氨基糖苷类药物在联合用药时缩小抗菌药物对鲍曼不动杆菌耐药突变选择窗中的作用

目的探讨氨基糖苷类药物与其他抗鲍曼不动杆菌药物联合应用时，在缩小抗菌药物对鲍曼不动杆菌的耐药突变选择窗的作用。方法选择阿米卡星、妥布霉素及奈替米星3种氨基糖苷类药物，同时选择4种临床常用的抗鲍曼不动杆菌药物：头孢哌酮-舒巴坦、亚胺培南-西司他丁、环丙沙星及左氧氟沙星进行试验。应用E试验法测定4种抗鲍曼不动杆菌药物和3种氨基糖苷类药物对鲍曼不动杆菌ATCC19606的MIC；琼脂平皿稀释法测定4种抗鲍曼不动杆菌药物单药及联合3种氨基糖苷类药物后对鲍曼不动杆菌ATCC19606的防耐药突变浓度，计算选择指数，根据联合前后选择指数的变化，观察氨基糖苷类药物和其他抗菌药物联合后对其耐药突变选择窗的影响。结果头孢哌酮-舒巴坦、亚胺培南-西司他丁、环丙沙星、左氧氟沙星单药对鲍曼不动杆菌ATCC19606的选择指数分别为：16、〉32、16、32；联合阿米卡星后其选择指数分别为：1、2、4、4；联合妥布霉素后其选择指数分别为：2、2、8、8；联合奈替米星后其选择指数分别为：2、4、8、16。结论4种抗鲍曼不动杆菌药物在分别联合3种氨基糖苷类药物后，对鲍曼不动杆菌的耐药突变选择窗明显缩小，可以有效减少耐药突变株产生，以联合阿米卡星后的作用最为明显。     

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.     

An update on the medical management of listeriosis

It is still not quite well understood why there is no optimal or even a satisfactory antibiotic therapy for listeriosis. Although almost all Listeria strains that induce sepsis, meningitis and encephalitis, as well as many other manifestations – in particular, in immunocompromised individuals – are susceptible to most of the common antibiotics, the cure rate is only ～ 70%. The most effective regimen still consists of a combination of an aminopenicillin (amoxicillin or ampicillin) plus an aminoglycoside. In vitro, this combination is bactericidal, whereas aminopenicillin alone only exerts a weak bactericidal activity against Listeriae. These antibiotics only poorly penetrate the cerebrospinal fluid and thus, only high doses given over a prolonged period of 2 – 3 weeks are curative. Furthermore, Listeria monocytogenes belongs to the group of facultative intracellular bacteria, which means that a certain population is inaccessible for antibiotics. Theoretically, a drug which is endowed with bactericidal activity superior to that of ampicillin would be preferable. Furthermore, the candidate drug should easily cross the blood–brain barrier into the CNS, be able to accumulate within host cells, reach the cytoplasm and be active under these unusual conditions. Because of all these arguments, the new quinolones are of particular interest; but broad clinical data are still lacking. It is unclear as to whether antibiotics alone will be sufficient to increase the prognosis. Adjunctive therapy with immunomodulators, which are able to reconstitute the defective defence capacities, would presumably create the conditions necessary to finally resolve listeriosis.     

新技术在氨基糖苷类药物质控方面的应用和进展

目的总结氨基糖苷类药物质控的分析方法,分析其特点和发展方向。方法查阅药典及文献中此类药物的质控方法,并进行归纳总结。结果与讨论随着新技术在药物分析中的应用,氨基糖苷类药物检测方法正向着灵敏度更高、专属性更强的新型检测器或新方法代替老方法的方向发展。     

Meropenem Plus Amikacin Versus Piperacillin-Tazobactam Plus Netilmicin as Empiric Therapy for High-Risk Febrile Neutropenia in Children

