Antibiotic Residues in UK Foods: Exploring the Exposure Pathways and Associated Health Risks.

While the use of antibiotics has been reported as extensive in the rearing of agricultural animals, insufficient information is available on the antibiotic residues in animal products and the adverse impact that consistent low-level exposure to antibiotics might have on the human body and its microbiome. The aim of this study was to estimate the antibiotic concentrations that humans are exposed to via their diet using the concentration of antibiotics in animal food products and water and an online survey on dietary intake. A total of 131 participants completed the dietary intake survey, with the majority belonging to the omnivorous diet group (76.3%). Distinct dietary trends were observed in the omnivorous and unknown groups eating animal products, with specific food types dominating each meal: pork (e.g., ham) and dairy products (e.g., milk, yoghurt) during breakfast, beef (e.g., burgers) and chicken (e.g., chicken breast) products during lunch, and fish (e.g., salmon fillet) during dinner. In total, 34 different animal-based food and drink products were tested for the presence of ten different antibiotics. Of all the products tested, over 35% exceeded the acceptable daily antibiotic intake for amoxicillin, ampicillin, and enrofloxacin.

Optimising intravenous salbutamol in children: a phase 2 study.

OBJECTIVE: The ß2-agonists such as salbutamol are the mainstay of asthma management. Pharmacokinetic-pharmacodynamic (PKPD) models to guide paediatric dosing are lacking. We explored the relationship between salbutamol dose, serum concentration, effectiveness and adverse effects in children by developing a PKPD model. DESIGN: A prospective cohort study of children admitted to hospital with acute asthma, who received intravenous salbutamol. SETTING: Children were recruited in two cohorts: the emergency departments of two London hospitals or those retrieved by the Children's Acute Transport Service to three London paediatric intensive care units. PATIENTS: Patients were eligible if aged 1-15 years, admitted for acute asthma and about to receive or receiving intravenous salbutamol. INTERVENTIONS: Treatment was according to local policy. Serial salbutamol plasma levels were taken. Effectiveness measurements were recorded using the Paediatric Asthma Severity Score (PASS). Toxicity measurements included lactate, pH, glucose, heart rate, blood pressure and arrhythmias. PKPD modelling was performed with non-linear mixed-effect models. MAIN OUTCOMES: Fifty-eight children were recruited with 221 salbutamol concentration measurements from 54 children. Median (range) age was 2.9 (1.1-15.2) years, and weight was 13.6 (8-57.3) kg. Ninety-five PASS measurements and 2078 toxicity measurements were obtained. RESULTS: A two-compartment PK model adequately described the time course of salbutamol-plasma concentrations. An EMAX (maximum drug effect) concentration-effect relationship described PASS and toxicity measures. PKPD simulations showed an infusion of 0.5 µg/kg/min (maximum 20 µg/min) for 4 hours after bolus achieves >90% maximal bronchodilation for 12 hours. CONCLUSIONS: A paediatric PKPD model for salbutamol is described. An infusion of 0.5 µg/kg/min after bolus achieves effective bronchodilation. Higher rates are associated with greater tachycardia and hyperglycaemia.

Emergence of phenotypic and genotypic antimicrobial resistance in Mycobacterium tuberculosis.

Concentration dependency of phenotypic and genotypic isoniazid-rifampicin resistance emergence was investigated to obtain a mechanistic understanding on how anti-mycobacterial drugs facilitate the emergence of bacterial populations that survive throughout treatment. Using static kill curve experiments, observing two evolution cycles, it was demonstrated that rifampicin resistance was the result of non-specific mechanisms and not associated with accumulation of drug resistance encoding SNPs. Whereas, part of isoniazid resistance could be accounted for by accumulation of specific SNPs, which was concentration dependent. Using a Hollow Fibre Infection Model it was demonstrated that emergence of resistance did not occur at concentration-time profiles mimicking the granuloma. This study showed that disentangling and quantifying concentration dependent emergence of resistance provides an improved rational for drug and dose selection although further work to understand the underlying mechanisms is needed to improve the drug development pipeline.

