Restoring #colistin sensitivity in colistin-resistant #Ecoli: Combinatorial use of MarR inhibitor with efflux pump inhibitor (Sci Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Sci Rep. 2019 Dec 25;9(1):19845. doi: 10.1038/s41598-019-56325-x.

Restoring colistin sensitivity in colistin-resistant E. coli: Combinatorial use of MarR inhibitor with efflux pump inhibitor.

Sundaramoorthy NS1, Suresh P2, Selva Ganesan S2, GaneshPrasad A1, Nagarajan S3.

Author information: 1 Center for Research on Infectious Diseases, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India. 2 Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India. 3 Center for Research on Infectious Diseases, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India. sai@scbt.sastra.edu.

 

Abstract

Antibiotics like colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB). Resistance to colistin severely restricts therapeutic options. To tackle this dire situation, urgent measures to restore colistin sensitivity are needed. In this study, whole-genome sequencing of colistin-resistant E. coli strain was performed and the genome analysis revealed that the strain belonged to the sequence type ST405. Multiple mutations were observed in genes implicated in colistin resistance, especially those related to the L-Ara-4-N pathway but mgrB was unmutated and mcr1-9 genes were missing. MarR inhibitor salicylate was used to re-sensitize this strain to colistin, which increased the negative charge on the cell surface especially in colistin resistant E. coli (U3790 strain) and thereby facilitated a decrease in colistin MIC by 8 fold. It is indeed well known that MarR inhibition by salicylate triggers the expression of AcrAB efflux pumps through MarA. So, in order to fully restore colistin sensitivity, a potent efflux pump inhibitor (BC1), identified earlier by this group was employed. The combination of colistin with both salicylate and BC1 caused a remarkable 6 log reduction in cell counts of U3790 in time-kill assay. Infection of muscle tissue of zebrafish with U3790 followed by various treatments showed that the combination of colistin + salicylate + BC1 was highly effective in reducing bioburden in infected muscle tissue by 4 log fold. Thus, our study shows that a combination of MarR inhibitor to enhance colistin binding and efflux pump inhibitor to reduce colistin extrusion was highly effective in restoring colistin sensitivity in colistin-resistant clinical isolate of E. coli in vitro and in vivo.

PMID: 31882661 DOI: 10.1038/s41598-019-56325-x

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Colistin; Enterobacteriaceae.

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#Ceftazidime – #avibactam to treat life-threatening #infections from #carbapenem #resistant #pathogens in critically ill mechanically ventilated patients (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Ceftazidime-avibactam to treat life-threatening infections from carbapenem resistant pathogens in critically ill mechanically ventilated patients

Vasiliki Tsolaki, Konstantinos Mantzarlis, Athanasios Mpakalis, Ergina Malli, Fotios Tsimpoukas, Athanasia Tsirogianni, Konstantinos Papagiannitsis, Paris Zygoulis, Maria-Eirini Papadonta, Efthimia Petinaki, Demosthenes Makris, Epaminondas Zakynthinos

DOI: 10.1128/AAC.02320-19

 

ABSTRACT

Data on the effectiveness of ceftazidime-avibactam (CAZ-AVI) in critically ill, mechanically ventilated patients are limited. The present retrospective observational cohort study, which was conducted in two general Intensive Care Units (ICUs) in central Greece, compared critically-ill, mechanically ventilated patients suffering from carbapenem-resistant enterobacteriaceae (CRE) infections receiving CAZ-AVI to patients who received appropriate available antibiotic therapy. Clinical, microbiological outcomes and safety issues were evaluated. A secondary analysis in patients with blood stream infections (BSI) was conducted. Forty-one patients that received CAZ-AVI (CAZ-AVI group) were compared to thirty-six patients receiving antibiotics other than CAZ-AVI (control group). There was significant improvement in the SOFA score on Day 4 and 10 in the CAZ-AVI compared to the control group (p=0.006, and p=0.003 respectively). Microbiological eradication was accomplished in 33/35 (94.3%) in CAZ-AVI group vs 21/31 (67.7%) patients in control group (p=0.021) and clinical cure was observed in 33/41 (80.5%) vs 19/36 (52.8%) patients (p=0.010), respectively. The results were similar in BSI subgroups for both outcomes (p=0.038 and p=0.014, respectively). 28-day survival was 85.4% in the CAZ-AVI and 61.1% in the control group (log Rank=0.035), while there were 2 and 12 relapses in each group (p=0.042). A CAZ-AVI containing regime was independent predictor of survival and clinical cure (OR 5.575, p=0.012 and OR 5.125, p=0.004, respectively) along with illness severity. In conclusion, no significant side effects were reported. A CAZ-AVI containing regime is more effective than other available antibiotic agents for the treatment of CRE infections in the high-risk, mechanically-ventilated, ICU population.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Ceftazidime; Avibactam; Intensive care.

