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Galia Rahav - One of the best experts on this subject based on the ideXlab platform.
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outcome of carbapenem resistant klebsiella pneumoniae bloodstream infections
Clinical Microbiology and Infection, 2012Co-Authors: Debby Bendavid, R Kordevani, Nathan Keller, Alex Marzel, Ohad Galmor, Yasmin Maor, Galia RahavAbstract:Abstract The aim of this study was to evaluate the impact of carbapenem-resistant K. pneumoniae bloodstream infections on mortality. During the study period 42, 68 and 120 patients were identified with carbapenem-resistant, extended-spectrum b -lactamase producers (ESBL) and susceptible K. pneumoniae bloodstream infections, respectively. Patients with carbapenem-resistant K. pneumoniae had higher rates of prior antimicrobial exposure, other nosocomial infections, and use of invasive devices. Infection-related mortality was 48% for carbapenem-resistant, 22% for ESBL producers and 17% for susceptible K. pneumoniae . Independent risk factors for infection-related mortality were Pitt bacteraemia score, Charlson score and carbapenem resistance.
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potential role of active surveillance in the control of a hospital wide outbreak of carbapenem resistant klebsiella pneumoniae infection
Infection Control and Hospital Epidemiology, 2010Co-Authors: Debby Bendavid, Nathan Keller, Yasmin Maor, Gili Regevyochay, R Dalit N Shachar, Amir Zlotkin, Gill Smollan, Galia RahavAbstract:Background. The recent emergence of carbapenem resistance among Enterobacteriaceae is a major threat for hospitalized patients, and effective strategies are needed. Objective. To assess the effect of an intensified intervention, which included active surveillance, on the incidence of infection with carbapenem-resistant Klebsiella pneumoniae . Setting. Sheba Medical Center, a 1,600-bed tertiary care teaching hospital in Tel Hashomer, Israel. Design. Quasi-experimental study. Methods. The medical records of all the patients who acquired a carbapenem-resistant K. pneumoniae infection during 2006 were reviewed. An intensified intervention was initiated in May 2007. In addition to contact precautions, active surveillance was initiated in high-risk units. The incidence of clinical carbapenem-resistant K. pneumoniae infection over time was measured, and interrupted time-series analysis was performed. Results. The incidence of clinical carbapenem-resistant K. pneumoniae infection increased 6.42-fold from the first quarter of 2006 up to the initiation of the intervention. In 2006, of the 120 patients whose clinical microbiologic culture results were positive for carbapenem-resistant K. pneumoniae , 67 (56%) developed a nosocomial infection. During the intervention period, the rate of carbapenem-resistant K. pneumoniae rectal colonization was 9%. Of the 390 patients with carbapenem-resistant K. pneumoniae colonization or infection, 204 (52%) were identified by screening cultures. There were a total of 12,391 days of contact precautions, and of these, 4,713 (38%) were added as a result of active surveillance. After initiation of infection control measures, we observed a significant decrease in the incidence of carbapenem-resistant K. pneumoniae infection. Conclusions. The use of active surveillance and contact precautions, as part of a multifactorial intervention, may be an effective strategy to decrease rates of nosocomial transmission of carbapenem-resistant K. pneumoniae colonization or infection.
Debby Bendavid - One of the best experts on this subject based on the ideXlab platform.
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outcome of carbapenem resistant klebsiella pneumoniae bloodstream infections
Clinical Microbiology and Infection, 2012Co-Authors: Debby Bendavid, R Kordevani, Nathan Keller, Alex Marzel, Ohad Galmor, Yasmin Maor, Galia RahavAbstract:Abstract The aim of this study was to evaluate the impact of carbapenem-resistant K. pneumoniae bloodstream infections on mortality. During the study period 42, 68 and 120 patients were identified with carbapenem-resistant, extended-spectrum b -lactamase producers (ESBL) and susceptible K. pneumoniae bloodstream infections, respectively. Patients with carbapenem-resistant K. pneumoniae had higher rates of prior antimicrobial exposure, other nosocomial infections, and use of invasive devices. Infection-related mortality was 48% for carbapenem-resistant, 22% for ESBL producers and 17% for susceptible K. pneumoniae . Independent risk factors for infection-related mortality were Pitt bacteraemia score, Charlson score and carbapenem resistance.
