Empowering Older Antibiotics.

Avycaz combines an older cephalosporin antibiotic, ceftazidime, and the ß-lactamase inhibitor avibactam. Ceftazidime targets penicillin-binding proteins (PBPs) in the bacterial periplasm that are required for cell wall synthesis. Avibactam blocks ß-lactamases (ß-L) in the periplasm, which would otherwise inactivate the antibiotics resulting in drug resistance.

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.).

Predictive phage therapy for Escherichia coli urinary tract infections: Cocktail selection for therapy based on machine learning models.

This study supports the development of predictive bacteriophage (phage) therapy: the concept of phage cocktail selection to treat a bacterial infection based on machine learning (ML) models. For this purpose, ML models were trained on thousands of measured interactions between a panel of phage and sequenced bacterial isolates. The concept was applied to Escherichia coli associated with urinary tract infections. This is an important common infection in humans and companion animals from which multidrug-resistant (MDR) bloodstream infections can originate. The global threat of MDR infection has reinvigorated international efforts into alternatives to antibiotics including phage therapy. E. coli exhibit extensive genome-level variation due to horizontal gene transfer via phage and plasmids. Associated with this, phage selection for E. coli is difficult as individual isolates can exhibit considerable variation in phage susceptibility due to differences in factors important to phage infection including phage receptor profiles and resistance mechanisms. The activity of 31 phage was measured on 314 isolates with growth curves in artificial urine. Random Forest models were built for each phage from bacterial genome features, and the more generalist phage, acting on over 20% of the bacterial population, exhibited F1 scores of >0.6 and could be used to predict phage cocktails effective against previously untested strains. The study demonstrates the potential of predictive ML models which integrate bacterial genomics with phage activity datasets allowing their use on data derived from direct sequencing of clinical samples to inform rapid and effective phage therapy.

Repurposing HDAC inhibitors to enhance ribonuclease 4 and 7 expression and reduce urinary tract infection.

With the emergence of antibiotic-resistant bacteria, innovative approaches are needed for the treatment of urinary tract infections. Boosting antimicrobial peptide expression may provide an alternative to antibiotics. Here, we developed reporter cell lines and performed a high-throughput screen of clinically used drugs to identify compounds that boost ribonuclease 4 and 7 expression (RNase 4 and 7), peptides that have antimicrobial activity against antibiotic-resistant uropathogens. This screen identified histone deacetylase (HDAC) inhibitors as effective RNase 4 and RNase 7 inducers. Validation studies in primary human kidney and bladder cells confirmed pan-HDAC inhibitors as well as the HDAC class I inhibitor, MS-275, induce RNase 4 and RNase 7 to protect human kidney and bladder cells from uropathogenic Escherichia coli. When we administered MS-275 to mice, RNase 4 and 7 expression increased and mice were protected from acute transurethral E. coli challenge. In support of this mechanism, MS-275 treatment increased acetylated histone H3 binding to the RNASE4 and RNASE7 promoters. Overexpression and knockdown of HDAC class I proteins identified HDAC3 as a primary regulator of RNase 4 and 7. These results demonstrate the protective effects of enhancing RNase 4 and RNase 7, opening the door to repurposing medications as antibiotic conserving therapeutics for urinary tract infection.

Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials.

