Antibiotic strategies in the era of multidrug resistance.

The rapid emergence and dissemination of antibiotic-resistant microorganisms in ICUs worldwide threaten adequate antibiotic coverage of infected patients in this environment. The causes of this problem are multifactorial, but the core issues are clear: the emergence of antibiotic resistance is highly correlated with selective pressure resulting from inappropriate use of these drugs. Because a significant increase in mortality is observed when antibiotic therapy is delayed in infected ICU patients, initial therapy should be broad enough to cover all likely pathogens. Receipt of unnecessary prolonged broad-spectrum antibiotics, however, should be avoided. Local microbiologic data are extremely important to predict the type of resistance that may be present for specific causative bacteria, as is prior antibiotic exposure, and antibiotic choices should thus be made at an individual patient level.

Advances in antibiotic therapy in the critically ill.

Infections occur frequently in critically ill patients and their management can be challenging for various reasons, including delayed diagnosis, difficulties identifying causative microorganisms, and the high prevalence of antibiotic-resistant strains. In this review, we briefly discuss the importance of early infection diagnosis, before considering in more detail some of the key issues related to antibiotic management in these patients, including controversies surrounding use of combination or monotherapy, duration of therapy, and de-escalation. Antibiotic pharmacodynamics and pharmacokinetics, notably volumes of distribution and clearance, can be altered by critical illness and can influence dosing regimens. Dosing decisions in different subgroups of patients, e.g., the obese, are also covered. We also briefly consider ventilator-associated pneumonia and the role of inhaled antibiotics. Finally, we mention antibiotics that are currently being developed and show promise for the future.

TEACHING VALUES IN MEDICINE VIA AWARENESS CREATED THROUGH ART.

The design of a new medical education building sought through art to create awareness of important values in physicians. An antique silk embroidery depicting Aesculapius crowning a man charged to protect the medical profession from quackery is placed at the beginning of the space leading into the simulation laboratories to highlight the importance of competency. A charcoal drawing by an important regional artist conveys the message that trust can arise from vulnerability, with optimal mentoring being the outcome. A round table with an authentic French Art Deco lantern and a commissioned table designed as an interpretation of the lantern create the sense of importance that fosters critical thinking and professionalism. An outdoor terrace was designed to challenge residents and medical students to become in touch with their capacity for humanism in medicine. Included among the various elements to nurture this core value are an outdoor classroom, conversation gardens, open spaces under plane trees (which are within the family of trees under which Hippocrates taught), and a reflection cove (reminiscent of those sought by poets who travelled to Ravello, Italy, in an attempt to find the meaning of life). The major focal point on the terrace is a commissioned Dale Chihuly sculpture of red reeds intended to encourage art as a form of healing and as a source of humanism.

The value of diastolic function parameters in the prediction of left atrial appendage thrombus in patients with nonvalvular atrial fibrillation.

BACKGROUND: Left ventricular diastolic impairment and consequently elevated filling pressure may contribute to stasis leading to left atrial appendage thrombus (LAAT) in nonvalvular atrial fibrillation (AF). We investigated whether transthoracic echocardiographic parameters can predict LAAT independent of traditional clinical predictors. METHODS: We conducted a retrospective cohort study of 297 consecutive nonvalvular AF patients who underwent transthoracic echocardiogram followed by a transesophageal echocardiogram within one year. Multivariate logistic regression analysis models were used to determine factors independently associated with LAAT. RESULTS: Nineteen subjects (6.4%) were demonstrated to have LAAT by transesophageal echocardiography. These patients had higher mean CHADS2 scores [2.6 ± 1.2 vs. 1.9 ± 1.3, P = 0.009], higher E:e' ratios [16.6 ± 6.1 vs. 12.0 ± 5.4, P = 0.001], and lower mean e' velocities [6.5 ± 2.1 cm/sec vs. 9.1 ± 3.2 cm/sec, P = 0.001]. Both E:e' and e' velocity were associated with LAAT formation independent of the CHADS2 score, warfarin therapy, left ventricular ejection fraction (LVEF), and left atrial volume index (LAVI) [E:e' odds-ratio = 1.14 (95% confidence interval = 1.03 - 1.3), P = 0.009; e' velocity odds-ratio = 0.68 (95% confidence interval = 0.5 - 0.9), P = 0.007]. Similarly, diastolic function parameters were independently associated with spontaneous echo contrast. CONCLUSION: The diastolic function indices E:e' and e' velocity are independently associated with LAAT in nonvalvular AF patients and may help identify patients at risk for LAAT.

