In Vitro Activity of Ceftibuten/VNRX-5236 against Urinary Tract Infection Isolates of Antimicrobial-Resistant Enterobacterales

Oral Treatment ◽

Multidrug Resistant ◽

Culture Collection ◽

Active Inhibitor ◽

Oral Agents ◽

Ceftibuten/VNRX-7145 is a cephalosporin/boronate β-lactamase inhibitor combination under development as an oral treatment for complicated urinary tract infections caused by Enterobacterales producing serine β-lactamases (Ambler class A, C and D). In vivo , VNRX-7145 (VNRX-5236 etzadroxil) is cleaved to the active inhibitor, VNRX-5236. We assessed the in vitro activity of ceftibuten/VNRX-5236 against 1,066 urinary isolates of Enterobacterales from a 2014-2016 global culture collection. Each isolate tested was pre-selected to possess a multidrug-resistant (MDR) phenotype that included non-susceptibility to amoxicillin-clavulanate and resistance to levofloxacin. MICs were determined by CLSI broth microdilution. VNRX-5236 was tested at a fixed concentration of 4 μg/ml. Ceftibuten/VNRX-5236 inhibited 90% of all isolates tested (MIC 90 ) at 2 μg/ml; MIC 90 s for ESBL- ( n =566), serine carbapenemase- ( n =116), and acquired AmpC-positive ( n =58) isolate subsets were ≤0.25, >32, and 8 μg/ml, respectively. At concentrations of ≤1, ≤2, and ≤4 μg/ml, ceftibuten/VNRX-5236 inhibited 89.1, 91.7, and 93.1% of all isolates tested; 96.5, 97.7, and 98.4% of ESBL-positive isolates; 75.9, 81.9, and 81.9% of serine carbapenemase-positive isolates; and 70.7, 81.0, and 87.9% of acquired AmpC-positive isolates. Ceftibuten/VNRX-5236 at concentrations of ≤1, ≤2, and ≤4 μg/ml inhibited 85-89, 89-91, and 91-92% of isolates that were not susceptible (defined by CLSI and EUCAST breakpoint criteria) to nitrofurantoin, trimethoprim-sulfamethoxazole, and/or fosfomycin, (as part of their MDR phenotype), oral agents commonly prescribed to treat uncomplicated urinary tract infections. The potency of ceftibuten/VNRX-5236 (MIC 90 , 2 μg/ml) was similar (within one doubling-dilution) to intravenous-only agents ceftazidime-avibactam (MIC 90 2 μg/ml) and meropenem-vaborbactam (MIC 90 1 μg/ml). Continued investigation of ceftibuten/VNRX-5236 is warranted.

1293. In vitro Activity of Ceftibuten in Combination with VNRX-5236 against Clinical Isolates of Enterobacterales from Urinary Tract Infections Collected in 2018-2020

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1485 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S735-S735

Author(s):

Meredith Hackel ◽

Mark G G Wise ◽

Daniel F Sahm

Keyword(s):

