Modulation of microbial growth and antimicrobial activity of aminoglycosides by oxygen tensions in gram-negative bacteria

Abstract

Oxygen tensions alter microbial growth, antimicrobial activity, and host responses to infections. In particular, hyperoxia is bactericidal for microorganisms with deficient antioxidant defenses and influences the activity of several classes of antimicrobial agents. I hypothesized that hyperoxia can augment the bacteriostatic and bactericidal effects of protein synthesis inhibitors by increasing the generation of reactive oxygen species. To test this hypothesis, I have characterized the interactions between hyperoxia and aminoglycosides on the growth of gram-negative bacteria. Growth inhibition was quantitated by determining the postantibiotic effect (PAE; the period of bacterial growth suppression that follows a brief exposure to an antibiotic) under normoxic and hyperoxic conditions. I found that hyperoxia (100% O{dollar}\sb2{dollar}, 101.3 kPa) enhanced the PAE of tobramycin against P. aeruginosa. The delay in growth recovery was associated with reduced rates of protein synthesis. Hyperbaric oxygen (100% O{dollar}\sb2{dollar}, 274.5 kPa) further suppressed the growth recovery of P. aeruginosa. I next examined the effects of hyperoxia on bacterial growth and killing by aminoglycosides in the family Enterobacteriaceae. While hyperoxia did not influence bacterial growth, hyperoxia markedly influenced the bactericidal activity of aminoglycosides in a strain-specific manner. This finding extends the range of oxygen tensions that are known to influence the bactericidal activity of tobramycin. Finally, I investigated the role of reactive oxygen species in the hyperoxic enhancement of the tobramycin-induced PAE in P. aeruginosa. Hyperoxia is known to increase the intracellular flux of reactive oxygen species. I found that hyperoxia induced antioxidant defenses and that tobramycin blocked this induction. However, antioxidants did not decrease the susceptibility of tobramycin-exposed P. aeruginosa to hyperoxia. I conclude that hyperoxia influences the bacteriostatic and bactericidal activities of aminoglycosides against gram-negative bacteria. These findings have potential implications for the treatment of infections in patients exposed to high fractional inspired oxygen concentrations.