The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.

BACKGROUND: Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. OBJECTIVES: The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. METHODS: NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. RESULTS: For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively). CONCLUSIONS: NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.

Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings.

BACKGROUND: Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum ß-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting. OBJECTIVES: To assess the pharmacodynamics of flomoxef and amikacin in combination. METHODS: The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs. RESULTS: Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L. CONCLUSIONS: We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance.

BACKGROUND: Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO's recommended empirical regimen of ampicillin and gentamicin. OBJECTIVES: We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. METHODS: We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. RESULTS: Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. CONCLUSIONS: These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials.

Amoxicillin duration and dose for community-acquired pneumonia in children: the CAP-IT factorial non-inferiority RCT.

BACKGROUND: Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children. OBJECTIVES: To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia. DESIGN: A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland. SETTING: Paediatric emergency departments, paediatric assessment/observation units and inpatient wards. PARTICIPANTS: Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge. INTERVENTIONS: Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio. MAIN OUTCOME MEASURES: The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication. RESULTS: A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants [median age 2.5 (interquartile range 1.6-2.7) years; 52% male] were randomised to either 3 (n = 413) or 7 days (n = 401) of trial medication at either lower (n = 410) or higher (n = 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p = 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms. LIMITATIONS: End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children. CONCLUSIONS: Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms. FUTURE WORK: Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 60. See the NIHR Journals Library website for further project information.

Pneumonia (an acute lung infection) is a common diagnosis in young children worldwide. To cure this, some children are given antibiotics, but we do not currently know the best amount (dose) to give and the ideal number of days (duration) of treatment. Taking antibiotics causes changes in bacteria, making them more resistant to treatment. This may be affected by the dose and duration, and is important because resistant bacteria are harder to treat and could spread to other people. Amoxicillin is the most common antibiotic treatment for children with pneumonia. CAP-IT (Community-Acquired Pneumonia: a protocol for a randomIsed controlled Trial) tested if lower doses and shorter durations of amoxicillin are as good as higher doses and longer durations, and whether or not these affect the presence of resistant bacteria. In total, 824 children in the UK and Ireland with pneumonia participated. They received either high- or low-dose amoxicillin for 3 or 7 days following discharge from hospital. To ensure that neither doctors nor parents were influenced by knowing which group a child was in, we included dummy drugs (placebo). We measured how often children were given more antibiotics for respiratory infections in the 4 weeks after starting the trial medicine. To check for resistant bacteria, a nose swab was collected before starting treatment and again after 4 weeks. One in every eight participating children was given additional antibiotics. We found no important difference in this proportion between 3 days and 7 days of amoxicillin treatment, or between lower or higher doses. Although children's coughs took slightly longer to go away when they received only 3 days of antibiotics, rash was reported slightly more often in children taking 7 days of antibiotics. There was no effect of dose of amoxicillin on any of the symptom measurements. No effect of duration of treatment or dose was observed for antibiotic resistance in bacteria living in the nose and throat.

Potential Antibiotics for the Treatment of Neonatal Sepsis Caused by Multidrug-Resistant Bacteria.

Neonatal sepsis causes up to an estimated 680,000 deaths annually worldwide, predominantly in low- and middle-income countries (LMICs). A significant and growing proportion of bacteria causing neonatal sepsis are resistant to multiple antibiotics, including the World Health Organization-recommended empiric neonatal sepsis regimen of ampicillin/gentamicin. The Global Antibiotic Research and Development Partnership is aiming to develop alternative empiric antibiotic regimens that fulfil several criteria: (1) affordable in LMIC settings; (2) activity against neonatal bacterial pathogens, including extended-spectrum ß-lactamase producers, gentamicin-resistant Gram-negative bacteria, and methicillin-resistant Staphylococcus aureus (MRSA); (3) a licence for neonatal use or extensive experience of use in neonates; and (4) minimal toxicities. In this review, we identify five antibiotics that fulfil these criteria: amikacin, tobramycin, fosfomycin, flomoxef, and cefepime. We describe the available characteristics of each in terms of mechanism of action, resistance mechanisms, clinical pharmacokinetics, pharmacodynamics, and toxicity profile. We also identify some knowledge gaps: (1) the neonatal pharmacokinetics of cefepime is reliant on relatively small and limited datasets, and the pharmacokinetics of flomoxef are also reliant on data from a limited demographic range and (2) for all reviewed agents, the pharmacodynamic index and target has not been definitively established for both bactericidal effect and emergence of resistance, with many assumed to have an identical index/target to similar class molecules. These five agents have the potential to be used in novel combination empiric regimens for neonatal sepsis. However, the data gaps need addressing by pharmacokinetic trials and pharmacodynamic characterisation.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum ß-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA < 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

Fifteen-minute consultation: the complexities of empirical antibiotic selection for serious bacterial infections-a practical approach.

