PREDICTORS OF EFFECT OF AMPICILLIN-SULBACTAM AGAINST TEM-1 BETA-LACTAMASE-PRODUCING ESCHERICHIA-COLI IN AN IN-VITRO DYNAMIC-MODEL - ENZYME-ACTIVITY VERSUS MIC

The clinical outcome in patients treated with ampicillin-sulbactam may not always be predictable by disc susceptibility testing or with the MIC as determined with a constant level (4 mu g/ml) of the beta-lactam ase inhibitor (MIC(1)). The enzyme activities (EA) and the MICs estima ted at a constant ratio of ampicillin to sulbactam of 2:1 (MIG(2)) for 15 TEM-1 beta-lactamase-producing strains of Escherichia coli were ex amined as alternatives to MIC(1) as predictors of the antibacterial ef fects of this combined drug as studied in an in vitro model which simu lates ampicillin-sulbactam pharmacokinetic profiles observed in human peripheral tissues. Integral parameters describing the area under the bacterial count-time curve (AUBC), the area between the normal growth curve, and the killing curve of bacteria exposed to antibiotic (ABBC), and the second parameter expressed as a percentage of its maximal hyp othetical value (ABBC/ABBC(max)) were calculated. All three parameters correlated well with EA (AUBC, r = 0.93; ABBC, r = -0.88; ABBC/ABBC(m ax), r = -0.91) and with MIC(2) (r = 0.94, -0.94, and -0.95, respectiv ely) but not with MIC(1). Both EA and MIC(2) can be considered reliabl e predictors of the antibacterial effect of ampicillin-sulbactam in an in vitro model. These correlations suggest that in vitro kinetic-dyna mic models might be useful to reexamine established susceptibility bre akpoints obtained with data based on the MIC(1) (MICs obtained with co nstant levels of beta-lactamase inhibitors). These data also suggest t hat quantitative determinations of bacterial beta-lactamase production and MICs based on the component concentration ratio observed in vivo might be useful predictors of the effect of ampicillin-sulbactam and o ther beta-lactam-inhibitor combinations.