Target Attainment Rates Research Articles

Lipid Lowering Treatment and Follow Up in Recent Post Acute Coronary Syndrome Patients: Real-World Evidence from the Multicenter Observational Prospective - Post Acute Coronary Syndrome Italian Study (PACSI)

PURPOSE: Patients suffering from an acute coronary syndrome are at very high risk for recurrent events. Early targeted pharmacological intervention primarily aimed at controlling plasma LDL-cholesterol (LDL-C) levels can result in the reduction of recurrent cardiovascular events. This study aimed to evaluate real-life evidence from the Italian setting to document current practice of secondary prevention in patients after acute coronary syndrome (ACS), specifically assessing: (i) the rate of LDL-C target (<70 mg/dl) achievement after 6-10 weeks from index event and at later follow-up, (ii) the distance from LDL-C target during follow up, (iii) adherence rate and visit attendance. METHODS Multicenter observational prospective clinical study ACS patients, evaluating target attainment rate at 6 weeks (V0) and 18 months (V2). RESULTS Approximately 97.4% patients enrolled (N=524) received statin-based therapy, and 3.6% received ezetimibe at discharge; mean LDL-C values decreased from 113.0±44.7 mg/dL at discharge to 71.3±26.5 mg/dl at V0. Among patients with known LDL-C for main time-points, 51.7% achieved target LDL-C at V0, 45.8% at V2. Among patients not reaching the target, the mean distance from target was 23.5±20.7 mg/dL. Attainment of target LDL-C was similar in patients receiving intensive or low-moderate statin-based treatment (approximately 50%). LDL-C target attainment was associated with lower LDL-C value at discharge and smoking status. Adherence to statin treatment was high (96.2%) throughout, similarly to medical appointment attendance at V2 (84.7%). CONCLUSION Despite most ACS patients receiving intensive statin-based regimens, only approximately half achieved LDL-C target, suggesting the need for further optimizing drug selection, combination and dosage.

Pharmacokinetic Modeling, Simulation, and Development of a Limited Sampling Strategy of Cycloserine in Patients with Multidrug-/Extensively Drug-Resistant Tuberculosis.

Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokinetic model of cycloserine to assess drug exposure and to develop a limited sampling strategy for cycloserine exposure monitoring. Patients with multidrug-/extensively drug-resistant tuberculosis who were treated for > 7days with cycloserine were eligible for inclusion. Patients received cycloserine 500mg (body weight ≤ 50kg) or 750mg (body weight > 50kg) once daily. MW/Pharm 3.83 (Mediware, Groningen, The Netherlands) was used to parameterize the population pharmacokinetic model. The model was compared with pharmacokinetic values from the literature and evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset. Monte Carlo simulations were used to develop a limited sampling strategy. Cycloserine plasma concentration vs time curves were obtained from 15 hospitalized patients (nine male, six female, median age 35years). Mean dose/kg body weight was 11.5mg/kg (standard deviation 2.04mg/kg). Median area under the concentration-time curve over 24h (AUC0-24h) of cycloserine was 888h mg/L (interquartile range 728-1252h mg/L) and median maximum concentration of cycloserine was 23.31mg/L (interquartile range 20.14-33.30mg/L). The final population pharmacokinetic model consisted of the following pharmacokinetic parameters [mean (standard deviation)]: absorption constant Ka_po of 0.39 (0.31) h-1, distribution over the central compartment (Vd) of 0.54 (0.26) L/kg LBM, renal clearance as fraction of the estimated glomerular filtration rate of 0.092 (0.038), and metabolic clearance of 1.05 (0.75) L/h. The population pharmacokinetic model was successfully evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset of Chinese patients (difference of 14.6% and 19.5% in measured and calculated concentrations and AUC0-24h, respectively). Root-mean-squared-errors found in predicting the AUC0-24h using a one- (4h) and a two- (2h and 7h) limited sampling strategy were 1.60% and 0.14%, respectively. This developed population pharmacokinetic model can be used to calculate cycloserine concentrations and exposure in patients with multidrug-/extensively drug-resistant tuberculosis. This model was successfully validated by internal and external validation methods. This study showed that the AUC0-24h of cycloserine can be estimated in patients with multidrug-/extensively drug-resistant tuberculosis using a 1- or 2-point limited sampling strategy in combination with the developed population pharmacokinetic model. This strategy can be used in studies to correlate drug exposure with clinical outcome. This study also showed that good target attainment rates, expressed by time above the minimal inhibitory concentration, were obtained for cycloserine with a minimal inhibitory concentration of 5 and 10mg/L, but low rates with a minimal inhibitory concentration of 20 and 32.5mg/L.