B-type natriuretic peptide predicts left atrial appendage thrombus in patients with nonvalvular atrial fibrillation.

PURPOSE: To investigate whether plasma B-type Natriuretic peptide (BNP), a surrogate of left ventricular filling pressure (LVFP), is predictive of left atrial appendage thrombus (LAAT) in patients with nonvalvular atrial fibrillation (AF) independent of known clinical risk predictors. METHODS: We conducted a retrospective cohort study of 297 consecutive subjects with AF who underwent a clinically indicated transesophageal echocardiogram (TEE) to evaluate for LAAT and spontaneous echo contrast (SEC). Among those, 136 had a clinically indicated BNP level. Using multivariate logistic regression analysis models, we determined factors independently predictive of the primary endpoint of LAAT and the secondary endpoint of either LAAT or SEC. RESULTS: Nineteen subjects (6.4%) had LAAT and they were found to have a higher mean CHADS2 score (2.53 vs 1.76, P = 0.01) and mean BNP level [1949 vs. 819 pg/mL, P = 0.001] than those without LAAT. None of the patients with a BNP level ≤500 pg/mL had LAAT. Multivariate logistic regression analysis demonstrated that BNP was predictive of LAAT and the composite of LAAT/SEC independent of the CHADS2 score and warfarin therapy [OR = 1.23 and 1.6 per 500 pg/mL increment in BNP, P-values = 0.03 and 0.001; respectively]. Moreover, adding BNP to the predictive model negated the influence of the CHADS2 score. CONCLUSION: These data indicate that BNP is an independent predictor of LAAT in AF and may complement the role of the CHADS2 score in predicting stroke risk.

Successful implementation of Medical Education Faculty Development Project at Saint George University of Beirut in the immediate post triple blow to Beirut.

Background: The aim of this study is to explore the efficacy of the Faculty Development Program (FDP) implemented at the Saint George University of Beirut-Faculty of Medicine (SGUB FM) under exceptional circumstances as the triple blow to Beirut. Methods: The Faculty Development, directed towards a cohort of 35 faculty members, is composed of two major components: methodology of teaching and techniques of assessment. The Kirkpatrick's assessment model, in combination with a specifically designed psychological questionnaire, were chosen to assess the effectiveness of the faculty development initiative. Results: Results of the different questionnaires were interpreted individually, then through the lens of the psychological questionnaire. A majority of faculty (55%) were significantly affected psychologically by Beirut's triple blow and 77% of all participants found the workshops to be of excellent quality (Kirkpatrick's Level I). Moreover, Kirkpatrick's level II results yielded a 76% mean percentage of correct answers to post-workshops MCQs and a significant improvement in the mean results of the self-assessment questionnaires, administered before and after each workshop. Results also show that the more a trainee is psychologically affected, the less he/she performs as evidenced by a decrease in the satisfaction rate as well as in the score of the cognitive MCQs and of the self-assessment questionnaires. Conclusions: This study was able to highlight that significant learning can occur amidst exceptional circumstances like the Beirut triple blow and administration should invest in professional growth to retain its faculty.

Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules.

Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-A resolution, revealing a 60-A-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.

Predictors and severity of probable acute stress disorder following the Beirut Port Blast.

Background: The Beirut Port Blast on August 4, 2020 is the largest (non-nuclear) explosion on record. St George Hospital University Medical Center (SGHUMC), a leading academic medical centre in Lebanon, adjacent to the Port, sustained a massive loss in lives and infrastructure. Objective: The current study uses the baseline data of an ongoing longitudinal study to explore the prevalence, severity, and predictors of probable Acute Stress Disorder (ASD) among health workers at SGHUMC following the blast. Methods: In the context of COVID-19 tests administered 9-15 days after the blast, SGHUMC staff were asked to complete a questionnaire that included socio-demographic details, the Beirut Port Exposure Inventory, and the Acute Stress Disorder Scale (ASDS). Results: A total of 570 health workers participated in the study. The prevalence of probable DSM-5 ASD [95%CI] was 38.34% [31.41; 45.32]. Many specific exposures were related, on a bivariate level, to ASD be it as a probable DSM-5 diagnosis or its severity as measured by the ASDS. A classification and regression tree (CART) analysis identified the highest risk predictors of probable DSM-5 ASD diagnosis to be: being a female, seeing dead or mutilated bodies, death of a close one, and being scared at the time of the explosion. Nurses carried the highest risks of all health workers with a probable DSM-5 ASD prevalence of 51.28%, (OR = 3.72 [95% CI: 2.22; 6.25]). Being scared at the time of the blast was the most single predictor of probable ASD. Conclusion: Both the prevalence and severity of probable DSM-5 ASD in this sample are higher than most reported in the literature, which may be explained by the severity of the trauma and the ongoing stress in the context of the pandemic. Fear at the time of the explosion was independently the most predictive parameter of probable ASD.

