Application of pharmacokinetic/pharmacodynamic concepts to the development of treatment regimens for sporadic canine urinary tract infections: Challenges and paths forward

Abstract Antimicrobial efficacy can be predicted based on infection site exposure to the antimicrobial agent relative to the in vitro susceptibility of the pathogen to that agent. When infections occur in soft tissues (e.g., muscle, blood, and ligaments), exposure at the infection site is generally assumed to reflect an equilibrium between the unbound concentrations in plasma and that in the interstitial fluids. In contrast, for sporadic urinary tract infections (UTIs) in dogs and uncomplicated UTIs in humans, the primary site of infection is the bladder wall. Infection develops when bacteria invade the host bladder urothelium (specifically, the umbrella cells that form the urine‐contacting layer of the stratified uroepithelium) within which these bacteria can avoid exposure to host defenses and antimicrobial agents. Traditionally, pathogen susceptibility has been estimated using standardized in vitro tests that measure the minimal concentration that will inhibit pathogen growth (MIC). When using exposure–response relationships during drug development to explore dose optimization, these relationships can either be based upon an assessment of a correlation between clinical outcome, drug exposure at the infection site, and pathogen MIC, or upon benchmark exposure‐response relationships (i.e., pharmacokinetic/pharmacodynamic indices) typically used for the various drug classes. When using the latter approach, it is essential that the unbound concentrations at the infection site be considered relative to the MIC within the biological matrix to which the pathogen will be exposed. For soft tissue infections, this typically is the unbound plasma concentrations versus MICs determined in standardized media such as cation‐adjusted Mueller Hinton broth, which is how many indices were originally established. However, for UTIs, it is the unbound drug concentrations within the urine versus the MICs in the actual urine biophase that needs to be considered. The importance of these relationships and how they are influenced by drug resistance, resilience, and inoculum are discussed in this review using fluoroquinolones and beta‐lactams as examples.