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.

Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle

“…However, PK/PD targets cannot always be derived for all antibacterial agents from studies in experimental animals. The investigational agent MCB3837, a small-molecule prodrug with structural elements of an oxazolidinone and a quinolone being converted to the active substance MCB3681, provides such an example [6]. Alternative strategies thus had to be identified to prove the principle that MCB3681 is antibacterially efficacious in vivo.…”

“…Alternative strategies thus had to be identified to prove the principle that MCB3681 is antibacterially efficacious in vivo. The evaluation of the effects of an investigational agent on indicator organisms or colonizers of the human resident microflora of healthy volunteers may provide an alternative to traditional proof-of-principle studies [6]. In contrast to the well-established and validated evaluation of the ecology of an antibacterial agent by describing fluctuations of mean viable counts of the human resident microflora within the entire study population during the study period [7][8][9], the intraindividual analysis of its effects on the population densities of indicator organisms or colonizers of the commensal skin, nasal, oropharyngeal and intestinal microflora, paralleled by an evaluation of local drug concentrations as a proof of its in vivo efficacy, has so far not been applied.…”

Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks?

“…This apparent discrepancy between pre-clinical and clinical study data and authority-approved indications remains unexplained. The more important it is to scrutinize the relevance of preclinical findings in proof of principle studies at the earliest possible time using alternative strategies [ 51 , 52 ].…”

Early Clinical Assessment of the Antimicrobial Activity of Finafloxacin Compared to Ciprofloxacin in Subsets of Microbiologically Characterized Isolates

“…However, this guideline has been discussed controversially (5), and early responses may not correlate with clinical and microbiological responses at the test-of-cure visit, which is the ultimate goal of antibiotic therapy. However, a recent quantitative analysis of microbiological and/or pharmacodynamic parameters as well as recent clinical trials have confirmed that early evaluation of patients prevented inappropriate or ineffective therapy (6,7). It was demonstrated previously that the more rapid and more pronounced bactericidal in vitro activity of amoxicillin than that of ampicillin is clinically relevant.…”