The overall study aim was to identify the relevant preclinical teicoplanin pharmacokinetic (PK)/pharmacodynamic (PD) indices to predict efficacy and suppression of resistance in MRSA infection.
A ...hollow-fibre infection model and a neutropenic murine thigh infection model were developed. The PK/PD data generated were modelled using a non-parametric population modelling approach with Pmetrics. The posterior Bayesian estimates derived were used to study the exposure-effect relationships. Monte Carlo simulations from previously developed population PK models in adults and children were conducted to explore the probability of target attainment (PTA) for teicoplanin dosage regimens against the current EUCAST WT susceptibility range.
There was a concentration-dependent activity of teicoplanin in both the in vitro and in vivo models. A total in vivo AUC/MIC of 610.4 (total AUC of 305.2 mg·h/L) for an MRSA strain with an MIC of 0.5 mg/L was needed for efficacy (2 log10 cell kill) against a total bacterial population. A total AUC/MIC ratio of ∼1500 (total AUC of ∼750 mg·h/L) was needed to suppress the emergence of resistance. The PTA analyses showed that adult and paediatric patients receiving a standard regimen were only successfully treated for the in vivo bactericidal target if the MIC was ≤0.125 mg/L in adults and ≤0.064 mg/L in children.
This study improves our understanding of teicoplanin PD against MRSA and defines an in vivo AUC/MIC target for efficacy and suppression of resistance. Additional studies are needed to further corroborate the PK/PD index in a variety of infection models and in patients.
Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ ...significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.
F901318 is an orotomide, which is a new class of antifungal agent with activity against Aspergillus spp. Here, we describe the pharmacodynamics of F901318 against Aspergillus flavus and define the ...drug exposure targets required for efficacy in clinical studies.
Abstract
Background
Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics (PD) of the lead compound F901318 is required to plan safe and effective regimens for clinical use.
Methods
The pharmacokinetics (PK) and PD of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships.
Results
F901318 minimum inhibitory concentrations (MICs) ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model, a minimum concentration:MIC of 10 resulted in suppression of galactomannan; however, values of approximately 10 and 9–19 when assessed by survival of mice or the decline in galactomannan, respectively, were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan.
Conclusions
F901318 is a potential new agent for the treatment of invasive infections caused by A flavus with PDs that are comparable with other first-line triazole agents.
The aim of this study was to improve the understanding of the pharmacokinetic-pharmacodynamic relationships of fosfomycin against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli ...strains that have different fosfomycin MICs. Our methods included the use of a hollow fiber infection model with three clinical ESBL-producing E. coli strains. Human fosfomycin pharmacokinetic profiles were simulated over 4 days. Preliminary studies conducted to determine the dose ranges, including the dose ranges that suppressed the development of drug-resistant mutants, were conducted with regimens from 12 g/day to 36 g/day. The combination of fosfomycin at 4 g every 8 h (q8h) and meropenem at 1 g/q8h was selected for further assessment. The total bacterial population and the resistant subpopulations were determined. No efficacy was observed against the Ec42444 strain (fosfomycin MIC, 64 mg/liter) at doses of 12, 24, or 36 g/day. All dosages induced at least initial bacterial killing against Ec46 (fosfomycin MIC, 1 mg/liter). High-level drug-resistant mutants appeared in this strain in response to 12, 15, and 18 g/day. In the study arms that included 24 g/day, once or in a divided dose, a complete extinction of the bacterial inoculum was observed. The combination of meropenem with fosfomycin was synergistic for bacterial killing and also suppressed all fosfomycin-resistant clones of Ec2974 (fosfomycin MIC, 1 mg/liter). We conclude that fosfomycin susceptibility breakpoints (≤64 mg/liter according to CLSI for E. coli urinary tract infections only) should be revised for the treatment of serious systemic infections. Fosfomycin can be used to treat infections caused by organisms that demonstrate lower MICs and lower bacterial densities, although relatively high daily dosages (i.e., 24 g/day) are required to prevent the emergence of bacterial resistance. The ratio of the area under the concentration-time curve for the free, unbound fraction of fosfomycin versus the MIC (fAUC/MIC) appears to be the dynamically linked index of suppression of bacterial resistance. Fosfomycin with meropenem can act synergistically against E. coli strains in preventing the emergence of fosfomycin resistance.