Amikacin Initial Dose in Critically Ill Patients: a Nonparametric Approach To Optimize A Priori Pharmacokinetic/Pharmacodynamic Target Attainments in Individual Patients.

Amikacin is commonly used for probabilistic antimicrobial therapy in critically ill patients with sepsis. Its narrow therapeutic margin makes it challenging to determine the right individual dose that ensures the highest efficacy target attainment rate (TAR) in this setting. This study aims to develop a new initial dosing approach for amikacin by optimizing the a priori TAR in this population. A population pharmacokinetic model was built with a learning data set from critically ill patients who received amikacin. It was then used to design an initial dosing approach maximizing a priori TAR for a target ratio of ≥8 for the peak concentration to the MIC (Cmax/MIC) or of ≥75 for the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC0-24/MIC). In the 166 patients included, 53% had amikacin Cmax of ≥64 mg/liter with a median dose of 23.4 mg/kg. A two-compartment model with creatinine clearance and body surface area as covariates best described the data and showed good predictive performance. Our dosing approach was successful in optimizing TAR for Cmax/MIC, with a rate of 92.9% versus 67.9% using a 30-mg/kg regimen, based on an external subset of data and assuming a MIC of 8 mg/liter. Mean optimal doses were higher (3.5 ± 0.5 g) than with the 30-mg/kg regimen (2.1 ± 0.3 g). Suggested doses varied with the MIC, the target index, and desired TAR threshold. A dosing algorithm based on the method is proposed for a large range of patient covariates. Clinical studies are necessary to confirm efficacy and safety of this optimized dosing approach.

Early Bayesian Dose Adjustment of Vancomycin Continuous Infusion in Children: a Randomized Controlled Trial.

Methicillin-resistant staphylococcal infections are a global burden. Area under the serum concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio is the pharmacokinetic (PK) parameter that best predicts vancomycin efficacy. Its therapeutic range is narrow, difficult to achieve because of a wide intersubject variability, especially in children, and is not routinely targeted since the AUC is rarely available. We investigated if an early Bayesian dose adjustment would increase the rate of vancomycin target attainment, in the first 24 hours of treatment (H24), in children.We conducted a single-centre randomized controlled trial in 4 pediatric departments of Necker-Enfants Malades hospital (Paris, France). Patients aged 3 months to 17 years for whom intravenous vancomycin was started were eligible and randomized in a 1:1 ratio: routine care were compared with an early vancomycin therapeutic drug monitoring (3h after treatment initiation) followed by an early Bayesian dose adjustment using a previously published population-based PK model that included age, bodyweight and serum creatinine as covariates. The primary outcome was the proportion of patients of each group achieving vancomycin therapeutic range at H24, defined by AUC0-24/MIC≥400 and AUC0-24 ≤800mg-h/L.Ninety-nine patients were enrolled: 49 were randomized to the Bayesian group and 50 to the control group. Modified intention-to-treat analysis included 82 patients: 85% of Bayesian group patients achieved H24 vancomycin target versus 57% of control group patients (p=0.007) with no difference regarding iatrogenic events. Early Bayesian dose adjustment increased the proportion of children achieving vancomycin target at H24, which may improve clinical outcomes of methicillin-resistant staphylococcal infections.

