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Experimental Therapeutics

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

Eran Diamant, Avi Pass, Osnat Rosen, Alon Ben David, Amram Torgeman, Ada Barnea, Arnon Tal, Amir Rosner, Ran Zichel
Eran Diamant
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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Avi Pass
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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Osnat Rosen
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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Alon Ben David
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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Amram Torgeman
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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Ada Barnea
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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Arnon Tal
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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Amir Rosner
bVeterinary Center for Pre-clinical Research, Israel Institute for Biological Research, Ness Ziona, Israel
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Ran Zichel
aDepartment of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel
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DOI: 10.1128/AAC.02379-17
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    FIG 1

    Rabbit respiratory parameters. Shown is a representative depiction of individual data collected from 14 independent measurements of a preexposed, unanesthetized rabbit. (A) Minute volume (MV) is the air volume consumption per minute. (B) Rate is the number of inhalations per minute. (C) Tidal volume (TV) is the air volume per inhalation. UL, upper limit; LL, lower limit; M, mean (UL = M + 2 × SD; LL = M − 2 × SD).

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    FIG 2

    Characterization of respiration physiology in intoxicated rabbits. Following exposure to 2 RbIMLD50, respiration parameters were analyzed and tested for suitability to serve as clinical symptoms. (A) Time from intoxication to a statistically significant deviation from the mean value of each of the three parameters. For each pair of parameters, means were compared by a t test. (B) The time to symptoms (TTS) was determined for each rabbit (n = 9) based on the MV parameter. TPE, time postexposure. (C) Correlation between time to death (TTD) and TTS for the MV symptom.

  • FIG 3
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    FIG 3

    Antitoxin is fully protective when administered immediately after symptom onset. (Top) MV values were monitored before and after exposure to 2 RbIMLD50 of BoNT/E with 30 IU/kg of antitoxin (left) or without antitoxin (control) (right). UL, upper limit; LL, lower limit; M, mean. (Bottom) Inhalation profile during the disease course, expressed as MV (liters per minute) by time (seconds). For each time point, the MV value is indicated in a rectangle with a white background (normal) or a gray background (symptomatic). TPE, time postexposure. Data are representative of results from at least 4 treated and 9 untreated control rabbits, collected in 4 independent experiments.

  • FIG 4
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    FIG 4

    Efficacy of delayed antitoxin treatment following symptom onset. Rabbits were intoxicated with 2 RbIMLD50 of BoNT/E and treated with 30 IU/kg of antitoxin at different time points following the onset of the MV clinical symptom: immediately (0 h) and 2, 5, and 8 h after symptom onset. Each plotted symbol refers to an individual animal.

  • FIG 5
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    FIG 5

    Antitoxin treatment efficacy is dependent on toxin and antitoxin doses. (A) Rabbits were exposed to either 2 or 5 RbIMLD50 of BoNT/E without antitoxin treatment, and the TTS and TTD were then monitored and compared. (B) Rabbits were exposed to either 2 or 5 RbIMLD50 of BoNT/E and treated with either 30 or 120 IU/kg of antitoxin immediately after symptom onset. Protection levels among the different toxin and antitoxin combinations were compared. (C) Influence of antitoxin dose on TTD. Each plotted symbol refers to data for an individual animal.

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A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy
Eran Diamant, Avi Pass, Osnat Rosen, Alon Ben David, Amram Torgeman, Ada Barnea, Arnon Tal, Amir Rosner, Ran Zichel
Antimicrobial Agents and Chemotherapy Mar 2018, 62 (4) e02379-17; DOI: 10.1128/AAC.02379-17

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A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy
Eran Diamant, Avi Pass, Osnat Rosen, Alon Ben David, Amram Torgeman, Ada Barnea, Arnon Tal, Amir Rosner, Ran Zichel
Antimicrobial Agents and Chemotherapy Mar 2018, 62 (4) e02379-17; DOI: 10.1128/AAC.02379-17
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KEYWORDS

botulinum
postsymptom
therapy

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