Background
Smoking at the time of surgery is associated with postoperative complications. Quitting smoking before surgery is linked to fewer complications during the hospital stay. This work analysed ...whether a smoking cessation intervention before surgery is economically worthwhile when funded by the National Health System (NHS) in Spain.
Methods
The economic analysis considered costs and benefits of the intervention to the NHS for the year 2016. The population who would benefit comprised adult smokers who were ready to quit and for whom surgery requiring admission to hospital was planned. The intervention, a combination of medical counselling and use of a smoking cessation drug which should occur 12 weeks before surgery, considered one attempt only to quit smoking. Benefits were costs avoided by averting postoperative complications if cessation was successful. The analysis compared the net economic outcome (benefit minus cost of intervention) and the return on investment, for intervention funded by the NHS versus the current situation without funding.
Results
Smoking cessation increased by 21·7 per cent with funding; the rate was 32·5 per cent when funded versus 10·7 per cent without funding, producing 9611 extra quitters. The cost per averted smoker was €1753 with a benefit of €503, achieving a net economic benefit of €4·8 million per year. Given the annual cost of the intervention (€17·4 million, of which €5·6 million (32·5 per cent) represents drugs), the return on investment was 28·7 per cent annually, equivalent to €1·29 per €1 of investment.
Conclusion
From the perspective of the Spanish NHS, the benefit of funding smoking cessation before surgery, in terms of healthcare cost savings, appears to greatly outweigh the costs.
Antecedentes
Ser fumador activo hasta el momento de la cirugía se asocia con complicaciones postoperatorias. Se ha descrito una disminución de las complicaciones durante la hospitalización al abandonar el hábito de fumar antes de la cirugía. Este trabajo analizó si una intervención preoperatoria para dejar de fumar es económicamente beneficiosa cuando se financia por el Sistema Nacional de Salud (SNS) en España.
Métodos
En el análisis económico se consideraron tantos los costes como los beneficios de la intervención para el SNS, en euros, correspondientes al año 2016. La población que se beneficiaría eran fumadores adultos dispuestos a dejar de fumar, en los que se programase una intervención quirúrgica con hospitalización. La intervención, una combinación de asesoramiento médico y tratamiento farmacológico para dejar de fumar, se llevó a cabo a las 12 semanas antes de la cirugía, considerando únicamente un intento para dejar de fumar. Los beneficios fueron los costes evitados por una reducción en la tasa de complicaciones postoperatorias en los casos en los que se hubiese conseguido la eliminación del hábito. El análisis comparó el resultado económico neto (beneficio menos coste de la intervención) y el retorno de la inversión (return on investment, ROI), cuando la intervención era financiada por el SNS en comparación con la situación actual sin financiamiento público.
Resultados
La tasa de abandono del hábito tabáquico aumentó en un 21,8%; 32,5% cuando se financiaba frente al 10,7% sin financiación, consiguiendo un extra de 9.611 personas que dejaron de fumar. El coste por fumador rescatado fue de €1753 con un beneficio de €503, por lo que el beneficio económico neto conseguido fue de €4,8 millones por año. Dado que el coste anual de la intervención (€17,4 millones, de los cuales €5,6 millones corresponden a fármacos (32%)), el ROI anual fue del 28,7% con un beneficio de €1,29 por cada €1 de inversión.
Conclusión
Desde la perspectiva del SNS español, los beneficios de financiar el abandono del hábito de fumar en el preoperatorio de los pacientes, en términos de ahorro de costes parecen ser muy superiores a los costes de la intervención.