BACKGROUND: Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and a unique binding site, providing well balanced inhibition of two type II topoisomerase enzymes. Oral gepotidacin is under investigation to treat uncomplicated urinary tract infections. We aimed to compare the efficacy and safety of oral gepotidacin with that of nitrofurantoin in adolescent and adult female individuals with uncomplicated urinary tract infections. METHODS: EAGLE-2 and EAGLE-3 were phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority (10% margin) trials, in which patients were enrolled at 219 centres worldwide. Patients assigned female at birth, non-pregnant, aged 12 years or older, weighing 40 kg or more, with two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain, and with evidence of urinary nitrite, pyuria, or both were eligible for inclusion. Patients were randomly assigned (1:1) centrally by interactive response technology to receive oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days), with randomisation stratified by age category and history of recurrent uncomplicated urinary tract infections. Patients, investigators, and the sponsor study team were masked to treatment assignment. The primary endpoint, therapeutic response (success or failure) at test-of-cure (ie, day 10-13), was evaluated in randomly assigned patients with nitrofurantoin-susceptible qualifying uropathogens (≥105 colony-forming units [CFU] per mL) and who received at least one dose of study treatment. Conforming to regulatory guidance, therapeutic success was defined as combined clinical success (ie, complete symptom resolution) and microbiological success (ie, reduction of qualifying uropathogens to <103 CFU/mL) without other systemic antimicrobial use. Safety analyses included patients who were randomly assigned and who received at least one dose of study treatment. The trials are registered with ClinicalTrials.gov, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), and are completed. FINDINGS: Studies were undertaken from Oct 17, 2019, to Nov 30, 2022 (EAGLE-2), and from April 23, 2020, to Dec 1, 2022 (EAGLE-3). 1680 patients in EAGLE-2 and 1731 patients in EAGLE-3 were screened for eligibility, of whom 1531 and 1605 were randomly assigned, respectively (767 in the gepotidacin group and 764 in the nitrofurantoin group in EAGLE-2, and 805 in the gepotidacin group and 800 in the nitrofurantoin group in EAGLE-3). After an interim analysis, which was prospectively agreed as a protocol amendment, both studies were stopped for efficacy. Thus, the primary analysis population included only patients who, at the time of the interim analysis data cutoff, had the opportunity to reach the test-of-cure visit or were known to not have attained therapeutic success before the test-of-cure visit. In EAGLE-2, 162 (50·6%) of 320 patients assigned gepotidacin and 135 (47·0%) of 287 patients assigned nitrofurantoin had therapeutic success (adjusted difference 4·3%, 95% CI -3·6 to 12·1). In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8). Gepotidacin was non-inferior to nitrofurantoin in both studies and superior to nitrofurantoin in EAGLE-3. The most common adverse event with gepotidacin was diarrhoea (observed in 111 [14%] of 766 patients in EAGLE-2 and in 147 [18%] of 804 patients in EAGLE-3), whereas the most common adverse event with nitrofurantoin was nausea (in 29 [4%] of 760 patients in EAGLE-2 and in 35 [4%] of 798 patients in EAGLE-3). Cases were mostly mild or moderate. No life-threatening or fatal events occurred. INTERPRETATION: Gepotidacin is an efficacious oral antibiotic with acceptable safety and tolerability profiles. As a first-in-class investigational oral antibiotic with activity against common uropathogens, including clinically important drug-resistant phenotypes, gepotidacin has the potential to offer substantial benefit to patients. FUNDING: GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection.

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).

In adult inpatients with a UTI, CPOE-based vs. routine stewardship reduced extended-spectrum antibiotic use.

SOURCE CITATION: Gohil SK, Septimus E, Kleinman K, et al. Stewardship prompts to improve antibiotic selection for urinary tract infection: the INSPIRE randomized clinical trial. JAMA. 2024;331:2018-2028. 38639723.

In women with uncomplicated UTIs, gepotidacin was noninferior to nitrofurantoin for therapeutic response at 10 to 13 d.

SOURCE CITATION: Wagenlehner F, Perry CR, Hooton TM, et al. Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials. Lancet. 2024;403:741-755. 38342126.

In complicated UTIs, cefepime-taniborbactam increased treatment success vs. meropenem at 19 to 23 d.

SOURCE CITATION: Wagenlehner FM, Gasink LB, McGovern PC, et al; CERTAIN-1 Study Team. Cefepime-taniborbactam in complicated urinary tract infection. N Engl J Med. 2024;390:611-622. 38354140.

Identification of a copper-responsive small molecule inhibitor of uropathogenic Escherichia coli.