Comparative assessment of viral dynamic models for SARS-CoV-2 for pharmacodynamic assessment in early treatment trials.

Pharmacometric analyses of time series viral load data may detect drug effects with greater power than approaches using single time points. Because SARS-CoV-2 viral load rapidly rises and then falls, viral dynamic models have been used. We compared different modelling approaches when analysing Phase II-type viral dynamic data. Using two SARS-CoV-2 datasets of viral load starting within 7 days of symptoms, we fitted the slope-intercept exponential decay (SI), reduced target cell limited (rTCL), target cell limited (TCL) and TCL with eclipse phase (TCLE) models using nlmixr. Model performance was assessed via Bayesian information criterion (BIC), visual predictive checks (VPCs), goodness-of-fit plots, and parameter precision. The most complex (TCLE) model had the highest BIC for both datasets. The estimated viral decline rate was similar for all models except the TCL model for dataset A with a higher rate (median [range] day-1 : dataset A; 0.63 [0.56-1.84]; dataset B: 0.81 [0.74-0.85]). Our findings suggest simple models should be considered during pharmacodynamic model development.

Improving the Drug Development Pipeline for Mycobacteria: Modelling Antibiotic Exposure in the Hollow Fibre Infection Model.

Mycobacterial infections are difficult to treat, requiring a combination of drugs and lengthy treatment times, thereby presenting a substantial burden to both the patient and health services worldwide. The limited treatment options available are under threat due to the emergence of antibiotic resistance in the pathogen, hence necessitating the development of new treatment regimens. Drug development processes are lengthy, resource intensive, and high-risk, which have contributed to market failure as demonstrated by pharmaceutical companies limiting their antimicrobial drug discovery programmes. Pre-clinical protocols evaluating treatment regimens that can mimic in vivo PK/PD attributes can underpin the drug development process. The hollow fibre infection model (HFIM) allows for the pathogen to be exposed to a single or a combination of agents at concentrations achieved in vivo-in plasma or at infection sites. Samples taken from the HFIM, depending on the analyses performed, provide information on the rate of bacterial killing and the emergence of resistance. Thereby, the HFIM is an effective means to investigate the efficacy of a drug combination. Although applicable to a wide variety of infections, the complexity of anti-mycobacterial drug discovery makes the information available from the HFIM invaluable as explored in this review.

Population pharmacokinetics and pharmacodynamics of investigational regimens' drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): a prospective nested study protocol in a randomised controlled trial.

INTRODUCTION: Drug-resistant tuberculosis (TB) remains a global health threat, with little over 50% of patients successfully treated. Novel regimens like the ones being studied in the TB-PRACTECAL trial are urgently needed. Understanding anti-TB drug exposures could explain the success or failure of these trial regimens. We aim to study the relationship between the patients' exposure to anti-TB drugs in TB-PRACTECAL investigational regimens and their treatment outcomes. METHODS AND ANALYSIS: Adults with multidrug-resistant TB randomised to investigational regimens in TB-PRACTECAL will be recruited to a nested pharmacokinetic-pharmacodynamic (PKPD) study. Venous blood samples will be collected at 0, 2 and 23 hours postdose on day 1 and 0, 6.5 and 23 hours postdose during week 8 to quantify drug concentrations in plasma. Trough samples will be collected during week 12, 16, 20 and 24 visits. Opportunistic samples will be collected during weeks 32 and 72. Drug concentrations will be quantified using liquid chromatography-tandem mass spectrometry. Sputum samples will be collected at baseline, monthly to week 24 and then every 2 months to week 108 for MICs and bacillary load quantification. Full blood count, urea and electrolytes, liver function tests, lipase, ECGs and ophthalmology examinations will be conducted at least monthly during treatment.PK and PKPD models will be developed for each drug with nonlinear mixed effects methods. Optimal dosing will be investigated using Monte-Carlo simulations. ETHICS AND DISSEMINATION: The study has been approved by the Médecins sans Frontières (MSF) Ethics Review Board, the LSHTM Ethics Committee, the Belarus RSPCPT ethics committee and PharmaEthics and the University of Witwatersrand Human Research ethics committee in South Africa. Written informed consent will be obtained from all participants. The study results will be shared with public health authorities, presented at scientific conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04081077; Pre-results.

