Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system.

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 µg/cm2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 µg/cm2 (based on 331 sensitisers) and an HPC DST of 1.0 µg/cm2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner.

Antimicrobial Resistance Spectrum Conferred by pRErm46 of Emerging Macrolide (Multidrug)-Resistant Rhodococcus equi.

Clonal multidrug resistance recently emerged in Rhodococcus equi, complicating the therapeutic management of this difficult-to-treat animal- and human-pathogenic actinomycete. The currently spreading multidrug-resistant (MDR) "2287" clone arose in equine farms upon acquisition, and coselection by mass macrolide-rifampin therapy, of the pRErm46 plasmid carrying the erm(46) macrolide-lincosamide-streptogramin resistance determinant, and of an rpoBS531F mutation. Here, we screened a collection of susceptible and macrolide-resistant R. equi strains from equine clinical cases using a panel of 15 antimicrobials against rapidly growing mycobacteria (RGM) and nocardiae and other aerobic actinomycetes (NAA). R. equi isolates-including MDR ones-were generally susceptible to linezolid, minocycline, tigecycline, amikacin, and tobramycin according to Staphylococcus aureus interpretive criteria, plus imipenem, cefoxitin, and ceftriaxone based on Clinical and Laboratory Standards Institute (CLSI) guidelines for RGM/NAA. Susceptibility to ciprofloxacin and moxifloxacin was borderline according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Molecular analyses linked pRErm46 to significantly increased MICs for trimethoprim-sulfamethoxazole and doxycycline, in addition to clarithromycin, within the RGM/NAA panel, and to streptomycin, spectinomycin, and tetracycline resistance. pRErm46 variants with spontaneous deletions in the class 1 integron (C1I) region, observed in ≈30% of erm(46)-positive isolates, indicated that the newly identified resistances were attributable to the C1I's sulfonamide (sul1) and aminoglycoside (aaA9) resistance cassettes and adjacent tetRA(33) determinant. Most MDR isolates carried the rpoBS531F mutation of the 2287 clone, while different rpoB mutations (S531L, S531Y) detected in two cases suggest the emergence of novel MDR R. equi strains.

Assessment and Reproducibility of Quantitative Structure-Activity Relationship Models by the Nonexpert.

Model reliability is generally assessed and reported as an intrinsic component of quantitative structure-activity relationship (QSAR) publications; it can be evaluated using defined quality criteria such as the Organisation for Economic Cooperation and Development (OECD) principles for the validation of QSARs. However, less emphasis is afforded to the assessment of model reproducibility, particularly by users who may wish to use model outcomes for decision making, but who are not QSAR experts. In this study we identified a range of QSARs in the area of absorption, distribution, metabolism, and elimination (ADME) prediction and assessed their adherence to the OECD principles, as well as investigating their reproducibility by scientists without expertise in QSAR. Here, 85 papers were reviewed, reporting over 80 models for 31 ADME-related endpoints. Of these, 12 models were identified that fulfilled at least 4 of the 5 OECD principles and 3 of these 12 could be readily reproduced. Published QSAR models should aim to meet a standard level of quality and be clearly communicated, ensuring their reproducibility, to progress the uptake of the models in both research and regulatory landscapes. A pragmatic workflow for implementing published QSAR models and recommendations to modellers, for publishing models with greater usability, are presented herein.

A Randomized, Controlled, Phase III Clinical Trial to Evaluate the Efficacy and Tolerability of Risorine with Conventional Rifampicin in the Treatment of Newly Diagnosed Pulmonary Tuberculosis Patients.

BACKGROUND: The overall goals for treatment of Tuberculosis (TB) are to cure individual patient and to minimize the transmission of Mycobacterium tuberculosis. At the time of study conduction, the standard treatment for newly diagnosed tuberculosis patients consisted of an intensive phase for two months with four drugs (HRZE), followed by continuation phase for four months with two drugs (HR). Rifampicin, which is very effective against Mycobacterium tuberculosis, in both the phases of treatment, has certain concerns, which includes, decreased bioavailability with chronic use and hepatotoxicity. To overcome these concerns a new boosted formulation of Rifampicin (Risorine) with bio-enhancer Piperine was developed. Piperine has been found to increase bioavailability of several drugs including Amoxicillin, Cefotaxime, Theophylline and Propranolol. Risorine is a fixed dose combination that contains Rifampicin 200 mg + Isoniazid 300 mg + Piperine 10 mg. AIM AND OBJECTIVE: The aim of the present study was to validate the therapeutic efficacy and tolerability of Risorine formulation containing regimen with a conventional regimen in the management of patients with newly diagnosed pulmonary tuberculosis. METHODS: Total 216 patients with sputum positive and treatment naïve pulmonary tuberculosis were enrolled in the study after fulfillment of inclusion / exclusion criteria. These patients were randomized to receive either a conventional anti-TB therapy (n = 117) or a similar regimen containing Risorine (n = 99) for 6 months. During the study period, symptomatic improvement, sputum conversion and radiological improvement were monitored at regular intervals. RESULTS: Of the 216 enrolled patients, 75% in the Risorine group and 79% in the control group completed the study. At 4 weeks the sputum conversion rate was significantly superior in Risorine group (93%) than the control group (84%), which was consistence throughout the study. Cure rate at the end of 24 weeks, was higher in Risorine group (92%) than in the control group (82%). Elevation of liver enzymes were observed in 3 patients in the Risorine group and in 9 patients in control group. CONCLUSIONS: Risorine, a novel formulation of low dose Rifampicin (200 mg), a bio enhancer Piperine (10 mg) and standard dose Isoniazid (300 mg) when given along with Ethambutol and Pyrazinamide was comparable in efficacy with standard WHO therapy using conventional formulation. Risorine provides more Rifampicin in blood compare to GI tract as well as maintaining higher blood levels on chronic therapy compared to conventional Rifampicin with better safety profile. Risorine gives higher sputum conversion rate during the Intensive Phase which is maintained till the end of study. Further a trend was also noticed towards better tolerability with newer formulation, Risorine. H = Isoniazid, R = Rifampicin, Z = Pyrazinamide and E = Ethambutol.

