Phenothiazines as anti-multi-drug resistant tubercular agents

Pulmonary tuberculosis (TB) has again become a global problem: it infects 2.2 billion people world-wide, caused the deaths of over 3 million last year and will produce over 8 million new cases of TB this coming year. Although effective therapy is widely available for antibiotic susceptible strains of Mycobacterium tuberculosis, current drugs are relatively useless against multi-drug resistant infections (MDRTB). Mortality is almost complete within two years regardless of therapy, and in the case of co-infection with HIV/AIDS, mortality is 100% within a few months of diagnosis especially the M. tuberculosis strain in XDRTB. As of the time of this writing no new effective anti-TB drugs have been made available by the pharmaceutical industry and XDRTB. Because TB is an intracellular infection of the non-killing macrophage of the lung, any agent that is to prove effective must have activity against MDRTB and XDRTB strains that have been phagocytosed by the human macrophage. This review intents to provide cogent in vitro, ex vivo and in vivo evidence that supports the use of a variety of commonly available phenothiazines for the therapy of MDRTB and XDRTB, especially when the prognosis of the infection is poor and the use of the recommend agents can take place along lines of "compassionate therapy". In addition, we will describe the macrophage assay as indispensable when an agent is to be further studied for its effectiveness as an anti-TB drug. In vitro studies if not complemented by ex vivo studies will for the most part be dead-ended since few agents that have activity in vitro have any activity against phagocytosed M. tuberculosis.     

Inhibitors of Ca2+ and K+ transport enhance intracellular killing of M. tuberculosis by non-killing macrophages

BACKGROUND: Human monocyte-derived macrophages that have little killing activity of their own kill intracellular Staphylococcus aureus when cultured in the presence of inhibitors of calcium and potassium efflux pumps. The aim of this study was to evaluate the effect of inhibitors such as ouabain, reserpine and verapamil in the killing activity of macrophages infected with Mycobacterium tuberculosis. MATERIALS AND METHODS: Macrophages obtained from peripheral blood were infected with M. tuberculosis ATCC27294 H37Rv and treated with reserpine, ouabain and verapamil. RESULTS: After three days post-infection, macrophages treated with the inhibitors demonstrated an enhancement of the killing activity destroying the internalized bacteria. CONCLUSION: Whereas drugs that target the bacterium are predicted to lose effectiveness due to mutation of the bacterial target, drugs that enhance killing by macrophages that normally do not kill mycobacteria may yield a more effective form of infections therapy caused by multidrug resistant M. tuberculosis.     

Antibiotic resistance in the absence of selective pressure

Antibiotic resistance poses a serious threat to modern medical practice making treatment more difficult and is associated with increased mortality among patients infected with resistant organisms. There is clear evidence that acquisition of resistance is associated with a decrease in the fitness of the organisms at least in the short term. Evidence from in vitro experiments indicates that bacteria have the ability to adapt to this deficit and recover fitness on serial passage. More recent results show that identical organisms isolated from patients in outbreaks have an initial deficit but that adaptation occurs in vivo. Strategies directed towards controlling resistance must move beyond wishful thinking that supposes that these organisms will disappear merely with control of prescribing. In some cases, resistance will not disappear because there is no evolutionary disadvantage in being resistant once adaptation has taken place. It is important, therefore, that we direct our efforts towards preventing primary resistance emerging and in limiting the spread of resistant strains. Ultimately, we must look again to new drug discovery to improve our therapeutic armoury.     

