US FDA's Assessment of the Benefit-risk of Cefiderocol for its Initial Complicated Urinary Tract Infection Indication.
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ABSTRACT:
SUBMITTER: Echols RM
PROVIDER: S-EPMC8366820 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We present a 62-year-old woman who developed recurrent urinary tract infections in her early fifties and, after an evaluation by an infectious disease physician, was referred for a neurological consultation. Her history and neurological examination were consistent with spastic paraparesis and there was significant family history of a variety of neurological diagnoses suggesting a genetic disorder. Whole exome genetic testing revealed a novel change, a c.508 C > T variant in the SPAST gene. Our genetic and protein modeling analysis suggest that this is a disease-producing mutation confirming the diagnosis of hereditary spastic paraplegia type 4 (SPG4). This patient expands the spectrum of mutations that can cause this disorder and demonstrate the importance of recognizing the role of neurological disorders in causing neurogenic bladder and recurrent urinary tract infections.
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Project description:Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gram-negative bacteria, including carbapenem-resistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 ml/min, and it is adjusted for patients with <60 ml/min or ≥120 ml/min CrCL. A population pharmacokinetic (PK) model was constructed using 3,427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors, including infection sites and mechanical ventilation, were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was >90% against MICs of ≤4 μg/ml for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients, including the patients with augmented renal function, ventilation, and/or severe illness.
| S-EPMC8092503 | biostudies-literature
Project description:We report two cases of complicated Urinary Tract Infection, one with nephrostomy tube left in-situ and other with bladder outlet obstruction, caused by Trichosporon loubieri. Both patients responded well to antifungal treatment along with change/removal of catheters. In both the cases, correct identification of T. loubieri was done by IGS1 sequencing. Prompt identification and timely management headed to good clinical outcome. Hence, clinicians should be aware of T. loubieri as an emerging fungi causing human infections.
| S-EPMC6506559 | biostudies-literature
Project description:Hospital readmissions following severe infections are a major economic burden on the health care system and have a negative influence on patients' quality of life. Understanding the risk factors for readmission, particularly the extent to which they could be prevented, is of a great importance. In this study we evaluated potentially preventable risk factors for 60-day readmission in patients surviving hospitalization for complicated urinary tract infection (cUTI). This was a multinational, multicentre retrospective cohort study conducted in Europe and the Middle East. Our cohort included survivors of hospitalization due to cUTI during the years 2013-2014. The primary outcome was 60-day readmission following index hospitalization. Patient characteristics that could have influenced readmission: demographics, infection presentation and management, microbiological and clinical data; were collected via computerized medical records from infection onset up to 60 days after hospital discharge. Overall, 742 patients were included. The cohort median age was 68 years (interquartile range, (IQR) 55-80) and 43.3% (321/742) of patients were males. The all-cause 60-day readmission rate was 20.1% (149/742) and more than half were readmitted for infection [57.1%, (80/140)]. Recurrent cUTI was the most frequent cause for readmission [46.4% (65/140)]. Statistically significant risk factors associated with 60-day readmission in multivariable analysis were: older age (odds ratio (OR) 1.02 for an one-year increment, confidence interval (CI) 1.005-1.03), diabetes mellitus (OR 1.63, 95% CI 1.04-2.55), cancer (OR 1.7, 95% CI 1.05-2.77), previous urinary tract infection (UTI) in the last year (OR 1.8, 95% CI: 1.14-2.83), insertion of an indwelling bladder catheter (OR 1.62, 95% CI 1.07-2.45) and insertion of percutaneous nephrostomy (OR 3.68, 95% CI 1.67-8.13). In conclusion, patients surviving hospitalization for cUTI are frequently re-hospitalized, mostly for recurrent urinary infections associated with a medical condition that necessitated urinary interventions. Interventions to avoid re-admissions should target these patients.