Antibiotic Exposure Profiles in Trials Comparing Intensity of Continuous Renal Replacement Therapy.

To determine whether the probability of target attainment over 72 hours of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, meropenem) antibiotics were substantially influenced between intensive and less-intensive continuous renal replacement therapy groups in the Acute Renal Failure Trial Network trial and The RENAL Replacement Therapy Study trial. The probability of target attainment was calculated using pharmacodynamic targets of percentage of time that free serum concentrations (fT): 1) were above the target organism's minimum inhibitory concentration (≥ fT > 1 × minimum inhibitory concentration); 2) were above four times the minimum inhibitory concentration (≥ % fT > 4 × minimum inhibitory concentration); and 3) were always above the minimum inhibitory concentration (≥ 100% fT > minimum inhibitory concentration) for the first 72 hours of antibiotic therapy. Demographic data and effluent rates from the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials were used. Optimal doses were defined as the dose achieving greater than or equal to 90% probability of target attainment. Monte Carlo simulations using demographic data from Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials. Virtual critically ill patients requiring continuous renal replacement therapy. None. The pharmacodynamic target of fT greater than 1 × minimum inhibitory concentration led to similarly high rates of predicted response with antibiotic doses often used in continuous renal replacement therapy. Achieving 100% fT greater than minimum inhibitory concentration is a more stringent benchmark compared with T greater than 4 × minimum inhibitory concentration with standard antibiotic dosing. The intensity of effluent flow rates (less intensive vs intensive) did not substantially influence the probability of target attainment of antibiotic dosing regimens regardless of pharmacodynamic target. Antibiotic pharmacodynamic target attainment rates likely were not meaningfully different in the low- and high-intensity treatment arms of the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study Investigators trials.

Cerebrospinal pharmacokinetic and pharmacodynamic analysis of efficacy of meropenem in paediatric patients with bacterial meningitis

Meropenem is widely used for the treatment of paediatric patients with bacterial meningitis, but the pharmacodynamic (PD) basis for this has not been fully elucidated. A cerebrospinal pharmacokinetic (PK) and PD analysis was performed to identify the optimal dosage regimen for paediatric patients with inflamed central nervous system disease (bacterial men-ingitis). Paediatric data from three clinical studies were used to build a novel population PK model with a cerebrospinal fluid (CSF) compartment, assuming CSF clearance of 0.021 L/h from a physical-anatomical perspective. The bactericidal target attainment rates in CSF [50%T>MIC(CSF)], after various dosage regimens, were simulated on the basis of reported or observed minimum inhibitory concentration (MIC) distributions and a newly developed population PK model including CSF concentrations. The effects of increased dose and/or prolonged infusion on target attainment were investigated. Clinical data from 154 patients {mean age 30.6 [standard deviation (SD) 34.4] months, mean body weight 12.4 (SD 7.6) kg} were used for the population PK analysis. The flat profile of the CSF concentration-time curve and attainment of 50%T>MIC(CSF) did not change markedly when the duration of infusion was increased, whereas attainment of 50%T>MIC(CSF) was improved by increasing the dose from 20 to 40 mg/kg q8h for penicillin-resistant Streptococcus pneumoniae and Pseudomonas aeruginosa. Thirty-six patients who achieved satisfactory clinical cure showed at least 75.3%T>MIC(CSF). A high dose of meropenem (40 mg/kg q8h) is necessary to achieve clinical efficacy in paediatric patients with bacterial meningitis.

