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Microbiological characterisation of Enterobacterales baseline qualifying urinary pathogens obtained from 31st Online 9-12 July 2021 adult patients participating in the ALLIUM Phase 3 study comparing cefepime/enmetazobactam to piperacillin/tazobactam for the treatment of complicated urinary tract infections/acute pyelonephritis A BELLEY1, M. HACKEL 2 and P. VELICITAT1 1Allecra Therapeutics SAS, St. Louis, France; 2IHMA, Schaumberg, IL, USA INTRODUCTION RESULTS CONCLUSIONS • 1. E. coli and K. pneumoniae are the predominant 2A. Of the Enterobacterales baseline pathogens in the primary efficacy population (mMITT), 21.0% encoded an ESBL. Treatment options for infections caused by extended spectrum β-lactamase (ESBL)- • producing Gram-negative pathogens are limited and typically involve the use of Enterobacterales baseline pathogens in ALLIUM Table 2A. β-lactamase genotypes of the Enterobacterales baseline pathogens obtained in the mMITT population Urinary Enterobacterales baseline pathogens in ALLIUM were carbapenems, a class of antibacterial agents considered of ‘last-resort’ [1]. Table 1. Enterobacterales baseline pathogens obtained in the mMITT % (n) of species with β-lactamase genotype typical of those causing cUTI /AP, with a majority being E. coli and % (n) of isolates within species and mMITT+R populations Organism ESBL (±OSBL)1 producing β-lactamases (n=160) AmpC OSBL K. pneumoniae. Only +AmpC • Increased carbapenem usage has led to increased prevalence of carbapenem-resistance mMITT (n=663) mMITT+R (n=704) Enterobacterales species All Enterobacterales (n=663) 24.1 (160) 20.7 (137) 0.8 (5) 1.2 (8) 1.5 (10) • ESBL were the predominant β-lactamases encoded by more than determinants such as Klebsiella pneumoniae carbapenemases (KPC), metallo-β- n (%) n (%) E. coli (n=518) 23.4 (121) 20.5 (106) 0.6 (3) 0.8 (4) 1.6 (8) 20% of the Enterobacterales baseline pathogens, emphasising the lactamases and OXA-type carbapenemases [2,3]. Escherichia coli 518 (78.1) 526 (74.7) K. pneumoniae (n=66) 36.4 (24) 30.3 (20) 0.0 (0) 3.0 (2) 3.0 (2) Klebsiella pneumoniae 66 (10.0) 92 (13.1) P. mirabilis (n=38) 21.1 (8) 15.8 (6) 2.6 (1) 2.6 (1) 0.0 (0) critical need for novel carbapenem-sparing therapies. • There is a critical need for novel carbapenem-sparing therapies exhibiting potent activity Proteus mirabilis 38 (5.7) 40 (5.7) E. cloacae (n=10) 50.0 (5) 40.0 (4) 0.0 (0) 10.0 (1) 0.0 (0) C. braakii (n=1) 100 (1) 100 (1) 0.0 (0) 0.0 (0) 0.0 (0) • Unlike piperacillin/tazobactam, cefepime/enmetazobactam in vitro against ESBL-producing pathogens. Enterobacter cloacae 10 (1.5) 14 (2.0) C. freundii (n=2) 50 (1) 0.0 (0) 50 (1) 0.0 (0) 0.0 (0) antibacterial activity was unaffected by the presence of ESBL Serratia marcescens 7 (1.1) 7 (1.0) 1OSBL refers to original spectrum β-lactamases such as non-ESBL variants of SHV or TEM. th thereby supporting its development as a novel carbapenem- • The 4 generation cephalosporin cefepime combined with the novel extended spectrum Klebsiella oxytoca 6 (0.9) 6 (0.9) sparing therapy. β-lactamase (ESBL) inhibitor enmetazobactam is intended as a carbapenem-sparing Citrobacter koseri 3 (0.5) 3 (0.4) 2B. In