scholarly journals Efficacy of ETI-204 Monoclonal Antibody as an Adjunct Therapy in a New Zealand White Rabbit Partial Survival Model for Inhalational Anthrax

2015 ◽  
Vol 59 (4) ◽  
pp. 2206-2214 ◽  
Author(s):  
Bethany Biron ◽  
Katie Beck ◽  
David Dyer ◽  
Marc Mattix ◽  
Nancy Twenhafel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
New Zealand ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Adjunct Therapy ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Effective Therapeutic Strategy

ABSTRACTInhalational anthrax is characterized by extensive bacteremia and toxemia as well as nonspecific to mild flu-like symptoms, until the onset of hypotension, shock, and mortality. Without treatment, the mortality rate approaches 100%. Antibiotic treatment is not always effective, and alternative treatments are needed, such as monotherapy for antibiotic-resistant inhalational anthrax or as an adjunct therapy in combination with antibiotics. TheBacillus anthracisantitoxin monoclonal antibody (MAb) ETI-204 is a high-affinity chimeric deimmunized antibody which targets the anthrax toxin protective antigen (PA). In this study, a partial protection New Zealand White (NZW) rabbit model was used to evaluate the protective efficacy of the adjunct therapy with the MAb. Following detection of PA in the blood, NZW rabbits were administered either an antibiotic (doxycycline) alone or the antibiotic in conjunction with ETI-204. Survival was evaluated to compare the efficacy of the combination adjunct therapy with that of an antibiotic alone in treating inhalational anthrax. Overall, the results from this study indicate that a subtherapeutic regimen consisting of an antibiotic in combination with an anti-PA MAb results in increased survival compared to the antibiotic alone and would provide an effective therapeutic strategy against symptomatic anthrax in nonvaccinated individuals.

scholarly journals Establishment of a New Zealand White Rabbit Model for Lethal Toxin (LT) Challenge and Efficacy of Monoclonal Antibody 5E11 in the LT-Challenged Rabbit Model

Toxins ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 289 ◽  
Author(s):  
Duanyang Zhang ◽  
Weicen Liu ◽  
Zhonghua Wen ◽  
Bing Li ◽  
Shuling Liu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Lethal Toxin ◽  
Anthrax Spores ◽  
Level 3 ◽  
Anthrax Protective Antigen ◽  
Biosafety Level

Anthrax caused by Bacillus anthracis is a lethal infectious disease, especially when inhaled, and the mortality rate approaches 100% without treatment. The anthrax antitoxin monoclonal antibody (MAb) 5E11 is a humanized antibody that targets the anthrax protective antigen (PA). The efficacy of 5E11 needs proper animal models. However, anthrax spores are extremely dangerous, so experiments must be conducted under Biosafety Level 3 conditions. Considering the critical effects of lethal toxin (LT) on hosts during infection, we report the establishment of a LT-challenged rabbit model, which caused 100% mortality with a dose of 2 mg PA + 1 mg LF, while a 4 mg PA + 2 mg LF challenge could limit death to within three days. Then, we evaluated 5E11 efficacy against LT. A prophylactic study showed that the i.v. administration of 40 mg/kg 5E11 four days before lethal dose LT challenge could lead to 100% survival. In therapeutic studies, the i.v. administration of 40 mg/kg 5E11 10 min after lethal dose LT challenge could provide complete protection. Overall, we developed a new LT-challenged rabbit model, and our results indicate that 5E11 shows potential for the clinical application in anthrax treatment.

scholarly journals Development of Protective Immunity in New Zealand White Rabbits Challenged with Bacillus anthracis Spores and Treated with Antibiotics and Obiltoxaximab, a Monoclonal Antibody against Protective Antigen

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Lisa N. Henning ◽  
Sarah Carpenter ◽  
Gregory V. Stark ◽  
Natalya V. Serbina
Keyword(s):  
Monoclonal Antibody ◽  
New Zealand ◽  
Bacillus Anthracis ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Survival Rates ◽  
Anamnestic Response ◽  
Content Type ◽  
Treatment Regimens