Comparative LC-MS/MS and HPLC-UV Analyses of Meropenem and Piperacillin in Critically Ill Patients

Therapeutic drug monitoring (TDM) of beta-lactam antibiotics has become a valuable tool to guide dosing in critically ill patients. The main goal of the study was to compare two routinely used techniques for beta-lactam TDM in intensive care unit (ICU) patient samples, namely isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) and high-performance liquid chromatography combined with ultra-violet detection (HPLC-UV). A set of 80 sera/plasma samples from ICU patients receiving therapeutic meropenem or piperacillin dosage was investigated. Sample duplicates and quality assessment samples were assayed in parallel with an in-house LC-MS/MS and a commercially available IVD HPLC-UV kit. A pharmacokinetic and pharmacodynamic (PK/PD) target with ≥ 22.5 mg/L for piperacillin and ≥ 8.0 mg/L for meropenem was used for medical assessment of trough sample (n = 40) antibiotic concentrations. There was no difference between serum and Li-heparin plasmas. Concentration deviations were found for 4% of meropenem and 17% of piperacillin samples. Eliminating the influence of the systemic bias of approximately 10% for piperacillin, measurement discrepancies ≥ 25% between LC-MS/MS and HPLC-UV analyses were only observed for ≈ 4 - 6% of all samples. In the same way, identical PK/PD target attainment rates of 50 - 60% could be obtained. After correction of the analytical bias for piperacillin measurements, both methods showed comparable results, also with respect to clinical decision limits. HPLC-UV analysis is an adequate TDM methodology for testing of beta-lactam antibiotics in centers where no special knowledge in LC-MS/MS based TDM is present. However, potential matrix effects, interferences, and calibration issues for both methods must be taken into account.

Non-achievement of LDL-cholesterol targets in patients with diabetes at very-high cardiovascular risk receiving statin treatment: Incidence and risk factors

BackgroundCardiovascular diseases are the first cause of mortality in patients with diabetes, and LDL-cholesterol is a well-established cardiovascular risk factor. This study aimed to assess rate of LDL-cholesterol target attainment among patients with diabetes at very-high cardiovascular risk treated with statins, and to identify predictive factors of non-attainment of target in this population. MethodsPatients were recruited in the Nutrition-Diabetes unit of Montpellier University Hospital, France, from 2014 to 2017. We included all consecutive patients with type 1 or type 2 diabetes receiving statin treatment and at very-high cardiovascular risk according to 2016 ESC guidelines, therefore having a LDL-cholesterol target of <1.8 mmol/L. LDL-cholesterol levels were measured upon admission. Variables independently associated with non-attainment of LDL-Cholesterol target were assessed using multivariable logistic regression. Results654 patients were included. Mean age was 63.8 years (SD 11.0), 41.9% were women and 42.3% had a history of cardiovascular disease. 59% of patients did not achieve LDL-cholesterol target, with a median value (interquartile range) of 2.4 mmol/L (2.1–2.9) versus 1.4 mmol/L (1.1–1.6) in patients at target. Risk of non-attainment of LDL-cholesterol target value was increased in women (odds ratio [95% confidence interval]: 2.27 [1.62–3.17]) and decreased in patients with history of coronary artery disease (0.64 [0.45–0.89]) or history of stroke or transient ischemic attack (0.59 [0.33–1.07]). ConclusionsManagement of dyslipidemia is suboptimal, even in very-high risk patients with diabetes under statins. Lipid-lowering treatment should be intensified, in particular in very high risk patients with diabetes who are women or in primary cardiovascular prevention.Clinical Trial number: NCT03449784

Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial.

The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis. Neonates were randomized 1:1 to fluconazole (loading dose 25mg kg-1 ; maintenance dose 12mg kg-1 day-1 or 20mg kg-1 day-1 , respectively, for infants <30weeks or ≥30weeks' corrected gestational age) or micafungin (loading dose 15mg kg-1 day-1 ; maintenance dose 10mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36weeks' corrected gestational age or hospital discharge. Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported. Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.

Determinants of amikacin first peak concentration in critically ill patients.

