Bioterrorism

History shows us that individuals have used and likely will continue to use biological agents for terrorism purposes. Bioterrorism agents can be easily disseminated, cause severe disease and high mortality rates if cases are not treated properly, and pose significant challenges for management and response. A robust public health surveillance system that includes laboratory (including routine reportable disease surveillance), syndromic, and environmental surveillance is crucial for detection of the release of a bioterrorism agent and the resulting cases. This detection can then set into motion a robust and comprehensive public health response to minimize morbidity and mortality. A large-scale bioterrorism event would be unprecedented, straining and challenging every facet of medical and public health response and would quickly become a global emergency because of both the potential risk of infection and the shock to the global economy. A robust public health and medical workforce is necessary to respond effectively and efficiently to these types of events.

150. Updated Clinical Guidelines for Treatment and Prophylaxis of Plague

Background Plague still occurs naturally in the western United States, Latin America, Asia, and Africa. Yersinia pestis, the causative agent of plague, is a Tier 1 bioterrorism agent due to its potential for aerosol release and high fatality rates. Recommendations for treatment and post-exposure prophylaxis (PEP) of plague were published in 2000 and included limited first-line options for treating plague, namely streptomycin or gentamicin. Doxycycline or ciprofloxacin were recommended for PEP. However, since 2000 new human clinical data and animal data have become available, and the FDA has approved additional antimicrobials for plague. Methods CDC developed updated, evidence-based guidelines for treatment and prophylaxis of plague using a comprehensive process. To collect evidence on relative efficacy of various antimicrobials for treatment of plague, the guidelines team conducted systematic literature reviews and analyzed U.S. surveillance data. Results of these investigations were published in Clinical Infectious Diseases in 2020. We also hosted several meetings with subject matter experts and clinical organizations (IDSA, AAP, etc.), federal agencies, and others to review relevant data and gather individual input on treatment and prophylaxis of plague. Results The forthcoming plague guidelines will include several important updates. First-line treatment options have been expanded to include ciprofloxacin, levofloxacin, and moxifloxacin in addition to streptomycin and gentamicin. For PEP, levofloxacin and moxifloxacin are now first-line options in addition to doxycycline and ciprofloxacin. Trimethoprim-sulfamethoxazole is now one of several new alternative options for PEP. The updated guidelines also include recommendations for treatment of clinical forms of plague other than pneumonic. Additional special populations such as immunocompromised persons and neonates are also covered. Conclusion Plague remains a threat, both as a naturally occurring disease and as a potential bioterrorism weapon, and preparedness and early recognition are key to effective response. The updated clinical guidelines will be a useful tool for clinicians to manage antimicrobial treatment and PEP for plague. Disclosures All Authors: No reported disclosures

Reevaluating the Risk of Smallpox Reemergence

Introduction Smallpox, caused by variola virus, was eradicated in 1980, but remains a category A bioterrorism agent. A decade ago, smallpox ranked second after anthrax in a multifactorial risk priority scoring analysis of category A bioterrorism agents. However, advances in genetic engineering and synthetic biology, including published methods for synthesizing an Orthopoxvirus, require the assumptions of this scoring for smallpox and other category A agents to be reviewed. Materials and Methods The risk priority framework was reviewed and revised to account for the capability for creation of synthetic or engineered smallpox and other category A agents. Results The absolute score for all agents increased because of gene editing and synthetic biology capability, which was not present when the framework was developed more than a decade ago, although new treatments revised scores downward for smallpox, Ebola, and botulism. In the original framework, smallpox scored 0 for global availability, given the high security around known seed stocks of variola in two laboratories in the United States and Russia. Now, smallpox can be created using synthetic biology, raising the score for this criterion to 2. Other agents too, such as Ebola, score higher for availability, based on synthetic biology capability. When advances in synthetic biology and genetic engineering are considered, smallpox and anthrax are now equally ranked the highest category A bioterrorism agents for planning and preparedness. Conclusions Revision of a risk priority framework for category A bioterrorism agents shows that smallpox should be elevated in priority for preparedness planning, and that gene editing and synthetic biology raises the overall risk for all agents. The ranking of categories A, B, and C agents should also be revisited, as there is an endless possibility of engineered threats that may be more severe than any agent on the category A list.

