scholarly journals Pilot Ex Vivo and In Vitro Evaluation of a Novel Foley Catheter with Antimicrobial Periurethral Irrigation for Prevention of Extraluminal Biofilm Colonization Leading to Catheter-Associated Urinary Tract Infections (CAUTIs)

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Nylev Vargas-Cruz ◽  
Joel Rosenblatt ◽  
Ruth A Reitzel ◽  
Anne-Marie Chaftari ◽  
Ray Hachem ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Foley Catheter ◽  
Irrigation Treatment ◽  
Multidrug Resistant ◽  
Indwelling Catheter ◽  
Carbapenem Resistant ◽  
Colonization Model ◽  
Tract Infections

CAUTI remains a serious healthcare issue for incontinent patients whose urine drainage is managed by catheters. A novel double-balloon Foley catheter was developed which was capable of irrigating the extraluminal catheter surfaces within the periurethral space between the urethral-bladder junction and meatus. The catheter has a retention cuff that is inflated to secure the catheter in the bladder and a novel irrigation cuff proximal to the urethral-bladder junction capable of providing periurethral irrigation from the urethral-bladder junction to the meatus. Uniform periurethral irrigation was demonstrated in an ex vivo porcine model by adding a dye to the antimicrobial urethral irrigation solution. An in vitro biofilm colonization model was adapted to study the ability of periurethral irrigation with a newly developed antimicrobial combination consisting of polygalacturonic acid + caprylic acid (PG + CAP) to prevent axial colonization of the extraluminal urethral indwelling catheter shaft by common uropathogens. The extraluminal surface of control catheters that were not irrigated formed biofilms along the entire axial urethral tract after 24 hours. Significant (p<0.001) inhibition of colonization was seen against multidrug-resistant Pseudomonas aeruginosa (PA), carbapenem-resistant Escherichia coli (EC), and carbapenem-resistant Klebsiella pneumoniae (KB). For other common uropathogens including Candida albicans (CA), Proteus mirabilis (PR), and Enterococcus faecalis (EF), a first irrigation treatment completely inhibited colonization of half of the indwelling catheter closest to the bladder and a second treatment largely disinfected the remaining intraurethral portion of the catheter towards the meatus. The novel Foley catheter and PG + CAP antimicrobial irrigant prevented biofilm colonization in an in vitro CAUTI model and merits further testing in an in vivo CAUTI prevention model.

scholarly journals In Vitro and In Vivo Characterization of Tebipenem, an Oral Carbapenem

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Nicole Cotroneo ◽  
Aileen Rubio ◽  
Ian A. Critchley ◽  
Chris Pillar ◽  
Michael J. Pucci
Keyword(s):  
Bacterial Resistance ◽  
Unmet Need ◽  
Multidrug Resistant ◽  
Oral Agent ◽  
Gram Negative ◽  
Improved Stability ◽  
Tebipenem Pivoxil ◽  
Tract Infections

ABSTRACT The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability against β-lactamase enzymes and, therefore, a wider spectrum of activity. However, all carbapenems currently marketed for adult patients are intravenous agents, and there is an unmet need for an oral agent to treat patients that otherwise do not require hospitalization. Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr or SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. Tebipenem-PI-HBr is currently in development for the treatment of complicated urinary tract infections (cUTI). Microbiological data are presented here that demonstrate equivalency of tebipenem with intravenous carbapenems such as meropenem and support its use in infections in which the potency and spectrum of a carbapenem are desired. The results from standard in vitro microbiology assays as well as efficacy in several in vivo mouse infection models suggest that tebipenem-PI-HBr could be a valuable oral agent available to physicians for the treatment of infections, particularly those caused by antibiotic-resistant Gram-negative pathogens.

