Clinical laboratory approach to estimating the effective administration dose of imipenem/cilastatin. Evaluation of the disk susceptibility test and its interpretation system

In vitro activities of imipenem/cilastatin (IPM/CS) against 413 clinical isolates were studied through the evaluation of MICs and the results of disk susceptibility tests. The MICs were determined using the agar dilution method at an inoculum level of 10(6) CFU/ml. The MIC80s of imipenem (IPM) against Staphylococcus aureus and Staphylococcus epidermidis were 25 and 1.56 micrograms/ml, respectively, showing a bimodal MIC distribution. However, the distribution of MICs against other bacteria studied was of monomodal pattern. Group A Streptococcus, Enterococcus faecalis were inhibited by IPM at dose levels less than 0.025 and 6.25 micrograms/ml, respectively. IPM inhibited Escherichia coli at 0.20 microgram/ml, Klebsiella pneumoniae at 0.39 microgram/ml, Pseudomonas aeruginosa at 3.13 micrograms/ml except one strain showed a MIC of 25 micrograms/ml, Serratia spp. at 3.13 micrograms/ml except one with MIC greater than 100 micrograms/ml, Citrobacter freundii at 0.78 microgram/ml and Enterobacter spp. at 0.39 microgram/ml. Indole (-) Proteus and indole (+) Proteus were inhibited by this drug at levels of 3.13 and 1.56 micrograms/ml, respectively. The reliability of the IPM disk diffusion susceptibility test in quantitative estimation of antimicrobial activities was well demonstrated using commercialized 8 mm diameter Showa disks containing 30 micrograms antibiotic and also disks containing 1-30 micrograms prepared in this laboratory. For the interpretation of the Showa disk susceptibility test, a 4 category system was used. In the 4 category system for Showa IPM disk the following classification of inhibitory zone diameters has been proposed; ( ) MIC less than or equal to 3 micrograms/ml, (++) MIC greater than 3-15 micrograms/ml, (+) MIC greater than 15-60 micrograms/ml, (-) MIC greater than 60 micrograms/ml. The results of the test using Showa 30 micrograms disk against various clinical isolates were accurately classified into the 4 groups, showing false positive 8 out of 304 strains (2.6%) and false negative 1 of 304 strains (0.3%). With Showa 30 micrograms disks subclassification of strains with MIC less than 3 micrograms/ml cannot be achieved. In this study, however, the differentiation of strains with MICs less than 1 microgram/ml was made with disks containing 5-10 micrograms, which afforded to set MIC break points at 1 and 3 micrograms/ml. According to current concepts on pharmacokinetics for antibiotics including the penetration of drugs into tissues and