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High heterogeneity of #MDR #Enterobacteriaceae #fecal levels in hospitalized patients is partially driven by intravenous #betalactams (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

High heterogeneity of multidrug-resistant Enterobacteriaceae fecal levels in hospitalized patients is partially driven by intravenous beta-lactams.

Ana Djukovic, Eva M. González-Barberá, Jaime Sanz, Alejandro Artacho, Iván Peñaranda, Beatriz Herrera, María Jose Garzón, Miguel Salavert, Jose Luis López-Hontangas, Karina B. Xavier, Bernhard Kuster, Laurent Debrauwer, Jean-Marc Rolain, Miguel Sanz, Joao Xavier, Carles Ubeda

DOI: 10.1128/AAC.01415-19

 

ABSTRACT

Multidrug-resistant Enterobacteriaceae (MRE) colonize the intestine asymptomatically from where they can breach into the bloodstream and cause life-threatening infections, especially in heavily colonized patients. Despite the clinical relevance of MRE colonization levels, we know little about how they vary in hospitalized patients and the clinical factors that determine those levels. Here we conducted one of the largest studies of MRE fecal levels by tracking longitudinally 133 acute leukemia patients and monitoring their MRE levels over time through extensive culturing. MRE were defined as Enterobactericeae species that acquired non-susceptibility to ≥1 agent in ≥3 antimicrobial categories. In addition, due to the selective media used, the MRE had to be resistant to third-generation cephalosporins. MRE were detected in 60% of the patients, but their fecal levels varied considerably among patients and within the same patient (>6 and 4 orders of magnitude, respectively). Multivariate analysis of clinical metadata revealed an impact of intravenous beta-lactams (i.e. meropenem and piperacillin-tazobactam), which significantly diminished the fecal MRE levels in hospitalized patients. Consistent with a direct action of beta-lactams, we found an effect only when the patient was colonized with strains sensitive to the administered beta-lactam (p<0.001) but not with non-susceptible strains. We report previously unobserved inter and intra-individual heterogeneity in MRE fecal levels, suggesting that quantitative surveillance is more informative than qualitative surveillance of hospitalized patients. In addition, our study highlights the relevance of incorporating antibiotic treatment and susceptibility data of gut colonizing pathogens for future clinical studies and in clinical decision-making.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Beta-lactams; Cephalosporins; Enterobacteriaceae.

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Do #vegetarians less frequently carry #ESBL/pAmpC-producing #Escherichia coli/Klebsiella pneumoniae compared with non-vegetarians? (J Antimicrob Chemother., abstract)

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

Do vegetarians less frequently carry ESBL/pAmpC-producing Escherichia coli/Klebsiella pneumoniae compared with non-vegetarians?

Anouk P Meijs, Esther F Gijsbers, Paul D Hengeveld, Christiaan Veenman, Annika M van Roon, Angela H A M van Hoek, Sabine C de Greeff, Engeline van Duijkeren, Cindy M Dierikx

Journal of Antimicrobial Chemotherapy, dkz483, https://doi.org/10.1093/jac/dkz483

Published: 25 November 2019

 

Abstract

Background

ESBL and plasmid-mediated AmpC (pAmpC)-producing Enterobacteriaceae are frequently found on meat products in Dutch retail, especially on poultry.

Objectives

We investigated whether vegetarians are at lower risk of carrying ESBL/pAmpC-producing Escherichia coli/Klebsiella pneumoniae (ESBL-E/K) compared with persons who consume meat.

