Evaluation of the INCREMENT-CPE, Pitt Bacteremia and qPitt Scores in Patients with Carbapenem-Resistant Enterobacteriaceae Infections Treated with Ceftazidime–Avibactam

Background The aim of this study was to evaluate the predictive performance of the INCREMENT-CPE (ICS), Pitt bacteremia score (PBS) and qPitt for mortality among patients treated with ceftazidime–avibactam for carbapenem-resistant Enterobacteriaceae (CRE) infections. Methods Retrospective, multicenter, cohort study of patients with CRE infections treated with ceftazidime–avibactam between 2015 and 2019. The primary outcome was 30-day all-cause mortality. Predictive performance was determined by assessing discrimination, calibration and precision. Results In total, 109 patients were included. Thirty-day mortality occurred in 18 (16.5%) patients. There were no significant differences in discrimination of the three scores [area under the curve (AUC) ICS 0.7039, 95% CI 0.5848–0.8230, PBS 0.6893, 95% CI 0.5709–0.8076, and qPitt 0.6847, 95% CI 0.5671–0.8023; P > 0.05 all pairwise comparisons]. All scores showed adequate calibration and precision. When dichotomized at the optimal cut-points of 11, 3, and 2 for the ICS, PBS, and qPitt, respectively, all scores had NPV > 90% at the expense of low PPV. Patients in the high-risk groups had a relative risk for mortality of 3.184 (95% CI 1.35–8.930), 3.068 (95% CI 1.094–8.606), and 2.850 (95% CI 1.016–7.994) for the dichotomized ICS, PBS, and qPitt, scores respectively. Treatment-related variables (early active antibiotic therapy, combination antibiotics and renal ceftazidime–avibactam dose adjustment) were not associated with mortality after controlling for the risk scores. Conclusions In patients treated with ceftazidime–avibactam for CRE infections, mortality risk scores demonstrated variable performance. Modifications to scoring systems to more accurately predict outcomes in the era of novel antibiotics are warranted

How Many Words Does a Picture Really Tell? Cross-sectional Descriptive Study of Pictogram Evaluation by Youth

BACKGROUND: Communicating health-related instructions with pictograms is useful, but such graphics can be interpreted in different ways. It is crucial to understand which pictogram components are best for accurate communication. OBJECTIVES: To catalogue pictograms used to label drugs in clinical practice; to identify the common graphic elements for defined categories of pictograms, by performing a semiotic analysis (studying how signs are perceived and how they should be designed); to identify the key graphic elements common to pictograms preferred by users; and to develop suggestions for future pictogram design on the basis of users’ input. METHODS: Literature and Internet searches were performed to identify pictograms and pictogram categories. A call for pictograms was also circulated through the International Pharmaceutical Federation (FIP). Youth at a Canadian pediatric hospital were asked to rate pictograms (including storyboards and prescription labels generated by FIP pictogram software) in terms of how best they represented their intended meanings. Pictograms for which at least 80% of participants “somewhat agreed”, “agreed”, or “strongly agreed” that the graphic conveyed the intended meaning were designated as “preferred” and were selected for analysis. Elements appearing in at least 50% of these preferred pictograms were highlighted as key graphic elements for design of future pictograms. RESULTS: In total, 21 categories were identified for pictograms used in clinical practice, and a total of 204 pictograms were analyzed. Eighty-six participants took part in the survey. For each pictogram category, certain elements were identified as “preferred” and as “key graphic elements”, whereas other elements met neither designation. For all 21 pictogram categories, at least 80% of survey respondents agreed that the FIP storyboard conveyed the intended meaning. CONCLUSIONS: Certain key, preferred graphic elements are required for pharmaceutical pictograms to convey their intended meaning. The overlap between preferred and key pictogram elements indicates that both must be considered in development of future pictograms. Redesign of existing pictograms with consideration of the best semiotic elements is in progress

How Many Words Does a Picture Really Tell? Cross-sectional Descriptive Study of Pictogram Evaluation by Youth

