Focus: Antimicrobial Resistance: Gut Microbiota Modulation and Prevention of Dysbiosis as an Alternative Approach to Antimicrobial Resistance: A Narrative Review

Background: The importance of gut microbiota in human health is being increasingly studied. Imbalances in gut microbiota have been associated with infection, inflammation, and obesity. Antibiotic use is the most common and significant cause of major alterations in the composition and function of the gut microbiota and can result in colonization with multidrug-resistant bacteria. Methods: The purpose of this review is to present existing evidence on how microbiota modulation and prevention of gut dysbiosis can serve as tools to combat antimicrobial resistance. Results: While the spread of antibiotic-resistant pathogens requires antibiotics with novel mechanisms of action, the number of newly discovered antimicrobial classes remains very low. For this reason, the application of alternative modalities to combat antimicrobial resistance is necessary. Diet, probiotics/prebiotics, selective oropharyngeal or digestive decontamination, and especially fecal microbiota transplantation (FMT) are under investigation with FMT being the most studied. But, as prevention is better than cure, the implementation of antimicrobial stewardship programs and strict infection control measures along with newly developed chelating agents could also play a crucial role in decreasing colonization with multidrug resistant organisms. Conclusion: New alternative tools to fight antimicrobial resistance via gut microbiota modulation, seem to be effective and should remain the focus of further research and development.     

Secure Surveillance of Antimicrobial Resistant Organism Colonization or Infection in Ontario Long Term Care Homes

Background

There is stigma attached to the identification of residents carrying antimicrobial resistant organisms (ARO) in long term care homes, yet there is a need to collect data about their prevalence for public health surveillance and intervention purposes.

Objective

We conducted a point prevalence study to assess ARO rates in long term care homes in Ontario using a secure data collection system.

Methods

All long term care homes in the province were asked to provide colonization or infection counts for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and extended-spectrum beta-lactamase (ESBL) as recorded in their electronic medical records, and the number of current residents. Data was collected online during the October-November 2011 period using a Paillier cryptosystem that allows computation on encrypted data.

Results

A provably secure data collection system was implemented. Overall, 82% of the homes in the province responded. MRSA was the most frequent ARO identified at 3 cases per 100 residents, followed by ESBL at 0.83 per 100 residents, and VRE at 0.56 per 100 residents. The microbiological findings and their distribution were consistent with available provincial laboratory data reporting test results for AROs in hospitals.

Conclusions

We describe an ARO point prevalence study which demonstrated the feasibility of collecting data from long term care homes securely across the province and providing strong privacy and confidentiality assurances, while obtaining high response rates.     

Genetics of Antimicrobial Resistance

Antimicrobial resistant strains of bacteria are an increasing threat to animal and human health. Resistance mechanisms to circumvent the toxic action of antimicrobials have been identified and described for all known antimicrobials currently available for clinical use in human and veterinary medicine. Acquired bacterial antibiotic resistance can result from the mutation of normal cellular genes, the acquisition of foreign resistance genes, or a combination of these two mechanisms. The most common resistance mechanisms employed by bacteria include enzymatic degradation or alteration of the antimicrobial, mutation in the antimicrobial target site, decreased cell wall permeability to antimicrobials, and active efflux of the antimicrobial across the cell membrane. The spread of mobile genetic elements such as plasmids, transposons, and integrons has greatly contributed to the rapid dissemination of antimicrobial resistance among several bacterial genera of human and veterinary importance. Antimicrobial resistance genes have been shown to accumulate on mobile elements, leading to a situation where multidrug resistance phenotypes can be transferred to a susceptible recipient via a single genetic event. The increasing prevalence of antimicrobial resistant bacterial pathogens has severe implications for the future treatment and prevention of infectious diseases in both animals and humans. The versatility with which bacteria adapt to their environment and exchange DNA between different genera highlights the need to implement effective antimicrobial stewardship and infection control programs in both human and veterinary medicine.     

