Advances in Clinical Research of Temocillin

替莫西林是第一个上市的对多种β-内酰胺酶稳定的青霉素类抗生素.它对大多数超广谱β-内酰胺酶和AmpC酶非常稳定,对大多数革兰阴性菌有较强的抗菌活性,但对革兰阳性菌活性低.近几年的研究证明替莫西林有望成为“碳青霉烯类抗生素”的替代者.     

(6S)或(7S)-甲氧基β-内酰胺类抗生素

(6S)或(7S)-甲氧基-β-内酰胺类抗生素具有良好的耐酶作用.目前已有多个品种上市,例如:头孢西丁、头孢美唑、拉氧头孢和替莫西林.其(6S)或(7S)-甲氧基造成的空间位阻是该类药物耐酶的关键所在.这种空间位阻作用使得其自身的结构对β-内酰胺酶稳定,从而解决或减少了大量使用β-内酰胺类抗生素而引起的细菌耐药性问题.化学合成这类药物可根据甲氧基取代C-6位氢原子的方法不同分为直接法和间接法.     

β-内酰胺类/β-内酰胺酶抑制剂合剂成人住院医嘱初步点评模式的建立和应用

<正>近年来,革兰阴性菌对β-内酰胺类/β-内酰胺类抗生素的耐药性不断增加,最重要的耐药机制是细菌产生各种β-内酰胺酶。β-内酰胺酶抑制剂能够抑制大部分β-内酰胺酶,恢复β-内酰胺类抗生素的抗菌活性。因此,β-内酰胺类抗生素/β-内酰胺酶抑制剂合剂在临床抗感染中的地位不断提升,已成为临床治疗多种耐药细菌感染的重要选择。目前我国临床使用的β-内酰胺类抗生素/β-内酰胺酶抑制剂合剂的种类和规格繁多,临床医师对该类合剂     

26例氨曲南不良反应报告文献分析

<正>氨曲南(Aztreonam)是单环β-内酰胺类抗生素,通过抑制细菌细胞壁的合成而起杀菌作用,主要用于治疗革兰阴性需氧菌引起的感染。由于氨曲南不用皮试,且与青霉素之间无交叉过敏反应,不诱导细菌产生β-内酰胺酶,同时对细菌产生的大多数β-内酰胺酶高度稳定,在临床上得到了广泛     

亚胺培南、帕尼培南、美罗培南的临床应用评价

碳青霉烯是一组新型β-内酰胺类抗生素 ,对革兰阳性菌(Ｇ )和革兰阴性菌 (Ｇ - )、需氧菌、厌氧菌都有很强的抗菌活性。该类抗生素具有抗菌谱广 ,抗菌活性强 ,对β-内酰胺酶稳定以及毒性低等特点。目前 ,该类抗生素在临床用得较多的品种主要有亚胺培南、帕尼培南、美罗培南。     

氨曲南的临床应用

氨曲南,英文名称aztreonam,缩写为AZT,是第一个应用于临床的单环β-内酰胺类抗生素,对需氧革兰阴性菌有很强的抗菌活性,对多种质粒介导和染色体介导的β-内酰胺酶稳定,主要治疗敏感需氧革兰阴性杆菌所引起的各种感染。本文主要对其药理作用及临床应用作一综述。     

AmpC酶和超广谱β-内酰胺酶研究进展及临床治疗对策

产超广谱β-内酰胺酶(ESBLs)和头孢菌素酶(AmpC酶)是革兰阴性杆菌对β-内酰胺类抗生素耐药的主要机制.AmpC酶是对第三代头孢菌素耐药而不能被β-内酰胺酶抑制剂所抑制,有染色体介导的AmpC酶和质粒介导AmpC酶,前者分诱导表达和非诱导表达,后者可随耐药质粒复制、接合、转化及转座子移位,在革兰阴性杆菌内或种间传播.ESBLs是由质粒介导的能水解大多数青霉素、头孢菌素和氨曲南等β-内酰胺类抗生素且活性能被酶抑制剂抑制的一类β-内酰胺酶,主要由肺炎克雷伯菌和大肠埃希菌产生,也可由其它肠杆菌科细菌、不动杆菌属、铜绿假单胞菌产生.碳青霉烯类抗生素是治疗产AmpC酶和ES-BLs革兰阴性杆菌感染的首选药物.     