结核菌耐药的基因及治疗

近年来．随着化疗药物的广泛应用。耐药结核病,尤其是耐多药结核病（MDR-TB）对全球结核病控制造成严重威协。高耐药率和耐多药菌株以及广泛耐药结核病的不断扩散,正日益成为全球结核病控制中的一个重大问题。而我国多耐药结核病疫情属全世界22个高负担国家之一。     

空洞型耐多药肺结核患者耐药性分析及治疗方案探索

目的探讨耐多药肺结核患者耐药性产生原因及治疗方法。方法对2012年10月～2013年10月间，本院收治的68例空洞型耐多药肺结核患者耐药性进行分析，并探讨治疗方法。结果本次调研发现，患者治疗依从性差，是导致多重耐药肺结核的因素，其次，治疗方法的不合理同样导致患者感染，因此针对患者采用个性化的治疗是治疗耐多药肺结核患者的重要手段，本次实验中，观察组患者使用个性化的耐药菌敏感药物进行治疗，治疗效果优于对照组（χ^2=4．239，P=0．036〈0．05）。结论导致患者耐多药感染的主要因素是由于治疗依从性差及治疗方案的不合理，因此对患者进行教育和心理疏导以及个体化全面治疗，有助于耐多药肺结核治疗。     

Mechanistic investigation of resistance via drug-inactivating enzymes in Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a serious major health concern that has existed from millennia. According to annual WHO report 2016, it is considered as world’s ninth highest killer disease by single infectious agent, ranking above HIV/AIDS. To worsen the scenario the development of multi-drug resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB) have significantly reduced the success rate of TB treatment. Several efforts are being made to handle pharmacodynamic resistance (MDR and XDR-TB) involving designing of new inhibitors, targeting mutated target or by multi-targeting agents. However, the issue of pharmacokinetic resistance in TB is not being addressed appropriately till date. Pharmacokinetic mode of resistance involves an intrinsic mechanism of bacterial drug resistance via expression of various enzymes and efflux pumps that are responsible for the loss of activity of the therapeutic agents. Mycobacterium tuberculosis is also intrinsically resistant to various approved agents via pharmacokinetic mechanism of resistance. Several bacterial enzymes are encoded that either degrade or modifies the drugs and renders them ineffective. Targeting such inactivating bacterial enzymes provides a novel approach to make the current therapy effective and combat the problem of resistance. This review provides an insight into different bacterial enzymes which are responsible for pharmacokinetic drug resistance in TB. The structure attributes and mechanism of catalysis employed by these enzymes to inactivate drug have also been discussed which may provide basis for developing novel therapeutic agents for resistant TB.     

Semisynthetic derivatives of mannopeptimycin antibiotics active against multi-drug resistant Gram-positive bacteria

The incidence of hospital infections due to Gram-positive bacteria is continuously increasing. Most of these organisms have become resistant to first-line antibacterial agents and they pose a serious clinical problem as current therapeutic options are limited. It follows an urgent need for new agents, possibly provided with novel mechanisms of action, that prove to be effective against multi-drug resistant Gram-positive pathogens, particularly methicillin-resistant staphylococci, including strains of Staphylococcus aureus with reduced susceptibility to glycopeptides, penicillin-resistant pneumococci and vancomycin-resistant enterococci. In this patent, American Cyanamide Co. presents a new class of glycopeptide derivatives of the natural products mannopeptimycins, which do not belong to the vancomycin family, that show interesting activity against most of the above resistant Gram-positive bacteria. Some of these compounds are worthy of further development to be considered as a possible alternative to other innovative antibiotics that have been launched into the market recently or are currently undergoing clinical development.     

A new evolutionary and pharmacokinetic-pharmacodynamic scenario for rapid emergence of resistance to single and multiple anti-tuberculosis drugs

The current understanding of the mechanism of anti-tuberculosis drug resistance has been shaped by the history of development of anti-tuberculosis drugs in the past 60 years and was arrived at as part of inductive generalization. Recently, these standard beliefs have been tested in controlled hollow fiber systems experiments. Drug resistance in Mycobacterium tuberculosis was shown to be related to pharmacokinetic-pharmacodynamic (PK/PD) factors, and factors such as pharmacokinetic variability. Poor PK/PD exposures owing to our current non-optimized dosing regimens initiate a chain of evolution driven events, starting with induction of multi-drug efflux pumps, followed by the development of chromosomal mutations in time, which together lead to high level resistance multi-drug resistant tuberculosis and extremely drug resistant tuberculosis.     