Smoking at the time of surgery is associated with postoperative complications. Quitting smoking before surgery is linked to fewer complications during the hospital stay. This work analysed whether a smoking cessation intervention before surgery is worthwhile economically when funded by the National Health System in Spain. The benefit of funding smoking cessation before surgery, in terms of healthcare cost savings, greatly outweighed the costs, with a substantial return on investment.
Benefits from funding smoking cessation
There is uncertainty about the optimal teicoplanin regimens for neonates. The study aim was to determine the population pharmacokinetics (PK) of teicoplanin in neonates, evaluate currently ...recommended regimens and explore the exposure-effect relationships.
An open-label PK study was conducted. Neonates from 26 to 44 weeks post-menstrual age were recruited (n = 18). The teicoplanin regimen was a 16 mg/kg loading dose, followed by 8 mg/kg once daily. Therapeutic drug monitoring and dose adjustment were not conducted. A standard two-compartment PK model was developed, followed by models that incorporated weight. A PK/pharmacodynamic (PD) model with C-reactive protein serial measurements as the PD input was fitted to the data. Monte Carlo simulations (n = 5000) were performed using Pmetrics. The AUCs at steady state and the proportion of patients achieving the recommended drug exposures (i.e. C
>15 mg/L) were determined. The study was registered in the European Clinical Trials Database Registry (EudraCT: 2012-005738-12).
The PK allometric model best accounted for the observed data. The PK parameters medians were: clearance = 0.435 × (weight/70)
(L/h); volume = 0.765 (L); K
= 1.3 (h
); and K
= 0.629 (h
). The individual time-course of C-reactive protein was well described using the Bayesian posterior estimates for each patient. The simulated median AUC
was 302.3 mg·h/L and the median C
at 120 h was 12.9 mg/L; 38.8% of patients attained a C
>15 mg/L by 120 h.
Teicoplanin population PK is highly variable in neonates, weight being the best descriptor of PK variability. A low percentage of neonates were able to achieve C
>15 mg/L. The routine use of therapeutic drug monitoring and improved knowledge on the PD of teicoplanin is required.
The aim of this study was to develop a population pharmacokinetic (PK) model for teicoplanin across childhood age ranges to be used as Bayesian prior information in the software constructed for ...individualized therapy. We developed a nonparametric population model fitted to PK data from neonates, infants, and older children. We then implemented this model in the BestDose multiple-model Bayesian adaptive control algorithm to show its clinical utility. It was used to predict the dosages required to achieve optimal teicoplanin predose targets (15 mg/liter) from day 3 of therapy. We performed individual simulations for an infant and a child from the original population, who provided early first dosing interval concentration-time data. An allometric model that used weight as a measure of size and that also incorporated renal function using the estimated glomerular filtration rate (eGFR), or the ratio of postnatal age (PNA) to serum creatinine concentration (SCr) for infants <3 months old, best described the data. The median population PK parameters were as follows: elimination rate constant (Ke) = 0.03 · (wt/70)
· Renal (h
);
= 19.5 · (wt/70) (liters); Renal = eGFR
(ml/min/1.73 m
), or Renal = PNA/SCr (μmol/liter). Increased teicoplanin dosages and alternative administration techniques (extended infusions and fractionated multiple dosing) were required in order to achieve the targets safely by day 3 in simulated cases. The software was able to predict individual measured concentrations and the dosages and administration techniques required to achieve the desired target concentrations early in therapy. Prospective evaluation is now needed in order to ensure that this individualized teicoplanin therapy approach is applicable in the clinical setting. (This study has been registered in the European Union Clinical Trials Register under EudraCT no. 2012-005738-12.).
CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize ...vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens.
A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations.
There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg · h/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups.
The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.
Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the ...optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation SD) were as follows: CL, 0.019/0.023 (0.01) × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h(-1) (8.16 h(-1)); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h(-1) (8.93 h(-1)). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations. (This trial has been registered in the European Clinical Trials Database Registry EudraCT under registration number 2012-005738-12.).
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