阿莫西林／克拉维酸和替卡西林／克拉维酸对人类粒性细胞活性的影响

阿莫西林是氨苄西林的半合成羟基衍生物,其杀菌活性及肠道吸收情况均较氨苄西林好,且组织分布更广.替卡西林是一个非肠道抗生素,与氨苄西林及阿莫西林具有相似的广谱活性,且对铜绿假单胞菌也有作用,当今产β-内酰胺酶菌株日益广泛流行,影响了很多β-内酰胺类抗生素在治疗大多数细菌感染中的应用.众所周知,细菌对β-内酰胺类的耐药性,主要是由于产生了能将β-内酰胺环水解,并使其转化为无活性衍生物的β-内酰胺酶.解决β-内酰胺酶引起耐药的主要方法,是将β-内酰胺类抗生素与酶抑制剂如克拉维酸、舒巴坦及tazobactam联用,制成耐β-内酰胺酶的合剂,在治疗由这类微生物引起的感染中起到增效作用.克拉维酸盐对多种β-内酰胺酶都是一个强力的抑制剂,1997年Reading等报道克拉维酸     

青霉烯及其代表药物法罗培南的研究进展

青霉烯是一类非典型的β-内酰胺类抗生素。与其它的β-内酰胺类抗生素包括碳青霉烯类相比,其结构明显不同。因其具有广谱的抗菌活性,对β-内酰胺酶的高度稳定性,对青霉素结合蛋白的高亲和力等主要特点,而受到广泛关注。其代表药物法罗培南是第一个开发上市的青霉烯类抗生素,对需氧及厌氧性革兰阳性菌、革兰阴性菌均显示出广谱的抗菌活性,是一类新的抗感染药物。对青霉烯类抗生素的结构特点、作用机制、体内外研究等进行综述。     

替加环素致全血细胞减少不良反应1例

替加环素是继多西环素、美他环素、米诺环素后开发的新一代四环素类抗生素,2005年由美国FDA批准上市,对革兰阳性或革兰阴性需氧菌、厌氧菌等具有广谱的抗菌活性,尤其对耐甲氧西林金黄色葡萄球菌、耐万古霉素肠球菌、泛耐药鲍曼不动杆菌以及产超广谱β-内酰胺酶革兰阴性菌具有较高的抗菌活性,主要用于治疗成年患者复杂皮肤及软组织感染、复杂的腹腔内感染、社区获得性肺炎[1,2]。替加环素     

What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol,ciprofloxacin, colistin,fosfomycin, minocycline,nitrofurantoin, temocillin and tigecycline