| S-EPMC7994309 | biostudies-literature
Project description:F344 rats chronically infected with Ureaplasma parvum develop two distinct profiles: asymptomatic urinary tract infection (UTI) and UTI complicated by struvite urolithiasis. To identify factors that affect disease outcome, we characterized the temporal host immune response during infection by histopathologic analysis and in situ localization of U. parvum. We also used differential quantitative proteomics to identify distinguishing host cellular responses associated with complicated UTI. In animals in which microbial colonization was limited to the mucosal surface, inflammation was indistinguishable from that which occurred in sham-inoculated controls, and the inflammation resolved by 72 h postinoculation (p.i.) in both groups. However, inflammation persisted in animals with microbial colonization that extended into the deeper layers of the submucosa. Proteome profiling showed that bladder tissues from animals with complicated UTIs had significant increases (P < 0.01) in proteins involved in apoptosis, oxidative stress, and inflammation. Animals with complicated UTIs (2 weeks p.i.) had the highest concentrations of the proinflammatory protein S100A8 (P <or= 0.005) in bladder tissues, and the levels of S100A8 positively correlated with those of proinflammatory cytokines GRO/KC (P <or= 0.003) and interleukin-1 alpha (P <or= 0.03) in urine. The bladder uroepithelium was a prominent cell source of S100A8-S100A9 in animals with complicated UTIs (2 weeks p.i.), which was not detected in animals with asymptomatic UTIs (2 weeks p.i.) or in any bladder tissues harvested at earlier p.i. time points. Based on these results, we surmise that invasive colonization of the bladder triggers chronic inflammation and immune dysregulation, which may be critical to struvite formation.
| S-EPMC2747944 | biostudies-literature
Project description:Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.
| S-EPMC5786804 | biostudies-other
Project description:Antimicrobial bacteria resistance is an important problem in children with recurrent urinary tract infections (rUTI), thus it is crucial to search for alternative therapies. Autologous bacterial lysates (ABL) may be a potential treatment for rUTI. Twenty-seven children with rUTI were evaluated for one year, urine and stool cultures were performed, 10 colonies of each culture were selected and those identified as Escherichia coli were characterized by serology. For patients who presented ≥105 UFC/mL, an ABL was manufactured and administered orally (1 mL/day) for a month. Twelve children were monitored for ≥1-year, 218 urine and 11 stool samples were analyzed. E. coli (80.5%) was the main bacteria isolated from urine and feces (72%). E. coli of classical urinary serotypes (UPEC), O25:H4, O75:HNM, and O9:HNM were identified in patients with persistent urinary infection (pUTI). In 54% of patients treated with ABL, the absence of bacteria was observed in urine samples after 3 months of treatment, 42% of these remained without UTI between 10-12 months. It was observed that the use of ABL controlled the infection for almost 1 year in more than 60% of the children. We consider it necessary to develop a polyvalent immunogen for the treatment and control of rUTI.
| S-EPMC8470462 | biostudies-literature
Project description:Diabetes mellitus and hyperglycemia are associated with increased susceptibility to bacterial infections and poor treatment outcomes. This post hoc evaluation of the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) aimed to evaluate baseline characteristics, efficacy, and safety in patients with and without diabetes treated with ceftolozane/tazobactam and comparators. Ceftolozane/tazobactam is an antibacterial with potent activity against Gram-negative pathogens and is approved for the treatment of cIAI (with metronidazole) and cUTI (including pyelonephritis).Patients from the phase 3 ASPECT studies with (n = 245) and without (n = 1802) diabetes were compared to evaluate the baseline characteristics, efficacy, and safety of ceftolozane/tazobactam and active comparators.Significantly more patients with than without diabetes were 65 years of age or older; patients with diabetes were also more likely to weigh ?75 kg at baseline (57.1% vs 44.5%), to have renal impairment (48.5% vs 30.2%), or to have APACHE II scores ?10 (33.8% vs 17.0%). More patients with diabetes had comorbidities and an increased incidence of complicating factors in both cIAI and cUTI. Clinical cIAI and composite cure cUTI rates across study treatments were lower in patients with than without diabetes (cIAI, 75.4% vs 86.1%, P = 0.0196; cUTI, 62.4% vs 74.7%, P = 0.1299) but were generally similar between the ceftolozane/tazobactam and active comparator treatment groups. However, significantly higher composite cure rates were reported with ceftolozane/tazobactam than with levofloxacin in patients without diabetes with cUTI (79.5% vs 69.9%; P = 0.0048). Significantly higher rates of adverse events observed in patients with diabetes were likely due to comorbidities because treatment-related adverse events were similar between groups.In this post hoc analysis, patients with diabetes in general were older, heavier, and had a greater number of complicating comorbidities. Patients with diabetes had lower cure rates and a significantly higher frequency of adverse events than patients without diabetes, likely because of the higher rates of medical complications in this subgroup. Ceftolozane/tazobactam was shown to be at least as effective as comparators in treating cUTI and cIAI in this population.cIAI, NCT01445665 and NCT01445678 (both trials registered prospectively on September 26, 2011); cUTI, NCT01345929 and NCT01345955 (both trials registered prospectively on April 28, 2011).