危重患者多重耐药鲍曼不动杆菌感染的药学监护分析

目的:探讨临床药师对多重耐药鲍曼不动杆菌感染的危重患者实施药学监护的特点。方法:回顾性分析36例危重患者感染多重耐药鲍曼不动杆菌的病原菌分布、细菌耐药情况、治疗结果及进行药学监护的情况。结果:多重耐药鲍曼不动杆菌耐药情况严重,危重患者感染后治疗困难。结论:临床药师应深入临床,发挥药学专长,加强药学监护,参与危重患者多重耐药鲍曼不动杆菌感染治疗方案的制订,这对于抗感染药物的合理应用,防止耐药菌株产生是非常重要的。     

Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps

Global rates of pulmonary tuberculosis (TB) continue to increase. Moreover, resistance of the causative organism Mycobacterium tuberculosis to the two most effective anti-TB medications continue to rise. Now, multi-drug resistant TB (MDR-TB) has progressed to extensively drug resistant TB (XDR-TB) - a M. tuberculosis organism that is resistant to the most effective second line drugs available for the treatment of TB. This review provides detailed, significant evidence that supports the use of an old neuroleptic compound, thioridazine (TZ), for the management of MDR-TB and XDR-TB infections and which has been shown to inhibit efflux pumps of bacteria. The argument has been previously presented but no one seems to be listening - and the disease continues unabated when there is a very good probability that the suggested drug will prove to be effective. When the prognosis is poor, available therapy predictably ineffective and death is inevitable, compassionate therapy with TZ should be contemplated. The risks are small and the rewards great.     

力克肺疾丁胺卡那治疗耐多药肺结核疗效分析

目的　评价力克肺疾片联合丁胺卡那霉素治疗耐药物性肺结核的临床疗效及不良反应。方法　选取耐多药肺结核患者 135例 ,治疗组 70例采用 3DKOThE/ 9DOThE方案 ,对照组 6 5例采用 3KOThE/ 9OThE方案。结果　治疗 12个月后 ,治疗组痰菌阴转率 ,病灶吸收好转率明显高于对照组 (P <0 .0 5 )。结论　含力克肺疾片方案优于对照组 ,适用于耐多药肺结核的治疗。     

Screening strategies to identify new antibiotics

The emergence of multi-drug resistant bacteria is one of the most critical medical problems currently facing humankind, which will only get worse if no new antibacterial drugs are launched. This article will first review commonly used screening strategies used to identify potential new antibiotics and then discuss novel screening methods. In addition, new assays, methods, biological targets and compounds with novel modes of action undergoing pre-clinical or clinical development are briefly discussed.     

Mechanisms of antimicrobial resistance: their clinical relevance in the new millennium

Antimicrobials show selective toxicity. Suitable targets for antimicrobials to act at include the bacterial cell wall, bacterial protein and folic acid synthesis, nucleic acid metabolism in bacteria and the bacterial cell membrane. Acquired antimicrobial resistance generally can be ascribed to one of five mechanisms. These are production of drug-inactivating enzymes, modification of an existing target, acquisition of a target by-pass system, reduced cell permeability and drug removal from the cell. Introduction of a new antimicrobial into clinical practice is usually followed by the rapid emergence of resistant strains of bacteria in some species that were initially susceptible. This has reduced the long-term therapeutic value of many antimicrobials. It used to be thought that antibacterial resistance was mainly a hospital problem but now it is also a major problem in the community. Organisms in which resistance is a particular problem in the community include members of the Enterobacteriaceae, including Salmonella spp. and Shigella spp., Mycobacterium tuberculosis, Streptococcus pneumoniae, Haemophilus influenzae and Neisseria gonorrhoeae. Multi-resistant Gram-negative rods, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci are major causes of concern in the hospital setting. Prevalence of antibacterial resistance depends both on acquisition and spread. Decreasing inappropriate usage of antimicrobials should lessen the rate of acquisition, and spread can be minimised by sensible infection control measures.     

