Aline Fuchs

Pharmacometric Approaches to Personalize Use of Primarily Renally Eliminated Antibiotics in Preterm and Term Neonates

Sepsis remains a major cause of mortality and morbidity in neonates, and, as a consequence, antibiotics are the most frequently prescribed drugs in this vulnerable patient population. Growth and dynamic maturation processes during the first weeks of life result in large inter‐ and intrasubject variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics. In this review we (1) summarize the available population PK data and models for primarily renally eliminated antibiotics, (2) discuss quantitative approaches to account for effects of growth and maturation processes on drug exposure and response, (3) evaluate current dose recommendations, and (4) identify opportunities to further optimize and personalize dosing strategies of these antibiotics in preterm and term neonates. Although population PK models have been developed for several of these drugs, exposure‐response relationships of primarily renally eliminated antibiotics in these fragile infants are not well understood, monitoring strategies remain inconsistent, and consensus on optimal, personalized dosing of these drugs in these patients is absent. Tailored PK/PD studies and models are useful to better understand relationships between drug exposures and microbiological or clinical outcomes. Pharmacometric modeling and simulation approaches facilitate quantitative evaluation and optimization of treatment strategies. National and international collaborations and platforms are essential to standardize and harmonize not only studies and models but also monitoring and dosing strategies. Simple bedside decision tools assist clinical pharmacologists and neonatologists in their efforts to fine‐tune and personalize the use of primarily renally eliminated antibiotics in term and preterm neonates.

Gentamicin Exposure and Sensorineural Hearing Loss in Preterm Infants

Objective To evaluate the impact of gentamicin exposure on sensorineural hearing loss (SNHL) in very low birth weight (VLBW) infants. Methods Exposure to gentamicin was determined in infants born between 1993 and 2010 at a gestational age < 32 weeks and/or with a birthweight < 1500 g, who presented with SNHL during the first 5 years of life. For each case, we selected two controls matched for gender, gestational age, birthweight, and year of birth. Results We identified 25 infants affected by SNHL, leading to an incidence of SNHL of 1.58% in our population of VLBW infants. The proportion of infants treated with gentamicin was 76% in the study group and 70% in controls (p = 0.78). The total cumulated dose of gentamicin administered did not differ between the study group (median 10.2 mg/kg, Q1-Q3 1.6–13.2) and the control group (median 7.9 mg/kg, Q1-Q3 0–12.8, p = 0.47). The median duration of gentamicin treatment was 3 days both in the study group and the control group (p = 0.58). Maximum predicted trough serum levels of gentamicin, cumulative area under the curve and gentamicin clearance were not different between cases and controls. Conclusion The impact of gentamicin on SNHL can be minimized with treatments of short duration, monitoring of blood levels and dose adjustment.

Monitoring drug therapy.

Drug development has improved over recent decades, with refinements in analytical techniques, population pharmacokinetic-pharmacodynamic (PK-PD) modelling and simulation, and new biomarkers of efficacy and tolerability. Yet this progress has not yielded improvements in individualization of treatment and monitoring, owing to various obstacles: monitoring is complex and demanding, many monitoring procedures have been instituted without critical assessment of the underlying evidence and rationale, controlled clinical trials are sparse, monitoring procedures are poorly validated and both drug manufacturers and regulatory authorities take insufficient account of the importance of monitoring. Drug concentration and effect data should be increasingly collected, analyzed, aggregated and disseminated in forms suitable for prescribers, along with efficient monitoring tools and evidence-based recommendations regarding their best use. PK-PD observations should be collected for both novel and established critical drugs and applied to observational data, in order to establish whether monitoring would be suitable. Methods for aggregating PK-PD data in systematic reviews should be devised. Observational and intervention studies to evaluate monitoring procedures are needed. Miniaturized monitoring tests for delivery at the point of care should be developed and harnessed to closed-loop regulated drug delivery systems. Intelligent devices would enable unprecedented precision in the application of critical treatments, i.e. those with life-saving efficacy, narrow therapeutic margins and high interpatient variability. Pharmaceutical companies, regulatory agencies and academic clinical pharmacologists share the responsibility of leading such developments, in order to ensure that patients obtain the greatest benefit and suffer the least harm from their medicines.

