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Clinical Infectious Diseases : An... Jun 2020Diphtheria, once a major cause of childhood morbidity and mortality, all but disappeared following introduction of diphtheria vaccine. Recent outbreaks highlight the...
BACKGROUND
Diphtheria, once a major cause of childhood morbidity and mortality, all but disappeared following introduction of diphtheria vaccine. Recent outbreaks highlight the risk diphtheria poses when civil unrest interrupts vaccination and healthcare access. Lack of interest over the last century resulted in knowledge gaps about diphtheria's epidemiology, transmission, and control.
METHODS
We conducted 9 distinct systematic reviews on PubMed and Scopus (March-May 2018). We pooled and analyzed extracted data to fill in these key knowledge gaps.
RESULTS
We identified 6934 articles, reviewed 781 full texts, and included 266. From this, we estimate that the median incubation period is 1.4 days. On average, untreated cases are colonized for 18.5 days (95% credible interval [CrI], 17.7-19.4 days), and 95% clear Corynebacterium diphtheriae within 48 days (95% CrI, 46-51 days). Asymptomatic carriers cause 76% (95% confidence interval, 59%-87%) fewer cases over the course of infection than symptomatic cases. The basic reproductive number is 1.7-4.3. Receipt of 3 doses of diphtheria toxoid vaccine is 87% (95% CrI, 68%-97%) effective against symptomatic disease and reduces transmission by 60% (95% CrI, 51%-68%). Vaccinated individuals can become colonized and transmit; consequently, vaccination alone can only interrupt transmission in 28% of outbreak settings, making isolation and antibiotics essential. While antibiotics reduce the duration of infection, they must be paired with diphtheria antitoxin to limit morbidity.
CONCLUSIONS
Appropriate tools to confront diphtheria exist; however, accurate understanding of the unique characteristics is crucial and lifesaving treatments must be made widely available. This comprehensive update provides clinical and public health guidance for diphtheria-specific preparedness and response.
Topics: Child; Diphtheria; Disease Outbreaks; Humans; Vaccination
PubMed: 31425581
DOI: 10.1093/cid/ciz808 -
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 -
Health Security 2015Concern about use of anthrax as a bioweapon prompted development of novel anthrax antitoxins for treatment. Clinical guidelines for the treatment of anthrax recommend... (Review)
Review
Concern about use of anthrax as a bioweapon prompted development of novel anthrax antitoxins for treatment. Clinical guidelines for the treatment of anthrax recommend antitoxin therapy in combination with intravenous antimicrobials; however, a large-scale or mass anthrax incident may exceed antitoxin availability and create a need for judicious antitoxin use. We conducted a systematic review of antitoxin treatment of inhalation anthrax in humans and experimental animals to inform antitoxin recommendations during a large-scale or mass anthrax incident. A comprehensive search of 11 databases and the FDA website was conducted to identify relevant animal studies and human reports: 28 animal studies and 3 human cases were identified. Antitoxin monotherapy at or shortly after symptom onset demonstrates increased survival compared to no treatment in animals. With early treatment, survival did not differ between antimicrobial monotherapy and antimicrobial-antitoxin therapy in nonhuman primates and rabbits. With delayed treatment, antitoxin-antimicrobial treatment increased rabbit survival. Among human cases, addition of antitoxin to combination antimicrobial treatment was associated with survival in 2 of the 3 cases treated. Despite the paucity of human data, limited animal data suggest that adjunctive antitoxin therapy may improve survival. Delayed treatment studies suggest improved survival with combined antitoxin-antimicrobial therapy, although a survival difference compared with antimicrobial therapy alone was not demonstrated statistically. In a mass anthrax incident with limited antitoxin supplies, antitoxin treatment of individuals who have not demonstrated a clinical benefit from antimicrobials, or those who present with more severe illness, may be warranted. Additional pathophysiology studies are needed, and a point-of-care assay correlating toxin levels with clinical status may provide important information to guide antitoxin use during a large-scale anthrax incident.