Cefiderocol: A new cephalosporin stratagem against multidrug resistant gram-negative bacteria

2021 ◽  
Author(s):  
Sharon Ong’uti ◽  
Mary Czech ◽  
Elizabeth Robilotti ◽  
Marisa Holubar
Keyword(s):  
Clinical Trials ◽  
Multidrug Resistant ◽  
Cell Entry ◽  
Phase Iii ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Phase Iii Clinical Trials ◽  
Carbapenem Resistant ◽  
Tract Infections

Abstract Cefiderocol is a novel injectable siderophore cephalosporin which hijacks the bacterial iron transport machinery to facilitate cell entry and achieve high periplasmic concentrations. It has broad in vitro activity against gram-negative bacteria, including multidrug resistant (MDR) organisms like carbapenem resistant Enterobacterales (CRE), carbapenem resistant Pseudomonas aeruginosa and Acinetobacter baumannii. It was approved by the Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and nosocomial pneumonia based on clinical trials demonstrating noninferiority to comparators. In this review, we summarize the available in vitro and clinical data, including recent evidence from 2 phase III clinical trials (APEKS-NP and CREDIBLE-CR), and discuss the place of cefiderocol in the clinician’s armamentarium against MDR gram-negative infections.

scholarly journals Multicenter Evaluation of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Inhibitory Activity against Meropenem-Nonsusceptible Pseudomonas aeruginosa from Blood, Respiratory Tract, and Wounds

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Mordechai Grupper ◽  
Christina Sutherland ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Activity ◽  
Clinical Utility ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Broth Microdilution ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT The recent escalation of occurrences of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of the carbapenem class of compounds for this prevalent health care-associated pathogen. Here, we compared the in vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem-nonsusceptible Pseudomonas aeruginosa nonduplicate clinical isolates from 34 U.S. hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood, or wound) and nonsusceptibility to other β-lactam antimicrobials was considered. An extensive genotypic search for enzymatically driven β-lactam resistance mechanisms revealed the exclusive presence of the VIM metallo-β-lactamase among only 4% of the subset of isolates nonsusceptible to ceftazidime-avibactam, ceftolozane-tazobactam, or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem-nonsusceptible Pseudomonas aeruginosa. Further in vitro and in vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multidrug-resistant Pseudomonas aeruginosa.

scholarly journals Peptidoglycan sensing prevents quiescence and promotes quorum-independent growth of uropathogenic Escherichia coli

2019 ◽  
Author(s):  
Eric C. DiBiasio ◽  
Hilary J. Ranson ◽  
James R. Johnson ◽  
David C. Rowley ◽  
Paul S. Cohen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Structural Integrity ◽  
Recurrent Infection ◽  
Multidrug Resistant ◽  
Quiescent State ◽  
E Coli ◽  
Tract Infections ◽  
Patients Experience

AbstractThe layer of peptidoglycan surrounding bacteria provides structural integrity for the bacterial cell wall. Many organisms, including human cells and diverse bacteria, detect peptidoglycan fragments that are released as bacteria grow. Uropathogenic Escherichia coli (UPEC) strains are 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 sole carbon source; at low density, the bacteria remain viable but enter a quiescent, non-proliferative state. Of all clinical UPEC isolates tested to date, 35% (51/145) enter this quiescent state, including archetypal strains CFT073 (from classic endemic lineage ST73) and JJ1886 (from recently emerged, multidrug-resistant pandemic lineage ST131). We further show that quorum-dependent UPEC quiescence is prevented and reversed by small molecules, called proliferants, that stimulate growth, such as L-lysine, L-methionine, and peptidoglycan (PG) stem peptides, including an isolated PG pentapeptide from Staphylococcus aureus. Together, our results indicate that (i) uptake of L-lysine and (ii) PG peptide sensing by UPEC modulate the quorum-regulated decision to proliferate and further demonstrate that PG fragments are important for intra- and interspecies signaling in pathogenic E. coli.

scholarly journals ANTIMICROBIAL ACTIVITY OF PINEAPPLE (ANANAS COMOSUS L. MERR) EXTRACT AGAINST MULTIDRUG-RESISTANT OF PSEUDOMONAS AERUGINOSA: AN IN VITRO STUDY

