Point-of-care Testing in Complicated Urinary Tract Infection: Evaluation of the Vivalytic One Urinary Tract Infection Analyser for Detecting Uropathogenic Bacteria and Antimicrobial Resistance in Urine Samples of Urological Patients in a Point-of-care Set

Urinary tract infections (UTIs) are some of the most encountered infections in clinical practice, exhibiting increasing antimicrobial resistance. Bacterial species identification and antimicrobial resistance testing at point of care (POCT) could improve adequate initial antibiotic therapy and antimicrobial stewardship. In this work, the Vivalytic UTI test, which represents a qualitative PCR-based microarray test, able to detect specific uropathogenic bacteria and associated antimicrobial resistance genes was evaluated at POCT. In September 2023, we used this point-of-care testing (POCT) to analyse 126 consecutive urine samples of patients with complicated UTI. Samples processed with the Vivalytic UTI POCT were preselected for the presence of bacteriuria by screening with urine flow cytometry (cut-off ≥70 bacteria per microlitre). We performed the POCT before and after sample transport, and compared the results to standard urine culture and antibiotic sensitivity tests according to the European Committee on Antimicrobial Susceptibility Testing. Nineteen different bacterial species were detected. Sixteen species reached a diagnostic accuracy of ≥90.27% with negative predictive values of ≥93.67%. The POCT was able to detect bacterial species under the estimated concentration of 104-5 × 104 CFU/ml. The concordant (Vivalytic vs. culture) antimicrobial resistance gene detection rate reached a higher accuracy after transport (≥84.15%) compared to POC-testing before transport (≥81.71%), except for Vancomycin. Aerococcus urinae, Enterococcus hirae, Hafnia alvei, and Staphylococcus lugdunensis are not part of the POCT test panel; these were detected by urine culture only in 19% of cases. The Vivalytic UTI POCT displayed high sensitivity and specificity in identifying uropathogenic bacteria and antibiotic resistance markers to be further evaluated in clinical practice. However, it would be helpful to expand the resistance to include information about more commonly used antibiotics like aminopenicillins, cephalosporines and fluoroquinolones. In this study, we tested 126 consecutive urine samples of urological patients with complicated urinary tract infections (UTIs) by using the Vivalytic UTI point-of-care testing before and after sample transport. We found out that the sample transport to some extent influences the pathogen and resistance detection rate of the Vivalytic UTI assay. Compared to standard-of-care diagnostics, pathogen identification was more accurate before sample transport, while the concordant antimicrobial resistance gene detection rate reached higher accuracy after transport.

Hartmann J ，Fritzenwanker M ，Imirzalioglu C ，Hain T ，Michael Arneth B ，Wagenlehner F ... -  《European Urology Focus》

Ceftazidime with avibactam for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

Harnan S ，Kearns B ，Scope A ，Schmitt L ，Jankovic D ，Hamilton J ，Srivastava T ，Hill H ，Ku CC ，Ren S ，Rothery C ，Bojke L ，Sculpher M ，Woods B ... -  《-》

Genedrive kit for detecting single nucleotide polymorphism m.1555A>G in neonates and their mothers: a systematic review and cost-effectiveness analysis.

Shabaninejad H ，Kenny RP ，Robinson T ，Stoniute A ，O'Keefe H ，Still M ，Thornton C ，Pearson F ，Beyer F ，Meader N ... -  《-》

Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial.

