Szechwan Lovage Rhizome Extract Improves Renal Function and Alleviates Inflammatory Responses in Pyelonephritis Rats Infected with Escherichia Coli via IL-6/STAT3 Axis.

The objective of this study was to probe the effect and mechanism of Szechwan Lovage Rhizome (Chuanxiong, CX) extract on renal function (RF) and inflammatory responses (IRs) in acute pyelonephritis (APN) rats infected with Escherichia coli (E. coli). Fifteen SD rats were randomized to intervention, model and control groups. Rats in the control were fed normally without treatment, rats in the APN model were infected with E. coli, and rats in the intervention group were intragastrically administered CX extract after infection with E. coli. HE staining detected pathological changes in the kidney tissues in rats. Levels of renal function indexes and inflammatory factors (IFs) were measured by ELISA and an automatic biochemical analyzer. Besides, levels of IL-6/signal transducer and activator of transcription 3 (STAT3) pathway-related genes in rat kidney tissue were detected by qRT-PCR and western blot. the experimental results showed that IL-1ß, IL-8, TNF-α and RF levels were the highest in the model group and the lowest in the control group, with those of the intervention group in between (P<0.05). Besides, the IL-6/STAT3 axis was markedly activated in the model group but inhibited in the intervention group (P<0.05). Subsequently, activated IL-6/STAT3 signal promoted IFs (IL-1ß, IL-8 and TNF-α) and RF (BUN, Scr, ß2-MG and UA), but this effect was offset after CX treatment (P<0.05). In conclusion, CX extract could improve RF and inhibit IRs of APN rats infected with E. coli by inhibiting the IL-6/STAT3 axis, which may be a new choice for APN treatment in the future.

Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial.

BACKGROUND: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. METHODS: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). RESULTS: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum ß-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. CONCLUSIONS: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. CLINICAL TRIAL REGISTRATION: NCT03357614.

[Systematic review and Meta-analysis of efficacy and safety of Ningmitai Capsules in treatment of urinary tract infection].

This study aims to evaluate the effectiveness and safety of Ningmitai Capsules in the treatment of urinary tract infection.To be specific, articles on the treatment of urinary tract infection with Ningmitai Capsules were retrieved from China National Know-ledge Infrastructure(CNKI), Wanfang, VIP, SinoMed, Cochrane Library, PubMed, EMbase, and Web of Science(from establishment to October 2021).Eligible randomized controlled trials(RCTs) were screened out, and ROB and RevMan 5.3 of Cochrane were employed for data integration and Meta-analysis.Finally, 17 articles were included, involving 1 972 cases, with 1 045 in the experimental group and 927 in the control group.The Meta-analysis results are as follows.Ningmitai Capsules combined with conventional antibiotics was superior to sensitive antibiotics alone in the treatment of acute pyelonephritis in aspects of clinical cure rate(RR=1.94, 95%CI[1.58, 2.37], P<0.000 01), reduction in the count of red blood cells in the urine(MD=-3.22, 95%CI[-3.23,-3.21], P<0.000 01), decrease in the count of white blood cells in the urine(MD=-2.34, 95%CI[-2.59,-2.10], P<0.000 01), and time for the disappearance of the symptoms(MD_(time for urinary tract irritation disappeared)=-2.19, 95%CI[-2.69,-1.68], P<0.000 01; MD_(time for waist aches disappeared)=-3.58, 95%CI[-4.20,-2.97], P<0.000 01; MD_(time for heating disappeared)=-0.57, 95%CI[-0.81,-0.33], P<0.000 01).The combination of either cephalosporin or quinolone with Ningmitai Capsules can improve clinical cure rate of acute pyelonephritis(RR_(combined with cephalosporin)=1.94, 95%CI[1.56, 2.42], P<0.000 01; RR_(combined with quinolone)=1.91, 95%CI[1.16, 3.15], P=0.01).The clinical cure rate(RR=1.91, 95%CI[1.47, 2.49], P<0.000 01) of diabetes complicated with urinary tract infection by Ningmitai Capsules was higher than that by quinolones.The clinical cure rate(RR=1.22, 95%CI[1.09, 1.37], P=0.000 5) of non-gonococcal urethritis by Ningmitai Capsules combined with conventional tetracycline and macrolide antibiotics was higher than that by conventional antibiotics.Ningmitai Capsules combined with conventional antibiotics/Ningmitai Capsules alone was superior to conventional antibiotics alone in the treatment of urinary tract infection in terms of the clinical cure rate(RR=1.35, 95%CI[1.17, 1.56], P<0.000 1) and incidence of adverse reactions(RR=0.32, 95%CI[0.15, 0.68], P=0.003), particularly the combination with quinolone antibiotics(RR=1.30, 95%CI[1.04, 1.61], P=0.02).The main adverse reactions were mild gastrointestinal discomfort, nausea, vomiting, and dry mouth.In summary, Ningmitai Capsules combined with conventional sensitive antibiotics/Ningmitai Capsules alone can improve the clinical cure rate of patients with urinary tract infection.Ningmitai Capsules combined with conventional sensitive antibiotics can significantly reduce the time for symptom disappearance of acute pyelonephritis and down-regulate the counts of red and white blood cells in the urine compared with antibiotics alone, and no serious adverse reactions have been found.However, in light of the low proportion of quality eligible articles, experiments with rigorous design, large sample size, and complete outcome in-dexes should be carried out in the future to verify the clinical efficacy and safety of Ningmitai Capsules in the treatment of urinary tract infection.

