Continuous vs intermittent administration of antimicrobial agents: tissue penetration and efficacy

Two experimental models, fibrin clot and pyelonephritis, were used to study the in-fluence of continuous and intermittent administration of antimicrobial agents on penetration of drug into tissues and efficacy in vivo. In the fibrin-clot model, clots in-fected with Streptococcus faecalis were inserted subcutaneously into rabbits; in the pyelonephritis model, Escherichia coli was injected into the left kidneys of rats. In the experiments with rabbits, the bactericidal activity of the serum against S. faecalis was two to eight times greater after bolus injections of a combination of penicillin G and gentamicin than after continuous infusion of a similar dose of either drug alone. Synergism in vivo, as determined by counts of live bacteria in the clots, was demonstrated after bolus injections of these two drugs, but constant infusion of the combination was not synergistic. In the experiments with rats, two types of pyelonephritis were produced: a severe infection induced by direct inoculation of E. coli into the left kidney and a less severe infection caused by reflux of infected urine into the right ureter and right kidney. Treatment with gentamicin or ampicillin alone or in com-bination, or with the combination trimethoprim-sulfamethoxazole, was started 24 h