Topics: Administration, Intravenous; Animals; Anthrax; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Bacterial; Antitoxins; Bioterrorism; Drug Therapy, Combination; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Mass Casualty Incidents; Rabbits; Respiratory Tract Infections
PubMed: 26690378
DOI: 10.1089/hs.2015.0032 -
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 -
Toxins Apr 2017Latrodectism or envenomation by widow-spiders is common and clinically significant worldwide. Alpha-latrotoxin is the mammalian-specific toxin in the venom that results... (Review)
Review
Latrodectism or envenomation by widow-spiders is common and clinically significant worldwide. Alpha-latrotoxin is the mammalian-specific toxin in the venom that results in toxic effects observed in humans. Symptoms may be incapacitating and include severe pain that can persist for days. The management of mild to moderate latrodectism is primarily supportive while severe cases have variously been treated with intravenous calcium, muscle relaxants, widow-spider antivenom and analgesic opioids. The object of this systematic review is to examine the literature on the clinical effectiveness of past and current treatments for latrodectism. MEDLINE, EMBASE and Google Scholar were searched from 1946 to December 2016 to identify clinical studies on the treatment of latrodectism. Studies older than 40 years and not in English were not reviewed. There were only two full-publications and one abstract of placebo-controlled randomised trials on antivenom use for latrodectism. Another two randomised comparative trials compared the route of administration of antivenom for latrodectism. There were fourteen case series (including two abstracts), fourteen case reports and one letter investigating drug treatments for latrodectism with the majority of these also including antivenom for severe latrodectism. Antivenom with opioid analgesia is often the major treatment reported for latrodectism however; recent high quality evidence has cast doubt on the clinical effectiveness of this combination and suggests that other treatments need to be investigated.
Topics: Animals; Antivenins; Humans; Spider Bites; Treatment Outcome
PubMed: 28430165
DOI: 10.3390/toxins9040148 -
Toxins Dec 2018Toxin-antitoxin (TA) systems are known to play various roles in physiological processes, such as gene regulation, growth arrest and survival, in bacteria exposed to...
Toxin-antitoxin (TA) systems are known to play various roles in physiological processes, such as gene regulation, growth arrest and survival, in bacteria exposed to environmental stress. Type II TA systems comprise natural complexes consisting of protein toxins and antitoxins. Each toxin and antitoxin participates in distinct regulatory mechanisms depending on the type of TA system. Recently, peptides designed by mimicking the interfaces between TA complexes showed its potential to activate the activity of toxin by competing its binding counterparts. Type II TA systems occur more often in pathogenic bacteria than in their nonpathogenic kin. Therefore, they can be possible drug targets, because of their high abundance in some pathogenic bacteria, such as . In addition, recent bioinformatic analyses have shown that type III TA systems are highly abundant in the intestinal microbiota, and recent clinical studies have shown that the intestinal microbiota is linked to inflammatory diseases, obesity and even several types of cancer. We therefore focused on exploring the putative relationship between intestinal microbiota-related human diseases and type III TA systems. In this paper, we review and discuss the development of possible druggable materials based on the mechanism of type II and type III TA system.
Topics: Animals; Antimicrobial Cationic Peptides; Bacterial Physiological Phenomena; Bacterial Proteins; Bacterial Toxins; Gastrointestinal Microbiome; Humans; Molecular Targeted Therapy; Toxin-Antitoxin Systems
PubMed: 30518070
DOI: 10.3390/toxins10120515 -
PLoS Neglected Tropical Diseases Feb 2023Snakebite envenoming is a serious and life-threatening medical condition that predominantly affects people living in rural communities across Africa, Asia, and Latin... (Meta-Analysis)
Meta-Analysis Review
Assessing knowledge and awareness regarding snakebite and management of snakebite envenoming in healthcare workers and the general population: A systematic review and meta-analysis.
BACKGROUND
Snakebite envenoming is a serious and life-threatening medical condition that predominantly affects people living in rural communities across Africa, Asia, and Latin America. As our climate changes, there is a growing concern that negative human-snake interactions will increase. Our ability to prevent and manage snakebite requires effective antivenoms as well as knowledge regarding the prevention and management of snakebite among healthcare workers and affected communities across the globe. This systematic review aims to assess existing levels of knowledge regarding snakebite prevention and management in both healthcare workers and affected communities.
