NET EFFECT OF INOCULUM SIZE ON ANTIMICROBIAL ACTION OF AMPICILLIN-SULBACTAM - STUDIES USING AN IN-VITRO DYNAMIC-MODEL

To examine the predictable effect of inoculum size on the kinetics of the antimicrobial action of ampicillin-sulbactam, five TEM-1 beta-lact amase-producing Escherichia call strains were studied in an in vitro d ynamic model at two different initial inocula (N(0)s). All bacteria we re exposed to ampicillin-sulbactam in a simulated system reflecting th e pharmacokinetic profiles in human tissue after the administration of a single intravenous dose of ampicillin (2 g) plus sulbactam (1 g). E ach strain was studied at low (4.0 to 5.2 log CFU/ml) and high (5.0 to 7.1 log CFU/ml) N(0)s. Despite pronounced differences in susceptibili ties, the patterns of the killing curves observed with a given strain at different N(0)s were similar. As expected; viable bacterial counts increased with inoculum size, Striking visual contrasts in the respect ive curves for each organism were reflected by the area under the bact erial count-time curve (AUBC) but not by the difference between the N- 0 and the lowest bacterial counts (N-min) at the nadir of the killing curve: the N-0-associated changes in the AUBC on average were 75%, ver sus 2.5% for log N-0 - log N-min. To examine qualitative differences i n antimicrobial effects at different N(0)s (i.e., the net effect of th e inoculum), the difference in the high and low N(0)s was subtracted f rom each point on the killing curve obtained at the higher N-0 for eac h strain. These adjusted curves were virtually superimposable on the o bserved killing curves obtained at the lower N-0, Moreover, by using a djusted data, the AUBC values were similar at the two inocula, althoug h slight (average, 11%) but systematic increases in the AUBC occurred at high N(0)s. Thus, there mas only a weak net effect of inoculum size on the antibacterial effect of ampicillin-sulbactam, Due to similar s lopes of the AUBC-log N-0 plots, the antibacterial action at different N(0)s may be easily predicted by an approximate equation; the predict ed AUBCs were unbiased and well correlated with the observed AUBCs (r = 0.997). Compiled data obtained with normalized AUBCs for different s trains at different N(0)s yielded a positive correlation (r = 0.963) b etween the N-0-normalized AUBC and the MIC of ampicillin-sulbactam. Th e adjustment and normalization procedure described might be a useful t ool for revealing the net effect of the inoculum and to predict the in oculum effect if there are no qualitative differences in antimicrobial action at different inocula.