ABSTRACTBackground: Communicating health-related instructions with pictograms is useful, but such graphics can be interpreted in different ways. It is crucial to understand which pictogram components are best for accurate communication.Objectives: To catalogue pictograms used to label drugs in clinical practice; to identify the common graphic elements for defined categories of pictograms, by performing a semiotic analysis (studying how signs are perceived and how they should be designed); to identify the key graphic elements common to pictograms preferred by users; and to develop suggestions for future pictogram design on the basis of users’ input.Methods: Literature and Internet searches were performed to identify pictograms and pictogram categories. A call for pictograms was also circulated through the International Pharmaceutical Federation (FIP). Youth at a Canadian pediatric hospital were asked to rate pictograms (including storyboards and prescription labels generated by FIP pictogram software) in terms of how best they represented their intended meanings. Pictograms for which at least 80% of participants “somewhat agreed”, “agreed”, or “strongly agreed” that the graphic conveyed the intended meaning were designated as “preferred” and were selected for analysis. Elements appearing in at least 50% of these preferred pictograms were highlighted as ke graphic elements for design of future pictograms.Results: In total, 21 categories were identified for pictograms used in clinical practice, and a total of 204 pictograms were analyzed. Eighty-six participants took part in the survey. For each pictogram category, certain elements were identified as “preferred” and as “key graphic elements”, whereas other elements met neither designation. For all 21 pictogram categories, at least 80% of survey respondents agreed that the FIP storyboard conveyed the intended meaning.Conclusions: Certain key, preferred graphic elements are required for pharmaceutical pictograms to convey their intended meaning. The overlap between preferred and key pictogram elements indicates that both must be considered in development of future pictograms. Redesign of existing pictograms with consideration of the best semiotic elements is in progress.RÉSUMÉContexte : La communication des instructions concernant la santé à l’aide de pictogrammes est utile, mais ces graphiques peuvent être interprétés de différentes façons. Il est crucial de connaître quels éléments de ces picto - grammes sont les plus adéquats pour permettre une communication précise.Objectifs : Répertorier les pictogrammes utilisés pour étiqueter les médicaments en pratique clinique; déterminer les éléments graphiques courants pour chaque catégorie de pictogrammes, en effectuant une analyse sémiotique (étude de la perception des signes et de leur représentation graphique); définir les éléments graphiques clés communs aux pictogrammes préférés des usagers; et formuler des suggestions pour la conception de futurs pictogrammes en tenant compte des commentaires des usagers.Méthodes : Une recherche bibliographique et une recherche dans Internet ont été menées pour déterminer les pictogrammes et les catégories de pictogrammes. Une demande de soumission de pictogrammes a aussi été diffusée par l’entremise de la Fédération internationale pharmaceutique (FIP). Dans un hôpital pour enfants du Canada, on a demandé à des jeunes d’évaluer les pictogrammes (y compris des étiquettes de médicaments prescrits et des scénarios illustrés générés par le logiciel de pictogrammes de la FIP) quant à l’exactitude de leur représentation du message qu’on voulait livrer. Les pictogrammes pour lesquels au moins 80 % des participants étaient « plutôt d’accord », « d’accord » ou « tout à fait d’accord » que le graphique livrait le message voulu ont été jugés comme étant « préférés » et retenus aux fins d’analyse. Les éléments apparaissant dans au moins 50% des pictogrammes préférés ont été sélectionnés comme éléments graphiques clés pour la conception de futurs pictogrammes.Résultats : En tout, 21 catégories de pictogrammes utilisés dans la pratique clinique ont été déterminées, 204 pictogrammes ont été analysés et 86 participants ont répondu au sondage. Pour chaque catégorie de pictogrammes, certains éléments ont été définis comme étant « préférés » et comme des « éléments graphiques clés », alors que d’autres éléments n’ont satisfait ni l’une ni l’autre de ces désignations. Pour les pictogrammes de l’ensemble des 21 catégories, au moins 80 % des répondants ont affirmé que le scénario illustré généré par le logiciel de la FIP communiquait le message qu’on voulait livrer.Conclusions : Certains éléments graphiques clés et préférés sont requis afin que les pictogrammes pharmaceutiques communiquent le message qu’on veut livrer. Le chevauchement entre les éléments graphiques préférés et les éléments graphiques clés indiquent que les deux doivent être pris en compte dans la création de futurs pictogrammes. La reconception des pictogrammes existants qui tient compte des meilleurs éléments sémiotiques est en cours

A Combined Molecular Dynamics and Rapid Kinetics Approach to Identify Conserved Three-Dimensional Communication Networks in Elongation Factor Tu

