Heterogeneity in enterotoxigenic Escherichia coli and shigella infections in children under 5 years of age from 11 African countries: a subnational approach quantifying risk, mortality, morbidity, and stunting.

BACKGROUND: Diarrhoea, a global cause of child mortality and morbidity, is linked to adverse consequences including childhood stunting and death from other diseases. Few studies explore how diarrhoeal mortality varies subnationally, especially by cause, which is important for targeting investments. Even fewer examine indirect effects of diarrhoeal morbidity on child mortality. We estimated the subnational distribution of mortality, morbidity, and childhood stunting attributable to enterotoxigenic Escherichia coli (ETEC) and shigella infection in children younger than 5 years from 11 eastern and central African countries. These pathogens are leading causes of diarrhoea in young children and have been linked to increased childhood stunting. METHODS: We combined proxy indicators of morbidity and mortality risk from the most recent Demographic and Health Surveys with published relative risks to estimate the potential distribution of diarrhoeal disease risk. To estimate subnational burden, we used country-specific or WHO region-specific morbidity and mortality estimates and distributed them subnationally by three indices that integrate relevant individual characteristics (ie, underweight, probability of receiving oral rehydration treatment of diarrhoea, and receiving vitamin A supplementation) and household characteristics (ie, type of drinking water and sanitation facilities). FINDINGS: Characterising ETEC and shigella subnational estimates of indirect morbidity (infection-attributable stunting) and indirect mortality (stunting-related deaths from other infectious diseases) identified high-risk areas that could be missed by traditional metrics. Burundi and Democratic Republic of the Congo had the highest ETEC-associated and shigella-associated mortality and stunting rates. Mozambique, Democratic Republic of the Congo, and Zimbabwe had the greatest subnational heterogeneity in most ETEC and shigella mortality measures. Inclusion of indirect ETEC and shigella mortality in burden estimates resulted in a 20-30% increase in total ETEC and shigella mortality rates in some subnational areas. INTERPRETATION: Understanding the indirect mortality and morbidity of diarrhoeal pathogens on a subnational level will strengthen disease control strategies and could have important implications for the relative impact and cost-effectiveness of new enteric vaccines. Because our methods rely on publicly available data, they could be employed for national planning. FUNDING: Bill & Melinda Gates Foundation.

Vaccination With Mouse Dendritic Cells Loaded With an IpaD-IpaB Fusion Provides Protection Against Shigellosis.

Diarrheal diseases are a major cause of morbidity and mortality worldwide. They are most prevalent in settings with inadequate sanitation, poor hygiene and contaminated water. An important diarrheal pathogen in such settings is Shigella. No commercially available vaccine exists against shigellosis and immunity to the pathogen is serotype-restricted. We have previously shown that a polypeptide fusion of the Type Three Secretion Apparatus (T3SA) proteins IpaB and IpaD (named DBF) was efficacious as a vaccine against Shigella. Vaccination using different administration routes indicated that protection conferred by DBF did not fully correlate with antibodies. To define the immune responses involved in protection, we studied cellular responses to intranasal immunization with the DBF and the adjuvant dmLT. We found dendritic cell (DC) activation at the nasal associated lymphoid tissue (NALT). Activation markers CD86 and MHCII significantly increase in cells from immunized mice. Antigen exposure in vitro further confirmed the upregulation of CD80 and CD40 in primary dendritic cells. Animals immunized with antigen-primed dendritic cells were protected against Shigella infection, at levels comparable to the efficacy of immunization with the protein vaccine formulation. Therefore, we show that antigen-primed DCs are enough to provide immunity, and propose a mechanism of protection against Shigella spp. based on DC-mediated antigen presentation to T cells.

Capturing the true burden of Shigella and ETEC: The way forward.

The mortality and morbidity burden estimation of diarrheal diseases (DD), and Shigella and Enterotoxigenic E. Coli (ETEC) varies among different studies and by the models used for producing these estimates. Understanding the real burden of these important pathogens will guide public health and policy makers to prioritize resources for accelerating interventions against these enteric infections. In addition, long term effects, in the form of growth faltering, cognitive impairment and decreased school performance are important aspects of burden that has not been well captured. Efforts to incorporate these effects and refine their estimation, in the form of Disability Adjusted Life years (DALYs) are very important to inform the burden of diarrheal diseases and Shigella and ETEC specifically. The Institute for Health Metrics and Evaluation (IHME) at the University of Washington conducted a workshop at the VASE 2018 meeting to discuss IHME Global Burden of Diseases (GBD) modelling methods for diarrheal diseases, with a focus on ETEC and Shigella estimates in relation to other pathogens, including limitations, areas of improvements, and IHME plans for future GBD iterations.

Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the Global Burden of Disease Study 1990-2016.

BACKGROUND: Shigella and enterotoxigenic Escherichia coli (ETEC) are bacterial pathogens that are frequently associated with diarrhoeal disease, and are a significant cause of mortality and morbidity worldwide. The Global Burden of Diseases, Injuries, and Risk Factors study 2016 (GBD 2016) is a systematic, scientific effort to quantify the morbidity and mortality due to over 300 causes of death and disability. We aimed to analyse the global burden of shigella and ETEC diarrhoea according to age, sex, geography, and year from 1990 to 2016. METHODS: We modelled shigella and ETEC-related mortality using a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We used a compartmental meta-regression tool to model the incidence of shigella and ETEC, which enforces an association between incidence, prevalence, and remission on the basis of scientific literature, population representative surveys, and health-care data. We calculated 95% uncertainty intervals (UIs) for the point estimates. FINDINGS: Shigella was the second leading cause of diarrhoeal mortality in 2016 among all ages, accounting for 212 438 deaths (95% UI 136 979-326 913) and about 13·2% (9·2-17·4) of all diarrhoea deaths. Shigella was responsible for 63 713 deaths (41 191-93 611) among children younger than 5 years and was frequently associated with diarrhoea across all adult age groups, increasing in elderly people, with broad geographical distribution. ETEC was the eighth leading cause of diarrhoea mortality in 2016 among all age groups, accounting for 51 186 deaths (26 757-83 064) and about 3·2% (1·8-4·7) of diarrhoea deaths. ETEC was responsible for about 4·2% (2·2-6·8) of diarrhoea deaths in children younger than 5 years. INTERPRETATION: The health burden of bacterial diarrhoeal pathogens is difficult to estimate. Despite existing prevention and treatment options, they remain a major cause of morbidity and mortality globally. Additional emphasis by public health officials is needed on a reduction in disease due to shigella and ETEC to reduce disease burden. FUNDING: Bill & Melinda Gates Foundation.

Prediction of Shigellosis outcomes in Israel using machine learning classifiers.

Shigellosis causes significant morbidity and mortality in developing and developed countries, mostly among infants and young children. The World Health Organization estimates that more than one million people die from Shigellosis every year. In order to evaluate trends in Shigellosis in Israel in the years 2002-2015, we analysed national notifiable disease reporting data. Shigella sonnei was the most commonly identified Shigella species in Israel. Hospitalisation rates due to Shigella flexenri were higher in comparison with other Shigella species. Shigella morbidity was higher among infants and young children (age 0-5 years old). Incidence of Shigella species differed among various ethnic groups, with significantly high rates of S. flexenri among Muslims, in comparison with Jews, Druze and Christians. In order to improve the current Shigellosis clinical diagnosis, we developed machine learning algorithms to predict the Shigella species and whether a patient will be hospitalised or not, based on available demographic and clinical data. The algorithms' performances yielded an accuracy of 93.2% (Shigella species) and 94.9% (hospitalisation) and may consequently improve the diagnosis and treatment of the disease.

Antibiotic resistance and molecular characterization of shigella isolates recovered from children aged less than 5 years in Manhiça, Southern Mozambique.

