New therapies and vaccines for bacterial meningitis

Acute bacterial meningitis remains an important cause of morbidity and mortality worldwide. There have recently been major advances in the prevention of the major causes of bacterial meningitis following improvements in vaccinology. The success of immunisation against Haemophilus influenzae type b infection is being mirrored with serogroup C conjugated meningococcal vaccine and pneumococcal conjugate vaccine. However, there remain major challenges, notably, serogroup B meningococcal infection and shifts in epidemiology caused by vaccine introduction. In addition, much of the world's population is unvaccinated. Therefore, improvements in management of acute bacterial meningitis are vital. In this review we attempt to summarise important advances in both prevention and treatment of acute bacterial meningitis.     

New therapies and vaccines for meningococcal disease

Meningococcal disease (MCD) is an important cause of morbidity and mortality. The pathophysiology consists of a complex interaction of bacterial and host factors, triggered by the release of endotoxin which initiates the inflammatory cascade, resulting in multi-organ failure, coagulopathy, capillary leak, metabolic derangement and eventually death. Prompt recognition and aggressive management are essential in reducing mortality. Over the past decade, there has been intense research into novel therapies and vaccines, with largely disappointing results. Therapies have been broadly divided into anti-endotoxin and anti-TNF-α therapies, treatment aimed at correcting coagulopathy and at blood purification and anti-inflammatory cytokine therapy. The reasons for the disappointing results in the search for new therapeutic strategies are difficult to identify. The disordered physiology in MCD results from a complex interaction of several mediators; therefore attempts to correct this by altering just one step represents a gross oversimplification of the process. In addition, the experimental model of endotoxaemia, which is often used, is a poor representation of an acutely ill patient with rapidly progressive shock. There have been several small or poorly designed trials, which have failed to reach definite conclusions. In order to yield conclusive results any future trials must be multicentre, randomised, controlled trials, but these are expensive and, in practice, difficult to conduct. The BPI trial (vide infra) was a significant step forward in this regard and demonstrated the ability to organise a large multicentred trial which can act as a template for future trials. Although the results were not significant there was an overall trend towards improved outcome in the treatment arm. Whilst the development of effective therapies and vaccines are awaited, the priorities at present must be the prompt recognition and aggressive management of disease.     

New therapies for pneumococcal meningitis

The treatment of pneumococcal meningitis remains a major challenge, as reflected by the continued high morbidity and case fatality of the disease. The worldwide increase of penicillin-resistant pneumococci and more recently cephalosporin- and vancomycin-tolerant pneumococci has jeopardised the efficacy of standard treatments based on extended spectrum cephalosporins alone or in combination with vancomycin. This review provides a summary of newly developed antibiotics tested in the rabbit meningitis model. In particular, newer β-lactam monotherapies (cefepime, meropenem, ertapenem), recently developed quinolones (garenoxacin, gemifloxacin, gatifloxacin, moxifloxacin) and a lipopeptide antibiotic (daptomycin) are discussed. A special emphasis is placed on the potential role of combination treatments with some of the new compounds, which are of interest based on the background of increasing resistance problems due to their often synergistic activity in the rabbit model of pneumococcal meningitis.     

Emerging drugs for acute bacterial meningitis

The management of acute bacterial meningitis is based on early antibiotic treatment to prevent unfavorable outcome (death and permanent sequelae). β-Lactam antibiotics, particularly third-generation cephalosporins, are effective against most agents of community-acquired acute bacterial meningitis. Resistance to β-lactams evolves, particularly in Streptococcus pneumoniae, that may lead to treatment failure. Evaluation of other antibiotics such as fourth-generation cephalosporin, new penems and quinolones is warranted. Adjunctive therapy aims to reduce tissue injuries provoked by the inflammatory response. The use of dexamethasone is still a matter of debate, but seems to be helpful under conditions of rapid etiological diagnosis and prompt management. Other drugs that neutralize bacterial factors or host mechanisms involved in induction of inflammatory response are under development.     

伤寒疫苗的现状及展望

伤寒仍是发展中国家的主要公共卫生问题,控制伤寒的最有效措施是接种疫苗.此文介绍了早期伤寒疫苗和现行伤寒疫苗的的安全性和有效性,讨论了伤寒Vi多糖结合疫苗的研发现状及应用前景.     