Urinary tract infections (UTIs) are a major global health problem and are caused predominantly by uropathogenic Escherichia coli (UPEC). UTIs are a leading cause of prescription antimicrobial use. Incessant increase in antimicrobial resistance in UPEC and other uropathogens poses a serious threat to the current treatment practices. Copper is an effector of nutritional immunity that impedes the growth of pathogens during infection. We hypothesized that copper would augment the toxicity of select small molecules against bacterial pathogens. We conducted a small molecule screening campaign with a library of 51,098 molecules to detect hits that inhibit a UPEC ΔtolC mutant in a copper-dependent manner. A molecule, denoted as E. coli inhibitor or ECIN, was identified as a copper-responsive inhibitor of wild-type UPEC strains. Our gene expression and metal content analysis results demonstrate that ECIN works in concert with copper to exacerbate Cu toxicity in UPEC. ECIN has a broad spectrum of activity against pathogens of medical and veterinary significance including Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. Subinhibitory levels of ECIN eliminate UPEC biofilm formation. Transcriptome analysis of UPEC treated with ECIN reveals induction of multiple stress response systems. Furthermore, we demonstrate that L-cysteine rescues the growth of UPEC exposed to ECIN. In summary, we report the identification and characterization of a novel copper-responsive small molecule inhibitor of UPEC.IMPORTANCEUrinary tract infection (UTI) is a ubiquitous infectious condition affecting millions of people annually. Uropathogenic Escherichia coli (UPEC) is the predominant etiological agent of UTI. However, UTIs are becoming increasingly difficult to resolve with antimicrobials due to increased antimicrobial resistance in UPEC and other uropathogens. Here, we report the identification and characterization of a novel copper-responsive small molecule inhibitor of UPEC. In addition to E. coli, this small molecule also inhibits pathogens of medical and veterinary significance including Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus.

Plant phenolics inhibit focal adhesion kinase and suppress host cell invasion by uropathogenic Escherichia coli.

Traditional folk treatments for the prevention and management of urinary tract infections (UTIs) and other infectious diseases often include plants and plant extracts that are rich in phenolic compounds. These have been ascribed a variety of activities, including inhibition of bacterial interactions with host cells. Here, we tested a panel of four well-studied phenolic compounds-caffeic acid phenethyl ester (CAPE), resveratrol, catechin, and epigallocatechin gallate-for the effects on host cell adherence and invasion by uropathogenic Escherichia coli (UPEC). These bacteria, which are the leading cause of UTIs, can bind and subsequently invade bladder epithelial cells via an actin-dependent process. Intracellular UPEC reservoirs within the bladder are often protected from antibiotics and host defenses and likely contribute to the development of chronic and recurrent infections. In cell culture-based assays, only resveratrol had a notable negative effect on UPEC adherence to bladder cells. However, both CAPE and resveratrol significantly inhibited UPEC entry into the host cells, coordinate with attenuated phosphorylation of the host actin regulator Focal Adhesion Kinase (FAK or PTK2) and marked increases in the numbers of focal adhesion structures. We further show that the intravesical delivery of resveratrol inhibits UPEC infiltration of the bladder mucosa in a murine UTI model and that resveratrol and CAPE can disrupt the ability of other invasive pathogens to enter host cells. Together, these results highlight the therapeutic potential of molecules like CAPE and resveratrol, which could be used to augment antibiotic treatments by restricting pathogen access to protective intracellular niches.IMPORTANCEUrinary tract infections (UTIs) are exceptionally common and increasingly difficult to treat due to the ongoing rise and spread of antibiotic-resistant pathogens. Furthermore, the primary cause of UTIs, uropathogenic Escherichia coli (UPEC), can avoid antibiotic exposure and many host defenses by invading the epithelial cells that line the bladder surface. Here, we identified two plant-derived phenolic compounds that disrupt activation of the host machinery needed for UPEC entry into bladder cells. One of these compounds, resveratrol, effectively inhibited UPEC invasion of the bladder mucosa in a mouse UTI model, and both phenolic compounds significantly reduced host cell entry by other invasive pathogens. These findings suggest that select phenolic compounds could be used to supplement existing antibacterial therapeutics by denying uropathogens shelter within host cells and tissues and help explain some of the benefits attributed to traditional plant-based medicines.