Urinary Tract ◽

Oral Treatment ◽

Vitro Activity ◽

In Vitro Activity ◽

Independent Contractor ◽

Active Inhibitor ◽

Oral Agents ◽

Abstract Background Increasing resistance among agents commonly prescribed to treat urinary tract infections indicate that new oral agents are urgently needed. Ceftibuten in combination with VNRX-7145 is under development as an oral treatment for complicated urinary tract infections caused by serine β-lactamase-producing Enterobacterales, including isolates carrying ESBLs and carbapenemases. In vivo, VNRX-7145 (VNRX-5236 etzadroxil) is cleaved into to the active inhibitor, VNRX-5236. This study assessed the in vitro activity of ceftibuten/VNRX-5236 against 592 isolates of Enterobacterales from urinary tract infections (UTIs) from a 2018-2020 global culture collection. Methods MICs of ceftibuten with VNRX-5236 fixed at 4 µg/mL and comparators were determined following CLSI M07-A11 guidelines against 592 Enterobacterales. Isolates were from community and hospital UTI infections collected from 133 sites in 31 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints. Results A substantial percentage of isolates were non-susceptible to extended-spectrum β-lactams, levofloxacin (LVX), trimethoprim-sulfamethoxazole (SXT), and amoxicillin-clavulanate (AMC) (Table). The addition of VNRX-5236 reduced ceftibuten MIC90 values by ≥8-fold to ≥128-fold, depending on the resistant subset. Ceftibuten/VNRX-5236 had potent activity against all Enterobacterales, with MIC50/90 values of 0.06/0.25 µg/mL and 98.3% inhibited at ≤2 µg/mL. Ceftibuten/VNRX-5236 maintained activity against resistant subsets (MIC90 range, 0.5 to 2 µg/mL; 91.5% to 97.1% inhibited at ≤2 µg/mL), including serine carbapenemase-positive isolates (MIC90 0.5 µg/mL; 100% inhibited at ≤1 µg/mL). Ceftibuten/VNRX-5236 in vitro potency was similar to that of newer parenteral and investigational oral therapies. Results Table Conclusion Ceftibuten/VNRX-5236 exhibited promising in vitro activity against recent Enterobacterales from UTIs, and may have potential as an oral treatment option for complicated urinary tract infections, including those caused by serine β-lactamase-expressing Enterobacterales (ESBL, KPC, OXA-48/OXA-48-like) for which there are currently few oral treatment options available. Disclosures Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Mark G G. Wise, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

FimH Antagonists for the Oral Treatment of Urinary Tract Infections: From Design and Synthesis to in Vitro and in Vivo Evaluation

Journal of Medicinal Chemistry ◽

10.1021/jm101011y ◽

2010 ◽

Vol 53 (24) ◽

pp. 8627-8641 ◽

Cited By ~ 131

Author(s):

Tobias Klein ◽

Daniela Abgottspon ◽

Matthias Wittwer ◽

Said Rabbani ◽

Janno Herold ◽

...

Keyword(s):

Urinary Tract ◽

Oral Treatment ◽

In Vivo Evaluation ◽

Design And Synthesis ◽

Quinolones for the Treatment ofNeisseria GonorrhoeaeandChlamydia Trachomatis

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/s1064744993000250 ◽

1993 ◽

Vol 1 (2) ◽

pp. 108-113 ◽

Cited By ~ 1

Author(s):

Sebastian Faro

Keyword(s):

Urinary Tract ◽

Soft Tissue ◽

Chlamydia Trachomatis ◽

Single Agent ◽

Moderate Activity ◽

Sexually Transmitted ◽

The most commonly sexually transmitted bacteria areNeisseria gonorrhoeaeandChlamydia trachomatis.The quinolones ofloxacin and ciprofloxacin have been shown to have activity against both of these bacteria in vitro and in vivo. Ofloxacin is particularly well suited for the treatment ofN. gonorrhoeaeandC. trachomatiscervical infection, which can be considered the earliest manifestation of pelvic inflammatory disease (PID). Not only can ofloxacin be effectively used as a single agent, it is also useful in treating urinary tract infections caused by Enterobacteriaceae. Although it has moderate activity against anaerobes in general, ofloxacin does have activity against the anaerobes commonly isolated from female patients with soft tissue pelvic infections. Thus, ofloxacin has the potential for being utilized to treat early salpingitis.

Assessment of Fosfomycin for Complicated or Multidrug-Resistant Urinary Tract Infections: Patient Characteristics and Outcomes

Chemotherapy ◽

10.1159/000449422 ◽

2016 ◽

Vol 62 (2) ◽

pp. 100-104 ◽

Cited By ~ 18

Author(s):

Stephanie E. Giancola ◽

Monica V. Mahoney ◽

Michael D. Hogan ◽

Brian R. Raux ◽

Christopher McCoy ◽

...

