Pharmacokinetic Characteristics of Antimicrobials and Optimal Treatment of Urosepsis

Abstract

Urosepsis accounts for approximately 25% of all sepsis cases and may develop from a community-acquired or nosocomial urinary tract infection (UTI). Nevertheless, the underlying UTI is almost exclusively a complicated one with involvement of the parenchymatous urogenital organs (e.g. kidneys, prostate) and mostly associated with any kind of obstructive uropathy. If urosepsis originates from a nosocomial infection, a broad spectrum of Gram-negative and Gram-positive pathogens have to be expected, which are often multiresistant. In urosepsis, as in other types of sepsis, the severity of sepsis depends mostly upon the host response. The treatment of urosepsis follows the generally accepted rules of the 'Surviving Sepsis' campaign guidelines. Early normalisation of blood pressure and early adequate empirical antibacterial therapy with optimised dosing are equally important to meet the requirements of early goal-directed therapy. In most cases of urosepsis, early control of the infectious focus is possible and as important. Optimal supportive measures need to follow the early phase of resuscitation. To lower mortality from urosepsis, an optimal interdisciplinary approach between intensive care, anti-infective therapy and urology is essential, assisted by easy access to the necessary laboratory and imaging diagnostic procedures. Although most antibacterials achieve high urinary concentrations, there are several unique features of complicated UTI, and thus urosepsis, that influence the activity of antibacterial substances: (i) renal pharmacokinetics differ in unilateral and bilateral renal impairment and in unilateral and bilateral renal obstruction; (ii) variations in pH may influence the activity of certain antibacterials; and (iii) biofilm infection is frequently found under these conditions, which may increase the minimal inhibitory concentrations (MIC) of the antibacterials at the site of infection by several hundred folds. Assessment of antibacterial pharmacodynamic properties in such situations should take into account not only the MIC as determined in vitro and the plasma concentrations of the free (unbound) drug, which are the guiding principles for many infections, but also the actual renal excretion and urinary bactericidal activity of the antibacterial substance. In the treatment of urosepsis, it is important to achieve optimal exposure to antibacterials both in plasma and in the urinary tract. The role of drugs with low renal excretion rates is therefore limited. Since urosepsis quite often originates from catheter-associated UTI and urological interventions, optimal catheter care and optimal strategies to prevent nosocomial UTI may be able to reduce the frequency of urosepsis.