Carbapenem-resistant Enterobacteriaceae present an increasing and diverse problem, including strains of multiple species with metallo-β-lactamases (IMP, NDM or VIM) and non-metallo (KPC and OXA-48) enzymes as well as those combining an extended-spectrum β-lactamase (ESBL) or AmpC enzyme with porin loss. Most strains, except those with OXA-48 alone, are broadly resistant to β-lactams and have multiple aminoglycoside-modifying enzymes; those with NDM-1 carbapenemase typically also have 16S rRNA methylases, conferring complete aminoglycoside resistance. In this study, the activity of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline was evaluated against 81 carbapenem-resistant Enterobacteriaceae isolates from the UK. Testing was performed by the Clinical and Laboratory Standards Institute (CLSI) agar dilution method. Chloramphenicol, ciprofloxacin and nitrofurantoin inhibited <25% of the isolates at the breakpoint, whereas colistin was active against 75/81 isolates (92.6%), the exceptions being four Klebsiella pneumoniae and Enterobacter cloacae isolates along with members of inherently resistant genera. Fosfomycin was active against 49/81 isolates (60.5%), including 7/7 Escherichia coli, 16/20 Enterobacter and Citrobacter spp., but only 25/52 Klebsiella spp. Tigecycline was active against 38/81 isolates (46.9%) and was intermediate against another 27 (33.3%), with resistance scattered amongst K. pneumoniae and Enterobacter spp. The activity of colistin, fosfomycin and tigecycline was unrelated to the isolates' carbapenem resistance mechanisms. Temocillin was fully active [minimum inhibitory concentration (MIC) ≤8 mg/L] against only 4/81 isolates (4.9%), but inhibited a further 22 isolates (27.2%) at the British Society for Antimicrobial Chemotherapy (BSAC) urinary breakpoint (32 mg/L), predominantly comprising those isolates with combinations of impermeability and an ESBL or AmpC enzyme, along with 6/11 isolates producing KPC carbapenemases. Studies with transconjugants and transformants confirmed the small effect of KPC enzymes against temocillin, whereas OXA-48 and NDM-1 conferred clear resistance.     

Anti-anaerobic activity of a new β-lactamase inhibitor NXL104 in combination with β-lactams and metronidazole

NXL104 is a new β-lactamase inhibitor (BLI) that inhibits class A and class C β-lactamase enzymes. In this study, the activity of NXL104 in combination with the third-generation cephalosporins ceftazidime (CAZ) and ceftriaxone (CRO) or with piperacillin (PIP) was evaluated against 316 anaerobic bacteria. Minimum inhibitory concentrations (MICs) were determined using an agar dilution method. The BLIs NXL104 or tazobactam (TAZ) were added to the β-lactams at a fixed concentration of 4 mg/L. A triple combination of NXL104 with an 8:1 ratio of CAZ and metronidazole (MTZ) was also tested. The activities of CAZ, CRO and PIP in combination with NXL104 were enhanced against many of the bacteria. MIC(50) values (MIC for 50% of the organisms) for CAZ+NXL104 were 8-16-fold lower than those of CAZ against Gram-negative anaerobes. Antibiotic resistance rates against all anaerobic strains were: CAZ, 37.7%; CRO, 31%; CAZ+NXL104, 15.2%; CRO+NXL104, 5.4%; and MTZ, 4.1%. No resistant strains could be observed with PIP+TAZ, PIP+NXL104 or the triple combination MTZ+CAZ+NXL104. In conclusion, the triple combination of MTZ+CAZ+NXL104 demonstrated potent antibacterial activity against anaerobes representing most clinical species. It appears appropriate for the treatment of polymicrobial infections, since CAZ+NXL104 also exhibits potent activity against β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. It is currently being tested in phase 2 clinical trials for the treatment of complicated intra-abdominal infections.     

38株多重耐药鲍曼不动杆菌超广谱酶基因的研究

目的:了解辽宁医学院附属第一医院38株多重耐药鲍曼不动杆菌超广谱酶基因存在状况。方法:用微量稀释法测定临床分离的38株多重耐药鲍曼不动杆菌对14种抗生素的耐药性,采用多重聚合酶链反应(PCR)、基因测序技术对鲍曼不动杆菌进行超广谱酶基因测定。结果:38株多重耐药鲍曼不动杆菌对14种抗生素高度耐药。检出TEM基因阳性33株(86.84%)、PER-1基因阳性5株(13.16%)、SHV基因阳性1株(2.63%),未检出CTX、GES和VEB基因;其中5株TEM、PER-1基因均阳性,1株TEM、SHV基因均阳性。结论:我院分离的多重耐药鲍曼不动杆菌携带多种超广谱酶基因;应重视合理使用抗生素,减少多重耐药的产生。     