Elongation factor (EF) Tu delivers aminoacyl-tRNAs to the actively translating bacterial ribosome in a GTP-hydrolysis-dependent process. Rapid recycling of EF-Tu, catalyzed by EF-Ts, is required for efficient protein synthesis in vivo. Here we report a combined theoretical and experimental approach aimed at identifying three-dimensional communication networks in EF-Tu. As an example, we focus on the mechanistic role of second-shell residue Asp109. We constructed full-length structural models of EF-Tu from Escherichia coli in the GDP-/GTP-bound state and performed several 10-ns-long molecular-dynamics simulations. During these simulations, the side chain of Asp109 formed a previously undetected transient hydrogen bond to His22, an invariant residue in the phosphate-binding loop (P-loop). To experimentally validate our molecular-dynamics results and further analyze the role of this hydrogen bond, we determined all rate constants for the multistep reaction between EF-Tu (wild-type and two mutants), EF-Ts, GDP, and GTP using the stopped-flow technique. This mutational analysis revealed that the side chain of Asp109 is important for acceleration of GDP, but not for GTP dissociation by EF-Ts. The possibility that the Asp109 side chain has a role in transition-state stabilization and coupling of P-loop movements with rearrangements at the base side of the nucleotide is discussed

Evaluation of the INCREMENT-CPE, Pitt Bacteremia and qPitt Scores in Patients with Carbapenem-Resistant Enterobacteriaceae Infections Treated with Ceftazidime-Avibactam

BACKGROUND: The aim of this study was to evaluate the predictive performance of the INCREMENT-CPE (ICS), Pitt bacteremia score (PBS) and qPitt for mortality among patients treated with ceftazidime-avibactam for carbapenem-resistant Enterobacteriaceae (CRE) infections. METHODS: Retrospective, multicenter, cohort study of patients with CRE infections treated with ceftazidime-avibactam between 2015 and 2019. The primary outcome was 30-day all-cause mortality. Predictive performance was determined by assessing discrimination, calibration and precision. RESULTS: In total, 109 patients were included. Thirty-day mortality occurred in 18 (16.5%) patients. There were no significant differences in discrimination of the three scores [area under the curve (AUC) ICS 0.7039, 95% CI 0.5848-0.8230, PBS 0.6893, 95% CI 0.5709-0.8076, and qPitt 0.6847, 95% CI 0.5671-0.8023; P \u3e 0.05 all pairwise comparisons]. All scores showed adequate calibration and precision. When dichotomized at the optimal cut-points of 11, 3, and 2 for the ICS, PBS, and qPitt, respectively, all scores had NPV \u3e 90% at the expense of low PPV. Patients in the high-risk groups had a relative risk for mortality of 3.184 (95% CI 1.35-8.930), 3.068 (95% CI 1.094-8.606), and 2.850 (95% CI 1.016-7.994) for the dichotomized ICS, PBS, and qPitt, scores respectively. Treatment-related variables (early active antibiotic therapy, combination antibiotics and renal ceftazidime-avibactam dose adjustment) were not associated with mortality after controlling for the risk scores. CONCLUSIONS: In patients treated with ceftazidime-avibactam for CRE infections, mortality risk scores demonstrated variable performance. Modifications to scoring systems to more accurately predict outcomes in the era of novel antibiotics are warranted

Real-World Experience With Ceftazidime-Avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections

Background: We conducted this study to describe the clinical characteristics, microbiology, and outcomes of patients treated with ceftazidime-avibactam (CZA) for a range of multidrug-resistant Gram-negative (MDR-GN) infections. Methods: This is a multicenter, retrospective cohort study conducted at 6 medical centers in the United States between 2015 and 2019. Adult patients who received CZA (≥72 hours) were eligible. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure, and/or failure to resolve or improve signs or symptoms of infection on CZA. Results: In total, data from 203 patients were evaluated. Carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas spp were isolated from 117 (57.6%) and 63 (31.0%) culture specimens, respectively. The most common infection sources were respiratory (37.4%), urinary (19.7%), and intra-abdominal (18.7%). Blood cultures were positive in 22 (10.8%) patients. Clinical failure, 30-day mortality, and 30-day recurrence occurred in 59 (29.1%), 35 (17.2%), and 12 (5.9%) patients, respectively. On therapy, CZA resistance developed in 1 of 62 patients with repeat testing. Primary bacteremia or respiratory tract infection and higher SOFA score were positively associated with clinical failure (adjusted odds ratio [aOR] = 2.270, 95% confidence interval [CI] = 1.115-4.620 and aOR = 1.234, 95% CI = 1.118-1.362, respectively). Receipt of CZA within 48 hours of infection onset was protective (aOR, 0.409; 95% CI, 0.180-0.930). Seventeen (8.4%) patients experienced a potential drug-related adverse effect (10 acute kidney injury, 3 Clostridioides difficile infection, 2 rash, and 1 each gastrointestinal intolerance and neutropenia). Conclusions: Ceftazidime-avibactam is being used to treat a range of MDR-GN infections including Pseudomonas spp as well as CRE