2016-2018年清镇市第一人民医院铜绿假单胞菌的分布及耐药性分析

目的 探讨2016-2018年清镇市第一人民医院铜绿假单胞菌感染的临床分布特征及耐药性变迁,为临床合理选用抗生素治疗提供参考。方法 收集2016-2018年清镇市第一人民医院临床标本中铜绿假单胞菌的检出情况、病区分布、标本来源及药敏结果等资料,并进行统计分析。结果 共分离出铜绿假单胞菌215株,以痰液标本来源为主,占84.2%,感染病区以呼吸内科、ICU和神经外科占前3位,分别占33.9%、18.1%、17.7%。铜绿假单胞菌对复方新诺明、氨苄西林、头孢唑林、氨苄西林/舒巴坦和头孢曲松的耐药率在90.0%以上,对阿米卡星的耐药率最低。与2016年相比较,2018年铜绿假单胞菌对哌拉西林、头孢他啶、哌拉西林/他唑巴坦、头孢吡肟的耐药率呈下降趋势,对庆大霉素、妥布霉素、阿米卡星、环丙沙星、左氧氟沙星、亚胺培南的耐药率呈上升趋势。结论 2016-2018年铜绿假单胞菌对多种抗生素耐药呈上升趋势,临床应加强铜绿假单胞菌感染监控及耐药性监测,密切关注耐药性变迁,合理选用抗生素治疗。     

Microbial pharmacodynamics of piperacillin in neutropenic mice of systematic infection due toPseudomonas aeruginosa

Mathematical solutions for two possible pharmacodynamic interactions (linear nonsaturable and nonlinear saturable) between antibiotics and microorganisms derived from the incorporation of clinically relevant antibiotic dosage regimens such as single bolus dosing, multiple doses, and constant infusion at steady state have been obtained. It is concluded that the saturable nonlinear interaction model between the tested antibiotic and microorganism appears appropriate. The model and its derived equations are capable of describing in vivobacterial growth of P. aeruginosaafter single bolus dosing and multiple doses of piperacillin as described by a linear one-compartment pharmacokinetic model. The activity of piperacillin against P. aeruginosain the neutropenic mouse systemic infection model can be described by an equation with three dynamic parameters: the bacterial growth rate constant k _app ,0.02345min ^–1, the bacterial killing rate constant k _kill ,0.02623 min ^–1, and the Michaelis-Menten type saturation constant K_m, 0.05467 g/ml. The concept and derived equations for the optimal dosing interval and minimum critical concentration are of clinical importance for the proper selection of antibiotic dosage regimens.     

Higher versus standard amikacin single dose in emergency department patients with severe sepsis and septic shock: a randomised controlled trial

Recent studies suggest that intensive care unit patients treated with amikacin frequently do not attain the desired pharmacokinetic/pharmacodynamic (PK/PD) target, i.e. peak amikacin concentration (C_peak) to minimum inhibitory concentration (MIC) ratio of ≥8, when a single dose of 15?mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this prospective randomised controlled study was to determine PK/PD target attainment in ED patients presenting with severe sepsis or septic shock treated with 15?mg/kg versus 25?mg/kg amikacin. Patients were randomly assigned to receive amikacin 25?mg/kg or 15?mg/kg. Amikacin C_peak values were determined. The primary outcome was target attainment defined as C_peak/MIC?≥?8 both using EUCAST susceptibility breakpoints and actually documented MICs as denominator. A total of 104 patients were included. The EUCAST-based target was attained in 76% vs. 40% of patients assigned to the 25?mg/kg vs. 15?mg/kg dose groups (P?<0.0001). Target attainment using actual MICs (median of 2?mg/L, documented in 48 isolated Gram-negative pathogens) was achieved in 95% vs. 94% of patients in the 25?mg/kg vs. 15?mg/kg dose groups (P?=?0.969). Risk factors associated with PK/PD target failure were identified in the multivariable analysis. At least 25?mg/kg amikacin as a single dose should be used in ED patients with severe sepsis and septic shock to attain the EUCAST-based PK/PD target. However, when using local epidemiology as denominator, 15?mg/kg appears to be sufficient. [ClinicalTrials.gov ID: NCT02365272.     