ABSTRACT The recommended management of inhalational anthrax, a high-priority bioterrorist threat, includes antibiotics and antitoxins. Obiltoxaximab, a chimeric monoclonal antibody against anthrax protective antigen (PA), is licensed under the U.S. Food and Drug Administration's (FDA's) Animal Rule for the treatment of inhalational anthrax. Because of spore latency, disease reemergence after treatment cessation is a concern, and there is a need to understand the development of endogenous protective immune responses following antitoxin-containing anthrax treatment regimens. Here, acquired protective immunity was examined in New Zealand White (NZW) rabbits challenged with a targeted lethal dose of Bacillus anthracis spores and treated with antibiotics, obiltoxaximab, or a combination of both. Survivors of the primary challenge were rechallenged 9 months later and monitored for survival. Survival rates after primary and rechallenge for controls and animals treated with obiltoxaximab, levofloxacin, or a combination of both were 0, 65, 100, and 95%, and 0, 100, 95, and 89%, respectively. All surviving immune animals had circulating antibodies to PA and serum toxin-neutralizing titers prior to rechallenge. Following rechallenge, systemic bacteremia and toxemia were not detected in most animals, and the levels of circulating anti-PA IgG titers increased starting at 5 days postrechallenge. We conclude that treatment with obiltoxaximab, alone or combined with antibiotics, significantly improves the survival of rabbits that received a lethal inhalation B. anthracis spore challenge dose and does not interfere with the development of immunity. Survivors of primary challenge are protected against reexposure, have rare incidents of systemic bacteremia and toxemia, and have evidence of an anamnestic response.

scholarly journals Recombinant Protective Antigen Anthrax Vaccine Improves Survival when Administered as a Postexposure Prophylaxis Countermeasure with Antibiotic in the New Zealand White Rabbit Model of Inhalation Anthrax

2012 ◽  
Vol 19 (8) ◽  
pp. 1158-1164 ◽  
Author(s):  
Elizabeth K. Leffel ◽  
James S. Bourdage ◽  
E. Diane Williamson ◽  
Matthew Duchars ◽  
Thomas R. Fuerst ◽  
...  
Keyword(s):  
Immune Response ◽  
New Zealand ◽  
Survival Rate ◽  
Protective Antigen ◽  
Zealand White Rabbit ◽  
Postexposure Prophylaxis ◽  
Content Type ◽  
New Zealand White Rabbit ◽  
Inhalation Anthrax ◽  
Recombinant Protective Antigen

ABSTRACTInhalation anthrax is a potentially lethal form of disease resulting from exposure to aerosolizedBacillus anthracisspores. Over the last decade, incidents spanning from the deliberate mailing ofB. anthracisspores to incidental exposures in users of illegal drugs have highlighted the importance of developing new medical countermeasures to protect people who have been exposed to “anthrax spores” and are at risk of developing disease. The New Zealand White rabbit (NZWR) is a well-characterized model that has a pathogenesis and clinical presentation similar to those seen in humans. This article reports how the NZWR model was adapted to evaluate postexposure prophylaxis using a recombinant protective antigen (rPA) vaccine in combination with an oral antibiotic, levofloxacin. NZWRs were exposed to multiples of the 50% lethal dose (LD50) ofB. anthracisspores and then vaccinated immediately (day 0) and again on day 7 postexposure. Levofloxacin was administered daily beginning at 6 to 12 h postexposure for 7 treatments. Rabbits were evaluated for clinical signs of disease, fever, bacteremia, immune response, and survival. A robust immune response (IgG anti-rPA and toxin-neutralizing antibodies) was observed in all vaccinated groups on days 10 to 12. Levofloxacin plus either 30 or 100 μg rPA vaccine resulted in a 100% survival rate (18 of 18 per group), and a vaccine dose as low as 10 μg rPA resulted in an 89% survival rate (16 of 18) when used in combination with levofloxacin. In NZWRs that received antibiotic alone, the survival rate was 56% (10 of 18). There was no adverse effect on the development of a specific IgG response to rPA in unchallenged NZWRs that received the combination treatment of vaccine plus antibiotic. This study demonstrated that an accelerated two-dose regimen of rPA vaccine coadministered on days 0 and 7 with 7 days of levofloxacin therapy results in a significantly greater survival rate than with antibiotic treatment alone. Combination of vaccine administration and antibiotic treatment may be an effective strategy for treating a population exposed to aerosolizedB. anthracisspores.

scholarly journals Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Vien T. M. Le ◽  
Hoan N. Le ◽  
Marcos Gabriel Pinheiro ◽  
Kenneth J. Hahn ◽  
Mary L. Dinh ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Production ◽  
Protective Efficacy ◽  
Survival Rates ◽  
Rabbit Model ◽  
Rank Test ◽  
Necrotizing Pneumonia ◽  
Time Curve ◽  
Content Type

