ENDOTOXIN PROMOTES SYNERGISTIC LETHALITY DURING CONCURRENT ESCHERICHIA-COLI AND CANDIDA-ALBICANS INFECTION

Previous studies have suggested that the lipopolysaccharide (LPS, endotoxin) component of the gram-negative bacterial cell wall is a key virulence factor that serves to enhance mortality during infections in which fungi and gram-negative bacteria are copathogens. To test this hypothesis, mice were challenged ip with Escherichia coli 0111:B4, Candida albicans, or both, and the effect of administration of anti-E. coli 0111:B4 LPS monoclonal antibody (mAb) 8G9 on endotoxemia, bacteremia, and mortality was assessed. E. coli (2 × 107 colony-forming units (CFU)) plus C. albicans (6 × 107 CFU) infection produced 100% mortality at 7 days, compared to the relatively low mortality caused by infection with either E. coli or C. albicans alone (20 and 3%, respectively, P < 0.01). Administration of mAb 8G9 to animals receiving both pathogens reduced mortality (100% versus 14%, P < 0.05), endotoxemia (3653 ± 3187 versus 2 ± 2 endotoxin units (EU), P < 0.01), and bacteremia (4.2 ± 2.3 versus 1.1 ± 2.1 log(CFU/ml), P < 0.01) compared to animals receiving saline alone. In a separate series of experiments, purified E. coli 0111:B4 LPS was administered in place of viable E. coli. The simultaneous injection of 200 μg E. coli LPS and C. albicans (6 × 107 CFU) produced 93% mortality at 7 days, compared to the low mortality that occurred following injection with either E. coli 0111:B4 LPS or C. albicans alone (21 and 3% respectively, P < 0.01). In this model, treatment with 8G9 mAb in animals receiving both E. coli LPS and C. albicans also resulted in a reduction in endotoxemia (8917 ± 4566 versus 991 ± 906 EU, P < 0.01) and mortality (93% versus 50%, P < 0.05) compared to animals receiving saline. These data support the contention that endotoxin is a critical virulence factor that serves to produce synergistic lethality during simultaneous gram-negative bacterial and C. albicans infection. Furthermore, these findings suggest that anti-LPS mAbs may be of particular benefit in treating critically ill patients with concurrent gram-negative bacterial and fungal infection. © 1992.