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potential role of active surveillance in the control of a hospital wide outbreak of carbapenem resistant klebsiella pneumoniae infection
Infection Control and Hospital Epidemiology, 2010Co-Authors: Debby Bendavid, Nathan Keller, Yasmin Maor, Gili Regevyochay, R Dalit N Shachar, Amir Zlotkin, Gill Smollan, Galia RahavAbstract:Background. The recent emergence of carbapenem resistance among Enterobacteriaceae is a major threat for hospitalized patients, and effective strategies are needed. Objective. To assess the effect of an intensified intervention, which included active surveillance, on the incidence of infection with carbapenem-resistant Klebsiella pneumoniae . Setting. Sheba Medical Center, a 1,600-bed tertiary care teaching hospital in Tel Hashomer, Israel. Design. Quasi-experimental study. Methods. The medical records of all the patients who acquired a carbapenem-resistant K. pneumoniae infection during 2006 were reviewed. An intensified intervention was initiated in May 2007. In addition to contact precautions, active surveillance was initiated in high-risk units. The incidence of clinical carbapenem-resistant K. pneumoniae infection over time was measured, and interrupted time-series analysis was performed. Results. The incidence of clinical carbapenem-resistant K. pneumoniae infection increased 6.42-fold from the first quarter of 2006 up to the initiation of the intervention. In 2006, of the 120 patients whose clinical microbiologic culture results were positive for carbapenem-resistant K. pneumoniae , 67 (56%) developed a nosocomial infection. During the intervention period, the rate of carbapenem-resistant K. pneumoniae rectal colonization was 9%. Of the 390 patients with carbapenem-resistant K. pneumoniae colonization or infection, 204 (52%) were identified by screening cultures. There were a total of 12,391 days of contact precautions, and of these, 4,713 (38%) were added as a result of active surveillance. After initiation of infection control measures, we observed a significant decrease in the incidence of carbapenem-resistant K. pneumoniae infection. Conclusions. The use of active surveillance and contact precautions, as part of a multifactorial intervention, may be an effective strategy to decrease rates of nosocomial transmission of carbapenem-resistant K. pneumoniae colonization or infection.
Craig A Townsend - One of the best experts on this subject based on the ideXlab platform.
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Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Daniel R. Marous, Evan P. Lloyd, Andrew R. Buller, Kristos A. Moshos, Tyler L. Grove, Anthony J. Blaszczyk, Squire J. Booker, Craig A TownsendAbstract:Despite their broad anti-infective utility, the biosynthesis of the paradigm carbapenem antibiotic, thienamycin, remains largely unknown. Apart from the first two steps shared with a simple carbapenem, the pathway sharply diverges to the more structurally complex members of this class of β-lactam antibiotics, such as thienamycin. Existing evidence points to three putative cobalamin-dependent radical S-adenosylmethionine (RS) enzymes, ThnK, ThnL, and ThnP, as potentially being responsible for assembly of the ethyl side chain at C6, bridgehead epimerization at C5, installation of the C2-thioether side chain, and C2/3 desaturation. The C2 substituent has been demonstrated to be derived by stepwise truncation of CoA, but the timing of these events with respect to C2–S bond formation is not known. We show that ThnK of the three apparent cobalamin-dependent RS enzymes performs sequential methylations to build out the C6-ethyl side chain in a stereocontrolled manner. This enzymatic reaction was found to produce expected RS methylase coproducts S-adenosylhomocysteine and 5′-deoxyadenosine, and to require cobalamin. For double methylation to occur, the Carbapenam substrate must bear a CoA-derived C2-thioether side chain, implying the activity of a previous sulfur insertion by an as-yet unidentified enzyme. These insights allow refinement of the central steps in complex carbapenem biosynthesis.
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Non-heme iron oxygenases generate natural structural diversity in carbapenem antibiotics.