The objective of this study was to assess antibiotic resistance and the molecular epidemiology of shigella isolates from a case-control study of diarrhoea, conducted from 2007 to 2012 in children aged less than 5 years in Manhiça district, southern Mozambique. All isolates were tested for antimicrobial susceptibility using the disc diffusion method. Polymerase chain reaction was used to detect different molecular mechanisms of antibiotic resistance. Serotyping was performed using specific antisera. The clonal relationship of Shigella flexneri and Shigella sonnei was assessed by pulsed-field gel electrophoresis (PFGE). Of the 67 shigella isolates analysed, 59 were diarrhoeal cases and eight were controls. S. flexneri (70.1%; 47/67) was the most common species, followed by S. sonnei (23.9%; 16/67). The most prevalent S. flexneri serotypes were 2a (38.3%; 18/47), 6 (19.2%; 9/47) and 1b (14.9%; 7/47). High rates of antimicrobial resistance were observed for trimethoprim-sulfametoxazole (92.5%; 62/67), tetracycline (68.7%; 46/67), chloramphenicol (53.7%; 36/67) and ampicillin (50.7%; 34/67). Multi-drug resistance (MDR) was present in 55.2% (37/67) of the isolates and was associated with a case fatality rate of 8.1% (3/37). PFGE revealed 22 clones (16 S. flexneri and 6 S. sonnei), among which P1 (31.9%; 15/47), P9 (17%; 8/47) and P2 (10.6%; 5/47) were the most prevalent clones of S. flexneri. In conclusion, S. flexneri was the most prevalent species, with MDR isolates mainly belonging to three specific clones (P1, P9 and P2). The case fatality rate observed among MDR isolates is a matter of concern, indicating the need for appropriate treatment.

Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis.

BACKGROUND: Shigella infections are a leading cause of diarrhoeal death among children in low-income and middle-income countries. WHO guidelines reserve antibiotics for treating children with dysentery. Reliance on dysentery for identification and management of Shigella infection might miss an opportunity to reduce Shigella-associated morbidity and mortality. We aimed to systematically review and evaluate Shigella-associated and dysentery-associated mortality, the diagnostic value of dysentery for the identification of Shigella infection, and the efficacy of antibiotics for children with Shigella or dysentery, or both. METHODS: We did three systematic reviews (for mortality, diagnostic value, and antibiotic treatment of Shigella and dysentery), and meta-analyses where appropriate, of studies in resource-limited settings. We searched MEDLINE, Embase, and LILACS database for studies published before Jan 1, 2017, in English, French, and Spanish. We included studies of human beings with diarrhoea and accepted all study-specific definitions of dysentery. For the mortality and diagnostic value searches, we excluded studies that did not include an effect estimate or data necessary to calculate this estimate. The search for treatment included only randomised controlled trials that were done after Jan 1, 1980, and assessed antibiotics in children (aged <18 years) with dysentery or laboratory-confirmed Shigella. We extracted or calculated odds ratios (ORs) and 95% CIs for relative mortality and did random-effects meta-analysis to arrive at pooled ORs. We calculated 95% CIs assuming a binomial distribution and did random-effects meta-regression of log-transformed sensitivity and specificity estimates for diagnostic value. We assessed the heterogeneity of papers included in these meta-analyses using the I2 statistic and evaluated publication bias using funnel plots. This review is registered with PROSPERO (CRD42017063896). FINDINGS: 3649 papers were identified and 60 studies were included for analyses: 13 for mortality, 27 for diagnostic value, and 20 for treatment. Shigella infection was associated with mortality (pooled OR 2·8, 95% CI 1·6-4·8; p=0·000) whereas dysentery was not associated with mortality (1·3, 0·7-2·3; p=0·37). Between 1977 and 2016, dysentery identified 1·9-85·9% of confirmed Shigella infections, with sensitivity decreasing over time (p=0·04). Ten (50%) of 20 included antibiotic trials were among children with dysentery, none were placebo-controlled, and two (10%) evaluated antibiotics no longer recommended for acute infectious diarrhoea. Ciprofloxacin showed superior microbiological, but not clinical, effectiveness compared with pivmecillinam, and no superior microbiological and clinical effectiveness compared with gatifloxacin. Substantial heterogeneity was reported for meta-analyses of the Shigella-associated mortality studies (I2=78·3%) and dysentery-associated mortality studies (I2=73·2%). Too few mortality studies were identified to meaningfully test for publication bias. No evidence of publication bias was found in this analysis of studies of diagnostic value. INTERPRETATION: Current WHO guidelines appear to manage dysentery effectively, but might miss opportunities to reduce mortality among children infected with Shigella who present without bloody stool. Further studies should quantify potential decreases in mortality and morbidity associated with antibiotic therapy for children with non-dysenteric Shigella infection. FUNDING: Bill & Melinda Gates Foundation and the Center for AIDS Research International Core.

Risk factors and outcome of Shigella encephalopathy in Bangladeshi children.