In Vivo/in Vitro Correlation of Experimental Sustained-Release Theophylline Formulations

A novel multiparticulate sustained-release theophylline formulation, which consisted of spherical drug pellets coated with a rate-controlling membrane, was evaluated in vivo. Two preparations that differ solely in the coat thickness, and hence rate of in vitro drug release, were studied in comparison with a solution of the drug. Both preparations produced serum concentration profiles that are reflective of a slow and sustained rate of absorption. The in vivo release versus time profiles calculated using a deconvolution procedure showed that the two preparations differed in the rate but not the extent of drug release. Satisfactory correlation was also obtained between the in vivo and the in vitro results. When the two preparations were further compared using the parameters, time to reach peak concentration (T _p), peak concentration (C _p), and total area under the serum concentration versus time curves (AUC), a statistically significant difference was observed in the T _p and C _p values but not the AUC values, suggesting that the preparations differed in the rate but not the extent of absorption. In addition, the extent of absorption from both preparations was comparable to that obtained with the drug solution.     

Development and in Vitro-in Vivo Evaluation of a Multiparticulate Sustained Release Formulation of Diltiazem

Purpose. To develop and evaluate the in vitro/in vivo performance of diltiazem sustained release pellets that were prepared by the Wurster column process. Methods. Pellets containing diltiazem were prepared by spraying a slurry of micronized diltiazem hydrochloride, pharmaceutical glaze and alcohol onto an appropriate mesh fraction of nonpareil seeds using the Wurster column. A two-step drug layering process was used to increase drug loading from 60% to 75%. The oven-dried diltiazem basic pellets were coated with eth-ylcellulose/dibutyl sebacate coating solution to yield diltiazem sustained release pellets. An open, randomized Latin square, three-way crossover clinical study was used to evaluate the in vivo performance of the coated product. Results. Altering the mesh fraction of the starting nonpareil seeds for this layering process was found to affect the release characteristics of drug from the pellets. An oven-drying step was required to stabilize the diltiazem basic pellets. The thicker the drug loading layer the longer the oven drying is needed to stabilize the pellets. The diltiazem sustained release pellets produced by these methods displayed sustained release dissolution profiles both in vitro and in vivo. Diltiazem basic pellets coated with a 0.6% ethylcellulose/dibutyl sebacate coating showed a different rate of absorption (lower C _max and higherT _max) and the same extent of absorption as compared to Cardizem^® tablets. Conclusions. Clinical data confirmed that this formulation approach is an effective means to produce a diltiazem sustained release product.     

重症监护病房铜绿假单胞菌耐药性分析及对策

目的:分析ICU感染的铜绿假单胞菌耐药情况.方法:收集2007.7～2008.12入住ICU患者的基本资料及各类标本,标本进行细菌培养及药敏试验,对患者耐药情况进行分析.结果:共分离出199株铜绿假单胞菌菌株,美洛培南敏感率为96.2%、阿米卡星敏感率为69.6%、头孢哌酮/舒巴坦敏感率为65.4%、哌拉西林/他唑巴坦敏感率为61.6%、亚胺培南敏感率为57.2%、头孢吡肟敏感率为32.4%、头孢他啶敏感率为28.3%;通过分析发现,住院时间长、使用抗菌药物、侵入治疗、呼吸衰竭、手术等均为铜绿假单胞菌耐药的危险因素.结论:ICU铜绿假单胞菌耐药现象已十分突出,对多重耐药菌株的感染应以预防为主,建立耐药监控体系,控制耐药的发展及扩散.     

明目蒺藜丸联合聚乙烯醇滴眼液治疗干眼症的临床研究

目的 制备他达拉非片并考察其体内外释药特性。方法 以溶出度为评价指标,筛选他达拉非片各辅料用量及包衣增重。用相似因子（f₂）法比较自制制剂与参比制剂在0.5% SDS溶液、含0.5% SDS的0.1 mol/L的盐酸溶液、含0.5% SDS的pH 4.5醋酸钠缓冲液、含0.5% SDS的pH 6.8磷酸盐缓冲液中溶出曲线的相似性。比较二者在Beagle犬体内的药动学特征。结果 他达拉非片处方为他达拉非20 mg、乳糖50M 227.625 mg、羟丙基纤维素L 10.5 mg、交联羧甲基纤维素钠19.6 mg、SDS 0.525 mg、微晶纤维素M102 70 mg、硬脂酸镁1.75 mg,包衣增质量范围2%～4%。自制与参比制剂在4种溶出介质中的f₂均大于65,二者体外溶出行为相似。2种制剂在Beagle体内的药动学参数AUC_0~t、C_max、t_max均无显著性差异,自制他达拉非片的相对生物利用度为（101.67±8.99）%。结论 成功制备他达拉非片,其体外溶出和体内药动学行为与参比制剂相似。     