Potentially life-threatening infections require immediate antibiotic therapy. Most early stage antibiotic treatment for these infections is empirical, that is, covering a range of possible target bacteria while awaiting culture results. Empirical antibiotic regimens need to reflect the epidemiology of most likely causative bacteria, type of infection and patient risk factors. Summary data from relevant isolates in similar patients help to identify appropriate empirical regimens. At present, such data are mostly presented as hospital or other aggregate antibiograms, showing antimicrobial susceptibility testing results by bacterial species. However, a more suitable method is to calculate weighted incidence syndromic combination antibiograms for different types of infections and regimens, allowing head-to-head comparisons of empirical regimens. Once there is confirmatory or negative microbiological evidence of infection, empirical regimens should be adapted to the identified bacterial species and susceptibilities or discontinued.

Selecting appropriate empirical antibiotic regimens for paediatric bloodstream infections: application of a Bayesian decision model to local and pooled antimicrobial resistance surveillance data.

OBJECTIVES: The objective of this study was to evaluate the ability of weighted-incidence syndromic combination antibiograms (WISCAs) to inform the selection of empirical antibiotic regimens for suspected paediatric bloodstream infections (BSIs) by comparing WISCAs derived using data from single hospitals and from a multicentre surveillance dataset. METHODS: WISCAs were developed by estimating the coverage of five empirical antibiotic regimens for childhood BSI using a Bayesian decision tree. The study used microbiological data on ∼2000 bloodstream isolates collected over 2 years from 19 European hospitals. We evaluated the ability of a WISCA to show differences in regimen coverage at two exemplar hospitals. For each, a WISCA was first calculated using only their local data; a second WISCA was calculated using pooled data from all 19 hospitals. RESULTS: The estimated coverage of the five regimens was 72%-86% for Hospital 1 and 79%-94% for Hospital 2, based on their own data. In both cases, the best regimens could not be definitively identified because the differences in coverage were not statistically significant. For Hospital 1, coverage estimates derived using pooled data gave sufficient precision to reveal clinically important differences among regimens, including high coverage provided by a narrow-spectrum antibiotic combination. For Hospital 2, the hospital and pooled data showed signs of heterogeneity and the use of pooled data was judged not to be appropriate. CONCLUSIONS: The Bayesian WISCA provides a useful approach to pooling information from different sources to guide empirical therapy and could increase confidence in the selection of narrow-spectrum regimens.

Current management of late onset neonatal bacterial sepsis in five European countries.

UNLABELLED: Late onset neonatal sepsis (LOS) has a high mortality and the optimal management is poorly defined. We aimed to evaluate new expert panel-derived criteria to define LOS and characterize the current management and antibiotic susceptibility of LOS-causing organisms in Europe. A prospective observational study enrolled infants aged 4 to 90 days in five European countries. Clinical and laboratory findings as well as empiric treatment were recorded and patients were followed until the end of antibiotic therapy. Failure was defined as a change of primary antibiotic, no resolution of clinical signs, appearance of new signs/pathogens or death. Antibiotic therapy was considered appropriate if the organism was susceptible to at least one empiric antibiotic. 113 infants (median age 14 days, 62 % ≤1500 g) were recruited; 61 % were culture proven cases (28 CoNS, 24 Enterobacteriaceae, 11 other Gram-positives and 6 Gram-negative non-fermentative organisms). The predictive value of the expert-panel criteria to identify patients with a culture proven LOS was 61 % (95 % CI 52 % to 70 %). Around one third of Enterobacteriaceae were resistant to ampicillin + or cefotaxime + gentamicin but only 10 % to meropenem. Empiric treatment contained a total of 43 different antibiotic regimens. All-cause mortality was 8 % with an additional 45 % classified as failure of empiric therapy, mainly due to change of primary antibiotics (42/60). CONCLUSIONS: The expert panel-derived diagnostic criteria performed well identifying a high rate of culture proven sepsis. Current management of LOS in Europe is extremely variable suggesting an urgent need of evidence-based guidelines.

Use of antibacterial agents in the neonate: 50 years of experience with vancomycin administration.

Neonatal sepsis, classified as either early or late onset, has specific pathogen distribution and infection rates in the different neonatal age groups. It is a major cause of mortality and morbidity and administration of antibiotics is urgently required for suspected or proven infection. Vancomycin is the first choice treatment of late onset sepsis due to resistant staphylococci. Although it has been used for more than 50 years, prescription remains a challenge in neonatal intensive care units for many reasons, including: high pharmacokinetic variability, numerous presentations, lack of consensus on dosing regimen and therapeutic drug monitoring. In addition, recent concerns about the increase in minimal inhibition concentration and other more generic problems have prompted reappraisal of the rational use of vancomycin. This article highlights the goal of optimising vancomycin therapy in the neonate and discusses future research directions. Specific attention is given to dosing optimisation of vancomycin to avoid resistance and maximise the likelihood of achieving the therapeutic target. Modelling and simulation approaches have clear advantages in dosing optimisation of antimicrobial agents in the neonate. Neonatologists and paediatric pharmacologists should work closely together to achieve this goal.