[Microbial resistance to antibiotics from the clinical viewpoint. Paradoxical therapy failures and the significance of pharmacokinetic-pharmacodynamic interactions in vivo].
Antimicrobial efficacy in vivo is not exclusively defined by the activity of an antibiotic as determined in the in vitro susceptibility test where constant inocula of log-phase bacteria are exposed to a steady concentration of drug for short periods of time in a well defined biochemical environment tailored to optimize antimicrobial activity. In vivo, many additional factors come into play which may be decisive for the clinical result of antimicrobial therapy. Clinically, high numbers of bacteria in various states of growth and metabolic activity are to be eliminated in an environment which may be unfavorable for antimicrobial activity. Low pH, low pO2, the presence of proteins, cell debris and biofilms, are all known to interfere with antimicrobial activity in vivo. Moreover, drug concentrations in vivo are fluctuating and vary greatly depending on a variety of pharmacokinetic factors. Finally, clinical treatment usually lasts for days. The impact of the pharmacokinetic profile of an antibiotic on its in vivo activity may be decisive. It is dependent on both, the type of drug in question and its target organisms. The time of supra-MIC concentrations appears to be the main parameter for the activity of macrolides, clindamycin, linezolide and betalactam antibiotics, particularly against gram-negative organisms. In contrast, peak concentrations and the AUC/MIC relationship are key parameters for the activity of aminoglycosides and fluoroquinolones. Regarding upcoming resistant bacterial strains, an as yet ill-defined mutation-prevention concentration has recently been discussed. Thus, in addition to the aim of eliminating target bacteria at the site of infection, in vivo concentrations of antibiotics may be important for both, the suppression of antimicrobial resistance and its epidemic spread. We are looking forward to prospective clinical trials to better understand the clinical relevance of the discussed phenomena.
Rossi
M
M
Infektiologie, Kantonsspital Luzern.
Gerber
A U
AU
D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000097:blood / Q000188:drug therapy*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004351:Drug Resistance / Q000502:physiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D017211:Treatment Failure
D000900:Anti-Bacterial Agents