(Z)-2 - [(5-氨基-[1,2,4]噻二唑-3-基)-羧基-亚甲基氨基氧基]-2-甲基-丙酸叔丁酯的制备方法

摘要：本文探索头孢洛扎中间体的制备方法。首先将起始物料2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸与甲醇进行 反应得到化合物1,然后化合物1与盐酸羟胺反应得到化合物2,其次化合物2与α-溴代异丁酸叔丁酯进行缩合反应得到化合物3, 最后通过水解反应制备(Z)-2-[(5-氨基-[1,2,4]噻二唑-3-基)-羧基-亚甲基氨基氧基]-2-甲基-丙酸叔丁酯(简称TATD)。该产品的纯度 与总摩尔收率分别为99.1%、66.1%,且反应原料易得,适合工业化规模生产。     

头孢卡品内酯化合物盐酸盐的合成及结构确证

首先将D-7-ACA与BTPA作为起始原料,进行缩合反应及内酯化反应得到中间体1;然后中间体1再经过脱保护反应得到头孢卡品内酯化合物,最后与盐酸成盐反应得到产物头孢卡品内酯化合物盐酸盐。该工艺得到的头孢卡品内酯化合物盐酸盐收率及纯度较高,原料易得。通过结构确证(紫外吸收光谱、红外吸收光谱、质谱以及核磁共振波普数据)证实了头孢卡品内酯化合物盐酸盐化学结构的正确性。     

新型抗菌药物头孢洛扎关键中间体UBT的制备方法

本论文进行了抗菌药头孢洛扎关键中间体UBT的制备方法研究。首先将起始原料1-甲基-5-氨基-4-乙氧羰基吡唑与三苯基氯甲烷反应得到中间体1;然后中间体1在碱性条件下进行水解反应得到中间体2;最后中间体2通过与DPPA、BocEDA一锅法反应制备得UBT。本工艺得到的UBT总收率及纯度较高,原料易得,适合工业化生产。     

硫酸头孢匹罗的合成工艺改进

目的 改进第四代头孢菌素类药物硫酸头孢匹罗的合成工艺。 方法 以7-苯乙酰胺基-3-氯甲基头孢烷酸对甲氧基苄酯（GCLE）为起始原料，先与2,3-环戊烯并吡啶反应，然后脱去4位羧基保护，再脱去7位苯乙酰基保护并对7位进行取代，最后成硫酸盐。 结果与结论 目标化合物结构经¹H-NMR、IR谱得到确证。改进后总收率为34%。     

7-氨基-3-乙烯基头孢烷酸的合成

目的研究7-氨基-3-乙烯基头孢烷酸的合成方法。方法以7-苯乙酰氨基-3-氯甲基头孢烷酸对甲氧苄酯为起始原料，采用化学法和酶解法制得目标化合物，总收率分别达到55．6％和58．5％。结果与结论该工艺原料易得，反应条件温和，收率有所提高，具有工业生产价值。     

药物中间体头孢烷酸盐酸盐的制备

目的：合成四代头孢盐酸头孢吡肟中间体7-氨基-3-[1-(1-甲基吡咯烷)甲基]-头孢烷酸盐酸盐(A)。方法：以7-ACA为起始原料，经硅烷化保护、碘代、取代、脱保护、成盐，反应制备得到(A)。运用IR、1^H—NMR进行结构鉴定。结果：合成化合物A的总收率为43．3％(以7-ACA计)。结论：本合成工艺条件温和，反应总收率较高，适合工业化生产。     

抗癌药物丙卡巴肼的合成工艺优化研究

目的对丙卡巴肼的合成工艺进行优化。方法以对甲苯甲酸为起始原料,经氯化亚砜回流得酰氯产物,再与异丙胺反应得N-异丙基对甲苯甲酰胺(3),化合物3经N-溴代丁二酰亚胺(NBS)溴代生成化合物4;甲基肼的硫酸盐在甲酸作用下生成中间体5;4与5反应得到抗癌药物丙卡巴肼。结果与结论优化了丙卡巴肼的合成工艺,以5步反应、总收率45.9%、单步收率75%～90%合成目标化合物。所有化合物的结构均经1H-NMR、13C-NMR和MS确证。     

头孢替唑钠的合成工艺研究

目的 改进头孢替唑钠的合成工艺。 方法 以7-氨基头孢烷酸 （7-ACA）为起始原料,与1H-四氮唑乙酸-1,3,4-噻二唑-2-硫酯（2）反应得中间体7-（1H-四氮唑乙酰氨基）头孢烷酸（3）,以甲磺酸为催化剂,3与2-巯基-1,3,4-噻二唑经亲核取代反应制得头孢替唑酸（4）,4与碳酸氢钠反应得到目标化合物。结果与结论 目标化合物的结构经¹H-NMR 和 HR-MS 确证,改进后的合成工艺操作简便,总收率达69.6%,降低了成本,有利于工业化生产。     