An automated approach to identify scientific publications reporting pharmacokinetic parameters.

Pharmacokinetic (PK) predictions of new chemical entities are aided by prior knowledge from other compounds. The development of robust algorithms that improve preclinical and clinical phases of drug development remains constrained by the need to search, curate and standardise PK information across the constantly-growing scientific literature. The lack of centralised, up-to-date and comprehensive repositories of PK data represents a significant limitation in the drug development pipeline.In this work, we propose a machine learning approach to automatically identify and characterise scientific publications reporting PK parameters from in vivo data, providing a centralised repository of PK literature. A dataset of 4,792 PubMed publications was labelled by field experts depending on whether in vivo PK parameters were estimated in the study. Different classification pipelines were compared using a bootstrap approach and the best-performing architecture was used to develop a comprehensive and automatically-updated repository of PK publications. The best-performing architecture encoded documents using unigram features and mean pooling of BioBERT embeddings obtaining an F1 score of 83.8% on the test set. The pipeline retrieved over 121K PubMed publications in which in vivo PK parameters were estimated and it was scheduled to perform weekly updates on newly published articles. All the relevant documents were released through a publicly available web interface (https://app.pkpdai.com) and characterised by the drugs, species and conditions mentioned in the abstract, to facilitate the subsequent search of relevant PK data. This automated, open-access repository can be used to accelerate the search and comparison of PK results, curate ADME datasets, and facilitate subsequent text mining tasks in the PK domain.

Exploring a combined biomarker for tuberculosis treatment response: protocol for a prospective observational cohort study.

INTRODUCTION: An improved understanding of factors explaining tuberculosis (TB) treatment response is urgently needed to help clinicians optimise and personalise treatment and assist scientists undertaking novel treatment regimen trials. Promising outcome proxy measures, including sputum bacillary load and host immune response, are widely reported with variable results. However, they have not been studied together in combination with antibiotic exposure. The aim of this observational cohort study is to investigate which antibiotic exposures correlate with sputum bacillary load and which with the host immune response. Subsequently, we will explore if these correlations can be used to inform a candidate combined biomarker predicting cure. METHODS AND ANALYSIS: All patients aged ≥ 18, diagnosed with drug-sensitive pulmonary TB (culture or molecular test), eligible for standard anti-TB treatment, at selected London, UK TB Services, will be invited to participate in this observational cohort study (target sample size=210). Patients will be asked to give blood for host transcriptomics and antibiotic plasma exposure, in addition to standard of care sputum samples for bacillary load. Antibiotic plasma concentrations will be quantified using a validated liquid chromatograph triple quadrupole mass spectrometer (LC-MS/MS) assay and sputum bacillary load by mycobacterial growth incubator tube time to positivity. Expression from a total of 35 prespecified host blood genes will be quantified using NanoString®. Antibiotic exposure, sputum bacillary load and host blood transcriptomic time series data will be analysed using nonlinear mixed-effects models. Correlations between combinations of longitudinal biomarkers and microbiological cure at the end of treatment and remaining relapse free for 1 year thereafter will be analysed using logistic regression and Cox proportional hazard models. ETHICS AND DISSEMINATION: The observational cohort study has been approved by the UK's HRA REC (20/SW/0007). Written informed consent will be obtained. Results will be disseminated via publication, presentation and through engagement with institutes/companies developing novel anti-TB treatment combinations.

Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting.