Journal of the American Chemical Society, 2010Co-Authors: Micah J. Bodner, Rongfeng Li, Ryan M. Phelan, Michael F. Freeman, Craig A TownsendAbstract:Carbapenems are a clinically important antibiotic family. More than 50 naturally occurring Carbapenam/ems are known and are distinguished primarily by their C-2/C-6 side chains where many are only differentiated by the oxidation states of these substituents. With a limited palette of variations the carbapenem family comprises a natural combinatorial library, and C-2/C-6 oxidation is associated with increased efficacy. We demonstrate that ThnG and ThnQ encoded by the thienamycin gene cluster in Streptomyces cattleya oxidize the C-2 and C-6 moieties of carbapenems, respectively. ThnQ stereospecifically hydroxylates PS-5 (5) giving N-acetyl thienamycin (2). ThnG catalyzes sequential desaturation and sulfoxidation of PS-5 (5), giving PS-7 (7) and its sulfoxide (9). The enzymes are relatively substrate selective but are proposed to give rise to the oxidative diversity of carbapenems produced by S. cattleya, and orthologues likely function similarly in allied streptomyces. Elucidating the roles of ThnG and ThnQ...
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rate limiting steps and role of active site lys443 in the mechanism of Carbapenam synthetase
Biochemistry, 2007Co-Authors: Samantha O Arnett, Barbara Gerratana, Craig A TownsendAbstract:Carbapenam synthetase (hereafter named CPS) catalyzes the formation of the β-lactam ring in the biosynthetic pathway to (5R)-carbapen-2-em-3-carboxylate, the simplest of the carbapenem antibiotics. Kinetic studies showed remarkable tolerance to substrate stereochemistry in the turnover rate but did not distinguish between chemistry and a nonchemical step such as product release or conformational change as being rate-determining. Also, X-ray structural studies and modest sequence homology to β-lactam synthetase, an enzyme that catalyzes the formation of a monocyclic β-lactam ring in a similar ATP/Mg2+-dependent reaction, implicate K443 as an essential residue for substrate binding and intermediate stabilization. In these experiments, we use pH−rate profiles, deuterium solvent isotope effects, and solvent viscosity measurements to examine the rate-limiting step in this complex overall process of substrate adenylation and intramolecular ring formation. Mutagenesis and chemical rescue demonstrate that K443 is...
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carboxymethylproline synthase from pectobacterium carotorova a multifaceted member of the crotonase superfamily
Biochemistry, 2004Co-Authors: Barbara Gerratana, And Anthony Stapon, Samantha O Arnett, Craig A TownsendAbstract:: The simplest carbapenem antibiotic, (5R)-carbapen-2-em-3-carboxylic acid, is biosynthesized from primary metabolites in Pectobacterium carotorova by the action of three enzymes, carboxymethylproline synthase (hereafter named CarB), Carbapenam synthetase, and carbapenem synthase. CarB, a member of the crotonase superfamily, catalyzes the formation of (2S,5S)-5-carboxymethylproline from malonyl-CoA and l-pyrroline-5-carboxylate. In this study we show that, in addition, CarB catalyzes the independent decarboxylation of malonyl-CoA and methylmalonyl-CoA and the hydrolysis of CoA esters such as acetyl-CoA and propionyl-CoA. The steady-state rate constants for these reactions are reported. We have identified the intermediates in the CarB reactions with l-pyrroline-5-carboxylate and malonyl-CoA or methylmalonyl-CoA as the CoA esters of (2S,5S)-5-carboxymethylproline and (2S,5S)-6-methyl-5-carboxymethylproline, respectively. The data provided indicate that these intermediates partition between completing turnover and dissociating from the enzyme. On the basis of the steady-state rate constants measured for the CarB-catalyzed hydrolysis of synthetic (2S,5S)-5-carboxymethylprolyl-CoA and for the CarB reaction with malonyl-CoA and l-pyrroline-5-carboxylate, we have calculated the rate constants for each step of these reactions. The results identify CarB as a particularly interesting member of the crotonase superfamily that combines in one net reaction three activities of this superfamily, decarboxylation, C-C bond formation, and CoA ester hydrolysis.