the mMITT+R population, 22.9% of the Enterobacterales baseline pathogens encoded an ESBL whereas 1.8% option to treat serious infections caused by ESBL-producing pathogens [4,5]. Citrobacter freundii 2 (0.5) 2 (0.3) encoded a β-lactamases conferring resistance to carbapenems (MBL, OXA-48 or KPC). Table 2B. β-lactamase genotypes of the Enterobacterales baseline pathogens obtained in the mMITT+R population Enterobacter bugandensis 2 (0.5) 2 (0.3) • Superior treatment outcomes with cefepime/enmetazobactam (FPE) compared to % (n) of isolates within % (n) of species with β-lactamase genotype Klebsiella variicola 2 (0.5) 2 (0.3) Organism species producing ESBL (±OSBL)1 piperacillin/tazobactam (PTZ) was demonstrated in the ALLIUM Phase 3 study of adult AmpC KPC OSBL patients with cUTI/AP [6]. Morganella morganii 2 (0.5) 2 (0.3) β-lactamases (n=195) Only +AmpC +AmpC+MBL2 +MBL +OXA REFERENCES Providencia rettgeri 2 (0.5) 2 (0.3) All Enterobacterales (n=704) 27.7 (195) 22.2 (156) 0.7 (5) 0.7 (5) 0.4 (3) 0.6 (4) 1.3 (9) 0.1 (1) 1.7 (12) [1] Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: Past, present, and future. Antimicrob Citrobacter amalonaticus 1 (0.2) 1 (0.1) E. coli (n=526) 23.6 (124) 20.5 (108) 0.6 (3) 0.0 (0) 0.0 (0) 0.0 (0) 1.0 (5) 0.0 (0) 1.5 (8) Agents Chemother 2011;55:4943–60. https://doi.org/10.1128/AAC.00296-11. • In this study, the in vitro susceptibility profile and β-lactamase genotypes of K. pneumoniae (n=92) 54.3 (50) 34.8 (32) 0.0 (0) 4.3 (4) 3.3 (3) 4.3 (4) 2.2 (2) 1.1 (1) 4.3 (4) [2] Castanheira M, Deshpande LM, Mendes RE, Canton R, Sader HS, Jones RN. Variations in the occurrence of Citrobacter braakii 1 (0.2) 1 (0.1) Enterobacterales baseline qualifying urinary pathogens obtained from ALLIUM patients P. mirabilis (n=40) 22.5 (9) 14.6 (6) 2.4 (1) 2.4 (1) 0.0 (0) 0.0 (0) 2.4 (1) 0.0 (0) 0.0 (0) resistance phenotypes and carbapenemase genes among Enterobacteriaceae isolates in 20 Years of the SENTRY were investigated. Enterobacter, non-speciated 1 (0.2) 1 (0.1) Antimicrobial Surveillance Program. Open Forum Infect Dis 2019;6:S23–33. https://doi.org/10.1093/ofid/ofy347. E. cloacae (n=14) 64.3 (9) 57.1 (8) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 7.1 (1) 0.0 (0) 0.0 (0) [3] Guo W, Sun F, Liu F, Cao L, Yang J, Chen Y, et al. Antimicrobial resistance surveillance and prediction of Gram- Enterobacter xianfangensis 0 (0.0) 1 (0.1) E. xiangfangensis (n=1) 100 (1) 100 (1) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) negative bacteria based on antimicrobial consumption in a hospital setting: A 15-year retrospective study. Med C. braakii (n=1) 100 (1) 100 (1) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) (United States) 2019;98:37(e17157). https://doi.org/10.1097/MD.0000000000017157. Proteus vulgaris 1 (0.2) 1(0.1) C. freundii (n=2) 50.0 (1) 0.0 (0) 50.0 (1) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) [4] Papp-Wallace KM, Bethel CR, Caillon J, Barnes MD, Potel G, Bajaksouzian S, et al. Beyond piperacillin- tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. Antimicrob Agents Serratia liquefaciens 1 (0.2) 1 (0.1) 1 2 OSBL refers to original spectrum β-lactamases such as non-ESBL variants of SHV or TEM. MBL