Antimicrobial Treatment of Human Plague: A Systematic Review of the Literature on Individual Cases, 1937–2019

Background Yersinia pestis remains endemic in Africa, Asia, and the Americas and is a known bioterrorism agent. Treatment with aminoglycosides such as streptomycin or gentamicin is effective when initiated early in illness but can have serious side effects. Alternatives such as fluoroquinolones, tetracyclines, and sulfonamides are potentially safer but lack robust human data on efficacy. Methods We searched PubMed Central, Medline, Embase, and other databases for articles in any language with terms related to plague and antimicrobials. Articles that contained case-level information on antimicrobial treatment and patient outcome were included. We abstracted information related to patient demographics, clinical features, treatment, and fatality. Results Among 5837 articles screened, we found 762 published cases of treated plague reported from 1937 to 2019. Fifty-nine percent were male; median age was 22 years (range, 8 days–80 years). The case fatality rate was 20% overall. Most patients had primary bubonic (63%), pneumonic (21%), or septicemic (5%) plague, with associated case fatality rates of 17%, 27%, and 38%, respectively. Among those treated with an aminoglycoside (n = 407 [53%]), the case fatality rate was 13%. Among those treated with a sulfonamide (n = 322 [42%]), tetracycline (n = 171 [22%]), or fluoroquinolone (n = 61 [8%]), fatality was 23%, 10%, and 12%, respectively. Case fatality rate did not substantially differ between patients treated with 1 vs 2 classes of antimicrobials considered to be effective for plague. Conclusions In addition to aminoglycosides, other classes of antimicrobials including tetracyclines, fluoroquinolones, and sulfonamides are effective for plague treatment, although publication bias and low numbers in certain treatment groups may limit interpretation.

Plague: Still a Threat, but Evidence and Preparedness Are Keys to Fighting Back

Yersinia pestis continues to cause naturally occurring outbreaks in certain regions worldwide and is a potential bioterrorism agent. This supplement presents new data on plague to advance current knowledge and inform new clinical guidelines for treatment and prophylaxis.

Proposal of a Taxonomic Nomenclature for the Bacillus cereus Group Which Reconciles Genomic Definitions of Bacterial Species with Clinical and Industrial Phenotypes

ABSTRACT The Bacillus cereus group comprises numerous closely related species, including bioterrorism agent B. anthracis, foodborne pathogen B. cereus, and biopesticide B. thuringiensis. Differentiating organisms capable of causing illness or death from those used in industry is essential for risk assessment and outbreak preparedness. However, current species definitions facilitate species-phenotype incongruences, particularly when horizontally acquired genes are responsible for a phenotype. Using all publicly available B. cereus group genomes (n = 2,231), we show that current species definitions lead to overlapping genomospecies clusters, in which 66.2% of genomes belong to multiple genomospecies at a conventional 95 average nucleotide identity (ANI) genomospecies threshold. A genomospecies threshold of ≈92.5 ANI is shown to reflect a natural gap in genome similarity for the B. cereus group, and medoid genomes identified at this threshold are shown to yield resolvable genomospecies clusters with minimal overlap (six of 2,231 genomes assigned to multiple genomospecies; 0.269%). We thus propose a nomenclatural framework for the B. cereus group which accounts for (i) genomospecies using resolvable genomospecies clusters obtained at ≈92.5 ANI, (ii) established lineages of medical importance using a formal collection of subspecies names, and (iii) heterogeneity of clinically and industrially important phenotypes using a formalized and extended collection of biovar terms. We anticipate that the proposed nomenclature will remain interpretable to clinicians, without sacrificing genomic species definitions, which can in turn aid in pathogen surveillance; early detection of emerging, high-risk genotypes; and outbreak preparedness. IMPORTANCE Historical species definitions for many prokaryotes, including pathogens, have relied on phenotypic characteristics that are inconsistent with genome evolution. This scenario forces microbiologists and clinicians to face a tradeoff between taxonomic rigor and clinical interpretability. Using the Bacillus cereus group as a model, a conceptual framework for the taxonomic delineation of prokaryotes which reconciles genomic definitions of species with clinically and industrially relevant phenotypes is presented. The nomenclatural framework outlined here serves as a model for genomics-based bacterial taxonomy that moves beyond arbitrarily set genomospecies thresholds while maintaining congruence with phenotypes and historically important species names.

Drug Development against Smallpox: Present and Future

ABSTRACT Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years, the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus de novo, implying that VARV could, in theory, be resurrected. Because of this new perspective, the WHO Advisory Committee on VARV Research released new recommendations concerning research on poxviruses that strongly encourages pursuing the development of new antiviral drugs against orthopoxviruses. In 2018, the U.S. FDA advised in favor of two molecules for smallpox treatment, tecovirimat and brincidofovir. This review highlights the difficulties to develop new drugs targeting an eradicated disease, especially as it requires working under the FDA “animal efficacy rule” with the few, and imperfect, animal models available.

