Antitoxin Treatment Research Articles

Toxin inhibition: Examining tetracyclines, clindamycin, and linezolid.

The purpose of this review is to discuss the role of toxin inhibition in select infections and to provide recommendations for appropriate antimicrobial selection when toxin inhibition is indicated. For select organisms, specifically Clostridioides difficile, Staphylococcus aureus, and Streptococcus pyogenes, toxin production plays an integral role in overall disease pathogenesis and progression. Some expert recommendations include utilization of an antimicrobial with toxin inhibition properties as primary or adjunctive therapy for certain infections due to these organisms, but evolving data have made the choice of antitoxin agent less clear. Clindamycin has been the long-standing standard of care agent for toxin inhibition in necrotizing S. aureus and S. pyogenes infections, but linezolid shows promise as an alternative either in the setting of drug shortages or simply when clindamycin is not optimal, while tetracyclines require further study for this indication. The role for adjunctive toxin inhibition in C. difficile infection (CDI) is less defined, as current first-line therapies already have antitoxin properties. Toxin inhibition plays a key role in successful management of patients with infections due to toxin-producing organisms. Adjunctive therapy with a tetracycline could be considered in severe, fulminant CDI, but the associated benefit is variable. The benefit of antitoxin treatment for necrotizing S. aureus and S. pyogenes has been more consistently documented. Recent studies support linezolid as an alternative to clindamycin as an adjunctive S. aureus treatment or as monotherapy when appropriate.

Neurotropic Effect of Botulinum Toxin and the Potential of Specific Serum Therapy in Botulism (Review)

INTRODUCTION. The outbreak of foodborne botulism that occurred in Russia in June 2024 once again demonstrated the danger of this rather rare but severe infectious disease caused by ingesting botulinum neurotoxin. The only aetiological treatment for botulism is currently the administration of antitoxins against various serotypes of botulinum toxin. However, antitoxins do not provide rapid regression of neurological symptoms, which may raise doubts about the effectiveness of the selected treatment option. It is impossible to assess the potential of specific treatment without understanding the mechanisms of action of botulinum toxin and antitoxin.AIM. This study aimed to systemise information on the mechanism underlying the damaging effect of botulinum neurotoxin, aetiological antitoxin treatment, and the patient recovery process.DISCUSSION. The mechanism underlying the damaging effect of botulinum neurotoxin consists in the destruction of SNARE proteins in presynaptic cholinergic nerve terminals, which disrupts the release of acetylcholine into the synaptic cleft and the transmission of excitation between neurons. The lack of acetylcholine at the neuromuscular junction results in a distinctive form of persistent flaccid paralysis. The specific mechanism of action of botulinum toxin determines the treatment strategy, which includes a set of life-sustaining measures and the earliest possible antiserum administration. If used within 48 hours from the onset of symptoms, botulinum antitoxin binds botulinum toxin circulating in the blood, which stops the progression of paralysis and prevents further disorders in patients. However, botulinum antitoxin cannot neutralise the effect of the toxin that has already bound to nerve receptors, so clinical symptoms may worsen within 12 hours after antiserum administration. Restoration of normal neuronal transmission occurs through the formation of new axonal sprouts and can take a long time.CONCLUSIONS. Antitoxin administration is effective and irreplaceable in the aetiological treatment of botulism. Nevertheless, the duration of recovery depends on the speed of reinnervation and restoration of transmission at the neuromuscular junction.

Quantifying in vitro B. anthracis growth and PA production and decay: a mathematical modelling approach

Protective antigen (PA) is a protein produced by Bacillus anthracis. It forms part of the anthrax toxin and is a key immunogen in US and UK anthrax vaccines. In this study, we have conducted experiments to quantify PA in the supernatants of cultures of B. anthracis Sterne strain, which is the strain used in the manufacture of the UK anthrax vaccine. Then, for the first time, we quantify PA production and degradation via mathematical modelling and Bayesian statistical techniques, making use of this new experimental data as well as two other independent published data sets. We propose a single mathematical model, in terms of delay differential equations (DDEs), which can explain the in vitro dynamics of all three data sets. Since we did not heat activate the B. anthracis spores prior to inoculation, germination occurred much slower in our experiments, allowing us to calibrate two additional parameters with respect to the other data sets. Our model is able to distinguish between natural PA decay and that triggered by bacteria via proteases. There is promising consistency between the different independent data sets for most of the parameter estimates. The quantitative characterisation of B. anthracis PA production and degradation obtained here will contribute towards the ambition to include a realistic description of toxin dynamics, the host immune response, and anti-toxin treatments in future mechanistic models of anthrax infection.