refers to metallo-β-lactamases. Chemother 2019:DOI: 10.1128/AAC.00105-19. https://doi.org/10.1128/AAC.00105-19. [5] Morrissey I, Magnet S, Hawser S, Shapiro S, Knechtle P. In vitro activity of cefepime-enmetazobactam against METHODS 3. Cefepime/enmetazobactam exhibited comparable in vitro antibacterial activity to meropenem and was more potent than piperacillin/tazobactam against the Enterobacterales Gram-negative isolates collected from United States and European hospitals during 2014-2015. Antimicrob Agents Chemother 2019:DOI: 10.1128/AAC.00514-19. • A total of 1034 cUTI/AP patients randomized 1:1 in a double-blind, multicenter trial received either 2 g baseline pathogens. cefepime/0.5 g enmetazobactam or 4 g piperacillin/0.5 g tazobactam q8h by 2h infusion for 7-14 days. [6] Kaye K, Belley A, Barth P, Kashyap S, Lahlou O, Motta P, Knechtle P, Velicitat P. Cefepime-enmetazobactam demonstrates superiority to piperacillin-tazobactam in a subgroup of patients with complicated urinary tract • Ninety sites in Europe (Belarus, Bulgaria, Croatia, Estonia, Georgia, Hungary, Latvia, Lithuania, Poland, Table 3A. Summary of MIC and susceptibility results of the Enterobacterales baseline pathogens and selected Table 3B. Summary of MIC and susceptibility results of the Enterobacterales baseline pathogens and infections/acute pyelonephritis caused by Extended Spectrum β-Lactamase-producing Enterobacterales. Abstract Russia, Serbia, Slovakia, Spain, and Ukraine), North and Central America (United States and Mexico), South organism groups in the mMITT population selected organism groups in the mMITT+R population LB-4. IDWeek 2020 Virtual Conference. October 21-25, 2020. America (Argentina and Peru) and South Africa enrolled patients. The study was designed according to MIC (µg/ml) CLSI EUCAST MIC (µg/ml) CLSI EUCAST [7] Clinical Laboratory Standards Institute (CLSI), 2018. Methods for Dilution Antimicrobial Susceptibility Tests for Organism group/antibacterial agent Organism group/antibacterial agent Bacteria That Grow Aerobically; Approved Standards – Eleventh Edition. CLSI document M07-A11 (ISBN 1-56238- current regulatory guidelines and was conducted in accordance with the Declaration of Helsinki, all MIC MIC Range %S %I %R %S %R MIC MIC Range %S %I %R %S %R applicable country laws and regulations, and in compliance with Good Clinical Practice Guidelines. 50 90 50 90 836-3). CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA. All Enterobacterales (n=663) All Enterobacterales (n=704) [8] Belley A, Huband MD, Fedler KA, Watters AA, Flamm RK, Shapiro S, et al. Development of broth microdilution • Urine samples were collected using local standard practices and target baseline pathogens (BP) were sent Cefepime1 0.06 64 ≤0.008->64 79.5 4.7 15.8 77.7 18.4 Cefepime1 0.06 >64 ≤0.008->64 75.9 4.7 19.5 74.0 21.9 MIC and disk diffusion antimicrobial susceptibility test quality control ranges for the combination of cefepime and to the central laboratory (IHMA, Schaumburg, IL) for confirmation of identification, antimicrobial Meropenem ≤0.015 0.03 ≤0.015-0.5 100.0 0.0 0.0 100.0 0.0 Meropenem ≤0.015 0.06 ≤0.015->32 97.9 0.6 1.6 98.4 1.3 the novel -lactamase inhibitor enmetazobactam.