利奈唑胺、去甲万古霉素等抗菌药物对耐甲氧西林金黄色葡萄球菌的抗菌活性

目的:研究北京市三家医院耐甲氧西林金黄色葡萄球菌(MRSA)耐药现状,评价利奈唑胺、去甲万古霉素等药物的抗菌活性。方法:收集解放军总医院、北京医院、北京协和医院三家医院分离的非重复MRSA111株,头孢西丁纸片法确认MRSA,采用琼脂稀释法测定抗菌药物的最低抑菌浓度(MIC)。结果:111株MRSA,对β-内酰胺类的耐药率为100%,对红霉素的耐药率为92.8%,对氨基糖苷类(奈替米星、庆大霉素)的耐药率为99.1%,对氟喹酮类(加替沙星、莫西沙星、左氧氟沙星)的耐药率为91.9%~99.1%,对氯霉素的耐药率为3.6%,对去甲万古霉素、利奈唑胺全部敏感,对去甲万古霉素MIC50和MIC90分别为0.5和1μg/mL,对利奈唑胺的MIC50和MIC90均为2μg/mL。结论:北京三家医院分离的MRSA对本研究的大多数抗菌药物均耐药,去甲万古霉素和利奈唑胺对于MRSA有很高的抗菌活性。     

临床分离产AmpC β-内酰胺酶阴沟肠杆菌的耐药性分析

目的研究我院临床分离阴沟肠杆菌的产AmpC酶耐药情况及ampC基因型。方法收集临床分离的耐药阴沟肠杆菌15株；检测产AmpC酶和超广谱β-内酰胺酶（ESBLs）的菌株；测定MIC值；PCR扩增检测ampC基因及序列测定。结果15株菌中8株菌（53．3％）产AmpC酶，3株菌（20．0％）产ESBLs。产AmpC酶的菌株除对亚胺培南全敏感外。对其它抗菌药不同程度耐药。ampC基因与阴沟肠杆菌ECLC074的ampC基因高度同源。结论产AmpC酶是阴沟肠杆菌对阻内酰胺类抗生素耐药的主要机制之一。阴沟肠杆菌ECLC074 ampC基因是我院主要的阴沟肠杆菌ampC基因型。产AmpC酶的阴沟肠杆菌常呈多重耐药，亚胺堵南是治疗此类菌所致感染的最有效药物。     

Cefuroxime: a review of its antibacterial activity, pharmacological properties and therapeutic use.

Cefuroxime is a new semisynthetic cephalosporin for parenteral administration. It is resistant to destruction by beta-lactamases produced by staphylococci and most Gram-negative aerobic bacteria and is active against many bacteria resistant to cephalothin. Cefuroxime is the most active of the cephalosporins against gonococci and Haemophilus influenzae particularly against beta-lactamase producing strains. Given by intramuscular or intravenous injection cefuroxime is effective against a wide variety of infections caused by Gram-positive or Gram-negative aerobes, but has no effect against infections caused by Pseudomonas aeruginosa or B. fragilis. Cefuroxime is of value in the treatment of respiratory infections due to Haemophilus influenzae and Streptocococcus pneumoniae and is useful against cephalosporin-resistant Klebsiella and Enterobacter infections. Cefuroxime is an alternative to spectinomycin for the treatment of beta-lactamase producing Neisseria gonorrhoeae infections. It is generally well tolerated and appears not to be nephrotoxic when given alone at usual dosages.     

α-Substituted β-oxa isosteres of fosmidomycin: synthesis and biological evaluation

Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. α-Aryl-substituted β-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum . The most active derivative inhibits IspC protein of P. falciparum (PfIspC) with an IC(50) value of 12 nM and shows potent in vitro antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition in vitro.     