2017 ◽  
Vol 6 (5) ◽  
pp. 118 ◽  
Author(s):  
Rahmat Sayyid Zharfan ◽  
Priyo Budi Purwono ◽  
Arifa Mustika
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Minimum Bactericidal Concentration ◽  
Agar Plate ◽  
Multidrug Resistant ◽  
Ananas Comosus ◽  
Tract Infections

Pseudomonas aeruginosa is the main cause of nosocomial infection which is responsible for 10% of hospital-acquired infection. Pseudomonas aeruginosa tends to mutate and displays potential for development of antibiotic resistance. Approximately, 10% of global bacterial isolates are found as Multidrug-resistant Pseudomonas aeruginosa. Pseudomonas aeruginosa have a quite tremendous severity index, especially on pneumonia and urinary tract infections, even sepsis, which 50% mortality rate. Pineapple (Ananas comosus L. Merr) has antimicrobial properties. The active antimicrobial compounds in Ananas comosus L. Merr include saponin and bromelain. This research aims to find the potency of antimicrobial effect of pineapple (Ananas comosus L. Merr) extract towards Multidrug-resistant Pseudomonas aeruginosa. Multidrug-resistant Pseudomonas aeruginosa specimen is obtained from patient’s pus in orthopaedic department, Dr Soetomo Public Hospital, Surabaya. Multidrug-resistant Pseudomonas aeruginosa specimen is resistant to all antibiotic agents except cefoperazone-sulbactam. This research is conducted by measuring the Minimum Inhibitory Concentration (MIC) through dilution test with Mueller-Hinton broth medium. Pineapple extract (Ananas comosus L. Merr.) is dissolved in aquadest, then poured into test tube at varying concentrations (6 g/ml; 3 g/ml; 1.5 g/ml; 0.75 g/ml, 0.375 g/ml; and 0.1875 g/ml). After 24 hours’ incubation, samples are plated onto nutrient agar plate, to determine the Minimum Bactericidal Concentration (MBC). The extract of pineapple (Ananas comosus L. Merr) has antimicrobial activities against Multidrug-resistant Pseudomonas aeruginosa. Minimum Inhibitory Concentration (MIC) could not be determined, because turbidity changes were not seen. The Minimum Bactericidal Concentration (MBC) of pineapple extract (Ananas comosus L. Merr) to Multidrug-resistant Pseudomonas aeruginosa is 0.75 g/ml. Further study of in vivo is needed.

scholarly journals 1164. In vitro Antimicrobial Efficacy of Novel Antimicrobial Dacron Vascular Grafts in the Inhibition of Multidrug-Resistant Gram-Negative Biofilm

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S416-S416
Author(s):  
Nylev Vargas-Cruz ◽  
Joel Rosenblatt ◽  
Ruth A Reitzel ◽  
Kamal Khalil ◽  
Issam I Raad
Keyword(s):  
Biofilm Formation ◽  
Bacterial Colonization ◽  
Vascular Grafts ◽  
Multidrug Resistant ◽  
Antimicrobial Efficacy ◽  
Gram Negative ◽  
In Vivo Testing ◽  
Colonization Model

