Use of Fever Duration to Guide Management of Urinary Tract Infection.

BACKGROUND: The appropriate duration of antimicrobial therapy for febrile urinary tract infection (fUTI) in children has not been established. This study examined the optimal duration of treatment for fUTI in children. METHODS: We created a protocol that used fever duration to determine the duration of antibiotic administration. Transvenous antibiotics were administered until 3 days after resolution of fever, followed by oral antibiotics for 1 week. Diagnosis of fUTI was based on a fever of 37.5°C or higher and a quantitative culture of catheterized urine yielded a bacteria count of ≥5 × 104. Acute focal bacterial nephritis (AFBN) and pyelonephritis (PN) were diagnosed on the basis of contrast-enhanced computed tomography (eCT) findings. We retrospectively reviewed treatment outcomes. RESULTS: Of the 78 patients treated according to our protocol, data from 58 were analyzed-49 children (30 boys) had PN and nine (three boys) had AFBN. Blood test results showed that patients with AFBN had significantly higher white blood cell counts and C-reactive protein levels than did those with PN; however, urinary findings and causative bacteria did not differ between groups. Time to resolution of fever and duration of intravenous antibiotic administration were significantly longer in patients with AFBN than in those with PN. However, average duration of AFBN treatment was 14.2 days, which was shorter than the previously reported administration period of 3 weeks. No recurrence was observed in AFBN patients. CONCLUSIONS: A protocol that used fever duration to determine the duration of antimicrobial treatment was useful. Invasive examinations, such as eCT, were not required.

Cefepime-taniborbactam and CERTAIN-1: Can we treat carbapenem-resistant infections?

Wagenlehner and colleagues1 demonstrated non-inferiority and superiority with respect to a primary endpoint of composite success (microbiological plus clinical) of cefepime/taniborbactam vs. meropenem in treating complicated urinary tract infections and acute pyelonephritis caused by carbapenem-susceptible gram-negative bacteria in adults. A major area of interest in real-world application of cefepime/taniborbactam is its potential role in treating carbapenem-resistant infections, which deserves further investigation.

Clinicopathologic Spectrum and Outcomes of Infections Diagnosed on Graft Biopsies and Nephrectomy in Live Renal Allograft Recipients: An Institutional Experience.

OBJECTIVES: Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. MATERIALS AND METHODS: Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. RESULTS: BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. CONCLUSIONS: BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.

Empirical antimicrobial prescribing for pyelonephritis in patients discharged from 15 US Emergency Departments: an opportunity for improvement.

BACKGROUND: Urinary tract infections (UTIs) are commonly treated in the emergency department (ED), and unfortunately, resistance to first-line agents is increasing. OBJECTIVES: To characterize treatment of pyelonephritis in a nationally representative sample of ED patients and to identify patient- and treatment-specific factors associated with receiving initial inactive antibiotics. METHODS: We conducted a multicentre, observational cohort study utilizing the Emergency Medicine PHARMacotherapy Research NETwork (EMPHARM-NET), comprising 15 geographically diverse US EDs. All patients ≥18 years of age with a diagnosis of pyelonephritis between 2018 and 2020 were included. The primary endpoint was the proportion of patients who received initial inactive empirical antibiotic therapy and to identify predictive factors of inactive antibiotic therapy. RESULTS: Of the 3714 patients evaluated, 223 had culture-positive pyelonephritis. Median patient age was 50.1 years and patients were mostly female (78.3%). Overall, 40.4% of patients received an IV antibiotic, most commonly ceftriaxone (86.7%). The most frequently prescribed antibiotics were cefalexin (31.8%), ciprofloxacin (14.3%), cefdinir (13.5%) and trimethoprim/sulfamethoxazole (12.6%). Overall, 10.3% of patients received initial inactive therapy. After adjustment in a multivariable analysis, long-acting IV antibiotic was predictive of inactive therapy (OR 0.23, 95% CI 0.07-0.83). CONCLUSIONS: In our prospective, multicentre observational study, we found that only 40.4% of patients with pyelonephritis received empirical IV antibiotics in the ED, contributing to inactive therapy. Receipt of long-acting IV antibiotics was independently associated with a decreased rate of initial inactive therapy. This reinforces guideline recommendations to administer long-acting IV antibiotics empirically in the ED upon suspicion of pyelonephritis.

Regulation of renal aquaporin water channels in acute pyelonephritis.

