Antimicrobial Action and Pharmacokinetics/Pharmacodynamics: The Use of AUIC to Improve Efficacy and Avoid Resistance

Abstract

In in-vitro and in animal models, antibiotics show good relationships between concentration and response, when response is quantified as the rate of bacterial eradication. The strength of these in-vitro relationships promises their utility for dosage regimen design and predictable cure of human infections. Resistance is also predictable from these parameters, fostering a rational means of using dosing adjustments to avoid or minimize the development of resistant organisms.

Newly developed computerized methods for the quantitation of susceptibility allow testing of integrated kinetic-susceptibility models in patients. Our attention has focused recently on fluoroquinolones, since they are relatively nontoxic and provide the necessary range of dosage needed to elucidate correlations between concentration and response in the Intensive Care Unit patient. Studies conducted in patients with nosocomial Gram-negative pneumonia reveal good correlations between bacterial eradication and integration of concentration with bacterial susceptibility. In patients, the best correlation parameters are time over MIC, and the ratio of 24-hour AUC to MIC (AUIC).

Patients with serious infections like nosocomial pneumonia require bactericidal antimicrobial activity. Studies in our laboratory demonstrate that the minimum effective antimicrobial action is an area under the inhibitory titer (AUIC) of 125, where AUIC is calculated as the 24-hour serum AUC divided by the MIC of the pathogen. This target AUIC may be achieved with either a single antibiotic or it can be the sum of AUIC values of two or more antibiotics. There is considerable variability in the actual AUIC value for patients when antibiotics are given in their usually recommended dosages. Examples of this variance will be provided using aminoglycosides, fluoroquinolones, beta-lactams, macrolides and vancomycin. The achievement of minimally effective antibiotic action, consisting of an AUIC of at least 125, is associated with bacterial eradication in about 7 days for beta-lactams and quinolones. When AUIC is increased to 250, the quinolone ciprofloxacin (which displays in vivo concentration dependent bacterial killing) can eliminate the bacterial pathogen in 1-2 days. Beta lactams, even when dosed to an AUIC of 250, often require longer treatment duration to eliminate the bacterial pathogen, because the in vivo bacterial killing rate is slower with beta-lactams than with the quinolones. This remains true even at AUIC values of 250 for both compounds, which is theoretically identical dosing.

Antibiotic activity indices allow clinicians to evaluate individualized patient regimens. Furthermore, antibiotic activity is a predictable clinical endpoint with predictable clinical outcome. This value is also highly predictive of the development of bacterial resistance. Antimicrobial regimens that do not achieve an AUIC of at least 125 cannot prevent the selective pressure that leads to overgrowth of resistant bacterial sub-populations. Indeed, there is considerable anxiety that conventional respiratory tract infection management strategies, which prescribe antibacterial dosages that may attain AUIC values below 125, are contributing to the pandemic rise in bacterial resistance levels.