The rate of antibiotic resistance continues to grow, outpacing small-molecule-drug development efforts. Novel therapies are needed to combat this growing threat, particularly for the treatment of urinary tract infections (UTIs), which are one of the largest contributors to antibiotic use and associated antibiotic resistance. LBP-EC01 is a novel, genetically enhanced, six-bacteriophage cocktail developed by Locus Biosciences (Morrisville, NC, USA) to address UTIs caused by Escherichia coli, regardless of antibiotic resistance status. In this first part of the two-part phase 2 ELIMINATE trial, we aimed to define a dosing regimen of LBP-EC01 for the treatment of uncomplicated UTIs that could advance to the second, randomised, controlled, double-blinded portion of the study. This first part of ELIMINATE is a randomised, uncontrolled, open-label, phase 2 trial that took place in six private clinical sites in the USA. Eligible participants were female by self-identification, aged between 18 years and 70 years, and had an uncomplicated UTI at the time of enrolment, as well as a history of at least one drug-resistant UTI caused by E coli within the 12 months before enrolment. Participants were initially randomised in a 1:1:1 ratio into three treatment groups, but this part of the trial was terminated on the recommendation of the safety review committee after a non-serious tolerability signal was observed based on systemic drug exposure. A protocol update was then implemented, comprised of three new treatment groups. Groups A to C were dosed with intraurethral 2 × 1012 plaque-forming units (PFU) of LBP-EC01 on days 1 and 2 by catheter, plus one of three intravenous doses daily on days 1-3 of LBP-EC01 (1 mL of 1 × 1010 PFU intravenous bolus in group A, 1 mL of 1 × 109 PFU intravenous bolus in group B, and a 2 h 1 × 1011 PFU intravenous infusion in 100 mL of sodium lactate solution in group C). In all groups, oral trimethoprim-sulfamethoxazole (TMP-SMX; 160 mg and 800 mg) was given twice daily on days 1-3. The primary outcome was the level of LBP-EC01 in urine and blood across the treatment period and over 48 h after the last dose and was assessed in patients in the intention-to-treat (ITT) population who received at least one dose of LBP-EC01 and had concentration-time data available throughout the days 1-3 dosing period (pharmacokinetic population). Safety, a secondary endpoint, was assessed in enrolled patients who received at least one dose of study drug (safety population). As exploratory pharmacodynamic endpoints, we assessed E coli levels in urine and clinical symptoms of UTI in patients with at least 1·0 × 105 colony-forming units per mL E coli in urine at baseline who took at least one dose of study drug and completed their day 10 test-of-cure assessment (pharmacodynamic-evaluable population). This trial is registered with ClinicalTrials.gov, NCT05488340, and is ongoing. Between Aug 22, 2022, and Aug 28, 2023, 44 patients were screened for eligibility, and 39 were randomly assigned (ITT population). Initially, eight participants were assigned to the first three groups. After the protocol was updated, 31 participants were allocated into groups A (11 patients), B (ten patients), and C (ten patients). One patient in group C withdrew consent on day 2 for personal reasons, but as she had received the first dose of the study drug was included in the modified ITT population. Maximum urine drug concentrations were consistent across intraurethral dosing, with a maximum mean concentration of 6·3 × 108 PFU per mL (geometric mean 8·8 log10 PFU per mL and geometric SD [gSD] 0·3). Blood plasma level of bacteriophages was intravenous dose-dependent, with maximum mean concentrations of 4·0 × 103 (geometric mean 3·6 log10 PFU per mL [gSD 1·5]) in group A, 2·5 × 103 (3·4 log10 PFU per mL [1·7]) in group B, and 8·0 × 105 (5·9 log10 PFU per mL [1·4]) in group C. No serious adverse events were observed. 44 adverse events were reported across 18 (46%) of the 39 participants in the safety population, with more adverse events seen with higher intravenous doses. Three patients in groups 1 to 3 and one patient in group C, all of whom received 1 × 1011 LBP-EC01 intravenously, had non-serious tachycardia and afebrile chills after the second intravenous dose. A rapid reduction of E coli in urine was observed by 4 h after the first treatment and maintained at day 10 in all 16 evaluable patients; these individuals had complete resolution of UTI symptoms by day 10. A regimen consisting of 2 days of intraurethral LBP-EC01 and 3 days of concurrent intravenous LBP-EC01 (1 × 1010 PFU) and oral TMP-SMX twice a day was well tolerated, with consistent pharmacokinetic profiles in urine and blood. LBP-EC01 and TMP-SMX dosing resulted in a rapid and durable reduction of E coli, with corresponding elimination of clinical symptoms in evaluable patients. LBP-EC01 holds promise in providing an alternative therapy for uncomplicated UTIs, with further testing of the group A dosing regimen planned in the controlled, double-blind, second part of ELIMINATE. Federal funds from the US Department of Health and Human Services, Administration for Strategic Preparedness and Response, and Biomedical Advanced Research and Development Authority (BARDA).

Kim P ，Sanchez AM ，Penke TJR ，Tuson HH ，Kime JC ，McKee RW ，Slone WL ，Conley NR ，McMillan LJ ，Prybol CJ ，Garofolo PM ... -  《-》

Serum and urine nucleic acid screening tests for BK polyomavirus-associated nephropathy in kidney and kidney-pancreas transplant recipients.

