羰基二咪唑酰化剂用于头孢菌素的合成

头孢菌素合成常采用混合酸酐法、DCC法、活化酯法等肽类合成方法。羰基二咪唑(简称CDI,I)法也属肽类合成方法。最近有文献报道,将此法用于头孢菌素C_3·位乙酰氧基的改造以及氨苄青霉素α-氨基的修饰。但用于头孢菌素C_7位缩合未见报道。本文采用     

In vitro activity of ceftriaxone and other cephalosporins against 602 clinical isolates of staphylococci from geographically diverse medical centers

The in vitro activity of ceftriaxone and six additional antimicrobial agents (ceftizoxime, cefoperazone, cefuroxime, fleroxacin, ciprofloxacin, and trimethoprim/sulfamethoxazole) was assessed or 602 recent clinical isolates of staphylococci from six geographically distinct medical centers in North America. All seven antimicrobial agents were active (90–100% of strains susceptible) against oxacillin-susceptible (OS) strains of Staphylococcus aureus (OSSA) and coagulase-negative staphylococci (OSCNS) but had limited activity against oxacillin resistant (OR) staphylococci. Our assessment of the in vitro antistaphylococcal activity of ceftriaxone against contemporary isolates of Staphylococcus aureus and coagulase-negative staphylococci indicates that the activity versus OS staphylococci has not changed over the past decade despite widespread use of the drug. It appears that these agents will continue to be useful for empiric therapy in those centers in which OR strains are uncommon.Corresponding author.     

Possible coumarin-like mechanism of action for cephalosporins

Summary In three patients treated with cephalosporins (one patient with latamoxef, two patients with cefazedone) vitamin K₁ was injected to investigate whether this was followed by an increase in vitamin K₁ 2,3-epoxide plasma concentrations as compared to controls. Such a rise in K₁-epoxide concentrations in the plasma can be demonstrated following treatment with coumarins. This reflects an inhibition of the vitamin K₁-epoxide reductase in the liver. Coumarins are thought to induce hypoprothrombinaemia by such a mechanism. In all three patients we found a considerable increase in the vitamin K₁-epoxide plasma concentrations following injection of 10 mg vitamin K₁, whereas in normal subjects only traces of K₁-epoxide could be detected (<0.030 µg/ml). The K₁-epoxide concentrations found in our three patients treated with cephalosporins were 0.12, 0.16 and 0.19 µg/ml, respectively. This indicates that latamoxef or cefazedone might reduce clotting factor synthesis by a coumarin-like mechanism of action in these patients. Although the effect of cephalosporins in enhancing vitamin K₁-epoxide plasma concentrations is less than that of coumarins, it might cause severe hypoprothrombinaemia in the presence of latent vitamin K deficiency.Abbreviation PT prothrombin time - TT thrombin time - PTT partial thromboplastin time - PC platelet count - ICU intensive care unit - EEG electroencephalogram - K₁-epoxide vitamin K₁ 2,3-epoxide     

An efficient synthesis of 3-(E)-hydroxypropenyl cephem derivatives, key intermediates for 3-(E)-ammoniopropenylcephalosporin antibiotics

An efficient synthesis of 3-(E)-hydroxy- and 3-(E)-acetoxypropenylcephem derivatives, key intermediates for the synthesis of 3-(E)-propenylcephalosporins was achievedvia Stille coupling reaction of 3-trifloxycephem with 3-(E)-tributylstannylallylic alcohol.     

A comparison of ceftazidime and aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn

We report a prospective, non-blind, randomised, multicentre, parallel group, multinational investigation to compare ceftazidime to aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. In each of the 15 study centres either ceftazidime alone (CAZ) or ceftazidime + ampicillin (CAZ+AMP) was compared to an aminoglyocoside/ampicillin combination (AG+AMP). In all cases treatment was based on an intention to treat. Bacteria considered to be pathogenic were isolated from 176/1316 (13.4%) patients. The incidence of proven infection varied from 39% in a Yugoslav centre to 6% in a British centre; a further 489/1316 (37.1%) patients fulfilled the criteria for clinically suspected sepsis. A total of 210 bacterial isolates from 197 infection sites in 176 patients were considered to be clinically significant. The cure rate for evaluable patients with proven infection who were treated with CAZ+AMP (97%, 30/31) was significantly higher than that for the corresponding patients treated with AG+AMP (66%, 26/39), (P<0.002). The difference in cure rate between CAZ monotherapy (79%, 34/43) and AG+AMP (86%, 32/37) was not significant. Treatment failed in 28/150 (18.7%) evaluable patients. There were significantly fewer failures (P<0.001) with CAZ+AMP than with AG+AMP therapy. There were 55 staphylococcal infections. Treatment was successful in 16/19 evaluable patients treated with CAZ or CAZ+AMP and in 16/29 evaluable patients treated with AG+AMP. None of the study centres encountered problems with ceftazidime resistant bacteria. The cure rate for patients with only clinical and radiological evidence of sepsis was greater than 94% in all treatment groups. Of the study population 65 (4.9%) died, 15 deaths were attributed to infection, pathogenic bacteria were only isolated from 10. The mortality rate for infected babies was 5.7% compared to 4.8% for those without confirmed infection. All the deaths associated with infection were due to Gram-positive bacteria. This study suggests that the practice of continuing antibiotic therapy once pretreatment cultures are known to be negative should be seriously reconsidered. It is concluded that CAZ+AMP is superior to either AG+AMP or ceftazidime monotherapy for the treatment of infection in the newborn. Further studies are required to confirm these observations in neonates with proven infection.The ESPID Neonatal Sepsis Study Group: Recruitment >=50 patients included Prof. R. Dagan, Soroka Medical Centre, Beer-Sheva, Israel; Dr. I. Tessin, Hospital of Molndal, Molndal, Sweden; Dr. D. Harvey and Dr. J. de Louvois, Queen Charlotte's and Chelsea Hospital, London, UK; Dr. B. Trollfors and Dr. K. Thiringer, Ostra Sjukuset, Goteborg, Sweden; Dr. A. Valido, Maternidade, Dr. Alfredo Costa, Lisbon, Portugal; Dr. H. Baumer, Freedom Fields Hospital, Plymouth, UK: Prof. J. Brines and Dr. Diez, University of Valencia, Valencia, Spain; Dr. L. Benic, Dr. J. Kajfes Hospital, Zagreb, Yugoslavia; and Prof. J. Badoual, Hopital St. Vincent de Paul, Paris, France.Recruitment <50 patients included Prof. L. Corbeel, UZ Gasthuisberg, Leuven, Belgium; Prof. R. Roos, Univ.-Kinderklinik, Munich, FRG; Dr. D. Kafetzisa, University of Athens, Athens, Greece; Dr. S. Pedersen, Kolding Sykehus, Kolding, Denmark; and Prof. A. Columbo, Ospedali Riunuti di Bergamo, Bergamo, Italy.     