Acute pyelonephritis (APN) is most frequently caused by uropathogenic Escherichia coli (UPEC), which ascends from the bladder to the kidneys during a urinary tract infection. Patients with APN have been reported to have reduced renal concentration capacity under challenged conditions, polyuria, and increased aquaporin-2 (AQP2) excretion in the urine. We have recently shown increased AQP2 accumulation in the plasma membrane in cell cultures exposed to E. coli lysates and in the apical plasma membrane of inner medullary collecting ducts in a 5-day APN mouse model. This study aimed to investigate if AQP2 expression in host cells increases UPEC infection efficiency and to identify specific bacterial components that mediate AQP2 plasma membrane insertion. As the transepithelial water permeability in the collecting duct is codetermined by AQP3 and AQP4, we also investigated whether AQP3 and AQP4 localization is altered in the APN mouse model. We show that AQP2 expression does not increase UPEC infection efficiency and that AQP2 was targeted to the plasma membrane in AQP2-expressing cells in response to the two pathogen-associated molecular patterns (PAMPs), lipopolysaccharide and peptidoglycan. In contrast to AQP2, the subcellular localizations of AQP1, AQP3, and AQP4 were unaffected both in lysate-incubated cell cultures and in the APN mouse model. Our finding demonstrated that cellular exposure to lipopolysaccharide and peptidoglycan can trigger the insertion of AQP2 in the plasma membrane revealing a new regulatory pathway for AQP2 plasma membrane translocation, which may potentially be exploited in intervention strategies.NEW & NOTEWORTHY Acute pyelonephritis (APN) is associated with reduced renal concentration capacity and increased aquaporin-2 (AQP2) excretion. Uropathogenic Escherichia coli (UPEC) mediates changes in the subcellular localization of AQP2 and we show that in vitro, these changes could be elicited by two pathogen-associated molecular patterns (PAMPs), namely, lipopolysaccharide and peptidoglycan. UPEC infection was unaltered by AQP2 expression and the other renal AQPs (AQP1, AQP3, and AQP4) were unaltered in APN.

Cefepime-Taniborbactam in Complicated Urinary Tract Infection.

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).

Clinical and microbiological characteristics of female patients with acute pyelonephritis who experienced urinary tract infections within the previous year.

BACKGROUND: This study aimed to examine the clinical and microbiological characteristics of female patients with recurrent acute pyelonephritis (APN). METHODS: A retrospective cohort study was conducted at a tertiary care hospital in South Korea from July 2019 to December 2021. All female patients aged ≥ 19 years who were diagnosed with community-acquired APN on admission were enrolled. The recurrent group included patients with APN who experienced urinary tract infections within the previous year. The clinical characteristics, types of causative organisms, major antibiotic resistance, and molecular characteristics of Escherichia coli strains were compared between the recurrent and non-recurrent groups. RESULTS: A total of 285 patients with APN were analyzed, including 41 (14.4%) in the recurrent group. Compared to the non-recurrent group, the recurrent group had a higher Charlson Comorbidity Index (1.8 ± 2.1 vs. 1.1 ± 1.5; P = 0.01) and a higher proportion of bladder abnormalities, such as neurogenic bladder (12.2% vs. 2.0%; P = 0.001) and urinary catheterization (12.2% vs. 1.6%; P < 0.001). Escherichia coli was the most common causative organism in both groups. The proportion of Klebsiella pneumoniae (17.1% vs. 4.7%; P = 0.007) and Pseudomonas aeruginosa (5.7% vs. 0.5%; P = 0.014) as a causative organism was higher in the recurrent group. Regarding the microbiological characteristics of Escherichia coli, there were no significant differences in the proportion of antibiotic resistance, phylogenetic groups, resistance genes, and virulence factors between the two groups. Multivariable analysis showed that neurogenic bladder and a history of admission or antibiotic use during 1 year prior to inclusion were significantly associated with recurrent APN. CONCLUSIONS: The proportion of causative organisms except Escherichia coli was higher in the recurrent group than in the non-recurrent group. Neurogenic bladder and a history of admission or antibiotic use during 1 year prior to inclusion were risk factors for recurrent APN.

[EFFECT OF ETHNICITY ON BACTERIAL RESISTANCE AND OBSTETRICAL OUTCOMES AMONG PREGNANT WOMEN ADMITTED TO MATERNAL-FETAL MEDICINE UNIT WITH THE DIAGNOSIS OF PYELONEPHRITIS DURING 2017-2020].