BACKGROUND: Although, Shigella encephalopathy, a serious extra-intestinal complication of shigellosis, significantly increases the risks of death, data are very limited on predicting factors particularly related to electrolyte profiles in children below five years of age with Shigella encephalopathy. Our objective was to determine the clinical as well as laboratory predicting factors and outcome of children with Shigella encephalopathy. METHODOLOGY/PRINCIPAL FINDINGS: In this unmatched case-control design, children aged 2-59 months having a positive stool culture for Shigella and who had their serum electrolytes been done from July 2012 to June 2015 were studied. Children with Shigella encephalopathy, defined as having abnormal mentation, constituted the cases, and those without encephalopathy constituted the controls. During the study period, we identified a total of 541 children less than five years of age, who had Shigella in their stool culture. Only 139 children fulfilled the study criteria and among them 69 were cases and 70 were controls. The cases more often had fatal outcome compared to the controls (7% vs. 0%, P = 0.02). In logistic regression analysis, the cases were independently associated with shorter duration (1.2 ± 0.4 days) of diarrhea prior to admission, dehydrating diarrhea, sepsis and hyponatremia (p<0.05 for all). Among 139 Shigella isolates, S. flexneri (88/139, 63%) and S. sonnei(34/139, 24%) were the dominant species. S. dysenteriae was not isolated throughout the study period. S.sonnei was more frequently isolated from the cases (24/69, 35%) than the controls (10/70, 14%), whereas the isolation of S. flexneri was comparable between the groups (40/69, 58% vs 48/70, 69%). A total of 94 (67.6%) isolates were resistant to trimethoprim-sulphamethoxazole, 84 (60.4%) to ciprofloxacin, 66/138 (48%) to ampicillin, 5 (3.5%) to ceftriaxone, 17 (12.2%) to mecillinum and 35 (25%) to azithromycin. CONCLUSIONS/SIGNIFICANCE: The case-fatality-rate was significantly higher among the children with Shigella encephalopathy compared to those without encephalopathy. Early identification and aggressive management of simple risk factors for Shigella encephalopathy may help to reduce morbidity and deaths in such children especially in resource-limited settings.

Lethality of First Contact Dysentery Epidemics on Pacific Islands.

Infectious diseases depopulated many isolated Pacific islands when they were first exposed to global pathogen circulation from the 18th century. Although the mortality was great, the lack of medical observers makes determination of what happened during these historical epidemics largely speculative. Bacillary dysentery caused by Shigella is the most likely infection causing some of the most lethal island epidemics. The fragmentary historical record is reviewed to gain insight into the possible causes of the extreme lethality that was observed during first-contact epidemics in the Pacific. Immune aspects of the early dysentery epidemics and postmeasles infection resulting in subacute inflammatory enteric disease suggest that epidemiologic isolation was the major lethality risk factor on Pacific islands in the 19th century. Other possible risk factors include human leukocyte antigen homogeneity from a founder effect and pathogen-induced derangement of immune tolerance to gut flora. If this analysis is correct, then Pacific islands are currently at no greater risk of emerging disease epidemics than other developing countries despite their dark history.

Aetiology-Specific Estimates of the Global and Regional Incidence and Mortality of Diarrhoeal Diseases Commonly Transmitted through Food.

BACKGROUND: Diarrhoeal diseases are major contributors to the global burden of disease, particularly in children. However, comprehensive estimates of the incidence and mortality due to specific aetiologies of diarrhoeal diseases are not available. The objective of this study is to provide estimates of the global and regional incidence and mortality of diarrhoeal diseases caused by nine pathogens that are commonly transmitted through foods. METHODS AND FINDINGS: We abstracted data from systematic reviews and, depending on the overall mortality rates of the country, applied either a national incidence estimate approach or a modified Child Health Epidemiology Reference Group (CHERG) approach to estimate the aetiology-specific incidence and mortality of diarrhoeal diseases, by age and region. The nine diarrhoeal diseases assessed caused an estimated 1.8 billion (95% uncertainty interval [UI] 1.1-3.3 billion) cases and 599,000 (95% UI 472,000-802,000) deaths worldwide in 2010. The largest number of cases were caused by norovirus (677 million; 95% UI 468-1,153 million), enterotoxigenic Escherichia coli (ETEC) (233 million; 95% UI 154-380 million), Shigella spp. (188 million; 95% UI 94-379 million) and Giardia lamblia (179 million; 95% UI 125-263); the largest number of deaths were caused by norovirus (213,515; 95% UI 171,783-266,561), enteropathogenic E. coli (121,455; 95% UI 103,657-143,348), ETEC (73,041; 95% UI 55,474-96,984) and Shigella (64,993; 95% UI 48,966-92,357). There were marked regional differences in incidence and mortality for these nine diseases. Nearly 40% of cases and 43% of deaths caused by these nine diarrhoeal diseases occurred in children under five years of age. CONCLUSIONS: Diarrhoeal diseases caused by these nine pathogens are responsible for a large disease burden, particularly in children. These aetiology-specific burden estimates can inform efforts to reduce diarrhoeal diseases caused by these nine pathogens commonly transmitted through foods.