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.

Rotula aquatica Lour. mitigates oxidative stress and inflammation in acute pyelonephritic rats.

The current study evaluates the efficacy of methanolic extract of Rotula aquatica Lour. (MERA) against inflammatory changes associated with acute pyelonephritis. The antioxidant enzymes such as SOD, CAT, GPx, GR and oxidative stress markers like GSH content, malondialdehyde (MDA) level, nitrate level, reactive oxygen species (ROS) level and renal toxicity markers were evaluated in this study. The mRNA level expression of Toll-like receptor 4 (TLR-4), nuclear transcription factor kappa B (NF-κB), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and Tamm Horsfall protein (THP) were studied by RT-PCR analysis. The oral administration of MERA increases the antioxidant enzyme status in pyelonephritis rat. The elevated levels of oxidative stress markers in pyelonephritic rats were ameliorated by the administration of MERA at 100 mg/kg and 200 mg/kg bwt of the rat. The mRNA level expression of major genes were restored to normal level by MERA.

Antimicrobial resistance profiles and genes in uropathogenic Enterobacteriaceae in reproductive-age women in St. Petersburg, Russia: implication for treatment of pyelonephritis in pregnancy.

BACKGROUND: Urinary tract infections (UTIs) are common in women, and during pregnancy can cause significant morbidity. Growing and greatly varying antimicrobial resistance (AMR) of Enterobacteriaceae, responsible for most UTIs, necessitates regular local AMR surveillance. In obstetric population, where beta-lactams are the mainstay for treatment of severe UTIs, particular focus should be placed on beta-lactam resistance. This study aimed to evaluate AMR rates and frequency of extended spectrum beta-lactamase (ESBL) and carbapenemase genes in uropathogenic Enterobacteriaceae among reproductive-age women in St. Petersburg, Russia. MATERIALS/METHODS: Urine samples were collected from consecutive reproductive-age women, who attended the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology from October 2017 to November 2019, and cultured according to routine procedures. Susceptibility to antibiotics and ESBL production was determined using the disc diffusion method according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. All urine samples and Enterobacteriaceae isolates were tested for ESBL and carbapenemase genes using real-time PCR. RESULTS: Enterobacteriaceae were detected in 91 (56 pregnant and 35 non-pregnant) of 119 (76%) included women. The vast majority of Enterobacteriaceae strains were susceptible to nitrofurantoin, fosfomycin and meropenem (99-100%). The frequency of strains susceptible to penicillins and cephalosporins ranged from 59% to 82%; 78% of strains were susceptible to ciprofloxacin. ESBL production was phenotypically detected in 15 (16%) Enterobacteriaceae strains, with CTX-M genes revealed in all cases. In all corresponding urine samples, CTX-M genes were also detected. The remaining 104 urine samples were negative for CTX-M genes. In none of the isolates and urine samples, carbapenemase genes were present. CONCLUSIONS: The frequency of ESBL producing Enterobacteriaceae was relatively high (16%), with CTX-M genes detected in all cases in both urine and urine cultures. Rapid PCR detection of CTX-M genes directly in urine samples from women with pyelonephritis can be valuable for timely informing treatment choices.