OBJECTIVES: This systematic review focuses on the use of the in vitro hollow fibre infection model (HFIM) for microbial culture. We summarize the direction of the field to date and propose best-practice principles for reporting of the applications. METHODS: Searches in six databases (MEDLINE®, EMBASE®, PubMed®, BIOSIS®, SCOPUS® and Cochrane®) up to January 2020 identified 129 studies meeting our inclusion criteria. Two reviewers independently assessed and extracted data from each publication. The quality of reporting of microbiological and technical parameters was analysed. RESULTS: Forty-seven out of 129 (36.4%) studies did not report the minimum pharmacokinetic parameters required in order to replicate the pharmacokinetic profile of HFIM experiments. Fifty-three out of 129 (41.1%) publications did not report the medium used in the HFIM. The overwhelming majority of publications did not perform any technical repeats [107/129 (82.9%)] or biological repeats [97/129 (75.2%)]. CONCLUSIONS: This review demonstrates that most publications provide insufficient data to allow for results to be evaluated, thus impairing the reproducibility of HFIM experiments. Therefore, there is a clear need for the development of laboratory standardization and improved reporting of HFIM experiments.

Systematic Review and Patient-Level Meta-Analysis of SARS-CoV-2 Viral Dynamics to Model Response to Antiviral Therapies.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral loads change rapidly following symptom onset, so to assess antivirals it is important to understand the natural history and patient factors influencing this. We undertook an individual patient-level meta-analysis of SARS-CoV-2 viral dynamics in humans to describe viral dynamics and estimate the effects of antivirals used to date. This systematic review identified case reports, case series, and clinical trial data from publications between January 1, 2020, and May 31, 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A multivariable Cox proportional hazards (Cox-PH) regression model of time to viral clearance was fitted to respiratory and stool samples. A simplified four parameter nonlinear mixed-effects (NLME) model was fitted to viral load trajectories in all sampling sites and covariate modeling of respiratory viral dynamics was performed to quantify time-dependent drug effects. Patient-level data from 645 individuals (age 1 month to 100 years) with 6,316 viral loads were extracted. Model-based simulations of viral load trajectories in samples from the upper and lower respiratory tract, stool, blood, urine, ocular secretions, and breast milk were generated. Cox-PH modeling showed longer time to viral clearance in older patients, men, and those with more severe disease. Remdesivir was associated with faster viral clearance (adjusted hazard ratio (AHR) = 9.19, P < 0.001), as well as interferon, particularly when combined with ribavirin (AHR = 2.2, P = 0.015; AHR = 6.04, P = 0.006). Combination therapy should be further investigated. A viral dynamic dataset and NLME model for designing and analyzing antiviral trials has been established.

Population Pharmacokinetics of Intraventricular Vancomycin in Neonatal Ventriculitis, A Preterm Pilot Study.

AIM: Intraventricular vancomycin is an effective treatment for neonatal ventriculitis, as the cerebrospinal fluid (CSF) vancomycin levels reach adequate concentrations to achieve microbiological cure. There is no robust data on intraventricular vancomycin pharmacokinetics in the preterm population. This pilot population pharmacokinetic modelling study examines the pharmacokinetic behaviour of intraventricular vancomycin in the preterm population of < 28 weeks gestation, to inform the feasibility of future prospective studies. METHODS: The study comprised 8 preterm infants with neonatal ventriculitis (median gestation age 25.3 weeks; range 23.9 - 27.7). Population pharmacokinetics (non-linear mixed effects modelling) were described with one- and two-compartment models to fit plasma concentrations of vancomycin. A CSF compartment was added to the plasma modelling and mass transfer examined. Three covariates (serum creatinine, ventricular index (VI) and CSF protein) were tested on the final model. Area under the curve (AUC) and average CSF concentration (C average) predictions were generated from the final model and compared with time to microbiological cure. RESULTS: A one-compartment model provided the best fit to the data. There was no appreciable transfer between plasma and CSF. None of the covariates provided a significant reduction in the objective function value (OFV). Generally, time to sterilisation with higher CSF AUC (0-24) and C average tends to be shorter, however this should be interpreted with caution as data is erratic. CONCLUSION: This pilot population pharmacokinetic analysis provides important information to warrant changes in the management of intraventricular vancomycin treatment in the preterm population, such as the current use of VI as a dosing parameter. Further study with a larger data pool is necessary to investigate the influence of VI on CSF vancomycin and ascertain dosing strategies.

