#Ceftazidime – #Avibactam in Combination With #Fosfomycin: A Novel #Therapeutic Strategy Against #MDR #Pseudomonas aeruginosa (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa

Krisztina M Papp-Wallace, Elise T Zeiser, Scott A Becka, Steven Park, Brigid M Wilson, Marisa L Winkler, Roshan D’Souza, Indresh Singh, Granger Sutton, Derrick E Fouts, Liang Chen, Barry N Kreiswirth, Evelyn J Ellis-Grosse, George L Drusano, David S Perlin, Robert A Bonomo

The Journal of Infectious Diseases, jiz149, https://doi.org/10.1093/infdis/jiz149

Published: 17 May 2019

 

Abstract

Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to β-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a “mechanism-based approach” to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-β-lactamases.

Pseudomonas aeruginosa, β-lactams, fosfomycin, combination therapy

Topic:  pseudomonas aeruginosa – ceftazidime – fosfomycin – lactams – infection – mice – avibactam – avibactam/ceftazidime

Issue Section: Major Article

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Avibactam; Ceftazidime; Fosfomycin.

——

Advertisements

Effect of 5-Day #Nitrofurantoin vs Single-Dose #Fosfomycin on Clinical Resolution of Uncomplicated Lower #UTI in Women – A RCT (JAMA, abstract)

[Source: Journal of the American Medical Association, full page: (LINK). Abstract, edited.]

Original Investigation / April 22, 2018

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women – A Randomized Clinical Trial

Angela Huttner, MD1,2; Anna Kowalczyk, MS3; Adi Turjeman, MSc4; et al Tanya Babich, MSc4; Caroline Brossier, RN1; Noa Eliakim-Raz, MD4,5; Katarzyna Kosiek, MD, PhD6; Begoña Martinez de Tejada, MD, PhD7; Xavier Roux, MD8; Shachaf Shiber, MD9; Ursula Theuretzbacher, PhD10; Elodie von Dach, PhD2,11; Dafna Yahav, MD4,12; Leonard Leibovici, MD4,5; Maciek Godycki-Ćwirko, MD, PhD3,6; Johan W. Mouton, MD, PhD13; Stephan Harbarth, MD1,2

Author Affiliations: 1 Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; 2 Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; 3 Centre for Family and Community Medicine, Medical University of Lodz, Lodz, Poland; 4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 5 Department of Internal Medicine E, Rabin Medical Center, Beilinson Campus, Peta-Tiqva, Israel; 6 Faculty of Health Sciences, Division of Public Health, Medical University of Lodz, Lodz, Poland; 7 Obstetrics Division, Department of Obstetrics and Gynecology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; 8 Department of Internal Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; 9 Department of Emergency Medicine, Rabin Medical Center, Beilinson Campus, Peta-Tiqva, Israel; 10 Center for Anti-Infective Agents, Vienna, Austria; 11 Clinical Trials Unit, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; 12 Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tiqva, Israel; 13 Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands

JAMA. Published online April 22, 2018. doi:10.1001/jama.2018.3627

 

Key Points

  • Question  – What is the effect of 5-day nitrofurantoin, compared with single-dose fosfomycin, on clinical resolution of uncomplicated lower urinary tract infection (UTI) in women?
  • Findings  – In this randomized clinical trial that included 513 women with uncomplicated UTI, clinical resolution at 28 days occurred in 70% of patients in the nitrofurantoin group vs 58% of patients in the fosfomycin group, a statistically significant difference.
  • Meaning  – Five-day nitrofurantoin may be a better alternative to single-dose fosfomycin for treating uncomplicated UTI in women.

 

Abstract

Importance 

The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI).

Objective 

To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis.

Design, Setting, and Participants 

Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel.

Interventions 

Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection.

Main Outcomes and Measures 

The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events.

Results 

Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively).

Conclusions and Relevance 

Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion.

Trial Registration  ClinicalTrials.gov Identifier: NCT01966653

Keywords: UTI; Nitrofurantoin; Fosfomycin; Antibiotics.

——-

#Fosfomycin efficacy and emergence of resistance among #Enterobacteriaceae in an in vitro dynamic #bladder #infection model (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model

Iain J Abbott, Joseph Meletiadis, Imane Belghanch, Rixt A Wijma, Lamprini Kanioura, Jason A Roberts, Anton Y Peleg, Johan W Mouton

Journal of Antimicrobial Chemotherapy, dkx441, https://doi.org/10.1093/jac/dkx441

Published: 14 December 2017

 

Abstract

Background

Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen.

