Abstract
Purpose: A combination therapy for combined injury (CI) using a non-specific immunomodulator, synthetic trehalose dicorynomycolate and monophosphoryl lipid A (STDCM-MPL), was evaluated to augment oral antimicrobial agents, levofloxacin (LVX) and amoxicillin (AMX), to eliminate endogenous sepsis and modulate cytokine production.Materials and methods: Female B6D2F1/J mice received 9.75 Gy cobalt-60 gamma-radiation and wound. Bacteria were isolated and identified in three tissues. Incidence of bacteria and cytokines were compared between treatment groups.Results: Results demonstrated that the lethal dose for 50% at 30 days (LD50/30) of B6D2F1/J mice was 9.42 Gy. Antimicrobial therapy increased survival in radiation-injured (RI) mice. Combination therapy increased survival after RI and extended survival time but did not increase survival after CI. Sepsis began five days earlier in CI mice than RI mice with Gram-negative species predominating early and Gram-positive species increasing later. LVX plus AMX eliminated sepsis in CI and RI mice. STDCM-MPL eliminated Gram-positive bacteria in CI and most RI mice but not Gram-negative. Treatments significantly modulated 12 cytokines tested, which pertain to wound healing or elimination of infection.Conclusions: Combination therapy eliminates infection and prolongs survival time but does not assure CI mouse survival, suggesting that additional treatment for proliferative-cell recovery is required.
Highlights
Potential nuclear accidents and terrorist attacks pose serious and credible threats to health and safety throughout the world (Benjamin et al 2009, Singh et al 2012b)
We have shown that natural trehalose dimycolate (TDM) or synthetic trehalose dicorynomycolate (STDCM), which is a synthetic derivative of TDM with diminished toxicity, when either were administered 1 h after 10.25 Gy g-radiation, reduced endogenous infection, increased survival, and enhanced hematopoiesis after 6.5 Gy g photons (Madonna et al 1989)
We investigated the possibility that a combination of systemic oral antimicrobial agents, which are active against Grampositive and Gram-negative bacteria, together with a nonspecific immunomodulator, which stimulates proliferative cells, can eradicate polymicrobial sepsis and extend survival time or enhance 30-day survival in a mouse model of lethal g-radiation exposure followed by skin wounding
Summary
Potential nuclear accidents and terrorist attacks pose serious and credible threats to health and safety throughout the world (Benjamin et al 2009, Singh et al 2012b). Effective therapy for polymicrobial sepsis following lethal radiation injury (RI) or CI will be even more complex than for single-agent sepsis (Brook 1988). Eliminating polymicrobial sepsis will require antimicrobial agents, which are effective against both Gram-positive and Gram-negative facultative species, while maintaining the integrity of the beneficial anaerobic intestinal resident bacteria (Brook and Ledney 1992). Administration of antimicrobial agents can eliminate polymicrobial infection and extend survival time but they will not assure survival from cellular injuries in proliferative tissues. There are no known United States Food and Drug Administration (US FDA)-approved non-antimicrobial therapies that will alleviate the injurious sequelae induced by CI and promote recovery of proliferative tissue. Not all antimicrobial agents can be used successfully because of variable susceptibility of bacterial species, among the resident intestinal bacteria (Brook et al 1988, Elliott et al 1995)
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