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

BACKGROUND: This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. METHODS: Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. RESULTS: Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid C MAX (P < .05), isoniazid C MAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05). CONCLUSIONS: Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as C MAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.

Ethambutol disposition in humans: Challenges and limitations of whole-body physiologically-based pharmacokinetic modelling in early drug development.

Whole-body physiologically based pharmacokinetic (WB-PBPK) models have become an important tool in drug development, as they enable characterization of pharmacokinetic profiles across different organs based on physiological (systems-specific) and physicochemical (drug-specific) properties. However, it remains unclear which data are needed for accurate predictions when applying the approach to novel candidate molecules progressing into the clinic. In this work, as case study, we investigated the predictive performance of WB-PBPK models both for prospective and retrospective evaluation of the pharmacokinetics of ethambutol, considering scenarios that reflect different stages of development, including settings in which the data are limited to in vitro experiments, in vivo preclinical data, and when some clinical data are available. Overall, the accuracy of PBPK model-predicted systemic and tissue exposure was heavily dependant on prior knowledge about the eliminating organs. Whilst these findings may be specific to ethambutol, the challenges and potential limitations identified here may be relevant to a variety of drugs, raising questions about (1) the minimum requirements for prospective use of WB-PBPK models during the characterization of drug disposition and (2) implication of uncertainty for dose selection in humans.

Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial.

Treosulfan is given off-label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan-fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two-compartment model. During follow-up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC(0-∞) ) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23-1.74), and the hazard ratio for low engraftment was 0.61 (0.36-1.04). A cumulative AUC(0-∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC(0-∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease.

Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection.

Here, we evaluate protocol requirements to mimic therapeutically relevant drug concentrations at the site of infection (i.e. lung lesion) in an in-vitro hollow fibre model of infection using pulmonary tuberculosis as a paradigm. Steady-state pharmacokinetic profiles in plasma, lung tissue and lung lesion homogenate were simulated for isoniazid, rifampicin and pyrazinamide and moxifloxacin. An R-shiny User Interface was developed to support conversion of in-vivo pharmacokinetic CMAX, TMAX and T1/2 estimates into pump settings. A monotherapy protocol mimicking isoniazid in lung lesion homogenate (isoniazid CMAX = 1,200 ng/ml, TMAX = 2.2 hr and T1/2 = 4.7 hr), and two combination therapy protocols including drugs with similar (isoniazid and rifampicin (CMAX = 400 ng/ml)) and different half-lives (isoniazid and pyrazinamide (CMAX = 28,900 ng/ml and T1/2 = 8.0 hr)) were implemented in a hollow-fiber system. Drug levels in the perfusate were analysed using ultra-high-performance liquid chromatographic-tandem mass spectrometric detection. Steady state pharmacokinetic profiles measured in the hollow fiber model were similar to the predicted in-vivo steady-state lung lesion homogenate pharmacokinetic profiles. The presented approach offers the possibility to use pharmacological data to study the effect of target tissue exposure for drug combinations. Integration with pharmacokinetics modelling principles through a web interface will provide access to a wider community interested in the evaluation of efficacy of anti-tubercular drugs.

Can phenotypic data complement our understanding of antimycobacterial effects for drug combinations?

