Preventive chemotherapy and the fight against neglected tropical diseases

Preventive chemotherapy is the public health strategy recommended by the WHO against a set of neglected tropical diseases that includes four groups of helminth infections (lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted helminthiasis) and one chlamydial (trachoma) infection. This article presents the characteristics of preventive chemotherapy interventions directed against each disease targeted by this strategy and provides an update on the status of their implementation worldwide.     

A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates

Blinding trachoma is an ancient neglected tropical disease caused by Chlamydia trachomatis for which a vaccine is needed. We describe a live-attenuated vaccine that is safe and efficacious in preventing trachoma in nonhuman primates, a model with excellent predictive value for humans. Cynomolgus macaques infected ocularly with a trachoma strain deficient for the 7.5-kb conserved plasmid presented with short-lived infections that resolved spontaneously without ocular pathology. Multiple infections with the attenuated plasmid-deficient strain produced no inflammatory ocular pathology but induced an anti-chlamydial immune response. Macaques vaccinated with the attenuated strain were either solidly or partially protected after challenge with virulent plasmid-bearing organisms. Partially protected macaques shed markedly less infectious organisms than controls. Immune correlates of protective immunity were not identified, but we did detect a correlation between MHC class II alleles and solid versus partial protection. Epidemiological models of trachoma control indicate that a vaccine with this degree of efficacy would significantly reduce the prevalence of infection and rates of reinfection, known risk factors which drive blinding disease.     

Developments in diagnosis and treatment of visceral leishmaniasis during the last decade and future prospects

Human visceral leishmaniasis (VL) continues to be a life-threatening neglected tropical disease, with close to 200 million people at risk of infection globally. Epidemics and resurgence of VL are associated with negligence by the policy makers, economic decline and population movements. Control of the disease is hampered by the lack of proficient vaccination, rapid diagnosis in a field setting and severe side effects of current drug therapies. The diagnosis of VL relied largely on invasive techniques of detecting parasites in splenic and bone marrow aspirates. rK39 and PCR, despite problems related to varying sensitivities and specificities and field adaptability, respectively, are considered the best options for VL diagnosis today. No single therapy of VL currently offers satisfactory efficacy along with safety. The field of VL research only recently shifted toward actively identifying new drugs for safe and affordable treatment. Oral miltefosine and safe AmBisome along with better use of amphotericin B have been rapidly implemented in the last decade. A combination therapy will substantially reduce the required dose and duration of drug administration and reduce the chance of the development of resistance. In addition, identification of asymptomatic cases, vector control and treatment of post-kala-azar dermal leishmaniasis would allow new perspectives in VL control and management.     

New strategies to combat filariasis

Two of the major filarial infections, lymphatic filariasis (LF) and onchocerciasis, affect 150 million people, while 1 billion living in endemic areas are at risk of infection. Public health programs to control these infections have successfully existed for years and have evolved from activities driven by the WHO into global programs with public-private partnerships. Currently, these programs use yearly mass application of drugs that mainly kill the larval stages (the microfilariae), with the aim of preventing uptake by the transmitting insect vectors and thus, to block transmission and reduce the infections to such levels that in 15-30 years from now, they will no longer pose a public health problem. While the programs have been very successful in general, there are drawbacks such as coverage being too low within the population, reappearance of infection by migration of infected people into controlled areas, targeting of a stage (the microfilaria) that does not induce pathology in LF and thus lowers compliance, and the potential development of drug resistance, first indications of which have been clearly observed in onchocerciasis. In addition, even without drawbacks, program scopes are not the eradication of filarial infections, which is, however, an ultimate goal of control activities. There is therefore an unequivocal call for the development of higher efficient, complementary chemotherapeutical approaches that lead to a long-lasting reduction of the pathology-inducing worm stages; that is, microfilariae in onchocerciasis and adult worms in LF, or to a macrofilaricidal effect. The recent discovery that depletion of Wolbachia endosymbionts by tetracycline antibiotics leads to long-lasting sterility of adult female worms in onchocerciasis and a macrofilaricidal effect in LF fulfils these requirements. Successful regimens have already been published and agreed upon for use by expert panels. While these regimens are still too long for mass application, the antiwolbachial chemotherapy can currently be applied in the form of a suitable doxycycline regimen for 6 weeks for the treatment of individuals, and exploited in the future for the development of new drugs suitable for mass application. In addition, first data suggest that Wolbachia may also be major mediators of lymphangiogenesis and that their depletion is associated with reduction of lymph vessel-specific vascular endothelial growth factors and reduced lymph vessel size.     