Antecedentes: La explosión del Puerto de Beirut el 4 de agosto de 2020 es la explosión (no nuclear) más grande registrada. El Centro Médico Universitario del Hospital St George (SGHUMC), un centro médico académico líder en el Líbano, adyacente al puerto, sufrió una pérdida masiva de vidas e infraestructura. Objetivo: El estudio actual utiliza los datos iniciales de un estudio longitudinal en curso para explorar la prevalencia, gravedad y predictores del probable Trastorno de Estrés Agudo (TEA) entre los trabajadores de la salud en SGHUMC después de la explosión. Métodos: En el contexto de las pruebas de COVID-19 administradas entre 9 y 15 días después de la explosión, se le pidió al personal de SGHUMC que completara un cuestionario que incluía detalles sociodemográficos, el Inventario de Exposición del Puerto de Beirut y la Escala de Trastorno de Estrés Agudo (ETEA). Resultados: Un total de 570 trabajadores de la salud participaron en el estudio. La prevalencia de probable TEA DSM-5 [IC 95%] fue del 38,34% [31,41; 45.32]. Muchas exposiciones específicas se relacionaron, en un nivel bivariado, con TEA, ya sea como un diagnóstico probable del DSM-5 o su gravedad medida por el ETEA. Un análisis del árbol de clasificación y regresión (CART, por sus siglas en inglés) identificó que los predictores de riesgo más alto del diagnóstico probable de TEA según el DSM-5 son: ser mujer, ver cuerpos muertos o mutilados, la muerte de alguien cercano y tener miedo en el momento de la explosión. Las enfermeras tenían los riesgos más altos de todos los trabajadores de la salud con una prevalencia probable de TEA según el DSM-5 del 51,28%, (OR = 3,72 [IC del 95%: 2,22; 6.25]). Sentirse aterrorizados en el momento de la explosión fue el predictor más determinante de probable TEA. Conclusión: Tanto la prevalencia como la gravedad del probable TEA DSM-5 en esta muestra son más altas que la mayoría de las reportadas en la literatura, lo que puede explicarse por la gravedad del trauma y el estrés continuo en el contexto de la pandemia. El miedo en el momento de la explosión fue independientemente el parámetro más predictivo de probable TEA.

Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection.

The CETP inhibitor, torcetrapib, was prematurely terminated from phase 3 clinical trials due to an increase in cardiovascular and noncardiovascular mortality. Because nearly half of the latter deaths involved patients with infection, we have tested torcetrapib and other CETPIs to see if they interfere with lipopolysaccharide binding protein (LBP) or bactericidal/permeability increasing protein (BPI). No effect of these potent CETPIs on LPS binding to either protein was detected. Purified CETP itself bound weakly to LPS with a Kd >or= 25 microM compared with 0.8 and 0.5 nM for LBP and BPI, respectively, and this binding was not blocked by torcetrapib. In whole blood, LPS induced tumor necrosis factor-alpha normally in the presence of torcetrapib. Furthermore, LPS had no effect on CETP activity. We conclude that the sepsis-related mortality of the ILLUMINATE trial was unlikely due to a direct effect of torcetrapib on LBP or BPI function, nor to inhibition of an interaction of CETP with LPS. Instead, we speculate that the negative outcome seen for patients with infections might be related to the changes in plasma lipoprotein composition and metabolism, or alternatively to the known off-target effects of torcetrapib, such as aldosterone elevation, which may have aggravated the effects of sepsis.

Implementing a Narrative Medicine Curriculum During the Internship Year: An Internal Medicine Residency Program Experience.