METHODS
This review was conducted on studies reporting quantitative measurements to evaluate knowledge and practice regarding snakebite prevention and management published in major databases between 1 January 2000 and 31 December 2021. Random effects modelling was used to obtain the pooled proportion. Heterogeneity (I2) was tested, and sensitivity analyses performed.
RESULTS
Out of 3,697 records, 16 studies from 12 countries assessing 7,640 participants were included. Four of the studies were ranked as good quality studies, 9 as fair, and 3 as poor. This study results demonstrated that 56% of the study population answered the knowledge question correctly (95% CI 48% to 63%, p < 0.001). High heterogeneity was observed (I2 = 97.29%), with marginal publication bias (Egger's regression test, p = 0.0814). Participants had relatively higher knowledge concerning use of antivenom as preferred treatment, followed by snakebite prevention, knowledge of signs and symptoms of snakebite, knowledge of first-aid, and knowledge of treatment. Participants had lower knowledge relating to types of snakes and the identification of snakes.
CONCLUSION
Adequate knowledge about snakebites and its management among the general population and healthcare workers was 56%. Healthcare workers and communities across Asia showed higher relative knowledge compared to those in Africa and the Middle East. These data suggest that further education is needed in both the general population and among healthcare workers to ensure that appropriate preventative and patient management techniques are being utilised in snakebite endemic regions. Greater local awareness of the risks and appropriate management of snakebite is required to reduce the burden of snakebite mortality and morbidity.
Topics: Animals; Humans; Snake Bites; Snakes; Antivenins; Health Personnel; Africa
PubMed: 36757933
DOI: 10.1371/journal.pntd.0011048 -
The Cochrane Database of Systematic... Apr 2019Botulism is an acute paralytic illness caused by a neurotoxin produced by Clostridium botulinum. Supportive care, including intensive care, is key, but the role of other... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Botulism is an acute paralytic illness caused by a neurotoxin produced by Clostridium botulinum. Supportive care, including intensive care, is key, but the role of other medical treatments is unclear. This is an update of a review first published in 2011.
OBJECTIVES
To assess the effects of medical treatments on mortality, duration of hospitalization, mechanical ventilation, tube or parenteral feeding, and risk of adverse events in botulism.
SEARCH METHODS
We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase on 23 January 2018. We reviewed bibliographies and contacted authors and experts. We searched two clinical trials registers, WHO ICTRP and clinicaltrials.gov, on 21 February 2019.
SELECTION CRITERIA
Randomized controlled trials (RCTs) and quasi-RCTs examining the medical treatment of any of the four major types of botulism (infant intestinal botulism, food-borne botulism, wound botulism, and adult intestinal toxemia). Potential medical treatments included equine serum trivalent botulism antitoxin, human-derived botulinum immune globulin intravenous (BIG-IV), plasma exchange, 3,4-diaminopyridine, and guanidine.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodology.Our primary outcome was in-hospital death from any cause occurring within four weeks from randomization or the beginning of treatment. Secondary outcomes were death from any cause occurring within 12 weeks, duration of hospitalization, duration of mechanical ventilation, duration of tube or parenteral feeding, and proportion of participants with adverse events or complications of treatment.
MAIN RESULTS
A single RCT met the inclusion criteria. Our 2018 search update identified no additional trials. The included trial evaluated BIG-IV for the treatment of infant botulism and included 59 treatment participants and 63 control participants. The control group received a control immune globulin that did not have an effect on botulinum toxin. Participants were followed during the length of their hospitalization to measure the outcomes of interest. There was some violation of intention-to-treat principles, and possibly some between-treatment group imbalances among participants admitted to the intensive care unit and mechanically ventilated, but otherwise the risk of bias was low. There were no deaths in either group, making any treatment effect on mortality inestimable. There was a benefit in the treatment group on mean duration of hospitalization (BIG-IV: 2.60 weeks, 95% confidence interval (CI) 1.95 to 3.25; control: 5.70 weeks, 95% CI 4.40 to 7.00; mean difference (MD) -3.10 weeks, 95% CI -4.52 to -1.68; moderate-certainty evidence); mechanical ventilation (BIG-IV: 1.80 weeks, 95% CI 1.20 to 2.40; control: 4.40 weeks, 95% CI 3.00 to 5.80; MD -2.60 weeks, 95% CI -4.06 to -1.14; low-certainty evidence); and tube or parenteral feeding (BIG-IV: 3.60 weeks, 95% CI 1.70 to 5.50; control: 10.00 weeks, 95% CI 6.85 to 13.15; MD -6.40 weeks, 95% CI -10.00 to -2.80; moderate-certainty evidence), but not on proportion of participants with adverse events or complications (BIG-IV: 63.08%; control: 68.75%; risk ratio 0.92, 95% CI 0.72 to 1.18; absolute risk reduction 0.06, 95% CI 0.22 to -0.11; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
We found low- and moderate-certainty evidence supporting the use of BIG-IV in infant intestinal botulism. A single RCT demonstrated that BIG-IV probably decreases the duration of hospitalization; may decrease the duration of mechanical ventilation; and probably decreases the duration of tube or parenteral feeding. Adverse events were probably no more frequent with immune globulin than with placebo. Our search did not reveal any evidence examining the use of other medical treatments including serum trivalent botulism antitoxin.