3-羟基头孢菌素的合成研究

3-羟基头孢菌素是合成头孢唑肟、头孢布烯、头孢克罗、头孢沙定的重要中间体,现对以青霉素G、7-氨基头孢烷酸及头孢菌素C为原料合成3-羟基头孢菌素化合物的合成路线进行综述,并对各条路线进行评价。     

2-位亚甲基头孢类抗生素的设计、合成与生物活性

目的 设计合成具有抗菌活性的2-位亚甲基头孢类抗生素.方法 以7-苯乙酰氨基-3-氯甲基-头孢-3-烯-4-羧酸对甲氧基苄酯(GCLE)为起始原料,经Mannich反应、酶解、缩合等反应制得2-位亚甲基头孢类抗生素.通过微量稀释法测定了其对标准金黄色葡萄球菌、标准肺炎克雷伯杆菌的最小抑菌浓度.结果 合成了4个新化合物8a～8d,利用1H-NMR和MS确证了结构,初步测试显示较好的抗菌活性.结论 初步生物活性试验结果显示化合物8a、8b和8d对标准金黄色葡萄球菌的抗菌活性均与头孢克肟和头孢地尼相当,化合物8a、8b对标准肺炎克雷伯杆菌的抗菌活性与头孢克肟和头孢地尼相当.     

In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against β-lactamase-producing Escherichia coli in a hollow-fibre infection model

The proliferation of multidrug-resistant Gram-negative pathogens has been exacerbated by a lack of novel agents in current development by pharmaceutical companies. Ceftolozane/tazobactam was recently approved by the FDA for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. In the present study, the activity of ceftolozane/tazobactam against four isogenic Escherichia coli strains was investigated in a hollow-fibre infection model simulating various clinical dosing regimens. The four investigational E. coli strains included #2805 (no β-lactamase), #2890 (AmpC β-lactamase), #2842 (CMY-10 β-lactamase) and #2807 (CTX-M-15 β-lactamase). Each strain was exposed to regimens simulating 1?g ceftolozane, 2?g ceftolozane, 1?g ceftolozane/0.5?g tazobactam, and 2?g ceftolozane/1?g tazobactam utilising a starting inoculum of ca. 10⁶ CFU/mL. Whereas 1?g of ceftolozane eradicated strains #2805 and #2842 without subsequent regrowth, 1?g ceftolozane/0.5?g tazobactam was required to eradicate strain #2890. For strain #2890, ceftolozane monotherapy led to bacterial growth on plates impregnated with 20?mg/L ceftolozane by 24?h, whilst combination treatment with tazobactam completely suppressed the development of ceftolozane resistance. In contrast, none of the regimens, including 2?g ceftolozane/1?g tazobactam, were able to entirely suppress bacterial growth in strain #2807, with bacterial counts exceeding 10⁸?CFU/mL by 48?h and ceftolozane-resistant populations being amplified after 24?h. Thus, the combination of ceftolozane and tazobactam achieved bactericidal activity followed by sustained killing over 10 days for three of four isogenic E. coli strains. Ceftolozane/tazobactam is a promising new agent to counter multidrug-resistant Gram-negative bacteria.     

Ceftolozane/Tazobactam Pharmacokinetics in a Critically Ill Adult Receiving Continuous Renal Replacement Therapy

Limited data are available on ceftolozane/tazobactam dosing in patients receiving continuous renal replacement therapy (CRRT). Thus we performed a pharmacokinetic analysis of intravenous ceftolozane/tazobactam in a critically ill patient receiving CRRT at our medical center. A 47‐year‐old critically ill man with multidrug‐resistant Pseudomonas aeruginosa pneumonia, bacteremia, and osteomyelitis was receiving ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) every 8 hours while receiving continuous venovenous hemodiafiltration (CVVHDF). After the fifth dose of ceftolozane/tazobactam, plasma samples were obtained at 1‐, 2‐, 4‐, 6‐, and 8‐hour time points. Two additional post‐hemodialysis filter plasma samples were obtained to assess CVVHDF clearance. The maximum and minimum plasma concentrations for ceftolozane were 163.9 μg/ml and 79.4 μg/ml, respectively. The area under the plasma concentration–time curve from 0–8 hours (AUC_0–8) was 689 μg hour/ml; the plasma half‐life was 13.3 hours. The ceftolozane CVVHDF clearance and total clearance were 2.4 L/hour and 2.9 L/hour, respectively. Compared with a patient with normal renal function, this patient receiving CVVHDF had decreased ceftolozane clearance. A ceftolozane/tazobactam dosage of 1.5 g every 8 hours should adequately achieve a desired drug concentration above the minimum inhibitory concentration of 8 μg/ml for the treatment of pneumonia. Additional pharmacokinetic data are needed to confirm our results and for alternative forms of CRRT.     

