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

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.

Download Full-text

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 ◽

Urinary Tract Infections ◽

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.

Download Full-text

Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03774-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 289-298 ◽

Cited By ~ 49

Author(s):

Karen O'Dwyer ◽

Aaron T. Spivak ◽

Karen Ingraham ◽

Sharon Min ◽

David J. Holmes ◽

...

Keyword(s):

Escherichia Coli ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Bacterial Resistance ◽

Multidrug Resistant ◽

Trna Synthetase ◽

Content Type ◽

Development Of Resistance ◽

Tract Infections ◽

Abdominal Infections

ABSTRACTGSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with ≥32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing ofEscherichia coliisolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistantEscherichia coliisolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.)

Download Full-text

Fecal Microbiota Transfer for Multidrug-Resistant Gram-Negatives: A Clinical Success Combined With Microbiological Failure

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx047 ◽

2017 ◽

Vol 4 (2) ◽

Cited By ~ 21

Author(s):

Janneke E. Stalenhoef ◽

Elisabeth M. Terveer ◽

Cornelis W. Knetsch ◽

Peter J. van‘t Hof ◽

Imro N. Vlasveld ◽

...

Keyword(s):

Escherichia Coli ◽

Pseudomonas Aeruginosa ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Clinical Success ◽

Multidrug Resistant ◽

Fecal Microbiota ◽

Intestinal Colonization ◽

Tract Infections ◽

Microbiota Diversity

Abstract Combined fecal microbiota transfer and antibiotic treatment prevented recurrences of urinary tract infections with multidrug-resistant (MDR) Pseudomonas aeruginosa, but it failed to eradicate intestinal colonization with MDR Escherichia coli. Based on microbiota analysis, failure was not associated with distinct diminished microbiota diversity.

Download Full-text

Compared with Cotrimoxazole Nitroxoline Seems to Be a Better Option for the Treatment and Prophylaxis of Urinary Tract Infections Caused by Multidrug-Resistant Uropathogens: An In Vitro Study

Antibiotics ◽

10.3390/antibiotics10060645 ◽

2021 ◽

Vol 10 (6) ◽

pp. 645

Author(s):

Ulrich Dobrindt ◽

Haleluya T. Wami ◽

Torsten Schmidt-Wieland ◽

Daniela Bertsch ◽

Klaus Oberdorfer ◽

...

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Multidrug Resistant ◽

Indwelling Catheters ◽

Structural Characterisation ◽

Phenotypic Resistance ◽

E Coli ◽

Multiresistant Bacteria ◽

Tract Infections

The resistance of uropathogens to various antibiotics is increasing, but nitroxoline remains active in vitro against some relevant multidrug resistant uropathogenic bacteria. E. coli strains, which are among the most common uropathogens, are unanimously susceptible. Thus, nitroxoline is an option for the therapy of urinary tract infections caused by multiresistant bacteria. Since nitroxoline is active against bacteria in biofilms, it will also be effective in patients with indwelling catheters or foreign bodies in the urinary tract. Cotrimoxazole, on the other hand, which, in principle, can also act on bacteria in biofilms, is frequently inactive against multiresistant uropathogens. Based on phenotypic resistance data from a large number of urine isolates, structural characterisation of an MDR plasmid of a recent ST131 uropathogenic E. coli isolate, and publicly available genomic data of resistant enterobacteria, we show that nitroxoline could be used instead of cotrimoxazole for intervention against MDR uropathogens. Particularly in uropathogenic E. coli, but also in other enterobacterial uropathogens, the frequent parallel resistance to different antibiotics due to the accumulation of multiple antibiotic resistance determinants on mobile genetic elements argues for greater consideration of nitroxoline in the treatment of uncomplicated urinary tract infections.

