不动杆菌对替加环素及多黏菌素耐药机制研究进展

不动杆菌属细菌是临床常见的非发酵糖菌,广泛分布于医院环境中,是引起多种院内感染的重要条件致病菌.随着临床抗菌药物的大量使用,不动杆菌逐渐出现了多重耐药甚至全耐药株,有效抗菌药物极少,给临床感染的治疗带来极大困难.近年来发现替加环素和多黏菌素治疗多重耐药革兰阴性菌感染特别是鲍曼不动杆菌有较好疗效,但随着研究的不断深入,逐渐发现不动杆菌对替加环素及多黏菌素也存在耐药性,本文就目前国内外不动杆菌对替加环素及多黏菌素耐药机制进行简要综述.不动杆菌对替加环素耐药机制主要与AdeABC外排泵系统有关,对多黏菌素的耐药机制主要为外膜LPS修饰.还需要针对不动杆菌对替加环素及多黏菌素的耐药机制进一步研究,从而指导临床合理使用抗菌药物.     

Semi-mechanistic PK/PD modelling of combined polymyxin B and minocycline against a polymyxin-resistant strain of Acinetobacter baumannii

ObjectivesTo expand on previous reports of synergy between polymyxin B (PMB) and minocycline (MIN) against Acinetobacter baumannii; and to gain insight into the qualitative and quantitative determinants of their synergy.MethodsA semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed on the basis of data from in vitro time-kill experiments with determination of resistant bacterial count to describe the effects of PMB and MIN alone and in combination. The model was enriched by complementary experiments providing information on the characteristics of the resistant subpopulation.ResultsThe model successfully described the data and made possible quantification of the strength of interaction between the two drugs and formulation of hypotheses about the mechanisms of the observed interaction. The effect of the combination was driven by MIN, with PMB acting as an helper drug; simulations at clinically achievable concentrations showed that 1.5 mg/L MIN +0.2 mg/L PMB is expected to produce sustained killing over 30 hours, while 0.3 mg/L MIN +1 mg/L PMB is met by bacterial regrowth. Interaction equations showed that maximal synergy is reached for PMB concentrations ≥0.1 mg/L and MIN concentrations ≥1 mg/L.ConclusionsSemi-mechanistic PK/PD modelling was used to investigate the quantitative determinants of synergy between PMB and MIN on a PMB-resistant A. baumannii strain. The developed model, improving on usual study techniques, showed asymmetry in the drug interaction, as PMB acted mostly as a helper to MIN, and provided simulations as a tool for future studies.     

毛细管电泳法测定硫酸多黏菌素B中的有关物质

目的 建立一种用毛细管电泳测定硫酸多黏菌素B中有关物质的分析方法。方法 以含30mmol/L羟丙基-β-环糊精、5%异丙醇的130mmol/L三乙醇胺溶液(用磷酸调节pH至2.5)为运行缓冲液，熔融石英毛细管总长60cm，有效长度51.5cm，内径50μm，分离电压24kV，柱温25℃，进行了线性、检测限、精密度等方法学考察试验，并将该方法应用于硫酸多黏菌素B原料药及制剂的检测中。结果 实现了多黏菌素B中主要组分B1、B2、B3、B1-I与相邻杂质的分离，对比了不同来源硫酸多黏菌素B有关物质的差异。结论 本方法灵敏度较高、重复性较好，为硫酸多黏菌素B的质量控制提供了一种可行的分析方法。     

多黏菌素的药理作用和治疗多重耐药鲍曼不动杆菌的研究进展

随着全球多重耐药鲍曼不动杆菌的感染率、致死率日益增多,且对碳青霉烯类耐药现象十分常见,多黏菌素作为治疗多重耐药鲍曼不动杆菌的最后防线被引入临床.本文旨在对多黏菌素的化学结构、作用机制、耐药机制、单用及联合应用和毒性作用进行综述,以期对临床科学合理用药和进一步研究提供参考.     

Carbapenem-resistant Klebsiella pneumoniae bacteremia: factors correlated with clinical and microbiologic outcomes

We undertook a retrospective cohort study describing general outcomes and specific factors associated with positive outcomes in bacteremia due to carbapenem-resistant Klebsiella pneumoniae (CRKP). Forty-eight patients were included, of which 42% died at 30 days. Forty-two percent of patients were in septic shock at the time of the first positive blood culture, and 42% were recipients of solid organ transplants. Lack of microbiologic eradication at 7 days was independently associated with 30-day mortality. Adjunctive procedures performed for source control and microbiologic eradication at 7 days were associated with a favorable clinical response at 7 days. Time to initiation and receipt at any time of antimicrobials with in vitro activity against CRKP were not associated with improved survival. Breakthrough bacteremia occurred in 8 cases, all in patients receiving tigecycline. Our data suggest that severity of illness, rapid microbiologic eradication, and source control are crucial factors in the outcomes of patients with CRKP bacteremia.     

Adenosine alters the vascular effects of a diacylglycerol analogue and polymyxin B

Endothelium-denuded rat aorta rings were used to study the possible relationship between protein kinase C and the mechanism of adenosine-induced smooth muscle relaxation. Adenosine (5 × 10⁻⁴M) partially relaxed the aortic rings contracted by either a depolarising amount of KCl (4 × 10⁻² M) or activation of protein kinase C with l-oleoyl-2- acetyl-sn-glycerol (10⁻⁶ M). The same amount of adenosine blocked the further relaxation obtained in the presence of polymyxin B (5 × 10⁻⁵ M), a protein kinase C blocking agent. These results suggest a possible interaction in vascular smooth muscle between adenosine and protein kinase C.     

Apparent involvement of protein kinase C in the central glucoregulatory action of insulin

We have studied the possible involvement of the calcium- and phospholipid/diacylglycerol-dependent enzyme, protein kinase C (PKC) in mediating insulin action in the central nervous system (CNS) by testing the effect of direct activation or blockade of the CNS PKC system on the plasma glucose responses to central insulin injection in mice. Insulin (0.1–1 μg), injected into the CNS, produced rapid transient hypoglycemia. This effect appeared to involve interaction of insulin with specific receptors, since insulin analogs exhibiting diminished receptor binding affinity and peripheral bioactivity compared to the native hormone were much less active (i.e., insulin >>> acetyl 3 insulin > proinsulin > IGF-I) or not active at all (i.e., insulin chain A and B). Central injection of the specific PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.01–0.5 μg), but not the inactive TPA analog, 4-orbol or the unstable synthetic diacylglycerol analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), significantly enhanced the hypoglycemic response to co-administered insulin (0.5 μg) or the insulin derivative, acetyl 3 insulin (2.5 μg). Central TPA had no effect on basal glucose levels. Furthermore, central administration of the selective PKC blockers, polymyxin B (PMB, 1–25 μg) or 1-β-galactosylsphingosine (psychosine, 0.5–10 μg) but not their respective inactive analogs, polymyxin E and sphingomyelin, strongly inhibited the hypoglycemic response to insulin (1 μg) or acetyl 3 insulin (5 μg). PMB and psychosine, injected alone had no effect on basal glucose levels. These findings, of a significant enhancement or blockade of the hypoglycemic response to central insulin following direct, selective activation or inhibition, respectively, of the CNS PKC system are consistent with the view that PKC might play a role in the mediation of insulin action in the CNS.