RESUMEN
OBJECTIVES: Bacillus anthracis infection is a worldwide zoonosis that affects the most vulnerable population and has a high mortality rate without treatment, especially in non-cutaneous presentations. Cutaneous scarification is still common in some regions of the world for the treatment of certain diseases as part of traditional medicine. We describe a series of cutaneus anthrax from a rural setting in Angola where cutaneus scarification is common. CASE PRESENTATION: This is a retrospective observational study describing a series of cutaneous anthrax cases from Cubal (Angola), many of whom were treated with skin scarification before admission. A total of 26 cases were diagnosed from January 2010 to December 2018. None of the cases were confirmed and eight (30.8%) were probable cases according to the Centers for the Disease Control and Prevention anthrax case definition. The median age was 11 (4.7-30.5) years, 17 (65.4%) had lesions on the head, face, or neck and 15 (57.7%) were treated with cutaneous scarification. Nine (34.6%) patients died. Traditional cutaneous scarification was significantly associated with cutaneous superinfection, respiratory, systemic involvement, and death. CONCLUSION: Our case series points to increased complications and worse outcome of cutaneous anthrax disease if treated with skin scarification.
Asunto(s)
Carbunco , Bacillus anthracis , Enfermedades Cutáneas Bacterianas , Niño , Humanos , Angola , Carbunco/diagnóstico , Carbunco/tratamiento farmacológico , Carbunco/epidemiología , Antibacterianos/uso terapéutico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/epidemiología , Enfermedades Cutáneas Bacterianas/diagnóstico , Estudios RetrospectivosRESUMEN
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, ß-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.
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Carbunco , Antiinfecciosos , Bacillus anthracis , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Animales , Carbunco/tratamiento farmacológico , Carbunco/prevención & control , Antibacterianos/farmacología , Antiinfecciosos/uso terapéutico , Combinación Cilastatina e Imipenem/farmacología , Combinación Cilastatina e Imipenem/uso terapéutico , Ciprofloxacina/uso terapéutico , Doxiciclina/uso terapéutico , Glicopéptidos/farmacología , Glicopéptidos/uso terapéutico , Humanos , Levofloxacino/uso terapéutico , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Modelos Animales , Tetraciclinas/uso terapéutico , Estados Unidos , beta-Lactamas/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: The chemotherapeutic management of infections has become challenging due to the global emergence of antibiotic resistant pathogenic bacteria. The recent expansion of studies on plant-derived natural products has lead to the discovery of a plethora of phytochemicals with the potential to combat bacterial drug resistance via various mechanisms of action. This review paper summarizes the primary antibiotic resistance mechanisms of bacteria and also discusses the antibiotic-potentiating ability of phytoextracts and various classes of isolated phytochemicals in reversing antibiotic resistance in anthrax agent Bacillus anthracis and emerging superbug bacteria. METHODS: Growth inhibitory indices and fractional inhibitory concentration index were applied to evaluate the in vitro synergistic activity of phytoextract-antibiotic combinations in general. FINDINGS: A number of studies have indicated that plant-derived natural compounds are capable of significantly reducing the minimum inhibitory concentration of standard antibiotics by altering drug-resistance mechanisms of B. anthracis and other superbug infection causing bacteria. Phytochemical compounds allicin, oleanolic acid, epigallocatechin gallate and curcumin and Jatropha curcas extracts were exceptional synergistic potentiators of various standard antibiotics. CONCLUSION: Considering these facts, phytochemicals represents a valuable and novel source of bioactive compounds with potent antibiotic synergism to modulate bacterial drug-resistance.