Focus: Antimicrobial Resistance: The Status of Carbapenem Resistance in Cystic Fibrosis: A Systematic Review and Meta-Analysis

Background: Antibiotic resistance in cystic fibrosis (CF) is a well-known phenomenon. However, the comprehensive epidemiological impact of antibiotic resistance in CF is not clearly documented. So, this meta-analysis evaluated the proportion rates of carbapenem resistance (imipenem, meropenem, and doripenem) in CF based on publication date (1979-2000, 2001-2010, and 2011-2021), continents, pathogens, and antimicrobial susceptibility testing (AST). Methods: We searched studies in PubMed, Scopus, and Web of Science (until April 2021). Statistical analyses were conducted using STATA software (version 14.0). Results: The 110 studies included in the analysis were performed in 25 countries and investigated 13,324 pathogens associated with CF. The overall proportion of imipenem, meropenem, and doripenem resistance in CF were 43% (95% CI 36-49), 48% (95% CI 40-57), 28% (95% CI 23-33), and 45% (95% CI 32-59), respectively. Our meta-analysis showed that trends of imipenem, meropenem, and doripenem-resistance had gradual decreases over time (1979-2021). This could be due to the limited clinical effectiveness of these antibiotics to treat CF cases over time. Among the opportunistic pathogens associated with CF, the highest carbapenem resistance rates were shown in Stenotrophomonas maltophilia, Burkholderia spp., Pseudomonas aeruginosa, and Staphylococcus aureus. The highest and lowest carbapenem resistance rates among P. aeruginosa in CF patients were shown against meropenem (23%) and doripenem (39%). Conclusions: We showed that trends of carbapenem resistance had decreased over time (1979-2021). This could be due to the limited clinical effectiveness of these antibiotics to treat CF cases over time. Plans should be directed to fight biofilm-associated infections and prevent the emergence of mutational resistance. Systematic surveillance for carbapenemase-producing pathogens in CF by molecular surveillance is necessitated.     

ICU患者艰难梭菌分离培养与流行病学特征研究

目的 了解ICU患者艰难梭菌的定植和感染情况,为预防艰难梭菌的流行提供参考。方法 收集2016年9月至2017年6月福建医科大学附属第一医院ICU中139例住院时间＞7 d的患者的粪便样本,对其进行选择性厌氧培养和质谱鉴定。对艰难梭菌培养阳性标本进行毒素基因（tcdA、tcdB、cdtA、cdtB）的PCR检测以及毒素A、B表型检测。收集所有患者的临床资料,并对艰难梭菌培养阳性患者的临床特征和实验室检查结果进行单因素分析和多因素回归分析。结果 艰难梭菌检出率为17.27%（24/139）。其中,14株艰难梭菌的tcdA和tcdB基因检测阳性,占58.3%（14/24）;10株为tcdA和tcdB基因检测阴性,占41.7%（10/24）。所有菌株二元毒素基因（ctdA/ctdB）均未检出。单因素分析提示,高龄、长时间住院、高淋巴细胞数、使用β-内酰胺类抗生素是艰难梭菌定植的高危因素;多因素回归分析提示,使用β-内酰胺类抗生素是艰难梭菌定植的独立危险因素（OR=3.881,P=0.039）。结论 我院ICU可能存在艰难梭菌感染和传播的风险,对具有高龄、长期住院以及使用抗生素等高危因素的患者应进行艰难梭菌的监测,以防艰难梭菌的传播、感染和艰难梭菌相关性腹泻的发生。     

Mini-review: Antimicrobial central venous catheters--recent advances and strategies

Central venous catheters (CVCs) nowadays constitute critical devices used in medical care, namely in intensive care units. However, CVCs also represent one of the indwelling medical devices with enhanced risk of nosocomial device-related infection. Catheter-related infections (CRIs) are a major cause of patient morbidity and mortality, often justifying premature catheter removal and an increase in costs and use of resources. Adhesion and subsequent biofilm formation on the surfaces of indwelling catheters is elemental to the onset of pathogenesis. Seeking the prevention of CVC colonisation and CRI, a variety of approaches have been studied, tested and, in some cases, already applied in clinical practice. This review looks at the current preventive strategies often used to decrease the risk of CRIs due to colonization and biofilm formation on catheter surfaces, as well as at the more recent approaches under investigation.     

