Epidemiology, impact and control of rabies in Nepal : a systematic review

Background: Rabies is a vaccine-preventable viral zoonosis belonging to the group of neglected tropical diseases. Exposure to a rabid animal may result in a fatal acute encephalitis if effective post-exposure prophylaxis is not provided. Rabies occurs worldwide, but its burden is disproportionately high in developing countries, including Nepal. We aimed to summarize current knowledge on the epidemiology, impact and control of rabies in Nepal. Methods: We performed a systematic review of international and national scientific literature and searched grey literature through the World Health Organization Digital Library and the library of the National Zoonoses and Food Hygiene Research Centre, Nepal, and through searching Google and Google Scholar. Further data on animal and human rabies were obtained from the relevant Nepalese government agencies. Finally, we surveyed the archives of a Nepalese daily to obtain qualitative information on rabies in Nepal. Findings: So far, only little original research has been conducted on the epidemiology and impact of rabies in Nepal. Per year, rabies is reported to kill about 100 livestock and 10–100 humans, while about 1,000 livestock and 35,000 humans are reported to receive rabies post-exposure prophylaxis. However, these estimates are very likely to be serious underestimations of the true rabies burden. Significant progress has been made in the production of cell culture-based anti-rabies vaccine and rabies immunoglobulin, but availability and supply remain a matter of concern, especially in remote areas. Different state and non-state actors have initiated rabies control activities over the years, but efforts typically remained focalized, of short duration and not harmonized. Communication and coordination between veterinary and human health authorities is limited at present, further complicating rabies control in Nepal. Important research gaps include the reporting biases for both human and animal rabies, the ecology of stray dog populations and the true contribution of the sylvatic cycle. Interpretation: Better data are needed to unravel the true burden of animal and human rabies. More collaboration, both within the country and within the region, is needed to control rabies. To achieve these goals, high level political commitment is essential. We therefore propose to make rabies the model zoonosis for successful control in Nepal

Ecological drivers of gut microbiome and antimicrobial resistance in swine

Doctor of PhilosophyDepartment of Diagnostic Medicine/PathobiologyTiruvoor G. NagarajaVictoriya VolkovaThe pig gastrointestinal tract hosts a large and diverse microbial community, representing a complex and dynamic ecosystem. The microbial communities are not uniformly distributed and differ across the locations of the gastrointestinal tract. The microbial community composition influences the prevalence and distribution of antimicrobial resistance (AMR) in the gut. The microbial taxonomic composition, richness, and diversity are influenced by age of the pig, dietary composition, and antimicrobial drug use. The association between antimicrobial use and AMR development is of interest because of public health implications. Several studies in swine and cattle have reported a decrease in AMR in fecal bacteria with animal age; however, exact dynamics and contributing factors are largely unknown. Investigations on the AMR dynamics in gut microbiome during the production phase of food animals could aid in the design of a framework to address the problem of AMR in the food chain in a sustainable manner. The primary hypothesis of our study was that the dynamics of gut microbiome and AMR in swine are largely a function of age and dietary composition. Therefore, the objectives of the studies were: 1. Perform a scoping review of the literature on the age-dependence of AMR of fecal bacteria in food animals. 2. Conduct longitudinal studies to evaluate the dynamics of fecal bacteriome and mycobiome taxonomic compositions and AMR prevalence between cohorts of production pigs (n=12) from birth to harvest and breeding sows (two cohorts, n=6 and n=12) from 3 weeks through first farrowing and weaning, to test the hypothesis that the dynamics are a function of age, rather than the production system. 3. Investigate interactions between the age-related dynamics and effects of diet (levels and sources of fiber) and antimicrobial treatments (injectable ceftiofur or penicillin G) in influencing the fecal microbiome taxonomic composition and AMR in finisher pigs. 4. Conduct a study to describe bacterial community composition associated with luminal contents and mucosal epithelium from different segments of the gut of piglets. Culture-based and metagenomic analyses coupled with statistical modeling were utilized to monitor microbiome changes and estimate and infer AMR occurrence in gut bacterial communities in relation to age and diet. The scoping review of published data suggested that the animal-level prevalence and within-animal abundance of AMR in enteric or fecal bacteria decreased with age during the production life-span in pigs, in beef and dairy cattle. The age-dependent dynamics of fecal bacteriome and mycobiome taxonomic compositions and associated animal-level prevalence and within-animal abundance of AMR were similar in a cohort of production pigs and two cohorts of breeding sows. The highest AMR prevalence and abundance occurred at the youngest age-points and decreased with age and stabilized around 5 to 6 months of age. The data suggested a strong age-dependence and additional independent diet effects on the fecal microbiome composition and AMR. Data also showed that the concentrations of ceftiofur metabolites in swine feces were lower on day 3 compared to day 1 of the 3-day ceftiofur treatment, irrespective of the animal diet or gender. In a study conducted in piglets (6-7 weeks old: n=3), luminal contents and mucosa were collected from the stomach, duodenum, ileum (at two locations), cecum, spiral colon, and the rectum. The bacterial community composition and AMR genes were determined, and the study showed that the bacterial taxonomic composition and AMR gene repertoire changed throughout the gastrointestinal tract of piglets. Genes encoding bacterial resistance or reduced susceptibility to tetracyclines, β-lactams, aminoglycosides, and glycopeptides were most abundant AMR genes in the samples. In summary, age and diet, in addition to the use of antimicrobials, play an important role in the establishment and maintenance of gut microbial diversity and AMR in pigs

