早期联用MEP和大剂量rhGH对严重烫伤大鼠肠源性感染的影响

目的探讨早期联用美罗培南(MEP)和大剂量重组人生长激素(rhGH)对严重烫伤免疫抑制大鼠肠源性感染的影响。方法Wistar大鼠54只随机分为对照组、烧伤组和治疗组(C1组、C2组、C3组),后两大组制成25%总体表面积(TBSA)Ⅲ°烫伤免疫抑制模型,伤后2h给予rhGH1.33IU/kg、MEP20mg/kg,伤后8、24h检测门静脉血清内毒素(LPS)、腔静脉血清肿瘤坏死因子-α(TNF-α)含量,肝功能变化和肠道细菌移位率。结果C3(MEP+rhGH治疗)组LPS和TNF-α含量均显著低于其他组(P<0.01),与对照组差异无统计学意义(P>0.05),C3组未发现肠道细菌移位且肝功能检测指标显著低于其他组(P<0.01),与对照组差异无统计学意义(P>0.05)。结论早期联用MEP和rhGH治疗严重烫伤免疫抑制大鼠能显著减轻或防止肠道细菌/内毒素移位,减少炎症介质释放,保护脏器功能。     

早期短程应用美洛培南治疗严重烧伤的临床对比研究

目的研究早期短程应用美洛培南对严重烧伤的治疗效果。方法前瞻性地选择特重度以上烧伤患者49名。治疗组21名伤后24h应用美洛培南3～5天。对照组28名，伤后24h应用头孢三、四代抗生素3～5天。观察患者SIRS、创面脓毒血症、MODS发生率，死亡率及治愈好转率。结果治疗组SIRS发生率与对照组比较无差异，创面脓毒血症、MODS发生率及死亡率显著低于对照组，治愈好转率明显高于对照组。结论早期短程应用美洛培南可以减少创面脓毒血症、MODS的发生，降低死亡率，提高严重烧伤患者的治愈好转率，对SIRS的发生率影响不大。     

美罗培南在家兔胆汁中的药物浓度-时间分布的实验研究

目的研究美罗培南在家兔胆汁中的浓度及其分布规律,为预防和治疗胆道感染用药提供参考和依据。方法家兔行胆总管造瘘术,先留取空白胆汁,静脉注射美罗培南后分别于不同时间点采集胆汁标本。行专属性试验后,取空白胆汁加美罗培南对照品和流动相,配成0.5~500μg/ml不同浓度的系列胆汁样品,经高效液相色谱仪分析,采用外标法行药物色谱峰面积定量,以胆汁样品药物浓度对色谱峰面积进行线性回归,得回归方程。注射美罗培南后的家兔胆汁样品经预处理后用高效液相色谱仪测定峰面积,按标准曲线回归方程计算得出胆汁药物浓度,从而了解美罗培南的胆汁药物浓度-时间分布情况。结果专属性试验显示,在本研究的流动相色谱条件下测定药物,胆汁杂质峰、美罗培南药物色谱峰分离效果良好。标准曲线回归方程为S=2209.10C-1251.34,r=0.9999,美罗培南的最低定量限为0.5μg/ml。家兔静脉注射美罗培南(75mg/kg)后即时在胆汁中达(38.36±14.17)μg/ml,远远超过其对革兰阴性杆菌的最小抑菌浓度(MIC90)0.031~2μg/ml,之后美罗培南的胆汁药物浓度随时间而迅速降低。用药后180min,胆汁中的药物均被完全消除。结论美罗培南在胆汁中能达到较高的有效杀菌浓度,可作为预防和治疗胆道感染的较佳的药物。由于消除速度较快,临床用药应缩短间隔时间。     

美罗培南治疗慢性盆腔炎的临床研究

目的观察美罗培南治疗慢性盆腔炎的临床疗效和安全性。方法将90例盆腔炎患者随机分为1．5g治疗组45例（A组）和头孢米诺3．0g对照组45例（B组），每天分3次使用，疗程均为7～14d。比较两组临床疗效、细菌学改变及不良反应情况。结果A、B组临床有效率分别为97．78％、95．56％，二者比较差异无统讣学意义（P〉0．05）。结论美罗培南治疗慢性盆腔炎安全、有效。     

美罗培南对临床分离致病菌的体外抗菌活性研究

目的评价美罗培南的体外抗菌活性方法采用琼脂二倍稀释法测定美罗培南及对照药亚胺培南、头孢吡肟、头孢他啶、头孢哌酮／舒巴坦、环内沙星对412株临床分离致病菌的体外抗菌活性。结果显示，对多种革兰氏阴性菌，美罗培南均有较强的抗菌作用，其抗菌作用强于对照药亚胺培南、头孢吡肟、头孢他啶、环丙沙星、奈替米星；对大肠埃希氏菌、克雷泊氏菌属、产气肠杆菌、志贺氏菌属、沙门氏菌属、柠檬酸菌属、变形菌属、沙雷氏菌属MIC90≤0．008～0．25mg/L，是亚胺培南MIC9o的1／4～1／16，对阴沟肠杆菌、不动杆菌属与亚胺培南的抗菌作用相当，分别为0．25、0．5mg／L：对流感嗜血杆菌美罗培南的MIC90为0．125mg／L，是亚胺培南的1／16，是第四代头孢菌素头孢吡肟的1/4：对铜绿假单孢菌美罗培南的MIC90为4mg／L，低于亚胺培南8mg／L。对革兰氏阳性菌作用稍差于亚胺培南，优予其他4种对照药。     

Infections by multidrug-resistant Gram-negative Bacteria: What's new in our arsenal and what's in the pipeline?