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Carbunco/tratamiento farmacológico , Antibacterianos/farmacología , Bacillus anthracis/química , Sinergismo Farmacológico , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/farmacología , Factores Biológicos , Farmacorresistencia Microbiana/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Fitoquímicos/farmacologíaRESUMEN
Anti-toxin agents for severe B. anthracis infection will only be effective if they add to the benefit of the two mainstays of septic shock management, antibiotic therapy and titrated hemodynamic support. Both of these standard therapies could negate benefits related to anti-toxin treatment. At present, three anthrax anti-toxin antibody preparations have received US Food and Drug Administration (FDA) approval: Raxibacumab, Anthrax Immune Globulin Intravenous (AIGIV) and ETI-204. Each agent is directed at the protective antigen component of lethal and edema toxin. All three agents were compared to placebo in antibiotic-treated animal models of live B. anthracis infection, and Raxibacumab and AIGIV were compared to placebo when combined with standard hemodynamic support in a 96 h canine model of anthrax toxin-associated shock. However, only AIG has actually been administered to a group of infected patients, and this experience was not controlled and offers little insight into the efficacy of the agents. To provide a broader view of the potential effectiveness of these agents, this review examines the controlled preclinical experience either in antibiotic-treated B. anthracis models or in titrated hemodynamic-supported toxin-challenged canines. The strength and weaknesses of these preclinical experiences are discussed.
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Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antígenos Bacterianos , Antitoxinas/uso terapéutico , Toxinas Bacterianas , Choque Séptico/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Bacillus anthracis/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Hemodinámica , Humanos , Inmunoglobulinas Intravenosas , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Inhalational anthrax is rare and clinical experience limited. Expert guidelines recommend treatment with combination antibiotics including protein synthesis-inhibitors to decrease toxin production and increase survival, although evidence is lacking. METHODS: Rhesus macaques exposed to an aerosol of Bacillus anthracis spores were treated with ciprofloxacin, clindamycin, or ciprofloxacin + clindamycin after becoming bacteremic. Circulating anthrax lethal factor and protective antigen were quantitated pretreatment and 1.5 and 12 hours after beginning antibiotics. RESULTS: In the clindamycin group, 8 of 11 (73%) survived demonstrating its efficacy for the first time in inhalational anthrax, compared to 9 of 9 (100%) with ciprofloxacin, and 8 of 11 (73%) with ciprofloxacin + clindamycin. These differences were not statistically significant. There were no significant differences between groups in lethal factor or protective antigen levels from pretreatment to 12 hours after starting antibiotics. Animals that died after clindamycin had a greater incidence of meningitis compared to those given ciprofloxacin or ciprofloxacin + clindamycin, but numbers of animals were very low and no definitive conclusion could be reached. CONCLUSION: Treatment of inhalational anthrax with clindamycin was as effective as ciprofloxacin in the nonhuman primate. Addition of clindamycin to ciprofloxacin did not enhance reduction of circulating toxin levels.
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Carbunco/sangre , Carbunco/prevención & control , Antígenos Bacterianos/sangre , Bacillus anthracis/efectos de los fármacos , Bacillus anthracis/fisiología , Toxinas Bacterianas/sangre , Ciprofloxacina/uso terapéutico , Clindamicina/uso terapéutico , Infecciones del Sistema Respiratorio/sangre , Infecciones del Sistema Respiratorio/prevención & control , Animales , Carbunco/microbiología , Carbunco/mortalidad , Antibacterianos/uso terapéutico , Biomarcadores , Ciprofloxacina/farmacología , Clindamicina/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Macaca mulatta , Pronóstico , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/mortalidad , Resultado del TratamientoRESUMEN
Bacillus anthracis is the causative agent of anthrax disease, presents with high mortality, and has been at the center of bioweapon efforts. The only currently U.S. FDA-approved vaccine to prevent anthrax in humans is anthrax vaccine adsorbed (AVA), which is protective in several animal models and induces neutralizing antibodies against protective antigen (PA), the cell-binding component of anthrax toxin. However, AVA requires a five-course regimen to induce immunity, along with an annual booster, and is composed of undefined culture supernatants from a PA-secreting strain. In addition, it appears to be ineffective against strains that lack anthrax toxin. Here, we investigated a vaccine formulation consisting of recombinant proteins from a surface-localized heme transport system containing near-iron transporter (NEAT) domains and its efficacy as a vaccine for anthrax disease. The cocktail of five NEAT domains was protective against a lethal challenge of inhaled bacillus spores at 3 and 28 weeks after vaccination. The reduction of the formulation to three NEATs (IsdX1, IsdX2, and Bslk) was as effective as a five-NEAT domain cocktail. The adjuvant alum, approved for use in humans, was as protective as Freund's Adjuvant, and protective vaccination correlated with increased anti-NEAT antibody reactivity and reduced bacterial levels in organs. Finally, the passive transfer of anti-NEAT antisera reduced mortality and disease severity, suggesting the protective component is comprised of antibodies. Collectively, these results provide evidence that a vaccine based upon recombinant NEAT proteins should be considered in the development of a next-generation anthrax vaccine.