Antimicrobial Resistance in Invasive Non-typhoid Salmonella from the Democratic Republic of the Congo: Emergence of Decreased Fluoroquinolone Susceptibility and Extended-spectrum Beta Lactamases

Background

Co-resistance against the first-line antibiotics ampicillin, chloramphenicol and trimethoprim/sulphamethoxazole or multidrug resistance (MDR) is common in non typhoid Salmonella (NTS). Use of alternative antibiotics, such as fluoroquinolones or third generation cephalosporins is threatened by increasing resistance, but remains poorly documented in Central-Africa.

Methodology/Principal findings

As part of a microbiological surveillance study in DR Congo, blood cultures were collected between 2007 and 2011. Isolated NTS were assessed for serotype and antimicrobial resistance including decreased ciprofloxacin susceptibility and extended-spectrum beta-lactamase (ESBL) production. In total, 233 NTS isolates (representing 23.6% of clinically significant organisms) were collected, mainly consisting of Salmonella Typhimurium (79%) and Salmonella Enteritidis (18%). The majority of NTS were isolated in the rainy season, and recovered from children ≤2 years old. MDR, decreased ciprofloxacin susceptibility, azithromycin and cefotaxime resistance were 80.7%, 4.3%, 3.0% and 2.1% respectively. ESBL production was noted in three (1.3%) isolates. Decreased ciprofloxacin susceptibility was associated with mutations in codon 87 of the gyrA gene, while ESBLs all belonged to the SHV-2a type.

Conclusions/Significance

Presence of almost full MDR among NTS isolates from blood cultures in Central Africa was confirmed. Resistance to fluoroquinolones, azithromycin and third generation cephalosporins is still low, but emerging. Increased microbiological surveillance in DR Congo is crucial for adapted antibiotic therapy and the development of treatment guidelines.     

Efficacy of infection control interventions in reducing the spread of multidrug-resistant organisms in the hospital setting

Multidrug-resistant organisms (MDRO) continue to spread in hospitals globally, but the population-level impact of recommended preventive strategies and the relative benefit of individual strategies targeting all MDRO in the hospital setting are unclear. To explore the dynamics of MDRO transmission in the hospital, we develop a model extending data from clinical individual-level studies to quantify the impact of hand hygiene, contact precautions, reducing antimicrobial exposure and screening surveillance cultures in decreasing the prevalence of MDRO colonization and infection. The effect of an ongoing increase in the influx of patients colonized with MDRO into the hospital setting is also quantified. We find that most recommended strategies have substantial effect in decreasing the prevalence of MDRO over time. However, screening for asymptomatic MDRO colonization among patients who are not receiving antimicrobials is of minimal value in reducing the spread of MDRO.     

Factors Influencing Succession: Lessons from Large, Infrequent Natural Disturbances

Disturbance events vary in intensity, size, and frequency, but few opportunities exist to study those that are extreme on more than one of these gradients. This article characterizes successional processes that occur following infrequent disturbance events that are exceptional in their great intensity or large size. The spatial variability in disturbance intensity within large, infrequent disturbances (LIDs) often leads to a heterogeneous pattern of surviving organisms. These surviving organisms dictate much of the initial successional pattern on large disturbances where the opportunities for seeds to disperse into the middle of the disturbance are limited. The traditional distinction between primary and secondary succession is insufficient to capture the tremendous variability in succession following LIDs. Disturbance size influences succession where long-distance colonization by propagules is important. Observations from LIDs suggest the following interrelated hypotheses about trends in succession with increasing distance from seed sources when disturbanceintensity is high: (a) initial densities of organisms will be lower; (b) nucleation processes, in which recovering patches serve as foci for additional colonization and expand spatially, will be more important; (c) competitive sorting will be less important relative to chance arrival in determination of community composition, and (d) community composition will be initially less predictable; and (e) the rate of recovery of community composition will be slower. Prediction of succession following LIDs without considering contingencies such as the abundance, types, and spatial distribution of residuals, and distance to seed sources is likely to be unsuccessful for large portions of the landscape. Abundance and spatial arrangement of survivors and arrival patterns of propagules may be the pivotal factors determining how succession differs between intense disturbances of large and small extent. Received 14 July 1998; accepted 18 September 1998     