INTRODUCTION: Antibiotic resistance is a worldwide concern. No study has ever examined the correlation between ethnicity and antibiotic resistance. We examined those parameters among hospitalized pregnant patients diagnosed with pyelonephritis. AIMS: Should ethnic origin play a role in optimizing antibiotic therapy? To better comprehend, we have chosen a cohort of hospitalized pregnant patients with a pyelonephritis diagnosis. METHODS: A total of 105 cases of patients hospitalized in the Shamir Medical Center between the years 2017-2020 were analysed. Feto-maternal outcomes and antibiotic resistance in relation to ethnicity were plotted statistically using chi-square tests (Arab, 40%; North Africa, 13%; Europe-Ashkenaz,10%; Ethiopia/Iran/Kavkaz/Iraq/other, 3%; Turkey/Uzbekistan/Yemen 2%). RESULTS: Ethnic groups included Arab (40%), others referred as "None-Arab". The antibiotic resistance panel revealed differences comparing the two largest groups (Arab% VS non-Arab%), whereas there was no correlation between any ethnic group and obstetrics parameter. Arab women were more resistant to ciprofloxacin (33% vs 7%, P= 0.026) and less sensitive to imipenem (60% vs 90.9%, P= 0.03); less sensitive to ceftriaxone and cefuroxime. CONCLUSIONS: There was a correlation between ethnic origin of pregnant patients diagnosed with pyelonephritis and antibiotic resistance. We hope ethnicity, might, in some cases, assist physicians choosing the optimal therapy.

Androgen exposure impairs neutrophil maturation and function within the infected kidney.

Urinary tract infections (UTIs) in men are uncommon yet carry an increased risk for severe pyelonephritis and other complications. In models of Escherichia coli UTI, C3H/HeN mice develop high-titer pyelonephritis (most with renal abscesses) in a testosterone-dependent manner, but the mechanisms underlying this phenotype are unknown. Here, using female mouse models, we show that androgen exposure impairs neutrophil maturation in the upper and lower urinary tract, compounded by a reduction of neutrophil function within the infected kidney, enabling persistent high-titer infection and promoting abscess formation. Following intravesical inoculation with uropathogenic E. coli (UPEC), kidneys of androgen-exposed C3H mice showed delayed local pro-inflammatory cytokine responses while robustly recruiting neutrophils. These were enriched for an end-organ-specific population of aged but immature neutrophils (CD49d+, CD101-). Compared to their mature counterparts, these aged immature kidney neutrophils exhibited reduced function in vitro, including impaired degranulation and diminished phagocytic activity, while splenic, bone marrow, and bladder neutrophils did not display these alterations. Furthermore, aged immature neutrophils manifested little phagocytic activity within intratubular UPEC communities in vivo. Experiments with B6 conditional androgen receptor (AR)-deficient mice indicated rescue of the maturation defect when AR was deleted in myeloid cells. We conclude that the recognized enhancement of UTI severity by androgens is attributable, at least in part, to local impairment of neutrophil maturation in the urinary tract (largely via cell-intrinsic AR signaling) and a kidney-specific reduction in neutrophil antimicrobial capacity.IMPORTANCEAlthough urinary tract infections (UTIs) predominantly occur in women, male UTIs carry an increased risk of morbidity and mortality. Pyelonephritis in androgen-exposed mice features robust neutrophil recruitment and abscess formation, while bacterial load remains consistently high. Here, we demonstrate that during UTI, neutrophils infiltrating the urinary tract of androgen-exposed mice exhibit reduced maturation, and those that have infiltrated the kidney have reduced phagocytic and degranulation functions, limiting their ability to effectively control infection. This work helps to elucidate mechanisms by which androgens enhance UTI susceptibility and severity, illuminating why male patients may be predisposed to severe outcomes of pyelonephritis.

Poor performance status is a risk factor for higher detection of Gram positive coccus in stone-related pyelonephritis.

INTRODUCTION: We aimed to investigate the detection rate of causative organisms in stone-related pyelonephritis and to compare their distribution according to patient backgrounds. METHODS: We retrospectively identified patients with stone-related pyelonephritis. Clinical data were collected between November 2012 and August 2020 at Wakayama Medical University Hospital, including on patient backgrounds and causative organisms. Patients were categorized by Eastern Cooperative Oncology Group performance status (PS) as the good PS group (0, 1) and the poor PS group (2-4). Bacteria were divided into Gram-positive cocci (GPC) or non-GPC groups and logistic regression analysis was used to examine factors that predict detection of GPC. RESULTS: Seventy-nine patients had stone-related pyelonephritis, 54 (68.4 %) in the good PS group and 25 (31.6 %) in the poor PS group. In the good PS group, Escherichia coli (67 %) was followed by Klebsiella species (9 %), while in the poor PS group, Escherichia coli (20 %) was followed by Enterococci and Staphylococci (12 %). GPC detection rate was significantly higher in the poor PS group than in the good PS group (40.0 % vs 14.8 %, p = 0.016), and multivariate logistic regression analysis showed that poor PS was an independent factor predicting detection of GPC (OR = 6.54, p = 0.02). CONCLUSIONS: The distribution of the causative organisms in stone pyelonephritis was similar to that in common complicated urinary tract infections. Poor PS may be an independent predictor of GPC detection in patients with stone pyelonephritis.