Amikacin antimicrobial effect has been correlated with the ratio of the peak concentration (Cmax ) to the minimum inhibitory concentration. A target Cmax ≥ 60-80 mg/L has been suggested. It has been shown that such target is not achieved in a large proportion of critically ill patients in intensive care units. A retrospective analysis was performed to examine the determinants of Cmax ≥ 80 mg/L on the first peak in 339 critically ill patients treated by amikacin. The influence of available variables on Cmax target attainment was analyzed using a classification and regression tree (CART) and logistic regression. Mean Cmax in the 339 patients was 73.0 ± 23.9 mg/L, with a target attainment rate (TAR, Cmax ≥ 80 mg/L) of 37.5%. In CART analysis, the strongest predictor of amikacin target peak attainment was dose per kilogram of lean body weight (dose/LBW). TAR was 60.1% in patients with dose/LBW ≥ 37.8 vs. 19.9% in patients with lower dose/LBW (OR = 6.0 (95% CI: 3.6-10.2)). Renal function was a secondary predictor of Cmax . Logistic regression analysis identified dose per kilogram of ideal body weight (OR = 1.13 (95% CI: 1.09-1.17)) and creatinine clearance (OR = 0.993 (95% CI: 0.988-0.998)) as predictors of target peak achievement. Based on our results, an amikacin dose ≥ 37.8 mg/kg of LBW should be used to optimize the attainment of Cmax ≥ 80 mg/L after the first dose in critically ill patients. An even higher dose may be necessary in patients with normal renal function.

Integration of pharmacokinetic-pharmacodynamic for dose optimization of doxycycline against Haemophilus parasuis in pigs.

The aims of this study were to establish optimal doses of doxycycline (dox) against Haemophilus parasuis on the basis of pharmacokinetic-pharmacodynamic (PK-PD) integration modeling. The infected model was established by intranasal inoculation of organism in pigs and confirmed by clinical signs, blood biochemistry, and microscopic examinations. The recommended dose (20mg/kg b.w.) was administered in pigs through intramuscular routes for PK studies. The area under the concentration 0- to 24-hr curve (AUC0-24 ), elimination half-life (T½ke ), and mean residence time (MRT) of dox in healthy and H.parasuis-infected pigs were 55.51±5.72 versus 57.10±4.89μg·hr/ml, 8.28±0.91 versus 9.80±2.38hr, and 8.43±0.27 versus 8.79±0.18hr, respectively. The minimal inhibitory concentration (MIC) of dox against 40 H.parasuis isolates was conducted through broth microdilution method, the corresponding MIC50 and MIC90 were 0.25 and 1μg/ml, respectively. The Ex vivo growth inhibition data suggested that dox exhibited a concentration-dependent killing mechanism. Based on the observed AUC24hr /MIC values by modeling PK-PD data in H.parasuis-infected pigs, the doses predicted to obtain bacteriostatic, bactericidal, and elimination effects for H.parasuis over 24hr were 5.25, 8.55, and 10.37mg/kg for the 50% target attainment rate (TAR), and 7.26, 13.82, and 18.17mg/kg for 90% TAR, respectively. This study provided a more optimized alternative for clinical use and demonstrated that the dosage 20mg/kg of dox by intramuscular administration could have an effective bactericidal activity against H.parasuis.

PK-PD Integration Modeling and Cutoff Value of Florfenicol against Streptococcus suis in Pigs.