Methods

Vegetarians, pescatarians (vegetarians who eat fish) and non-vegetarians (persons who eat meat at least three times per week) were asked to send in a faecal sample and a questionnaire. ESBL-E/K were cultured and MLSTs were determined. ESBL/pAmpC genes were analysed using PCR and sequencing. The risk of ESBL-E/K carriage in the three study groups was analysed using multivariable logistic regression.

Results

Prevalence of ESBL-E/K carriage was 8.0% in vegetarians (63/785; 95% CI 6.3–10.1), 6.9% in pescatarians (27/392; 95% CI 4.8–9.8) and 3.8% in non-vegetarians (14/365; 95% CI 2.3–6.3). Multivariable analysis showed an OR for ESBL-E/K carriage of 2.2 for vegetarians (95% CI 1.2–4.0) and 1.6 for pescatarians (95% CI 0.8–3.2) compared with non-vegetarians. The predominant MLST was E. coli ST131 and the most common ESBL genes were blaCTX-M-15, blaCTX-M-27, blaCTX-M-14 and blaCTX-M-1 in all diet groups. Independent risk factors for ESBL-E/K carriage were travel to Africa/Latin America/Asia (OR 4.6; 95% CI 2.8–7.7) in the past 6 months and rarely/never washing hands before food preparation (OR 2.5; 95% CI 1.2–5.0).

Conclusions

Vegetarians and pescatarians did not have a lower risk of ESBL-E/K carriage compared with non-vegetarians, indicating that eating meat is not an important risk factor for ESBL-E/K carriage.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; E. Coli; Klebsiella pneumoniae; Food Safety.

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#Clinical characteristics, #risk factors, and #outcomes of #patients hospitalized in the #US #military health system with #carbapenem-resistant #Enterobacteriaceae infection (Am J Infect Control, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Infect Control. 2019 Nov 20. pii: S0196-6553(19)30897-1. doi: 10.1016/j.ajic.2019.10.006. [Epub ahead of print]

Clinical characteristics, risk factors, and outcomes of patients hospitalized in the US military health system with carbapenem-resistant Enterobacteriaceae infection.

Adams DJ1, Susi A2, Nylund CM2.

Author information: 1 Department of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA; Department of Pediatrics, Uniformed Services University, Bethesda, MD. Electronic address: s9dadams@gmail.com. 2 Department of Pediatrics, Uniformed Services University, Bethesda, MD.

 

Abstract

BACKGROUND:

We aimed to characterize the epidemiology, identify risk factors, and measure outcomes of carbapenem-resistant Enterobacteriaceae (CRE) infections among hospitalized patients.

METHODS:

We performed a retrospective study of hospitalized patients with CRE infection using records from the US military health system database. Cases included patients admitted for ≥2 days from 2008-2015, with a clinical culture growing any Enterobacteriaceae reported as resistant to a carbapenem. Multivariable logistic regression was used to identify comorbid conditions and procedures associated with CRE infection, and a high-dimensional propensity score was used for a case-mix adjusted evaluation of CRE-associated in-hospital mortality, length of stay, and hospitalization costs.

RESULTS:

From 1,162,686 hospitalized patients, we identified 143 with CRE infection over the 7-year study period. Conditions associated with CRE infection included manipulation of the gastrointestinal tract, musculoskeletal trauma, orthopedic procedures, septicemia, and both recent and remote exposure to broad-spectrum β-lactam antibiotics. Patients hospitalized with CRE infection had significantly higher hospitalization costs (attributable difference, $206,664; P < .001), longer hospital stays (attributable difference, 28.8 days; P < .001), and increased odds of in-hospital mortality (adjusted odds ratio, 3.34; 95% confidence interval, 1.82-6.12).

CONCLUSIONS:

CRE are a significant threat to hospitalized patients. Our study quantifies the health care burden associated with CRE infection in the inpatient setting and highlights the importance of initiatives aimed at curbing the spread of these costly infections.

Published by Elsevier Inc.

KEYWORDS: Drug resistance; Hospital costs; Hospital mortality

PMID: 31757476 DOI: 10.1016/j.ajic.2019.10.006

Keywords: Antibiotics; Drugs; Resistance; Carbapenem; Enterobacteriaceae; USA.