Sequelae of Lassa Fever: Postviral Cerebellar Ataxia

Lassa fever is a zoonotic disease endemic in some West African countries. It is exported to countries in America, Asia, and Europe. Antivirals against Lassa fever are important to provide a cure in patients with the disease and provide protection against it. In addition, due to the potential utilization of Lassa virus as a bioterrorism agent, vaccines against the disease can be utilized as a counterterrorism measure. Developing antiviral compounds and vaccines against the disease requires understanding of the pathogenesis of Lassa fever and its disease course, including the signs, symptoms, complications, and sequelae. An important sequela of Lassa fever is ataxia. A few cases of postviral ataxia following Lassa fever have been described in the literature. This review focuses on highlighting these cases, the gaps in scientific knowledge where further research is needed, and possible ways of diagnosing postviral ataxia after Lassa fever in resource-limited settings.

1636. Antibiotic Treatment of Human Plague: A Systematic Literature Review of Worldwide Cases, 1937–2016

Background Yersinia pestis remains endemic in countries throughout Africa, Asia, and the Americas and is a tier 1 bioterrorism agent. Antibiotic treatment with aminoglycosides such as streptomycin or gentamicin is effective when initiated early in the course of illness but can have serious side effects. Alternatives such as fluoroquinolones, tetracyclines, and sulfonamides are potentially safer but currently lack robust human data on their efficacy. Methods We searched PubMed Central, Medline, Embase, CINAHL, and other databases for articles in any language with terms related to plague, Yersinia pestis, and antibiotics. Articles that contained case-level information on antibiotic treatment and patient outcome were included. We abstracted information related to patient demographics, clinical features of plague, treatment, and survival using a standardized form. Results Among 4,874 articles identified and screened, we found 723 published cases of treated plague reported between 1937 and 2016. Fifty-two percent of patients were male; median age was 22 years (range: 8 days-80 years). Cases were most commonly reported from the United States (21%), India (13%), China (11%), Vietnam (10%), and Madagascar (10%). Overall, the case fatality rate was 21%. The majority of patients had primary bubonic (64%), pneumonic (21%), or septicemic (4%) plague, of which survival was 83%, 71%, and 55%, respectively. Among those treated with an aminoglycoside (n = 386, 53%), survival was 86%. Among those treated with a tetracycline (n = 145, 20%), fluoroquinolone (n = 45, 6%), or sulfonamide (n = 311, 43%), survival was 90%, 84%, and 77%, respectively. Survival rates did not substantially differ between patients treated with one vs. two classes of antibiotics (table). Conclusion Published cases of treated plague offer an opportunity to evaluate the treatment efficacy of different antibiotic classes. In addition to aminoglycosides, tetracyclines, fluoroquinolones, and sulfonamides appear to be effective for plague treatment, although publication bias and low numbers in certain treatment groups may limit interpretation. Disclosures All authors: No reported disclosures.

Proposal of a taxonomic nomenclature for the Bacillus cereus group which reconciles genomic definitions of bacterial species with clinical and industrial phenotypes

ABSTRACTThe Bacillus cereus group comprises numerous closely related species, including bioterrorism agent B. anthracis, foodborne pathogen B. cereus, and biopescticide B. thuringiensis. Differentiating organisms capable of causing illness or death from those used in industry is essential for risk assessment and outbreak preparedness. However, current species definitions facilitate species-phenotype incongruencies, particularly when horizontally acquired genes are responsible for a phenotype. Using all publicly available B. cereus group genomes (n = 2,231), we show that current genomospecies definitions lead to overlapping species clusters, and that an average nucleotide identity (ANI) genomospecies threshold of ≈92.5 reflects a natural gap in core genome similarity. We propose a taxonomy for the B. cereus group which accounts for (i) genomospecies using separable species clusters formed at a threshold of ≈92.5 ANI, and (ii) phenotypes relevant to public health and industry. We anticipate that the proposed nomenclature will remain interpretable to clinicians, without sacrificing genomic species definitions, which can in turn aid in pathogen surveillance, early detection of emerging, high-risk genotypes, and outbreak preparedness. Furthermore, the nomenclatural framework outlined here serves as a model for genomics-based bacterial taxonomy which moves beyond arbitrarily set genomospecies thresholds, while maintaining congruence with phenotypes and historically important species names.