International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. ascending UTI. To complete the assessment of iron receptors as vaccine candidates, an additional six UPEC iron receptors were evaluated. Of the six vaccine candidates tested in this study (FyuA, FitA, IroN, the gene product of the CFT073 locus = 0.0018) against UPEC colonization. Intranasal immunization induced a robust and long-lived humoral immune response. In addition, the levels of FyuA-specific serum IgG correlated with bacterial loads in the kidneys [Spearman’s rank correlation coefficient (14) = ?0.72, = 0.0018], providing a surrogate of protection. FyuA is the fourth UPEC iron receptor to be identified from our screens, in addition to IutA, Hma, and Remetinostat IreA, which were previously demonstrated to elicit protection against UPEC challenge. Together, these iron receptor antigens will facilitate the development of a broadly protective, multivalent UTI vaccine to effectively target diverse strains of UPEC. INTRODUCTION The human urinary tract Remetinostat is one of the most-common sites for bacterial infection, second only to the respiratory tract (1). Most urinary tract infections (UTI) are caused when pathogenic bacteria, commonly found in the gastrointestinal tract, colonize the perineum and traverse the urethra to cause an infection in the bladder, clinically termed cystitis. Left untreated, cystitis can progress to pyelonephritis as colonizing bacteria ascend the ureters to cause a secondary infection in the kidneys (2). In severe cases, invading bacteria can breach epithelial and endothelial barriers in the kidney to gain access to the bloodstream, leading to systemic infection and sepsis, a serious and sometimes fatal complication (3). While most UTIs seldom cause life-threatening or long-term health problems, the regularity with which they occur generates a substantial economic and public health burden (4). An estimated half of all women and 12% of men will experience a UTI in their lifetime, and almost a quarter of women who have one UTI will experience a second within 6 to 12 months (5). Commonly, these infections become recurrent, with an estimated three percent of women suffering from very frequent and often constant UTI (6). At the community level, frequent UTIs tax health care and financial resources, requiring over five million physician office visits, two million emergency room visits (7), and 500,000 hospitalizations Rabbit polyclonal to AKAP13 annually in the United States (8), with associated annual costs estimated at $3.5 billion (9). To prevent more-serious infection and speed recovery, patients with UTI are generally treated with a course of antibiotics, and individuals with recurrent infection may be prescribed antibiotics prophylactically (10). However, uropathogen resistance rates to first- and second-line antibiotic therapies are climbing steadily, which can complicate treatment and lead to therapeutic failure (11C13). For example, the resistance rate of community-acquired UTI isolates to the first-line antibiotic trimethoprim-sulfamethoxazole (TMP-SMX) currently exceeds 20% in most areas (11). Likewise, between 6 and 11% of community-acquired UTI isolates are resistant to the second-line fluoroquinolone agents ciprofloxacin and levofloxacin (14C16), and alarmingly, roughly 25% of catheter-associated UTIs are fluoroquinolone resistant (17). Multidrug resistance is also on the rise, so that now over 10% of cystitis isolates are resistant to at least three different classes of antimicrobial agents (15). Together, frequent and recurrent infection along with rising rates of antimicrobial resistance compromise effective long-term treatment for UTI, making the development of alternative management therapies for UTI essential. Vaccine development represents a rational alternative approach to UTI prevention whereby the most common cause of UTI, uropathogenic (UPEC), can be specifically targeted (18C20). UPEC represent a heterogeneous group of extraintestinal pathogenic strains that are responsible for roughly 75 to 80% of all uncomplicated, or community-acquired, UTIs (21) and an estimated 60% of complicated UTIs (22), or UTIs that occur in individuals where natural barriers to infection have been eroded by underlying conditions such as pregnancy or catheterization. Although UPEC strains can reside in the human gastrointestinal tract without causing disease, once in the urinary tract, they use an arsenal of virulence factors to colonize and survive in this alternative ecological niche, inducing a robust inflammatory immune response (23). While certain virulence factors can be more prevalent among UPEC strains, as of yet, no core set of virulence factors required for UPEC to cause UTI have been determined, making the identification of optimal UPEC vaccine targets a challenge (24). Given that conventional vaccinology approaches targeting established UPEC virulence factors have yet to produce a commercially Remetinostat available vaccine Remetinostat for UTI, we undertook.
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases
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