Protective Effects of Omega-3 Fatty Acids Supplementation Against Renal Parenchymal Scarring in Children with Acute Pyelonephritis: Results of a Pilot Clinical Trial.

AIM: This trial aimed to determine if supplementation with omega-3 fatty acids as an adjunct therapy to antibiotic treatment can have protective effects against renal scar formation after acute pyelonephritis (APN) in pediatric patients. BACKGROUND: Current evidence points out that besides antibiotic treatment, early administration of antioxidant and anti-inflammatory compounds may be effective in reducing the occurrence of renal damage following APN in children. OBJECTIVE: The main endpoint of the trial was the comparison of the development of renal scarring formation after APN in an omega-3 fatty acids-treated group and in a control-treated group. METHODS: This prospective randomized, controlled trial study was conducted from March 2016 to May 2018 on 60 children with a diagnosis APN in a tertiary hospital in Iran. After the diagnosis of APN based on the clinical signs and symptoms, urine analysis, urine culture, and dimercaptosuccinic acid renal scan (DMSA scan), the patients were randomly allocated into either the control group (n=30 patients: received standard antibiotic treatment only) or the intervention group (n=30 patients: received standard antibiotic-treatment in combination with oral omega-3 fatty acids based on the children's weight for three consecutive days). A second DMSA scan was performed for the patients at a minimum of six months after treatment. The development of renal scars was evaluated by comparing the baseline DMSA scan lesions with the follow-up DMSA scan lesions. RESULTS: Fifty patients, including 26 and 24 individuals in the control and intervention groups, respectively, completed the entire course of the study. Renal parenchymal involvement based on the baseline DMSA scan was similar in the two groups (p-value =0.85, 0.90, and 0.53 regarding the right, left, and both kidney units together, respectively). Although comparison of the follow-up DMSA scan lesions to the baseline DMSA scan lesions considering the right and left kidneys as separate units between two groups did not reach the significant level, when considering both left and right kidney units together, results showed a statistically significant difference between groups in favor of the intervention group (p-value =0.04). CONCLUSION: Although preliminary, the results of this study showed that administration of omega-3 fatty acids, a natural supplement with well-known anti-inflammatory and antioxidant properties, as an adjunct therapy to standard antibiotic treatment might significantly reduce the incidence of the occurrence renal scarring following APN in children. Confirmation of these results requires further studies.

[Clinical and pathogenetic aspects of the treatment and prevention of pyelonephritis in children].