The aim of this study was to evaluate the efficacy and safety of meropenem plus amikacin compared with piperacillin-tazobactam plus netilmicin for initial empirical antibiotic treatment of high-risk febrile neutropenia in children with cancer. Patients with hematologic malignancy (leukemia or stage III/IV non-Hodgkin lymphoma) who presented with fever and neutropenia (ANC < 500/mm³) and patients with solid tumors who presented with fever and severe neutropenia (ANC < 100/mm³) were considered to be at high risk and eligible for this study. In this prospective study, 33 patients with 50 febrile neutropenic episodes received iv meropenem (20 mg/kg every 8 h) plus amikacin (15 mg/kg/d in 2 divided doses) (in 31 episodes) or piperacillin/tazobactam (100 mg/4 mg/kg every 8 h) plus netilmicin (7 mg/kg every 24 h) (in 19 episodes). Clinical response was determined at 72 h and at completion of the therapy. The groups were comparable in terms of age, sex, initial ANC, use of growth factors, and classification of the infections. An infection was documented microbiologically in 12 episodes (39%) in the meropenem plus amikacin group and in 8 episodes (42%) in the piperacillin/tazobactam plus netilmicin group. Of the 22 microbiological isolates, 37% were gram-positives, 45% were gram-negatives, and 18% were fungi. Most of the clinically documented infections were of lower respiratory tract, gastrointestinal mucosa, or urinary tract origin. The mean duration of neutropenia was 9 days in both groups. Fever persisted for 1–30 days (mean 3 vs. 5 days). The success rate with initial empiric therapy was 52% in the meropenem plus amikacin and 42% in the piperacillin/tazobactam plus netilmicin group, respectively (p= .5). Total success rate (with or without modification) was 97% vs. 90% in the episodes. Three patients died due to infection (1 vs. 2 patients). No major adverse effects were observed in each group. Empirical therapy with meropenem plus amikacin or piperacillin/tazobactam plus netilmicin for high-risk febrile neutropenia is equally effective and safe in pediatric cancer patients.     

广州市聋校听力障碍学生线粒体DNA12S rRNA A1555G突变调查分析

目的调查广州市非综合征性耳聋高危人群中线粒体DNA 12S rRNA A1555G的突变情况,为我市防聋宣教提供理论依据。方法利用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术对188例聋校听力障碍学生、100例听力正常的健康体检者进行临床评估及基因检测。结果188例聋校听力障碍学生及100例听力正常的健康体检患者均未发现线粒体DNA A1555G位点突变,突变率为0,明显低于全国平均水平。结论虽然在经济较为发达的广州地区线粒体DNA A1555G突变检出率较低,但仍为预测我市耳聋高危人群耳毒性风险、合理使用氨基糖甙类抗生素提供分子学依据,为进一步研究我市耳聋基因易感性奠定基础。     

氨基糖苷类药物耳毒性的斑马鱼模型的研究

氨基糖苷类抗生素因其抗菌谱广、抗菌能力强,半个多世纪以来一直是临床上常用的抗菌素之一。但氨基糖苷类抗生素具有很强的耳毒和肾毒作用,在药物致聋因素中排在首位。本研究以庆大霉素(gentamycin)、新霉素(neomycin)、链霉素(streptomycin)等3种氨基糖苷类抗生素为代表性药物,研究其对斑马鱼胚胎发育的毒性作用和对幼体毛细胞的损伤作用,并探索了该损伤与听觉相关基因之间的联系。结果显示:①3种药物的致死作用都具有明显的浓度依赖性,其致死作用的强弱顺序为链霉素>新霉素>庆大霉素;②3种药物处理的5 dpf(day past fertilization)幼体出现身体失衡及体位异常,以及耳囊结构的异常变化;③毛细胞染色实验可观察到,3种药物作用的毛细胞和神经丘均出现明显的损伤和数量减少;④与听觉器官发育相关的基因eya1、val、otx2、dlx6a均随3种抗生素药物浓度的升高,出现差异性的表达水平下调。本研究首次探索了这3种耳毒性氨基糖苷类抗生素处理与斑马鱼听囊结构和听觉基因表达的相关性;并证明利用斑马鱼建立简便、准确、直观、快速地检测药物耳毒性的模型和检测方法的可行性。