Clinical characteristics and prognosis of 8 cases of severe infant botulism

Objective: To summarize the clinical characteristics and prognosis of severe infant botulism and evaluate the therapeutic effect of botulinum antitoxin in the pediatric intensive care unit (PICU). Methods: The clinical data of 8 cases diagnosed with infantile botulism were retrospectively analyzed in the PICU of Beijing Children's Hospital from October 2019 to August 2023. Data of basic demographic information, clinical manifestations, laboratory tests, treatment and prognosis of each child were collected and analyzed using descriptive statistical methods. Results: Eight laboratory-confirmed cases of infant botulism were included in this study, all of which were male infants with an age of 6.0 (3.3,6.8) months. Three of the children were from Inner Mongolia Autonomous Region, 2 of them were from Hebei, and the other 3 were from Beijing, Shandong and Xinjiang Uyghur Autonomous Region, respectively. All the patients were previously healthy. In 4 of these cases, the possible cause was the ingestion of either honey and its products or sealed pickled food by the mother or child before the onset of the disease. The first symptom was poor milk intake (4 cases), followed by shallow shortness of breath (7 cases), limb weakness (7 cases) and so on. The typical signs were bilateral dilated pupils (8 cases) and decreased limb muscle strength (8 cases). The main subtype was type B (7 cases), and only 1 case was classified as type A. Six of the children were treated with antitoxin therapy for a duration of 24 (19, 49) d. Seven of them had invasive mechanical ventilation. All the patients survived upon discharge with a follow-up period of 29 d to 3 years and 8 months. Six patients had fully recovered, and 2 recently discharged patients were gradually recovering. Conclusions: For infants with suspected contact or ingestion of botulinum and presented with bilateral pupillary paralysis, muscle weakness and clear consciousness, the stool should be collected for diagnostic testing using a mouse bioassay as soon as possible. Type B was the most common type. The antitoxin treatment was effectiveness and the prognosis was well.

Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.

Ricin, a highly potent plant-derived toxin, is considered a potential bioterrorism weapon due to its pronounced toxicity, high availability, and ease of preparation. Acute damage following pulmonary ricinosis is characterized by local cytokine storm, massive neutrophil infiltration, and edema formation, resulting in respiratory insufficiency and death. A designated equine polyclonal antibody-based (antitoxin) treatment was developed in our laboratory and proved efficacious in alleviating lung injury and increasing survival rates. Although short-term pathogenesis was thoroughly characterized in antitoxin-treated mice, the long-term damage in surviving mice was never determined. In this study, long-term consequences of ricin intoxication were evaluated 30 days post-exposure in mice that survived antitoxin treatment. Significant pulmonary sequelae were demonstrated in surviving antitoxin-treated mice, as reflected by prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance. The presented data highlight, for the first time to our knowledge, the possibility of long-term damage development in mice that survived lethal-dose pulmonary exposure to ricin due to antitoxin treatment.

Infant Botulism.

Infant Botulism.

Targeting the Inside of Cells with Biologicals: Toxin Routes in a Therapeutic Context.

Numerous toxins translocate to the cytosol in order to fulfil their function. This demonstrates the existence of routes for proteins from the extracellular space to the cytosol. Understanding these routes is relevant to multiple aspects related to therapeutic applications. These include the development of anti-toxin treatments, the potential use of toxins as shuttles for delivering macromolecular cargo to the cytosol or the use of drugs based on toxins. Compared with other strategies for delivery, such as chemicals as carriers for macromolecular delivery or physical methods like electroporation, toxin routes present paths into the cell that potentially cause less damage and can be specifically targeted. The efficiency of delivery via toxin routes is limited. However, low-delivery efficiencies can be entirely sufficient, if delivered cargoes possess an amplification effect or if very few molecules are sufficient for inducing the desired effects. This is known for example from RNA-based vaccines that have been developed during the coronavirus disease 2019 pandemic as well as for other approved RNA-based drugs, which elicited the desired effect despite their typically low delivery efficiencies. The different mechanisms by which toxins enter cells may have implications for their technological utility. We review the mechanistic principles of the translocation pathway of toxins from the extracellular space to the cytosol, the delivery efficiencies, and therapeutic strategies or applications that exploit toxin routes for intracellular delivery.

