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.).

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.

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.

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.

Immunomodulation therapy offers new molecular strategies to treat UTI.

Innovative solutions are needed for the treatment of bacterial infections, and a range of antibacterial molecules have been explored as alternatives to antibiotics. A different approach is to investigate the immune system of the host for new ways of making the antibacterial defence more efficient. However, the immune system has a dual role as protector and cause of disease: in addition to being protective, increasing evidence shows that innate immune responses can become excessive and cause acute symptoms and tissue pathology during infection. This role of innate immunity in disease suggests that the immune system should be targeted therapeutically, to inhibit over-reactivity. The ultimate goal is to develop therapies that selectively attenuate destructive immune response cascades, while augmenting the protective antimicrobial defence but such treatment options have remained underexplored, owing to the molecular proximity of the protective and destructive effects of the immune response. The concept of innate immunomodulation therapy has been developed successfully in urinary tract infections, based on detailed studies of innate immune activation and disease pathogenesis. Effective, disease-specific, immunomodulatory strategies have been developed by targeting specific immune response regulators including key transcription factors. In acute pyelonephritis, targeting interferon regulatory factor 7 using small interfering RNA or treatment with antimicrobial peptide cathelicidin was protective and, in acute cystitis, targeting overactive effector molecules such as IL-1ß, MMP7, COX2, cAMP and the pain-sensing receptor NK1R has been successful in vivo. Furthermore, other UTI treatment strategies, such as inhibiting bacterial adhesion and vaccination, have also shown promise.

AAUS guideline for acute uncomplicated pyelonephritis.

Patients with acute uncomplicated pyelonephritis often show impaired immune function that aggravates infectious diseases. Some of the therapeutic recommendations for UTIs have been revised recently, partly because of the emergence of antibiotic resistant bacteria such as quinolone-resistant Escherichia coli and Extended spectrum beta-lactamase (ESBL) producing bacteria, mainly E. coli and Klebsiella pneumoniae, which vary from country to country or between regions in frequency of emergence and spread. An era of antimicrobial resistance (AMR) has arrived, where the use of antibiotics should be reconsidered. Several newly established antimicrobial agents are commercially available for the treatment of resistant bacteria, such as penicillins or cephalosporins with beta-lactamase inhibitors. This new edition of Asian Association of UTI & STI (AAUS) guideline for acute uncomplicated pyelonephritis includes new recommendations for antibiotic use based on changing trends in antibiotic resistance.

A case of Brucella pyelonephritis: a rare case / Un caso de pielonefritis por Brucella: un caso raro

Brucellosis is a zoonotic disease, seen globally, especially in developing countries and it can affect many organs. Urinary involvement of this disease is a very rare. Pyelonephritis, interstitial nephritis, glomerulonephritis, nephropathy are the reported urinary involvements. In this study, we aimed to report a case of Brucella pyelonephritis, who had complaints mimicking acute bacterial pyelonephritis, with a history of polycystic kidney disease and calculi in the left kidney (AU)

La brucelosis es una enfermedad zoonótica, vista globalmente, especialmente en países en vías de desarrollo y puede afectar muchos órganos. La afectación urinaria de esta enfermedad es muy rara. Pielonefritis, nefritis intersticial, glomerulonefritis y nefropatía son los compromisos urinarios reportados. En este estudio, nuestro objetivo fue informar un caso de pielonefritis por Brucella, que tenía síntomas que simulaban una pielonefritis bacteriana aguda, con antecedentes de poliquistosis renal y cálculos en el riñón izquierdo (AU)

A case of acute focal bacterial nephritis with acute kidney injury presenting as acute abdomen.

Acute focal bacterial nephritis (AFBN) refers to the bacterial infection of the renal parenchyma without abscess formation. Although AFBN has mainly been reported in pediatric patients, it may be underdiagnosed in adults as it resembles acute pyelonephritis in its clinical presentation. However, the symptoms suggesting acute abdomen is an important clue to diagnose AFBN, which requires additional imaging studies such as contrast-enhanced computed tomography (CECT). Here, we present the case of a 49-year-old female presenting to our emergency room with acute abdomen as well as acute kidney injury (AKI). CECT was performed to rule out critical etiologies of severe abdominal pain and the results revealed multifocal wedge-shaped shadows in the right kidney and diffuse enlargement of bilateral kidneys. We diagnosed the patient with AFBN and treated her through temporal hemodialysis (two sessions) and antibiotics for 23 days. Although AKI associated with AFBN has rarely been reported, her renal dysfunction and other symptoms were completely improved. In conclusion, clinicians should be aware of AFBN and be cautious to avoid the unnecessary invasive interventions.

