Key Components for Antibiotic Dose Optimization of Sepsis in Neonates and Infants.

Sepsis in neonates and infants remains a major cause of death despite a decline in child mortality and morbidity over the last decades. A key factor in further reducing poor clinical outcomes is the optimal use of antibiotics in sepsis management. Developmental changes such as maturation of organ function and capacity of drug metabolizing enzymes can affect the pharmacokinetic profile and therefore the antibiotic exposure and response in neonates and infants. Optimal antibiotic treatment of sepsis in neonates and young infants is dependent on several key components such as the determination of treatment phase, the administered dose and the resulted drug exposure and microbiological response. During the initial phase of suspected sepsis, the primary focus of empirical treatment is to assure efficacy. Once bacterial infection as the cause of sepsis is confirmed the focus shifts toward a targeted treatment, ensuring an optimal balance between efficacy and safety. Interpretation of antibiotic exposure and microbiological response in neonates and infants is multifaceted. The response or treatment effect can be determined by the microbiological parameters (MIC) together with the characteristics of the pathogen (time- or concentration dependent). The antibiotic response is influenced by the properties of the causative pathogen and the unique characteristics of the vulnerable patient population such as reduced humoral response or reduced skin barrier function. Therapeutic drug monitoring (TDM) of antibiotics may be used to increase effectiveness while maximizing safety and minimizing the toxicity, but requires expertise in different fields and requires collaborations between physicians, lab technicians, and quantitative clinical pharmacologists. Understanding these clinical, pharmacological, and microbiological components and their underlying relationship can provide a scientific basic for proper antibiotic use and reduction of antibiotic resistance in neonates and infants. This highlights the necessity of a close multidisciplinary collaboration between physicians, pharmacists, clinical pharmacologists and microbiologist to assure the optimal utilization of antibiotics in neonates and young infants

Estimating antibiotic coverage from linked microbiological and clinical data from the Swiss Paediatric Sepsis Study to support empiric antibiotic regimen selection.

In light of rising antibiotic resistance, better methods for selection of empiric antibiotic treatment based on clinical and microbiological data are needed. Most guidelines target specific clinical infections, and variably adjust empiric antibiotic selection by certain patient characteristics. Coverage estimates reflect the probability that an antibiotic regimen will be active against the causative pathogen once confirmed and can provide an objective basis for empiric regimen selection. Coverage can be estimated for specific infections using a weighted incidence syndromic combination antibiograms (WISCAs) framework. However, no comprehensive data combining clinical and microbiological data for specific clinical syndromes are available in Switzerland. We therefore describe estimating coverage from semi-deterministically linked routine microbiological and cohort data of hospitalised children with sepsis. Coverage estimates were generated for each hospital and separately pooling data across ten contributing hospitals for five pre-defined patient risk groups. Data from 1,082 patients collected during the Swiss Paediatric Sepsis Study (SPSS) 2011-2015 were included. Preterm neonates were the most commonly represented group, and half of infants and children had a comorbidity. 67% of neonatal sepsis cases were hospital-acquired late-onset whereas in children 76% of infections were community-acquired. Escherichia coli, Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus were the most common pathogens. At all hospitals, ceftazidime plus amikacin regimen had the lowest coverage, and coverage of amoxicillin plus gentamicin and meropenem were generally comparable. Coverage was improved when vancomycin was included in the regimen, reflecting uncertainty about the empirically targeted pathogen spectrum. Children with community-acquired infections had high coverage overall. It is feasible to estimate coverage of common empiric antibiotic regimens from linked data. Pooling data by patient risk groups with similar expected pathogen and susceptibility profiles may improve coverage estimate precision, supporting better differentiation of coverage between regimens. Identification of data sources, selection of regimens and consideration of pathogens to target for improved empiric coverage is important

Swiss recommendations on perioperative antimicrobial prophylaxis in children

Infection following surgical procedures leads to significant morbidity and mortality in all age groups. Sterile techniques, antibiotic prophylaxis and improved postoperative wound care have contributed to the decline of surgical site infections since the early days of surgery. Recommendations on the use of perioperative antimicrobial prophylaxis exist for adults, but are rare for the paediatric population. Here, we provide a standardised approach to the effective use of antimicrobial agents for the prevention of surgical site infections in children contributing to a targeted and rational perioperative use of antibiotics in Switzerland