Development of Predictive Models to Inform a Novel Risk Categorization Framework for Antibiotic Resistance in Escherichia coli-Caused Uncomplicated Urinary Tract Infection.

BACKGROUND: In clinical practice, challenges in identifying patients with uncomplicated urinary tract infections (uUTIs) at risk of antibiotic nonsusceptibility may lead to inappropriate prescribing and contribute to antibiotic resistance. We developed predictive models to quantify risk of nonsusceptibility to 4 commonly prescribed antibiotic classes for uUTI, identify predictors of nonsusceptibility to each class, and construct a corresponding risk categorization framework for nonsusceptibility. METHODS: Eligible females aged ≥12 years with Escherichia coli-caused uUTI were identified from Optum's de-identified Electronic Health Record dataset (1 October 2015-29 February 2020). Four predictive models were developed to predict nonsusceptibility to each antibiotic class and a risk categorization framework was developed to classify patients' isolates as low, moderate, and high risk of nonsusceptibility to each antibiotic class. RESULTS: Predictive models were developed among 87 487 patients. Key predictors of having a nonsusceptible isolate to ≥3 antibiotic classes included number of previous UTI episodes, prior ß-lactam nonsusceptibility, prior fluoroquinolone treatment, Census Bureau region, and race. The risk categorization framework classified 8.1%, 14.4%, 17.4%, and 6.3% of patients as having isolates at high risk of nonsusceptibility to nitrofurantoin, trimethoprim-sulfamethoxazole, ß-lactams, and fluoroquinolones, respectively. Across classes, the proportion of patients categorized as having high-risk isolates was 3- to 12-fold higher among patients with nonsusceptible isolates versus susceptible isolates. CONCLUSIONS: Our predictive models highlight factors that increase risk of nonsusceptibility to antibiotics for uUTIs, while the risk categorization framework contextualizes risk of nonsusceptibility to these treatments. Our findings provide valuable insight to clinicians treating uUTIs and may help inform empiric prescribing in this population.

Raising the alarm: fosfomycin resistance associated with non-susceptible inner colonies imparts no fitness cost to the primary bacterial uropathogen.

IMPORTANCE: While fosfomycin resistance is rare, the observation of non-susceptible subpopulations among clinical Escherichia coli isolates is a common phenomenon during antimicrobial susceptibility testing (AST) in American and European clinical labs. Previous evidence suggests that mutations eliciting this phenotype are of high biological cost to the pathogen during infection, leading to current recommendations of neglecting non-susceptible colonies during AST. Here, we report that the most common route to fosfomycin resistance, as well as novel routes described in this work, does not impair virulence in uropathogenic E. coli, the major cause of urinary tract infections, suggesting a re-evaluation of current susceptibility guidelines is warranted.

Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection.

CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.

Zidovudine in synergistic combination with nitrofurantoin or omadacycline: in vitro and in murine urinary tract or lung infection evaluation against multidrug-resistant Klebsiella pneumoniae.