Análisis del patrón epidemiológico de la shigelosis en Barcelona entre 1988 y 2012: ¿es una infección de transmisión sexual emergente? / Analysis of the epidemiological pattern of Shigellosis in Barcelona between 1988 and 2012: is it an emerging sexually transmitted infection?

INTRODUCCIÓN: El objetivo de este estudio fue describir la evolución y las características epidemiológicas de los pacientes con shigelosis durante 25 años en una gran ciudad. MÉTODOS: La shigelosis es una enfermedad de declaración obligatoria en España desde 1988. Se analizan los casos de residentes en Barcelona incluidos en el registro entre 1988-2012. Se presenta un análisis descriptivo según sexo, edad, vía de transmisión y especies de Shigella. Se realizó un análisis de tendencias y de series temporales. RESULTADOS: De los 559 casos analizados, el 60,15% correspondían a hombres. Se observó un incremento sostenido de la tendencia en hombres desde 2008 (p < 0,05), sobre todo a expensas de los de hombres que no tenían antecedentes de toXIInfección alimentaria ni de viajes a zonas endémicas. El incremento de la tendencia fue mayor en hombres de 21 a 60 años, tanto para S. flexneri (desde 2009) como para S. sonnei (desde 2003). En 2012 se observó que, en los hombres con S. flexneri, el 63% tenían sexo con hombres. CONCLUSIONES: Se detectó un incremento de la tendencia en los casos en hombres que no tenían antecedentes de toXIInfección alimentaria ni de viajes a zonas endémicas. Este incremento apunta a un cambio en el patrón de la shigelosis, pasando a ser predominantemente masculina, y cuyo mecanismo principal serían las relaciones sexuales

INTRODUCTION: The aim of the study was to analyze the incidence, management and cost associated to hematological and dermatological adverse effects (AE) in chronic hepatitis C patients on triple therapy (TT) with telaprevir (TVR) or boceprevir (BOC). METHODS: An analysis was made on the data recorded on patients who started treatment with TVR or BOC associated with peginterferon alfa and ribavirin in a 12-week follow-up period. RESULTS: Fifty-three patients were included (TVR n = 36; BOC n = 17). Thrombocytopenia (83% TVR vs. 88% BOC) followed by neutropenia (89% TVR vs. 82% BOC) were the most common AE. Dermatological AE were observed in 32% of patients. Eleven patients required treatment discontinuation (all of them received TVR), and toxicity was the main reason for discontinuation (64%). The percentage of patients who required supportive treatment for management of AE was 66%. The most used supportive treatment was erythropoietin. Eight patients required emergency health care, and 2 were hospitalized due to AE. Total cost of additional supportive resources was 32,522 Euros (625 [SD = 876] Euros/patient) (TVR 759 [SD = 1,022] Euros/patient vs. BOC 349 [SD = 327] Euros/patient; P > .05). Patients with grade iii-iv toxicity required greater supportive care with higher costs, compared to patients with grade i-ii toxicity (849 [SD = 1,143] Euros/patient vs. 387 [SD = 397] Euros/patient; P = .053). CONCLUSION: The addition of new protease inhibitors to conventional treatment leads to a higher incidence of hematological AE in our study, compared to data described in clinical trials. The elevated incidence of AE involves the use of supportive care, increasing total costs of therapy

Estimating diarrheal illness and deaths attributable to Shigellae and enterotoxigenic Escherichia coli among older children, adolescents, and adults in South Asia and Africa.

