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

2017

2017 Dec

1098-4275

<p><strong>CONTEXT: </strong>Urinary tract infections (UTIs) represent common bacterial infections in children. No guidance on the conduct of pediatric febrile UTI clinical trials (CTs) exist.</p>

<p><strong>OBJECTIVE: </strong>To assess the criteria used for patient selection and the efficacy end points in febrile pediatric UTI CTs.</p>

<p><strong>DATA SOURCES: </strong>Medline, Embase, Cochrane central databases, and clinicaltrials.gov were searched between January 1, 1990, and November 24, 2016.</p>

<p><strong>STUDY SELECTION: </strong>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.</p>

<p><strong>DATA EXTRACTION: </strong>Two independent reviewers assessed study quality and performed data extraction.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>LIMITATIONS: </strong>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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

10.1542/peds.2017-2209

Pediatrics

29187579

Harmonisation in study design and outcomes in paediatric antibiotic clinical trials: a systematic review.

2016

e178-89

2016 Sep

1474-4457

<p>There is no global consensus on the conduct of clinical trials in children and neonates with complicated clinical infection syndromes. No comprehensive regulatory guidance exists for the design of antibiotic clinical trials in neonates and children. We did a systematic review of antibiotic clinical trials in complicated clinical infection syndromes (including bloodstream infections and community-acquired pneumonia) in children and neonates (0-18 years) to assess whether standardised European Medicines Agency (EMA) and US Food and Drug Administration (FDA) guidance for adults was used in paediatrics, and whether paediatric clinical trials applied consistent definitions for eligibility and outcomes. We searched MEDLINE, Cochrane CENTRAL databases, and ClinicalTrials.gov between Jan 1, 2000, and Nov 18, 2015. 82 individual studies met our inclusion criteria. The published studies reported on an average of 66% of CONSORT items. Study design, inclusion and exclusion criteria, and endpoints varied substantially across included studies. The comparison between paediatric clinical trials and adult EMA and FDA guidance highlighted that regulatory definitions are only variably applicable and used at present. Absence of consensus for paediatric antibiotic clinical trials is a major barrier to harmonisation in research and translation into clinical practice. To improve comparison of therapies and strategies, international collaboration among all relevant stakeholders leading to harmonised case definitions and outcome measures is needed.</p>

10.1016/S1473-3099(16)00069-4

Lancet Infect Dis

27375212

Variation in paediatric hospital antibiotic guidelines in Europe.

2016

72-6

2016 Jan

1468-2044

<p><strong>OBJECTIVE: </strong>To assess the availability and source of guidelines for common infections in European paediatric hospitals and determine their content and characteristics.</p>

<p><strong>DESIGN: </strong>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.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

10.1136/archdischild-2015-308255

Arch. Dis. Child.

26416900