PLoS currents · 2017
Estimation of Time Period for Effective Human Inhalational Anthrax Treatment Including Antitoxin Therapy.
СтатьяНазвание и аннотация: Перевод в очереди
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Rubinson Lewis, Corey Alfred, Hanfling Dan
Аннотация
INTRODUCTION: Infrequent natural human inhalational anthrax cases coupled with high bioterrorism risk have brought about use of animal models to serve as the basis for approval of novel treatments. For inhalational anthrax, protective antigen (PA) drives much of the mortality, and raxibacumab, an anti-PA monoclonal antibody, has been approved for therapeutic use using the Animal Rule. Given the paucity of human inhalational anthrax clinical data including PA kinetics, the post-exposure period for effective treatment of human disease remains unknown. The objective of this investigation was to extrapolate animal PA kinetics to a conceptual human model to estimate the post-exposure period for effective treatment of human inhalational anthrax.
METHODS: Human PA kinetic parameters were extrapolated from reported rabbit and monkey data. PA profiles were simulated with and without antibiotic induced PA clearance to represent antibiotic-sensitive and -resistant infections, respectively. Antitoxin levels equimolar to or greater than concurrent PA levels were considered protective.
RESULTS: For antibiotic sensitive infections, treatment with antibiotics alone ≤4 days after spore exposure prevents toxemia. Administration of raxibacumab together with antibiotics protects ≥ 80% of subjects for 3 additional days (7 days post exposure). In the setting of antibiotic resistance, raxibacumab would be protective for at least 6 days post exposure.
CONCLUSIONS: Although the animal model of disease does not reflect the potential impact of supportive care (e.g. fluid resuscitation received by critically ill patients) on PA kinetics and raxibacumab PK, the simulations suggest that administration of antitoxin in combination with antibiotics should provide a longer postexposure window for effective treatment than for antibiotics alone. In addition, raxibacumab administration soon after exposure to an antibiotic resistant strain should provide effective treatment.
METHODS: Human PA kinetic parameters were extrapolated from reported rabbit and monkey data. PA profiles were simulated with and without antibiotic induced PA clearance to represent antibiotic-sensitive and -resistant infections, respectively. Antitoxin levels equimolar to or greater than concurrent PA levels were considered protective.
RESULTS: For antibiotic sensitive infections, treatment with antibiotics alone ≤4 days after spore exposure prevents toxemia. Administration of raxibacumab together with antibiotics protects ≥ 80% of subjects for 3 additional days (7 days post exposure). In the setting of antibiotic resistance, raxibacumab would be protective for at least 6 days post exposure.
CONCLUSIONS: Although the animal model of disease does not reflect the potential impact of supportive care (e.g. fluid resuscitation received by critically ill patients) on PA kinetics and raxibacumab PK, the simulations suggest that administration of antitoxin in combination with antibiotics should provide a longer postexposure window for effective treatment than for antibiotics alone. In addition, raxibacumab administration soon after exposure to an antibiotic resistant strain should provide effective treatment.