[Development of purulent-destructive forms of acute pyelonephritis in patients with a history of new coronavirus infection Covid-19].

INTRODUCTION: Since 2019, more than 600 million cases of the new coronavirus infection Covid-19 have been reported worldwide. According to various studies, the development of a systemic inflammatory response and "cytokine storm" play an important role in the pathogenesis of kidney damage, which leads to impaired microcirculation, increased thrombus formation and the development of ischemic areas in the parenchyma. AIM: To study the frequency and possible causes of purulent forms of pyelonephritis in patients who have had a new coronavirus infection Covid-19. MATERIALS AND METHODS: The prospective and retrospective study included the results of 403 patients with acute non-obstructive pyelonephritis in the pre-Covid period and those with a history of a new coronavirus infection. RESULTS: In patients with acute non-obstructive pyelonephritis without past urological history who had a new coronavirus infection, an increase in purulent-destructive forms from 5.0 to 17.0% was noted. One of the reasons is increased antibiotic resistance and the emergence of pan-resistant uropathogens due to irrational use of antibacterial drugs. CONCLUSION: The use of reserve antibacterial drugs in patients with acute pyelonephritis as empirical therapy and anticoagulants in order to improve microcirculation and prevent thrombosis is pathogenetically justified.

A randomized, controlled trial of prulifloxacin as conversion therapy after intravenous carbapenem in the treatment of acute pyelonephritis caused by third generation cephalosporin resistant pathogens: A pilot study.

The efficacy of converting to oral fluoroquinolones after initial intravenous antibiotics for the treatment of acute pyelonephritis (APN) caused by the third-generation cephalosporin resistant Enterobacteriaceae (3-GCrEC) needs to be investigated. The objective was to compare the clinical and bacteriological outcome of oral prulifloxacin with intravenous ertapenem for the treatment of APN caused by 3-GCrEC. A pilot, randomized controlled trial of patients with APN caused by 3-GCrEC was conducted at two hospitals from August 2015 to December 2020. Any intravenous antimicrobial drug was initially permitted for empirical therapy. On day 4, adult patients (aged >18 years) with either non-bacteremic or bacteremic APN were eligible for the study if their infection was caused by 3-GCrEC susceptible to the study drugs. The patients were randomly assigned to receive either oral prulifloxacin or intravenous ertapenem. The total duration of antimicrobial therapy was 14 days. Of the 21 enrolled patients, 11 were treated with prulifloxacin, and 10 were treated with ertapenem. At the test of cure visit, there was no statistically significant difference between the patients with overall clinical success who were treated with prulifloxacin (90.9%) and those treated with ertapenem (100%, p = 0.999). In addition, there was no statistically significant difference in microbiological eradication between the prulifloxacin and ertapenem groups (100% vs. 100%, p = 0.999). The converting to oral prulifloxacin after intravenous antibiotics therapy appears to be an alternative option for treatment of APN caused by 3-GCrEC. A further large randomized controlled trial should be investigated.

Cephalosporins for the treatment of uncomplicated pyelonephritis: A systematic review.

