title: Alternative strategies for proof-of-principle studies of antibacterial agents.
abstract: The proof that a new antibacterial agent is not only active in vitro but also effective in vivo under clinically relevant conditions is currently provided (i) by using appropriate nonclinical models of infection and pharmacokinetic-pharmacodynamic (PK-PD) analysis providing evidence of the likelihood of clinical efficacy and (ii) by examining the study drug in exploratory clinical trials, as well as dose and schedule finding during phase II of clinical development. This approach is both time-consuming and costly. Furthermore, PK-PD targets for any novel antibacterial agent cannot be derived from studies with experimental animals. Therefore, alternative strategies have to be identified to prove the principle that a novel antibacterial agent is active under clinically relevant conditions. This review summarizes evidence that the quantitative analysis of shifts in the viable counts of pathogens in infected patients or the evaluation of the PD effect of an investigational agent on indicator organisms of the human resident microflora or colonizers of healthy volunteers, if paralleled with PK monitoring of serum and the target site, provides an alternative to a classical proof-of-principle study in the course of a phase II study program.
authors.affiliation: University Medical Center Schleswig-Holstein, Institute for Infection Medicine, Kiel, Germany adalhoff@t-online.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Dalhoff
authors.affiliation: Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrej
authors.initials: A
authors.lastname: Weintraub
authors.affiliation: Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carl Erik
authors.initials: CE
authors.lastname: Nord
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017322:Clinical Trials, Phase II as Topic; D015169:Colony Count, Microbial; D003198:Computer Simulation; D016903:Drug Monitoring / Q000706:statistics & numerical data*; D015507:Drugs, Investigational / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D064307:Microbiota / Q000187:drug effects*; D015233:Models, Statistical
chemical_list: D000900:Anti-Bacterial Agents; D015507:Drugs, Investigational