Initial Recovery and Rebound of Type F Intestinal Colonization Botulism After Administration of Investigational Heptavalent Botulinum Antitoxin

Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, US Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Clinical Infectious Diseases (Impact Factor: 8.89). 09/2011; 53(9):e125-8. DOI: 10.1093/cid/cir550
Source: PubMed


Investigational heptavalent botulinum antitoxin (HBAT) is now the primary antitoxin for US noninfant botulism patients. HBAT
consists of equine Fab/F(ab')2 IgG fragments, which are cleared from circulation faster than whole immunoglobulins. Rebound
botulism after antitoxin administration is not previously documented but occurred in our patient 10 days after HBAT administration.

Full-text preview

Available from:
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Clostridium botulinum strain IBCA10-7060, isolated from a patient with infant botulism, produced botulinum neurotoxin type B (BoNT/B) and another BoNT that, by use of the standard mouse bioassay, could not be neutralized by any of the Centers for Disease Control and Prevention-provided monovalent polyclonal botulinum antitoxins raised against BoNT types A-G. Methods and results: The combining of antitoxins to neutralize the toxicity of known bivalent C. botulinum strains Ab, Ba, Af, and Bf also failed to neutralize the second BoNT. Analysis of culture filtrate by double immunodiffusion yielded a single line of immunoprecipitate with anti-A, anti-B, and anti-F botulinum antitoxins but not with anti-E antitoxin. A heptavalent F(ab')2 botulinum antitoxin A-G obtained from the US Army also did not neutralize the second BoNT. An antitoxin raised against IBCA10-7060 toxoid protected mice against BoNT/B (Okra) and against the second BoNT but did not protect mice against BoNT/A (Hall) or BoNT/F (Langeland). Conclusion: The second BoNT thus fulfilled classic criteria for being designated BoNT/H. IBCA10-7060 is the first C. botulinum type Bh strain to be identified. BoNT/H is the first new botulinum toxin type to be recognized in >40 years, and its recognition could not have been accomplished without the availability of the mouse bioassay.
    Preview · Article · Oct 2013 · The Journal of Infectious Diseases
  • [Show abstract] [Hide abstract]
    ABSTRACT: Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn2+ metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair.
    No preview · Article · Oct 2014 · Journal of Applied Statistics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Botulinum neurotoxins (BoNTs) are the most potent neurotoxins and are potential biothreat agents. All seven serotypes of BoNTs (/A through/G) consist of a 100 kDa heavy chain (Hc) and a 50 kDa light chain (Lc) linked by a single disulfide bond. BoNT Hc binds to its receptors on the neural membrane and sets the stage for endocytosis at the motor nerve terminals (MNTs). Within early endosomes BoNT undergoes pH-dependent separation of the Hc and Lc. The Hc translocates the Lc into the cytosol where BoNTs proteolyze selective SNARE complex proteins resulting in the attenuation of acetylcholine (ACh) release at MNT. This results in a flaccid, long-lasting neuroparalysis of the skeletal muscles. The persistence of BoNT/A, the principal serotype, Lc protease at the MNT accounts for the long-lasting paralysis and the difficulty to develop therapeutics against BoNT/A. The ease of production and dissemination of the neurotoxin makes it as a viable biothreat agent. The quest for antidotes to treat botulism is an ongoing process. Efforts to develop antidotes against BoNTs have also advanced our knowledge about endoexocytic mechanisms that mediate BoNT signaling at the MNT. This review describes the antidotes that have prophylactic and therapeutic potential to counteract BoNTs in cellular and neuromuscular model systems by neutralizing the toxin in the blood, preventing the binding/internalization of the toxin, inhibiting the translocation of the Lc from early endosomes to cytosol, disrupting the catalytic activity of the Lc endoprotease, and/or restoring neurotransmission by increasing presynaptic Ca2+-triggered exocytosis.
    No preview · Article · Jan 2015
Show more