Gatifloxacin: a new fluoroquinolone

Gatifloxacin is a new 8-methoxy-fluoroquinoline antimicrobial agent. It has enhanced activity against Gram-positive and atypical agents, while retaining broad-spectrum antiGram-negative activity. For example, the MIC₉₀ values for respiratory tract pathogens are less than or equal to 0.5 μg/ml for organisms such as Streptococcus pneumoniae (regardless of penicillin susceptibility), Haemophilus influenzae (β-lactamase positive or negative), Moraxella catarrhalis (β-lactamase positive or negative), Legionella species, Mycoplasma pneumoniae, methicillin-sensitive Staphylococcus aureus, β-haemolytic Streptococci (macrolide sensitive or resistant), Neisseria species, most Enterobacteriaceae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella species, _{species and}Yersinia enterocolitica. For methicillin-resistant S. aureus, ciprofloxacin-resistant S. aureus, Citrobacter freundii, Providencia species, Serratia species, Pseudomonas aeruginosa and other non-fermentative Gram-negative bacilli, the MIC₉₀ are elevated. Gatifloxacin is bactericidal and exhibits a post-antibiotic effect against Gram-positive and -negative bacteria. The standard dose is 400 mg once daily and is available in both oral and iv. formulation. Gatifloxacin appears to have a low propensity for the selection of resistant mutants. Clinical trial data supports the use of gatifloxacin for treatment of patients with respiratory tract, urinary tract, skin and soft tissue infections. The side effect profile for gatifloxacin is similar to that with other agents.     

流感嗜血杆菌对β内酰胺类和氟喹诺酮类药物的耐药机制

目的研究流感嗜血杆菌(Hi)对β内酰胺类和氟喹诺酮类的敏感性和耐药机制。方法用琼脂二倍稀释法,检测Hi对β内酰胺类和氟喹诺酮类敏感性;Nitrocefin显色反应对所有菌株进行β内酰胺酶检测,PCR扩增检测Hi的β内酰胺酶基因(TEM-1和ROB-1)以及氟喹诺酮的耐药决定区(QRDR),并对特异条带测序并分析。结果对183株受试Hi,氨苄西林的敏感率为73.2%(134/183);对氨苄西林/舒巴坦、头孢噻肟和头孢吡肟均敏感率达100%。检出环丙沙星和莫西沙星不敏感Hi分别为2株(2/183)和3株(3/184),其中1株对环丙沙星和莫西沙星均不敏感。有34株(18.6%)TEM-1基因阳性;34株菌都携TEM-1型β内酰胺酶基因,未发现ROB-1基因;所有氟喹诺酮不敏感菌株的GyrA和ParC均发现一或多个氨基酸改变,且GyrA主要发生在84位和88位。结论除对氨苄西林外,Hi对头孢菌素和氟喹诺酮类保持较高敏感性。Hi对氨苄西林的耐药主要是产生β内酰胺酶,且主要为TEM-1型。QRDR的氨基酸改变是Hi对氟喹诺酮不敏感的主要机制。     

Cefotaxime: microbiology, pharmacology, and clinical use

The microbiological activity, pharmacology, and clinical efficacy of the third-generation cephalosporin cefotaxime are reviewed. Cefotaxime has greater activity than other available first- and second-generation cephalosporins against Enterobacteriaceae. It is more active than older cephalosporins against Pseudomonas aeruginosa and Acinetobacter spp., but most strains are still considered resistant. Cefotaxime is also active against some gram-negative bacilli that are resistant to aminoglycosides, including amikacin. Cefotaxime has activity comparable with other cephalosporins against gram-positive cocci, except staphylococci and enterococci, which are resistant. Cefotaxime in combination with penicillins or aminoglycosides may be synergistic against selected gram-negative bacilli. Cefotaxime is metabolized in vivo to the desacetyl derivative, which is also microbiologically active. Cefotaxime appears to penetrate most body tissues and fluids, including cerebrospinal fluid. Clinical use of cefotaxime has resulted in response rates between 70 and 95% in most infections. The ultimate role of cefotaxime and other third-generation cephalosporins is not established since controlled clinical comparisons with standard antimicrobial regimens are lacking. Possibilities include the empiric and specific therapy of serious gram-negative bacillary infection probably in combination with a penicillin or an aminoglycoside. Cefotaxime appears to be potentially useful in the management of gram-negative bacillary meningitis.