Estimating antibiotic coverage from linked microbiological and clinical data from the Swiss Paediatric Sepsis Study to support empiric antibiotic regimen selection

In light of rising antibiotic resistance, better methods for selection of empiric antibiotic treatment based on clinical and microbiological data are needed. Most guidelines target specific clinical infections, and variably adjust empiric antibiotic selection by certain patient characteristics. Coverage estimates reflect the probability that an antibiotic regimen will be active against the causative pathogen once confirmed and can provide an objective basis for empiric regimen selection. Coverage can be estimated for specific infections using a weighted incidence syndromic combination antibiograms (WISCAs) framework. However, no comprehensive data combining clinical and microbiological data for specific clinical syndromes are available in Switzerland. We therefore describe estimating coverage from semi-deterministically linked routine microbiological and cohort data of hospitalised children with sepsis. Coverage estimates were generated for each hospital and separately pooling data across ten contributing hospitals for five pre-defined patient risk groups. Data from 1,082 patients collected during the Swiss Paediatric Sepsis Study (SPSS) 2011-2015 were included. Preterm neonates were the most commonly represented group, and half of infants and children had a comorbidity. 67% of neonatal sepsis cases were hospital-acquired late-onset whereas in children 76% of infections were community-acquired. Escherichia coli, Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus were the most common pathogens. At all hospitals, ceftazidime plus amikacin regimen had the lowest coverage, and coverage of amoxicillin plus gentamicin and meropenem were generally comparable. Coverage was improved when vancomycin was included in the regimen, reflecting uncertainty about the empirically targeted pathogen spectrum. Children with community-acquired infections had high coverage overall. It is feasible to estimate coverage of common empiric antibiotic regimens from linked data. Pooling data by patient risk groups with similar expected pathogen and susceptibility profiles may improve coverage estimate precision, supporting better differentiation of coverage between regimens. Identification of data sources, selection of regimens and consideration of pathogens to target for improved empiric coverage is important

Pharmacogenetic Analysis of Voriconazole Treatment in Children

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPKcdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections. Keywords: ABCC2; ABCG2; CYP2C19; CYP3A4; children; non-linear mixed effects modelling; pediatric pharmacology; pharmacogenetics; therapeutic drug monitoring; voriconazol

Detection of mostly viral pathogens and high proportion of antibiotic treatment initiation in hospitalised children with community-acquired pneumonia in Switzerland – baseline findings from the first two years of the KIDS-STEP trial

AIMS OF THE STUDY: Globally, since the introduction of conjugate-vaccines against encapsulated bacteria, respiratory viruses have caused most hospitalisations for community-acquired pneumonia. The aim of this study was to describe pathogens detected and their association with clinical findings in Switzerland. METHODS: Baseline data were analysed for all trial participants enrolled between September 2018 and September 2020 into the KIDS-STEP Trial, a randomised controlled superiority trial on the effect of betamethasone on clinical stabilisation of children admitted with community-acquired pneumonia. Data included clinical presentation, antibiotic use and results of pathogen detection. In addition to routine sampling, nasopharyngeal specimens were analysed for respiratory pathogens using a panel polymerase chain reaction test covering 18 viral and 4 bacterial pathogens. RESULTS: 138 children with a median age of 3 years were enrolled at the eight trial sites. Fever (obligatory for enrolment) had been present for median 5 days before admission. Most common symptoms were reduced activity (129, 93.5%) and reduced oral intake (108, 78.3%). Oxygen saturation <92% was found in 43 (31.2%). Forty-three participants (29.0%) were already on antibiotic treatment prior to admission and 104 participants (75.4%) received antibiotic treatment on admission. Pathogen testing results were available from 132 children: 31 (23.5%) had respiratory syncytial virus detected, 21 (15.9%) human metapneumovirus. The pathogens detected showed expected seasonal and age preponderance and were not associated with chest X-ray findings. CONCLUSIONS: In the context of the predominantly viral pathogens detected, the majority of antibiotic treatment is probably unnecessary. The ongoing trial, as well as other studies, will be able to provide comparative pathogen detection data to compare pre- and post-COVID-19-pandemic settings

Essential and Forgotten antibiotics:an inventory in low- and middle-income countries

