Current and emerging strategies to curb antibiotic-resistant urinary tract infections.

Rising rates of antibiotic resistance in uropathogenic bacteria compromise patient outcomes and prolong hospital stays. Consequently, new strategies are needed to prevent and control the spread of antibiotic resistance in uropathogenic bacteria. Over the past two decades, sizeable clinical efforts and research advances have changed urinary tract infection (UTI) treatment and prevention strategies to conserve antibiotic use. The emergence of antimicrobial stewardship, policies from national societies, and the development of new antimicrobials have shaped modern UTI practices. Future UTI management practices could be driven by the evolution of antimicrobial stewardship, improved and readily available diagnostics, and an improved understanding of how the microbiome affects UTI. Forthcoming UTI treatment and prevention strategies could employ novel bactericidal compounds, combinations of new and classic antimicrobials that enhance bacterial killing, medications that prevent bacterial attachment to uroepithelial cells, repurposing drugs, and vaccines to curtail the rising rates of antibiotic resistance in uropathogenic bacteria and improve outcomes in people with UTI.

Urinary Tract Infections in Children.

Despite the American Academy of Pediatrics guidelines for the evaluation, treatment, and management of urinary tract infections (UTIs), UTI diagnosis and management remains challenging for clinicians. Challenges with acute UTI management stem from vague presenting signs and symptoms, diagnostic uncertainty, limitations in laboratory testing, and selecting appropriate antibiotic therapy in an era with increasing rates of antibiotic-resistant uropathogens. Recurrent UTI management remains difficult due to an incomplete understanding of the factors contributing to UTI, when to assess a child with repeated infections for kidney and urinary tract anomalies, and limited prevention strategies. To help reduce these uncertainties, this review provides a comprehensive overview of UTI epidemiology, risk factors, diagnosis, treatment, and prevention strategies that may help pediatricians overcome the challenges associated with acute and recurrent UTI management.

Trans IL-6 signaling does not appear to play a role in renal scarring after urinary tract infection.

INTRODUCTION: While inflammation is an important innate defense mechanism against infection, it can also lead to local tissue damage. The trans signaling pathway of interleukin (IL)-6 is a known mediator of inflammation. We hypothesized that the trans IL-6 signaling pathway is associated with the development of post febrile urinary tract infection (UTI) renal scarring. OBJECTIVE: To compare soluble regulators of trans IL-6 signaling between patients with a history of febrile UTI who do or do not have renal scarring. STUDY DESIGN: After IRB-approval, we collected urine samples in pediatric patients with a history of febrile (≥38 °C) UTI (urine culture >50 K uropathogen) with documented presence or absence of renal scarring on imaging. Samples were collected at a time when patients were not actively infected. Enzyme-linked immunosorbent assays were performed on samples for markers of trans IL-6 signaling: IL-6, soluble (s) IL-6 receptor (R), and soluble (s)gp130, a buffer in trans IL-6 signaling. Values were normalized to urine creatinine. Results were analyzed by t-test or Mann-Whitney U. Spearman rank correlation was used. A p-value of <0.05 was considered significant. RESULTS: A total of 50 urines from patients with a history of febrile UTI were collected: 23 with and 27 without scarring. There was no difference between groups regarding age or gender. There was no significant difference in urine IL-6, sIL-6R, or sgp130 between those with and without scarring (Figure). While IL-6 values significantly correlated with sIL-6R and sgp130 in those without renal scarring, IL-6 did not correlate with sgp130 in those with scarring. Ratios of IL-6 to sgp130 and sIL-6R to sgp130 were not different between groups. DISCUSSION: The inflammatory response generated in response to infection is believed to be largely responsible for the development of renal scarring after UTI. IL-6 is a cytokine known to be induced during UTI with a pro-inflammatory pathway, known as trans signaling. This study investigated for differences in markers of trans IL-6 signaling between patients with a history of febrile UTI with and without renal scarring. There was no significant difference between the absolute values or ratio of these markers between groups. CONCLUSIONS: Markers of trans IL-6 signaling are not different between individuals with a history of febrile UTI with and without renal scarring in the non-acute setting.

Impact of successful pediatric ureteropelvic junction obstruction surgery on urinary HIP/PAP and BD-1 levels.

INTRODUCTION: In the pediatric patient whose ureteropelvic junction obstruction (UPJO) is not always symptomatic, imaging is the most common means of detecting surgical success. There is interest, however, in other means of post-operative monitoring. A panel of antimicrobial peptides (AMPs) has been previously found to be elevated in UPJO, but the impact of surgical correction on these AMPs is unknown. OBJECTIVE: To determine if elevated levels of candidate urinary AMP biomarkers of urinary tract obstruction decrease following UPJO repair. STUDY DESIGN: Pediatric patients undergoing surgical correction of an UPJO were recruited for participation. Bladder urine from uninfected consenting/assenting patients was collected immediately prior to surgery and then at least 6 months afterward. Based on prior studies demonstrating significant elevation of beta defensin 1 (BD-1), hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), cathelicidin (LL-37), and neutrophil gelatinase-associated lipocalin (NGAL) in patients with UPJO versus control patients, we performed enzyme-linked immunosorbent assays on these four AMPs to compare their expression before and after surgical intervention. If found to significantly decrease, AMP levels were compared to healthy controls. AMP levels were normalized to urine creatinine. Results were analyzed with paired t test or Wilcoxon test using Graphpad software. Correlation was calculated using Pearson or Spearman correlation. A p-value of <0.05 was considered significant. RESULTS: 13 UPJO patients were included in this study; 9 were male (69%). Age at surgery was a median of 4.3 years (average 6.1, range 0.4-18.4 years). Follow-up urine samples were collected a median of 27.4 months after surgery (average 27.4; range 7.8-45.3 months). All 13 patients had clinical improvement and/or signs of improved hydronephrosis on post-operative imaging. HIP/PAP and BD-1 significantly decreased in post-surgical samples compared to pre-surgical samples (p = 0.02 and 0.01, respectively); NGAL and LL-37 did not significantly change. Overall, HIP/PAP decreased in 12 patients (92%) and BD-1 decreased in 11 patients (85%). BD-1 levels after successful repair were not different from healthy controls (p = 0.06). DISCUSSION: Urinary biomarkers of obstruction should detect significant obstructive pathology as well as reflect its resolution. This would enable their use in post-operative monitoring and augment current methods of determining successful surgical outcome through imaging. CONCLUSIONS: The AMPs HIP/PAP and BD-1 are significantly elevated in UPJO but then significantly decrease after pyeloplasty, with BD-1 returning to healthy control levels. As a result, these AMPs could serve as markers of successful surgical intervention.