Asymptomatic Bacteriuria. Protection against, and differential diagnosis towards symptomatic Urinary Tract Infection

Sammanfattning: Urinary tract infections (UTIs) are among the most common infectious diseases in humans, with a subset of susceptible individuals who experience recurrent episodes. The increase in antibiotic resistance in gram-negative uropathogens, due to antibiotic overuse, is a strong rationale for developing therapeutic alternatives and to improve diagnostics. In patients with incomplete bladder emptying (e.g. due to spinal lesions and in institutionalized older patients) asymptomatic bacteriuria (ABU) is frequent. In these patient groups diagnosis of UTI is obscured by subjective symptoms being difficult to interpret, and by the already positive urine culture. As ABU is known to be protective against symptomatic episodes, unnecessary treatment should be avoided, and the identification of objective biomarkers to support treatment decision of a suspected UTI episode is thus much needed. This thesis investigated if the same protective capacity as in spontaneously developed ABU could be induced in patients subjected to deliberate inoculation with the ABU strain E. coli 83972, and analyzed the variation of local host responses in patients with E. coli 83972 ABU and its possible genetic background, the role of the local inflammatory mediator Interleukin 6 (IL-6) and its correlation to symptom severity in UTI, and if IL-6 could be used as a diag- nostic tool in treatment decision of UTI. The results demonstrate that E. coli 83972 bacteriuria protects against symptomatic episodes in UTI prone indi- viduals. This was shown in a placebo controlled inoculation study with cross-over design by demonstrating longer time to recurrences and fewer UTI episodes during E. coli 83972 bacteriuria as compared with control periods (Paper 1). In patients with long term E. coli 83972 ABU the level of mucosal host response to the standardized bacterial challenge demonstrates unique interindividual specific variation. Genetic analysis suggests this to depend on polymorphisms in specific genes coding for innate immunity (Paper II). Urinary concentrations of IL-6 correlate to symptom severity in UTI, and seem to be the superior biomarker for ABU/UTI differential diagnosis. This was demonstrated by analysis of symptom scoring in patients during long term E. coli 83972 ABU and during UTI episodes in the same patients. Furthermore, diagnostic thresholds for IL-6 in differentiating ABU/UTI were analyzed. (Paper III). The use of IL-6 as an added tool in ABU/UTI differential diagnosis was shown to be feasible in a nursing home setting, and reduced together with an educational intervention antibiotic prescription for UTI in a two phase interventional trial (Paper IV).