Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses.

Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple viruses are particularly desirable when laboratory-based viral identification may be challenging, e.g., in an outbreak setting. We are interested in identifying drugs that block both Ebola virus (EBOV) and Lassa virus (LASV), two unrelated but highly pathogenic hemorrhagic fever viruses that have caused outbreaks in similar regions in Africa and share features of virus entry: use of cell surface attachment factors, macropinocytosis, endosomal receptors, and low pH to trigger fusion in late endosomes. Toward this goal, we directly compared the potency of eight drugs known to block EBOV entry with their potency as inhibitors of LASV entry. Five drugs (amodiaquine, apilimod, arbidol, niclosamide, and zoniporide) showed roughly equivalent degrees of inhibition of LASV and EBOV glycoprotein (GP)-bearing pseudoviruses; three (clomiphene, sertraline, and toremifene) were more potent against EBOV. We then focused on arbidol, which is licensed abroad as an anti-influenza drug and exhibits activity against a diverse array of clinically relevant viruses. We found that arbidol inhibits infection by authentic LASV, inhibits LASV GP-mediated cell-cell fusion and virus-cell fusion, and, reminiscent of its activity on influenza virus hemagglutinin, stabilizes LASV GP to low-pH exposure. Our findings suggest that arbidol inhibits LASV fusion, which may partly involve blocking conformational changes in LASV GP. We discuss our findings in terms of the potential to develop a drug cocktail that could inhibit both LASV and EBOV.IMPORTANCE Lassa and Ebola viruses continue to cause severe outbreaks in humans, yet there are only limited therapeutic options to treat the deadly hemorrhagic fever diseases they cause. Because of overlapping geographic occurrences and similarities in mode of entry into cells, we seek a practical drug or drug cocktail that could be used to treat infections by both viruses. Toward this goal, we directly compared eight drugs, approved or in clinical testing, for the ability to block entry mediated by the glycoproteins of both viruses. We identified five drugs with approximately equal potencies against both. Among these, we investigated the modes of action of arbidol, a drug licensed abroad to treat influenza infections. We found, as shown for influenza virus, that arbidol blocks fusion mediated by the Lassa virus glycoprotein. Our findings encourage the development of a combination of approved drugs to treat both Lassa and Ebola virus diseases.

Failure of Syndrome-Based Diarrhea Management Guidelines to Detect Shigella Infections in Kenyan Children.

BACKGROUND: Shigella is a leading cause of childhood diarrhea mortality in sub-Saharan Africa. Current World Health Organization guidelines recommend antibiotics for children in non cholera-endemic areas only in the presence of dysentery, a proxy for suspected Shigella infection. METHODS: To assess the sensitivity and specificity of the syndromic diagnosis of Shigella-associated diarrhea, we enrolled children aged 6 months to 5 years presenting to 1 of 3 Western Kenya hospitals between November 2011 and July 2014 with acute diarrhea. Stool samples were tested using standard methods for bacterial culture and multiplex polymerase chain reaction for pathogenic Escherichia coli. Stepwise multivariable logit models identified factors to increase the sensitivity of syndromic diagnosis. RESULTS: Among 1360 enrolled children, median age was 21 months (interquartile range, 11-37), 3.4% were infected with human immunodeficiency virus, and 16.5% were stunted (height-for-age z-score less than -2). Shigella was identified in 63 children (4.6%), with the most common species being Shigella sonnei (53.8%) and Shigella flexneri (40.4%). Dysentery correctly classified 7 of 63 Shigella cases (sensitivity, 11.1%). Seventy-eight of 1297 children without Shigella had dysentery (specificity, 94.0%). The combination of fecal mucous, age over 23 months, and absence of excessive vomiting identified more children with Shigella-infection (sensitivity, 39.7%) but also indicated antibiotics in more children without microbiologically confirmed Shigella (specificity, 82.7%). CONCLUSIONS: Reliance on dysentery as a proxy for Shigella results in the majority of Shigella-infected children not being identified for antibiotics. Field-ready rapid diagnostics or updated evidence-based algorithms are urgently needed to identify children with diarrhea most likely to benefit from antibiotic therapy.