The aims of the present study were to establish optimal doses and provide an alternate COPD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w.) were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of Cmax, AUC0-24h, AUC, Ke, t1/2ke, MRT, Tmax, and Clb, were estimated as 4.44 μg/ml, 88.85 μg⋅h/ml, 158.56 μg⋅h/ml, 0.048 h-1, 14.46 h, 26.11 h, 4 h and 0.185 L/h⋅kg, respectively. The bioavailability of florfenicol was calculated to be 99.14% after I.M administration. A total of 124 Streptococcus suis from most cities of China were isolated to determine the minimum inhibitory concentration (MIC) of florfenicol. The MIC50 and MIC90 were calculated as 1 and 2 μg/ml. A serotype 2 Streptococcus suis (WH-2), with MIC value similar to MIC90, was selected as a representative for an in vitro and ex vivo pharmacodynamics study. The MIC values of WH-2 in TSB and plasma were 2 μg/ml, and the MBC/MIC ratios were 2 in TSB and plasma. The MPC was detected to be 3.2 μg/ml. According to inhibitory sigmoid Emax model, plasma AUC0-24h/MIC values of florfenicol versus Streptococcus suis were 37.89, 44.02, and 46.42 h for the bactericidal, bacteriostatic, and elimination activity, respectively. Monte Carlo simulations the optimal doses for bactericidal, bacteriostatic, and elimination effects were calculated as 16.5, 19.17, and 20.14 mg/kg b.w. for 50% target attainment rates (TAR), and 21.55, 25.02, and 26.85 mg/kg b.w. for 90% TAR, respectively. The PK-PD cutoff value (COPD) analyzed from MCS for florfenicol against Streptococcus suis was 1 μg/ml which could provide a sensitivity cutoff value. These results contributed an optimized alternative to clinical veterinary medicine and showed that the dose of 25.02 mg/kg florfenicol for 24 h could have a bactericidal action against Streptococcus suis after I.M administration. However, it should be validated in clinical practice in the future investigations.

Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration–time data. The mean ± standard deviation parameter estimates were 8.38 ± 9.91 L/h for drug clearance and 25.54 ± 3.65 L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90 mL/min/1.73 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) against susceptible Pseudomonas aerginosa isolates (MIC ≤16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.

O-10 An observational study on plasma protein binding and target attainment of teicoplanin in critically ill children

Background The objectives of this study were (i) to document teicoplanin plasma protein binding and, (ii) to evaluate target attainment rates using commonly used PK/PD targets in critically ill children. Methods Patients, admitted to the PICU in whom treat-ment with intravenous teicoplanin (10 mg/kg every 12 hour for 3 loading doses, followed by 6–10 mg/kg once daily) was indicated, were enrolled. Blood samples were collect-ed during first and/or assumed steady-state dose inter-vals. Noncompartmental analysis was used to estimate the (free) AUC24h for first and SS doses. Evaluated PK/PD targets included AUC/MIC ≥750 hour, free AUC (fAUC)/MIC ≥75 hour and total trough plasma concentration (Cmin) ≥10 mg/L. Correlation was assessed by means of a scatter plot and Spearman’s Rank Correlation Coefficient. Results 130 plasma samples were collected from 27 pa-tients (median age: 2.2 years; IQR: 0.8–4.8 years). The free teicoplanin fraction (n=26; median: 8.6%; IQR: 7.0%–11.7%) only varied slightly between patients. The targets of AUC/MIC (median: 823 hour; IQR: 702–949 hour) and fAUC/MIC (n=26; median: 72 hour; IQR: 55–86 hour) were achieved in 63% and 42% of patients respectively. The target Cmin (median: 16.0 mg/L; IQR: 10.3–17.9 mg/L) were reached in 78% of patients. Cmin correlated well with AUC/MIC (Spearman’s Rank Correlation Coefficient R=0.84; p 0.05). Conclusion Currently used teicoplanin dosing regimens frequently resulted in an AUC/MIC ratio and Cmin be-low widely accepted PK/PD targets. The fAUC/MIC ratio resulted in the lowest target attainment, despite plasma protein binding was similar to adults. Overall, target at-tainment rates varied widely depending upon the type of PK/PD target used. Future study is needed to define appropriate PK/PD indices in children.

Pharmacokinetic and Pharmacodynamic Evaluation of Marbofloxacin and PK/PD Modeling against Escherichia coli in Pigs.

