氨基糖苷类抗生素的发展历程

抗生素的定义，首先来自于20世纪40年代链霉素的发现。在随后的几十年中，其他氨基糖苷类抗生素家族被大量发现并广泛应用，一度成为抗革兰阴性菌感染的首选抗生素。但由于其毒副作用较大，并且细菌对其不断产生耐药性，加上其他结构类别的新型抗生素的不断发现，使其一度几乎退出历史舞台。然而随着多重耐药细菌引起的感染率急剧上升，人们开始关注氨基糖苷类抗生素作为几种重要的治疗革兰阴性病原体的方案之一，并且发掘了其在治疗感染性疾病、艾滋病和遗传性疾病的潜力，使这个“老牌”抗生素重焕生机。     

大肠埃希菌氨基糖苷酰基转移酶基因型的研究

目的了解大肠埃希菌的耐药谱、氨基糖苷酰基转移酶基因(aac)的分布规律及其与氨基糖苷类抗生素耐药的相关性。方法琼脂稀释法测定无菌体液分离的44株大肠埃希菌对阿米卡星等12种抗生素的耐药性,聚合酶联反应(PCR)法测定酰基转移酶基因型aac(3)-Ⅰ、Ⅱ和aac(6′)-Ⅰ。结果大肠埃希菌超广谱β-内酰胺酶(ESBLs)的发生率为45.45%(20/44),对亚胺培南(IPM)、美罗培南(MEM)的耐药率为0,对哌拉西林/他唑巴坦、头孢他啶的耐药率较低(<20%),对左氟沙星、环丙沙星的耐药率较高(>60%),对氨基糖苷类阿米卡星、庆大霉素、妥布霉素的耐药率分别为18.18%、56.82%、61.36%。氨基糖苷类耐药模式TG(妥布霉素、庆大霉素)>TGA(妥布霉素、庆大霉素、阿米卡星)>T(妥布霉素)>G(庆大霉素),分别占36.36%、18.18%、6.82%、2.27%。氨基糖苷酰基转移酶基因检出以aac(3)-Ⅱ最高,占52.27%(23/44),aac(6′)-Ⅰ次之,占29.55%(13/44),aac(3)-Ⅱ和aac(6′)-Ⅰ同时检出者占15.91%(7/44),未检出aac(3)-Ⅰ。ESBLs阳性株的aac(3)-Ⅱ、aac (6′)-Ⅰ检出率分别为60%、50%,高于ESBLs阴性株的45.81%、12.51%。TG模式与其耐药基因aac(3)-Ⅱ符合率较高,为93.75%(15/16)。结论本地分离大肠埃希菌氨基糖苷类耐药模式以TG为主,酰基转移酶基因以aac(3)-Ⅱ为主,aac(6′)-Ⅰ次之,aac(3)-Ⅰ罕见。     

Gentamicin ototoxicity: clinical features and the effect on the human vestibulo-ocular reflex

Conclusions. Gentamicin ototoxicity presents with gait imbalance and oscillopsia, but only rarely with hearing loss and vertigo. Sinusoidal rotational stimuli with high accelerations such as the bedside head-thrust test or rotational step changes in velocity are useful to diagnose bilateral vestibulopathy. Objective. To describe the salient clinical features and vestibular testing results in gentamicin ototoxicity. Patients and methods. A retrospective review of the quantitative vestibular function testing results for patients presenting to the UCLA Neurotology Clinic with gentamicin ototoxicity over the past 10 years (n=35). Results. All patients presented with imbalance and 33 out of 35 had oscillopsia. Three patients reported a noticeable change in hearing and five reported vertigo. Of the 35 patients, 15 were in renal failure at the time of gentamicin administration. Patients with pre-existing peripheral neuropathy compensated poorly. Sinusoidal rotational testing demonstrated profoundly decreased gain and increased phase lead over the entire frequency range, with a subset of patients having relatively preserved gain at the intermediate frequencies (0.8–1.6 Hz) and low acceleration (<30°/s). There was little or no response to high acceleration step changes in velocity. The time constant measured both by sinusoidal and step responses was ultra-low. All patients tested had a positive head-thrust test bilaterally.     

氨基糖苷类抗生素生物合成研究进展

作为曾经治疗细菌感染的一线临床药物,氨基糖苷类抗生素在人类与病源微生物的抗争中作出了不可磨灭的巨大贡献,也成就了这一类抗生素的辉煌。虽然,伴随着其耳毒性和肾毒性等毒副作用,以及日益严重的耐药性的严峻挑战,但借助现代科学技术的发展和认知水平的提高,氨基糖苷类抗生素许多不曾被了解的新的生物活性也正不断地丰富和拓展着它新的潜能,使之依然成为人类医药宝库中不可或缺的重要一员。基于此,本文从分子遗传学、生物化学及结构生物学角度对常见的天然和化学半合成氨基糖苷抗生素生物合成的研究进展进行简要的概述。     