Treatment of childhood Plasmodium falciparum malaria: current challenges

Malaria continues to be a major cause of mortality and morbidity in tropical countries. Infection with Plasmodium falciparum may be asymptomatic, cause an uncomplicated febrile illness or give rise to severe disease complicated by coma, acidosis or severe anemia. Treatment of the febrile illness with two drugs--preferably in the form of an artemisinin-containing combination therapy--is now widely recommended, both for greater efficacy and in order to delay the evolution of drug resistance. The clinical picture of severe malaria differs according to the age and immune status of the individual; treatment requires a range of supportive measures, as well as an efficacious antimalarial drug. Insecticide-treated bednets and presumptive treatment programs are increasingly deployed in malaria control programs, while vaccines are showing promise.     

Antimicrobial stewardship programs: methods of operation and suggested outcomes

The judicious use of antibiotics is an important strategy to preserving efficacy in the treatment of infectious diseases. Infectious disease practitioners are poised to provide patient-specific recommendations for appropriate agents and to optimize dosage and duration of therapy. Antimicrobial stewardship programs (involving pharmacists, physicians and other healthcare providers) are increasing in number as antibiotic resistance increases with a disproportionately small number of new agents being developed. Two strategies for antimicrobial stewardship are currently endorsed by national organizations and include preauthorization/formulary restriction and prospective audit with feedback. As it is important for programs to choose appropriate clinical and financial outcomes goals in order to assure sustainability, we review these strategies and discuss the impact of each on clinical outcomes and costs.     

Progress and challenges in the discovery of macrofilaricidal drugs

Control of human filarial infections currently depends on chemotherapeutic strategies predominantly directed at microfilariae. Doxycycline therapy in an extended daily dose regimen sterilizes and kills adult stages, but the utility of this drug for routine field use remains an issue of concern. No macrofilaricidal drugs with efficacy after one or two doses are available for use, delaying the achievement of the elimination or eradication of onchocerciasis and lymphatic filariasis. Moxidectin, a macrocyclic lactone, is currently in clinical trials for onchocerciasis. A few other drugs that have already been approved for use in veterinary practice or in human medicine for other indications are available for investigation. Early drug discovery pipelines are poorly populated and the process of macrofilaricide discovery and development remains highly challenging. In particular, the lack of convenient, validated animal models in an antifilarial drug discovery pathway is an unresolved issue.     

Progress and challenges in the discovery of macrofilaricidal drugs

Control of human filarial infections currently depends on chemotherapeutic strategies predominantly directed at microfilariae. Doxycycline therapy in an extended daily dose regimen sterilizes and kills adult stages, but the utility of this drug for routine field use remains an issue of concern. No macrofilaricidal drugs with efficacy after one or two doses are available for use, delaying the achievement of the elimination or eradication of onchocerciasis and lymphatic filariasis. Moxidectin, a macrocyclic lactone, is currently in clinical trials for onchocerciasis. A few other drugs that have already been approved for use in veterinary practice or in human medicine for other indications are available for investigation. Early drug discovery pipelines are poorly populated and the process of macrofilaricide discovery and development remains highly challenging. In particular, the lack of convenient, validated animal models in an antifilarial drug discovery pathway is an unresolved issue.     

Impact of azithromycin administration for trachoma control on the carriage of antibiotic-resistant Streptococcus pneumoniae

Community distribution of azithromycin has an important role to play in trachoma control. Previous studies have suggested that this may increase the prevalence of macrolide-resistant Streptococcus pneumoniae. S. pneumoniae was isolated from children under 7 years of age in Rombo District, northern Tanzania, before and 2 and 6 months after community-wide administration of azithromycin. Overall carriage rates were 11, 12, and 7%, respectively. Only one macrolide-resistant isolate carrying the mef gene was obtained 6 months after azithromycin administration. This contrasted with cotrimoxazole and penicillin resistance, both of which were common (cotrimoxazole resistance, 42, 43, and 47%, and penicillin resistance, 21, 17, and 16% at baseline, 2 months, and 6 months, respectively). There was a significant association between cotrimoxazole and penicillin resistance (P < 0.0001, Fisher's exact). These data suggest that in communities where macrolide resistance is rare, azithromycin distribution for trachoma control is unlikely to increase the prevalence of resistant organisms.     

Ocular Chlamydia trachomatis infection: elimination with mass drug administration

Introduction: Ocular Chlamydia trachomatis infection, the causative agent for trachoma, is responsible for 1.9 million cases of visual loss worldwide. Mass Drug Administration (MDA) with azithromycin to entire trachoma-endemic districts is part of the World Health Organization’s public health strategy for trachoma elimination.