Therapy of community-acquired acute bacterial meningitis: the clock is running

Despite antibiotic therapy and supportive intensive medical care, bacterial meningitis remains a disease with high mortality and morbidity. Rapid recognition of symptoms is crucial to direct physicians quickly towards appropriate diagnostic measures and, initially, empiric antibiotic therapy. It has become evident that time from arrival at the hospital to application of the first dose of antibiotics is a crucial independent factor that influences outcome. Here, we review the clinical and laboratory presentation of community-acquired bacterial meningitis and the antibiotic regiments that are currently recommended for its treatment; future therapeutic options are also discussed. Finally, suggestions for the approach to a patient with suspected bacterial meningitis are presented.     

对1例急性细菌性脑膜炎患者的药学监护

1例50a男性患者,因急性细菌性脑膜炎合并感染性休克入神经内科监护室治疗,转入前曾使用多种抗生素,感染控制不佳。在监护室治疗期间,临床药师参与患者抗感染治疗方案的制定,参照急性细菌性脑膜炎诊疗指南,根据患者可能致病菌,结合患者肌酐清除率,建议给予去甲万古霉素联合足剂量美罗培南抗感染治疗,3d后感染得到有效控制;为预防神经系统后遗症,在使用抗生素同时应给予激素治疗,综合考虑激素的剂量、疗程和减药等问题后,建议采用氢化可的松,3d后患者度过病情危险期;鉴于患者输液的特殊性,在了解药物的物理化学性质后,确定合理的输液顺序,确保患者安全、有效地接受药物治疗。     

1例儿童细菌性脑膜炎的治疗分析与药学监护

目的探讨儿童细菌性脑膜炎药物治疗及药学监护的策略。方法借助相关指南及文献,对1例儿童细菌性脑膜炎的抗感染治疗、万古霉素的血药浓度监测(TDM)和剂量调整进行分析及讨论,向临床医生提供药物治疗措施和建议。结果通过对儿童细菌性脑膜炎的用药分析,结合病原学及药敏结果停用美罗培南,加用利福平;根据万古霉素监测浓度,延长其输注时间以达目标范围,医生部分采纳临床药师建议,患者病情好转出院。结论临床药师应依据药物治疗相关指南及最新研究证据为临床提供用药建议,以促进临床用药合理有效。     

细菌多糖-蛋白结合疫苗研究进展

细菌多糖-蛋白结合疫苗在预防由b型流感嗜血杆菌、脑膜炎球菌和肺炎链球菌引起的侵袭性疾病方面起了非常重要的作用.此文就细菌多糖-蛋白结合疫苗结合方法、载体蛋白应用及免疫干扰现象的研究进展作一综述.     

Novel therapies and vaccines against the human respiratory syncytial virus

Introduction: Human respiratory syncytial virus (hRSV) is the leading cause of acute lower respiratory tract infections worldwide in infants, as well as an important pathogen affecting the elderly and immunocompromised individuals. Despite more than a half a century of research, no licensed vaccines are available and only palivizumab has been approved to use in humans, mostly recommended or limited to high risk infants. Therefore, novel therapeutic and preventive drugs need to be developed to fight this major human pathogen.

Areas covered: This review discusses current therapeutic approaches in preclinical and clinical stages, aimed at controlling or preventing hRSV infection. These methods include passive immunization, experimental drugs, vaccine candidates and maternal immunization.

Expert opinion: Based on the results of various immunization strategies and therapeutic approaches, it is likely that the most effective strategy against hRSV will be a prophylactic tool aimed at developing a strong antiviral T-cell response capable of both, promoting the generation of hRSV-specific high affinity antibodies and leading the protective immunity required to prevent the disease caused by this virus. Alternatively, if prophylactic strategies fail, antiviral drugs and novel passive immunity strategies could significantly contribute to reducing hospitalization rates in susceptible individuals.     