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Vacunas contra el Carbunco/inmunología , Carbunco/prevención & control , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Neutralizantes/biosíntesis , Antígenos Bacterianos/inmunología , Bacillus anthracis/efectos de los fármacos , Administración por Inhalación , Compuestos de Alumbre/administración & dosificación , Animales , Carbunco/inmunología , Carbunco/microbiología , Carbunco/mortalidad , Vacunas contra el Carbunco/administración & dosificación , Vacunas contra el Carbunco/genética , Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/genética , Bacillus anthracis/inmunología , Bacillus anthracis/patogenicidad , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Proteínas Portadoras/administración & dosificación , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Complemento C5/deficiencia , Femenino , Adyuvante de Freund/administración & dosificación , Humanos , Inmunogenicidad Vacunal , Ratones Noqueados , Análisis de Supervivencia , Vacunación/métodosRESUMEN
The in vivo efficacy of liposomal encapsulated ciprofloxacin in two formulations, lipoquin and apulmiq, were evaluated against the causative agent of anthrax, Bacillus anthracis. Liposomal encapsulated ciprofloxacin is attractive as a therapy since it allows for once daily dosing and achieves higher concentrations of the antibiotic at the site of initial mucosal entry but lower systemic drug concentrations. The in vivo efficacy of lipoquin and apulmiq delivered by intranasal instillation was studied at different doses and schedules in both a post exposure prophylaxis (PEP) therapy model and in a delayed treatment model of murine inhalational anthrax. In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control. Ciprofloxacin, lipoquin and apulmiq provided a high level of protection (87-90%) after 7 days of therapy when administered within 24 hours of exposure. Reducing therapy to only three days still provided protection of 60-87%, if therapy was provided within 24 hours of exposure. If treatment was initiated 48 hours after exposure the survival rate was reduced to 46-65%. These studies suggest that lipoquin and apulmiq may be attractive therapies as PEP and as part of a treatment cocktail for B. anthracis.
Asunto(s)
Carbunco/tratamiento farmacológico , Ciprofloxacina/uso terapéutico , Liposomas/química , Administración Intranasal , Animales , Carbunco/microbiología , Carbunco/mortalidad , Bacillus anthracis/patogenicidad , Ciprofloxacina/química , Modelos Animales de Enfermedad , Composición de Medicamentos , Femenino , Ratones , Ratones Endogámicos BALB C , Tasa de SupervivenciaRESUMEN
The most promising means of controlling anthrax, a lethal zoonotic disease during the early infection stages, entail restricting the resilient infectious form, i.e., the spores from proliferating to replicating bacilli in the host. The extractible antigen (EA1), a major S-layer protein present on the vegetative cells and spores of Bacillus anthracis, is highly immunogenic and protects mice against lethal challenge upon immunization. In the present study, mice were immunized with r-EA1C, the C terminal crystallization domain of EA1, to generate a neutralizing monoclonal antibody EA752-862, that was evaluated for its anti-spore and anti-bacterial properties. The monoclonal antibody EA752-862 had a minimum inhibitory concentration of 0.08 mg/ml, was bactericidal at a concentration of 0.1 mg/ml and resulted in 100% survival of mice against challenge with B. anthracis vegetative cells. Bacterial cell lysis as observed by scanning electron microscopy and nucleic acid leakage assay could be attributed as a possible mechanism for the bactericidal property. The association of mAb EA752-862 with spores inhibits their subsequent germination to vegetative cells in vitro, enhances phagocytosis of the spores and killing of the vegetative cells within the macrophage, and subsequently resulted in 90% survival of mice upon B. anthracis Ames spore challenge. Therefore, owing to its anti-spore and bactericidal properties, the present study demonstrates mAb EA752-862 as an efficient neutralizing antibody that hinders the establishment of early infection before massive multiplication and toxin release takes place.