Focus: Antimicrobial Resistance: Global status of Azithromycin and Erythromycin Resistance Rates in Neisseria gonorrhoeae: A Systematic Review and Meta-analysis

Background: The widespread development of antibiotic resistance or decreased susceptibility in Neisseria gonorrhoeae (NG) infection is a global and significant human public health issue. Objectives: Therefore, this meta-analysis aimed to estimate worldwide resistance rates of NG to the azithromycin and erythromycin according to years, regions, and antimicrobial susceptibility testing (AST). Methods: We systematically searched the published studies in PubMed, Scopus, and Embase from 1988 to 2021. All analyses were conducted using Stata software. Results: The 134 reports included in the meta-analysis were performed in 51 countries and examined 165,172 NG isolates. Most of the included studies were from Asia (50 studies) and Europe (46 studies). In the metadata, the global prevalence over the past 30 years were 6% for azithromycin and 48% for erythromycin. There was substantial change in the prevalence of macrolides NG resistance over time (P <0.01). In this metadata, among 58 countries reporting resistance data for azithromycin, 17 (29.3%) countries reported that >5% of specimens had azithromycin resistance. Conclusions: The implications of this study emphasize the rigorous or improved antimicrobial stewardship, early diagnosis, contact tracing, and enhanced intensive global surveillance system are crucial for control of further spreading of gonococcal emergence of antimicrobial resistance (AMR).     

Focus: Antimicrobial Resistance: Inhaled Bacteriophage Therapy for Multi-Drug Resistant Achromobacter

The rise of antimicrobial resistant (AMR) bacteria is a global public health threat. AMR Achromobacter bacteria pose a challenging clinical problem, particularly for those with cystic fibrosis (CF) who are predisposed to chronic bacterial lung infections. Lytic bacteriophages (phages) offer a potential alternative to treat AMR infections, with the possible benefit that phage selection for resistance in target bacteria might coincide with reduced pathogenicity. The result is a genetic “trade-off,” such as increased sensitivity to chemical antibiotics, and/or decreased virulence of surviving bacteria that are phage resistant. Here, we show that two newly discovered lytic phages against Achromobacter were associated with stabilization of respiratory status when deployed to treat a chronic pulmonary infection in a CF patient using inhaled (nebulized) phage therapy. The two phages demonstrate traits that could be generally useful in their development as therapeutics, especially the possibility that the phages can select for clinically useful trade-offs if bacteria evolve phage resistance following therapy. We discuss the limitations of the current study and suggest further work that should explore whether the phages could be generally useful in targeting pulmonary or other Achromobacter infections in CF patients.     

Controlling Antimicrobial Resistance through Targeted,Vaccine-Induced Replacement of Strains