Keyword(s):

Urinary Tract ◽

Bacterial Resistance ◽

Clinical Success ◽

Patient Characteristics ◽

Multidrug Resistant ◽

Enterococcus Spp ◽

Tract Infections ◽

Microbiological Cure

Background: Bacterial resistance among uropathogens is on the rise and has led to a decreased effectiveness of oral therapies. Fosfomycin tromethamine (fosfomycin) is indicated for uncomplicated urinary tract infections (UTIs) and displays in vitro activity against multidrug-resistant (MDR) isolates; however, clinical data assessing fosfomycin for the treatment of complicated or MDR UTIs are limited. Methods: We conducted a retrospective evaluation of patients who received ≥1 dose of fosfomycin between January 2009 and September 2015 for treatment of a UTI. Patients were included if they had a positive urine culture and documented signs/symptoms of a UTI. Results: Fifty-seven patients were included; 44 (77.2%) had complicated UTIs, 36 (63.2%) had MDR UTIs, and a total of 23 (40.4%) patients had a UTI that was both complicated and MDR. The majority of patients were female (66.7%) and elderly (median age, 79 years). Overall, the most common pathogens isolated were Escherichia coli (n = 28), Enterococcus spp. (n = 22), and Pseudomonas aeruginosa (n = 8). Twenty-eight patients (49.1%) were clinically evaluable; the preponderance achieved clinical success (96.4%). Fifteen out of 20 (75%) patients with repeat urine cultures had a microbiological cure. Conclusions: This retrospective study adds to the limited literature exploring alternative therapies for complicated and MDR UTIs with results providing additional evidence that fosfomycin may be an effective oral option.

Cephazolin Sodium — An in Vivo and in Vitro Evaluation of 100 Patients with Urinary Tract Infections in a District General Hospital

Penicillins and Cephalosporins ◽

10.1007/978-1-4684-3126-1_49 ◽

1976 ◽

pp. 311-314

Author(s):

Diana M. D. Rimmer

Keyword(s):

Urinary Tract ◽

General Hospital ◽

District General Hospital ◽

In Vitro Evaluation ◽

Peptidoglycan Sensing Prevents Quiescence and Promotes Quorum-Independent Colony Growth of Uropathogenic Escherichia coli

Journal of Bacteriology ◽

10.1128/jb.00157-20 ◽

2020 ◽

Vol 202 (20) ◽

Author(s):

Eric C. DiBiasio ◽

Hilary J. Ranson ◽

James R. Johnson ◽

David C. Rowley ◽

Paul S. Cohen ◽

...

Keyword(s):

Escherichia Coli ◽

Urinary Tract ◽

Recurrent Infection ◽

Colony Growth ◽

Quiescent State ◽

Content Type ◽

ABSTRACT Uropathogenic Escherichia coli (UPEC) is the leading cause of human urinary tract infections (UTIs), and many patients experience recurrent infection after successful antibiotic treatment. The source of recurrent infections may be persistent bacterial reservoirs in vivo that are in a quiescent state and thus are not susceptible to antibiotics. Here, we show that multiple UPEC strains require a quorum to proliferate in vitro with glucose as the carbon source. At low cell density, the bacteria remain viable but enter a quiescent, nonproliferative state. Of the clinical UPEC isolates tested to date, 35% (51/145) enter this quiescent state, including isolates from the recently emerged, multidrug-resistant pandemic lineage ST131 (i.e., strain JJ1886) and isolates from the classic endemic lineage ST73 (i.e., strain CFT073). Moreover, quorum-dependent UPEC quiescence is prevented and reversed by small-molecule proliferants that stimulate colony formation. These proliferation cues include d-amino acid-containing peptidoglycan (PG) tetra- and pentapeptides, as well as high local concentrations of l-lysine and l-methionine. Peptidoglycan fragments originate from the peptidoglycan layer that supports the bacterial cell wall but are released as bacteria grow. These fragments are detected by a variety of organisms, including human cells, other diverse bacteria, and, as we show here for the first time, UPEC. Together, these results show that for UPEC, (i) sensing of PG stem peptide and uptake of l-lysine modulate the quorum-regulated decision to proliferate and (ii) quiescence can be prevented by both intra- and interspecies PG peptide signaling. IMPORTANCE Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs). During pathogenesis, UPEC cells adhere to and infiltrate bladder epithelial cells, where they may form intracellular bacterial communities (IBCs) or enter a nongrowing or slowly growing quiescent state. Here, we show in vitro that UPEC strains at low population density enter a reversible, quiescent state by halting division. Quiescent cells resume proliferation in response to sensing a quorum and detecting external signals, or cues, including peptidoglycan tetra- and pentapeptides.