Asunto(s)
Carbunco/prevención & control , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Bacillus anthracis/inmunología , Esporas Bacterianas/inmunología , Animales , Carbunco/inmunología , Antibacterianos/biosíntesis , Antibacterianos/química , Antibacterianos/farmacología , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Antibacterianos/química , Anticuerpos Antibacterianos/aislamiento & purificación , Anticuerpos Antibacterianos/farmacología , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/aislamiento & purificación , Anticuerpos Neutralizantes/farmacología , Antígenos Bacterianos/inmunología , Bacillus anthracis/efectos de los fármacos , Sitios de Unión , Femenino , Inmunización , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Esporas Bacterianas/efectos de los fármacosRESUMEN
Polysaccharides isolated from natural plants may represent a novel source of vaccine adjuvants. In this research, we focused on a natural plant polysaccharide, PCP-I, which is derived from Poria cocos, a Chinese traditional herbal medicine. We chose the anthrax protective antigen (PA) as a model to evaluate the adjuvant ability of PCP-I in enhancing the immunogenicity and protection of a PA-based anthrax vaccine. According to our results, PCP-I could significantly enhance anthrax specific anti-PA antibodies, toxin-neutralizing antibodies, anti-PA antibody affinity, as well as IgG1 and IgG2a levels. Besides, PCP-I increased the frequency of PA-specific memory B cells, increased the proliferation of PA-specific splenocytes, significantly stimulated the secretion of IL-4, and enhanced the activation of Dendritic cells (DCs) in vitro. The combination of PCP-I and CpG significantly enhanced the level of anti-PA antibodies and neutralizing antibodies, particularly PA-specific IgG2a, and shifted the Th2-bias to a Th1/Th2 balanced response. In addition, PCP-I with or without CpG could significantly improve the survival rate of immunized mice following challenge with the anthrax lethal toxin. These findings suggest that PCP-I may be a promising vaccine adjuvant that warrants further study.
Asunto(s)
Vacunas contra el Carbunco , Carbunco , Bacillus anthracis , Wolfiporia , Animales , Carbunco/prevención & control , Anticuerpos Antibacterianos , Antígenos Bacterianos , Toxinas Bacterianas , Ratones , Ratones Endogámicos BALB C , PolisacáridosRESUMEN
BACKGROUND: Knowledge, attitudes, and practices (KAP) surveys regarding zoonotic diseases are crucial to understanding the extent of knowledge among citizens and for guiding health-related education programs. METHOD: Employing a structured questionnaire, we interviewed residents (n = 388) in three districts of northern Tanzania (Karatu n = 128, Monduli n = 114, Babati n = 146) to assess knowledge, attitudes and reported practices regarding three zoonotic diseases that occur in the region (anthrax, brucellosis, and rabies). We used generalized linear mixed effects models and multi-model inference to identify demographic correlates of knowledge. RESULTS: Proportional average district- and disease- specific knowledge scores ranged from 0.14-0.61. We found positive correlations between age and knowledge of symptoms, causes and treatments of anthrax (three districts), brucellosis (three districts), and rabies (one district). Gender, ethnic identity, formal education and ownership of livestock or dogs had variable effects on knowledge among the interviewed population. Risk perceptions regarding different diseases varied across districts and were positively correlated with knowledge of the specific diseases. Direct interactions with livestock and domestic dogs were reported to occur across all demographic groups, suggesting that most people living in rural settings of our study area are potentially exposed to zoonotic diseases. Behaviors which may favor transmission of specific pathogens (such as consumption of raw milk or meat) were occasionally reported and varied by district. Wildlife was generally regarded as negative or neutral with regard to overall veterinary and human health. CONCLUSION: The combination of variable knowledge about zoonotic diseases in the three districts, reported occurrence of practices that are conducive to pathogen transmission, and previously documented circulation of pathogens causing anthrax, brucellosis and rabies in our study system, call for health education programs embedded in a holistic One Health approach.