Download Full-text

Seeds extract of three Artocarpus species: Their in-vitro antibacterial activities against multidrug-resistant (MDR) Escherichia coli isolates from urinary tract infections (UTIs)

Biodiversitas Journal of Biological Diversity ◽

10.13057/biodiv/d221028 ◽

2021 ◽

Vol 22 (10) ◽

Author(s):

Muhammad Evy Prastiyanto

Keyword(s):

Antibacterial Activity ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Antibacterial Agents ◽

Antibacterial Activities ◽

Multidrug Resistant ◽

E Coli ◽

Tract Infections ◽

Seed Extracts

Abstract. Prastiyanto ME. 2021. Seeds extract of three Artocarpus species: Their in-vitro antibacterial activities against multidrug-resistant (MDR) Escherichia coli isolates from urinary tract infections (UTIs). Biodiversitas 22: 4362-4368. Multidrug-resistant (MDR)-E. coli is a major cause and has become a very serious problem in urinary tract infections (UTIs). As a result, it requires an antibacterial agent derived from biological materials. It has been reported that the seeds of three species of Artocarpus (A. heterophyllous, A. champeden, and A. camansi) have antibacterial properties against Methicillin-Resistant Staphylococcus aureus (MRSA). However, there are three other Artocarpus species in Indonesia, i.e., keledang (A. lanceipolius), tarra (A. elasticus), and terap (A. Odoratissimus) whose antibacterial property has not been investigated. To minimize the research gap, this study aims to determine the antibacterial activity of seed extracts of A. lanceipolius, A. elasticus, and A. odoratissimus against MDR-E. coli isolates of UTIs. Antibacterial activity was evaluated using the agar well diffusion assay. The microdilution method was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. The results revealed that the seed extracts of A. lanceipolius, A. elasticus, and A. odoratissimus have the potential as antibacterial agents against MDR-E. coli isolate of UTIs. A. elasticus seed extract shows the widest zone of inhibition in the range of 7.0-13.3 mm and the smallest MIC and MBC values ??of 6.25-12.5 mg/mL and 12.5-25 mg/mL, respectively. In conclusion, A. lanceipolius, A. elasticus, and A. odoratissimus seed extracts have the potential to be developed as antibacterial agents against UTI-causing MDR-E. coli. Further in vivo research and determining the mode of action of antibacterial activity are needed.

Download Full-text

Multidrug resistance and risk factors associated with community-acquired urinary tract infections caused by Escherichia coli in Venezuela

Biomédica ◽

10.7705/biomedica.v39i2.4030 ◽

2019 ◽

Vol 39 ◽

pp. 96-107 ◽

Cited By ~ 1

Author(s):

Militza Guzmán ◽

Elsa Salazar ◽

Vicmaris Cordero ◽

Ana Castro ◽

Andreína Villanueva ◽

...

Keyword(s):

Risk Factors ◽

Escherichia Coli ◽

Urinary Tract ◽

Urinary Tract Infections ◽

High Frequency ◽

Multidrug Resistant ◽

E Coli ◽

Regional Health Authorities ◽

Tract Infections

Introduction: The treatment of urinary tract infections has become more challenging due to the increasing frequency of multidrug-resistant Escherichia coli in human populations.Objective: To characterize multidrug-resistant E. coli isolates causing community-acquired urinary tract infections in Cumaná, Venezuela, and associate possible risk factors for infection by extended-spectrum beta-lactamases (ESBL)-producing isolates.Materials and methods: We included all the patients with urinary tract infections attending the urology outpatient consultation and emergency unit in the Hospital de Cumaná, Estado Sucre, Venezuela, from January through June, 2014. blaTEM, blaSHV and blaCTX-M genes detection was carried out by PCR.Results: We found a high prevalence of multidrug-resistant E. coli (25.2%) with 20.4% of the isolates producing ESBL. The ESBL-producing isolates showed a high frequency (66.7%) of simultaneous resistance to trimethoprim-sulphamethoxazole, fluoroquinolones and aminoglycosides compared to non-producing isolates (2.4%). Of the resistant isolates, 65.4% carried the blaTEM gene, 34.6% the blaCTX-M and 23.1% the blaSHV. The blaCTX-M genes detected belonged to the CTX-M-1 and CTX-M-2 groups. Plasmid transfer was demonstrated by in vitro conjugation in 17 of the 26 ESBL-producing isolates. All three genes detected were transferred to the transconjugants. Age over 60 years, complicated urinary tract infections and previous use of a catheter predisposed patients to infection by ESBL-producing E. coli.Conclusions: The high frequency of multidrug-resistant ESBL-producing isolates should alert the regional health authorities to take measures to reduce the risk of outbreaks caused by these types of bacteria in the community.