Methods

A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25–64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h.

Results

Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (Tmax 3.8 ± 0.5 h; Cmax 2630.1 ± 245.7 mg/L; AUC0-24 33 932.5 ± 1964.2 mg·h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC50 4 to 64 mg/L, MIC90 64 to > 1024 mg/L, P = 0.0039; resistant subpopulation MIC50 128 to > 1024 mg/L, MIC90 >1024 mg/L, P = 0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI50 of fAUC0-24/MIC = 1922, fCmax/MIC = 149 and fTime>4×MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed.

Conclusions

Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Fosfomycin; E. Coli; E. Cloacae; Enterobacteriaceae; Klebsiella Pneumoniae.

——-

Co-location of the #multiresistance #gene cfr and the #fosfomycin resistance gene fosD on a novel #plasmid in #Staphylococcus arlettae from #chicken farm (AAC, abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Co-location of the multiresistance gene cfr and the fosfomycin resistance gene fosD on a novel plasmid in Staphylococcus arlettae from chicken farm

Bi-Hui Liu a,b,c,  Chang-Wei Lei a,b,c,  An-Yun Zhang a,b,c, Yun Pan a,b,c, Ling-Han Kong a,b,c,  Rong Xiang a,b,c, Yong-Xiang Wang a,b,c, Yan-Xian Yang a,b,c and Hong-Ning Wang a,b,c#

Author Affiliations: a College of Life Science, Sichuan University, Chengdu, People’s Republic of China; b Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, Chengdu, People’s Republic of China; c Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, Chengdu, People’s Republic of China

 

ABSTRACT

A novel 63,558-bp plasmid pSA-01 harbouring nine antibiotic resistance genes, including cfr, erm(C), tet(L), erm(T), aadD, fosD, fexB, aacA-aphD and erm(B), was characterized in Staphylococcus arlettae strain SA-01 isolated from chicken farm in China. The co-location of cfr and fosD genes was detected for the first time in S. arlettae plasmid. The detection of two IS431-mediated circular forms containing resistance genes in SA-01 suggested that IS431 may facilitate dissemination of antibiotic resistance genes.

 

FOOTNOTES

#Corresponding author. Mailing address: College of Life science, Sichuan University, NO. 29 Wangjiang Road, Chengdu, Sichuan, China, 610064., Phone: +86-28-8547-1599. Fax: +86-28-8547-1599., E-mail: whongning@163.com

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Fosfomycin; Poultry; China; Staphylococcus Arlettae.

——

Emergence of #Plasmid-Mediated #Fosfomycin #Resistance Genes among #Escherichia coli Isolates, #France (@CDC_EIDjournal, abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 23, Number 9—September 2017 / Dispatch

Emergence of Plasmid-Mediated Fosfomycin-Resistance Genes among Escherichia coli Isolates, France

Yahia Benzerara, Salah Gallah, Baptiste Hommeril, Nathalie Genel, Dominique Decré, Martin Rottman, and Guillaume Arlet

Author affiliations: Assistance Publique des Hôpitaux de Paris Hôpitaux Universitaires Est Parisiens Paris, France (Y. Benzerara, S. Gallah, B. Hommeril, D. Decré, G. Arlet); Université Pierre et Marie Curie, Sorbonne Université, Paris (N. Genel, D. Decré, G. Arlet); Assistance Publique des Hôpitaux de Paris Hôpitaux Universitaires Paris Ile de France Ouest, Hôpital Raymond Poincaré, Garches, France (M. Rottman); Université de Versailles Saint-Quentin-en-Yvelines, St-Quentin en Yvelines, France (M. Rottman)

 

Abstract

FosA, a glutathione S-transferase that inactivates fosfomycin, has been reported as the cause of enzymatic resistance to fosfomycin. We show that multiple lineages of FosA-producing extended spectrum β-lactamase Escherichia coli have circulated in France since 2012, potentially reducing the efficacy of fosfomycin in treating infections with antimicrobial drug resistant gram-negative bacilli.

Keywords: Antibiotics; Drugs Resistance; Fosfomycin; E. Coli; France.

——