Cephazolin Sodium—An In Vivo and In Vitro Evaluation of 100 Patients with Urinary Tract Infections

Scottish Medical Journal ◽

10.1177/003693307502000517 ◽

1975 ◽

Vol 20 (5) ◽

pp. 259-260

Author(s):

Diana M. D. Rimmer

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

General Hospital ◽

Antimicrobial Agents ◽

Random Group ◽

A random group of 100 patients in a general hospital were treated with cephazolin sodium for proven urinary tract infections. Sixty-six per cent had conditions predisposing to urinary tract infection. Under these somewhat difficult conditions the original infecting organism remained absent from the urine of 75 per cent of the 70 patients followed in the 3rd to 6th week period. This compares very favourably with response to other antimicrobial agents currently used in urinary tract infections.

Experience with Fosfomycin for Treatment of Urinary Tract Infections Due to Multidrug-Resistant Organisms

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00402-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5744-5748 ◽

Cited By ~ 105

Author(s):

Elizabeth A. Neuner ◽

Jennifer Sekeres ◽

Gerri S. Hall ◽

David van Duin

Keyword(s):

Urinary Tract ◽

Multidrug Resistant ◽

Solid Organ ◽

Content Type ◽

Failure Group ◽

Tract Infections ◽

Microbiological Cure ◽

Esbl Producers

ABSTRACTFosfomycin has shown promisingin vitroactivity against multidrug-resistant (MDR) urinary pathogens; however, clinical data are lacking. We conducted a retrospective chart review to describe the microbiological and clinical outcomes of urinary tract infections (UTIs) with MDR pathogens treated with fosfomycin tromethamine. Charts for 41 hospitalized patients with a urine culture for an MDR pathogen who received fosfomycin tromethamine from 2006 to 2010 were reviewed. Forty-one patients had 44 urinary pathogens, including 13 carbapenem-resistantKlebsiella pneumoniae(CR-Kp), 8Pseudomonas aeruginosa, and 7 vancomycin-resistantEnterococcus faecium(VRE) isolates, 7 extended-spectrum beta-lactamase (ESBL) producers, and 9 others.In vitrofosfomycin susceptibility was 86% (median MIC, 16 μg/ml; range, 0.25 to 1,024 μg/ml). Patients received an average of 2.9 fosfomycin doses per treatment course. The overall microbiological cure was 59%; failure was due to either relapse (24%) or reinfection UTI (17%). Microbiological cure rates by pathogen were 46% for CR-Kp, 38% forP. aeruginosa, 71% for VRE, 57% for ESBL producers, and 100% for others. Microbiological cure (n= 24) was compared to microbiological failure (n= 17). There were significantly more solid organ transplant recipients in the microbiological failure group (59% versus 21%;P= 0.02). None of the patients in the microbiological cure group had a ureteral stent, compared to 24% of patients within the microbiological failure group (P= 0.02). Fosfomycin demonstratedin vitroactivity against UTIs due to MDR pathogens. For CR-KP, there was a divergence betweenin vitrosusceptibility (92%) and microbiological cure (46%). Multiple confounding factors may have contributed to microbiological failures, and further data regarding the use of fosfomycin for UTIs due to MDR pathogens are needed.

Escherichia coli CFT073 Fitness Factors during Urinary Tract Infection: Identification Using an Ordered Transposon Library

Applied and Environmental Microbiology ◽

10.1128/aem.00691-20 ◽

2020 ◽

Vol 86 (13) ◽

Cited By ~ 1

Author(s):

Allyson E. Shea ◽

Juan Marzoa ◽

Stephanie D. Himpsl ◽

Sara N. Smith ◽

Lili Zhao ◽

...