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Carbunco/psicología , Brucelosis/psicología , Conocimientos, Actitudes y Práctica en Salud , Rabia/psicología , Zoonosis/psicología , Adulto , Animales , Femenino , Conductas Relacionadas con la Salud , Educación en Salud , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Población Rural , Encuestas y Cuestionarios , Tanzanía/epidemiologíaRESUMEN
Inhalational anthrax caused by Bacillus anthracis, a spore-forming Gram-positive bacterium, is a highly lethal infection. Antibodies targeting the protective antigen (PA) binding component of the toxins have recently been authorized as an adjunct to antibiotics, although no conclusive evidence demonstrates that anthrax antitoxin therapy has any significant benefit. We discuss here the rational basis of anti-PA development regarding the pathogenesis of the disease. We argue that inductive reasoning may induce therapeutic bias. We identified anthrax animal model analysis as another bias. Further studies are needed to assess the benefit of anti-PA antibodies in the treatment of inhalational anthrax, while a clearer consensus should be established around what evidence should be proven in an anthrax model.
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Carbunco/inmunología , Carbunco/terapia , Anticuerpos Antibacterianos/uso terapéutico , Bacillus anthracis/inmunología , Inmunoterapia , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos Bacterianos/inmunología , Antitoxinas/uso terapéutico , Toxinas Bacterianas/inmunología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , HumanosRESUMEN
INTRODUCTION: Cutaneous anthrax (CA), a zoonotic infectious disease is an important endemic public health disease in rural areas around the world, accounting for 95% of anthrax cases. METHODOLOGY: Fifty patients with CA were diagnosed by the presence of characteristic skin lesions and positive response to treatment. Twenty-nine patients had been treated with oral ciprofloxacin or doxycyclin for 14 days and 21 patients had been treated with intramuscular procaine penicillin for 7 days. The demographic risk factors, characteristics and treatment of CA in rural areas were evaluated. The responses to two different systemic medications were compared using χ2 test. RESULTS: Twenty-two males and 28 females were included in this study. The predominant skin lesions were black eschar, ulcer and swelling of the skin. The predilection sites were the hand and fingers. The most common route of contamination for both male and female patients was handling raw meat. The most common occupation was housewife for female patients and animal industry for male patients. The patients under ciprofloxacin or doxycyclin administration responded better to treatment; pain at lesion site and new lesions at the time of treatment were significantly lower. Secondary infection appeared to be higher in patients under procaine penicillin administration, although this difference was not statistically significant. CONCLUSIONS: In rural areas that lack medical facilities with diagnostic tools, in the presence of black eschar, rapid diagnosis and treatment of CA is essential. The administration of a broad-spectrum antibiotic is recommended as the first line treatment of suspected CA.