Download Full-text

Experience with fosfomycin in the treatment of complicated urinary tract infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae

Therapeutic Advances in Infectious Disease ◽

10.1177/2049936119858883 ◽

2019 ◽

Vol 6 ◽

pp. 204993611985888 ◽

Cited By ~ 3

Author(s):

Luka Bielen ◽

Robert Likic

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Oral Treatment ◽

Beta Lactamase ◽

In Vitro Susceptibility ◽

Extended Spectrum Beta Lactamase ◽

Extended Spectrum ◽

Tract Infections ◽

Microbiological Cure

Background: The aim of this study was to evaluate the efficacy of fosfomycin in the treatment of complicated urinary tract infections (cUTIs) caused by extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. Methods: We retrospectively evaluated 42 ambulatory patients with cUTIs caused by ESBL-producing Enterobacteriaceae at the Outpatient Internal Medicine Clinic of the University Clinical Hospital Centre Zagreb in the period from June 2012 to June 2014. ESBL production was confirmed by double disk synergy test according to Jarlier. In vitro susceptibility to fosfomycin of ESBL-producing Escherichia coli, Klebsiella pneumoniae and Citrobacter freundii isolates was tested according to the European Committee on Antimicrobial Susceptibility Testing methodology. Results: In 42 patients with cUTIs, 43 urinary pathogens susceptible to fosfomycin were isolated in the urine cultures, including 34 E. coli ESBL, seven K. pneumoniae ESBL and two C. freundii ESBL isolates. On average, patients had 2.2 complicating factors (CFs) and received 3.6 fosfomycin doses per treatment course. The overall microbiological cure was 50%, clinical cure was 71% and ESBL eradication rate was 74%. Patients with between zero and one CFs received significantly fewer fosfomycin doses than patients with two or more CFs ( p = 0.022). Three kidney transplant patients achieved microbiological cure following prolonged fosfomycin administration. No statistically significant correlation was found between the presence of individual CFs and treatment outcome. Conclusions: Fosfomycin may be a valid option for oral treatment of cUTIs caused by ESBL-producing pathogens. The optimal duration of fosfomycin treatment for cUTIs remains to be determined.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01304-21 ◽

2021 ◽

Author(s):

James A. Karlowsky ◽

Meredith A. Hackel ◽

Daniel F. Sahm

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Oral Treatment ◽

Multidrug Resistant ◽

Culture Collection ◽

Active Inhibitor ◽

Oral Agents ◽

Tract Infections

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.

Download Full-text

Is Cefoxitin a Carbapenem Sparing Agent in the Management of Urinary Tract Infections Caused by ESBL Producing Enterobacterales?

Hospital Pharmacy ◽

10.1177/00185787211066460 ◽

2021 ◽

pp. 001857872110664

Author(s):

Wasim S. El Nekidy ◽

Manal M. Abdelsalam ◽

Ahmad R. Nusair ◽

Rania El Lababidi ◽

Ruba Z. Dajani ◽

...