Botulism in Spain: Epidemiology and Outcomes of Antitoxin Treatment, 1997–2019

Botulism is a low incidence but potentially fatal infectious disease caused by neurotoxins produced mainly by Clostridium botulinum. There are different routes of acquisition, food-borne and infant/intestinal being the most frequent presentation, and antitoxin is the treatment of choice in all cases. In Spain, botulism is under surveillance, and case reporting is mandatory. This retrospective study attempts to provide a more complete picture of the epidemiology of botulism in Spain from 1997 to 2019 and an assessment of the treatment, including the relationship between a delay in antitoxin administration and the length of hospitalization using the Cox proportional hazards test and Kruskal-Wallis test, and an approach to the frequency of adverse events, issues for which no previous national data have been published. Eight of the 44 outbreaks were associated with contaminated commercial foods involving ≤7 cases/outbreak; preserved vegetables were the main source of infection, followed by fish products; early antitoxin administration significantly reduces the hospital stay, and adverse reactions to the antitoxin affect around 3% of treated cases.

Antitoxin Use in the Prevention and Treatment of Anthrax Disease: A Systematic Review.

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. 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. 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. 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.

Non-invasive management of suppurative skin nodule (metastatic cutaneous abscess): a suspected case of tuberculous gumma: “a case report.”

The paradigm of cutaneous adverse drug reactions (CADRs) due to the resurgence of Dushi-visha (~cumulative poison) is less reported. Clinical evidence of Dushi-visha is not commonly diagnosed in the clinics. This is the era of polypharmacy; the long duration of medication along with a multi-therapeutic approach causes drug intolerance and complicates with reduced assimilation. Improper elimination causes an increased concentration of these medicines in the plasma and produces toxic side effects. These cumulative endotoxins are termed as Dushi-visha in Ayurveda. A 60-year-old male diagnosed with abdominal tuberculosis had undergone anti-tubercular treatment and suffered from pyogenic abscess over back, and rectal area, around the umbilical area. Pus culture isolated coagulase-negative Staphylococcus. In due course of time, the patient took treatment but abscess continued to develop over different parts of the body. This is a suspected case of tuberculous gumma based on clinical presentation and history of the disease, and according to Ayurveda, this is a case of Dushi-visha. The classical treatment of an abscess is focussed on incision and drainage, but this case was handled with Vishaghna chikitsa (~anti-toxin treatment) and other potential treatments considering the resurgence of Dushi-visha without any surgical intervention. Many conditions, which generally seem idiopathic due to lack of proper history, may be due to reactivation of Dushi-visha. This case report opens up the way to clinically identify and potentially treat the condition with Ayurveda.

COVID-19 prediction through X-ray images using transfer learning-based hybrid deep learning approach

Over the past few months, the campaign against COVID-19 has developed into one of the world's most sought anti-toxin treatment scheme. It is fundamental to distinguish cases of COVID-19 precisely and quickly to help avoid this pandemic from taking a wrong turn with a proper medical reasoning and solution. While Reverse-Transcription Polymerase Chain Reaction (RT-PCR) has been useful in detection of corona virus, chest X-Ray techniques has proven to be more successful and beneficial at detection of the effects of virus. With the increase in COVID patients and the X-Rays done, it is currently possible to classify the X-Ray reports with transfer learning. This paper presents a novel approach, i.e., Hybrid Convolutional Neural Network (HDCNN), which integrates Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN) architecture for the finding of COVID-19 using the chest X-Ray. The transfer learning approach, namely slope weighted activation class planning (Grad-CAMs), is used with HDCNN to display images responsible for taking decisions. In this study, HDCNN is compared with other CNNs such as Inception-v3, ShuffleNet, SqueezeNet, VGG-19 and DenseNet. As a result, HDCNN has achieved an accuracy of 98.20%, precision of 97.31%, recall of 97.1% and F1 score of 0.97. Compared to other current deep learning models, the HDCNN has achieved better results, and this can be used for diagnosis purpose after proper approvals.

A Review of the Efficacy of FDA-Approved B. anthracis Anti-Toxin Agents When Combined with Antibiotic or Hemodynamic Support in Infection- or Toxin-Challenged Preclinical Models.

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.

