Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Postexposure Prophylaxis in Animal Models of Inhalational Anthrax.

The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative to Bacillus anthracis aerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery.

Efficacy Projection of Obiltoxaximab for Treatment of Inhalational Anthrax across a Range of Disease Severity.

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolized Bacillus anthracis spores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% compared to 0% and 0% for placebo (P = 0.0010 and P = 0.0013, respectively). Across four macaque studies, survival was 6.3% to 78.6% following 4 to 32 mg/kg obiltoxaximab. In two macaque studies, 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P = 0.0085, P = 0.0053, P = 0.0068). Pretreatment bacteremia and toxemia levels inversely correlated with survival. Overall, obiltoxaximab monotherapy neutralized PA and increased survival across the range of disease severity, indicating clinical benefit of toxin neutralization with obiltoxaximab in both early and late stages of inhalational anthrax.

Evolución clínica, parasitológica e histopatológica de pacientes chagásicos agudos tratados con benznidazol / Histopathologic, parasitologic and clinic evolution in acute chagasic myocarditis patients treated with benzinidazole

Diez y seis pacientes con miocardiopatía chagásica aguda comprobada con biopsia endomiocárdica y estudio seroparasitológico, tratados con benznidazol, fueron reevaluados a los 12 meses y a los 5 años (5 pacientes). El protocolo consistió en estudio clínico hemodinámico, ecocardiográfico y sero-parasitológico, más evaluación histológica, inmunohistoquímica (inmunofluorescencia indirecta IIT e inmunoperoxidasa PAP) y molecular (PCR) de las biopsias miocárdicas. Los resultados mostraron miocarditis persistente en el 100 por ciento (16/16) y 60 por ciento (3/5) de los pacientes al año y a los 5 años, respectivamente, con evidencias de disfunción ventricular izquierda leve, sin correlato clínico, en el 75 por ciento de los casos a los 5 años. Los métodos parasitológicos directos se negativizaron durante el seguimiento, pero la serología permaneció positiva en el 80 por ciento y 75 por ciento de los pacientes a los 12 meses y 5 años. Además, se pudo demostrar la presencia de parásitos tisulares (PAP), de su genoma (PCR) o de sus antígenos (IIT) en 91 por ciento (10/11) y 75 por ciento (3/4) de las biopsias estudiadas al año y a los 5 años de seguimiento. Concluimos que existe daño miocárdico constante en los pacientes chagásicos agudos, cuya evolución no parece ser modificada favorablemente por el tratamiento con benznidazol, porque a pesar de erradicar la parasitemia, no eliminó los parásitos tisulares, cuyo papel etiopatogenético en la fase crónica debe ser reconsiderado