Determinants of the efficacy of tobramycin therapy against isogenic nonmucoid and mucoid derivatives of Pseudomonas aeruginosa PAO1 growing in peritoneal chambers in mice

Abstract

Mice which were supporting the growth of Pseudomonas aeruginosa in chambers implanted in their peritoneums were given two intramuscular injections of tobramycin (15 mg/kg of body weight each) at an interval of 8 h. Three hours later, chambers were removed and their contents were assessed for viable counts. Controls revealed that tobramycin levels in the chambers were 3.8 micrograms/ml 15 min after injection of 15 mg of tobramycin per kg and remained above the in vitro MICs (0.5 to 1 microgram/ml) for the tested strains for 8 h. It was demonstrated that tobramycin therapy was less effective with higher inocula and with longer delay before administration. Thus, in vivo, the concentration of bacteria in the chambers at the time of the first tobramycin injection had a profound effect on the bactericidal efficacy of tobramycin therapy. No such concentration dependence was observed in mock in vitro therapy experiments. A phage-selected mucoid derivative of P. aeruginosa PAO1 showed only a marginal increase in in vitro aminoglycoside susceptibility and no major alteration in in vivo susceptibility compared with its isogenic nonmucoid parent strain.