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Group Versus ◽

Outcome Data ◽

Cure Rate ◽

Comorbidity Index ◽

Clinically Significant ◽

Tract Infections ◽

Microbiological Cure

Background: Cefoxitin has shown in vitro activity against Extended-Spectrum β-Lactamase (ESBL) producing Enterobacterales. Outcome data regarding cefoxitin as a carbapenem sparing agent in the management of urinary tract infections (UTI) are scarce. We sought to evaluate the clinical and microbiologic efficacy of cefoxitin as compared to ertapenem. Methods: A retrospective observational study was conducted at our quaternary care institution between May 2015 and March 2019. We identified all patients who received cefoxitin for the treatment of UTI during the study period and used Charlson Comorbidity Index to select a matching cohort from patients who received ertapenem. Primary end points were clinical and microbiological cure. Results: Thirty patients who received cefoxitin were matched with 55 patients who received ertapenem. Clinical cure was marginally in favor of ertapenem: 83.2% in cefoxitin group versus 96.8% in ertapenem group ( P = .042). However, 90-day recurrence was in favor of cefoxitin: 13.5% in cefoxitin group versus 34.8% in ertapenem group ( P = .045). Microbiologic cure was not significant between the 2 groups with 88.6% success in cefoxitin versus 100% in ertapenem. Additionally, the group difference on 30-day recurrence or relapse rates and the 90-day mortality rate were not clinically significant. Conclusion: Cefoxitin achieved similar microbiologic cure rate when compared to ertapenem for the treatment of UTI caused by ESBL-producing Enterobacterales. No significant differences were found in 30-day recurrence/relapse or mortality rates. Larger randomized controlled trials are required to identify the clinical sittings in which cefoxitin could be used as a carbapenem-sparing agent in the treatment of UTI.

Download Full-text

Characterization and Comparison of Enterococcus spp. Isolates from Feces of Healthy Dogs and Urine of Dogs with UTIs

Animals ◽

10.3390/ani11102845 ◽

2021 ◽

Vol 11 (10) ◽

pp. 2845

Author(s):

Dagmara Stępień-Pyśniak ◽

Fabrizio Bertelloni ◽

Marta Dec ◽

Giulia Cagnoli ◽

Dorota Pietras-Ożga ◽

...

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Virulence Genes ◽

Multidrug Resistant ◽

Opportunistic Pathogens ◽

Enterococcus Spp ◽

Resistant Strains ◽

Healthy Dogs ◽

Vancomycin Resistant ◽

Tract Infections

Enterococcus spp. are opportunistic pathogens of both humans and animals characterized by high resistance to antimicrobials. Dogs could be intestinal carriers or suffer from Enterococcus infections, mainly urinary tract infections (UTIs). This study aimed to analyze and compare Enterococcus spp. isolated from healthy dog stools and sick dog urine. Overall, 51 isolates (29 from stools and 22 from UTI) were characterized at species level and tested for antimicrobial resistance, biofilm production and presence of resistance and virulence genes. E. faecium and E. faecalis resulted as equally distributed in stools samples, while E. faecalis predominated among UTI isolates. HLAR phenotype was detected in 47.1% isolates; 64.7% isolates were resistant to ampicillin (47.1% with a MIC ≥ 64 µg/mL). High levels of resistance were recorded for fluoroquinolones (enrofloxacin 74.5%, ciprofloxacin 66.7%), clindamycin (84.3%), tetracycline (78.4%) and quinupristin–dalfopristin (78.4%). No vancomycin resistant strains were detected. All but one isolate were multidrug-resistant. Most detected resistance genes were tetM (70.5%), pbp4 (52.9%) and aph(3′)-IIIa (39.2%). All isolates were able to produce biofilm, but isolates from UTIs and belonging to E. faecalis more frequently resulted in strong biofilm producers. Most detected virulence genes were asa1 (52.9%), gelE (41.2%), cylA (37.3%) and esp (35.3%); all of them resulted as more frequently associated to E. faecalis. No particular differences emerged between isolates from feces and UTI, considering all evaluated aspects. Our results confirm pet dogs as carriers of multidrug-resistant enterococci; stool microflora could be considered as the most probable source of enterococcal UTI and E. faecalis carried by dogs seems to be more virulent than E. faecium, justifying its more frequent involvement in urinary tract infections.

Download Full-text