Abstract Background Vascular graft infections can be a devastating complication in vascular reconstructive surgery. Management of these infections is highly invasive and includes excision of the graft, debridement of infected material, and in situ reconstruction. There is a need for additional strategies for infection prevention in graft surgeries. The minocycline + rifampin + chlorhexidine (MRCH) triple combination had been previously demonstrated to be effective against biofilm formation in central venous catheters. In this study, we evaluated in vitro effectiveness and durability of MRCH coated Dacron vascular grafts in inhibiting multidrug-resistant Gram-negative biofilm formation. Methods Dacron vascular grafts were coated with MRCH based on a proprietary method. Antimicrobial efficacy at baseline and 3-week durability was assessed using a well-established in vitro biofilm colonization model. Multidrug-resistant Gram-negative pathogens tested include CRE Escherichia coli (EC), MDR Pseudomonas aeruginosa (PS) and CRE Klebsiella pneumoniae (KB). Antimicrobial durability was assessed for grafts that had been eluting in serum for 3 weeks prior to testing. Baseline and 3-week grafts were quantitatively culture to enumerate any biofilm viable biofilm colonization. Uncoated Dacron grafts were used as controls. Results At baseline and 3 weeks MRCH vascular grafts completely inhibited biofilm formation resulting in an 8-log10 reduction in bacterial colonization compared with uncoated grafts. Conclusion MRCH coated Dacron vascular grafts demonstrated in vitro effectiveness for at least 3 weeks in preventing biofilm colonization by multidrug-resistant Gram-negative pathogens. Further in vivo testing is warranted. Disclosures All authors: No reported disclosures.

scholarly journals 124. Microbiological Outcomes With Plazomicin (PLZ) Versus Meropenem (MEM) in Patients With Complicated Urinary Tract Infections (cUTI), Including Acute Pyelonephritis (AP) in the EPIC Study

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S7-S8
Author(s):  
Tiffany R Keepers ◽  
Deborah S Cebrik ◽  
Daniel J Cloutier ◽  
Allison Komirenko ◽  
Lynn Connolly ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Study Drug ◽  
Multidrug Resistant ◽  
Double Blind Study ◽  
In Vitro Activity ◽  
Double Blind ◽  
Carbapenem Resistant ◽  
Days Of Therapy ◽  
Tract Infections

Abstract Background PLZ is a next-generation aminoglycoside (AG) that is structurally protected from common AG-modifying enzymes (AMEs) in Enterobacteriaceae and with in vitro activity against multidrug-resistant Enterobacteriaceae, including ESBL-producing, AG-resistant, and carbapenem-resistant isolates. We report microbiological outcomes in the EPIC study, including outcomes for resistant pathogens and by the PLZ MIC. Methods EPIC was a multinational, randomized, double-blind study in hospitalized patients with cUTI or AP. Patients received IV PLZ (15 mg/kg q24h) or IV MEM (1 g q8h) for 4–7 days, followed by optional oral therapy, for a total of 7–10 days of therapy. The extended mMITT population included patients with ≥1 qualifying baseline pathogen (≥105 CFU/mL urine) who received study drug. Microbiological outcomes were assessed at TOC (day 15–19). Isolate identification and susceptibility testing were conducted by a central laboratory. Whole-genome sequencing was used to identify AME and β-lactamase genes. Results Of 609 patients enrolled, 407 (66.8%) were included in the extended mMITT population. The most common uropathogen was Escherichia coli (63.4%) followed by Klebsiella pneumoniae (19.7%). PLZ and MEM MIC50/90 for Enterobacteriaceae were 0.5/2 μg/mL (range: ≤0.06–&gt;128 mg/mL) and 0.015/0.06 mg/mL (range: ≤0.004–128 mg/mL), respectively. ESBL and AG-NS phenotypes were found in 29% and 27% of isolates, respectively. Genotyping detected β-lactamase and AME genes in 32.5% and 36.8% of isolates, respectively, most commonly blaCTX-M-15 (n = 98), blaOXA-1/OXA-30 (n = 82), aac(6′)Ib-cr (n = 79), and aac(3)-IIa (n = 56). Rates of microbiological eradication are shown in Table 1. All Enterobacteriaceae in the PLZ group with a PLZ MIC of 4 µg/mL (6/6) were eradicated at TOC (Table 2). Across 49 patients with concurrent bacteremia, 100% (27/27) and 96% (24/25) of Enterobacteriaceae were cleared from the blood at TOC in the PLZ and MEM groups, respectively. Conclusion PLZ demonstrated comparable or higher microbiological eradication rates compared with MEM for common Gram-negative uropathogens, including resistant pathogens. The results support PLZ as a potential treatment option for cUTI, including AP, caused by Enterobacteriaceae with PLZ MICs of ≤4 mg/mL. Disclosures T. R. Keepers, Achaogen, Inc.: Employee, Salary. D. S. Cebrik, Achaogen, Inc.: Employee, Salary. D. J. Cloutier, Achaogen, Inc.: Employee and Shareholder, Salary. A. Komirenko, Achaogen, Inc.: Employee and Shareholder, Salary. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. Krause, Achaogen, Inc.: Employee, Salary.