INTRODUCTION: Treatment of pyelonephritis in children should be combined, long-term and individual-based. The success of the therapy in children largely depends on the prompt appointment and the correct choice of antimicrobial therapy. AIM: To evaluate the efficiency of the dietary supplement "Cystenium II" in a group of children aged 7 to 14 years with a diagnosis of acute and chronic recurrent pyelonephritis in the acute phase. MATERIALS AND METHODS: A total of 60 children aged 7 to 14 years with a diagnosis of acute or chronic recurrent pyelonephritis in the acute stage were included in the study. The clinical group consisted of 30 patients (mean age 12.1+/-1.8 years), while the control group included 30 patients of mean age 11.2+/-1.7 years. In the control group patients received only standard antibiotic therapy, while in the clinical group it was combined with a dietary supplement "Cystenium II" 1 tablet 2 times a day with meals for 14 days. After the course of antibacterial treatment, the children in the clinical group continued to take the studied dietary supplement for another 14 days in order to prevent the recurrence of pyelonephritis. The results of treatment (patient's condition, presence of pain, dysuria, fever) were assessed on the 3rd, 7th, 14th day, 1 and 6 months after the start of treatment. A urinalysis was performed at the baseline, on the 7th and 14th days, as well as after 1 and 6 months. Urine culture was performed before and after antibiotic therapy at the baseline, on the 14th day, 1 and 6 months after the start of treatment. RESULTS: The main indicators of urinalysis (leukocytes, red blood cells, protein) returned to normal values in 26 (86.7%) patients of the clinical group and in 23 (76.7%) patients of the control group on the 7th day after the start of treatment. At the completion of the basic therapy (after 14 days) normal clinical parameters (absence of leukocyturia, microhematuria, proteinuria) were observed in all patients of the clinical group and in 28 (93.3%) patients of the control group. After a month of follow-up, the disturbances in urinalysis (leukocytes, red blood cells, protein) in the control group were again seen in 3 (10%) patients, as well as after 6 months. However, in the clinical group all patients had normal urinalysis (absence of leukocyturia, microhematuria, proteinuria) after 1 month and only in 1 (3.3%) case leukocyturia, as well as an increase in the number of red blood cells and protein was detected by 6 months. DISCUSSION: According to our results, the use of dietary supplements "Cystenium II" (manufactured by Akvion, Russia), due to the constituents of D-mannose (450 mg), cranberry fruit extract with a standardized activity of 500 mg (36 mg of proanthocyanidins) and vitamin C (60 mg), may cause anti-inflammatory and anti-adhesive effects (resolving of leukocyturia and bacteriuria). This allows to use the dietary supplement Cystenium II in children from 7 years of age in the combination therapy of acute pyelonephritis, as well as exacerbation of chronic pyelonephritis. The obtained results showed a high overall therapeutic efficacy of combination therapy using Cystenium II after 6 months from the start of treatment (relapse in 1 patient), in contrast to the control group (relapse in 6 patients). CONCLUSIONS: the use of dietary supplement "Cystenium II" allowed to reduce the number of repeated courses of antibiotic therapy in children during 6 months of follow-up and, most likely, reduced the frequency of development of chronic pyelonephritis after an acute inflammation. Therefore, the wide clinical use of dietary supplements "Cystenium II" for the combined treatment of acute and exacerbation of chronic pyelonephritis in children older than 7 years seems to be very reasonable.

Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis.

BACKGROUND: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). METHODS: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. FINDINGS: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. INTERPRETATION: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Appropriateness of Antibiotic Prescriptions for Urinary Tract Infections.

INTRODUCTION: Urinary tract infections (UTI) are a common indication for antibiotic use in the emergency department (ED). With antibiotic resistance on the rise, it is essential that antibiotics be prescribed appropriately for UTIs. Our objective was to evaluate the appropriateness of antibiotic prescriptions by ED providers for uncomplicated cystitis and pyelonephritis. METHODS: We conducted a retrospective study of females ages 2-50 years seen in an academic ED from January 2017 to April 2018 diagnosed with UTI. We assessed the appropriateness of discharge antibiotic prescriptions, as determined by adherence to clinical practice guidelines, best evidence for the particular indication (cystitis vs pyelonephritis for children and adults), and the local antibiogram. RESULTS: A total of 421 patients were included in this study. Of these, 60 children and 198 adults were diagnosed with cystitis, and 47 children and 116 adults were diagnosed with pyelonephritis. Treatment in the absence of true infection was common, with culture-confirmed UTI occurring in only 17/50 (34%) of children and 60/129 (47%) of adults diagnosed with cystitis, and 23/40 (58%) of children and 58/87 (67%) of adults diagnosed with pyelonephritis, among patients who had urine cultures. The type of antibiotic prescribed was appropriate in 53/60 (88%) of children and 135/198 (68%) of adults with cystitis, and 38/47 (81%) of children and 53/116 (46%) of adults with pyelonephritis. The most common inappropriate antibiotic types were beta-lactams in adults (n = 92), nitrofurantoin for pyelonephritis (n = 16), and amoxicillin (n = 15). Dosing and duration errors were also common, occurring in 122/279 (44%) of prescriptions of an appropriate antibiotic type. The frequency of errors in the type of antibiotic prescribed was similar among provider types (attending physician, resident physician, and advanced practice clinician; p = 0.926). CONCLUSION: This study reveals room for improvement in antibiotic prescription practices across provider cohorts in the ED for the management of uncomplicated cystitis and pyelonephritis in females.