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In vitro activity of #ceftazidime / #avibactam against isolates of #carbapenem-non-susceptible #Enterobacteriaceae collected during the INFORM global surveillance programme (2015–17) (J Antimicrob Chemother., abstract)

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

In vitro activity of ceftazidime/avibactam against isolates of carbapenem-non-susceptible Enterobacteriaceae collected during the INFORM global surveillance programme (2015–17)

Iris Spiliopoulou, Krystyna Kazmierczak, Gregory G Stone

Journal of Antimicrobial Chemotherapy, dkz456, https://doi.org/10.1093/jac/dkz456

Published: 19 November 2019

 

Abstract

Objectives

To report data for ceftazidime/avibactam and comparators against meropenem-non-susceptible Enterobacteriaceae collected globally (excluding centres in the USA) from 2015 to 2017 as part of the International Network For Optimal Resistance Monitoring (INFORM) surveillance programme.

Methods

MICs and susceptibility were determined using EUCAST broth microdilution methodology and EUCAST breakpoints. Isolates were screened to detect genes encoding β-lactamases using multiplex PCR assays. MBL-positive isolates were those in which one or more of the IMP, VIM and/or NDM genes were detected.

Results

A total of 1460 meropenem-non-susceptible isolates were collected and, of the agents on the panel, susceptibility was highest to ceftazidime/avibactam, colistin and tigecycline [73.0%, 77.0% (1081/1403) and 78.1%, respectively]. Ceftazidime/avibactam was not active against MBL-positive isolates (n = 367); these isolates showed the highest rates of susceptibility to colistin (92.1%, 303/329), tigecycline (71.9%) and amikacin (46.6%). A total of 394 isolates were resistant to ceftazidime/avibactam and, of the 369 isolates that were screened, 98.4% were found to carry a gene encoding an MBL enzyme. Among isolates that were identified as carbapenemase positive and MBL negative (n = 910), susceptibility was highest to ceftazidime/avibactam (99.8%). Susceptibility was also highest to ceftazidime/avibactam among isolates that were carbapenemase negative and MBL negative (94/98, 95.9%).

Conclusions

These data highlight the need for continued surveillance of antimicrobial activity as well as the need for new antimicrobials to treat infections caused by meropenem-non-susceptible Enterobacteriaceae, for which the options are extremely limited.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Avibactam; Ceftazidime.

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#Prevalence and outcome of #bloodstream #infections due to third-generation #cephalosporin-resistant #Enterobacteriaceae in sub-Saharan #Africa: a systematic review (J Antimicrob Chemother., abstract)

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

Prevalence and outcome of bloodstream infections due to third-generation cephalosporin-resistant Enterobacteriaceae in sub-Saharan Africa: a systematic review

Rebecca Lester, Patrick Musicha, Nadja van Ginneken, Angela Dramowski, Davidson H Hamer, Paul Garner, Nicholas A Feasey

Journal of Antimicrobial Chemotherapy, dkz464, https://doi.org/10.1093/jac/dkz464

Published: 19 November 2019

 

Abstract

Background

The prevalence of bacterial bloodstream infections (BSIs) in sub-Saharan Africa (sSA) is high and antimicrobial resistance is likely to increase mortality from these infections. Third-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae are of particular concern, given the widespread reliance on ceftriaxone for management of sepsis in Africa.

Objectives

Reviewing studies from sSA, we aimed to describe the prevalence of 3GC resistance in Escherichia coli, Klebsiella and Salmonella BSIs and the in-hospital mortality from 3GC-R BSIs.

Methods

We systematically reviewed studies reporting 3GC susceptibility testing of E. coli, Klebsiella and Salmonella BSI. We searched PubMed and Scopus from January 1990 to September 2019 for primary data reporting 3GC susceptibility testing of Enterobacteriaceae associated with BSI in sSA and studies reporting mortality from 3GC-R BSI. 3GC-R was defined as phenotypic resistance to ceftriaxone, cefotaxime or ceftazidime. Outcomes were reported as median prevalence of 3GC resistance for each pathogen.

Results

We identified 40 articles, including 7 reporting mortality. Median prevalence of 3GC resistance in E. coli was 18.4% (IQR 10.5 to 35.2) from 20 studies and in Klebsiella spp. was 54.4% (IQR 24.3 to 81.2) from 28 studies. Amongst non-typhoidal salmonellae, 3GC resistance was 1.9% (IQR 0 to 6.1) from 12 studies. A pooled mortality estimate was prohibited by heterogeneity.