INTRODUCTION: While Shigellae and strains of enterotoxigenic Escherichia coli (ETEC) are important causes of diarrhea-associated morbidity and mortality among infants and young children (<5 years of age), their health impact in older age groups is unclear. We sought to quantify the overall burden of shigellosis and ETEC diarrhea among older children, adolescents, and adults in Africa and South Asia, the two regions with the highest levels of diarrhea-related morbidity and mortality worldwide. METHODS: We employed two distinct methodological approaches to estimate the burden of diarrhea due to Shigellae and ETEC among persons ≥ 5 years of age in the WHO regions of South Asia (SEAR) and Africa (AFR). Under method 1, we conducted a systematic review to identify the median proportion of total deaths due to diarrhea and then applied this figure to the number of all-cause deaths that occurred in 2010 among this age group. To estimate the total number of diarrhea deaths attributable to Shigellae and ETEC, we subsequently applied previously published estimates of the median percentage of diarrhea hospitalizations due to Shigellae and ETEC to the estimated number of diarrhea deaths. For method 2, we applied previously published incidence rates to 2010 population figures and estimated the total number of episodes due to Shigellae and ETEC using published estimates of the average proportion of pathogen-positive outpatients from studies of >4 pathogens. We then estimated the number of pathogen-specific deaths by determining the number of hospitalized patients and applying the case-fatality rate. RESULTS: By method 1, there were 19,451 deaths due to Shigellae and 42,973 due to ETEC in AFR, and 20,691 due to Shigellae and 45,713 due to ETEC in SEAR in 2010. By method 2, there were 15.0 million ETEC episodes and 30.4 million episodes due to Shigellae in AFR, and 28.7 million episodes due to ETEC and 58.1 million episodes due to Shigellae in SEAR in 2010. We were unable to identify published case-fatality rates for ETEC and thus could only estimate Shigellae-related deaths using method 2, by which there were 5,308 and 10,158 Shigellae-related deaths in AFR and SEAR in 2010, respectively. DISCUSSION: Methods 1 and 2 underscore the importance of Shigellae and ETEC as major causes of morbidity and mortality among older children, adolescents, and adults in AFR and SEAR. Understanding the epidemiology of these pathogens is imperative for the development and use of future vaccines and other preventative interventions.

Towards a non-living vaccine against Shigella flexneri: from the inactivation procedure to protection studies.

Shigellosis is one of the leading causes of diarrhea worldwide with more than 165 million cases annually. Hence, a vaccine against this disease is a priority, but no licensed vaccine is still available. Considering target population as well as intrinsic risks of live attenuated vaccines, non-living strategies appear as the most promising candidates. Remarkably, the preservation of antigenic properties is a major concern since inactivation methods of bacteria affect these qualities. We previously reported the use of a subcellular antigen complex for vaccination against shigellosis, based on outer membrane vesicles (OMVs) released from Shigella flexneri. Now, we describe in more detail the employment of binary ethylenimine (BEI) for inactivation of Shigella and its subsequent effect on the antigenic conservation of the vaccinal product. Results demonstrate the effectiveness of BEI treatment to completely inactivate Shigella cells without disturbing the antigenicity and immunogenicity of the OMVs. Thus, OMVs harvested after BEI inactivation were able to protect mice against an experimental infection with S. flexneri.

Antibiotics for the treatment of Cholera, Shigella and Cryptosporidium in children.

BACKGROUND: Diarrhea is a major contributor to the burden of morbidity and mortality in children; it accounts for a median of 11% of all deaths among children aged less than 5 years, amounting to approximately 0.8 million deaths per year. Currently there is a dearth of literature exploring the effectiveness of antibiotics for diarrhea due to Cholera, Shigella and cryptosporidiosis in children. METHODS: We reviewed the literature reporting the effect of antibiotics for the treatment of diarrhea due to Cholera, Shigella and Cryptosporidium in children under five years. We used a standardized abstraction and grading format and performed meta-analyses to determine the effect of the treatment with various antibiotics on mortality and rates of clinical and bacteriological/parasitological failure. The CHERG Standard Rules were applied to determine the final effect of treatment with antibiotics on diarrhea morbidity and mortality. RESULTS: For Cholera; the evidence was weak to recommend any effect on mortality. For Shigella; there was no data on mortality; either all-cause or cause specific, hence we used clinical failure rates as a proxy for Shigella deaths and propose that treatment of Shigella dysentery with antibiotics can result in a 82% reduction in diarrhea mortality due to Shigella. For cryptosporidiosis; there was data on all-cause mortality but the evidence was weak hence we used clinical failure rates as a proxy for mortality to estimate that antimicrobial treatment of diarrhea due to cryptosporidiosis can result in a 54% reduction in mortality. CONCLUSIONS: There is evidence to recommend antibiotic use for reduction of morbidity and mortality due to Cholera, Shigella and Cryptosporidium. We recommend that more clinical trials should be conducted to evaluate the efficacy and safety of first- and second- line drugs currently in use for treatment for diarrhea and dysentery in both developing and developed countries.