Pharmacokinetics and Metabolism of Transdermal Oxybutynin: In Vitro and in Vivo Performance of a Novel Delivery System

Purpose. The purpose of this work was to characterize in vitro/in vivo delivery and pharmacokinetics of oxybutynin (OXY) and its active metabolite, N-desethyloxybutynin (DEO), by a novel matrix transdermal system (TDS). Methods. Two in vivo, randomized, three-way crossover trials examined single/multiple OXY TDS doses. Abdomen, buttock, and hip application sites were compared and dose proportionality was evaluated. Model independent pharmacokinetics, elimination rate constants, and metabolite/drug ratios were derived from both plasma OXY and DEO concentrations. Results. Single/multiple applications of the OXY TDS to the abdomen yielded mean C _max OXY concentrations of 3.4 ± 1.1/6.6 ± 2.4 ng/mL and median t _max of 36/10 h, with steady state achieved during the second application. Plasma OXY and DEO concentrations decreased gradually after C _max until system removal. Buttock and hip applications resulted in bioequivalent OXY absorption. AUC ratios of DEO/OXY were 1.5 ± 0.4 (single dose) and 1.3 ± 0.3 (multiple dose). Mean in vitro OXY skin absorption (186 g/h) was comparable to the estimated in vivo delivery (163 g/h) over 96 h. Conclusions. Sustained delivery over 4 days and multiple sites allow a convenient, well-tolerated, twice-weekly OXY TDS dosing. A low incidence of anticholinergic side effects is expected during clinical use because of the avoidance of presystemic metabolism and low DEO plasma concentrations. The consistent delivery, absorption, and pharmacokinetics should result in an effective treatment of patients with overactive bladder.     

Interpretation and Utilization of Effect and Concentration Data Collected in an in Vivo Pharmacokinetic and in Vitro Pharmacodynamic Study

The effect (E) of some drugs may be monitored in vitro using the plasma drug concentration (C) following the in vivo dosing of drug. When using a specific analytical assay, counterclockwise hysteresis in the E vs C relationship can be explained only by the presence of an agonistic metabolite (M _A); the extent of hysteresis will depend upon the pharmacokinetics and relative "potency of C and M _A. If a nonspecific assay is used, plots of E vs C may actually relate to E vs total agonist (C + M _A), and unusual hysteresis may be observed, e.g., clockwise hysteresis when C is more "potent than M _A. Here, we simulate data for three models of relative C and M _A pharmacokinetics. The E vs C and E vs M _A data are simulated for both linear and noncompetitive agonist E _max models. When C and M _A are equally potent, hysteresis will not be observed in a plot of E vs C + M _A. However, when C and M _A are of differing "potencies, hysteresis will be observed (the direction of hysteresis is dependent on the relative potency of C and M _A). By appropriately "weighting a respective agonist (C or M _A), hysteresis will "collapse and the relative potencies of C and M _A can be estimated.     

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative bloodstream infections and/or ventilator-associated pneumonia