scholarly journals In vitro and in vivo antibacterial activity assays of carvacrol: A candidate for development of innovative treatments against KPC-producing Klebsiella pneumoniae

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246003
Author(s):  
Gleyce Hellen de Almeida de Souza ◽  
Joyce Alencar dos Santos Radai ◽  
Marcia Soares Mattos Vaz ◽  
Kesia Esther da Silva ◽  
Thiago Leite Fraga ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Klebsiella Pneumoniae ◽  
Bacterial Load ◽  
Antimicrobial Effect ◽  
Multidrug Resistant ◽  
Bacterial Cells ◽  
Carbapenem Resistant ◽  
Interesting Candidate

Dissemination of carbapenem-resistant Klebsiella pneumoniae poses a threat to the successful treatment of bacterial diseases and increases the need for new antibacterial agents development. The objective of this study was to determine the antimicrobial activity of carvacrol against multidrug-resistant K. pneumoniae. Carbapenemase production was detected by MALDI-TOF. The PCR and sequencing showed that the blaKPC-2, blaOXA-48, blaNDM-1, blaCTX-M-8 genes were present in carbapenem-resistant K. pneumoniae strains. The polymyxin-resistant K. pneumoniae strain exhibited alterations in mgrB gene. The antimicrobial activity of carvacrol was evaluated in vitro using broth microdilution and time-kill methods. For this, carbapenem-resistant K. pneumoniae and polymyxin-resistant strains, were evaluated. The in vitro results showed that carvacrol had antimicrobial activity against all isolates evaluated. The survival curves showed that carvacrol eradicated all of the bacterial cells within 4 h. The antimicrobial effect of carvacrol in vivo was determined using a mouse model of infection with Klebsiella pneumoniae carbapenemase (KPC). The treatment with carvacrol was associated with increased survival, and significantly reduced bacterial load in peritoneal lavage. In addition, groups treated with carvacrol, had a significant reduction in the total numbers of white cell and significantly increased of platelets when compared to the untreated group. In vivo and in vitro studies showed that carvacrol regimens exhibited significant antimicrobial activity against KPC-producing K. pneumoniae, making it an interesting candidate for development of alternative treatments.

Immunophenotypic Analysis of Myeloma Precursors: Antigens for Therapeutic Targeting

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-5-SCI-5
Author(s):  
Martin Perez-Andres ◽  
Bruno Paiva ◽  
Leandro Thiago ◽  
Nico A Bos ◽  
Dirk Hose ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Tumor Cells ◽  
Research Funding ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Ex Vivo ◽  
Multidrug Resistant