Mucosal immunization with Shigella flexneri outer membrane vesicles induced protection in mice.

Vaccination appears to be the only rational prophylactic approach to control shigellosis. Unfortunately, there is still no safe and efficacious vaccine available. We investigated the protection conferred by a new vaccine containing outer membrane vesicles (OMVs) from Shigella flexneri with an adjuvant based on nanoparticles in an experimental model of shigellosis in mice. OMVs were encapsulated in poly(anhydride) nanoparticles prepared by a solvent displacement method with the copolymer PMV/MA. OMVs loaded into NPs (NP-OMVs) were homogeneous and spherical in shape, with a size of 197nm (PdI=0.06). BALB/c mice (females, 9-week-old, 20±1g) were immunized by intradermal, nasal, ocular (20µg) or oral route (100µg) with free or encapsulated OMV. Thirty-five days after administration, mice were infected intranasally with a lethal dose of S. flexneri (1×10(7)CFU). The new vaccine was able to protect fully against infection when it was administered via mucosa. By intradermal route the NP-OMVs formulation increased the protection from 20%, obtained with free extract, to 100%. Interestingly, both OMVs and OMV-NP induced full protection when administered by the nasal and conjuntival route. A strong association between the ratio of IL-12p40/IL-10 and protection was found. Moreover, low levels of IFN-γ correlate with protection. Under the experimental conditions used, the adjuvant did not induce any adverse effects. These results place OMVs among promising candidates to be used for vaccination against Shigellosis.

Research progress in Shigella in the postgenomic era.

Gram-negative, facultative intracellular anaerobes of the genus Shigella, the principal etiologic agents of shigellosis, continue to pose a threat to public health. Shigellosis causes 1.1 million deaths with over 164 million annual cases. The Shigella spp. can be divided into four serogroups: Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei. The completion of seven Shigella genome sequences of representative strains from each of the Shigella species has introduced an era of whole-genome study. This paper reviews contemporary understanding of genomics, transcriptomics, proteomics and the structural biology of Shigella.

Decrease in shigellosis-related deaths without Shigella spp.-specific interventions, Asia.

In 1999, a review of the literature for 1966-1997 suggested that ≈1.1 million persons die annually of shigellosis, including ≈880,000 in Asia. Our recent review of the literature for 1990-2009 indicates that ≈125 million shigellosis cases occur annually in Asia, of which ≈14,000 are fatal. This estimate for illnesses is similar to the earlier estimate, but the number of deaths is 98% lower; that is, the lower estimate of deaths is associated with markedly reduced case-fatality rates rather than fewer cases. Shigella spp.-related deaths decreased substantially during a period without Shigella spp.-specific interventions. We speculate that nonspecific interventions, e.g., measles vaccination, vitamin A supplementation, and improved nutrition, may have led to the reduced number of shigellosis-related deaths.

Antibiotics for the treatment of dysentery in children.

BACKGROUND: Ciprofloxacin, ceftriaxone and pivmecillinam are the antibiotics currently recommended by the World Health Organization (WHO) for the treatment of dysentery in children; yet there have been no reviews of the clinical effectiveness of these antibiotics in recent years. METHODS: We reviewed all literature reporting the effect of ciprofloxacin, ceftriaxone and pivmecillinam for the treatment of dysentery in children in the developing countries. We used a standardized abstraction and grading format and performed meta-analyses to determine the effect of treatment with these antibiotics on rates of treatment failure, bacteriological failure and bacteriological relapse. The CHERG Standard Rules were applied to determine the final effect of treatment with these antibiotics on diarrhoea mortality. RESULTS: Eight papers were selected for abstraction. Treatment with ciprofloxacin, ceftriaxone or pivmecillinam resulted in a cure rate of >99% while assessing clinical failure, bacteriological failure and bacteriological relapse. CONCLUSIONS: The antibiotics recommended by the WHO--ciprofloxacin, ceftriaxone and pivmecillinam--are effective in reducing the clinical and bacteriological signs and symptoms of dysentery and thus can be expected to decrease diarrhoea mortality attributable to dysentery.