Limited treatment options and multidrug-resistant (MDR) Klebsiella pneumoniae present a significant therapeutic challenge, underscoring the need for novel approaches. Drug repurposing is a promising tool for augmenting the activity of many antibiotics. This study aimed to identify novel synergistic drug combinations against K. pneumoniae based on drug repurposing. We used the clinically isolated GN 172867 MDR strain of K. pneumoniae to determine the reversal resistance activity of zidovudine (AZT). The combined effects of AZT and various antibiotics, including nitrofurantoin (NIT) and omadacycline (OMC), were examined using the checkerboard method, growth curves, and crystal violet assays to assess biofilms. An in vitro combination activity testing was carried out in 12 isolates of K. pneumoniae. In vivo murine urinary tract and lung infection models were used to evaluate the therapeutic effects of AZT + NIT and AZT + OMC, respectively. The fractional inhibitory concentration index and growth curve demonstrated that AZT synergized with NIT or OMC against K. pneumoniae strains. In addition, AZT + NIT inhibited biofilm formation and cleared mature biofilms. In vivo, compared with untreated GN 172867-infected mice, AZT + NIT and AZT + OMC treatment decreased colony counts in multiple tissues (P < 0.05) and pathological scores in the bladder and kidneys (P < 0.05) and increased the survival rate by 60% (P < 0.05). This study evaluated the combination of AZT and antibiotics to treat drug-resistant K. pneumoniae infections and found novel drug combinations for the treatment of acute urinary tract infections. These findings suggest that AZT may exert significant anti-resistance activity.

Investigating trends in antibiotic resistance of Escherichia coli isolated from clinical urine specimens in the Orkney Islands.

Urinary tract infections (UTIs) are extremely common, affecting people of all ages and health statuses. Although UTIs do not usually cause severe illness, in some cases they can lead to more serious complications, especially if their initial treatment is ineffective due to antimicrobial resistance (AMR). AMR is an increasing issue, exacerbated by misdiagnosis and inappropriate prescribing of antibiotics, thus facilitating further resistance. The aim of this study was to investigate the rates of AMR in Escherichia coli isolated from clinical urine specimens tested at the Balfour Hospital, Orkney, and determine trends related to patient risk factors. Antibiotic susceptibilities were tested for 100 isolates of uropathogenic E. coli using the VITEK 2 Compact (bioMérieux), and data were analysed using percentage resistance rates. Resistance rates were compared by patient sex, age and source (hospital versus community). The findings showed higher AMR in males compared with females, particularly for trimethoprim (TMP), with 52% in males and only 12% in females. AMR tended to be higher in E. coli isolated from hospital inpatients than from community specimens, except for amoxicillin (AMX) and co-amoxiclav. Finally, the study found that AMR of E. coli isolates was greater in patients aged over 50 than 18-50 years old, particularly for AMX and TMP. The highest resistance rates across all patient demographics were for AMX, implying that the use of this antibiotic for the treatment of E. coli UTIs is not appropriate.

Cefazolin as a predictor of urinary cephalosporin activity in indicated Enterobacterales.

Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and Laboratory Standards Institute (CLSI) revisited this practice and determined that cefazolin is a more accurate proxy than cephalothin for uncomplicated urinary tract infections (uUTIs). Therefore, a cefazolin surrogacy breakpoint was established to predict the susceptibility of seven oral cephalosporins for Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis in the context of uUTIs. Clinical microbiology laboratories face several operational challenges when implementing the cefazolin surrogacy breakpoint, which may lead to confusion for the best path forward. Here, we review the historical context and data behind the surrogacy breakpoints, review PK/PD profiles for oral cephalosporins, discuss challenges in deploying the breakpoint, and highlight the limited clinical outcome data in this space.

When antimicrobial stewardship begins with microbiological test requests: the case of asymptomatic bacteriuria.

PURPOSE OF REVIEW: We aim to review the rationale, methods, and experiences with diagnostic stewardship targeted at urinary tract infection (UTI) and related urinary syndromes. RECENT FINDINGS: In the last 18 months, several articles have demonstrated the impact of diagnostic stewardship interventions at limiting inappropriate diagnosis of UTIs or inappropriate antibiotic-prescribing, targeting the urinary tract. Antimicrobial stewardship programs may create and implement interventions at the point of urine test ordering, urine test resulting, or at the point of prescribing antibiotics after results have returned. Specific design and implementation of stewardship interventions depends on context. To maximize their impact, interventions should be accompanied by education and garner buy-in from providers. SUMMARY: Diagnostic stewardship can decrease unnecessary antibiotics and inappropriate diagnosis of UTI with multifaceted interventions most likely to be effective. Remaining questions include how to reduce ASB treatment in new populations, such as those with immune compromise, and persistent unknowns regarding UTI diagnosis and diagnostics.