Studies on Virulence and Extended-Spectrum ß-Lactamase-Producing Uropathogenic Escherichia coli Isolates and Therapeutic Effect of Fosfomycin in Acute Pyelonephritis Mice.

The understanding about virulence factors (VFs) and the drug resistance of uropathogenic Escherichia coli (UPEC) helps us understand the pathogenesis of urinary tract infections (UTIs) and make better decisions for clinical treatment. This study examined the correlation between the extended-spectrum ß-lactamases (ESBLs) phenotype and VFs in UPEC strains. In addition, we validated the therapeutic potential of fosfomycin in acute pyelonephritis mice. From May 2017 to November 2018, 22 nonduplicate E coli. strains were isolated from UTI patients. PCR was utilized to detect the distribution of virulence genes. We also analyzed the ESBL phenotype in E coli. We further evaluated the therapeutic effect of intravenous fosfomycin treatment in the acute pyelonephritis (APN) model. All 22 UPEC strains expressed the type 1 fimbriae (FimH) gene and more than 50% (12/22) of strains produced ESBLs. The detection rates of the iron acquisition-associated genes ChuT and IutA were 77.3% (n = 17) and 50% (n = 11) and those of P fimbria papA and papC genes were 45% (n = 10) and 50% (n = 11), respectively. Though the VFs were closely related with pathologenicity, the relationship between VFs and ESBLs still needs further investigation. Furthermore, intravenous fosfomycin 800 mg/kg significantly reduced the bacterial load and the inflammatory infiltration in the bladder and kidney, maintaining the structural integrity of the kidney. Intravenous fosfomycin administration can be used for the treatment of acute pyelonephritis caused by highly pathogenic and drug-resistant UPEC strains.

Differences of virulence factors, and antimicrobial susceptibility according to phylogenetic group in uropathogenic Escherichia coli strains isolated from Korean patients.

BACKGROUND: Escherichia coli is among the most common uropathogens. Increased antibiotic resistance in Gram negative bacilli is global concern. Alternative therapeutic options including vaccines against uropathogenic E. coli (UPEC) have been developed. In this study, we compared the genotypic characteristics and antimicrobial susceptibility of UPEC according to phylogenetic groups. METHODS: We retrospectively reviewed the medical records of pyelonephritis patients with UPEC between February 2015 and June 2018. The study was conducted at a medical center in Korea. We compared the clinical and genotypic characteristics of UPEC according to phylogenetic groups. The phylogenetic groups and 29 virulence factors were identified using multiplex polymerase chain reaction. RESULTS: Phylogenetic group analysis revealed that most uropathogenic E. coli belonged to groups B2 and D: B2 (276, 77.7%), D (62, 17.5%), B1 (12, 3.4%), and A (5, 1.4%). Among the virulence factors, fyuA, fimH, traT, iutA, papG allele II, and papC were the most frequently observed. Phylogenetic group B2 was more closely related to virulence factors, including fimH, sfa/focED, focG, hlyA, cnf1, fyuA, and PAI, than group D. Groups B2 and D showed similar clinical presentations and complications. Group B2 had mostly healthcare-associated infections and antimicrobial resistance. Group D mostly had community-acquired infections. The K1 serotype was prevalent in group B2, and K5 was the most prevalent in group D. CONCLUSIONS: Phylogenetic group B2 had more proportions and types of virulence factors than group D. Group B2 showed a high presentation of virulence factors related to adhesions and toxins. An increased presentation of antimicrobial resistance and healthcare-associated infections was also noted. Considering the genetic characteristics of UPEC, alternative therapeutic options targeting frequent virulence factors might be considered in addition to antibiotics.