ABSTRACT The protective efficacy of tedizolid phosphate, a novel oxazolidinone that potently inhibits bacterial protein synthesis, was compared to those of linezolid, vancomycin, and saline in a rabbit model of Staphylococcus aureus necrotizing pneumonia. Tedizolid phosphate was administered to rabbits at 6 mg/kg of body weight intravenously twice daily, which yielded values of the 24-h area under the concentration-time curve approximating those found in humans. The overall survival rate was 83% for rabbits treated with 6 mg/kg tedizolid phosphate twice daily and 83% for those treated with 50 mg/kg linezolid thrice daily (P = 0.66 by the log-rank test versus the results obtained with tedizolid phosphate). These survival rates were significantly greater than the survival rates of 17% for rabbits treated with 30 mg/kg vancomycin twice daily (P = 0.003) and 17% for rabbits treated with saline (P = 0.002). The bacterial count in the lungs of rabbits treated with tedizolid phosphate was significantly decreased compared to that in the lungs of rabbits treated with saline, although it was not significantly different from that in the lungs of rabbits treated with vancomycin or linezolid. The in vivo bacterial production of alpha-toxin and Panton-Valentine leukocidin, two key S. aureus-secreted toxins that play critical roles in the pathogenesis of necrotizing pneumonia, in the lungs of rabbits treated with tedizolid phosphate and linezolid was significantly inhibited compared to that in the lungs of rabbits treated with vancomycin or saline. Taken together, these results indicate that tedizolid phosphate is superior to vancomycin for the treatment of S. aureus necrotizing pneumonia because it inhibits the bacterial production of lung-damaging toxins at the site of infection.

scholarly journals Differential Contribution of Bacillus anthracis Toxins to Pathogenicity in Two Animal Models

2012 ◽  
Vol 80 (8) ◽  
pp. 2623-2631 ◽  
Author(s):  
Haim Levy ◽  
Shay Weiss ◽  
Zeev Altboum ◽  
Josef Schlomovitz ◽  
Itai Glinert ◽  
...  
Keyword(s):  
Animal Models ◽  
Guinea Pigs ◽  
Protective Antigen ◽  
Comprehensive Evaluation ◽  
Lethal Factor ◽  
Rabbit Model ◽  
Content Type ◽  
Edema Factor ◽  
Genes Encoding ◽  
Guinea Pig Model

ABSTRACTThe virulence ofBacillus anthracis, the causative agent of anthrax, stems from its antiphagocytic capsule, encoded by pXO2, and the tripartite toxins encoded by pXO1. The accepted paradigm states that anthrax is both an invasive and toxinogenic disease and that the toxins play major roles in pathogenicity. We tested this assumption by a systematic study of mutants with combined deletions of thepag,lef, andcyagenes, encoding protective antigen (PA), lethal factor (LF), and edema factor (EF), respectively. The resulting seven mutants (single, double, and triple) were evaluated following subcutaneous (s.c.) and intranasal (i.n.) inoculation in rabbits and guinea pigs. In the rabbit model, virulence is completely dependent on the presence of PA. Any mutant bearing apagdeletion behaved like a pXO1-cured mutant, exhibiting complete loss of virulence with attenuation indices of over 2,500,000 or 1,250 in the s.c. or i.n. route of infection, respectively. In marked contrast, in guinea pigs, deletion ofpagor even of all three toxin components resulted in relatively moderate attenuation, whereas the pXO1-cured bacteria showed complete attenuation. The results indicate that a pXO1-encoded factor(s), other than the toxins, has a major contribution to the virulence mechanism ofB. anthracisin the guinea pig model. These unexpected toxin-dependent and toxin-independent manifestations of pathogenicity in different animal models emphasize the importance and need for a comprehensive evaluation ofB. anthracisvirulence in general and in particular for the design of relevant next-generation anthrax vaccines.

Autonomic and histopathological effects of percutaneous trigeminal ganglion compression in the rabbit

1990 ◽  
Vol 72 (6) ◽  
pp. 933-940 ◽  
Author(s):  
Mark C. Preul ◽  
Phillip B. Long ◽  
Jeffrey A. Brown ◽  
Manuel E. Velasco ◽  
Michael T. Weaver
Keyword(s):  
New Zealand ◽  
Trigeminal Ganglion ◽  
Zealand White Rabbit ◽  
Sensory Function ◽  
Content Type ◽  
Arterial Blood ◽  
Corneal Reflex ◽  
Hematoxylin And Eosin ◽  
And Control ◽  
Fine Print