Conclusions

Levels of 3GC resistance amongst bloodstream Enterobacteriaceae in sSA are high, yet the mortality burden is unknown. The lack of clinical outcome data from drug-resistant infections in Africa represents a major knowledge gap and future work must link laboratory surveillance to clinical data.

Keywords: Antibiotics; Drugs Resistance; Cephalosporins; Enterobacteriaceae; Bacteremia; Africa region.

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Comparison of the inoculum size effects of #antibiotics on IMP-6 β-lactamase-producing #Enterobacteriaceae co-harboring #plasmid-mediated #quinolone #resistance genes (PLOS One, abstract)

[Source: PLOS One, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Comparison of the inoculum size effects of antibiotics on IMP-6 β-lactamase-producing Enterobacteriaceae co-harboring plasmid-mediated quinolone resistance genes

Yoshihiko Ogawa, Ryuichi Nakano , Kei Kasahara, Tomoki Mizuno, Nobuyasu Hirai, Akiyo Nakano, Yuki Suzuki, Naoki Kakuta, Takashi Masui, Hisakazu Yano, Keiichi Mikasa

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Published: November 13, 2019 / DOI: https://doi.org/10.1371/journal.pone.0225210

 

Abstract

Almost all cases of carbapenemase-producing Enterobacteriaceae infections in Japan are caused by blaIMP-positive Enterobacteriaceae (especially blaIMP-6) and infections caused by other types of carbapenemase-producing Enterobacteriaceae are quite rare. We examined drug resistance genes co-harboring with blaIMP-6 and their inoculum size effects. We screened β-lactamase genes, plasmid-mediated quinolone resistance (PMQR) genes, and aminoglycoside-modifying enzyme genes by PCR and performed sequencing for 14 blaIMP-6-positive Enterobacteriaceae. Further, all PMQR-positive isolates were submitted to conjugation and inoculum effect evaluation. Our data showed that 13 of the 14 isolates harbored CTX-M-2 and one co-harbored CTX-M-2 and CTX-M-1 as extended-spectrum β-lactamases. All isolates carried one or more PMQRs; aac(6’)-Ib-cr was the most prevalent (92.8%), and was followed by oqxA (64.3%), qnrS (50%), oqxAB (21.4%), and qnrB (14.3%). However, Klebsiella pneumoniae contains chromosomal OqxAB. Inoculum size effects were significant in all strains for meropenem, 13 strains for imipenem, 7 for levofloxacin, and 3 for amikacin. We observed that 11 of the experimental strains (100%), 8 strains (72.7%), and 1 strain showed inoculum size effects for meropenem, imipenem, and amikacin, respectively. However, four strains harbored qnr genes and two strains harbored qnr genes and QRDR mutations concurrently; no inoculum size effect was seen for levofloxacin. The blaIMP-6-positive Enterobacteriaceae that we studied was found to harbor at least one plasmid-mediated drug resistance gene. The inoculum size effect for carbapenems was thought to be mainly due to IMP-6-type metallo-β-lactamase; however qnrB and qnrS also had a minimal impact on the inoculum size effect for levofloxacin.

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Citation: Ogawa Y, Nakano R, Kasahara K, Mizuno T, Hirai N, Nakano A, et al. (2019) Comparison of the inoculum size effects of antibiotics on IMP-6 β-lactamase-producing Enterobacteriaceae co-harboring plasmid-mediated quinolone resistance genes. PLoS ONE 14(11): e0225210. https://doi.org/10.1371/journal.pone.0225210

Editor: Shampa Anupurba, Institute of Medical Sciences, Banaras Hindu University, INDIA

Received: July 22, 2019; Accepted: October 29, 2019; Published: November 13, 2019

Copyright: © 2019 Ogawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript.

Funding: This study was supported by JSPS KAKENHI (grant number: 17K10027 and 16K09940).

Competing interests: The authors have declared that no competing interests exist.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Beta-lactams; Quinolones; Enterobacteriaceae.

