The clinical presentation of culture-positive and culture-negative, qPCR-attributable shigellosis in the Global Enteric Multicenter Study and derivation of a Shigella severity score: implications for pediatric Shigella vaccine trials

BACKGROUND: Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. METHODS: We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, qPCR-attributable Shigella (defined by an ipaH gene cycle threshold <27.9). Among Shigella MSD cases, we determined risk factors for death and derived a clinical severity score. RESULTS: Compared to culture-positive Shigella MSD cases (n=745), culture-negative/qPCR-attributable Shigella cases (n=852) were more likely to be under 12 months, stunted, have a longer duration of diarrhea, and less likely to have high stool frequency or a fever. There was no difference in dehydration, hospitalization, or severe classification from a modified Vesikari score. Twenty-two (1.8%) Shigella MSD cases died within the 14-days after presentation to health facilities, and 59.1% of these deaths were in culture-negative cases. Age < 12 months, diarrhea duration prior to presentation, vomiting, stunting, wasting, and hospitalization were associated with mortality. A model-derived score assigned points for dehydration, hospital admission, and longer diarrhea duration but was not significantly better at predicting 14-day mortality than a modified Vesikari score. CONCLUSIONS: A composite severity score consistent with severe disease or dysentery may be a pragmatic clinical endpoint for severe shigellosis in vaccine trials. Reliance on culture for microbiologic confirmation may miss a substantial number of Shigella cases but is currently required to measure serotype specific immunity

A double-blind placebo-controlled trial of azithromycin to reduce mortality and improve growth in high-risk young children with non-bloody diarrhoea in low resource settings: the Antibiotics for Children with Diarrhoea (ABCD) trial protocol

Background Acute diarrhoea is a common cause of illness and death among children in low- to middle-income settings. World Health Organization guidelines for the clinical management of acute watery diarrhoea in children focus on oral rehydration, supplemental zinc and feeding advice. Routine use of antibiotics is not recommended except when diarrhoea is bloody or cholera is suspected. Young children who are undernourished or have a dehydrating diarrhoea are more susceptible to death at 90 days after onset of diarrhoea. Given the mortality risk associated with diarrhoea in children with malnutrition or dehydrating diarrhoea, expanding the use of antibiotics for this subset of children could be an important intervention to reduce diarrhoea-associated mortality and morbidity. We designed the Antibiotics for Childhood Diarrhoea (ABCD) trial to test this intervention. Methods ABCD is a double-blind, randomised trial recruiting 11,500 children aged 2–23 months presenting with acute non-bloody diarrhoea who are dehydrated and/or undernourished (i.e. have a high risk for mortality). Enrolled children in Bangladesh, India, Kenya, Malawi, Mali, Pakistan and Tanzania are randomised (1:1) to oral azithromycin 10 mg/kg or placebo once daily for 3 days and followed-up for 180 days. Primary efficacy endpoints are all-cause mortality during the 180 days post-enrolment and change in linear growth 90 days post-enrolment. Discussion Expanding the treatment of acute watery diarrhoea in high-risk children to include an antibiotic may offer an opportunity to reduce deaths. These benefits may result from direct antimicrobial effects on pathogens or other incompletely understood mechanisms including improved nutrition, alterations in immune responsiveness or improved enteric function. The expansion of indications for antibiotic use raises concerns about the emergence of antimicrobial resistance both within treated children and the communities in which they live. ABCD will monitor antimicrobial resistance. The ABCD trial has important policy implications. If the trial shows significant benefits of azithromycin use, this may provide evidence to support reconsideration of antibiotic indications in the present World Health Organization diarrhoea management guidelines. Conversely, if there is no evidence of benefit, these results will support the current avoidance of antibiotics except in dysentery or cholera, thereby avoiding inappropriate use of antibiotics and reaffirming the current guidelines. Trial registration Clinicaltrials.gov, NCT03130114. Registered on April 26 2017

Three years after legalization of nonprescription pharmacy syringe sales in California: Where are we now?

In January 2005, passage of California Senate Bill 1159 enabled California’s county or city governments to establish disease prevention demonstration projects (DPDPs) through which pharmacies could subsequently register to legally sell up to 10 syringes to adults without a prescription. California’s 61 local health jurisdictions (LHJs) were surveyed annually in 2005–2007 to monitor the progress of DPDP implementation and assess program coverage, facilitators, and barriers. Completed surveys were returned by mail, fax, e-mail, phone, or internet. We analyzed 2007 survey data to describe current DPDP status; data from all years were analyzed for trends in approval and implementation status. By 2007, 17 (27.9%) LHJs approved DPDPs, of which 14 (82.4%) had registered 532 (17.8%) of the 2,987 pharmacies in these 14 LHJs. Although only three LHJs added DPDPs since 2006, the number of registered pharmacies increased 102% from 263 previously reported. Among the LHJs without approved DPDPs in 2007, one (2.3%) was in the approval process, seven (16.3%) planned to seek approval, and 35 (81.4%) reported no plans to seek approval. Of 35 LHJs not planning to seek approval, the top four reasons were: limited health department time (40%) or interest (34%), pharmacy disinterest (31%), and law enforcement opposition (26%). Among eight LHJs pursuing approval, the main barriers were “time management” (13%), educating stakeholders (13%), and enlisting pharmacy participation (13%). The17 LHJs with DPDP represent 52% of California’s residents; they included 62% of persons living with HIV and 59% of IDU-related HIV cases, suggesting that many LHJs with significant numbers of HIV cases have approved DPDPs. Outcome studies are needed to determine whether SB 1159 had the desired impact on increasing syringe access and reducing blood-borne viral infection risk among California IDUs

Three years after legalization of nonprescription pharmacy syringe sales in California: Where are we now?

In January 2005, passage of California Senate Bill 1159 enabled California’s county or city governments to establish disease prevention demonstration projects (DPDPs) through which pharmacies could subsequently register to legally sell up to 10 syringes to adults without a prescription. California’s 61 local health jurisdictions (LHJs) were surveyed annually in 2005–2007 to monitor the progress of DPDP implementation and assess program coverage, facilitators, and barriers. Completed surveys were returned by mail, fax, e-mail, phone, or internet. We analyzed 2007 survey data to describe current DPDP status; data from all years were analyzed for trends in approval and implementation status. By 2007, 17 (27.9%) LHJs approved DPDPs, of which 14 (82.4%) had registered 532 (17.8%) of the 2,987 pharmacies in these 14 LHJs. Although only three LHJs added DPDPs since 2006, the number of registered pharmacies increased 102% from 263 previously reported. Among the LHJs without approved DPDPs in 2007, one (2.3%) was in the approval process, seven (16.3%) planned to seek approval, and 35 (81.4%) reported no plans to seek approval. Of 35 LHJs not planning to seek approval, the top four reasons were: limited health department time (40%) or interest (34%), pharmacy disinterest (31%), and law enforcement opposition (26%). Among eight LHJs pursuing approval, the main barriers were “time management” (13%), educating stakeholders (13%), and enlisting pharmacy participation (13%). The17 LHJs with DPDP represent 52% of California’s residents; they included 62% of persons living with HIV and 59% of IDU-related HIV cases, suggesting that many LHJs with significant numbers of HIV cases have approved DPDPs. Outcome studies are needed to determine whether SB 1159 had the desired impact on increasing syringe access and reducing blood-borne viral infection risk among California IDUs

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 and Melinda Gates Foundation