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Carbunco/tratamiento farmacológico , Carbunco/epidemiología , Ciprofloxacina/uso terapéutico , Doxiciclina/uso terapéutico , Población Rural , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/epidemiología , Adolescente , Adulto , Antibacterianos/uso terapéutico , Femenino , Humanos , Masculino , Carne/microbiología , Persona de Mediana Edad , Adulto JovenAsunto(s)
Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antitoxinas/uso terapéutico , Bacillus anthracis , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Animales , Carbunco/etiología , Carbunco/prevención & control , Antibacterianos/farmacología , Anticuerpos Monoclonales/farmacología , Antitoxinas/farmacología , Bacillus anthracis/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Profilaxis Posexposición/métodos , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/prevención & controlRESUMEN
Bacillus anthracis and Yersinia pestis, the causative agents of anthrax and plague, respectively, are two of the deadliest pathogenic bacteria that have been used as biological warfare agents. Although Biothrax is a licensed vaccine against anthrax, no Food and Drug Administration-approved vaccine exists for plague. Here, we report the development of a dual anthrax-plague nanoparticle vaccine employing bacteriophage (phage) T4 as a platform. Using an in vitro assembly system, the 120- by 86-nm heads (capsids) of phage T4 were arrayed with anthrax and plague antigens fused to the small outer capsid protein Soc (9 kDa). The antigens included the anthrax protective antigen (PA) (83 kDa) and the mutated (mut) capsular antigen F1 and the low-calcium-response V antigen of the type 3 secretion system from Y. pestis (F1mutV) (56 kDa). These viral nanoparticles elicited robust anthrax- and plague-specific immune responses and provided complete protection against inhalational anthrax and/or pneumonic plague in three animal challenge models, namely, mice, rats, and rabbits. Protection was demonstrated even when the animals were simultaneously challenged with lethal doses of both anthrax lethal toxin and Y. pestis CO92 bacteria. Unlike the traditional subunit vaccines, the phage T4 vaccine uses a highly stable nanoparticle scaffold, provides multivalency, requires no adjuvant, and elicits broad T-helper 1 and 2 immune responses that are essential for complete clearance of bacteria during infection. Therefore, phage T4 is a unique nanoparticle platform to formulate multivalent vaccines against high-risk pathogens for national preparedness against potential bioterror attacks and emerging infections.IMPORTANCE Following the deadly anthrax attacks of 2001, the Centers for Disease Control and Prevention (CDC) determined that Bacillus anthracis and Yersinia pestis that cause anthrax and plague, respectively, are two Tier 1 select agents that pose the greatest threat to the national security of the United States. Both cause rapid death, in 3 to 6 days, of exposed individuals. We engineered a virus nanoparticle vaccine using bacteriophage T4 by incorporating key antigens of both B. anthracis and Y. pestis into one formulation. Two doses of this vaccine provided complete protection against both inhalational anthrax and pneumonic plague in animal models. This dual anthrax-plague vaccine is a strong candidate for stockpiling against a potential bioterror attack involving either one or both of these biothreat agents. Further, our results establish the T4 nanoparticle as a novel platform to develop multivalent vaccines against pathogens of high public health significance.
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Vacunas contra el Carbunco/inmunología , Carbunco/prevención & control , Antígenos Bacterianos/inmunología , Bacteriófago T4 , Vacuna contra la Peste/inmunología , Peste/prevención & control , Infecciones del Sistema Respiratorio/prevención & control , Animales , Anticuerpos Antibacterianos/sangre , Bacillus anthracis , Proteínas Bacterianas/inmunología , Toxinas Bacterianas/inmunología , Proteínas de la Cápside/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Nanopartículas , Proteínas Citotóxicas Formadoras de Poros/inmunología , Conejos , Ratas , Células TH1/inmunología , Células Th2/inmunología , Yersinia pestisRESUMEN
Treatment of anthrax is challenging, especially during the advanced stages of the disease. Recently, the Centers for Disease Control and Prevention (CDC) updated its recommendations for postexposure prophylaxis and treatment of exposed populations (before and after symptom onset). These recommendations distinguished, for the first time, between systemic disease with and without meningitis, a common and serious complication of anthrax. The CDC considers all systemic cases meningeal unless positively proven otherwise. The treatment of patients suffering from systemic anthrax with suspected or confirmed meningitis includes the combination of three antibiotics, i.e., a fluoroquinolone (levofloxacin or ciprofloxacin), a ß-lactam (meropenem or imipenem), and a protein synthesis inhibitor (linezolid or clindamycin). In addition, treatment with an antitoxin (anti-protective antigen antibodies) and dexamethasone should be applied. Since the efficacy of most of these treatments has not been demonstrated, especially in animal meningitis models, we developed an anthrax meningitis model in rabbits and tested several of these recommendations. We demonstrated that, in this model, ciprofloxacin, linezolid, and meropenem were ineffective as single treatments, while clindamycin was highly effective. Furthermore, combined treatments of ciprofloxacin and linezolid or ciprofloxacin and dexamethasone failed in treating rabbits with meningitis. We demonstrated that dexamethasone actually hindered blood-brain barrier penetration by antibiotics, reducing the effectiveness of antibiotic treatment of anthrax meningitis in this rabbit model.