Evaluating the emergence of nonsusceptibility among Pseudomonas aeruginosa respiratory isolates from a phase-3 clinical trial for treatment of nosocomial pneumonia (ASPECT-NP)

Objectives: The emergence of nonsusceptibility to ceftolozane/tazobactam and meropenem was evaluated among Pseudomonas aeruginosa (P. aeruginosa) lower respiratory tract isolates obtained from participants in the ASPECT-NP clinical trial.Methods: ASPECT-NP was a phase-3, randomised, double-blind, multicentre trial that demonstrated noninferiority of 3 g ceftolozane/tazobactam q8h versus 1 g meropenem q8h for treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia. Molecular resistance mechanisms among postbaseline nonsusceptible P. aeruginosa isolates and clinical outcomes associated with participants with emergence of nonsusceptibility were examined. Baseline susceptible and postbaseline nonsusceptible P. aeruginosa isolate pairs from the same participant underwent molecular typing.Results: Emergence of nonsusceptibility was not observed among the 59 participants with baseline susceptible P. aeruginosa isolates in the ceftolozane/tazobactam arm. Among 58 participants with baseline susceptible P. aeruginosa isolates in the meropenem arm, emergence of nonsusceptibility was observed in 13 (22.4%). Among participants who received ceftolozane/tazobactam and meropenem, 5.1% and 3.4% had a new infection with a nonsusceptible strain, respectively. None of the isolates with emergence of nonsusceptibility to meropenem developed co-resistance to ceftolozane/tazobactam. The molecular mechanisms associated with emergence of nonsusceptibility to meropenem were decreased expression or loss of OprD and overexpression of MexXY.Conclusions: Among participants with emergence of nonsusceptibility to meropenem, clinical outcomes were similar to overall clinical outcomes in the ASPECT-NP meropenem arm. Ceftolozane/tazobactam was more stable to emergence of nonsusceptibility versus meropenem; emergence of nonsusceptibility was not observed in any participants with baseline susceptible P. aeruginosa who received ceftolozane/tazobactam in ASPECT-NP.     

Pharmacokinetics and Pharmacodynamics of Ceftolozane/Tazobactam in Critically Ill Patients With Augmented Renal Clearance

ObjectiveTo determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection.MethodsARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated.ResultsMean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V_ss) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V_ss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate.ConclusionsIn patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam.ClinicalTrials.gov identifierNCT02387372     

Efficacy of ceftolozane/tazobactam,alone and in combination with colistin,against multidrug-resistant Pseudomonas aeruginosa in an in vitro biofilm pharmacodynamic model

Objectives

Ceftolozane/tazobactam is a potential tool for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa), but its efficacy against some difficult-to-treat infections has not been well defined.

硫酸多黏菌素E水溶液的表面张力和泡沫性能的研究

探讨泡沫分离技术有效应用于生物分离过程,指出被分离的生物表面活性物质在体系中的性能研究的重要性。本文以硫酸多黏菌素E水溶液为体系,研究硫酸多黏菌素E浓度、杂蛋白、无机离子、pH值和温度对硫酸多黏菌素E溶液表面张力和泡沫性能的影响,为硫酸多黏菌素E实现泡沫分离提供依据。     

In-vitro activity of ceftolozane/tazobactam against Pseudomonas aeruginosa collected in the Study for Monitoring Antimicrobial Resistance Trends (SMART) between 2016 and 2019 in China

Ceftolozane/tazobactam (an antipseudomonal cephalosporin) in combination with a well-established β-lactamase inhibitor has not been approved to date in clinical practice in China. The aim of this study was to evaluate the in-vitro activity of ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa with various resistance patterns. P. aeruginosa (n=2178) specimens were collected from multiple sources in seven geographic regions of China between 2016 and 2019. All isolates were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and minimum inhibitory concentrations of various antimicrobial agents (ceftolozane/tazobactam, amikacin, tobramycin, ceftazidime, cefepime, colistin, levofloxacin, aztreonam, meropenem, imipenem and piperacillin/tazobactam) were determined using the Clinical and Laboratory Standards Institute's broth microdilution method. P. aeruginosa demonstrated considerably high rates of multi-drug resistance (MDR, 57.3%), extensive drug resistance (XDR, 43.5%) and difficult-to-treat resistance (DTR, 16.8%). The overall susceptibility of P. aeruginosa to ceftolozane/tazobactam was 81.9%, and ceftolozane/tazobactam showed diverse activity against the three resistant subsets, ranging from 28.5% against DTR P. aeruginosa to 68.9% against MDR P. aeruginosa. P. aeruginosa, MDR P. aeruginosa, XDR P. aeruginosa and DTR P. aeruginosa derived from the East (Jiangzhe area) region maintained significantly lower susceptibility to ceftolozane/tazobactam compared with P. aeruginosa, MDR P. aeruginosa, XDR P. aeruginosa and DTR P. aeruginosa from other regions. The susceptibility rates of P. aeruginosa isolated from diverse sources to ceftolozane/tazobactam were similar to isolates from bloodstream infections, with the highest being 88.6%. Compared with other antimicrobial agents, ceftolozane/tazobactam was more active than the β-lactams tested but was slightly less active than amikacin. Amikacin demonstrated the best activity against P. aeruginosa and the three resistant subsets. Ceftolozane/tazobactam demonstrated considerable in-vitro activity against P. aeruginosa, MDR P. aeruginosa, XDR P. aeruginosa and DTR P. aeruginosa, indicating that it could be an optional therapeutic agent against P. aeruginosa.     

