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Clinical Infectious Diseases : An... Oct 2022Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies.
METHODS
We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans.
RESULTS
We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, β-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx.
CONCLUSIONS
These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.
Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Anthrax; Anti-Bacterial Agents; Anti-Infective Agents; Bacillus anthracis; Cilastatin, Imipenem Drug Combination; Ciprofloxacin; Doxycycline; Glycopeptides; Humans; Levofloxacin; Lipopeptides; Models, Animal; Tetracyclines; United States; beta-Lactams
PubMed: 36251546
DOI: 10.1093/cid/ciac591 -
Clinical Infectious Diseases : An... Oct 2022Bacillus anthracis, the causative agent of anthrax, is a high-consequence bacterial pathogen that occurs naturally in many parts of the world and is considered an agent...
Bacillus anthracis, the causative agent of anthrax, is a high-consequence bacterial pathogen that occurs naturally in many parts of the world and is considered an agent of biowarfare or bioterrorism. Understanding antimicrobial susceptibility profiles of B. anthracis isolates is foundational to treating naturally occurring outbreaks and to public health preparedness in the event of an intentional release. In this systematic review, we searched the peer-reviewed literature for all publications detailing antimicrobial susceptibility testing of B. anthracis. Within the set of discovered articles, we collated a subset of publications detailing susceptibility testing that followed standardized protocols for Food and Drug Administration-approved, commercially available antimicrobials. We analyzed the findings from the discovered articles, including the reported minimal inhibitory concentrations. Across the literature, most B. anthracis isolates were reported as susceptible to current first-line antimicrobials recommended for postexposure prophylaxis and treatment. The data presented for potential alternative antimicrobials will be of use if significant resistance to first-line antimicrobials arises, the strain is bioengineered, or first-line antimicrobials are not tolerated or available.
Topics: Anthrax; Anti-Infective Agents; Bacillus anthracis; Bioterrorism; Humans; Microbial Sensitivity Tests
PubMed: 36251548
DOI: 10.1093/cid/ciac520 -
PloS One 2017B. anthracis anti-toxin agents are approved and included in the Strategic National Stockpile based primarily on animal infection trials. However, in the only anthrax... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
B. anthracis anti-toxin agents are approved and included in the Strategic National Stockpile based primarily on animal infection trials. However, in the only anthrax outbreak an approved anti-toxin agent was administered in, survival did not differ comparing recipients and non-recipients, although recipients appeared sicker.
OBJECTIVE
Employ a systematic review and meta-analysis to investigate preclinical studies supporting anthrax anti-toxin agents.
DATA SOURCE
PubMed, EMBASE, and Scopus.
STUDY ELIGIBILITY
Compared survival with an anti-toxin agent versus control in B. anthracis challenged, antibiotic treated animals.
STUDY METHODS
Examine model and study design and the effect of anti-toxin agents on relative risk of death(95%CI) (RR).
RESULTS
From 9 studies, 29 experiments were analyzed which included 4 species (748 animals) and 5 agents; LFI, AIG, AVP-21D9, Raxibacumab, and ETI-204. Only five experiments were blinded and no experiment included the cardiopulmonary support sick B. anthracis patients receive. Only one agent in a single un-blinded experiment reduced RR significantly [0.45(0.22,0.940]. However, in six studies testing an agent in more than one experiment in the same species, agents had consistent survival effects across experiments [I2 = 0, p≥0.55 in five and I2 = 42%, p = 0.16 in one]. Within each species, agents had effects on the side of benefit; in one study testing AVP-21D9 in mice [0.11(0.01,1.82)] or guinea pigs [0.70(0.48,1.03)]; across eight rabbit studies testing LFI, Raxibacumab, AIG or ETI-204 [0.62(0.45,0.87); I2 = 17.4%, p = 0.29]; and across three monkey studies testing Raxibacumab, AIG or ETI-204 [0.66(0.34,1.27); I2 = 25.3%, p = 0.26]. Across all agents and species, agents decreased RR [0.64(0.52,0.79); I2 = 5.3%, p = 0.39].
LIMITATIONS
Incidence of selective reporting not identifiable.
CONCLUSIONS
Although overall significant, individually anti-toxin agents had weak beneficial effects. Lack of study blinding and relevant clinical therapies further weakened studies. Although difficult, preclinical studies with more robust designs and results are warranted to justify the resources necessary to maintain anti-toxin agents in national stockpiles.
Topics: Animals; Anthrax; Anti-Bacterial Agents; Antigens, Bacterial; Antitoxins; Bacillus anthracis; Disease Models, Animal; Humans; Research Design; Treatment Outcome
PubMed: 28797061
DOI: 10.1371/journal.pone.0182879 -
Clinical Infectious Diseases : An... Oct 2022Bacillus anthracis can cause anthrax and is a potential bioterrorism agent. The 2014 Centers for Disease Control and Prevention recommendations for medical... (Review)
Review
BACKGROUND
Bacillus anthracis can cause anthrax and is a potential bioterrorism agent. The 2014 Centers for Disease Control and Prevention recommendations for medical countermeasures against anthrax were based on in vitro data and expert opinion. However, a century of previously uncompiled observational human data that often includes treatment and outcomes is available in the literature for analysis.