Is Piperacillin-Tazobactam Effective for the Treatment of Pyelonephritis Caused by Extended-Spectrum ß-Lactamase-Producing Organisms?

BACKGROUND: Limited data exist regarding the efficacy of piperacillin-tazobactam (TZP) for the management of nonbacteremic pyelonephritis caused by extended-spectrum ß-lactamase (ESBL)-producing organisms. METHODS: We conducted a multicenter observational study comparing clinical outcomes of adults hospitalized with ESBL-producing pyelonephritis who were receiving TZP versus carbapenems, using an inverse probability of treatment weighted propensity score analysis. Patients were eligible for inclusion if all of the following criteria were met: (1) urine cultures growing Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, or Proteus mirabilis at ≥50 000 colony-forming units/mL; (2) identification of an ESBL gene; (3) pyuria (≥10 white blood cells per high powered field in the urine); and (4) dysuria and fever plus at least 1 of the following symptoms: emesis, rigors, hypotension, or flank pain. RESULTS: There were 186 patients included in the propensity score-weighted cohort; 45 (24%) received TZP and 141 (76%) received a carbapenem. Of these 186 patients, 27% were admitted to the intensive care unit, 48% were immunocompromised, and 45% had underlying urologic abnormalities. There were no differences between the 2 groups in the proportion of patients (20% vs 25%) with recurrent cystitis or pyelonephritis with the same ESBL-producing organism within 30 days (odds ratio, 0.75; 95% confidence interval, .31-1.81; P = .52). There were no differences in the resolution of clinical symptoms by Day 7 or in 30-day mortality. There was 1 (2%) patient in the TZP arm and 11 (8%) patients in the carbapenem arm who had incident carbapenem-resistant organisms isolated within 30 days (P = .09). CONCLUSIONS: TZP may be a reasonable alternative to carbapenems for the management of ESBL-producing pyelonephritis and may mitigate the risk of emergence of carbapenem-resistant organisms, compared with carbapenem therapy.

Comparative Pharmacokinetics of Gallic Acid, Protocatechuic Acid, and Quercitrin in Normal and Pyelonephritis Rats after Oral Administration of a Polygonum capitatum Extract.

Polygonum capitatum Buch.-Ham. ex D. Don is traditionally used by Hmong for the treatment of urinary tract infections and pyelonephritis. Information regarding the pharmacokinetic behavior of the extract in the condition of pyelonephritis is lacking. In the present study, we aimed to compare the pharmacokinetic properties of gallic acid (GA), protocatechuic acid (PCA), and quercitrin (QR)-the main bioactive constituents in the herb-in normal and pyelonephritis rats. The plasma samples were collected at various time points after administration of a single dose of Polygonum capitatum extract. The plasma level of GA, PCA, and QR at the designed time points was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and drug concentration versus time plots were constructed to estimate the pharmacokinetic parameters. The AUC(0-t), AUC(0-∞), MRT(0-t), and CL of GA, PCA, and QR in pyelonephritis rats was significantly different from those of the normal rats. The results indicated that the three constituents have higher rate of uptake and slower rate of elimination in the rats with pyelonephritis, suggesting altered rate and extent of drug metabolism.

Trend of antibiotics usage for acute pyelonephritis in Korea based on national health insurance data 2010-2014.