Variation in fluoroquinolone pharmacodynamic parameter values among isolates of two bacterial pathogens of bovine respiratory disease

To design an antimicrobial treatment regimen for a bacterial disease, data on the drug pharmacodynamics (PD) against selected drug-susceptible strains of the pathogen are used. The regimen is applied across such strains in the field, assuming the PD parameter values remain the same. We used time-kill experiments and PD modeling to investigate the fluoroquinolone enrofloxacin PD against different isolates of two bovine respiratory disease pathogens: four Mannheimia haemolytica and three Pasteurella multocida isolates. The models were fitted as mixed-effects non-linear regression; the fixed-effects PD parameter values were estimated after accounting for random variation among experimental replicates. There was both inter- and intra- bacterial species variability in the PD parameters Hill-coefficient and Emax (maximal decline of bacterial growth rate), with more variable PD responses among M. haemolytica than among P. multocida isolates. Moreover, the Hill-coefficient was correlated to the isolate's maximal population growth rate in the absence of antimicrobial exposure (a.k.a. specific growth rate; Spearman's ρ = 0.98, p-value = 0.003, n = 6 isolates excluding one outlier). Thus, the strain's properties such as growth potential may impact its PD responses. This variability can have clinical implications. Modifying the treatment regimen depending on phenotypic properties of the pathogen strain causing disease may be a precision medicine approach

Number of rabies outbreaks reported during 2005–2014 to the Veterinary Epidemiology Center of the Directorate of Animal Health, Department of Livestock Services, Ministry of Agricultural Development.

<p>See <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004461#pntd.0004461.s004" target="_blank">S4 File</a> for raw data and abbreviations.</p

Estimated mean number of rabies deaths in Global Burden of Disease studies.

<p>WHO: World Health Organization Global Health Estimates [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004461#pntd.0004461.ref051" target="_blank">51</a>]; GBD2010: Global Burden of Disease 2010 Study [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004461#pntd.0004461.ref052" target="_blank">52</a>]; GBD2013: Global Burden of Disease 2013 Study [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004461#pntd.0004461.ref053" target="_blank">53</a>].</p

Animal rabies cases and number of vaccinated animals during 2005–2014, as reported to the Veterinary Epidemiology Center of the Directorate of Animal Health, Department of Livestock Services, Ministry of Agricultural Development.

<p>Animal rabies cases and number of vaccinated animals during 2005–2014, as reported to the Veterinary Epidemiology Center of the Directorate of Animal Health, Department of Livestock Services, Ministry of Agricultural Development.</p

Median number of dog bites reported during 2004–2013 to the Department of Health Services, Ministry of Health and Population.

<p>See <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004461#pntd.0004461.s004" target="_blank">S4 File</a> for raw data and abbreviations.</p

Flow diagram of systematic review.

<p>Flow diagram of systematic review.</p