We aimed to develop population pharmacokinetic (PK) models of ampicillin and sulbactam using pooled data analysis and to optimize dosing regimens of ampicillin-sulbactam (combination ratio of 2:1) in ...pediatric patients.
Population PK models of ampicillin and sulbactam were separately developed by simultaneously fitting plasma and urine data from pediatric patients in 14 published studies. Based on these models, we estimated the probability of attaining a pharmacodynamic (PD) target 50% of time that free drug concentrations above the minimum inhibitory concentration, 50% fT > minimum inhibitory concentration (MIC) against MIC90 MIC that blocked the growth of 90% of the strains of common bacteria in community-acquired pneumonia.
The analysis included 54 pediatric patients (0.083-16.42 years of age, 4.0-77.0 kg of body weight). A total of 284 plasma concentrations and 90 urinary excretions from 0 to 6 hours after administration were used for population PK modeling. The data were adequately described by 2-compartment models for ampicillin and sulbactam. Age was not a statistically significant covariate in the PK of either drug. The PK/PD breakpoint MICs for 45 mg/kg 3 times daily and 75 mg/kg 4 times daily (q.i.d.) were 0.25 and 1 μg/mL, respectively. For empiric therapy of community-acquired pneumonia, because MIC90 values for the main target pathogens is high (MIC90 = 2 μg/mL for Streptococcus pneumoniae and MIC90 = 4 μg/mL for Haemophilus influenzae), 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage in United States) might be better than 45 mg/kg 3 times daily (within approved dosage in Japan) to cover many pathogens.
From the results of this PK/PD approach, 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage) should be recommended in the empiric therapy of community-acquired pneumonia.
This study aims to define the penetration of ampicillin and sulbactam into prostate tissue, develop a prostatic pharmacokinetic model of each drug, and assess the appropriateness of ...ampicillin-sulbactam regimens for the treatment of prostatitis and the prophylaxis of postoperative infection, based on a pharmacokinetic and pharmacodynamic simulation. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-hour infusion of 1.5 g (1:0.5 g) or 3 g (2:1 g) ampicillin-sulbactam before transurethral resection of the prostate. Ampicillin and sulbactam concentrations in plasma and prostate tissue were measured. The prostate tissue/plasma ratios of both ampicillin and sulbactam were approximately 0.37 (area under the drug concentration-time curve), and penetration was similar. The prostatic population pharmacokinetic model, which included a covariate analysis, adequately predicted prostate tissue concentrations in our patient population. For therapeutic use, aiming for a bactericidal target of 50% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability against only Enterococcus faecalis in typical patients with a creatinine clearance (CL
) of 30 mL/min. For prophylactic use, aiming for a bacteriostatic target of 30% T > MIC, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability of attaining the bacteriostatic target against E. faecalis and Proteus species when CL
was 30 mL/min. Based on prostatic simulations, the present study provides helpful recommendations for the treatment of bacterial prostatitis and preoperative prophylaxis in prostatectomy.
What Is Known and Objective
Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on ...population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia.
Methods
This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 μg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses.
Results and Discussion
Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CLcr) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non‐thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 95% confidence interval (CI): 1.918–28.831 and 4.712 95% CI: 1.567–14.163; odds ratio for safety target achievement rate: 0.060 95% CI: 0.016–0.232 and 0.167 95% CI: 0.056–0.498 for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non‐thrombocytopenic groups, the safety target achievement rate was higher in the non‐thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more.
Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD‐induced thrombocytopenia.
What Is New and Conclusion
The risk of LZD‐induced thrombocytopenia, which increased with the duration of LZD therapy, may be predicted using the safety target achievement rate obtained by the blood concentration simulation.
Utility of safety target achievement rate based on PK/PD simulation for predicting linezolid‐induced thrombocytopenia‐stratified on the duration of linezolid therapy.
•Consumption of soluble dietary fibre PHGG in daily diets could improve the metabolic health profiles.•PHGG may offer protection against type-2 diabetes mellitus by affecting circulating ...metabolites.•Results support the potential of PHGG for beneficial impact on glycaemia and hyperlipidaemia over time in healthy subjects.•PHGG was better tolerated without any adverse effects.
Dietary fibre intakes have consistently been associated with reduced risk of diabetes and metabolic syndrome. We investigated in 12 healthy subjects if administration of dietary fibre partially hydrolysed guar gum (PHGG) induces beneficial impact on hyperglycaemia, hyperlipidaemia and incretins metabolic hormones. Administration of 6 g/PHGG with each meal for 12 months significantly lowered the postprandial plasma glucose (PG), reduced both the fasting and postprandial insulin (IRI) and triacylglycerol (TG) levels (p = 0.05). Low-density lipoprotein (LDL) was lower, whereas high-density lipoprotein (HDL) level was significantly increased (p < 0.01). Plasma leptin, high-sensitive C-reactive protein (hs-CRP) and fasting glucagon like peptide (GLP-1) were also lowered. In fact, 3 out of 6 glucose intolerant subjects turned out to be normal glucose tolerant after only 3 months of PHGG supplementation. Therefore, this preliminary study revealed that inclusion of PHGG in diets potentially impact on metabolic health profiles by affecting circulating metabolites that are responsible for glycaemia, hyperinsulinaemia and hyperlipidaemia factors.