The aim of this study was to evaluate the activity of marbofloxacin and establish the optimal dose regimens for decreasing the development of fluoroquinolone resistance in pigs against Escherichia coli with ex vivo pharmacokinetic/pharmacodynamic (PK/PD) modeling. The recommended dose (2 mg/kg body weight) of marbofloxacin was orally administered in healthy pigs. The ileum content and plasma were both collected for the determination of marbofloxacin. The main parameters of Cmax, AUC0-24 h, AUC, Ke, t1/2ke, MRT and Clb were 11.28 μg/g, 46.15, 77.81 μg⋅h/g, 0.001 h-1, 69.97 h, 52.45 h, 0.026 kg/h in ileum content, and 0.55 μg/ml, 8.15, 14.67 μg⋅h/ml, 0.023 h-1, 30.67 h, 34.83 h, 0.14 L/h in plasma, respectively In total, 218 E. coli strains were isolated from most cities of China. The antibacterial activity in vitro and ex vivo of marbofloxacin against E. coli was determined following CLSI guidance. The MIC90 of sensitive strains (142) was calculated as 2 μg/ml. The minimum inhibitory concentration (MIC) of HB197 was 2 and 4 μg/ml in broth and ileum fluids, respectively. In vitro mutant prevention concentration, growth and killing-time in vitro and ex vivo of marbofloxacin against selected HB197 were assayed for pharmacodynamic studies. According to the inhibitory sigmoid Emax modeling, the value of AUC0-24 h/MIC produced in ileum content was achieved, and bacteriostatic, bactericidal activity, and elimination were calculated as 16.26, 23.54, and 27.18 h, respectively. Based on Monte Carlo simulations to obtain 90% target attainment rate, the optimal doses to achieve bacteriostatic, bactericidal, and elimination effects were 0.85, 1.22, and 1.41 mg/kg.bw for 50% target, respectively, and 0.92, 1.33, and 1.53 mg/kg.bw for 90% target, respectively, after oral administration. The results in this study provided a more optimized alternative for clinical use and demonstrated that the dosage 2 mg/kg of marbofloxacin by oral administration could have an effect on bactericidal activity against E. coli.

Pharmacokinetic-pharmacodynamic integration and modelling of oxytetracycline for the calf pathogens Mannheimia haemolytica and Pasteurella multocida.

A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-∞ )/MIC ratios of 30.0 and 24.3hr for M.haemolytica and P.multocida, respectively. Corresponding AUC0-∞ /MIC ratios based on MICs in broth were 656 and 745hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24hr /MIC ratios for 3log10 decrease in bacterial count of 27.5hr (M.haemolytica) and 60.9hr (P.multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197mg/kg (M.haemolytica) and 314mg/kg (P.multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5mg/kg) for M.haemolytica and P.multocida, respectively.

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling

BackgroundBacterial pneumonia in pigs occurs widely and requires antimicrobial therapy. It is commonly caused by the pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida. Marbofloxacin is an antimicrobial drug of the fluoroquinolone class, licensed for use against these organisms in the pig. In recent years there have been major developments in dosage schedule design, based on integration and modelling of pharmacokinetic (PK) and pharmacodynamic (PD) data, with the objective of optimising efficacy and minimising the emergence of resistance. From in vitro time-kill curves in pig serum, PK/PD breakpoint Area under the curve (AUC) 24h /minimum inhibitory concentration (MIC) values were determined and used in conjunction with published PK, serum protein binding data and MIC distributions to predict dosages based on Monte Carlo simulation (MCS).ResultsFor three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count, mean AUC24h/MIC values were 20.9, 45.2 and 71.7 h, respectively, for P. multocida and 32.4, 48.7 and 55.5 h for A. pleuropneumoniae. Based on these breakpoint values, doses for each pathogen were predicted for several clinical scenarios: (1) bacteriostatic and bactericidal levels of kill; (2) 50 and 90% target attainment rates (TAR); and (3) single dosing and daily dosing at steady state. MCS for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 0.44 and 0.95 mg/kg (P. multocida) and 0.28 and 0.66 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 0.28 and 0.59 mg/kg (P. multocida) and 0.22 and 0.39 mg/kg (A. pleuropneumoniae) were required for pigs aged 12 weeks. Doses were also predicted for pigs aged 16 and 27 weeks.ConclusionsPK/PD modelling with MCS approaches to dose determination demonstrates the possibility of tailoring clinical dose rates to a range of bacterial kill end-points.