METHODS
We reviewed treatment outcomes for patients hospitalized with anthrax. We stratified patients by meningitis status, route of infection, and systemic criteria, then analyzed survival by treatment type, including antimicrobials, antitoxin/antiserum, and steroids. Using logistic regression, we calculated odds ratios and 95% confidence intervals to compare survival between treatments. We also calculated hospital length of stay. Finally, we evaluated antimicrobial postexposure prophylaxis (PEPAbx) using data from a 1970 Russian-language article.
RESULTS
We identified 965 anthrax patients reported from 1880 through 2018. After exclusions, 605 remained: 430 adults, 145 children, and 30 missing age. Survival was low for untreated patients and meningitis patients, regardless of treatment. Most patients with localized cutaneous or nonmeningitis systemic anthrax survived with 1 or more antimicrobials; patients with inhalation anthrax without meningitis fared better with at least 2. Bactericidal antimicrobials were effective for systemic anthrax; addition of a protein synthesis inhibitor(s) (PSI) to a bactericidal antimicrobial(s) did not improve survival. Likewise, addition of antitoxin/antiserum to antimicrobials did not improve survival. Mannitol improved survival for meningitis patients, but steroids did not. PEPAbx reduced risk of anthrax following exposure to B. anthracis.
CONCLUSIONS
Combination therapy appeared to be superior to monotherapy for inhalation anthrax without meningitis. For anthrax meningitis, neither monotherapy nor combination therapy were particularly effective; however, numbers were small. For localized cutaneous anthrax, monotherapy was sufficient. For B. anthracis exposures, PEPAbx was effective.
Topics: Adult; Anthrax; Anti-Bacterial Agents; Anti-Infective Agents; Antitoxins; Bacillus anthracis; Biological Warfare Agents; Bioterrorism; Child; Hospitals; Humans; Mannitol; Protein Synthesis Inhibitors; Respiratory Tract Infections; Treatment Outcome
PubMed: 36251553
DOI: 10.1093/cid/ciac536 -
Clinical Infectious Diseases : An... Oct 2022Bacillus anthracis is a high-priority threat agent because of its widespread availability, easy dissemination, and ability to cause substantial morbidity and mortality....
BACKGROUND
Bacillus anthracis is a high-priority threat agent because of its widespread availability, easy dissemination, and ability to cause substantial morbidity and mortality. Although timely and appropriate antimicrobial therapy can reduce morbidity and mortality, the role of adjunctive therapies continues to be explored.
METHODS
We searched 11 databases for articles that report use of anthrax antitoxins in treatment or prevention of systemic anthrax disease published through July 2019. We identified other data sources through reference search and communication with experts. We included English-language studies on antitoxin products with approval by the US Food and Drug Administration (FDA) for anthrax in humans, nonhuman primates, and rabbits. Two researchers independently reviewed studies for inclusion and abstracted relevant data.
RESULTS
We abstracted data from 12 publications and 2 case reports. All 3 FDA-approved anthrax antitoxins demonstrated significant improvement in survival as monotherapy over placebo in rabbits and nonhuman primates. No study found significant improvement in survival with combination antitoxin and antimicrobial therapy compared to antimicrobial monotherapy. Case reports and case series described 25 patients with systemic anthrax disease treated with antitoxins; 17 survived. Animal studies that used antitoxin monotherapy as postexposure prophylaxis (PEP) demonstrated significant improvement in survival over placebo, with greatest improvements coming with early administration.
CONCLUSIONS
Limited human and animal evidence indicates that adjunctive antitoxin treatment may improve survival from systemic anthrax infection. Antitoxins may also provide an alternative therapy to antimicrobials for treatment or PEP during an intentional anthrax incident that could involve a multidrug-resistant B. anthracis strain.
Topics: Animals; Anthrax; Anti-Bacterial Agents; Anti-Infective Agents; Antitoxins; Bacillus anthracis; Humans; Primates; Rabbits
PubMed: 36251559
DOI: 10.1093/cid/ciac532 -
Clinical Infectious Diseases : An... Jun 2016Bacillus anthracis, the causative agent of anthrax, is a potential bioterrorism agent. Anthrax meningitis is a common manifestation of B. anthracis infection, has high... (Review)
Review
BACKGROUND
Bacillus anthracis, the causative agent of anthrax, is a potential bioterrorism agent. Anthrax meningitis is a common manifestation of B. anthracis infection, has high mortality, and requires more aggressive treatment than anthrax without meningitis. Its rapid identification and treatment are essential for successful management of an anthrax mass casualty incident.
METHODS
Three hundred six published reports from 1880 through 2013 met predefined inclusion criteria. We calculated descriptive statistics for abstracted cases and conducted multivariable regression on separate derivation and validation cohorts to identify clinical diagnostic and prognostic factors for anthrax meningitis.
