Retrospective survey to evaluate the safety and efficacy of Japanese botulinum antitoxin therapy in Japan

Antimicrob Agents Chemother

Pass

Rosen

et al. 2018

Botulinum neurotoxins (BoNTs), the most poisonous substances known in nature, pose significant concern to health authorities. The only approved therapeutic for botulism is antitoxin. While administered to patients only after symptom onset, antitoxin efficacy is evaluated in animals mostly in relation to time postintoxication regardless of symptoms. This is most likely due to the difficulty in measuring early symptoms of botulism in animals. In this study, a rabbit spirometry model was developed to quantify early respiratory symptoms of type E botulism that were further used as a trigger for treatment. Impaired respiration, in the form of a reduced minute volume, was detected as early as 18.1 ± 2.9 h after intramuscular exposure to 2 rabbit 50% lethal doses (LD) of BoNT serotype E (BoNT/E), preceding any visible symptoms. All rabbits treated with antitoxin immediately following symptom onset survived. Postsymptom antitoxin efficacy was further evaluated in relation to toxin and antitoxin dosages as well as delayed antitoxin administration. Our system enabled us to demonstrate, for the first time, full antitoxin protection of animals treated with antitoxin after the onset of objective and quantitative type E botulism symptoms. This model may be utilized to evaluate the efficacy of antitoxins for additional serotypes of BoNT as well as that of next-generation anti-BoNT drugs that enter affected cells and act when antitoxin is no longer effective.

Section: Discussionmentioning

confidence: 99%

“…Successful treatment with antitoxin was demonstrated for type E botulism as well. The fatality rate of botulism was ϳ30% without antitoxin therapy but dropped to ϳ4 to 8% with the use of antitoxin therapy (18,19). The advantage of early antitoxin administration has also been demonstrated for heptavalent botulism antitoxin (HBAT) (14).…”

mentioning

confidence: 99%

A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy

Antimicrob Agents Chemother

Pass

Rosen

et al. 2018

“…Therefore, at a certain time point, after a critical amount of BoNT molecules are already within neurons, the efficacy of the antitoxin treatment dramatically declines. Indeed, data from studies conducted on animals and from human clinical cases support the notion that there is a critical "therapeutic time window" for effective antitoxin treatment [8,[13][14][15][16][17]. In cases where antitoxin is no longer effective, hospitalization under supportive intensive care and mechanical ventilation may be required.…”

Section: Introductionmentioning

confidence: 99%

A Rabbit Model for the Evaluation of Drugs for Treating the Chronic Phase of Botulism

Torgeman

Dor

et al. 2021

Toxins

Antitoxin, the only licensed drug therapy for botulism, neutralizes circulating botulinum neurotoxin (BoNT). However, antitoxin is no longer effective when a critical amount of BoNT has already entered its target nerve cells. The outcome is a chronic phase of botulism that is characterized by prolonged paralysis. In this stage, blocking toxin activity within cells by next-generation intraneuronal anti-botulinum drugs (INABDs) may shorten the chronic phase of the disease and accelerate recovery. However, there is a lack of adequate animal models that simulate the chronic phase of botulism for evaluating the efficacy of INABDs. Herein, we report the development of a rabbit model for the chronic phase of botulism, induced by intoxication with a sublethal dose of BoNT. Spirometry monitoring enabled us to detect deviations from normal respiration and to quantitatively define the time to symptom onset and disease duration. A 0.85 rabbit intramuscular median lethal dose of BoNT/A elicited the most consistent and prolonged disease duration (mean = 11.8 days, relative standard deviation = 27.9%) that still enabled spontaneous recovery. Post-exposure treatment with antitoxin at various time points significantly shortened the disease duration, providing a proof of concept that the new model is adequate for evaluating novel therapeutics for botulism.

“…Notably, the detection of observed symptoms in animals is subjective and can be difficult to determine. In addition, human patients report early botulism symptoms such as blurred vision, dry mouth and diplopia or just general feelings of being unwell long before the appearance of observable signs, such as ptosis and difficulty in speaking ( Mottate et al, 2016 ). By contrast, animals, especially rodents, do not present such facial symptoms and obviously cannot report their situation ( Hellmich et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

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

Torgeman

Schwartz

Disease Models &Amp; Mechanisms

et al. 2018

Botulinum 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.