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synthesis of 3s 5r Carbapenam 3 carboxylic acid and its role in carbapenem biosynthesis and the stereoinversion problem
Journal of the American Chemical Society, 2003Co-Authors: Anthony Stapon, Rongfeng Li, Craig A TownsendAbstract:(5R)-Carbapenem-3-carboxylic acid is the simplest structurally among the naturally occurring carbapenem β-lactam antibiotics. It is the produced from (3S,5S)-Carbapenam-3-carboxylic acid utilizing a remarkable stereoinversion/desaturation process by CarC (carbapenem synthase), an α-ketoglutarate dependent non-heme iron oxygenase. In this communication, we demonstrate for the first time that the epimeric (3S,5R)-Carbapenam-3-carboxylic acid is an intermediate in the overall catalytic cycle to the carbapenem antibiotic. The role of α-ketoglutarate in the stereoinversion and desaturation processes is also examined.
Julie Ann Justo - One of the best experts on this subject based on the ideXlab platform.
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impact of penicillin allergy on empirical carbapenem use in gram negative bloodstream infections an antimicrobial stewardship opportunity
Pharmacotherapy, 2018Co-Authors: Majdi N Alhasan, Emily C Acker, Joseph Kohn, Paul Brandon Bookstaver, Julie Ann JustoAbstract:Objectives Retrospective matched cohort study evaluating association between penicillin allergy and empirical carbapenem use in gram-negative bloodstream infections (BSI) and utility of antimicrobial stewardship interventions in reducing carbapenem utilization. Methods Hospitalized adults with community-onset gram-negative BSI from January 1, 2010 to June 30, 2015 at two large community hospitals in Columbia, SC were identified. Antimicrobial stewardship interventions targeting penicillin allergy and carbapenem utilization were fully implemented in January 1, 2014. Multivariate logistic regression was used to examine impact of penicillin allergy and antimicrobial stewardship interventions on empirical carbapenem use. Kaplan-Meier analysis was used to evaluate time to carbapenem de-escalation in patients with penicillin allergy before and after interventions. Results Patients with penicillin allergy (n=140) were more likely to receive empirical carbapenem therapy for community-onset gram-negative BSI compared to those without penicillin allergy (n=140) (27% vs. 12%, p=0.002). After adjustments in the multivariate model, penicillin allergy (odds ratio [OR] 3.98, 95% confidence intervals [CI]: 1.98-8.45) and prior β-lactam use (OR 2.72, 95% CI: 1.07-6.64) were independently associated with empirical carbapenem use, whereas antimicrobial stewardship interventions were associated with decline in carbapenem utilization (OR 0.41, 95% CI: 0.16-0.94). Among patients with penicillin allergy who were prescribed empirical carbapenems, median time to carbapenem de-escalation was significantly shorter in the post- versus pre-intervention period (2.0 vs. 4.2 days, p=0.004). Conclusion Penicillin allergy was a significant contributor to carbapenem use in community-onset gram-negative BSI. This was subject to modification by antimicrobial stewardship interventions which successfully reduced overall carbapenem use and duration of carbapenem therapy in patients with penicillin allergy. This article is protected by copyright. All rights reserved.
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Impact of Penicillin Allergy on Empirical Carbapenem Use in Gram‐Negative Bloodstream Infections: An Antimicrobial Stewardship Opportunity
Pharmacotherapy, 2017Co-Authors: Majdi N. Al-hasan, Emily C Acker, Joseph Kohn, Paul Brandon Bookstaver, Julie Ann JustoAbstract:Objectives Retrospective matched cohort study evaluating association between penicillin allergy and empirical carbapenem use in gram-negative bloodstream infections (BSI) and utility of antimicrobial stewardship interventions in reducing carbapenem utilization. Methods Hospitalized adults with community-onset gram-negative BSI from January 1, 2010 to June 30, 2015 at two large community hospitals in Columbia, SC were identified. Antimicrobial stewardship interventions targeting penicillin allergy and carbapenem utilization were fully implemented in January 1, 2014. Multivariate logistic regression was used to examine impact of penicillin allergy and antimicrobial stewardship interventions on empirical carbapenem use. Kaplan-Meier analysis was used to evaluate time to carbapenem de-escalation in patients with penicillin allergy before and after interventions. Results Patients with penicillin allergy (n=140) were more likely to receive empirical carbapenem therapy for community-onset gram-negative BSI compared to those without penicillin allergy (n=140) (27% vs. 12%, p=0.002). After adjustments in the multivariate model, penicillin allergy (odds ratio [OR] 3.98, 95% confidence intervals [CI]: 1.98-8.45) and prior β-lactam use (OR 2.72, 95% CI: 1.07-6.64) were independently associated with empirical carbapenem use, whereas antimicrobial stewardship interventions were associated with decline in carbapenem utilization (OR 0.41, 95% CI: 0.16-0.94). Among patients with penicillin allergy who were prescribed empirical carbapenems, median time to carbapenem de-escalation was significantly shorter in the post- versus pre-intervention period (2.0 vs. 4.2 days, p=0.004). Conclusion Penicillin allergy was a significant contributor to carbapenem use in community-onset gram-negative BSI. This was subject to modification by antimicrobial stewardship interventions which successfully reduced overall carbapenem use and duration of carbapenem therapy in patients with penicillin allergy. This article is protected by copyright. All rights reserved.