Resistant TB: Newer Drugs and Community Approach

Drug resistance in tuberculosis (TB) is a serious problem compromising both the treatment and control programs. Poor usage of the available anti TB drugs has led to progressive drug resistance-multi drug resistance (MDR), extensively drug-resistance (XDR) and even total drug resistance (TDR). While drug sensitive TB is completely curable, MDR-TB is difficult to treat, XDR and TDR are often fatal. Non availability of new drugs to treat drug resistant cases further complicates the problem. The Global Alliance for Tuberculosis Drug Developments, a non-profit organization with the World Health Organization (WHO) as a partner was formed in February 2000 for the development of new drugs. In the last decade this venture has resulted in several promising new antituberculosis drugs like TMC207 (diaryquinoline), PA-824 (nitroimidazo-oxazine), OPC-67683 (nitroimidazo-oxazole) and SQ 109 (diamine compound). Drug resistance in TB is a man made problem. Therefore, while global efforts towards new drug development must continue it is equally important to have a well defined community approach to prevent the emergence of drug resistance to the existing and newer drugs. The present review article discusses some recent drug patents for the treatment of tuberculosis and the appropriate community approach to prevent and treat drug resistant TB.     

2015—2019年天津市胸科医院血流感染多重耐药菌的菌株变迁及危险因素相关性分析

目的 分析天津市胸科医院血流感染多重耐药菌的菌株流行情况和危险因素,为其合理治疗及控制提供循证学依据。方法 收集2015年1月1日—2019年12月31日天津市胸科医院全血标本分离出的菌株,分析各类多重耐药菌株变迁趋势、耐药性,以及医院获得性血流感染的危险因素。结果 5年间全血标本共分离菌株1 207株,检出多重耐药菌134株,检出率11.10%。多重耐药菌株总体数量以及产超广谱β内酰胺酶（ESBLs）肠杆菌、耐碳青霉烯类鲍曼不动菌（CRAB）变化趋势均不大。产ESBLs细菌对头孢菌素类、喹诺酮类、复方新诺明等耐药严重,CRAB对除替加环素、米诺环素、粘菌素外的抗菌药物耐药率均较高。与对照组相比,糖尿病（OR=2.202,P=0.005）、低蛋白血症（OR=9.502,P=0.006）、机械通气（OR=0.051,P=0.002）、行外科手术（OR=8.056,P=0.012）、入住ICU（OR=5.200,P=0.035）是观察组患者发生多重耐药菌感染的独立危险因素。结论 临床医生应严格遵照抗菌药物分级管理制度,合理应用抗菌药,同时,密切关注菌株流行情况,重视感染的早期防控,积极预防和控制多重耐药菌的产生和流行。     

耐多药住院肺结核病临床分析及防治

目的探讨耐多药结核(MDR-TB)的临床特点,分析其耐药状况,并探索有效的防治对策。方法选择160例耐多药肺结核病人根据耐药情况进行统计学研究与回顾性分析。结果160例痰培养阳性患者经积极治疗后痰菌转阴率、病灶吸收率和空洞闭合率分别达到85.6%、68.3%和55.7%。结论耐多药肺结核病的发生多由不规则治疗所致,对其控制重在预防;加强合理有效的化疗和全程的督导治疗,必要时借助于外科治疗。     

中药化合物的抗菌及增效作用

随着细菌耐药性问题的日趋严重,以及多重耐药菌感染逐渐增多,细菌耐药性日渐成为临床疾病治疗的棘手问题。中药具有多途径抑菌的优势,在抗耐药菌方面也有一定的效果,本综述对具有抗菌及增效作用的中药单体化合物及其作用机制进行总结,中药单体化合物在抑制β-内酰胺酶、抑制代谢活动相关酶、抑制外排泵、改变细胞膜通透性、抑制细菌菌膜、消除耐药质粒方面具有一定的效果,并分析了一些可以与抗生素联合作用的中药单体化合物的抗菌机制,为抗耐药菌的新药发现与机制研究提供基础及参考。     