Abstract Abstract SCI-5 Multiple myeloma (MM) is a malignant disorder characterized by the (mono)clonal expansion of terminally-differentiated plasma cells (M-PC) in the bone marrow (BM) that produce and secrete a monoclonal immunoglobulin (Ig), detectable in the serum and/or urine. Infiltration by the expanded M-PC is easily identified in the involved tissues, through conventional morphology and immunophenotyping. However, the possibility exists that rather than M-PC, a less differentiated B-cell that represents a minor fraction of all tumor cells and retains self-renewal properties, is responsible for the outgrowth of the more differentiated M-PC compartment. In B-cell disorders, the idiotypic Ig produced by tumor cells and defined by its CDR3 sequence, acts as a genetic fingerprint for clonally-related B-cells. In MM, the specificity of the idiotype is further enhanced through modification of V genes by somatic hypermutation (SHM) at the germinal center (GC), since M-PC display extensively mutated VH genes which are stable throughout the disease. This suggests that in MM, malignant transformation could occur in a post-GC B-cell. Based on the CDR3 sequences of the Ig genes of M-PC, preliminary studies have identified tumor-associated circulating peripheral blood (PB) CD19+ B-cells, whose malignant/clonogenic potential remained to be demonstrated. More recently, the Matsui group has reported that while in MM cell lines both CD138− and CD138+ cells retain clonogenic capacity after in vitro serial plating clonogenic assays, in primary MM samples, such (ex vivo and in vivo) ability would be restricted to the CD34−/CD138− compartment. Of note, the clonogenic growth of these later cells significantly decreased after depletion by CD19, CD22, CD20 and CD45 antibodies, and it was associated with an in vitro multidrug-resistant functional phenotype (restricted to CD19+/CD27+, CD138− cells but not CD138+ cells) and the Hedgehog (Hh) stem cell-associated signaling pathway. These results point out the potential existence of a CD19+, CD20+, CD138− pre-PC compartment responsible for the expansion of M-PC in MM. In turn, evidence also exists in both the SCID-Hu model and in Rituximab treated MM patients, which suggests that plasmablasts/PC -but not pre-plasmablasts-, could act as MM “stem” cells, the precise characteristics of such cells remaining to be precisely defined. Alternatively, it could also be possible that both cell cellular components coexist and are relevant to MM progression through appropriate interaction with the BM stroma. Independently of all the above, trafficking of such cells through PB to BM niches could also play a key role in the spread of the tumor and its malignant behavior. In this regard, we recently confirmed that a relatively high percentage of MM patients (and a substantial fraction of all MGUS cases) show circulating PB PC with i) tumor-related clonal VH gene rearrangements and ii) an aberrant immunophenotypic profile which largely overlaps with that of BM M-PC from the same subjects; the only minor differences consisted of a significantly lower expression of CD38 and CD138, smaller size and internal complexity, features that indicate a slightly more immature plasmablastic/PC profile. Noteworthy, this was the only PB B-cell compartment for which clonally-related B-cells were detected with a sensitivity of <1 cell/50μ L in all cases investigated. In summary, accumulating evidence suggest the existence of a clonal hierarchy in MM but uncertainties remain as regards the precise immunophenotypic features of those cells responsible for tumor growth in primary patient samples, that could be of help in developing new targeted therapies. Disclosures: Sonneveld: Millennium: Consultancy; Celgene: Consultancy. Orfao:Becton/Dickinson Biosciences Europe: Patents & Royalties, Research Funding; Cytognos SL: Patents & Royalties; Alexion: Membership on an entity's Board of Directors or advisory committees; Vivia Biotech: Research Funding; Mundipharma: Research Funding.

scholarly journals Efficacy of Human Exposures of Gepotidacin (GSK2140944) againstEscherichia coliin a Rat Pyelonephritis Model

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Jennifer L. Hoover ◽  
Christine M. Singley ◽  
Philippa Elefante ◽  
Stephen Rittenhouse
Keyword(s):  
Time Course ◽  
Limit Of Detection ◽  
Multidrug Resistant ◽  
Mass Spectrometry Analysis ◽  
Maximal Response ◽  
Content Type ◽  
E Coli ◽  
Tract Infections

ABSTRACTGepotidacin is a first-in-class triazaacenaphthylene antibacterial that inhibits bacterial type II topoisomerases and hasin vitroactivity against a range of bacterial pathogens, includingEscherichia coli. Urinary tract infections often progress to pyelonephritis and are a worldwide problem due to the prevalence of multidrug-resistantE. colistrains. This study evaluated thein vivoefficacy of gepotidacin against four strains of multidrug-resistantE. coliin 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 log10compared 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-resistantE. coliand that further evaluation for clinical use is warranted.

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