铜绿假单胞菌氨基糖苷类耐药表型及耐药基因的检测

目的了解中山地区铜绿假单胞菌氨基糖苷类药物的耐药表型和基因表型的分布及其关系。方法采用VITEK-2Compact高级专家系统判定2010年1-9月896株铜绿假单胞菌对氨基糖苷类药物的耐药表型,并对其中15株多药耐药铜绿假单胞菌采用PCR的方法检测4种氨基糖苷类修饰酶基因。结果 896株铜绿假单胞菌及15株多药耐药铜绿假单胞菌对氨基糖苷类药物的耐药表型模式均主要为表型模式RESISTANT(GEN、NET、AMI、TOB),阳性株分别为468、12株;15株多药耐药菌株全部检出氨基糖苷类耐药基因:aac(6′)-Ⅰ、aac(6′)-Ⅱ、ant(2″)-Ⅰ、ant(3″)-Ⅰ分别为13、4、3、8株。结论临床分离的铜绿假单胞菌以单一耐药表型模式为主,推测该地区氨基糖苷类药物耐药的主要原因,是氨基糖苷类修饰酶基因的存在导致。     

Cystic fibrosis,aminoglycoside treatment and acute renal failure: the not so gentle micin

Aminoglycosides have a wide spectrum of gram-negative anti-bacterial activities and are available at low cost, which makes them commonly used drugs, especially for patients with cystic fibrosis (CF), who often suffer from chronic lung infections from Pseudomonas aeruginosa. Unfortunately, this treatment seems to have resulted in an increased incidence of acute renal failure (ARF) in patients with CF. A recent case–control study investigated risk factors for ARF in CF patients and suggested intravenous use of gentamicin as the prime culprit. Moreover, in most cases, at least one other risk factor, such as CF-related diabetes, pre-existing renal failure, dehydration or concurrent use of other nephrotoxic drugs, was present. We comment on the renal handling of aminoglycosides and the possible mechanisms of toxicity, as well as strategies for risk minimisation.     

大肠埃希菌尿液分离株氨基糖苷类获得性耐药基因研究

大肠埃希菌是医院感染的常见病原菌,随着临床抗菌药物的大量使用,该菌不仅对喹诺酮类抗菌药物的耐药率明显上升,对氨基糖苷类药物的耐药问题也日趋严重,给临床抗感染治疗带来严峻挑战.有关对氨基糖苷类药物的耐药机制,传统观点认为是细菌产生一种或多种针对抗菌药物的氨基糖苷类修饰酶（AMEs）[1-2].     

Pharmacokinetics of once and twice daily dosing of intravenous tobramycin in paediatric patients with cystic fibrosis

The optimal dosing of intravenous tobramycin for treatment of pulmonary exacerbations in paediatric cystic fibrosis (CF) patients has not been completely delineated. We performed a retrospective study evaluating the pharmacokinetics and pharmacodynamics of once daily dosing (ODD) of IV tobramycin compared to twice daily dosing (TDD). Fifty-nine and 44 patients were included in the ODD and TDD groups, respectively. Once daily dosing achieved higher C_max as compared to TDD (29.5?±?11.0 vs 19.0?±?4.9, P?P?P?C_max:MIC for MICs >1.0?mg/l. Twice daily dosing may be a viable alternative to ODD in treating organisms with MICs ≤?1.0?mg/l; however, with MICs >1.0?mg/l, ODD is likely necessary to achieve goal C_max:MIC ratios.     

Antibiotic related acute kidney injury in patients treated for open fractures

ObjectiveAntibiotic administration during the treatment of open fractures has been shown to reduce infection rates and is considered a critical step in the management of these injuries. The purpose of this study was to determine if aminoglycoside administration during the treatment of open fractures leads to acute kidney injury.MethodsPatient records at a level I trauma centre were reviewed for adult patients who presented in 2014 with open fractures were screened for inclusion. Patients were excluded with fractures of the phalanges, metatarsals, and metacarpals, with isolated traumatic arthrotomies, or pre-existing renal dysfunction. Charts were reviewed for patient age, gender, race, past medical history, medication history, injury severity score, intravenous dye studies and fracture type. Patients were divided into those given cefazolin (Group A) and cefazolin with gentamicin (Group B). Laboratory values were used to determine which patients developed kidney dysfunction as measured using the RIFLE criteria. Wilcoxon–Mann–Whitney test and Chi-square were used to compare interval and categorical variables, respectively. Significance was set at P < 0.05.ResultsOne-hundred and fifty-nine patients met inclusion criteria. Forty-one (25%) patients were given cefazolin alone and 113 (68%) patients were given cefazolin with gentamicin. Ten (18%) patients with Gustilo-Anderson type III fractures were given cefazolin alone and 67 (67%) patients with types I or II fractures were given a cefazolin with gentamicin. Baseline characteristics and risk factors for renal dysfunction did not vary between groups. Two (4.8%) patients in Group A and 5 (4%) patients in Group B developed acute kidney injury (P = 0.599).ConclusionsGentamicin use during the treatment of open fractures does not lead to increased rates of renal dysfunction when used in patients with normal baseline renal function.