JAC MW3302 Orig art

Among other investigators, Eagle first observed in the late 1940s that some penicillin-treated bacteria did not immediately resume normal growth upon removal of antibiotic from the culture medium. This phenomenon is now referred to as the postantibiotic effect (PAE). From a clinical perspective, PAE provides the theoretical argument that dosing of some antibiotics can be spread over a longer interval because antibiotic concentrations can fall below the MIC against the pathogens while some degree of growth inhibition still remains. In fact, the concept of PAE, in the optimization of dosing regimen in chemotherapy, has been adopted in the recently proposed once-daily aminoglycoside therapy. Although the duration of PAE and the degree of bactericidal activity (reflected by the bactericidal rate constant) in relation to antibiotic concentrations have both been independently examined in previous studies, the correlation between these two bacterial responses has never been quantified for any single antibiotic at different concentrations. The primary objective of the present study was to examine the correlation, if any, between bactericidal activity and PAE for five different antibiotic–bacterium combinations, using antibiotics with different mechanisms of action. Tobramycin, ciprofloxacin and dicloxacillin were employed as antibiotics that bind irreversibly to bacterial receptors, while trimethoprim and tetracycline were included as reversibly binding antibiotics. The working hypothesis for the present study was that, if repair of cellular damage is the leading cause of PAE, the level of bactericidal activity (an index of the extent of cellular damage) should correspond to the duration of PAE observed. This hypothesis is particularly relevant to antibiotics that bind irreversibly. Analysis was also extended to test if a similar correlation existed when different antibiotics and bacterial species were considered. The presence or absence of such a relationship should provide some information regarding the dominant factor governing PAE.