Antibiotic Dosing in Continuous Renal Replacement Therapy.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35mL/kg/h are used.

Population pharmacokinetics of cefepime in febrile neutropenia: implications for dose-dependent susceptibility and contemporary dosing regimens

Alterations in cefepime pharmacokinetic (PK) exposure and decreased bacterial susceptibility increase the risk of treatment failure. The impact of susceptible-dose-dependent (SDD) minimum inhibitory concentrations (MICs), i.e. 4–8 µg/mL, on target attainment rates for cefepime in febrile neutropenia (FN) is unclear. We sought to identify optimal cefepime regimens against SDD cefepime MICs in FN using a modelling and simulation approach. Creatinine clearance (CLCr) and body surface area (BSA) covariate-adjusted models of clearance were evaluated. Monte Carlo simulations representing 10 000 patients were completed to assess various dosing strategies (i.e. 3–8 g/day infused over 0.5–24 h, replaced every 6–24 h) and predict probabilities of target attainment (PTAs) for unbound cefepime. Nine patients received cefepime 2 g every 8 h (q8h) (0.5-h infusion). A two-compartment PK model with BSA- and CLCr-adjusted clearance was fit to the data. Mean population values for total clearance (6.3 ± 1.1 L/h), intercompartmental clearance (6.9 ± 2.8 L/h), and central (14.8 ± 3.8 L) and peripheral (10.9 ± 4.6 L) distribution volumes were all estimated with <50% CV. Simulated dosing regimens of 3–4 g/day administered as continuous infusions and doses of 2 g administered q6h (0–5 h infusion) to q8h (4-h infusion) achieved ≥90% PTA at MICs up to 8 µg/mL. Simulated regimens of 1 g q8h (4-h infusion) or 1 g q6h (0.5-h infusion) achieved ≥90% PTA only against MICs up to 4 µg/mL. High-dose prolonged infusion or more frequent cefepime regimens may be necessary to treat FN organisms with SDD MICs.

Pharmacokinetic and pharmacodynamic modeling of cyadox against Clostridium perfringens in swine

The purpose of this study was to evaluate the activity of cyadox against Clostridium perfringens in swine and optimize the dosage regimen using ex vivo pharmacokinetic-pharmacodynamic (PK-PD) modeling. After oral administration, the ileum fluid of pigs containing the free cyadox was collected by implanted ultrafiltration probes. The Tmax, AUC24h, and CL/F of free cyadox in the ileum fluid were 1.96 h, 106.40 μg/h/mL, and 0.27 L/kg/h, respectively. Cyadox displayed a concentration-dependent killing action against C. perfrignens. The minimum inhibitory concentration (MIC) of cyadox against 60 clinical isolates ranged from 0.5 to 8 μg/mL, with MIC50 and MIC90 values of 2 and 4 μg/mL, respectively. The MIC was 2 μg/mL against the pathogenic C. perfrignens isolate CPFK122995 in both broth and ileum fluid. According to the inhibitory sigmoid Emax modeling, the AUC24h/MIC ratios of ileum fluid required to achieve the bacteriostatic, bactericidal, and virtual bacterial elimination effects were 26.72, 39.54, and 50.69 h, respectively. Monte Carlo simulations for the 90% target attainment rate (TAR) predicted daily doses of 29.30, 42.56, and 54.50 mg/kg over 24 h to achieve bacteriostatic, bactericidal, and elimination actions, respectively. The results of this study suggest that cyadox is a promising antibacterial agent for the treatment of C. perfringens infections, and can be used to inform its clinical use.