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.
Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill ...patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r(2) of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.
Severe infections of the respiratory tracts of critically ill patients are common and associated with excess morbidity and mortality. Piperacillin is commonly used to treat pulmonary infections in ...critically ill patients. Adequate antibiotic concentration in the epithelial lining fluid (ELF) of the lung is essential for successful treatment of pulmonary infection.
To compare piperacillin pharmacokinetics/pharmacodynamics in the serum and ELF of healthy volunteers and critically ill patients.
Piperacillin concentrations in the serum and ELF of healthy volunteers and critically ill patients were compared using population methodologies.
Median piperacillin exposure was significantly higher in the serum and the ELF of critically ill patients compared with healthy volunteers. The IQR for serum piperacillin exposure in critically ill patients was six times greater than for healthy volunteers. The IQR for piperacillin exposure in the ELF of critically ill patients was four times greater than for healthy volunteers. The median pulmonary piperacillin penetration ratio was 0.31 in healthy volunteers and 0.54 in critically ill patients.
Greater variability in serum and ELF piperacillin concentrations is observed in critically ill patients compared with healthy adult subjects and must be considered in the development of dosage regimens. Pulmonary penetration of antimicrobial agents should be studied in critically ill patients, as well as healthy volunteers, during drug development to ensure appropriate dosing of patients with pneumonia.
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.).
Abstract The pharmacokinetics (PK) of antimicrobial agents administered to critically ill patients exhibit marked variability. This variability results from pathophysiological changes that occur in ...critically ill patients. Changes in volume of distribution, clearance, and tissue penetration all affect the drug concentrations at the site of infection. PK-pharmacodynamic indices (fCmax :MIC; AUC0–24 :MIC; f T>MIC ; fCmin :MIC) for both antimicrobial effect and suppression of emergence of resistance are described for many antimicrobial drugs. Changing the regimen by which antimicrobial drugs are delivered can help overcome the PK variability and optimise target attainment. This will deliver optimised antimicrobial chemotherapy to individual critically ill patients. Delivery of β-lactams antimicrobial agents by infusions, rather than bolus dosing, is effective at increasing the duration of the dosing interval that the drug concentration is above the MIC. Therapeutic drug monitoring, utilising population PK mathematical models with Bayesian estimation, can also be used to optimise regimens following measurement of plasma drug concentrations. Clinical trials are required to establish if patient outcomes can be improved by implementing these techniques.
A concise invasive candidosis guideline (based on the ESCMID candidaemia guideline) utilizing an informative biomarker serum β-1-3-d-glucan (BDG) was developed in 2013 by an antifungal stewardship ...(AFS) team and implemented with the help of an AFS champion in 2014. The main aims of the AFS programme were to reduce inappropriate use of antifungals and improve patient outcomes. The aim of this project was to evaluate the compliance of the ICU teams with the invasive candidosis guideline and the impact of the AFS programme on mortality and antifungal consumption on the ICUs (total of 71 beds).
All patients who were prescribed micafungin for suspected or proven invasive candidosis during 4 month audit periods in 2014 and 2016 were included. Prescriptions and patient records were reviewed against the guideline. Antifungal consumption and mortality data were analysed.
The number of patients treated for invasive candidosis decreased from 39 in 2014 to 29 in 2016. This was mainly due to the reduction in patients initiated on antifungal therapy inappropriately: 18 in 2014 and 2 in 2016. Antifungal therapy was stopped following negative biomarker results in 12 patients in 2014 and 10 patients in 2016. Crude mortality due to proven or probable invasive candidosis decreased to 19% from 45% over the period 2003-07. Antifungal consumption reduced by 49% from 2014 to 2016.
The AFS programme was successful in reducing the number of inappropriate initiations of antifungals by 90%. Concurrently, mortality due to invasive candidosis was reduced by 58%. BDG testing can guide safe cessation of antifungals in ICU patients at risk of invasive candidosis.
Objectives
Triazole antifungal drugs are the mainstay of treatment for patients with chronic pulmonary aspergillosis and are often used as steroid-sparing agents in patients with allergic ...aspergillosis. Peripheral neuropathy (PN) is a rare but reported side effect of triazole therapy in the acute management of invasive fungal infections, but its incidence during long-term triazole treatment for chronic aspergillosis is unknown. The goal of this study was to determine the incidence of PN in this context.
Patients and methods
A retrospective cohort study was carried out to collect data on all patients with chronic aspergillosis commenced on long-term triazole therapy at the National Aspergillosis Centre in Manchester between 2007 and 2010.
Results
Two hundred and twenty-two patients were commenced on triazole therapy. Ten percent developed PN after an average of 4 months. Seventeen percent of patients taking itraconazole, 9% taking voriconazole and 3% taking posaconazole developed PN. This is the first report of posaconazole-induced PN. Twenty-two episodes of PN presented as numbness or tingling in the extremities, while four episodes presented as predominant leg weakness. The majority of cases were axonal, length-dependent neuropathies that recovered after triazole medication was discontinued. Two patients had non-progressive but irreversible PN. Two patients were diagnosed with mononeuropathies.
Conclusions
A 10% incidence of PN was observed for patients commenced on triazole therapy for chronic aspergillosis. Patients on long-term triazole therapy should be monitored for neurological symptoms. If PN is suspected, diagnosis should include nerve conduction studies, exclusion of other causes and consideration of dose reduction or cessation of therapy.
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