新生儿病区多重耐药菌分布及耐药性分析

目的:通过对2016 年7 月至2017 年7 月河南省妇幼保健院住院患儿多重耐药菌的临床分布及耐药性分析,为临床抗菌药物的合理应用提供理论依据。 方法:应用珠海迪尔 DL-96 系统和手工实验相结合的方法进行细菌鉴定和抗菌药物敏感性试验,部分药敏试验结合 K-B 纸片扩散法。 药敏试验结果参照美国 CLSI 标准判读,将数据录入 WHONET 软件进行细菌分布及耐药性统计分析。 结果:河南省妇幼保健院在 2016 年 7 月至 2017 年 7 月住院的新生儿共检出阳性菌株 1 754 株,检出多重耐药菌 337 株,占 19.21%。 多重耐药菌中,耐碳青霉烯肺炎克雷伯菌(CRKPN)比例最高,占 45.70%;多重耐药菌主要分布在新生儿重症监护病房(NICU),且在新生儿和其他儿童病区中,CRKPN 检出率最高。 NICU 与新生儿普通病区相比,多重耐药菌和CRKPN 阳性率比较差异有统计学意义(P<0.01);新生儿病区与其他儿童病区相比,多重耐药菌和 CRKPN 阳性率比较差异有统计学意义(P<0.01)。 药敏结果显示肺炎克雷伯菌对氨苄西林耐药率 100%,对哌拉西林/他唑巴坦耐药率 80.3%,对碳青霉烯类药物美罗培南、亚胺培南的耐药率高达 65.2%,对复方磺胺甲噁唑的耐药率最低为 28.8%。 结论:我院新生儿病区多重耐药菌检出率较高,以 CRKPN 为主,提示应加强多重耐药菌株监测和抗菌药物监管。     

Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view

The efflux systems of bacteria protect cells from antibiotics and biocides by actively transporting compounds out of the cytoplasm and/or periplasm and thereby limit their steady-state accumulation at their site(s) of action. The impact of efflux systems on the efficacy of antibiotics used in human medicine and animal husbandry is becoming increasingly apparent from the characterization of drug-resistant strains with altered drug efflux properties. In most instances, efflux-mediated antibiotic resistance arises from mutational events that result in their elevated expression and, in the case of efflux pumps with broad substrate specificity, can confer multi-drug resistance (MDR) to structurally unrelated antibiotics. Knowledge of the role of efflux systems in conferring antibiotic resistance has now been successfully exploited in the pharmaceutical industry and contributed, in part, to the development of new members of the macrolide and tetracycline classes of antibiotics that circumvent the efflux-based resistance mechanisms that have limited the clinical utility of their progenitors. The therapeutic utility of compounds that inhibit bacterial drug efflux pumps and therein potentiate the activity of a co-administered antibiotic agent remains to be validated in the clinical setting, but the approach holds promise for the future in improving the efficacy and/or extending the clinical utility of existing antibiotics. This review discusses the potential of further exploiting the knowledge of efflux-mediated antibiotic resistance in bacteria toward the discovery and development of new chemotherapeutic agents.     

细节护理在多重耐药菌感染住院患儿中的应用效果分析

目的 分析对多重耐药菌感染住院患儿实施细节护理的效果.方法 将100例多重耐药菌感染住院患儿分为干预组与对照组.对照组实施常规护理,干预组则是在对照组基础上实施细节护理,比较两组护理效果.结果 干预组住院时间(10.3±3.2)d,对照组(16.5±4.6)d;干预组护理满意度96％,对照组82％.结论 对多重耐药菌感染住院患儿实施细节护理可缩短住院时间,提高患儿家属满意度.