Dose response of experimental Pseudomonas endophthalmitis to ciprofloxacin, gentamicin, and imipenem: evidence for resistance to "late" treatment of infections

Single intravitreal doses of ciprofloxacin, gentamicin, or imipenem were administered to rabbits with pseudomonas endophthalmitis for determination of the maximally effective dose. Treatment was given 24 hr ("early") or 48 hr ("late") after infection. With early treatment the dose-response relationship between the drug concentration and the diminution in bacterial counts in the vitreous humor was linear with all three drugs. By contrast, with late treatment the same vitreal concentrations had no significant effect on bacterial counts. The failure of late treatment was not due to an increased rate of clearance of drugs from the eyes and could not be reproduced with a similar bacterial inoculum in vitro. Bacteria cultured from treated eyes were fully sensitive when plated directly onto drug-containing agar. The poor bactericidal effect of late treatment may in part be related to transient phenotypic alterations in the bacteria in response to changes in the environment of infection such as hypoxia, low pH, and exhaustion of critical bacterial nutrients.