Antibiotic use for community-acquired pneumonia in neonates and children: WHO evidence review

Abstract Background Pneumonia is the most common cause of death in children worldwide, accounting for 15% of all deaths of children under 5 years of age. This review summarises the evidence for the empirical antibiotic treatment of community-acquired pneumonia in neonates and children and puts emphasis on publications since the release of the previous WHO Evidence Summary report published in 2014. Methods A systematic search for systematic reviews and meta-analyses of antibiotic therapy for community-acquired pneumonia was conducted between 1 January 2013 and 10 November 2016. Results The optimal dosing recommendation for amoxicillin remains unclear with limited pharmacological and clinical evidence. There is limited evidence from surveillance to indicate whether amoxicillin or broader spectrum antibiotics (e.g. third-generation cephalosporins) are being used most commonly for paediatric CAP in different WHO regions. Data are lacking on clinical efficacy in the context of pneumococcal, staphylococcal and mycoplasma disease and the relative contributions of varying first-line and step-down options to the selection of such resistance. Conclusion Further pragmatic trials are required to optimise management of hospitalised children with severe and very severe pneumonia.

Reviewing the WHO guidelines for antibiotic use for sepsis in neonates and children.

Abstract Background Guidelines from 2005 for treating suspected sepsis in low- and middle-income countries (LMIC) recommended hospitalisation and prophylactic intramuscular (IM) or intravenous (IV) ampicillin and gentamicin. In 2015, recommendations when referral to hospital is not possible suggest the administration of IM gentamicin and oral amoxicillin. In an era of increasing antimicrobial resistance, an updated review of the appropriate empirical therapy for treating sepsis (taking into account susceptibility patterns, cost and risk of adverse events) in neonates and children is necessary. Methods Systematic literature review and international guidelines were used to identify published evidence regarding the treatment of (suspected) sepsis. Results Five adequately designed and powered studies comparing antibiotic treatments in a low-risk community in neonates and young infants in LMIC were identified. These addressed potential simplifications of the current WHO treatment of reference, for infants for whom admission to inpatient care was not possible. Research is lacking regarding the treatment of suspected sepsis in neonates and children with hospital-acquired sepsis, despite rising antimicrobial resistance rates worldwide. Conclusions Current WHO guidelines supporting the use of gentamicin and penicillin for hospital-based patients or gentamicin (IM) and amoxicillin (oral) when referral to a hospital is not possible are in accordance with currently available evidence and other international guidelines, and there is no strong evidence to change this. The benefit of a cephalosporin alone or in combination as a second-line therapy in regions with known high rates of non-susceptibility is not well established. Further research into hospital-acquired sepsis in neonates and children is required.

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

ABSTRACT Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

Optimising β -lactam dosing in neonates: A review of pharmacokinetics, drug exposure and pathogens

BACKGROUND β-lactams are among the most frequently prescribed antibiotics for the treatment of neonatal sepsis. Survival of extremely preterm neonates necessitates an improved understanding of how β-lactams should be used in this vulnerable population. Appropriate dosing regimens for neonates remain unclear. We reviewed available data on the pharmacokinetics (PK) of β -lactam drugs in neonates. Pharmacokinetic/ pharmacodynamic (PK/PD) efficacy index surrogates and minimum inhibitory concentrations (MICs) used to support dosing regimens recommendation in the studies were also investigated. METHODS A comprehensive literature search was undertaken to identify studies that have investigated the PK/PD of β-lactam drugs in neonates. RESULTS Data available for the PK/PD of β-lactams in neonates are limited but confirm the importance of weight, gestational age and postnatal age as markers of growth and renal maturation. The contribution of tubular secretion in addition to glomerular filtration is highlighted. The development of methods to assay β-lactam protein binding in vivo has added greater understanding. Modelling and simulation techniques have aided dosing optimisation. However, there remains a gap in the understanding of PD parameters and the appropriate PK/PD index to target for improved clinical outcome which partly explains the various dosing recommendations. Improved data on the efficacy of β -lactams are needed in a context of increasing global antimicrobial resistance and variable geographic MIC distribution. CONCLUSION Prospective in vivo studies are required to validate PK/PD indexes associated with clinical efficacy. Current antimicrobial stewardship efforts should integrate PK/PD principles and dosing optimization, taking into account susceptibility of isolated microorganisms.