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Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antitoxinas/uso terapéutico , Bacillus anthracis/efectos de los fármacos , Meningitis Bacterianas/tratamiento farmacológico , Animales , Carbunco/patología , Sistema Nervioso Central/microbiología , Sistema Nervioso Central/patología , Ciprofloxacina/uso terapéutico , Clindamicina/uso terapéutico , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Combinación de Medicamentos , Imipenem/uso terapéutico , Levofloxacino/uso terapéutico , Linezolid/uso terapéutico , Meningitis Bacterianas/microbiología , Meningitis Bacterianas/patología , Meropenem/uso terapéutico , Conejos , Insuficiencia del TratamientoRESUMEN
Animal models have played a pivotal role in all stages of vaccine development. Their predictive value for vaccine effectiveness depends on the pathogen, the robustness of the animal challenge model, and the correlates of protection (if known). This article will cover key questions regarding bridging animal studies to efficacy trials in humans. Examples include human papillomavirus (HPV) vaccine in which animal protection after vaccination with heterologous prototype virus-like particles (VLPs) predicted successful efficacy trials in humans, and a recent approval of anthrax vaccine in accordance with the "Animal Rule." The establishment of animal models predictive of vaccine effectiveness in humans has been fraught with difficulties with low success rate to date. Challenges facing the use of animal models for vaccine development against Ebola and HIV will be discussed.
Asunto(s)
Modelos Animales de Enfermedad , Vacunas/uso terapéutico , Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/uso terapéutico , Animales , Carbunco/inmunología , Vacunas contra el Carbunco/efectos adversos , Vacunas contra el Carbunco/uso terapéutico , Aprobación de Drogas , Evaluación Preclínica de Medicamentos , Vacunas contra el Virus del Ébola/efectos adversos , Vacunas contra el Virus del Ébola/uso terapéutico , Humanos , Papillomaviridae/inmunología , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/uso terapéutico , Prueba de Estudio Conceptual , Especificidad de la EspecieRESUMEN
Inhalational anthrax is a highly lethal infection caused by Bacillus anthracis and a serious bioterrorism threat. Protective antigen (PA) is a critical component required for the virulence of Bacillus anthracis. Obiltoxaximab, a high-affinity monoclonal antibody that neutralizes PA, is approved in the United States for intravenous use for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate. Here, we explored the safety, pharmacokinetics (PK), and immunogenicity of obiltoxaximab administered by intramuscular injection at doses of 4, 8, 16, 20, and 24 mg/kg in healthy humans. Systemic exposures were approximately dose proportional, maximum serum concentrations were observed after 6-9 days, and terminal half-life ranged from 16 to 23 days. Average absolute intramuscular bioavailability was 64%. Obiltoxaximab was well tolerated, and local tolerability was acceptable up to 24 mg/kg intramuscularly, up to 6 injections per dose, and up to 5 mL per injection. No injection-site abscesses or hypersensitivity reactions occurred; no subjects developed treatment-emergent antitherapeutic antibodies over the study period of 71 days.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antitoxinas/efectos adversos , Hipersensibilidad a las Drogas/inmunología , Carbunco/tratamiento farmacológico , Carbunco/inmunología , Anticuerpos Monoclonales/administración & dosificación , Antígenos Bacterianos/inmunología , Antitoxinas/administración & dosificación , Área Bajo la Curva , Bacillus anthracis/efectos de los fármacos , Bacillus anthracis/inmunología , Toxinas Bacterianas/inmunología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Voluntarios Sanos , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/inmunologíaRESUMEN
The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD50). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.
