Integration of pharmacokinetic/pharmacodynamic modeling and simulation in the development of new anti-infective agents – minimum inhibitory concentration versus time-kill curves

Abstract

The selection of appropriate doses and dosing regimens is extremely important in antimicrobial therapy in order to increase the chances of clinical success and decrease the likelihood of toxic side effects and the development of resistance. Therefore, empirical treatment of bacterial infections is not reliable enough and more rational approaches are needed. Pharmacokinetic/pharmacodynamic (PK/PD) modeling provides a powerful tool to systematically link PK and PD properties in order to predict antimicrobial efficacy. However, commonly used minimum inhibitory concentration (MIC) based PK/PD indices, although easy to obtain, have a number of limitations. Thus, more reliable PK/PD indices need to be developed. The following article provides an overview of the present PK/PD approaches used in anti-infective therapy and discusses their role in improving drug therapy.

Effect of Protein Binding on the Pharmacological Activity of Highly Bound Antibiotics

“…While a twofold increase in the MIC was observed for both ceftriaxone against S. pneumoniae in the presence of BSA and ertapenem against E. coli in the presence of HSA, no significant differences in the EC 50 s were determined in the respective time-kill curve experiments. These differences in pharmacological outcome (MIC versus EC 50 ) are frequently attributed to the immanent high variability of the employed broth macrodilution (twofold) method (20,27). Nevertheless, the fact that there are tremendous differences between the MICs and EC 50 s of both ceftriaxone and ertapenem against both strains cannot simply be explained by variability or calculated free concentrations, since both antibiotics have very similarly reported protein binding values (ceftriaxone, 83 to 96%; ertapenem, 84 to 96%) (4,30,31,38).…”

“…To date, most studies evaluating the effect of protein binding on the potency of an antibiotic against a certain pathogen determine changes in the respective MIC (22). Whereas both bacterial growth and killing are dynamic processes, the MIC is a static, highly variable threshold value, incapable of predicting antibiotic activity at concentrations apart from the MIC (19,27). In comparison, the evaluation of growth and antibiotic-induced kill profiles over time (time-kill curves) provides more detailed information than the MIC.…”

“…In comparison, the evaluation of growth and antibiotic-induced kill profiles over time (time-kill curves) provides more detailed information than the MIC. Once experimentally determined, time-kill curves can be characterized by the simultaneous fit of appropriate mathematical models and quantitatively compared by respective outcome parameters, such as the concentration at half-maximum effect (EC 50 ) (27). Time-kill curves have, consequently, been suggested as an experimental method for the evaluation of protein binding effects on antimicrobial activity (28,40).…”

Evaluating the feasibility of lantibiotics as an alternative therapy against bacterial infections in humans

“…Second, most lantibiotics are not very stable at physiological pH. Although we do not anticipate problems arising from the hemolytic activity of lantibiotics, it can only be excluded to form a problem once more data that relate dosage to effectiveness are available [35]. Lantibiotics do not significantly affect organs, tissues or blood parameters in animals.…”

Analisi farmakozinetiko/farmakodinamikoa antimikrobianoen erabilera hobetzeko gaixo larrietan

“…Sinplifikatuz, «farmakoak gorputzari egiten diona» bezala definitu izan da. Terapia antimikrobianoan, farmakoaren esposizioa eta efektu mikrobiologiko edo klinikoa erlazionatzen duen jakintzagaia da [20,21].…”