ObjectivesTo describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative (CR-GN) bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP).MethodsCritically ill patients with different degrees of renal function who were treated with CI ceftazidime-avibactam for documented CR-GN infections, and who underwent therapeutic drug monitoring from April 2021 to March 2022, were retrospectively assessed. Ceftazidime and avibactam concentrations were determined at steady-state, and the free fraction (fC_ss) was calculated. The joint PK/PD target of ceftazidime-avibactam was considered as optimal when both C_ss/MIC ratio for ceftazidime ≥4 (equivalent to 100%fT>_4xMIC) and C_ss/C_T ratio for avibactam >1 (equivalent to 100% fT>C_T of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two was achieved, and suboptimal if neither of the two was achieved). The relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed.ResultsTen patients with documented CR-GN infections (5 BSIs, 4 VAP, 1 BSI+VAP) were retrieved. The joint PK/PD targets of ceftazidime-avibactam were optimal and quasi-optimal in eight and two cases, respectively. Microbiological failure occurred in two patients (one with VAP, one with BSI+VAP), one of whom developed ceftazidime-avibactam resistance. Both underwent renal replacement therapy, and failed despite attaining optimal joint PK/PD target and receiving fosfomycin co-treatment.ConclusionCI administration may enable optimal joint PK/PD targets of ceftazidime-avibactam to be achieved in most critical renal patients with CR-GN infections, and may help to minimize the risk of microbiological failure.     

2016-2018年中国医科大学附属盛京医院铜绿假单胞菌的分布及耐药性分析

目的 分析2016-2018年中国医科大学附属盛京医院铜绿假单胞菌的分布及耐药性,为临床合理使用抗菌药物提供参考。方法 收集中国医科大学附属盛京医院2016-2018年临床分离的1 465株铜绿假单胞菌,对其标本来源分布、科室分布和耐药性进行分析。结果 共分离出1 465株铜绿假单胞菌,痰液、尿液、引流液分别占53.9%、9.8%、9.1%;科室分布以ICU（23.3%）最多,其次为普外科（13.9%）、呼吸内科（13.4%）和新生儿呼吸内科（10.6%）。铜绿假单胞菌的耐药率2016-2018年变化不大,对头孢菌素类药物的耐药率较低,在12.75%~31.69%波动;对亚胺培南和美洛培南的耐药率分别为31.30%~33.46%、12.94%~29.11%,对阿米卡星的耐药率最低,为3.27%~4.54%。共分离出泛耐药铜绿假单胞菌37株,占2.5%。其中,2017年分离率最低,为1.39%。结论 应加强细菌耐药监测,采取有效措施控制耐药菌株传播,延缓泛耐药铜绿假单胞菌的出现和防止传播。     

Do Plasma Concentrations Obtained from Early Arterial Blood Sampling Improve Pharmacokinetic/Pharmacodynamic Modeling?

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC₅₀ ) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC₅₀ and K_eO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid E_max ) model could not describe the time course of effect of the NMBAs adequately.     

Design and in vivo evaluation of an indapamide transdermal patch

The aim of the present study was to develop and evaluate a novel drug-in-adhesive transdermal patch system for indapamide. Initial in vitro experiments were conducted to optimize formulation parameters prior to transdermal delivery in rats. The effects of the type of adhesive and the content of permeation enhancers on indapamide transport across excised rat skin were evaluated. The results indicated that DURO-TAK^® adhesive 87-2852 is a suitable and compatible polymer for the development of transdermal drug delivery systems for indapamide. The final formulation contained 4% N-dodecylazepan-2-one, 6% l-menthol and 3% isopropyl myristate. For in vivo studies patch systems were administered transdermally to rats while orally administered indapamide in suspension was used as a control. The PK parameters, such as the maximum blood concentration (C_max), time to reach the peak blood concentration (T_max), mean residence time (MRT), area under the curve (AUC_0–t) and terminal elimination half-life (T_1/2) were significantly (p < 0.05) different following transdermal administration compared with oral administration. In contrast to oral delivery, a sustained activity was observed over a period of 48 h after transdermal administration. This sustained activity was due to the controlled release of drug into the systemic circulation following transdermal administration.     

Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: Case example nelfinavir

The aim of this study was to evaluate the utility of biorelevant dissolution tests coupled with in silico simulation technology to forecast in vivo bioperformance of poorly water-soluble bases, using nelfinavir mesylate as a model compound.An in silico physiologically based pharmacokinetic (PBPK) model for poorly water-soluble, weakly basic drugs was used to generate plasma profiles of nelfinavir by coupling dissolution results and estimates of precipitation with standard gastrointestinal (GI) parameters and the disposition pharmacokinetics of nelfinavir. In vitro dissolution of nelfinavir mesylate film-coated tablets was measured in biorelevant and compendial media. Drug precipitation in the small intestine was estimated from crystal growth theory. GI parameters (gastric emptying rate and fluid volume) appropriate to the dosing conditions (fasting and fed states) were used in the PBPK model. The disposition parameters of nelfinavir were estimated by fitting compartmental models to the in vivo oral PK data. The in vivo performance in each prandial state was simulated with the PBPK model, and predicted values for AUC and C_max were compared to observed values.Dissolution results in FaSSIF-V2 and FeSSIF-V2, simulating the fasting and fed small intestinal conditions, respectively, correctly predicted that there would be a positive food effect for nelfinavir mesylate, but overestimated the food effect observed in healthy human volunteers. In order to better predict the food effect, an in silico PBPK simulation model using STELLA® software was evolved. Results with the model indicated that invoking drug precipitation in the small intestine is necessary to describe the in vivo performance of nelfinavir mesylate in the fasted state, whereas a good prediction under fed state conditions is obtained without assuming any precipitation. In vitro–in silico–in vivo relationships (IVISIV-R) may thus be a helpful tool in understanding the critical parameters that affect the oral absorption of poorly soluble weak bases.     

Liraglutide-loaded multivesicular liposome as a sustained-delivery reduces blood glucose in SD rats with diabetes

Subcutaneous liraglutide-loaded multivesicular liposomes (Lrg-MVLs) were developed as a sustained drug-delivery system for treating diabetes and their properties were characterized. The Lrg-MVLs prepared using a two-step water-in-oil-in-water double emulsification process had a spherical appearance with a mean diameter of 6.69?μm and an encapsulation efficiency of 82.23?±?4.78% without any initial burst release. Their pharmacodynamics (PD) and pharmacokinetics (PK) were also studied after a single subcutaneous administration to Sprague-Dawley (SD) rats with diabetes. The PD results demonstrated that Lrg-MVLs presented sustained glucose-lowering effects for nearly a week, while the pharmacokinetic parameters showed that the plasma liraglutide concentration of the designed preparation produced C_max of 81.979?±?12.140?pg/ml and an MRT_0–t of 88.224?±?3.893?h. Furthermore, retention of Lrg-MVLs at the injection site was studied semiquantitatively by an in vivo imaging system, which can be used to evaluate the drug release from MVLs in vivo. In conclusion, MVLs are a promising carrier for liraglutide and Lrg-MVLs deserve further study for the treatment of diabetes.     

Effect of Nanonization on Absorption of 301029: Ex Vivo and In Vivo Pharmacokinetic Correlations Determined by Liquid Chromatography/Mass Spectrometry

Purpose. To compare Caco-2 monolayer permeability and in vivo bioavailability of microparticle with nanoparticle 301029, a thiadiazole derivative, and to determine whether nanonization could improve oral bioavailability of the poorly soluble compound. Methods. The mean particle size of 301029 was reduced from 7 m to 280 nm by pearl milling. In the ex vivo assay, both microparticle and nanoparticle 301029 at the same concentration were separately added to apical side and were collected from basolateral side of Caco-2 monolayer. In the bioavailability study, the two particle sizes of 301029 were orally administered to rats, respectively, and blood samples were collected. Nanoparticle 301029 in culture medium and rat serum was detected by a liquid chomatography-mass spectrometer (LC/MS) coupled with atmospheric pressure chemical ionization (APCI). Results. Permeability rate and permeated amounts of nanoparticle 301029 across the Caco-2 monolayer were about four times higher than those of microparticle 301029. In a pharmacokinetic study, nanoparticle 301029 showed T_max about 1 h, whereas the microparticle 301029 showed T_max at 4 h. The C_max and AUC of nanoparticle 301029 were 3- to 4-fold greater than those of microparticle 301029, resulting in a significant increase in oral bioavailability of 301029 as compared with microparticle 301029. The ex vivo permeability and in vivo pharmacokinetic data indicate that nanoparticle formulation improves both absorption rate and absorption extent of the poorly soluble drug. Conclusions. Nanoparticle formulation enhances both Caco-2 monolayer permeability and rat oral bioavailability of the poorly soluble 301029. The result also demonstrates a close correlation between ex vivo Caco-2 permeability model and in vivo gastrointestinal absorption.     

Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A

AIMS

To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone.

METHODS

This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William''s design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg⁻¹ midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed C_max, AUC_last and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte C_max, AUC_last and AUC.

RESULTS

There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25.

CONCLUSION

The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug–drug interactions in vivo.     

An in Vitro Pharmacodynamic Model to Simulate Antibiotic Behavior of Acute Otitis Media with Effusion

The purpose of this investigation was to develop an in vitro pharmacodynamic model (IVPM) that would simultaneously simulate in vivo serum and middle ear amoxicillin pharmacokinetic characteristics of acute (purulent) otitis media and then utilize the IVPM to assess amoxicillin-mediated killing of a type 7F Streptococcus pneu-moniae (MIC = 0.002 mg/L). The IVPM consisted of a sterile central compartment and a membrane-bound infected peripheral compartment. Peak peripheral compartment amoxicillin concentrations occurred within 2 hr after its introduction into the central compartment and were approximately 30% of peak central compartment concentrations. Amoxicillin elimination from the central compartment was designed to provide a 1-hr t _1/2. Amoxicillin elimination from the peripheral compartment was slower than from the central compartment, with an average half-life of 2.3 hr. Significant concentration-related differences in maximal bacterial kill rates were not detected over the range of amoxicillin concentrations studied (0.26 to 14.6 mg/L). However, at peak central compartment amoxicillin concentrations of 2 mg/L, a lag phase in killing was observed. In general, the in vitro pharmacokinetic data derived from this model compare well with published in vivo data.     

The Role of Permeability in Drug ADME/PK,Interactions and Toxicity—Presentation of a Permeability-Based Classification System (PCS) for Prediction of ADME/PK in Humans

Purpose The objective was to establish in vitro passive permeability (P _e) vs in vivo fraction absorbed (f _a)-relationships for each passage through the human intestine, liver, renal tubuli and brain, and develop a P _e-based ADME/PK classification system (PCS). Materials and Methods P _e- and intestinal f _a-data were taken from an available data set. Hepatic f _a was calculated based on extraction ratios of the unbound fraction of drugs (with support from animal in vivo uptake data). Renal f _a (reabsorption) was estimated using renal pharmacokinetic data, and brain f _a was predicted using animal in vitro and in vivo brain P _e-data. Hepatic and intestinal f _a-data were used to predict bile excretion potential. Results Relationships were established, including predicted curves for bile excretion potential and minimum oral bioavailability, and a 4-Class PCS was developed: I (very high P _e; elimination mainly by metabolism); II (high P _e) and III (intermediate P _e and incomplete f _a); IV (low P _e and f _a). The system enables assessment of potential drug–drug transport interactions, and drug and metabolite organ trapping. Conclusions The PCS and high quality P _e-data (with and without active transport) are believed to be useful for predictions and understanding of ADME/PK, elimination routes, and potential interactions and organ trapping/toxicity in humans. This paper includes personal opinions of the author, which do not necessarily represent the views or policies of AstraZeneca.     

重症患者替加环素血药浓度的监测与PK/PD达标率的研究

目的对使用替加环素治疗的重症患者血药浓度进行监测,计算其PK/PD达标率,为临床更加合理地使用替加环素提供参考。方法采用回顾性分析方法,将纳入的45例重症患者分为高、低剂量组,收集第7次给药后的谷浓度、中浓度及峰浓度(Cmin、C1/2t、Cmax),计算2组AUC0-24、AUIC值及不同感染部位PK/PD达标率,观察2组不良反应情况。结果高剂量组的Cmin、C1/2t、Cmax、AUC0-24及PK/PD总达标率均显著高于低剂量组(P<0.05)。高剂量组在肺部、腹腔、皮肤及软组织感染的达标率均高于低剂量组,其中2组在肺部感染的达标率具有显著性差异(P<0.05)。2组随着病原菌最低抑菌浓度(minimum inhibitory concentration,MIC)的增高,PK/PD达标率显著下降。45例患者中发生不良反应共7例,2组不良反应的发生率无显著性差异。结论替加环素对重症患者安全性较好,对于重症患者肺部感染和皮肤及软组织感染,特别是具有高MIC的病原菌感染,可适当地提高替加环素的剂量。