Pharmakotherapie von Kindern mit akutem Abdomen

Reifung und Wachstum haben spezifische Auswirkungen auf die Pharmakokinetik (PK) und Pharmakodynamik (PD) und damit auf die Wirksamkeit und Sicherheit von Arzneimitteln im Kindesalter. Die eingeschrankte Verfugbarkeit verlasslicher Studiendaten bei Kindern erschwert die Pharmakotherapie in dieser Population, insbesondere bei off-label use oder unlicensed use. Die wichtigsten Aspekte der Pharmakotherapie sind die Wahl des Arzneimittels fur die Indikation, die Dosierung, die Anwendungsdauer und die Verabreichungsform. Dosierungen konnen indikationsspezifisch sein und mussen an die Altersgruppe und ggf. bei Grunderkrankungen an die Komedikation oder Organdysfunktionen angepasst werden. Gerade fur die antibiotische Therapie existieren weitere PKPD-Zielparameter, abhangig von der Art des Antibiotikums, die Einfluss auf die Dosierung und das Verabreichungsschema haben. Die Dauer der Pharmakotherapie ergibt sich aus der Indikation und soll bei akuten Erkrankungen in aller Regel begrenzt sein.

Drivers of antibiotic prescribing in children and adolescents with febrile lower respiratory tract infections

Background Knowledge of key drivers for antibiotic prescribing in pediatric lower respiratory tract infection (LRTI) could support rational antibiotic use. Thus, we aimed to determine the impact of clinical and laboratory factors on antibiotic prescribing in children and adolescents with febrile LRTI. Methods Pediatric patients from the standard care control group of a randomized controlled trial (ProPAED) investigating procalcitonin guided antibiotic treatment in febrile LRTI were included in a multivariate logistic regression analysis to evaluate the impact of laboratory and clinical factors on antibiotic prescribing. Results The standard care control group of the ProPAED study comprised 165 LRTI patients (median age: 2.7 years, range: 0.1–16), out of which 88 (55%) received antibiotic treatment. Factors significantly associated with antibiotic prescribing in patients with complete clinical and laboratory documentation (n = 158) were C-reactive protein (OR 5.8 for a 10-fold increase, 95%CI 2.2–14.9), white blood count beyond age-dependent reference range (OR 3.9, 95%CI 1.4–11.4), body temperature (OR 1.7 for an increase by 1°C, 95%CI 1.02–2.68), and pleuritic pain (OR 2.8, 95%CI 1.1–7.6). Dyspnea (OR 0.3, 95%CI 0.1–0.7) and wheezing (OR 0.3, 95%CI 0.13–0.95) were inversely associated with antibiotic prescribing. Conclusion Laboratory markers were strong drivers of antibiotic prescribing in children with febrile lower respiratory tract infections, in spite of their known poor prediction of antibiotic need. Building on current guidelines for antibiotic treatment in children with febrile LRTI, a reliable decision algorithm for safe antibiotic withholding considering the laboratory and clinical factors evaluated in this study has the potential to further reduce antibiotic prescribing.

Procalcitonin for Diagnostics and Treatment Decisions in Pediatric Lower Respiratory Tract Infections

Mortality and morbidity remain high in pediatric lower respiratory tract infections (LRTIs) despite progress in research and implementation of global diagnostic and treatment strategies in the last decade. Still, 120 million annual episodes of pneumonia affect children younger than 5 years each year leading to 1.3 million fatalities with the major burden of disease carried by low- and middle-income countries (95%). The definition of pneumonia is still challenging. Traditional diagnostic measures (i.e., chest radiographs, C-reactive protein) are unable to distinguish viral and from bacterial etiology. As a result, common antibiotic overuse contributes to growing antibiotic resistance. We present an overview of current evidence from observational and randomized controlled trials on a procalcitonin (PCT)-based diagnosis of pediatric LRTIs and discuss the need for an adequate PCT threshold for antibiotic treatment decision-making.