BACKGROUND: The objective of this study is to describe the changes in prescribing practices of antibiotics to treat acute pyelonephritis (APN) in Korea. METHODS: The claim data base of the Health Insurance Review and Assessment Service in Korea was used to select patients with ICD-10 codes N10 (acute tubulo-interstitial nephritis) or N12 (tubulo-interstitial nephritis, not specified as acute nor chronic) as the primary discharge diagnosis during 2010-2014. Consumption of each class of antibiotics was converted to Defined Daily Dose (DDD)/event. RESULTS: Throughout the five-year period, the average antibiotic consumption were 11.3 DDD per inpatient event and 6.0 DDD per outpatient event. The annual average antibiotic consumption increased for inpatients (P = 0.002), but remained stable for outpatients (P = 0.066). The use of parenteral antibiotics increased for inpatients (P < 0.001), but decreased for outpatients (P = 0.017). As for the the antibiotic classes, 3rd generation cephalosporins (3rd CEPs) was the most commonly prescribed (41.4%) for inpatients, followed by fluoroquinolones (FQs) (28.5%); for outpatient, FQs (54.8%) was the most commonly prescribed, followed by 3rd CEPs (13.1%). The use of 3rd CEPs (P < 0.001), beta-lactam/beta-lactamase inhibitors (P = 0.007), and carbapenems (P < 0.001) increased substantially for the treatment of hospitalized APN patients. In particular, carbapenems use increased 3.1-fold over the 5 years. CONCLUSIONS: Prescription of broad-spectrum antibiotics increased much for the treatment of APN in Korea during 2010-2014.

Unexpected Activity of Oral Fosfomycin against Resistant Strains of Escherichia coli in Murine Pyelonephritis.

Fosfomycin tromethamine activity is well established for oral treatment of uncomplicated lower urinary tract infections, but little is known about its potential efficacy in pyelonephritis. Ascending pyelonephritis was induced in mice infected with 6 strains of Escherichia coli (fosfomycin MICs, 1 µg/ml to 256 µg/ml). The urine pH was 4.5 before infection and 5.5 to 6.0 during infection. Animals were treated for 24 h with fosfomycin (100 mg/kg of body weight subcutaneously every 4 h), and the CFU were enumerated in kidneys 24 h after the last fosfomycin injection. Peak (20.5 µg/ml at 1 h) and trough (3.5 µg/ml at 4 h) levels in plasma were comparable to those obtained in humans after an oral dose of 3 g. Fosfomycin treatment significantly reduced the bacterial loads in kidneys (3.65 log10 CFU/g [range, 1.83 to 7.03 log10 CFU/g] and 1.88 log10 CFU/g [range, 1.78 to 5.74 log10 CFU/g] in start-of-treatment control mice and treated mice, respectively; P < 10-6). However, this effect was not found to differ across the 6 study strains (P = 0.71) or between the 3 susceptible and the 3 resistant strains (P = 0.09). Three phenomena may contribute to explain this unexpected in vivo activity: (i) in mice, the fosfomycin kidney/plasma concentration ratio increased from 1 to 7.8 (95% confidence interval, 5.2, 10.4) within 24 h in vitro when the pH decreased to 5, (ii) the fosfomycin MICs for the 3 resistant strains (64 to 256 µg/ml) decreased into the susceptible range (16 to 32 µg/ml), and (iii) maximal growth rates significantly decreased for all strains and were the lowest in urine. These results suggest that local fosfomycin concentrations and physiological conditions may favor fosfomycin activity in pyelonephritis, even against resistant strains.

Efficacy of Human Exposures of Gepotidacin (GSK2140944) against Escherichia coli in a Rat Pyelonephritis Model.