✓ The histopathological and autonomic effects of percutaneous trigeminal ganglion compression for trigeminal neuralgia were studied in New Zealand White rabbits. Drops in mean arterial blood pressure of 38% and in heart rate of 30% were observed during compression (p < 0.0001). Corneal reflex, pinprick sensation, and mastication strength were intact in 13 of 14 rabbits after compression. These findings resembled the effects of percutaneous compression in humans and suggested that the New Zealand White rabbit is a useful model for the study of percutaneous compression. Trigeminal sensory roots and ganglia from 14 rabbits killed at intervals from 1 to 84 days after percutaneous compression were sectioned and stained using immunoperoxidase for neurofilaments, hematoxylin and eosin, luxol fast blue, and cresyl echt violet. Focal axonal damage and demyelination were present 7 days after compression. No difference could be detected in the perikaryonal distribution of neurofilaments between compressed and control trigeminal ganglia. Focal demyelination and Schwann cell proliferation preceding remyelination were present in the trigeminal sensory root at 84 days. Differential injury of axons compared to trigeminal ganglion cell bodies suggests that axonal regeneration is possible and may contribute to the recovery of motor and sensory function in patients after percutaneous compression.

scholarly journals Long-term in vivo electromechanical reshaping for auricular reconstruction in the New Zealand white rabbit model

2015 ◽  
Vol 125 (9) ◽  
pp. 2058-2066 ◽  
Author(s):  
Karam W. Badran ◽  
Cyrus T. Manuel ◽  
Anthony Chin Loy ◽  
Christian Conderman ◽  
Yuk Yee Yau ◽  
...  
Keyword(s):  
New Zealand ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Auricular Reconstruction ◽  
New Zealand White Rabbit

Evaluation of three purely polypropylene meshes of different pore sizes in an onlay position in a New Zealand white rabbit model

Hernia ◽  
2014 ◽  
Vol 18 (6) ◽  
pp. 855-864 ◽  
Author(s):  
J. Jerabek ◽  
T. Novotny ◽  
K. Vesely ◽  
J. Cagas ◽  
V. Jedlicka ◽  
...  
Keyword(s):  
New Zealand ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Pore Sizes ◽  
New Zealand White Rabbit

scholarly journals Human Monoclonal Antibody AVP-21D9 to Protective Antigen Reduces Dissemination of the Bacillus anthracis Ames Strain from the Lungs in a Rabbit Model

2007 ◽  
Vol 75 (7) ◽  
pp. 3414-3424 ◽  
Author(s):  
Johnny W. Peterson ◽  
Jason E. Comer ◽  
Wallace B. Baze ◽  
David M. Noffsinger ◽  
Autumn Wenglikowski ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Rabbit Model ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Lethal Challenge ◽  
Tissue Sections ◽  
Inhalation Anthrax

ABSTRACT Dutch-belted and New Zealand White rabbits were passively immunized with AVP-21D9, a human monoclonal antibody to protective antigen (PA), at the time of Bacillus anthracis spore challenge using either nasal instillation or aerosol challenge techniques. AVP-21D9 (10 mg/kg) completely protected both rabbit strains against lethal infection with Bacillus anthracis Ames spores, regardless of the inoculation method. Further, all but one of the passively immunized animals (23/24) were completely resistant to rechallenge with spores by either respiratory challenge method at 5 weeks after primary challenge. Analysis of the sera at 5 weeks after primary challenge showed that residual human anti-PA levels decreased by 85 to 95%, but low titers of rabbit-specific anti-PA titers were also measured. Both sources of anti-PA could have contributed to protection from rechallenge. In a subsequent study, bacteriological and histopathology analyses revealed that B. anthracis disseminated to the bloodstream in some naïve animals as early as 24 h postchallenge and increased in frequency with time. AVP-21D9 significantly reduced the dissemination of the bacteria to the bloodstream and to various organs following infection. Examination of tissue sections from infected control animals, stained with hematoxylin-eosin and the Gram stain, showed edema and/or hemorrhage in the lungs and the presence of bacteria in mediastinal lymph nodes, with necrosis and inflammation. Tissue sections from infected rabbits dosed with AVP-21D9 appeared comparable to corresponding tissues from uninfected animals despite lethal challenge with B. anthracis Ames spores. Concomitant treatment with AVP-21D9 at the time of challenge conferred complete protection in the rabbit inhalation anthrax model. Early treatment increased the efficacy progressively and in a dose-dependent manner. Thus, AVP-21D9 could offer an adjunct or alternative clinical treatment regimen against inhalation anthrax.

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