Areas covered: Background on C. trachomatis and the epidemiology of trachoma are presented, followed by a review of the antibiotics for treatment and the need for a public health approach to trachoma elimination. The effectiveness of mass drug administration is presented, concluding with challenges to trachoma elimination in the future.

Expert opinion: MDA using azithromycin is a key component of the public health strategy for trachoma elimination. With high coverage in children, there is good evidence that MDA drops the community pool of infection. There are challenges to trachoma elimination by the year 2020, and the drug donation program for country MDAs will be integral to ongoing efforts.     

全国结核病流行病学抽样调查及各省耐药监测中耐药结核病疫情资料分析

目的 对我国耐药肺结核的流行现状展开分析,为制定相关政策提供科学依据。 方法 分析1990、2000 和2010年三次全国结核病流行病学抽样调查资料(未包括香港、澳门和台湾地区,以下同)中不同药物的初始耐药率以及获得性耐药率的变化趋势,比较全国12个省耐药率及耐多药率的差异。 结果 根据目前我国1990、2000、2010年三次结核病流行病学抽样调查结果显示, 异烟肼和链霉素的初始耐药率呈现上升趋势(PPPP结论 为了遏制耐多药肺结核,需要尽快提高耐多药肺结核规范化治疗管理的覆盖率,通过规范化治疗来治愈耐多药肺结核患者,以控制耐多药肺结核的传染源从而降低疫情。在开展耐多药肺结核控制的同时,不可降低普通肺结核治疗管理的质量。     

Worldwide blindness.

Blindness affects approximately 42 to 52 million people worldwide. This article examines the major causes of blindness, including cataract, trachoma, glaucoma, onchocerciasis, nutritional deficiencies, and ocular trauma. Numerous case studies supplement the text.     

Adverse Event Management in Mass Drug Administration for Neglected Tropical Diseases

The ethical challenges of reporting and managing adverse events (AEs) and serious AEs (SAEs) in the context of mass drug administration (MDA) for the treatment of neglected tropical diseases (NTDs) require reassessment of domestic and international policies on a global scale. Although the World Health Organization has set forth AE/SAE guidelines specifically for NTD MDA that incorporate suspected causality, and recommends that only SAEs get reported in this setting, most regulatory agencies continue to require the reporting of all SAEs exhibiting even a merely temporal relationship to activities associated with an MDA program. This greatly increases the potential for excess “noise” and undue risk aversion and is not only impractical but arguably unethical where huge proportions of populations are being treated for devastating diseases, and no good baseline exists against which to compare possible AE/SAE reports. Other population-specific variables that might change the way drug safety ought to be assessed include differing efficacy rates of a drug, background morbidity/mortality rates of the target disease in question, the growth rate of the incidence of disease, the availability of rescue or salvage therapies, and the willingness of local populations to take risks that other populations might not. The fact that NTDs are controllable and potentially eradicable with well-tolerated, effective, existing drugs might further alter our assessment of MDA safety and AE/SAE tolerability. At the same time, diffuseness of population, communication barriers, lack of resources, and other difficult surveillance challenges may present in NTD-affected settings. These limitations could impair the ability to monitor an MDA program?s success, as well as hinder efforts to obtain informed consent or provide rescue therapy. Denying beneficial research interventions and MDA programs intended to benefit millions requires sound ethical justification based on more than the identification of and rote response to AEs and SAEs.     

Sustainability Assessment of Community Forestry Practices in Nepal: Literature Review and Recommendations to Improve Community Management

Nepal’s Community Forestry Program is a sustainable forest management and livelihood enhancement program reformed from earlier programs of the previous century. The government’s initial policy was to provide the basic forest resources to local communities through their active participation in forest improvement and management. Nepal’s policy and development program was based on sustainability concepts. Community forestry can be sustainable and produce socially, economically, and ecologically beneficial results. A number of both qualitative and quantitative options have been applied to measure the sustainable use of forests and other natural resources in community forests, but classifying the results is challenging. Policy-makers, experts, and the communities should be involved in developing and improving criteria and indicators for community forest management, reflecting the diversity of perspectives that must be accounted for and the increasing worldwide demand for sustainability and governance. The main findings were that sustainability can be measured with numerous tools, but there are several challenges. A literature review revealed that nationally and internationally defined criteria and indicators have not been extensively applied in Nepal due to lack of technical and other expertise.     