BACKGROUND: The 2011 Infectious Diseases Society of America and European Society of Clinical Microbiology and Infectious Diseases guidelines recommend ciprofloxacin or sulfamethoxazole-trimethoprim (SMX-TMP) as first-line agents to treat uncomplicated acute pyelonephritis (APN). OBJECTIVE: With increasing antimicrobial resistance rates and recent changes in practice patterns, the objective of this systematic review was to describe the effectiveness of cephalosporins for uncomplicated APN in more recently published literature. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for reporting. We searched PubMed, Embase, and Scopus for publications between January 2010 and September 2022. Eligible articles detailed patients with uncomplicated APN, treated with first- to fourth-generation cephalosporins, and identified a clinical, microbiological, or health care utilization outcome. Studies with more than 30% of complicated APN patients, non-English-language studies, case reports, case series, pharmacodynamic or pharmacokinetic studies, and in vitro laboratory or animal studies were excluded. Screening, review, and extraction were performed independently by 2 researchers, plus a third for conflict resolution. Critical appraisal of studies was performed using Joanna Briggs Institute checklists. RESULTS: Eight studies met inclusion, including 5 cohort studies (62.5%), 2 randomized controlled trials (25%), and 1 nonrandomized experimental study (12.5%). Cephalosporins most used across the studies included cefazolin, cephalexin, cefuroxime, cefotaxime, cefdinir, cefditoren, and ceftriaxone. Outcomes assessed were diverse, including clinical or microbiological success and time to defervescence or symptom resolution. Cephalosporins displayed effectiveness for the treatment of acute uncomplicated APN regardless of study design or the presence of a comparison group. No trials reported inferiority of clinical treatment outcomes compared with a fluoroquinolone or SMX-TMP. CONCLUSION: Cephalosporins may be viable treatment options for the management of uncomplicated APN.

Incidence of renal scarring on technetium-99 m dimercaptosuccinic acid renal scintigraphy after acute pyelonephritis, acute focal bacterial nephritis, and renal abscess.

OBJECTIVE: To evaluate the association between the incidence of renal scarring on technetium-99 m dimercaptosuccinic acid (DMSA) renal scintigraphy and the severity of renal parenchymal infections, such as acute pyelonephritis (APN), acute focal bacterial nephritis (AFBN), and renal abscess, based on computed tomography (CT) diagnosis. METHODS: Sixty-one children with renal parenchymal infections were included and classified into two groups: those with (renal scarring group) and without renal scarring (non-renal scarring group) on chronic-phase DMSA renal scintigraphy. The severity of renal parenchymal infection was classified into three grades using CT: APN, AFBN, and renal abscess as grades 1, 2, and 3, respectively. The severity of renal parenchymal infection, vesicoureteral reflux (VUR) grade, and intrarenal reflux occurrence during voiding cystourethrography (VCUG) were evaluated between the renal and non-renal scarring groups. Fisher's exact test and Mann-Whitney U test were used for statistical analysis. RESULTS: Renal scars were detected in 28 (45.9%) of the 61 patients. We found that 2/9 (22.2%), 18/41 (43.9%), and 8/11 (72.7%) patients with APN (grade 1), AFBN (grade 2), and renal abscess (grade 3) had renal scarring, respectively. There was a significant difference in the grade of severity of renal parenchymal infection between the renal (median = 2 [interquartile range, 2-3]) and non-renal (median = 2 [interquartile range, 2-2]) scarring groups (p = 0.023). There was a significant difference in the grade of VUR between the renal (median = 3 [interquartile range, 0-4]) and non-renal (median = 0 [interquartile range, 0-2]) scarring groups (p = 0.004). No significant difference in intrarenal reflux occurrence was observed between the renal (present/absent: 3/25) and non-renal (present/absent: 0/29) scarring groups (p = 0.112). CONCLUSION: Our results showed that pediatric patients with renal scarring on chronic-phase DMSA renal scintigraphy tended to have a more severe renal infection.

Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial.

Importance: Cefepime/enmetazobactam is a novel ß-lactam/ß-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. Objective: To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis. Design, Setting, and Participants: A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Interventions: Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). Main Outcomes and Measures: The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Results: Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Conclusions and Relevance: Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis. Trial Registration: ClinicalTrials.gov Identifier: NCT03687255.

Protective role for C3aR in experimental chronic pyelonephritis.

Emerging evidence suggest that C3aR plays important roles in homeostasis, host defense and disease. Although it is known that C3aR is protective in several models of acute bacterial infections, the role for C3aR in chronic infection is largely unknown. Here we show that C3aR is protective in experimental chronic pyelonephritis. Global C3aR deficient (C3ar-/- ) mice had higher renal bacterial load, more pronounced renal histological lesions, increased renal apoptotic cell accumulation, tissue inflammation and extracellular matrix deposition following renal infection with uropathogenic E. coli (UPEC) strain IH11128, compared to WT control mice. Myeloid C3aR deficient (Lyz2-C3ar-/- ) mice exhibited a similar disease phenotype to global C3ar-/- mice. Pharmacological treatment with a C3aR agonist reduced disease severity in experimental chronic pyelonephritis. Furthermore, macrophages of C3ar-/- mice exhibited impaired ability to phagocytose UPEC. Our data clearly demonstrate a protective role for C3aR against experimental chronic pyelonephritis, macrophage C3aR plays a major role in the protection, and C3aR is necessary for phagocytosis of UPEC by macrophages. Our observation that C3aR agonist curtailed the pathology suggests a therapeutic potential for activation of C3aR in chronic infection.