| S-EPMC5414364 | biostudies-literature
Project description:PURPOSE:Significant debate persists regarding the appropriate workup in children with an initial urinary tract infection. Greatly preferable to all or none approaches in the current guideline would be a model to identify children at highest risk for a recurrent urinary tract infection plus vesicoureteral reflux to allow for targeted voiding cystourethrogram while children at low risk could be observed. We sought to develop a model to predict the probability of recurrent urinary tract infection associated vesicoureteral reflux in children after an initial urinary tract infection. MATERIALS AND METHODS:We included subjects from the RIVUR (Randomized Intervention for Children with Vesico-Ureteral Reflux) and CUTIE (Careful Urinary Tract Infection Evaluation) trials in our study, excluding the prophylaxis treatment arm of the RIVUR. The main outcome was defined as recurrent urinary tract infection associated vesicoureteral reflux. Missing data were imputed using optimal tree imputation. Data were split into training, validation and testing sets. Machine learning algorithm hyperparameters were tuned by the validation set with fivefold cross-validation. RESULTS:A total of 500 subjects, including 305 from the RIVUR and 195 from the CUTIE trials, were included in study. Of the subjects 90% were female and mean ± SD age was 21 ± 19 months. A recurrent urinary tract infection developed in 72 patients, of whom 53 also had vesicoureteral reflux (10.6% of the total). The final model included age, sex, race, weight, the systolic blood pressure percentile, dysuria, the urine albumin-to-creatinine ratio, prior antibiotic exposure and current medication. The model predicted recurrent urinary tract infection associated vesicoureteral reflux with an AUC of 0.761 (95% CI 0.714-0.808) in the testing set. CONCLUSIONS:Our predictive model using a novel machine learning algorithm provided promising performance to facilitate individualized treatment of children with an initial urinary tract infection and identify those most likely to benefit from voiding cystourethrogram after the initial urinary tract infection. This would allow for more selective application of this test, increasing the yield while also minimizing overuse.
| S-EPMC7373365 | biostudies-literature
Project description:Urinary tract infections are one of the most common health problems and entail a high consumption of health system resources. Due to the increase in global antibiotic resistances in recent years, it is increasingly common to find uropathogens with multiple resistance mechanisms, including quinolone-resistant bacteria, broad-spectrum β-lactamase producers and carbapenemase producers. In this scenario, the role of fosfomycin has gained considerable importance, given its spectrum of activity against multidrug resistant microorganisms (Gram-positive and Gram-negative), becoming an attractive alternative therapy. Regarding the use of fosfomycin in complicated urinary tract infections, there is increasing clinical experience with patients with infections caused by multidrug resistant bacteria, those with recurrent urinary tract infection and special populations such as those with kidney transplants. Randomized comparative studies and series are underway, which will provide greater evidence. Nevertheless, more studies are needed to confirm the enormous potential of fosfomycin in complicated urinary tract infection in the era of multiresistance.
| S-EPMC6555162 | biostudies-literature