RETRACTED: Application of IoT image detection and DWI combined with serum PCT detection in bone infection

Abstract IOT and DWI based image processing have been independently used for various purposes. The application field of agriculture exists and has achieved some success, but no combination of these two technologies still exists. For example, conventional biological markers such as C-reactive protein, white blood cells, the decision sensitive, sufficient heat treatment of the infection in the guide, without erythrocyte sedimentation rate, or specific clinical symptoms and signs. Procalcitonin (PCT) comprises several large invasive pathogenic bacteria, fungi, and the response of synthetic tissues and organs of the parasite. They are expanding proof backings the utilization of PCT as a marker to improve the determination of bacterial contaminations, prompting anti-infection treatment. Clinically, PCT levels and empiric anti-microbial treatment and the wellspring of the disease require anti-toxin treatment. The reason for the evaluation is, to sum up, the ebb and flow proof PCT assortment of irresistible illnesses clinical climate, and the unwavering quality of denoting an outline of the direction of a specialist with helpful likely anti-toxins.

Establishment of a Novel Oral Murine Model of Ricin Intoxication and Efficacy Assessment of Ovine Ricin Antitoxins.

Ricin, produced from the castor beans of Ricinus communis, is a cytotoxin that exerts its action by inactivating ribosomes and causing cell death. Accidental (e.g., ingestion of castor beans) and/or intentional (e.g., suicide) exposure to ricin through the oral route is an area of concern from a public health perspective and no current licensed medical interventions exist to protect from the action of the toxin. Therefore, we examined the oral toxicity of ricin in Balb/C mice and developed a robust food deprivation model of ricin oral intoxication that has enabled the assessment of potential antitoxin treatments. A lethal oral dose was identified and mice were found to succumb to the toxin within 48 h of exposure. We then examined whether a despeciated ovine F(ab′)2 antibody fragment, that had previously been demonstrated to protect mice from exposure to aerosolised ricin, could also protect against oral intoxication. Mice were challenged orally with an LD99 of ricin, and 89 and 44% of mice exposed to this otherwise lethal exposure survived after receiving either the parent anti-ricin IgG or F(ab′)2, respectively. Combined with our previous work, these results further highlight the benefit of ovine-derived polyclonal antibody antitoxin in providing post-exposure protection against ricin intoxication.

The Return of the Dragon Faucial Diphtheria

Diphtheria is caused by toxin producing strains of gram positive bacilli Corynebacterium diphtheriae. Epidemics occur when immunization coverage is inadequate. The characteristic pseudomembrane of diphtheria is formed by necrotic tissue, inflammatory exudates, fibrin and colonies of the organism and bleeds on removal. Other differentials of membranous tonsillitis include infectious mononucleosis, streptococcal pharyngitis and Vincent’s angina. Diphtheria should be considered in all cases of membranous tonsillitis in the appropriate epidemiological background, and antitoxin treatment should be initiated promptly.

The Return of the Dragon Faucial Diphtheria

Diphtheria is caused by toxin producing strains of gram positive bacilli Corynebacterium diphtheriae. Epidemics occur when immunization coverage is inadequate. The characteristic pseudomembrane of diphtheria is formed by necrotic tissue, inflammatory exudates, fibrin and colonies of the organism and bleeds on removal. Other differentials of membranous tonsillitis include infectious mononucleosis, streptococcal pharyngitis and Vincent’s angina. Diphtheria should be considered in all cases of membranous tonsillitis in the appropriate epidemiological background, and antitoxin treatment should be initiated promptly.

Cost savings associated with timely treatment of botulism with botulism antitoxin heptavalent product.

BackgroundBotulism is a rare, serious, and sometimes fatal paralytic illness caused by exposure to neurotoxins produced by Clostridium botulinum bacteria. Patients with documented or suspected exposure to botulinum toxin serotypes A-G can be treated with BAT® [Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)–(Equine)] product, which was approved in 2013 in the United States (US). Patients with botulism have demonstrated greater clinical benefit with early BAT product treatment (≤2 days from symptom onset) versus late treatment (>2 days).ObjectiveEconomic outcomes associated with improved clinical outcome benefits of BAT product treatment have not yet been reported. This ad hoc analysis aimed to estimate and compare costs associated with hospitalization, intensive care unit stay, and mechanical ventilation for patients with botulism administered BAT product treatment early or late.MethodsClinical outcomes data for early and late BAT product treatment were obtained from a patient registry conducted between October 2014 and July 2017. Total per patient mean daily costs were estimated based on information from published literature. Total population costs per group were calculated by multiplying estimated mean cost per patient by the average annual number of non-infant botulism cases in the US.ResultsMean per patient costs were 2.5 times lower for patients treated with BAT product early versus late. On average in the US, early BAT product treatment could save greater than $3.9 million per year versus late treatment.ConclusionSubstantial economic savings can be achieved with early BAT product treatment. The findings support the recommendation for public health authorities to ensure antitoxin treatment is readily available in sufficient quantities to manage botulism cases, including sporadic outbreaks and potential mass exposure biological attacks.