Vaccination has proven effective in controlling many infectious diseases. However, differential effectiveness with regard to pathogen genotype is a frequent reason for failures in vaccine development. Often, insufficient immune response is induced to prevent infection by the diversity of existing serotypes present in pathogenic populations of bacteria. These vaccines that target a too narrow spectrum of serotypes do not offer sufficient prevention of infections, and can also lead to undesirable strain replacements. Here, we examine a novel idea to specifically exploit the narrow spectrum coverage of some vaccines to combat specific, emerging multi- and pan-resistant strains of pathogens. Application of a narrow-spectrum vaccine could serve to prevent infections by some strains that are hard to treat, rather than offer the vaccinated individual protection against infections by the pathogenic species as such. We suggest that vaccines targeted to resistant serotypes have the potential to become important public health tools, and would represent a new approach toward reducing the burden of particular multi-resistant strains occurring in hospitals. Vaccines targeting drug-resistant serotypes would also be the first clinical intervention with the potential to drive the evolution of pathogenic populations toward drug-sensitivity. We illustrate the feasibility of this approach by modeling a hypothetical vaccine that targets a subset of methicillin-resistant Staphylococcus aureus (MRSA) genotypes, in combination with drug treatment targeted at drug-sensitive genotypes. We find that a combined intervention strategy can limit nosocomial outbreaks, even when vaccine efficacy is imperfect. The broader utility of vaccine-based resistance control strategies should be further explored taking into account population structure, and the resistance and transmission patterns of the pathogen considered.     

Antifungal Drug Resistance: Clinical Relevance and Impact of Antifungal Drug Use

Antifungal drug resistance significantly impacts treatment outcomes in patients with invasive fungal infections (IFIs). Although primary (intrinsic) resistance may occur independent of previous therapy, prior concomitant antifungal exposure increases the risk for secondary (acquired) resistance and subsequent colonization or infection with less-susceptible pathogens. Among various pathogen-antifungal combinations, this effect has been best studied clinically with azole exposure and the risk of Candida spp. with reduced susceptibility. The rapid development of secondary resistance to flucytosine in Candida spp. has limited its use as monotherapy. Secondary resistance to amphotericin B is infrequent. In contrast, secondary resistance in Aspergillus spp. is less of a concern. Recent reports of secondary resistance in patients receiving fluconazole for cryptococcal infections may justify susceptibility testing in the setting of prior therapy or treatment failure. Despite numerous patient-focused, drug-focused, and disease-focused strategies to improve treatment outcomes, clinical resistance (manifesting as treatment failures despite adequate antifungal therapy) continues to be problematic in patients with serious IFIs.     

Interfaces between bacterial and eukaryotic "neuroecology"

The sensory capacity of bacteria and macroalgae (seaweeds) is limited with respect to many modalities (visual, auditory) common in "higher" organisms such as animals. Thus, we expect that other modalities, such as chemical signaling and sensing, would play particularly important roles in their sensory ecology. Here, we discuss two examples of chemical signaling in bacteria and seaweeds: (1) the role of chemical defenses and quorum-sensing (QS) regulatory systems in bacterial colonization and infection of the red alga Delisea pulchra and their ecological consequences, and (2) the regulation of dispersal and differentiation by nitric oxide (NO) in bacterial biofilms. Consistent with the goals of neuroecology, in both cases, we investigate the links between specific signal-mediated molecular mechanisms, and ecological outcomes, for populations or assemblages of bacteria or seaweeds. We conclude by suggesting that because of the fundamental role played by chemical signaling in bacteria, bacterial systems, either by themselves or in interactions with other organisms, have much to offer for understanding general issues in neuroecology. Thus, further integration of microbiology with the biology of eukaryotes would seem warranted and is likely to prove illuminating.     

Enteric Bacterial Pathogens in Children with Diarrhea in Niger: Diversity and Antimicrobial Resistance

Background

Although rotavirus is the leading cause of severe diarrhea among children in sub-Saharan Africa, better knowledge of circulating enteric pathogenic bacteria and their antimicrobial resistance is crucial for prevention and treatment strategies.