The spread of multidrug-resistant bacteria is an ever-growing concern, particularly among Gram-negative bacteria because of their intrinsic resistance and how quickly they acquire and spread new resistance mechanisms. Treating infections caused by Gram-negative bacteria is a challenge for medical practitioners and increases patient mortality and cost of care globally. This vulnerability, along with strategies to tackle antimicrobial resistance development, prompts the development of new antibiotic agents and exploration of alternative treatment options. This article summarises the new antibiotics that have recently been approved for Gram-negative bacterial infections, looks down the pipeline at promising agents currently in phase I, II, or III clinical trials, and introduces new alternative avenues that show potential in combating multidrug-resistant Gram-negative bacteria.     

Using machine learning to optimize antibiotic combinations: dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii

ObjectivesIncreased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB.MethodsA. baumannii (N16870; MIC_meropenem = 16 mg/L, MIC_PMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 10⁸ cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters.ResultsMonotherapies resulted in regrowth to ~10¹⁰ cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC₅₀ (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 10⁸ cfu/mL starting inoculum to a point of 10⁰ cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be ‘loaded’ with 80.5% and 42.2% of the daily dose, respectively).ConclusionThis study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the ‘traditional’ indices of antibiotic action.     

Rapid detection of antibiotic resistance by MALDI-TOF mass spectrometry using a novel direct-on-target microdroplet growth assay

ObjectivesWe aimed to develop a universal phenotypic method, which allows easy and rapid antimicrobial susceptibility testing independently of underlying resistance mechanisms.MethodsWe established a novel direct-on-target microdroplet growth assay for the detection of antibiotic resistance within a few hours, which is based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The microorganisms were incubated with and without meropenem in nutrient broth as microdroplets directly on MALDI-TOF MS target. Subsequently, broth was separated from microbial cells by contacting the microdroplets with an absorptive material. The microorganisms grown in the presence of antibiotic were detected by MALDI-TOF MS. A total of 24 Klebsiella pneumoniae and 24 Pseudomonas aeruginosa isolates were used to assess performance for detection of meropenem resistance. The microdroplet volumes investigated were 2, 4, 6, 8 and 10 μL.ResultsThe best performance was achieved using 6-μL microdroplets. Applying this volume, all growth controls were successfully detected (definition of valid test), and all isolates were correctly categorized as susceptible or non-susceptible after an 18-h incubation. For K. pneumoniae, rate of valid tests, sensitivity and specificity all reached 100% after a 4-h incubation of 6-μL microdroplets. Using the same microdroplet volume for P. aeruginosa, incubation for 5 h resulted in 83.3% of valid tests with 100% sensitivity and 100% specificity.ConclusionsWe demonstrated easy, rapid and accurate resistance detection using carbapenem-resistant Gram-negative bacteria as an example. Our technology is suitable for automatization and expandable to further applications, e.g. simultaneous testing of multiple antibiotics as well as resistance determination directly from clinical samples.     

The exploration of population pharmacokinetic model for meropenem in augmented renal clearance and investigation of optimum setting of dose

In recent years, augmented renal clearance (ARC), in which renal function is excessively enhanced, has been reported, and its influence on β-lactam antibiotics has been investigated. In this study, we aimed to determine the optimum population pharmacokinetic model of meropenem in patients with sepsis with ARC, and evaluated dosing regimens based on renal function. Seventeen subjects (6 with ARC and 11 without) were enrolled in this study. Predicted meropenem concentrations were evaluated for bias and precision using the Bland–Altman method. To examine the dosing regimen, Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR). In patients with ARC, the bias (average of the predicted value and measured value residuals) of models constructed by Crandon et al. (2011), Roberts et al. (2009), and Jaruratanasirikul et al. (2015) were 5.96 μg/mL, 10.91 μg/mL, and 4.41 μg/mL, respectively. Following 2 g meropenem every 8 h (180 min infusion), CFR ≥ 90%, a criterion of success for empirical therapy, was achieved, even with creatinine clearance of 130–250 mL/min. For patients with sepsis and ARC, the model of Jaruratanasirikul et al. showed the highest degree of accuracy and precision and confirmed the efficacy of the meropenem dosing regimen in this patient population.