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#Carbapenem-containing #combination #antibiotic therapy against carbapenem-resistant uropathogenic #Enterobacteriaceae (Antimicrob Agents Chemother., abstract)

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

Carbapenem-containing combination antibiotic therapy against carbapenem-resistant uropathogenic Enterobacteriaceae

Maria Loose, Isabell Link, Kurt G. Naber, Florian M.E. Wagenlehner

DOI: 10.1128/AAC.01839-19

 

ABSTRACT

Objectives:

The increasing global prevalence of carbapenem-resistant Enterobacteriaceae (CRE) combined with the decline in effective therapies is a public healthcare crisis. After respiratory tract infections, urinary tract infections and associated urosepsis are the second most affected by CRE pathogens.

Methods:

By using checkerboard analysis, we tested eight different antibiotics in combination with carbapenems in CAMHB and artificial urine against seven CRE and three susceptible strains. To further determine whether these combinations are also effective in a dynamic model, we have performed growth curves analyses in a dynamic bladder model with three uropathogenic CRE strains. In this model we simulated the urinary pharmacokinetic after application of 1000 mg i.v. ertapenem alone or in combination with 500 mg i.v. levofloxacin, 1000 mg oral rifampicin or 3000 mg oral fosfomycin. Bacterial growth was measured for 48 h, simulating voiding of the bladder every 3 h.

Results:

According to the median fractional inhibitory concentration indices (∑FICI) values we found additive to synergistic results across all tested CRE strains for combinations of carbapenems with colistin sulphate, levofloxacin, fosfomycin, rifampicin and tigecycline in CAMHB and artificial urine. In the dynamic bladder model, all three CRE strains tested showed regrowth after treatment with ertapenem up to 48 hours. Regrowth could be prevented by combination with levofloxacin, fosfomycin or rifampicin.

Conclusion:

Carbapenem-containing combination therapy with fosfomycin or rifampicin could be an option for better treatment of UTIs caused by CRE strains. This should be further investigated in clinical studies.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; UTI.

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WCK 5222 (#Cefepime / #Zidebactam) Pharmacodynamic Target Analysis against Metallo-β-lactamase producing #Enterobacteriaceae in the #Neutropenic Mouse #Pneumonia Model (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

WCK 5222 (Cefepime/Zidebactam) Pharmacodynamic Target Analysis against Metallo-β-lactamase producing Enterobacteriaceae in the Neutropenic Mouse Pneumonia Model

Alexander J. Lepak, Miao Zhao, David R. Andes

DOI: 10.1128/AAC.01648-19

 

ABSTRACT

WCK 5222 is a combination of cefepime and the novel β-lactam enhancer (BLE) zidebactam. Zidebactam has a dual mechanism of action involving high-affinity penicillin binding protein (PBP) 2 binding as well as inhibition of Ambler class A, and C, enzymes. In the current study, we evaluated the effect of zidebactam on the cefepime pharmacodynamic target time above MIC (T>MIC) exposure required for efficacy against a diverse group of carbapenem-resistant Enterobacteriaceae (CRE) secondary to MBL-production. Plasma and ELF pharmacokinetic (PK) studies were performed for both cefepime (6.25, 25, and 100 mg/kg) and zidebactam (3.125, 12.5, and 50 mg/kg) after subcutaneous administration to mice. Only total drug was considered as protein binding is <10%. Both drugs exhibited similar PK exposures including terminal elimination half-life (cefepime ∼0.4 h, zidebactam 0.3-0.5 h). The penetration into ELF was concentration dependent for both drugs, reaching 50% and 70% for cefepime and zidebactam, respectively. Dose ranging studies were performed in lung-infected mice with one of eight MBL-producing clinical strains. WCK 5222 was administered in Q4- and Q8-hourly regimens to vary exposures from 0-100% T>MIC. The results were modelled to evaluate the relationship between cefepime T>MIC, when zidebactam was co-administered, and therapeutic effect. The results revealed a strong association between T>MIC and effect (R2 0.82). Net stasis in organism burden occurred at cefepime T>MIC exposures of only 18%. A 1-log kill endpoint was demonstrated for the group of organisms at approximately 31% T>MIC. These target exposures for stasis and 1-log kill are much lower than previously observed cephalosporin monotherapy PK/PD targets.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Cefepine; Zidebactam.

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