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A functional pharmacokinetic/pharmacodynamic (PK/PD) index that could simultaneously describe three controlling PD variables, i.e., bactericidal activity, postantibiotic effect (PAE), and susceptibility, in relation to pharmacokinetics, was designed using an in vitro kinetic model. Tobramycin was tested against one standard and five clinical strains of Pseudomonas aeruginosa. The organisms showed minimum inhibitory concentrations (MICs) ranging between 1 and >1000 microg/ml. The model allowed antibiotic concentrations to be reduced exponentially from initial concentrations at fixed multiples of MIC. Antibiotic removal was performed when the decreasing concentrations hit the MIC of individual strain to provide a wide range of AUC(>MIC) within an identical frame of AUC(>MIC)/MIC (AUIC) values. Viable counts were measured at antibiotic addition and before/after its removal for bactericidal activity and PAE assessments. A linear relationship was observed between PAE and bactericidal rate constants, though the pattern varied among different strains. Characterization of the exposure (AUC(>MIC))-effect relationships using the Emax model revealed that the less susceptible strains displayed lower Emax and higher EC50 for both antimicrobial effects. By employing the AUIC as a common frame of reference, regression analysis showed a significant linear correlation (p < 0.05) between the mean PAE and bactericidal rate data and, thereby simultaneously defining the four contributing factors of the PK/PD system. It appears that the AUIC, by conveying the pharmacokinetic and susceptibility information, could serve as a PK/PD index in bridging the interdependency of PAE and bactericidal activity. More importantly, the collective assessment of these four factors would allow more optimal evaluation of dosage regimens.

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Inoculum effect describes the inoculum size dependent changes in minimum inhibitory concentrations (MIC) exhibited by antibiotic-bacterium combinations demonstrating such effect. Traditionally, inoculum effect has been loosely defined based on the extent of increase in the MIC with respect to the increase in inoculum size. In most studies, assessment of MIC data has relied on the arbitrary selection of a point of reference for both baseline MIC and inoculum size. More importantly, this conventional method of assessment does not permit information conveyed in a complete MIC versus inoculum size profile to be fully explored. To undertake these issues, a mathematical model was developed for the description of the entire inoculum effect profile. With the employment of three key parameter estimates, i.e., the baseline MIC, the threshold inoculum size at which the increase in MIC commences, and the rate of increase in MIC with respect to inoculum size, both the shape and location of the profile could be adequately defined. To verify the application of this model, a series of four aminoglycosides were tested against standard strains of E. coli and S. aureus. Results showed a good degree of organism specificity and antibiotic-class dependency of the inoculum effect profiles. Analysis of the parameter estimates obtained provided further support for these observations. In conclusion, the mathematical model developed in the present study adequately described the inoculum effect exhibited by the various aminoglycoside-bacterium combinations tested. The parameter estimates generated by the modeling approach allowed comparison and quantitative analysis of the inoculum effect profiles with minimal difficulties.

The performance of the recently developed Fractional Maximal Effect (FME) method was evaluated along with the conventional checkerboard technique and time-kill method. Ciprofloxacin in combination with tobramycin was tested against Escherichia coli and Pseudomonas aeruginosa and in combination with tetracycline, chloramphenicol, erythromycin against Escherichia coli. Two combinations, amoxicillin-tetracycline (antagonistic) and tobramycin-ticarcillin (synergistic), were included as reference interactions. The FME method unequivocally showed an antagonistic interaction between ciprofloxacin and all the protein synthesis inhibitors (PSIs) tested, while the other two methods yielded variable results. At a total FME (TFME) level of 1, the FME method demonstrated a similar degree of antagonism against ciprofloxacin by tetracycline, chloramphenicol, and erythromycin, and much lower by tobramycin. Internal consistency of the FME operation was demonstrated by the identical conclusions obtained at both TFME levels of 0.5 and 1. The FME method appears to be a practical alternative for resolving the inconsistencies observed in conventional methods of antibiotic combination testing.