Studies to optimize the in vitro testing of piperacillin combined with tazobactam (YTR 830)

Abstract

The combination of piperacillin and the beta-lactamase inhibitor tazobactam (formerly YTR 830) was studied to determine optimal disk concentrations and dilution testing conditions. In addition, the potency of the combination was compared to that of piperacillin alone. The spectrum of piperacillin was greatly expanded by the addition to tazobactam principally against beta-lactamase producing strains of Haemophilus influenzae, Escherichia coli, Morganella morganii, Proteus vulgaris, Providencia stuartii, Shigella spp., Neisseria gonorrhoeae, and Staphylococcus spp. Tazobactam was active alone against Branhamella catarrhalis (minimum inhibitory concentration [MIC] 50, less than or equal to 1 microgram/ml), gonococci (MIC 50, 0.5-4 micrograms/ml), and N. meningitidis (MIC 50, less than or equal to 1 microgram/ml). Studies with beta-lactamase-producing type strains showed tazobactam to have high affinity for plasmid-mediated enzymes (TEM-1 and 2, SHV-1, HMS-1, and some CARB or OXA types) and not chromosomal beta-lactamases. Piperacillin/tazobactam inhibited 93% of fluoro-quinolone resistant strains at less than or equal to 64/8 micrograms/ml but failed to suppress the growth of 15 strains producing stably depressed cephalosporinases. Comparisons of piperacillin/tazobactam results determined with 100/10-, 100/20-, and 100/30-micrograms disks established the 100/10-micrograms disk as most usable. Among five different MIC combinations the ratio of eight parts piperacillin to one part tazobactam or fixed concentration tests at greater than or equal to 4 micrograms tazobactam/ml were preferred, each producing very low occurrences (less than or equal to 1.6%) of false-resistance or -susceptibility when compared to disk test results. MICs determined by agar and broth microdilution methods were essentially the same. The recommended breakpoints for piperacillin/tazobactam MICs were identical to those now found in the NCCLS susceptibility testing standards with the following exceptions: (1) for tests with H. influenzae and Staphylococcus spp.--susceptible at greater than or equal to 21 mm (MIC less than or equal to 16/2 micrograms/ml) and resistant less than or equal to 20 mm (MIC less or equal to 32/4 micrograms/ml); and (2) all remaining nonspeudomonas isolates would be interpreted by the NCCLS piperacillin enteric bacilli susceptibility criteria. This newer beta-lactamase inhibitor combination appears to be worthy of further in vivo trials guided by these or similar tentative in vitro susceptibility testing parameters.