脑脊液CK-BB测定在诊断细菌性脑膜炎中的意义

测定了怀疑为中枢神经系统感染的 85例患儿脑脊液中 CK-BB浓度。其中 ,经确诊无中枢神经系统感染患儿 17例 ,病毒性脑膜脑炎患儿 36例 ,细菌性脑膜炎患儿 32例。以上病例均常规作脑脊液检查 ,同时留取 3毫升脑脊液作 CK-BB浓度测定。结果显示 ,脑脊液中 CK-BB可作为鉴别细菌性脑膜炎和病毒性脑膜脑炎的一项可靠指标。     

Conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis: a randomized clinical trial

Objective: Efficacy of the conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis was compared.

Methods: In a randomized clinical trial 44 patients with acute bacterial meningitis were randomly assigned to the conventional- or high-dose vancomycin groups. Clinical and laboratory parameters were used for evaluation of response to the treatment regimens.

Results: In the high-dose group, leukocytosis and fever resolved significantly faster than those in the conventional group. Furthermore, the length of hospitalization was shorter and Glasgow Coma Scale at the end of 10th day was significantly lower in the high dose compared to the conventional group. Trend of creatinine clearance changes did not differ significantly between the two groups.

Conclusion: In comparison to the conventional-dose regimen, the high-dose vancomycin regimen was associated with significantly more favorable clinical response without increase in the incidence of nephrotoxicity in patients with acute bacterial meningitis.     

2010-2011年我院抗菌药物使用量与细菌耐药分析

目的分析上海市某医院抗菌药物使用量及临床分离菌对常用抗菌药物的耐药性情况,为临床合理用药提供参考。方法统计和分析2010-2011年间医院住院患者抗菌药物使用强度（DDDs）及主要临床分离菌对常用抗菌药物的耐药性。结果2年间临床选择以头孢霉素类、喹诺酮类、含β-内酰胺酶抑制剂类等抗菌药物为主,DDDs变化大的有头孢呋辛钠、左氧氟沙星、氨苄西林钠-舒巴坦钠等常用药物（DDDs降幅〉30％）。2011年大肠埃希杆菌和肺炎克雷伯菌对头孢呋辛钠耐药率下降明显（P〈0．05）,大肠埃希杆菌、鲍曼不动杆菌和金黄色葡萄球菌对左氧氟沙星耐药率下降也十分明显（P〈0．01）。其他临床常见菌对常用抗菌药物耐药率有超过50％的品种呈下降趋势。结论抗菌药物DDDs与细菌耐药性有一定相关性。医院应积极开展细菌耐药性监测,调整药物品种结构,促进临床合理用药,有利于减少细菌耐药性的产生。     

地塞米松在治疗成人细菌性脑膜炎的作用

目的了解成人细菌性脑膜炎是否能从地塞米松辅助治疗中获益。方法试验采用随机、双盲、安慰剂对照观察了100例临床诊断为细菌性脑膜炎患者,年龄为14～60岁,以地塞米松治疗能否降低患者2个月内死亡率或致残风险为观察目标。结果50例患者为地塞米松治疗组,50例为安慰剂组,其中27例为细菌学证实,47例脑脊液支持的疑诊病例,所有病例分析显示2月内致死及致残风险降低与地塞米松治疗有显著性相关（RR0．48,95％ CI 0．24～0．96,P〈0．05）。且在确诊病例地塞米松治疗2月内致死及致残风险降低与地塞米松治疗存有显著性相关（RR0．52,95％ CI 0．26～0．83,P〈0．01）。结论地塞米松治疗可能改善细菌性脑膜炎病例预后;且细菌学确诊病例地塞米松治疗似乎更有利于病情恢复。     

Bacterial meningitis: a review of effective pharmacotherapy

Acute bacterial meningitis is a serious and life-threatening neurological infectious disease. Despite the availability of effective antibiotics, supportive care facilities and recent advances in adjunctive strategies, for example, adjunctive dexamethasone, mortality and morbidity rates associated with bacterial meningitis remain unacceptably high. The review presents a brief overview of key clinical and epidemiological aspects of the disease and focuses on advances in pharmacotherapeutic strategies in adult patients with bacterial meningitis in the developed world.     