This study aimed to assess the dosing regimens of ampicillin/sulbactam for pneumonia based on pulmonary pharmacokinetic (PK)/pharmacodynamic (PD) target attainment. Using the literature data, we ...developed pulmonary PK models and estimated the probabilities of attaining PK/PD targets in lung tissue. Against bacteria other than
(the general treatment), the PK/PD target was set as both 50% time above the minimum inhibitory concentration (T > MIC) for ampicillin and 50% T > 0.5 MIC for sulbactam. For the
treatment, the PK/PD target was set as 60% T > MIC for sulbactam. The pulmonary PK/PD breakpoint was defined as the highest minimum inhibitory concentration (MIC) at which the target attainment probability in the lung tissue was ≥90%. The lung tissue/serum area under the drug concentration-time curve from 0 to 3 h (AUC
) ratios for ampicillin and sulbactam were 0.881 and 0.368, respectively. The ampicillin/sulbactam AUC
ratio in the lung tissue was 3.89. For the general treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 3 g four times daily in typical patients with creatinine clearance (CL
) of 60 mL/min was 2 μg/mL, which covered the MIC
(the MICs that inhibited the growth of 90% of the strains) of most gram-positive and gram-negative bacteria. For the
treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 9 g 4-h infusion three times daily (27 g/day) in patients with a CL
of 60 mL/min was 4 μg/mL, which covered the MIC
of
. A PK/PD evaluation for pneumonia should be performed in the lung tissue (the target site) rather than in the blood because sulbactam concentrations are lower in lung tissue. These findings should facilitate the selection of ampicillin/sulbactam regimens for pneumonia caused by various bacteria, including
.
Poor medication management in preoperative patients can lead to the cancellation of surgical procedures and perioperative complications, so we established a cooperative system between our hospital ...and community pharmacies to review preoperative medications. We asked community pharmacies to review home medications for preoperative patients and to discontinue some medications such as anticoagulants and antiplatelet agents before surgery. A high percentage of outpatient pharmacies responded, with 2 days being the median response time. In 55 patients who required medication reconciliation, all 24 patients who received preoperative pharmaceutical consultation underwent scheduled surgery. Of the 31 patients who did not receive pharmaceutical consultation, one patient's surgery had to be postponed due to noncompliance with medication. The establishment of a cooperative system between hospital and community pharmacies helped improve safety in perioperative patients.
Herein, we describe a case of an elderly patient with muscular dystrophy for whom control of the plasma vancomycin (VCM) concentration proved difficult when he developed a catheter-related ...bloodstream infection. The pharmacist initially carried out therapeutic drug monitoring using an estimate of the creatinine clearance (CLcr) level, which was based on the serum creatinine (SCr) and serum cystatin-C (CysC) levels, but was ultimately unable to control the plasma VCM concentration. Therefore, the plasma VCM concentration was predicted ex post facto using population pharmacokinetic parameters as a covariate; that is, directly including the glomerular filtration rate (GFRCysC) estimated from the CysC level, which is not affected by the muscle mass. As a result, the estimated VCM concentration was closer to the actual concentration than that predicted using CLcr. Furthermore, the results of examining the predictive accuracy according to the assessment of renal function at the time of initial VCM administration suggested that estimation of the trough concentration using GFRCysC might be useful in elderly patients with muscular dystrophy.
In recent years, antimicrobial resistance bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) have become a global problem. One of the countermeasures is to optimize the use of ...antimicrobial drugs, specifically to optimize the dosage and administration based on the therapeutic drug monitoring (TDM) and pharmacokinetics (PK)/pharmacodynamics (PD) theory. On the other hand, in clinical practice, clinical-pharmacometrics can be used for optimized management of individual patients of pharmaceutical products. Therefore, we aimed at individual optimization of infectious disease treatment for antimicrobial resistant bacteria, and tried a series of flows from model construction to clinical application, that is, practice of clinical pharmacometrics. In the context of individual optimization and optimization management of drug therapy in the medical field, it is considered that hospital pharmacists can contribute to the improvement of infectious disease treatment of antimicrobial resistance bacteria by contributing to the optimization of administration method. In addition, clinical pharmacometrics can be applied not only to antibacterial drugs but also to all drugs, and can be said to be a useful method for quantitatively evaluating the promotion of individualized administration methods for patients.
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