Methodology/Principal Findings

As a part of rotavirus gastroenteritis surveillance in Maradi, Niger, we performed stool culture on a sub-population of children under 5 with moderate-to-severe diarrhea between April 2010 and March 2012. Campylobacter, Shigella and Salmonella were sought with conventional culture and biochemical methods. Shigella and Salmonella were serotyped by slide agglutination. Enteropathogenic Escherichia coli (EPEC) were screened by slide agglutination with EPEC O-typing antisera and confirmed by detection of virulence genes. Antimicrobial susceptibility was determined by disk diffusion. We enrolled 4020 children, including 230 with bloody diarrhea. At least one pathogenic bacterium was found in 28.0% of children with watery diarrhea and 42.2% with bloody diarrhea. Mixed infections were found in 10.3% of children. EPEC, Salmonella and Campylobacter spp. were similarly frequent in children with watery diarrhea (11.1%, 9.2% and 11.4% respectively) and Shigella spp. were the most frequent among children with bloody diarrhea (22.1%). The most frequent Shigella serogroup was S. flexneri (69/122, 56.5%). The most frequent Salmonella serotypes were Typhimurimum (71/355, 20.0%), Enteritidis (56/355, 15.8%) and Corvallis (46/355, 13.0%). The majority of putative EPEC isolates was confirmed to be EPEC (90/111, 81.1%). More than half of all Enterobacteriaceae were resistant to amoxicillin and co-trimoxazole. Around 13% (46/360) Salmonella exhibited an extended-spectrum beta-lactamase phenotype.

Conclusions

This study provides updated information on enteric bacteria diversity and antibiotic resistance in the Sahel region, where such data are scarce. Whether they are or not the causative agent of diarrhea, bacterial infections and their antibiotic resistance profiles should be closely monitored in countries like Niger where childhood malnutrition pre-disposes to severe and invasive infections.     

A Novel Interaction between Plant-Beneficial Rhizobacteria and Roots: Colonization Induces Corn Resistance against the Root Herbivore Diabrotica speciosa

A number of soil-borne microorganisms, such as mycorrhizal fungi and rhizobacteria, establish mutualistic interactions with plants, which can indirectly affect other organisms. Knowledge of the plant-mediated effects of mutualistic microorganisms is limited to aboveground insects, whereas there is little understanding of what role beneficial soil bacteria may play in plant defense against root herbivory. Here, we establish that colonization by the beneficial rhizobacterium Azospirillum brasilense affects the host selection and performance of the insect Diabrotica speciosa. Root larvae preferentially orient toward the roots of non-inoculated plants versus inoculated roots and gain less weight when feeding on inoculated plants. As inoculation by A. brasilense induces higher emissions of (E)-β-caryophyllene compared with non-inoculated plants, it is plausible that the non-preference of D. speciosa for inoculated plants is related to this sesquiterpene, which is well known to mediate belowground insect-plant interactions. To the best of our knowledge, this is the first study showing that a beneficial rhizobacterium inoculant indirectly alters belowground plant-insect interactions. The role of A. brasilense as part of an integrative pest management (IPM) program for the protection of corn against the South American corn rootworm, D. speciosa, is considered.     

The DIOS framework for optimizing infectious disease surveillance: Numerical methods for simulation and multi-objective optimization of surveillance network architectures

Infectious disease surveillance systems provide vital data for guiding disease prevention and control policies, yet the formalization of methods to optimize surveillance networks has largely been overlooked. Decisions surrounding surveillance design parameters—such as the number and placement of surveillance sites, target populations, and case definitions—are often determined by expert opinion or deference to operational considerations, without formal analysis of the influence of design parameters on surveillance objectives. Here we propose a simulation framework to guide evidence-based surveillance network design to better achieve specific surveillance goals with limited resources. We define evidence-based surveillance design as an optimization problem, acknowledging the many operational constraints under which surveillance systems operate, the many dimensions of surveillance system design, the multiple and competing goals of surveillance, and the complex and dynamic nature of disease systems. We describe an analytical framework—the Disease Surveillance Informatics Optimization and Simulation (DIOS) framework—for the identification of optimal surveillance designs through mathematical representations of disease and surveillance processes, definition of objective functions, and numerical optimization. We then apply the framework to the problem of selecting candidate sites to expand an existing surveillance network under alternative objectives of: (1) improving spatial prediction of disease prevalence at unmonitored sites; or (2) estimating the observed effect of a risk factor on disease. Results of this demonstration illustrate how optimal designs are sensitive to both surveillance goals and the underlying spatial pattern of the target disease. The findings affirm the value of designing surveillance systems through quantitative and adaptive analysis of network characteristics and performance. The framework can be applied to the design of surveillance systems tailored to setting-specific disease transmission dynamics and surveillance needs, and can yield improved understanding of tradeoffs between network architectures.     