病原菌耐药性与抗菌药物消耗量相关性的研究进展

病原菌耐药性是指细菌使抗菌药物治疗作用下降的一种状态。耐药菌的出现使临床感染性疾病的治疗难度增加,抗菌药物的不合理使用是细菌耐药产生的主要原因,全国范围内或区域医疗机构内有效的抗菌药物管理策略,能够减少抗菌药物使用并逆转细菌耐药性的产生。国内外有关抗菌药物使用与病原菌耐药性相关性的研究较多,国内缺少对全国性或区域性的研究数据。通过综述近年来国内外有关金黄色葡萄球菌、粪肠球菌、屎肠球菌、大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、阴沟肠杆菌及其他病原菌的耐药性与常用抗菌药物消耗量的相关性,从宏观数据上把握两者间的关系,以期为医院感染的管理提供证据支持。     

Alginate-based aerogels as wound dressings for efficient bacterial capture and enhanced antibacterial photodynamic therapy

The development of novel wound dressings, such as aerogels, with rapid hemostasis and bactericidal capacities for pre-hospital care is necessary. To prevent the occurrence of bacterial resistance, antibacterial photodynamic therapy (aPDT) with broad-spectrum antibacterial ability and negligible bacterial resistance has been intensively studied. However, photosensitizers often suffer from poor water solubility, short singlet oxygen (¹O₂) half-life and restricted ¹O₂ diffusion distance. Herein, sodium alginate was covalently modified by photosensitizers and phenylboronic acid, and cross-linked by Ca(II) ions to generate SA@TPAPP@PBA aerogel after lyophilization as an antibacterial photodynamic wound dressing. Afterwards, its photodynamic and bacterial capture activities were intensively evaluated. Furthermore, its hemostasis and bactericidal efficiency against Staphylococcus aureus were assessed via in vitro and in vivo assays. First, chemical immobilization of photosensitizers led to an enhancement of its solubility. Moreover, it showed an excellent hemostasis capacity. Due to the formation of reversible covalent bonds between phenylboronic acid and diol groups on bacterial cell surface, the aerogel could capture S. aureus tightly and dramatically enhance aPDT. To sum up, the prepared aerogel illustrated excellent hemostasis capacity and antibacterial ability against S. aureus. Therefore, they have great potential to be utilized as wound dressing in clinical trials.     

头孢曲松治疗儿童细菌性感染156例

本文介绍头孢曲松治疗儿童细菌性感染156例。男82,女74,年龄1-12yr(7±5yr)。其中,败血症74例、细菌性脑膜炎52例、肺炎22例、骨髓炎8例。用药剂量22.5-100mg(kg·d),平均剂量为67±SD 14mg/(kg·d),疗程4-15d(8±4d);显效率117/156(75.0％),有效率31/156(19.9％),总有效率94.9％。作用迅速,副作用轻微。     

Safety and efficacy of meningococcal group C conjugate vaccines

The UK was the first country to implement a universal vaccination programme with conjugate polysaccharide vaccines against Neisseria meningitidis group C. This article reviews the pre- and postlicensure data on their efficacy and safety 3 years after the introduction of the programme. Local reactogenicity data compare favourably with other routine vaccinations and no specific increase in adverse reactions has been associated with their use in infant vaccination programmes. Self-limiting systemic reactions such as fever, myalgia, headaches and irritability have commonly been observed in prelicensure studies. Passive postlicensure safety monitoring of suspected adverse reactions has identified a large number of reports, generally of reactions deemed non-serious and reversible. An Expert Working Group has concluded the balance of benefits and risks to be overwhelmingly favourable. Further safety data are expected from large data-linkage studies. Present efficacy estimates, based on active surveillance of case numbers, vaccine failures and coverage rates, are approximately 90% for all age groups. A significant fall in the number of cases attributable to meningococcal group C infection has been observed in the age group of < 20 years. The annual number of fatalities from confirmed meningococcal C disease in the same population has fallen from 67 to 5 cases within a 2-year period.     

细菌生物被膜耐药屏蔽与相关感染的治疗

综述了细菌生物被膜耐药屏蔽的机制，主要包括生物被膜内细菌的生理状态、细菌生物被膜屏蔽以及其他方面的新进展，并提出了对细菌生物被膜相关感染的治疗方法。