Keyword(s):

Escherichia Coli ◽

Urinary Tract ◽

Human Urine ◽

Transposon Mutagenesis ◽

Content Type ◽

E Coli ◽

ABSTRACT Urinary tract infections (UTI), the second most diagnosed infectious disease worldwide, are caused primarily by uropathogenic Escherichia coli (UPEC), placing a significant financial burden on the health care system. High-throughput transposon mutagenesis combined with genome-targeted sequencing is a powerful technique to interrogate genomes for fitness genes. Genome-wide analysis of E. coli requires random libraries of at least 50,000 mutants to achieve 99.99% saturation; however, the traditional murine model of ascending UTI does not permit testing of large mutant pools due to a bottleneck during infection. To address this, an E. coli CFT073 transposon mutant ordered library of 9,216 mutants was created and insertion sites were identified. A single transposon mutant was selected for each gene to assemble a condensed library consisting of 2,913 unique nonessential mutants. Using a modified UTI model in BALB/c mice, we identified 36 genes important for colonizing the bladder, including purB, yihE, and carB. Screening of the condensed library in vitro identified yigP and ubiG to be essential for growth in human urine. Additionally, we developed a novel quantitative PCR (qPCR) technique to identify genes with fitness defects within defined subgroups of related genes (e.g., genes encoding fimbriae, toxins, etc.) following UTI. The number of mutants within these subgroups circumvents bottleneck restriction and facilitates validation of multiple mutants to generate individual competitive indices. Collectively, this study investigates the bottleneck effects during UTI, provides two techniques for evading those effects that can be applied to other disease models, and contributes a genetic tool in prototype strain CFT073 to the field. IMPORTANCE Uropathogenic Escherichia coli strains cause most uncomplicated urinary tract infections (UTI), one of the most common infectious diseases worldwide. Random transposon mutagenesis techniques have been utilized to identify essential bacterial genes during infection; however, this has been met with limitations when applied to the murine UTI model. Conventional high-throughput transposon mutagenesis screens are not feasible because of inoculum size restrictions due to a bottleneck during infection. Our study utilizes a condensed ordered transposon library, limiting the number of mutants while maintaining the largest possible genome coverage. Screening of this library in vivo, and in human urine in vitro, identified numerous candidate fitness factors. Additionally, we have developed a novel technique using qPCR to quantify bacterial outputs following infection with small subgroups of transposon mutants. Molecular approaches developed in this study will serve as useful tools to probe in vivo models that are restricted by anatomical, physiological, or genetic bottleneck limitations.

Antibacterial Activity of LCB10-0200 against Klebsiella pneumoniae

Antibiotics ◽

10.3390/antibiotics10101185 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1185

Author(s):

Sang-Hun Oh ◽

Young-Rok Kim ◽

Hee-Soo Park ◽

Kyu-Man Oh ◽

Young-Lag Cho ◽

...

Keyword(s):

Antibacterial Activity ◽

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Antibacterial Agent ◽

In Vitro Susceptibility ◽

In Vivo Models ◽

Klebsiella pneumoniae is one of the important clinical organisms that causes various infectious diseases, including urinary tract infections, necrotizing pneumonia, and surgical wound infections. The increase in the incidence of multidrug-resistance K. pneumoniae is a major problem in public healthcare. Therefore, a novel antibacterial agent is needed to treat this pathogen. Here, we studied the in vitro and in vivo activities of a novel antibiotic LCB10-0200, a siderophore-conjugated cephalosporin, against clinical isolates of K. pneumoniae. In vitro susceptibility study found that LCB10-0200 showed potent antibacterial activity against K. pneumoniae, including the beta-lactamase producing strains. The in vivo efficacy of LCB10-0200 was examined in three different mouse infection models, including systemic, thigh, and urinary tract infections. LCB10-0200 showed more potent in vivo activity than ceftazidime in the three in vivo models against the drug-susceptible and drug-resistant K. pneumoniae strains. Taken together, these results show that LCB10-0200 is a potential antibacterial agent to treat infection caused by K. pneumoniae.