Human neutrophil peptides 1-3 protect the murine urinary tract from uropathogenic Escherichia coli challenge.

Antimicrobial peptides (AMPs) are critical to the protection of the urinary tract of humans and other animals from pathogenic microbial invasion. AMPs rapidly destroy pathogens by disrupting microbial membranes and/or augmenting or inhibiting the host immune system through a variety of signaling pathways. We have previously demonstrated that alpha-defensins 1-3 (DEFA1A3) are AMPs expressed in the epithelial cells of the human kidney collecting duct in response to uropathogens. We also demonstrated that DNA copy number variations in the DEFA1A3 locus are associated with UTI and pyelonephritis risk. Because DEFA1A3 is not expressed in mice, we utilized human DEFA1A3 gene transgenic mice (DEFA4/4) to further elucidate the biological relevance of this locus in the murine urinary tract. We demonstrate that the kidney transcriptional and translational expression pattern is similar in humans and the human gene transgenic mouse upon uropathogenic Escherichia coli (UPEC) stimulus in vitro and in vivo. We also demonstrate transgenic human DEFA4/4 gene mice are protected from UTI and pyelonephritis under various UPEC challenges. This study serves as the foundation to start the exploration of manipulating the DEFA1A3 locus and alpha-defensins 1-3 expression as a potential therapeutic target for UTIs and other infectious diseases.

Treatment of asymptomatic bacteriuria in the first 2 months after kidney transplant: A controlled clinical trial.

BACKGROUND: The incidence of urinary tract infections (UTIs) in the first 2 months postrenal transplantation (pRT) is very high. We evaluate the efficacy of asymptomatic bacteriuria (AB) screening and treatment on the incidence of UTI in the first 2 months pRT METHODS: We conducted a randomized controlled clinical trial. A urine culture was obtained in all patients on the day of the bladder catheter removal, on week three, and before removal of the ureteral catheter. The intervention group received treatment for AB. The control group did not receive treatment. The primary outcomes were the cumulative incidence of UTI and/or graft pyelonephritis and the time to the first episode of UTI and/or graft pyelonephritis RESULTS: Eighty patients were randomized, 40 in each group, and the median follow-up was 63 days (IQR 54-70). The average age was 29.8 years and 33.7% (n = 27) were women. The incidences of UTI (n = 10, 25 % vs. n = 4, 10%, p = .07) and pyelonephritis (n = 6, 15% vs. n = 1, 2.5%, p = .04) were greater in the intervention group, as also shown in the survival analysis: UTI (HR2.8, 95% CI 0.8-9.1, p = .07) and pyelonephritis (HR 6.5, 95% CI 0.8-54.7, p = .08), respectively. The most commonly isolated bacterium was Escherichia coli (n = 28, 59.5%), and over half were E. coli with extended-spectrum beta-lactamases (n = 15). A major limitation was not obtaining the calculated sample size due to a delay in patient recruitment resulting from the COVID-19 pandemic CONCLUSION: Treatment of AB in the first 2 months pRT does not decrease the incidence of UTI or graft pyelonephritis and may actually increase their frequency. Routine treatment of AB during the first months after renal transplantation should not be a standard procedure.

Fungal Pyelonephritis and Fungemia Due to Obstructive Uropathy.

INTRODUCTION: Funguria is often a benign and common occurrence in the hospital. However, invasive fungal pyelonephritis due to obstructive uropathy is uncommon and can be difficult to treat. Typically, there are 2 mechanisms by which Candida albicans infects the upper urinary tract: by ascending from the lower urinary tract or via hematogenous spread to the kidneys. CASE PRESENTATION: We present a case of fungal pyelonephritis, likely due to obstructive uropathy, leading to fungemia in a 70-year-old man who had a recent history of colovesicular fistula and indwelling foley catheter. DISCUSSION: The patient had many identified risk factors contributing to the development of fungal pyelonephritis, including diabetes mellitus and structural urinary tract aberrancies, which were further complicated by his recent colovesicular fistula and repair. CONCLUSION: Although fungal pyelonephritis with fungemia is relatively rare, it should not be excluded from differential diagnostics. Despite a unique host of risk factors, a direct approach led to successful treatment.