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    POSSIBLE DETECTION OF PATHOGENIC BACTERIAL SPECIES INHABITING STREAMS IN GREAT SMOKY MOUNTAINS NATIONAL PARK A thesis presented to the faculty of the Graduate School of Western Carolina University in partial fulfillment of the requirement for the degree of Master of Science in Biology. By Kwame Agyapong Brown Director: Dr. Sean O’Connell Associate Professor of Biology and Biology Department Head Committee members: Dr. Sabine Rundle and Dr. Timothy Driscoll November 2016 ACKNOWLEDGEMENTS I would like to express my deepest gratitude to my adviser Dr. Sean O’Connell for his insightful mentoring and thoughtful contribution throughout this research. I would also like to acknowledge my laboratory teammates: Lisa Dye, Rob McKinnon, Kacie Fraser, and Tori Carlson for their diverse contributions to this project. This project would not have been possible without the generous support of the Western Carolina University Biology Department and stockroom; so I would like to thank the entire WCU biology faculty and Wesley W. Bintz for supporting me throughout my Masters program. Finally, I would like to thank my thesis committee members and reader: Dr. Sabine Rundle, Dr. Timothy Driscoll and Dr. Anjana Sharma for their contributions to this project. ii TABLE OF CONTENTS List of Tables ................................................................................................................................. iv List of Figures ..................................................................................................................................v
  • Water and Soil As Reservoirs for Mdr Genes

    Water and Soil As Reservoirs for Mdr Genes

    WATER AND SOIL AS RESERVOIRS FOR MDR GENES LUÍSA VIEIRA PEIXE UNIVERSITY OF PORTO . PORTUGAL ESCMID eLibrary 1 © by author Bacteria in the earth - appeared 3,5x109 years ago One gram of soil: up to 1010 bacterial cells & Species diversity of 4x103 to 5x104 species Antibiotics production: tens (daptomycin, vancomycin) to hundreds (erythromycin, streptomycin) of millions of years ago 2 Raynaud ESCMID & Nunan, Pone. 2014 eLibrary © by author Extensive Natural Collection of AMR Genes Antibiotic resistance is ancient: Soil, fresh and marine water phyla contain • TetM and VanA in DNA 30,000-year- old; a huge diversity of ARG genes. • Metallo-b-lactamases emerged one >> More diverse than the clinical ARG pool billion years ago. New MBL in soil Psychrobacter psychrophilus MR29-12 StrepR TetR Permafrost Siberian 15 000-35 000 anos AMR gene is the one that confers protection to a particular antibiotic (increase in MIC) when expressed. Resistome – all resistance genes of a community Network of predicted bacterial phyla for each AMR used in cross- soil comparisons (n=880) (Forsberg et al., Nature. 2014) Without human interference, selection for resistance already occurs naturally in microbial populations in soil, water and other habitats 3 Gudeta et al., FrontiersESCMID Microb. 2016; D’Costa et al, Nature. 2011; Forsberg et al, Nature.2014; Martinez J.L. Science.2010;eLibrary FEMS Microbiol Lett 296.2009; Riesenfeld et al, Envir. Microbiol. 2004 © by author What are AMR genes doing in these Bacteria? Protection against antibiotics ABR genes Physiological functions silencing E.g. detoxification; virulence, signal trafficking, intra- domain communication. 2’ N-acetyltransferase of Providencia stuartii - acetylation of peptidoglycan and gentamycin Antibiotic-producing microorganisms catQ ...Streptomyces...synthesize over half of all known antibiotics..
  • Outbreak of Carbapenem-Resistant Providencia Rettgeri in a Tertiary Hospital

    Outbreak of Carbapenem-Resistant Providencia Rettgeri in a Tertiary Hospital

    This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0. IN PRACTICE CLINICAL UPDATE Outbreak of carbapenem-resistant Providencia rettgeri in a tertiary hospital V S Tshisevhe,1,2 MB ChB, MBA, Dip HIV Man (SA), DTM&H; M R Lekalakala,3 BSc; MB ChB, DTM&H, MMed, PDIC; N Tshuma,4 BSc, MBA; S Janse van Rensburg,1 B Med Tech; N Mbelle,1,2 BSc, MSc, MB BCh, MMed, DTM&H, MAP, FCPath (SA) 1 Department of Medical Microbiology, Tshwane Academic Division, National Health Laboratory Service, Pretoria, South Africa 2 Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa 3 Department of Medical Microbiology, Polokwane National Health Laboratory Service, and Department of Medical Microbiology, Faculty of Health Sciences, University of Limpopo, Polokwane, South Africa 4 Community AIDS Response, Johannesburg, South Africa Corresponding author: V S Tshisevhe ([email protected]) The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria is a significant public health threat, as there are limited effective antimicrobial agents for infections caused by multidrug-resistant (MDR) bacteria. Several MDR bacteria are now frequently detected. Carbapenem resistance in Enterobacteriaceae is often plasmid mediated, necessitating stringent infection control practices. We describe an outbreak of carbapenem-resistant Providencia rettgeri involving 4 patients admitted to intensive care and high-care units at a tertiary hospital. Clinical and demographic characteristics of 4 patients with carbapenem-resistant P. rettgeri were documented. All P. rettgeri isolated in these cases had a carbapenem-resistant antibiogram, with resistance to imipenem, ertapenem and meropenem. These cases could be epidemiologically linked.