Asunto(s)
Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Bacillus anthracis/efectos de los fármacos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Tetraciclinas/uso terapéutico , Animales , Carbunco/microbiología , Carbunco/mortalidad , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Antígenos Bacterianos/inmunología , Bacillus anthracis/inmunología , Toxinas Bacterianas/inmunología , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Profilaxis Posexposición/métodos , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/mortalidad , Esporas Bacterianas , Tasa de Supervivencia , Tetraciclinas/farmacocinéticaRESUMEN
Bacillus anthracis is considered a likely agent to be used as a bioweapon, and the use of a strain resistant to the first-line antimicrobial treatments is a concern. We determined treatment efficacies against a ciprofloxacin-resistant strain of B. anthracis (Cipr Ames) in a murine inhalational anthrax model. Ten groups of 46 BALB/c mice were exposed by inhalation to 7 to 35 times the 50% lethal dose (LD50) of B. anthracis Cipr Ames spores. Commencing at 36 h postexposure, groups were administered intraperitoneal doses of sterile water for injections (SWI) and ciprofloxacin alone (control groups), or ciprofloxacin combined with two antimicrobials, including meropenem-linezolid, meropenem-clindamycin, meropenem-rifampin, meropenem-doxycycline, penicillin-linezolid, penicillin-doxycycline, rifampin-linezolid, and rifampin-clindamycin, at appropriate dosing intervals (6 or 12 h) for the respective antibiotics. Ten mice per group were treated for 14 days and observed until day 28. The remaining animals were euthanized every 6 to 12 h, and blood, lungs, and spleens were collected for lethal factor (LF) and/or bacterial load determinations. All combination groups showed significant survival over the SWI and ciprofloxacin controls: meropenem-linezolid (P = 0.004), meropenem-clindamycin (P = 0.005), meropenem-rifampin (P = 0.012), meropenem-doxycycline (P = 0.032), penicillin-doxycycline (P = 0.012), penicillin-linezolid (P = 0.026), rifampin-linezolid (P = 0.001), and rifampin-clindamycin (P = 0.032). In controls, blood, lung, and spleen bacterial counts increased to terminal endpoints. In combination treatment groups, blood and spleen bacterial counts showed low/no colonies after 24-h treatments. The LF fell below the detection limits for all combination groups yet remained elevated in control groups. Combinations with linezolid had the greatest inhibitory effect on mean LF levels.
Asunto(s)
Carbunco/tratamiento farmacológico , Antibacterianos/farmacología , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Administración por Inhalación , Animales , Bacillus anthracis/efectos de los fármacos , Ciprofloxacina/farmacología , Clindamicina/farmacología , Modelos Animales de Enfermedad , Doxiciclina/farmacología , Quimioterapia Combinada/métodos , Femenino , Linezolid/farmacología , Meropenem , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana/métodos , Rifampin/farmacología , Esporas Bacterianas/efectos de los fármacos , Tienamicinas/farmacologíaRESUMEN
Bacillus anthracis, the etiological agent of anthrax, is listed as a category A biothreat agent by the United States Centers for Disease Control and Prevention. The virulence of the organism is due to expression of two exotoxins and capsule, which interfere with host cellular signaling, alter host water homeostasis and inhibit phagocytosis of the pathogen, respectively. Concerns regarding the past and possible future use of B. anthracis as a bioterrorism agent have resulted in an impetus to develop more effective protective measures and therapeutics. In this study, green tea was found to inhibit the in vitro growth of B. anthracis. Epigallocatechin-3-gallate (EGCG), a compound found abundantly in green tea, was shown to be responsible for this activity. EGCG was bactericidal against both the attenuated B. anthracis ANR and the virulent encapsulated B. anthracis Ames strain. This study highlights the antimicrobial activity of green tea and EGCG against anthrax and suggests the need for further investigation of EGCG as a therapeutic candidate against B. anthracis.