Topics: Botulinum Toxins; Botulism; Critical Care; Hospitalization; Humans; Immunoglobulins; Immunoglobulins, Intravenous; Infant; Parenteral Nutrition; Randomized Controlled Trials as Topic; Respiration, Artificial
PubMed: 30993666
DOI: 10.1002/14651858.CD008123.pub4 -
PLoS Neglected Tropical Diseases Apr 2024Snakebite envenoming represents a significant and often neglected public health challenge, particularly in rural communities across tropical and subtropical regions. An... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Snakebite envenoming represents a significant and often neglected public health challenge, particularly in rural communities across tropical and subtropical regions. An estimated 1.2-5.5 million people are envenomed by snakebites annually. More than 125,000 of these bites are fatal, and 3-4 times as many results in disability/disfigurement. Despite its prevalence, collecting accurate epidemiological data on snakebite is challenging. This systematic review and meta-analysis collates global epidemiology data on snakebite morbidity and mortality.
METHODS
Medline, Embase, Cochrane and CINAHL Plus databases were searched for articles published between 2001-2022. Pooled incidence and mortality were obtained using random effects modelling, heterogeneity (I2) was tested, and sensitivity analyses performed. Newcastle-Ottawa Scale assessed study quality.
RESULTS
Out of the four databases, 5,312 articles were found. After removing duplicates, 3,953 articles were screened by title and abstract and 65 articles containing information on snakebite epidemiology, encompassing 663,460 snakebites, were selected for analysis. The people most at risk for snakebite were men (59%), engaged in agricultural labour (27.5%), and residing in rural areas (66.7%). More than half (57%) of the reported bites resulted in envenoming. Incidents occurred frequently in the summer season (38.5%), during daytime (56.7%), and bites were most often to the lower limb (56.4%). Envenoming severity was frequently mild (46.7%), treated in hospital (68.3%), and was treated with anti-venom (64.7%). The pooled global incidence and mortality was 69.4 /100,000 population (95%CI: 36.8 to 101.9) and 0.33/100,000 population (95%CI, 0.14 to 0.52) per year, respectively. Stratified by continents, Asia had the highest incidence of 130.7/100,000 population (95%CI: 48.3 to 213.1) while Europe has the lowest with 0.7/100,000 population (95%CI: -0.2 to 1.5). The highest mortality was reported in Asia at 0.96/100,000 population (95% CI: 0.22 to 1.70), and Africa 0.44/100,000 population (95%CI: -0.03 to 0.84). Incidence was highest among inhabitants of lower-middle-income countries 132.7/100,000 population (95%CI: 55.4 to 209.9) while mortality was highest in low-income countries at 0.85/100,000 population (95% CI: -0.06 to 2.31).
CONCLUSION
Incidence and mortality rates noted here highlight the global impact of snakebite and underscore the critical need to address the burden of snakebite envenoming. It also reveals that while reported snakebite incidence was higher in lower-middle-income countries, the burden of mortality was greatest among inhabitants of low-income countries, again emphasising the need for greater efforts to tackle this neglected tropical disease.
Topics: Male; Humans; Female; Snake Bites; Antivenins; Incidence; Asia; Prevalence
PubMed: 38574167
DOI: 10.1371/journal.pntd.0012080 -
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