Best Characteristics of Adolescent Gateway Drug Prevention Programs

This paper identifies the best characteristics of gateway drug prevention programs that have the effect of preventing or reducing the use of alcohol, tobacco, and marijuana by adolescents. A comprehensive literature review of the performance of school-, family-, and community-based drug prevention programs covering the last 20 years was conducted to identify the best characteristics of successful programs. Six characteristics were identified that are common to successful drug prevention programs: involving parents; teaching life and resistance skills and normative education; enacting laws and policies against adolescent drug use; encouraging peer participation; conducting a media campaign; and retaining program participants. School administrators, parents, and community leaders can use the knowledge in this paper to design drug prevention programs that can accommodate specific risk factors and types of gateway drug use by adolescents.     

Current practice of antibiotic prophylaxis for catheter procedures

The practice of giving prophylactic antibiotics to patients at the time of urinary catheter insertion, change or removal is variable since guidelines for their use have yet to be established. The use of prophylactic antibiotics to prevent urinary catheter-related infections and the possibility of bacteraemia and septicaemia, despite a lack of evidence for their efficacy, is a matter of concern in light of the reported overuse of, and increased resistance to, antibiotics. This article describes an audit of, and increased resistance to, antibiotics. This article describes an audit conducted in one trust to establish the current practice of antibiotic prophylaxis for urinary catheter procedures. The audit confirmed that in 60% of the recorded catheter procedures, patients were given antibiotics, usually gentamicin. Variations in gentamicin prophylaxis were revealed, including differences in the timing of administration relative to the catheter procedure. This audit revealed that intramuscular gentamicin was given simultaneously with the procedure or after the procedure in a number of cases, suggesting that on these occasions "prophylaxis" was suboptimal.     

Biosensors as rapid diagnostic tests for tropical diseases

Effective diagnosis of infectious pathogens is essential for disease identification and subsequent adequate treatment, to prevent drug resistance and to adopt suitable public health interventions for the prevention and control of epidemic outbreaks. Particular situations under which medical diagnostics operate in tropical environments make the use of new easy-to-use diagnostic tools the preferred (or even unique) option. These diagnostic tests and devices, usually based on biosensing methods, are being increasingly exploited as promising alternatives to classical, "heavy" lab instrumentation for clinical diagnosis, allowing simple, inexpensive and point-of-care testing. However, in many developing countries the lack of accessibility and affordability for many commercial diagnostic tests remains a major cause of high disease burden in such regions. We present a comprehensive overview about the problems of conventional medical diagnosis of infectious pathologies in tropical regions, while pointing out new methods and analytical tools for in-the-field and decentralized diagnosis of current major infectious tropical diseases. The review includes not only biosensor-based rapid diagnostic tests approved by regulatory entities and already commercialized, but also those at the early stages of research.     

A multifunctional nanostructured platform for localized sustained release of analgesics and antibiotics

The current delivery methods for pain medication, local anesthetics, antibiotics, and steroids present several limitations mainly due to their route of administration, which results in suboptimal pain management, potential systemic toxicity, and subtherapeutic levels which increases the risk of microorganisms developing antibiotic resistance. Our group developed a hybrid material consisting of nanoporous silicon (pSi) and poly(lactic-co-glycolic acid) (PLGA) nanoparticles, loaded with antibiotics and pain relief medications, respectively. The medications were delivered via a bioactive angiogenic gel of platelet-rich plasma (PRP). This system releases both molecules in a sustained and controlled fashion while simultaneously promoting wound healing and vascularization of the surgical site. The resulting advantages include improved medication efficacy at a lower total drug concentration, decreased risk of systemic toxicity, and for antibiotics, decreased risk of developing resistance. The versatile nature of our platform allows for a variety of different drugs, molecules, biological factors to be loaded and released by the gel. Moreover, by tuning the chemical and physical properties of each component, it is possible to tailor the release rate of each biomolecule to its desired therapeutic level. Therapeutic and antimicrobial agents were released at potent daily dosages for up to 7 days by combination of PLGA and pSi particles free or embedded within the PRP gel. When implanted in vivo, the composite gel was vascularized and infiltrated with endogenous cells by 2 weeks while exhibiting no symptoms of inflammation or immune response. This novel technology has the potential to dramatically affect the post-operative management of patients with an immediate improvement in post-operative pain management, decreased PACU and hospital length of stays, with subsequently decreased hospital and surgical costs. Furthermore, this unique and effective drug delivery platform technology may eliminate the need for subsequent treatments, repeat dosing, and dramatically improve patient convenience and patient compliance.