头孢地嗪钠的合成研究

研究第三代头孢菌素头孢地嗪钠的适合工业化生产的制备工艺，即7-氨基头孢烷酸(7-ACA)与2-(2-氨基噻唑-4-基)-(顺式)-2-甲氧亚胺乙酰硫代苯并噻唑活性酯(5)在二氯甲烷于5℃反应4h生成头孢噻肟酸(3)。收率90％，3在水-丙酮溶液中碳酸钠存在下与2-巯基-4-甲基．5-噻唑乙酸(4)在55～60℃反应4h生成头孢地嗪酸(2)，收率66．3％，最后2与异辛酸钠丙酮溶液在低温反应成盐得到头孢地嗪钠(1)，收率89．7％。三步反应总收率53．5％。所得产品含量99．5％(HPLC)。     

大肠埃希菌耐药性与头孢菌素类用量变化的相关性分析

目的通过调查医院1994～2002年大肠埃希菌对头孢类抗生素耐药性与该类药物年用量,探讨用药量和耐药性之间的相关性. 方法采用回顾性调查方法,对1994～2002年5种头孢菌素类的年用量与大肠埃希菌对这些药物的敏感性进行分析,计算各药DDDs,并用直线回归对耐药率与DDDs进行相关性分析. 结果9年来大肠埃希菌对5种头孢类抗生素的耐药率全部呈增长态势,其中使用频率较高的头孢唑林(CFZ)和头孢呋辛(CXM)的增长分别为25.9%和23.6%,使大肠埃希菌对这两药的耐药率接近40%;5种头孢类抗生素年用量变化不一,2002年与1994年相比CXM年用量增长了11倍,头孢他啶的年用量增长了3倍,头孢噻肟、头孢哌酮年用量呈波动性下降;耐药率和DDDs相关性分析显示,CXM用量与耐药率的变化呈显著正相关(r=0.768,P<0.05). 结论1994～2002年间大肠埃希菌对头孢类抗生素的耐药率逐年增长,头孢呋辛耐药率的增长与其年用量增加呈显著正相关.     

我院注射用头孢菌素类药物应用的调查

目的了解我院注射用头孢菌素类药物的使用现状,探讨该类药物的价格、用量和费用之间的内在关系,以期为临床合理用药提供资料和依据. 方法应用限定日剂量(DDDs)排序及金额排序法对注射用头孢菌素类药物的利用进行统计分析. 结果近3年来,该类药物无论是购药金额还是用药频度看总体上均呈现增长趋势;其中三代头孢占绝对主体优势,联合制剂头孢哌酮/舒巴坦的消耗金额连续两年雄居榜首;用药频度排序为头孢唑林、头孢曲松、头孢他啶;半合成广谱头孢烯类和四代头孢倍受临床青睐;头孢唑林用药频次和金额的同步性差. 结论为防止耐药率的增高,建议适当调整用药管理模式,坚持有规律的循环使用抗菌药物.     

Of stewardship,motherhood and apple pie

Antibiotic stewardship is universally agreed to be desirable, but optimal models for stewardship remain uncertain. UK stewardship targets the particular antibiotic families—cephalosporins and fluoroquinolones—blamed for the selection of Clostridium-difficile-associated disease. To balance this there have been dramatic increases in the use of penicillin–β-lactamase inhibitor combinations. By channelling selection pressure in this way, we hazard destroying the utility of these antibiotic classes in turn, as happened with gonorrhoea where penicillins, fluoroquinolones and cefixime were sequentially lost as therapies. Strikingly, in context, almost all carbapenemase-producers are highly resistant to penicillin–β-lactamase inhibitor combinations, which may select for them. There is an urgent need to explore an alternative stewardship model, seeking to limit total antibiotic use but to maintain heterogeneity in what is used, avoiding concentrated selection pressure. There is also a great need to improve and accelerate diagnostics for infection and resistance, reducing or removing the need for protracted empirical treatment with broad-spectrum agents.