Gepotidacin is a first-in-class triazaacenaphthylene antibacterial that inhibits bacterial type II topoisomerases and has in vitro activity against a range of bacterial pathogens, including Escherichia coli Urinary tract infections often progress to pyelonephritis and are a worldwide problem due to the prevalence of multidrug-resistant E. coli strains. This study evaluated the in vivo efficacy of gepotidacin against four strains of multidrug-resistant E. coli in a rat pyelonephritis model. Infected rats received controlled intravenous infusions of gepotidacin every 12 h for 4 days that recreated human systemic exposures from oral gepotidacin (800 or 1,500 mg twice daily for 4 days). Liquid chromatography-tandem mass spectrometry analysis of blood samples and kidney homogenates showed that gepotidacin levels were 6- to 7-fold higher in kidneys than in blood. Across experiments with 4-day gepotidacin treatments, bacterial CFU in kidneys were reduced by 2.9 to 4.9 log10 compared to pretreatment levels, and bladder CFU were reduced to the lower limit of detection (1.2 log10). The efficacies of 800- and 1,500-mg gepotidacin exposures were statistically similar. A time-course experiment indicated that a period of more than 24 h of gepotidacin treatment was required for efficacy and that 4 days were needed for maximal response. Overall, these results demonstrate that the recreated human exposures of gepotidacin studied were effective in an animal model of pyelonephritis caused by multidrug-resistant E. coli and that further evaluation for clinical use is warranted.

Inappropriate empirical antibiotic therapy does not adversely affect the clinical outcomes of patients with acute pyelonephritis caused by extended-spectrum ß-lactamase-producing Enterobacteriales.

Extended-spectrum ß-lactamase-producing Enterobacteriales (ESBL-PE) are often associated with inappropriate empirical therapy (IAT). The aim of this study was to investigate whether IAT of acute pyelonephritis (APN) caused by ESBL-PE is related to adverse outcomes. A retrospective cohort study was performed at a tertiary-care hospital from 2014 through 2016. Patients who had APN caused by ESBL-PE and were definitely treated with appropriate antibiotics for at least 7 days were enrolled. IAT was defined as when inappropriate empirical antibiotics were given 48 h or longer after initial diagnosis of APN. Primary endpoint was treatment failure defined as clinical and/or microbiologic failure. Secondary endpoints were length of hospital stay and recurrence of APN. Propensity score matching was used to adjust heterogeneity of each group. Among 175 eligible cases, 59 patients received IAT and 116 patients received appropriate empirical antimicrobial therapy (AT). Treatment failure was observed in five (8.4%) patients and nine (7.8%) patients in each group, respectively. After matching, the treatment failure rate was similar between both groups (adjusted odd ratio [aOR] 1.05; 95% confidence index [CI] 0.26-4.15). The length of hospital stay (median 11 days in the IAT group versus 11 days in the AT group; P = 0.717) and absence of recurrence within 2 months (90.3% in IAT and 86.7% in AT; P = 0.642) were also similar. IAT did not adversely affect the clinical outcome. In this regard, clinicians should be more cautious about indiscriminate prescription of broad-spectrum antibiotics such as carbapenem empirically for treatment of APN possibly caused by ESBL-PE.

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

BACKGROUND: ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. RESULTS: Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: -0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. CONCLUSIONS: ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. CLINICAL TRIAL REGISTRATION: NCT02753946.

ZTI-01 (fosfomycin for injection) in the treatment of hospitalized patients with complicated urinary tract infections.

Fosfomycin is a bactericidal antibiotic available since the 1970s whose intravenous formulation has been available in many countries outside the USA. Given the rise in drug-resistant bacteria, its introduction into the US market has become a necessity for addressing these organisms. This review provides an overview of the microbiology, clinical pharmacology and initial clinical experiences of the intravenous fosfomycin product (ZTI-01) that is undergoing clinical development in the USA for the treatment of complicated urinary tract infections and acute pyelonephritis.

Vitamin A supplementation is effective for improving the clinical symptoms of urinary tract infections and reducing renal scarring in girls with acute pyelonephritis: a randomized, double-blind placebo-controlled, clinical trial study.

