Synthetic Immunomodulators for Prevention of Fatal Infections in a Burned Guinea Pig Model

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Abstract
Individuals who have suffered severe trauma, such as burns, have a high incidence of infection associated with impaired host resistance. Nonspecific stimulators of host defense mechanisms, i.e., immunomodulators, may be of benefit in such situations. A small animal model (guinea pigs) was developed to study the efficacy of immunomodulators in burns. Anesthetized animals received a 20% total body surface area, full-thickness, scald burn. There was no mortality associated with this injury, but these animals were highly susceptible to challenge with Pseudomonas aeruginosa strain 1244 by direct injection into the burn wound within 24 h of injury. This susceptibility persisted .apprx. 7 days. The standard model adopted was to injure animals, then challenge with 1 LD50 of P. aeruginosa 96 h after injury. Using this model, 6 synthetic immunomodulators were tested: CP-20,961, CP-46,665, muramyl dipeptide, thymopoietin pentapeptide (TP-5), levamisole and Li. Drug administration began 24 h after injury and ended prior to challenge with P. aeruginosa at 96 h. CP-20,961, muramyl dipeptide, levamisole and Li all had no beneficial effect on survival. A single dosage (0.3 mg/kg, i.v.) of CP-46,665, administered 24 h post-injury, increased the survival rate from 50 to 85% and mean survival time (MST) from 8.2 days to 12.4 days. TP-5, given in 4 doses (0.1 mg/kg, i.v. each) every 24 h, increased the survival rate from 40% to 80% and MST from 6.9 days to 11.6 days. These data showed that immunomodulators could be beneficial in burns, but also that not all agents are effective in this particular situation.