Efficacy,pharmacokinetic and pharmacodynamic profile of ceftolozane + tazobactam in the treatment of complicated urinary tract infections

Introduction: Urinary tract infections (UTIs) are the second most common nosocomially acquired infections, responsible for approximately 21% of healthcare-associated pyelonephritis and 10.5% of urosepsis. Worldwide trends of increasing resistance resulted in the urgent need for novel antimicrobials that would be active against bacterial resistance mechanisms as an alternative to carbapenems, which are considered last resort antibiotics.

Areas covered: The current review is based on a Medline search of published English language literature and contains summary information regarding the evaluation of pharmacologic properties, efficacy, safety and activity of ceftolozane+tazobactam against common bacterial resistance mechanisms.

Expert opinion: In vivo and vitro studies demonstrated high activity of ceftolozane+tazobactam in the combination of 2:1 against a variety of uropathogens, including ESBL-producers. Phase II and Phase III studies performed in patients with complicated UTIs showed good tolerability and safety of ceftolozane+tazobactam when prescribed intravenously 1.5 g every 8 h for 7 days and at least non-inferiority to a high dose (750 mg) of levofloxacin. The pharmacokinetics of ceftolozane+tazobactam makes it a worthy alternative to carbapenems in cases of complicated UTIs, also caused by multidrug resistant uropathogens.     

Activity of ceftolozane-tazobactam against Gram-negative pathogens isolated from lower respiratory tract infections in the Asia-Pacific region: SMART 2015-2016

The aim of this study was to investigate the susceptibility of respiratory Gram-negative bacteria to ceftolozane/tazobactam and other antibiotics in the Asia-Pacific region during 2015-2016. MICs were determined using the CLSI standard broth microdilution method and interpreted accordingly. Pseudomonas aeruginosa (1574 isolates), Klebsiella pneumoniae (1226), Acinetobacter baumannii (627) and Escherichia coli (476) accounted for 73.1% of 5342 Gram-negative respiratory pathogens. Susceptibility to ceftolozane/tazobactam of individual Enterobacteriaceae was >80%, except for Enterobacter cloacae (76.6%). Ceftolozane/tazobactam inhibited 81.9% of K. pneumoniae and 91.9% of E. coli, with respective MIC₅₀/MIC₉₀ values of 0.5/>32 and 0.25/2 mg/L. For carbapenem-susceptible, ESBL-producing K. pneumoniae and E. coli, susceptibility was 65.5% and 93.3%, respectively, and respective MIC₅₀/MIC₉₀ values were 2/>32 and 0.5/2 mg/L. Bla_{CTX-M-1 group} was most prevalent in selected ESBL-producing K. pneumoniae (40 of 54 isolates) and E. coli (15 of 22 isolates), with ceftolozane/tazobactam susceptibility rates of 50% and 80%, respectively. Bla_SHV-ESBL was the second most prevalent, and ceftolozane/tazobactam inhibited 20% of 20 K. pneumoniae isolates with bla_SHV-ESBL. The only effective antibiotics for carbapenem-non-susceptible K. pneumoniae (111 isolates) and E. coli (24 isolates) were amikacin and colistin. Ceftolozane/tazobactam was effective against almost all tested P. aeruginosa and carbapenem-non-susceptible strains, with susceptibility of 92.3% and 72.8%, respectively; the respective MIC₅₀/MIC₉₀ values were 1/4 and 2/>32 mg/L. The high susceptibility of ceftolozane/tazobactam remained in different age groups, patient locations, recovery times and countries, except Vietnam. In conclusion, ceftolozane/tazobactam was effective against most respiratory Gram-negative pathogens in the Asia-Pacific region; however, the emergence of carbapenem resistance mandates ongoing surveillance.