Treatment, outcomes and characterization of pathogens in urinary tract infections caused by ESBL-producing Enterobacterales: a prospective multicentre study.

OBJECTIVES: Treatment options for urinary tract infections (UTIs) caused by ESBL-producing Enterobacterales are limited. Moreover, evidence to support therapeutic decisions is lacking. This study assessed current treatment strategies and patient and pathogen characteristics in relation to clinical and microbiological outcomes. METHODS: Patients with UTI caused by ESBL-producing Enterobacterales were prospectively recruited by investigators at 15 infectious disease hospital departments. Data were collected on patient characteristics, treatments, clinical and microbiological cure 10-14 days after the end of treatment, and relapse within 3 months. Bacterial isolates were subjected to MIC determination and WGS. RESULTS: In total, 235 patients (107 febrile UTI, 128 lower UTI) caused by Escherichia coli (n = 223) and Klebsiella spp. (n = 12) were included. Clinical and microbiological cure rates were 83% and 64% in febrile UTI, and 79% and 65% in lower UTI. Great variability in treatments was observed, especially in oral therapy for febrile UTI. No difference was seen in clinical outcomes with piperacillin/tazobactam (n = 28) compared with carbapenems (n = 41). Pivmecillinam was frequently used in lower UTI (n = 62), and was also associated with high clinical cure rates when used as initial therapy (10/10) or follow-up (7/8) for febrile UTI. Recurrent infection, diabetes mellitus and urogenital disease were associated (P < 0.05) with clinical failure and relapse. In E. coli, ST131 was significantly associated with relapse, and haemolysin with microbiological failure or relapse. CONCLUSIONS: Antibiotic treatments were highly variable. Patient and pathogen factors were identified as potential determinants of disease presentation and outcomes and may prove useful to guide individualized treatment and follow-up.

Temocillin for febrile urinary tract infections caused by ESBL-producing Enterobacteriaceae in children: a monocentric exposed/non-exposed study.

OBJECTIVES: To compare the efficacy of temocillin with standard of care (SOC) for treatment of ESBL-producing Enterobacteriaceae (ESBL-E) febrile urinary tract infection (ESBL-E FUTI) in children. METHODS: A monocentric retrospective study of children hospitalized with confirmed ESBL-E FUTI from January 2015 to May 2022 was conducted, comparing clinical cure and a 3 month relapse between two groups of patients: 'exposed' patients (EP) and 'non-exposed' patients (NEP) to temocillin. EP received temocillin for at least 3 days. They were matched (1:1 ratio) on age group, sex and presence of uropathy with NEP who received SOC antibiotic therapy. RESULTS: Thirty-six temocillin-treated children (EP) were matched with 36 SOC children (NEP); 72.2% were under 2 years old (n = 52) and 75.0% had a congenital uropathy (n = 54). EPs had more FUTI history (97.2%, n = 35) than NEPs (61.1%, n = 22) (P < 0.01). Clinical cure rate was 98.6% overall, with no difference between the two groups, as for the FUTI relapse rate, which was 37.1% for EPs versus 27.8% for NEPs (P = 0.45). In bivariate analyses, factors associated with relapses were congenital uropathy (91.3% versus 66.7%, P = 0.04) and subtypes of uropathy, with refluxing uropathy and posterior urethral valves being the more prevalent. Median duration of hospitalization was longer in the EPs (8.0 versus 5.0 days) (P = 0.01). CONCLUSIONS: The high clinical cure rate and comparable outcomes suggest that temocillin may be an effective therapeutic alternative to standard treatment for ESBL-E FUTI in children.