Increased Incidence of Urolithiasis and Bacteremia During Proteus mirabilis and Providencia stuartii Coinfection Due to Synergistic Induction of Urease Activity

Catheter-associated urinary tract infection (CaUTI), the most common health care-associated infection worldwide, accounts for up to 40% of hospital-acquired infections [1]. Data compiled over the last 30 years indicate that up to 86% of CaUTIs are polymicrobial, involving combinations of Proteus mirabilis, Providencia stuartii, Morganella morganii, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae [2–9]. P. mirabilis and P. stuartii are two of the most common causes of CaUTI, and the most consistently found to co-colonize [2, 5, 6, 8–10]. Both species are resistant to numerous antibiotics and have a remarkable ability to persist within the urinary tract despite catheter changes and antibiotic treatment [5, 6, 9]. Potential complications of CaUTI caused by P. mirabilis or P. stuartii include catheter blockage and urolithiasis due to urease activity. P. mirabilis is thought to be the main species responsible for crystalline biofilm formation on catheters and the resulting blockage, and P. stuartii is generally the second most common species isolated from blocked indwelling catheters [6, 10, 11]. Experimentally, a high inoculum of P. mirabilis (2 × 1010 CFU/mL) results in urolithiasis and severe pyelonephritis, while loss of urease activity severely reduces colonization, prevents stone formation, and limits kidney damage, indicating that urease is a major contributing factor to both the severity and persistence of P. mirabilis UTI [12–16]. P. stuartii BE2467 appears to possess two seemingly identical urease enzymes, one plasmid-encoded and one chromosomal [17], although the specific contribution of P. stuartii urease to colonization and severity of infection has yet to be addressed. Notably, urease activity in both of these species is induced by the presence of urea [18–20]. Bacteremia is another complication of P. mirabilis and P. stuartii CaUTI. In long term care facilities, bacteriuria is the source for 45%–55% of bacteremias [1]. Indeed, UTI is a common source of bacteremia for both P. mirabilis and P. stuartii [21–26]. Similar to bacteriuria, bacteremia in patients with long-term catheterization is also frequently polymicrobial [1, 26, 27]. It has been reported that 25% of P. mirabilis bacteremias and up to 51% of P. stuartii bacteremias are polymicrobial [22, 25, 28], suggesting that P. stuartii and P. mirabilis may promote development of bacteremia by other species or are more likely to reach the bloodstream during a polymicrobial infection. This is notable as the mortality rate for polymicrobial bacteremia is increased compared to the already high mortality rate of P. mirabilis or P. stuartii monospecies bacteremia [25, 26]. Despite the staggering data suggesting co-colonization and possible cooperation between P. mirabilis and P. stuartii, the impact of coinfection by these species has yet to be addressed experimentally. In this study, we used a mouse model of ascending UTI to determine the impact of P. mirabilis and P. stuartii coinfection on bacterial persistence, bacteremia, and urolithiasis, as well as the impact of urease on these parameters. The results clearly demonstrate that coinfection increases the incidence of urolithiasis and bacteremia in a urease-dependent manner and indicate synergistic induction of urease activity during co-culture.