OBJECTIVES: To demonstrate how phenotypic cell viability data can provide insight into antimycobacterial effects for the isoniazid/rifampicin treatment backbone. METHODS: Data from a Mycobacterium komossense hollow-fibre infection model comprising a growth control group, rifampicin at three different exposures (Cmax = 0.14, 0.4 and 1.47 mg/L with t½ = 1.57 h and τ = 8 h) and rifampicin plus isoniazid (Cmax rifampicin = 0.4 mg/L and Cmax isoniazid = 1.2 mg/L with t½ = 1.57 h and τ = 8 h) were used for this investigation. A non-linear mixed-effects modelling approach was used to fit conventional cfu data, quantified using solid-agar plating. Phenotypic proportions of respiring (alive), respiring but with damaged cell membrane (injured) and 'not respiring' (dead) cells data were quantified using flow cytometry and Sytox Green™ (Sigma-Aldrich, UK) and resazurin sodium salt staining and fitted using a multinomial logistic regression model. RESULTS: Isoniazid/rifampicin combination therapy displayed a decreasing overall antimicrobial effect with time (θTime1/2 = 438 h) on cfu data, in contrast to rifampicin monotherapy where this trend was absent. In the presence of isoniazid a phenotype associated with cell injury was displayed, whereas with rifampicin monotherapy a pattern of phenotypic cell death was observed. Bacterial killing onset time on cfu data correlated negatively (θTime50 = 28.9 h, θLAGRIF50 = 0.132 mg/L) with rifampicin concentration up to 0.165 mg/L and this coincided with a positive relationship between rifampicin concentration and the probability of phenotypic cell death. CONCLUSIONS: Cell viability data provide structured information on the pharmacodynamic interaction between isoniazid and rifampicin that complements the understanding of the antibacillary effects of this mycobacterial treatment backbone.

Revising Pediatric Vancomycin Dosing Accounting for Nephrotoxicity in a Pharmacokinetic-Pharmacodynamic Model.

This study aimed to suggest an initial pediatric vancomycin dose regimen through population pharmacokinetic-pharmacodynamic modeling. A population pharmacokinetic approach was used to analyze vancomycin concentration-time data from a large pediatric cohort. Pharmacokinetic target attainment for patients with bloodstream isolates was compared with clinical outcome using logistic regression and classification and regression trees. Change in serum creatinine during treatment was used as an indicator of acute nephrotoxicity. Probability of acute kidney injury (50% increase from baseline) or kidney failure (75% increase from baseline) was evaluated using logistic regression. An initial dosing regimen was derived, personalized by age, weight, and serum creatinine, using stochastic simulations. Data from 785 hospitalized pediatric patients (1 day to 21 years of age) with suspected Gram-positive infections were collected. Estimated (relative standard error) typical clearance, volume of distribution 1, intercompartmental clearance, and volume of distribution 2 were (standardized to 70 kg) 4.84 (2.38) liters/h, 39.9 (8.15) liters, 3.85 (17.3) liters/h, and 37.8 (10.2) liters, respectively. While cumulative vancomycin exposure correlated positively with the development of nephrotoxicity (713 patients), no clear relationship between vancomycin area under the plasma concentration-time curve and efficacy was found (102 patients). Predicted probability of acute kidney injury and kidney failure with the optimized dosing regimen at day 5 was 10 to 15% and 5 to 10%, increasing by approximately 50% on day 7 and roughly 100% on day 10 across all age groups. This study presents the first data-driven pediatric dose selection to date accounting for nephrotoxicity, and it indicates that cumulative vancomycin exposure best describes risk of acute kidney injury and acute kidney failure.

Pharmacokinetic-pharmacodynamic modelling to investigate in vitro synergy between colistin and fusidic acid against MDR Acinetobacter baumannii.

OBJECTIVES: The potential for synergy between colistin and fusidic acid in the treatment of MDR Acinetobacter baumannii has recently been shown. The aim of this study was to perform an extensive in vitro characterization of this effect using pharmacokinetic-pharmacodynamic modelling (PKPD) of time-kill experiments in order to estimate clinical efficacy. METHODS: For six clinical strains, 312 individual time-kill experiments were performed including 113 unique pathogen-antimicrobial combinations. A wide range of concentrations (0.25-8192 mg/L for colistin and 1-8192 mg/L for fusidic acid) were explored, alone and in combination. PKPD modelling sought to quantify synergistic effects. RESULTS: A PKPD model confirmed synergy in that colistin EC50 was found to decrease by 83% in the presence of fusidic acid, and fusidic acid maximum increase in killing rate (Emax) also increased 58% in the presence of colistin. Simulations indicated, however, that at clinically achievable free concentrations, the combination may be bacteriostatic in colistin-susceptible strains, but growth inhibition probability was <20% in a colistin-resistant strain. CONCLUSIONS: Fusidic acid may be a useful agent to add to colistin in a multidrug combination for MDR Acinetobacter baumannii.

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.