INTRODUCTION: Narrative medicine develops professional and communication skills that align with Accreditation Council for Graduate Medical Education competencies. However, little is known about a narrative medicine curriculum's impact on physicians in training during residency. Implementing a narrative medicine curriculum during residency can be challenging because of time constraints and limited opportunity for nonclinical education. METHODS: Six sessions were implemented throughout one academic year to expose first-year internal medicine residents (interns) to narrative medicine. Attendance and participation were documented. At the end of the year, interns completed an open-ended survey to gauge their perception of their experience with the sessions. RESULTS: In total, 17 interns attended at least 1 narrative medicine session, and each session averaged 5.4 attendees. Thirteen eligible interns completed the survey. Thematic analysis identified 3 predominant themes: Mindfulness, physician well-being, and professionalism. DISCUSSION: Overall, the narrative medicine sessions were well attended and the curriculum was well received. This intervention demonstrates the value of a narrative medicine curriculum during medical resident training. Large prospective studies are necessary to identify the long-term benefits of such a curriculum.

Impact of a national antimicrobial stewardship mentoring program: Insights and lessons learned.

PURPOSE: The impact of an interprofessional mentoring program to advance antimicrobial stewardship programs (ASPs) in selected U.S. hospitals and lessons learned are described. SUMMARY: A seven-step mentoring process with self-assessment, telephone calls, continuing education, a one-day onsite visit, action plan, and outcome data collection and analysis was provided to ASP teams at nine hospitals. Six hospitals completed the program. A significant improvement in the timeliness and appropriateness of i.v. antibiotic therapy (defined as a hang time within one hour after prescriber order entry and broad-spectrum coverage for gram-negative pathogens administered first when combination therapy was used) was observed in patients with sepsis over the 12-month period after implementation of the mentoring program. As a result of requiring hospital administration's participation in the mentoring program, increased funding became available at three hospitals for the microbiology laboratory to provide new rapid diagnostic tests and for pharmacist and physician time to devote to ASP activities. The collaboration and engagement of ASP team members, inclusion of hospital administrators and pharmacy directors in the onsite mentoring visits, and an experienced mentor team with an infectious diseases (ID) physician and ID pharmacist contributed to ASP success. Challenges included insufficient time to collect outcome metrics due to competing hospital priorities and loss of momentum over time. CONCLUSION: A mentoring program for antimicrobial stewardship provided the perspective that comes from experience. Engagement of hospital administration was a key factor for both developing and sustaining a stewardship program.

Expression, purification, crystallization and structure of human adipocyte lipid-binding protein (aP2).

Human adipocyte lipid-binding protein (aP2) belongs to a family of intracellular lipid-binding proteins involved in the transport and storage of lipids. Here, the crystal structure of human aP2 with a bound palmitate is described at 1.5 A resolution. Unlike the known crystal structure of murine aP2 in complex with palmitate, this structure shows that the fatty acid is in a folded conformation and that the loop containing Phe57 acts as a lid to regulate ligand binding by excluding solvent exposure to the central binding cavity.

Critical Illness in Patients With Asplenia.

The critically ill, asplenic patient presents a variety of management challenges. Historically, the focus of the care of the asplenic population has been the prevention and management of infection, including the often-fatal overwhelming postsplenectomy infection with encapsulated organisms such as Streptococcus pneumoniae. Recently, however, there has been increasing recognition of the spleen's function in areas outside of immunity because the asplenic state has been identified as a risk factor for such vascular complications as thrombosis and pulmonary hypertension resulting from dysregulated inflammation and coagulation. Because of the relatively small size of this population and the relative infrequency with which critical illness occurs in it, there are few controlled trials that can serve as a basis for therapeutic maneuvers; thus, optimal management requires an astute clinician with an understanding of the pathogenetic mechanisms underlying the reported consequences of splenectomy. The purpose of this review is to explore the pathophysiology of the asplenic state-impairment in adaptive immunity, loss of blood filtration, endothelial dysfunction, and dysregulated coagulation-and how it leads to infection, thrombosis, and pulmonary hypertension as well as to discuss the implications of these conditions on the management of the critically ill, splenectomized patient.

Inferior vena caval filters: key considerations.

Surgical interruption of the inferior vena cava (IVC) as a means to prevent pulmonary embolism and its consequences has been entertained since the end of the 19th century. Initial methods were crude, however, but their deficiencies led to the development of newer techniques. Despite increasing indications and use of permanent IVC filters there remains controversy regarding their efficacy and complications. The purpose of this article is to review the pertinent literature and, it is hoped, aid in the development of a rational approach to the use of IVC filters. The evolving data regarding the retrievable filters are also discussed.