Background: The World Health Organization Essential Medicines List (WHO-EML) includes ‘access’ antibiotics, judged essential to treat common infections. The European Society of Clinical Microbiology and Infectious Diseases Study Group for Antimicrobial Stewardship defined a list of ‘forgotten’ antibiotics, some old and often off-patent antibiotics, which have particular value for specific indications. Objective: To investigate which WHO-EML ‘access’ and ‘forgotten’ antibiotics are approved at national level in a sample of low- to middle-income countries (LMICs). Methods: The Scientific Committee used a consensus procedure to select 26 WHO-EML ‘access’ and 15 ‘forgotten’ antibiotics. Paediatric formulations were explored for 14 antibiotics. An internet-based questionnaire was circulated to 40 LMIC representatives. Antibiotics were defined as approved if an official drug regulatory agency and/or the national ministry of health licensed their use, making them, at least theoretically, available on the market. Results: Twenty-eight LMICs (11 in Africa, 11 in Asia and six in America) were surveyed. Nine WHO-EML ‘access’ antibiotics (amoxicillin, ampicillin, benzylpenicillin, ceftriaxone, clarithromycin, ciprofloxacin, doxycycline, gentamicin and metronidazole) were approved in all countries, and all 26 ‘access’ antibiotics were approved in more than two-thirds of countries. Among the 15 ‘forgotten’ antibiotics, only one was approved in more than two-thirds of countries. The median number of approved antibiotics per country was 30 (interquartile range 23–35). Six of 14 paediatric formulations (amoxicillin, amoxicillin-clavulanic acid, oral antistaphylococcal penicillin, cotrimoxazole, erythromycin and metronidazole) were approved in more than two-thirds of countries. Conclusions: WHO-EML ‘access’ antibiotics and the most frequently used formulations for paediatrics were approved in the vast majority of the 28 surveyed LMICs. This was not the case for many of the ‘forgotten’ antibiotics, despite their important role, particularly in areas with high prevalence of multi-drug-resistant bacteria

Ebola Virus Disease in Children, Sierra Leone, 2014-2015.

Little is known about potentially modifiable factors in Ebola virus disease in children. We undertook a retrospective cohort study of children <13 years old admitted to 11 Ebola holding units in the Western Area, Sierra Leone, during 2014-2015 to identify factors affecting outcome. Primary outcome was death or discharge after transfer to Ebola treatment centers. All 309 Ebola virus-positive children 2 days-12 years old were included; outcomes were available for 282 (91%). Case-fatality was 57%, and 55% of deaths occurred in Ebola holding units. Blood test results showed hypoglycemia and hepatic/renal dysfunction. Death occurred swiftly (median 3 days after admission) and was associated with younger age and diarrhea. Despite triangulation of information from multiple sources, data availability was limited, and we identified no modifiable factors substantially affecting death. In future Ebola virus disease epidemics, robust, rapid data collection is vital to determine effectiveness of interventions for children

Temporary exclusion of ill children from childcare centres in Switzerland: practice, problems and potential solutions.

BACKGROUND: In childcare centres, temporary exclusion of ill children, if their illness poses a risk of spread of harmful diseases to others, is a central approach to fight disease transmission. However, not all ill children need to be excluded. Previous studies suggested that childcare centre staff have difficulties in deciding whether or not to exclude an ill child, even when official ill-child guidelines are used. We aimed to describe, quantify and analyse these ambiguities and discuss potential solutions. METHODS: For this cross-sectional study, we sent postal surveys to 488 childcare centre directors in the Swiss Canton of Zurich, where no official ill-child guideline is in place. We asked for exclusion criteria for ill children and ambiguities faced when dealing with ill children. We checked whether existing guidelines provided solutions to the ambiguities identified. RESULTS: 249/488 (51%) directors responded to the survey. The most common exclusion criteria were fever (87.4%) and contagiousness (52.2%). Ambiguities were mostly caused by conjunctivitis (23.7%) and use of antipyretic drugs (22.9%). Roughly one third of the ambiguities identified could have been resolved with existing guidelines, another third if existing guidelines contained additional information. For the last third, clear written directives are difficult to formulate. CONCLUSIONS: Written recommendations may help to clarify when an ill child should temporarily be excluded. However, such a guideline should cover the topics antipyretic drugs and teething and have room for modification to local circumstances. Collaboration with a paediatrician may be of additional benefit

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

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