RESULTS
One hundred thirty-two of 363 (36%) cases with systemic anthrax met anthrax meningitis criteria. Severe headache, altered mental status, meningeal signs, and other neurological signs at presentation independently predicted meningitis in the derivation cohort and were tested as a 4-item assessment tool for use during anthrax mass casualty incidents. Presence of any 1 factor on admission had a sensitivity for finding anthrax meningitis of 89% (83%) in the adult (pediatric) validation cohorts. Anthrax meningitis was unlikely in the absence of any of these signs or symptoms (likelihood ratio [LR]- = 0.12 [0.19] for adult [pediatric] cohorts), while presence of 2 or more made meningitis very likely (LR+ = 26.5 [30.0]). Survival of anthrax meningitis was predicted by treatment with a bactericidal agent (P = .005) and use of multiple antimicrobials (P = .01).
CONCLUSIONS
We developed an evidence-based assessment tool for screening patients for meningitis during an anthrax mass casualty incident. Its use could improve both patient outcomes and resource allocation in such an event.
Topics: Adolescent; Adult; Anthrax; Bacillus anthracis; Bioterrorism; Child; Child, Preschool; Cognitive Dysfunction; Female; Headache; Humans; Male; Mass Casualty Incidents; Meningitis, Bacterial; Middle Aged
PubMed: 27025833
DOI: 10.1093/cid/ciw184 -
Clinical Infectious Diseases : An... Oct 2022Anthrax is a toxin-mediated zoonotic disease caused by Bacillus anthracis, with a worldwide distribution recognized for millennia. Bacillus anthracis is considered a...
BACKGROUND
Anthrax is a toxin-mediated zoonotic disease caused by Bacillus anthracis, with a worldwide distribution recognized for millennia. Bacillus anthracis is considered a potential biowarfare agent.
METHODS
We completed a systematic review for clinical and demographic characteristics of adults and children hospitalized with anthrax (cutaneous, inhalation, ingestion, injection [from contaminated heroin], primary meningitis) abstracted from published case reports, case series, and line lists in English from 1880 through 2018, assessing treatment impact by type and severity of disease. We analyzed geographic distribution, route of infection, exposure to anthrax, and incubation period.
RESULTS
Data on 764 adults and 167 children were reviewed. Most cases reported for 1880 through 1915 were from Europe; those for 1916 through 1950 were from North America; and from 1951 on, cases were from Asia. Cutaneous was the most common form of anthrax for all populations. Since 1960, adult anthrax mortality has ranged from 31% for cutaneous to 90% for primary meningitis. Median incubation periods ranged from 1 day (interquartile range [IQR], 0-4) for injection to 7 days (IQR, 4-9) for inhalation anthrax. Most patients with inhalation anthrax developed pleural effusions and more than half with ingestion anthrax developed ascites. Treatment and critical care advances have improved survival for those with systemic symptoms, from approximately 30% in those untreated to approximately 70% in those receiving antimicrobials or antiserum/antitoxin.
CONCLUSIONS
This review provides an improved evidence base for both clinical care of individual anthrax patients and public health planning for wide-area aerosol releases of B. anthracis spores.
Topics: Adult; Aerosols; Anthrax; Antitoxins; Bacillus anthracis; Biological Warfare Agents; Child; Heroin; Humans; Respiratory Tract Infections
PubMed: 36251560
DOI: 10.1093/cid/ciac534 -
One Health (Amsterdam, Netherlands) Jun 2023The disease anthrax occurs generally in herbivores and the causative organism () infects humans who come in contact with infected animals or their products The... (Review)
Review
The disease anthrax occurs generally in herbivores and the causative organism () infects humans who come in contact with infected animals or their products The persistence of anthrax spores for decades and its lethality contribute to its biowarfare potential. We conducted this systematic review along with risk mapping to investigate the spatio-temporal distribution, clinico-epidemiological, socio-behavioural and programmatic issues pertaining to anthrax in India over the last two decades. Peer reviewed quantitative and qualitative studies and grey literature comprising weekly reports of the 'Integrated Disease Surveillance Program' (IDSP), were accessed for extracting data. IDSP data were used for geo-referencing of the villages of anthrax cases; Pseudo-absence was generated to fit a Bayesian Additive Regression Trees (BART) model to develop anthrax risk map. The case fatality rate of cutaneous anthrax ranged from 2% to 38%, while the gastrointestinal and inhalational types were 100% fatal. Our synthesis revealed that human anthrax outbreaks in India were clustered around the eastern coastal regions. The states of Odisha, West Bengal, Andhra Pradesh and Jharkhand reported maximum number of outbreaks. Odisha reported a maximum number of 439 human anthrax cases since 2009, of which Koraput district contributed to 200 cases (46%). While handling or consumption of infected animal product were proximal drivers of these events, poverty, lack of awareness, traditional beliefs and local practices served as facilitatory factors. Other structural determinants were wild life-livestock interface, historical forest loss, soil pH, soil-water balance, organic carbon content, temperature, rainfall and humidity. The programmatic issues identified through this review were lack of active surveillance, non-availability of diagnostic facility at the periphery, delayed reporting, absence of routine livestock vaccination and lack of adequate veterinary services. Interventions based on One-health approach in the country merit immediate policy and program attention; high risk zones for anthrax identified during present investigation, should be prioritized.
PubMed: 37363236
DOI: 10.1016/j.onehlt.2023.100564