Anilinoquinazoline inhibitors of fructose 1,6-bisphosphatase bind at a novel allosteric site: synthesis, in vitro characterization, and X-ray crystallography.

The synthesis and in vitro structure-activity relationships (SAR) of a novel series of anilinoquinazolines as allosteric inhibitors of fructose-1,6-bisphosphatase (F16Bpase) are reported. The compounds have a different SAR as inhibitors of F16Bpase than anilinoquinazolines previously reported. Selective inhibition of F16Bpase can be attained through the addition of appropriate polar functional groups at the quinazoline 2-position, thus separating the F16Bpase inhibitory activity from the epidermal growth factor receptor tyrosine kinase inhibitory activity previously observed with similar structures. The compounds have been found to bind at a symmetry-repeated novel allosteric site at the subunit interface of the enzyme. Inhibition is brought about by binding to a loop comprised of residues 52-72, preventing the necessary participation of these residues in the assembly of the catalytic site. Mutagenesis studies have identified the key amino acid residues in the loop that are required for inhibitor recognition and binding.

Profiling posttransplant circulating antibodies in kidney transplantation using donor endothelial cells.

BACKGROUND: Pathogenesis of antibody (Ab) responses to transplant are yet not well defined. This study aimed to detect and to analyze posttransplant circulating allo-Abs reacting toward graft endothelial cells (ECs) using primary EC cultures prospectively isolated from the transplant donor at the time of transplantation. METHODS: This study shows a retrospective analysis performed using a dedicated EC crossmatch (ECXM) assay that we developed for the experimental assessment of donor-specific EC-reactive Abs. Donor-specific ECXM was performed by flow cytometry on posttransplant sera (n=256) from an historical cohort of 22 kidney allograft recipients. RESULTS: In this study, we show that 27.3% (6/22) of recipients have a positive ECXM that strictly correlates (100%, 6/6) with the presence of anti-human leukocyte antigen (HLA) Abs posttransplantation. ECXM identifies both donor-specific Abs (DSA; 50%) and non-DSA (50%) reactive to EC. DSA and non-DSA are mostly IgG1 and exhibit peak titers ranging from 1/8 to 1/1024. ECXM indicates that DSA correspond to anti-HLA class II Abs; this immunization is late (M3-M60) but persistent (still detected at M60). In contrast, non-DSA are non-HLA-type Abs reacting with third-party EC and reflecting an early but transient immunization (ended at M3-M12). Our findings demonstrate selective regulatory pathways initiated by anti-HLA class II and non-DSA in graft EC reflected by CCR4 and interleukin 1ß up-regulation, respectively. CONCLUSIONS: We provide evidence that circulating Abs in HLA-sensitized transplant recipients include both DSA and non-HLA/non-DSA able to bind to graft EC and induce specific gene transcription.

Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621.

The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72-96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer.

Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use.

CONTEXT: Previous surveillance studies have documented increasing rates of antimicrobial resistance in US intensive care units (ICUs) in the early 1990s. OBJECTIVES: To assess national rates of antimicrobial resistance among gram-negative aerobic isolates recovered from ICU patients and to compare these rates to antimicrobial use. DESIGN AND SETTING: Participating institutions, representing a total of 43 US states plus the District of Columbia, provided antibiotic susceptibility results for 35 790 nonduplicate gram-negative aerobic isolates recovered from ICU patients between 1994 and 2000. MAIN OUTCOME MEASURES: Each institution tested approximately 100 consecutive gram-negative aerobic isolates recovered from ICU patients. Organisms were identified to the species level. Susceptibility tests were performed, and national fluoroquinolone consumption data were obtained. RESULTS: The activity of most antimicrobial agents against gram-negative aerobic isolates showed an absolute decrease of 6% or less over the study period. The overall susceptibility to ciprofloxacin decreased steadily from 86% in 1994 to 76% in 2000 and was significantly associated with increased national use of fluoroquinolones. CONCLUSIONS: This study documents the increasing incidence of ciprofloxacin resistance among gram-negative bacilli that has occurred coincident with increased use of fluoroquinolones. More judicious use of fluoroquinolones will be necessary to limit this downward trend.