Safety and Clinical Outcomes of an Equine-derived Heptavalent Botulinum Antitoxin Treatment for Confirmed or Suspected Botulism in the United States.

Botulism is a rare, life-threatening paralytic illness. Botulism Antitoxin Heptavalent (A,B,C,D,E,F,G)-(Equine) (BAT) manufactured by Emergent BioSolutions Canada Inc is an equine-derived heptavalent botulinum antitoxin product indicated for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A-G in adults and pediatric patients. BAT product was US-licensed in 2013. In the United States, from October 2014 through July 2017, safety and clinical outcomes data were collected under a registry for patients treated with BAT product. Registry patients had a median age of 51 years (range, 32 days to 92 years). Among 162 patients, 7 (4.3%) experienced BAT product-related serious adverse events, including 1 (0.6%) report each of pneumonia, pneumonia aspiration, ventricular tachycardia, upper gastrointestinal hemorrhage, anaphylactic reaction, acute kidney injury, and acute myocardial infarction. Thirty-one (19.1%) patients had 41 BAT product-related adverse events. Six (3.7%) deaths were reported in the registry. All deaths were attributed to the underlying illness and were assessed as unlikely related to BAT product. Among 113 (69.8%) patients with a final diagnosis of botulism, those treated early (≤2 days) spent fewer days in the hospital (5 vs 15.5 days), in the intensive care unit (ICU) (4 vs 12 days), and on mechanical ventilation (6 vs 14.5 days) than those treated late (>2 days), respectively. BAT product was well tolerated in patients. Treatment with BAT product at ≤2 days of symptom onset was associated with shorter hospital and ICU stays, and shorter duration and need for mechanical ventilation, showing clinical benefit associated with early treatment.

Clinical features and outcomes of tetanus: a retrospective study.

Background: Tetanus is a serious disease resulting in muscle spasm, and even death.Methods: A retrospective, single-center study was conducted by analyzing demographic and clinical parameters.Results: The study included 12 males (70.6%) and 5 females (29.4%). The mean age of the patients was 56.71±9.05 years. Patient occupations included farming (47.0%), retired (23.5), homebound (23.5), and workers (6.0%). The causes of patient injuries were as follows: metal injury (52.9%), deep injury (29.4%), electrical injury (5.9%), maxillofacial region and knee injury (5.9%), and skin ulceration (5.9%). The disease duration ranged from 3 to 36 days, and the mean incubation period was 12.65±10.17 days. Four patients had co-morbidities. The infected patients were given tetanus antitoxin (TAT) and antibiotics treatment. One patient was given continuous renal replacement therapy (CRRT) and only one patient died.Conclusions: In our department, although tetanus is a serious disease, with effective treatment, patients have reasonable cure and low death rates.

Studying the differential efficacy of postsymptom antitoxin treatment in type A versus type B botulism using a rabbit spirometry model.

ABSTRACTBotulinum neurotoxin (BoNT) serotypes A, B and E are responsible for most cases of human botulism. The only approved therapy for botulism is antitoxin treatment administered to patients after symptom onset. However, a recent meta-analysis of antitoxin efficacy in human botulism cases over the past century concluded that a statistically significant reduction in mortality is associated with the use of type E and type A antitoxin, but not with type B antitoxin. Animal models could be highly valuable in studying postsymptom antitoxin efficacy (PSAE). However, the few attempts to evaluate PSAE in animals relied on subjective observations and showed ∼50% protection. Recently, we developed a novel spirometry model for the quantitative evaluation of PSAE in rabbits and used it to demonstrate full protection against BoNT/E. In the current study, a comparative evaluation of PSAE in botulism types A and B was conducted using this quantitative respiratory model. A lethal dose of each toxin induced a comparable course of disease both in terms of time to symptoms (TTS, 41.9±1.3 and 40.6±1.1 h, respectively) and of time to death (TTD, 71.3±3.1 and 66.3±1.7 h, respectively). However, in accordance with the differential serotypic PSAE observed in humans, postsymptom antitoxin treatment was fully effective only in BoNT/A-intoxicated rabbits. This serotypic divergence was reflected by a positive and statistically significant correlation between TTS and TTD in BoNT/A-intoxicated rabbits (r=0.91, P=0.0006), but not in those intoxicated with BoNT/B (r=0.06, P=0.88). The rabbit spirometry system might be useful in the evaluation toolkit of botulism therapeutics, including those under development and intended to act when antitoxin is no longer effective.