John Quale - One of the best experts on this subject based on the ideXlab platform.
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success of an infection control program to reduce the spread of carbapenem resistant klebsiella pneumoniae
Infection Control and Hospital Epidemiology, 2009Co-Authors: Sandeep Kochar, Simona Bratu, David Landman, Timothy Sheard, Roopali Sharma, Elaine Tolentino, George Allen, Michael Augenbraun, John QualeAbstract:Objective. To assess the effect of enhanced infection control measures with screening for gastrointestinal colonization on limiting the spread of carbapenem‐resistant Klebsiella pneumoniae in a New York City hospital endemic for this pathogen. Design. Retrospective observational study with pre‐ and postinterventional phases. Methods. Beginning in 2006, a comprehensive infection control program was instituted in a 10‐bed medical and surgical intensive care unit at a university‐based medical center. In addition to being placed in contact isolation, all patients colonized or infected with carbapenem‐resistant gram‐negative bacilli, vancomycin‐resistant Enterococcus, or methicillin‐resistant Staphylococcus aureus were cohorted to one end of the unit. Improved decontamination of hands and environmental surfaces was encouraged. In addition, routine rectal surveillance cultures were screened for the presence of carbapenem‐resistant pathogens. The number of patients per quarter with clinical cultures positive for...
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rapid spread of carbapenem resistant klebsiella pneumoniae in new york city a new threat to our antibiotic armamentarium
JAMA Internal Medicine, 2005Co-Authors: Simona Bratu, David Landman, Robin Haag, Rose A Recco, Antonella Eramo, Maqsood Alam, John QualeAbstract:Background Carbapenem antibiotics are used to treat serious infections caused by extended-spectrum β-lactamase–carrying pathogens. Carbapenem resistance has been unusual in isolates of Klebsiella pneumoniae . In this study, the prevalence and molecular epidemiologic characteristics of carbapenem-resistant K pneumoniae are analyzed, and the experience involving 2 hospital outbreaks is described. Methods A citywide surveillance study was conducted in hospitals in Brooklyn. An observational study involving subsequent outbreaks at 2 hospitals was undertaken. Isolates were genetically fingerprinted by ribotyping and were examined for the presence of KPC-type carbapenem-hydrolyzing β-lactamases. Results Of 602 isolates of K pneumoniae collected during the citywide surveillance study, 45% had extended-spectrum β-lactamases. Of the extended-spectrum β-lactamase–producing isolates, 3.3% carried the carbapenem-hydrolyzing β-lactamase KPC-2. Several isolates were reported by the clinical microbiology laboratories as being susceptible to imipenem. Although all the isolates were resistant using agar diffusion methods, minimal inhibitory concentrations of imipenem were substantially lower for several isolates using standard broth microdilution tests and were highly dependent on the inoculum used. Two hospitals experienced the rapid spread of carbapenem-resistant isolates involving 58 patients. Overall 14-day mortality for bacteremic patients was 47%. Most isolates belonged to a single ribotype. Conclusions Carbapenem-resistant K pneumoniae isolates are rapidly emerging in New York City. The spread of a strain that possesses a carbapenem-hydrolyzing β-lactamase has occurred in regional hospitals. Because these isolates are resistant to virtually all commonly used antibiotics, control of their spread is crucial. However, automated systems used for susceptibility testing may not accurately identify all these isolates, which will severely hamper control efforts.