What do I need to know about penicillin antibiotics?

The penicillins remain the class of antibiotics most commonly prescribed to children worldwide. In an era when the risks posed by antimicrobial resistance are growing, an understanding of antibiotic pharmacology and how to apply these principles in clinical practice is increasingly important. This paper provides an overview of the pharmacology of penicillins, focusing on those aspects of pharmacokinetics, pharmacodynamics and toxicity that are clinically relevant in paediatric prescribing. Penicillin allergy is frequently reported but a detailed history of suspected adverse reactions is essential to identify whether a clinically relevant hypersensitivity reaction is likely or not. The importance of additional factors such as antibiotic palatability, concordance and stewardship are also discussed, highlighting their relevance to optimal prescribing of the penicillins for children

What do I need to know about aminoglycoside antibiotics?

The aminoglycosides are broad-spectrum, bactericidal antibiotics that are commonly prescribed for children, primarily for infections caused by Gram-negative pathogens. The aminoglycosides include gentamicin, amikacin, tobramycin, neomycin, and streptomycin. Gentamicin is the most commonly used antibiotic in UK neonatal units. Aminoglycosides are polar drugs, with poor gastrointestinal absorption, so intravenous or intramuscular administration is needed. They are excreted renally. Aminoglycosides are concentration-dependent antibiotics, meaning that the ratio of the peak concentration to the minimum inhibitory concentration of the pathogen is the pharmacokinetic-pharmacodynamic index best linked to their antimicrobial activity and clinical efficacy. However, due to their narrow therapeutic index, the patient’s renal function should be monitored to avoid toxicity, and therapeutic drug monitoring is often required. Here we provide a review of aminoglycosides, with a particular focus on gentamicin, considering their pharmacokinetics and pharmacodynamics, and also practical issues associated with prescribing these drugs in a paediatric clinical setting

Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants.

Trough gentamicin therapeutic drug monitoring (TDM) is time-consuming, disruptive to neonatal clinical care and a patient safety issue. Bayesian models could allow TDM to be performed opportunistically at the time of routine blood tests. This study aimed to develop and prospectively evaluate a new gentamicin model and a novel Bayesian computer tool (neoGent) for TDM use in neonatal intensive care. We also evaluated model performance for predicting peak concentrations and AUC(0-t). A pharmacokinetic meta-analysis was performed on pooled data from three studies (1325 concentrations from 205 patients). A 3-compartment model was used with covariates being: allometric weight scaling, postmenstrual and postnatal age, and serum creatinine. Final parameter estimates (standard error) were: clearance: 6.2 (0.3) L/h/70kg; central volume (V) 26.5 (0.6) L/70kg; inter-compartmental disposition: Q=2.2 (0.3) L/h/70kg, V2=21.2 (1.5) L/70kg, Q2=0.3 (0.05) L/h/70kg, V3=148 (52.0) L/70kg. The model's ability to predict trough concentrations from an opportunistic sample was evaluated in a prospective observational cohort study that included data from 163 patients with 483 concentrations collected in five hospitals. Unbiased trough predictions were obtained: median (95% confidence interval (CI)) prediction error was 0.0004 (-1.07, 0.84) mg/L. Results also showed peaks and AUC(0-t) could be predicted (from one randomly selected sample) with little bias but relative imprecision with median (95% CI) prediction error being 0.16 (-4.76, 5.01) mg/L and 10.8 (-24.9, 62.2) mg h/L, respectively. NeoGent was implemented in R/NONMEM, and in the freely available TDMx software

Pharmacokinetics of penicillin G in preterm and term neonates.

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but poorly for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We described PK of penicillin G in neonates with gestational age (GA) ≥32 weeks and postnatal age 90% for MICs ≤2 mg/L with doses of 25,000 IU/kg/q12h. In neonates, regardless of GA, PK parameters of penicillin G are similar. The dose of 25,000 IU/kg/q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 hours of life

Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies.

Background: Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking. Objectives: To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS). Methods: Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed. Results: A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome. Conclusions: Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered

Comment on "Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials".

Pharmacolog

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children.

OBJECTIVES: The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. METHODS: Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. RESULTS: A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m2. Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. CONCLUSIONS: In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients

Optimisation of Neonatal Antimicrobial Therapy Using Pharmacokinetic-Pharmacodynamic Modelling

Bacterial infections, namely sepsis and meningitis, are among the major causes of morbidity and mortality during the neonatal period. In an era of increasing antimicrobial resistance, when few new types of antibiotics are being developed, antimicrobial therapy needs to be optimised to ensure that adequate doses are given. At the same time, since renal function is immature in neonates, the dosing regime needs to be designed to minimise toxicity. The studies described here aimed to address the following questions: what is the appropriate way to scale drug clearance in the paediatric population; how can treatment be individualised and optimised to help improve the therapeutic drug monitoring of gentamicin; what meropenem dose should be recommended for neonates and infants with sepsis or meningitis; and finally how can a modelling approach be used to facilitate the definition of neonatal sepsis. The above questions were addressed using distinct strategies. An extensive comparison of published models for scaling clearance was performed. Population pharmacokinetic models using data from large gentamicin and meropenem studies in neonates were developed, and then either implemented in provisional software, or used to make dose recommendations, respectively. Also, in a preliminary study, item response theory models were applied to pharmacodynamic data from neonates with sepsis. The use of allometric weight scaling with a postmenstrual age driven sigmoidal maturation function was recommended as a standard approach for scaling clearance. The population pharmacokinetic model developed using gentamicin data showed that specifically timed trough levels are not needed for therapeutic drug monitoring. The results of the meropenem study imply that the current recommended dosing regimen for neonates is appropriate for susceptible bacteria. Finally, the proof-of-concept study suggested that metabolic acidosis provided the most information about the sepsis status of neonates