BK polyomavirus-associated nephropathy (BKPyVAN) occurs when BK polyomavirus (BKPyV) affects a transplanted kidney, leading to an initial injury characterised by cytopathic damage, inflammation, and fibrosis. BKPyVAN may cause permanent loss of graft function and premature graft loss. Early detection gives clinicians an opportunity to intervene by timely reduction in immunosuppression to reduce adverse graft outcomes. Quantitative nucleic acid testing (QNAT) for detection of BKPyV DNA in blood and urine is increasingly used as a screening test as diagnosis of BKPyVAN by kidney biopsy is invasive and associated with procedural risks. In this review, we assessed the sensitivity and specificity of QNAT tests in patients with BKPyVAN. We assessed the diagnostic test accuracy of blood/plasma/serum BKPyV QNAT and urine BKPyV QNAT for the diagnosis of BKPyVAN after transplantation. We also investigated the following sources of heterogeneity: types and quality of studies, era of publication, various thresholds of BKPyV-DNAemia/BKPyV viruria and variability between assays as secondary objectives. We searched MEDLINE (OvidSP), EMBASE (OvidSP), and BIOSIS, and requested a search of the Cochrane Register of diagnostic test accuracy studies from inception to 13 June 2023. We also searched ClinicalTrials.com and the WHO International Clinical Trials Registry Platform for ongoing trials. We included cross-sectional or cohort studies assessing the diagnostic accuracy of two index tests (blood/plasma/serum BKPyV QNAT or urine BKPyV QNAT) for the diagnosis of BKPyVAN, as verified by the reference standard (histopathology). Both retrospective and prospective cohort studies were included. We did not include case reports and case control studies. Two authors independently carried out data extraction from each study. We assessed the methodological quality of the included studies by using Quality Assessment of Diagnostic-Accuracy Studies (QUADAS-2) assessment criteria. We used the bivariate random-effects model to obtain summary estimates of sensitivity and specificity for the QNAT test with one positivity threshold. In cases where meta-analyses were not possible due to the small number of studies available, we detailed the descriptive evidence and used a summative approach. We explored possible sources of heterogeneity by adding covariates to meta-regression models. We included 31 relevant studies with a total of 6559 participants in this review. Twenty-six studies included kidney transplant recipients, four studies included kidney and kidney-pancreas transplant recipients, and one study included kidney, kidney-pancreas and kidney-liver transplant recipients. Studies were carried out in South Asia and the Asia-Pacific region (12 studies), North America (9 studies), Europe (8 studies), and South America (2 studies). blood/serum/plasma BKPyV QNAT The diagnostic performance of blood BKPyV QNAT using a common viral load threshold of 10,000 copies/mL was reported in 18 studies (3434 participants). Summary estimates at 10,000 copies/mL as a cut-off indicated that the pooled sensitivity was 0.86 (95% confidence interval (CI) 0.78 to 0.93) while the pooled specificity was 0.95 (95% CI 0.91 to 0.97). A limited number of studies were available to analyse the summary estimates for individual viral load thresholds other than 10,000 copies/mL. Indirect comparison of thresholds of the three different cut-off values of 1000 copies/mL (9 studies), 5000 copies/mL (6 studies), and 10,000 copies/mL (18 studies), the higher cut-off value at 10,000 copies/mL corresponded to higher specificity with lower sensitivity. The summary estimates of indirect comparison of thresholds above 10,000 copies/mL were uncertain, primarily due to a limited number of studies with wide CIs contributed to the analysis. Nonetheless, these indirect comparisons should be interpreted cautiously since differences in study design, patient populations, and methodological variations among the included studies can introduce biases. Analysis of all blood BKPyV QNAT studies, including various blood viral load thresholds (30 studies, 5658 participants, 7 thresholds), indicated that test performance remains robust, pooled sensitivity 0.90 (95% CI 0.85 to 0.94) and specificity 0.93 (95% CI 0.91 to 0.95). In the multiple cut-off model, including the various thresholds generating a single curve, the optimal cut-off was around 2000 copies/mL, sensitivity of 0.89 (95% CI 0.66 to 0.97) and specificity of 0.88 (95% CI 0.80 to 0.93). However, as most of the included studies were retrospective, and not all participants underwent the reference standard tests, this may result in a high risk of selection and verification bias. urine BKPyV QNAT There was insufficient data to thoroughly investigate both accuracy and thresholds of urine BKPyV QNAT resulting in an imprecise estimation of its accuracy based on the available evidence. There is insufficient evidence to suggest the use of urine BKPyV QNAT as the primary screening tool for BKPyVAN. The summary estimates of the test sensitivity and specificity of blood/serum/plasma BKPyV QNAT test at a threshold of 10,000 copies/mL for BKPyVAN were 0.86 (95% CI 0.78 to 0.93) and 0.95 (95% CI 0.91 to 0.97), respectively. The multiple cut-off model showed that the optimal cut-off was around 2000 copies/mL, with test sensitivity of 0.89 (95% CI 0.66 to 0.97) and specificity of 0.88 (95% CI 0.80 to 0.93). While 10,000 copies/mL is the most commonly used cut-off, with good test performance characteristics and supports the current recommendations, it is important to interpret the results with caution because of low-certainty evidence.

Maung Myint T ，Chong CH ，von Huben A ，Attia J ，Webster AC ，Blosser CD ，Craig JC ，Teixeira-Pinto A ，Wong G ... -  《Cochrane Database of Systematic Reviews》