Resistance of various strains of mycobacteria to killing by activated macrophages in vivo

A variety of experimental infections with pathogenic mycobacteria are associated with the development of persistent disease, in which little or no changes in the numbers of the infectious organism can be detected. This report describes a simple experimental model designed to test the hypothesis that this persistence may reflect in part the ability of these organisms to resist the enhanced bacteriostatic and bactericidal properties acquired by host macrophages as a result of these mycobacterial infections. To examine this possibility mice were inoculated with test organisms at a time when these animals were expressing very high levels of nonspecific resistance, and hence macrophage activation, as a result of a prior intravenous infection with Mycobacterium bovis bacillus Calmette-Guerin (BCG). The results show that the test organisms fall into three groups; (a) those, such as Mycobacterium tuberculosis, which were sensitive to the presence of activated macrophages, (b) those, such as Mycobacterium avium and Mycobacterium kansasii, which were insensitive, and (c) one organism, Mycobacterium intracellulare, in which progressive growth of the infection was significantly improved. These results are consistent with the hypothesis that some mycobacteria, particularly those associated with persistent disease, possess an intrinsic resistance to host bactericidal and bacteriostatic mechanisms in vivo.     

The Feasibility of Canine Rabies Elimination in Africa: Dispelling Doubts with Data

Background

Canine rabies causes many thousands of human deaths every year in Africa, and continues to increase throughout much of the continent.

Methodology/Principal Findings

This paper identifies four common reasons given for the lack of effective canine rabies control in Africa: (a) a low priority given for disease control as a result of lack of awareness of the rabies burden; (b) epidemiological constraints such as uncertainties about the required levels of vaccination coverage and the possibility of sustained cycles of infection in wildlife; (c) operational constraints including accessibility of dogs for vaccination and insufficient knowledge of dog population sizes for planning of vaccination campaigns; and (d) limited resources for implementation of rabies surveillance and control. We address each of these issues in turn, presenting data from field studies and modelling approaches used in Tanzania, including burden of disease evaluations, detailed epidemiological studies, operational data from vaccination campaigns in different demographic and ecological settings, and economic analyses of the cost-effectiveness of dog vaccination for human rabies prevention.

Conclusions/Significance

We conclude that there are no insurmountable problems to canine rabies control in most of Africa; that elimination of canine rabies is epidemiologically and practically feasible through mass vaccination of domestic dogs; and that domestic dog vaccination provides a cost-effective approach to the prevention and elimination of human rabies deaths.     

Thematic review series: skin lipids. Antimicrobial lipids at the skin surface

The skin surface represents our interface with the external environment, and as such, is our first line of defense against microbial colonization and infection. Lipids at the skin surface are thought to underlie at least part of an antimicrobial barrier. Some of these lipids are synthesized in the epidermis and are carried to the surface as cells differentiate, whereas others are secreted onto the surface from the sebaceous glands. One such group, free sphingoid bases, are known to have broad antimicrobial activity, and our previous studies demonstrate their presence at the skin surface. Free sphingoid bases may be generated by enzymatic hydrolysis of epidermal ceramides. In addition, our preliminary results demonstrate potent antibacterial activity associated with two specific fatty acids derived from sebaceous triglycerides. Most remarkably, one of these fatty acids (sapienic acid, C16:1Delta6), in combination with a low concentration of ethanol, is very effective against methicillin-resistant Staphylococcus aureus (MRSA). In fact, this combination was far more effective than mupirocin with or without ethanol. Mupirocin is a "gold standard" for activity against MRSA.