INTRODUCTION: It is believed that tubulointerstitial inflammation plays a role in the formation of renal scarring secondary to acute pyelonephritis (APN). Vitamin A is an anti-inflammatory agent that is involved in the re-epithelialization of damaged mucosal surfaces. OBJECTIVE: The aim of this study was to evaluate the efficacy of vitamin A supplementation in combination with antibiotics for improving urinary tract infections (UTIs) symptoms and preventing renal scarring in girls with APN. STUDY DESIGN: This randomized, double-blind, placebo-controlled clinical trial was conducted on 90 girls aged 2 to 12 years old between 2015 and 2017. Patients with UTIs and first episode of APN diagnosed based on 99 mTc-DMSA scintigraphy (uptake defect) were assessed for eligibility. Patients were randomly divided into two groups that either received 10 days of oral vitamin A (intervention group) or 10 days of placebo (control group) in addition to antibiotics during the acute phase of infection. The clinical response was considered as the primary outcome [duration (positive days) of UTI symptoms during trial treatment period] and secondary outcomes (no change, improving and or worsening of 99 mTc-DMSA scan results 6 months after treatment from baseline). P < 0.05 was considered to be statistically significant. RESULTS: Seventy-four patients (vitamin A group: 36 patients, placebo: 38 patients) were included in the analysis. The mean age was 5.25 ± 1 year old. Three patients (7.89%) in the placebo group and 2 patients (5.55%) in the vitamin A group had vesicoureteral reflux (VUR) (p = 0.114). Duration of fever (vitamin A group: 1.8 days, placebo: 3.1 days, p = 0.0026), urinary frequency (1.3 days vs. 2.8 days, p = 0.003) and poor feeding (2.3 days vs. 4.2 days, p = 0.005) were significantly lower in the vitamin A group. Following the second 99 mTc-DMSA scan, worsening of lesions was observed among 8 (22.2%) and 17 (44.7%) patients in the vitamin A and placebo groups, respectively (p = 0.003). 63.8% (23 patients) of the vitamin A group and 21% (8 patients) of placebo group showed lesion improving in the photopenic region. (P < 0.0001) There was no evidence of vitamin A intolerance. DISCUSSION: Our results show the efficacy of vitamin A supplementation on reducing renal scarring secondary to APN and on fever, urinary frequency and poor feeding duration in girls with APN. CONCLUSION: Vitamin A supplementation is effective for improving the clinical symptoms of UTI and reducing renal injury and scarring following APN in girls with first APN. However, larger randomized clinical trials (RCTs) with longer follow up are needed to confirm these effects.

Temocillin breakpoints in pyelonephritis: evaluation in a murine model due to ESBL-producing Escherichia coli clinical isolates.

BACKGROUND: Due to a spectrum restricted to Enterobacteriaceae and stability against ESBL and AmpC enzymes, temocillin is of major interest for the treatment of pyelonephritis. But there are still uncertainties about the optimal regimen and clinical breakpoints. OBJECTIVES: To study in a murine model of pyelonephritis the activity of temocillin against Escherichia coli isolates with different MICs in order to evaluate clinical breakpoints. METHODS: Four clinical uropathogenic E. coli isolates with temocillin MICs of 8 mg/L (Ec8), 16 mg/L (Ec16), 32 mg/L (Ec32) and 64 mg/L (Ec64) were evaluated. Antibiotic 24 h T>MIC achieved in humans was reproduced in mice with either intravenous temocillin (2 g q12h or 2 g q8h) or intravenous imipenem (1 g q8h). Efficacy was assessed by bacterial count in kidneys. RESULTS: Compared with controls, temocillin at 2 g q12h was highly efficient against Ec8 (-3.32 log10 cfu/g and negative cultures in 93% of mice; P < 0.001); imipenem gave similar results. Temocillin at 2 g q12h also induced high reduction of bacterial count against Ec16 (-2.92 log10 cfu/g; P < 0.001), albeit cultures were negative in only 48% of mice. In contrast, no significant effect was observed in mice infected by Ec32 (-0.01 log10 cfu/g; P = 0.981) or Ec64 (-0.55 log10 cfu/g; P = 0.523). Even temocillin at 2 g q8h failed to control Ec32 infection (-1.55 log10 cfu/g; P = 0.197). CONCLUSIONS: This model suggests a clinical breakpoint up to 16 mg/L for non-severe pyelonephritis treated with temocillin at 2 g q12h, a value consistent with the few previous available data.