Gamification as a tool for enhancing graduate medical education.

INTRODUCTION: The last decade has seen many changes in graduate medical education training in the USA, most notably the implementation of duty hour standards for residents by the Accreditation Council of Graduate Medical Education. As educators are left to balance more limited time available between patient care and resident education, new methods to augment traditional graduate medical education are needed. OBJECTIVES: To assess acceptance and use of a novel gamification-based medical knowledge software among internal medicine residents and to determine retention of information presented to participants by this medical knowledge software. METHODS: We designed and developed software using principles of gamification to deliver a web-based medical knowledge competition among internal medicine residents at the University of Alabama (UA) at Birmingham and UA at Huntsville in 2012-2013. Residents participated individually and in teams. Participants accessed daily questions and tracked their online leaderboard competition scores through any internet-enabled device. We completed focus groups to assess participant acceptance and analysed software use, retention of knowledge and factors associated with loss of participants (attrition). RESULTS: Acceptance: In focus groups, residents (n=17) reported leaderboards were the most important motivator of participation. Use: 16 427 questions were completed: 28.8% on Saturdays/Sundays, 53.1% between 17:00 and 08:00. Retention of knowledge: 1046 paired responses (for repeated questions) were collected. Correct responses increased by 11.9% (p<0.0001) on retest. Differences per time since question introduction, trainee level and style of play were observed. Attrition: In ordinal regression analyses, completing more questions (0.80 per 10% increase; 0.70 to 0.93) decreased, while postgraduate year 3 class (4.25; 1.44 to 12.55) and non-daily play (4.51; 1.50 to 13.58) increased odds of attrition. CONCLUSIONS: Our software-enabled, gamification-based educational intervention was well accepted among our millennial learners. Coupling software with gamification and analysis of trainee use and engagement data can be used to develop strategies to augment learning in time-constrained educational settings.

A qualitative assessment of internal medicine resident perceptions of graduate medical education following implementation of the 2011 ACGME duty hour standards.

BACKGROUND: In 2011, the Accreditation Council of Graduate Medical Education implemented updated guidelines for medical resident duty hours, further limiting continuous work hours for first-year residents. We sought to investigate the impact of these restrictions on graduate medical education among internal medicine residents. METHODS: We conducted eight focus groups with internal medicine residents at the University of Alabama at Birmingham in 06/2012-07/2012. Discussion questions included, "How do you feel the 2011 ACGME work hour restrictions have impacted your graduate medical education?" Transcripts of the focus groups were reviewed and themes identified using a deductive/inductive approach. Participants completed a survey to collect demographic information and future practice plans. RESULTS: Thirty-four residents participated in our focus groups. Five themes emerged: decreased teaching, decreased experiential learning, shift-work mentality, tension between residency classes, and benefits and opportunities. Residents reported that since implementation of the guidelines, teaching was often deferred to complete patient-care tasks. Residents voiced concern that PGY-1 s were not receiving adequate clinical experience and that procedural and clinical reasoning skills are being negatively impacted. PGY-1 s reported being well-rested and having increased time for independent study. CONCLUSIONS: Residents noted a decline in teaching and are concerned with the decrease in "hands-on" clinical education that is inevitably impacted by fewer hours in the hospital, though some benefits were also reported. Future studies are needed to further elucidate the impact of decreased resident work hours on graduate medical education.

Influence of the timing of cardiac surgery on the outcome of patients with infective endocarditis and stroke.

BACKGROUND: The timing of cardiac surgery after stroke in infective endocarditis (IE) remains controversial. We examined the relationship between the timing of surgery after stroke and the incidence of in-hospital and 1-year mortalities. METHODS: Data were obtained from the International Collaboration on Endocarditis-Prospective Cohort Study of 4794 patients with definite IE who were admitted to 64 centers from June 2000 through December 2006. Multivariate logistic regression and Cox regression analyses were performed to estimate the impact of early surgery on hospital and 1-year mortality after adjustments for other significant covariates. RESULTS: Of the 857 patients with IE complicated by ischemic stroke syndromes, 198 who underwent valve replacement surgery poststroke were available for analysis. Overall, 58 (29.3%) patients underwent early surgical treatment vs 140 (70.7%) patients who underwent late surgical treatment. After adjustment for other risk factors, early surgery was not significantly associated with increased in-hospital mortality rates (odds ratio, 2.308; 95% confidence interval [CI], .942-5.652). Overall, probability of death after 1-year follow-up did not differ between 2 treatment groups (27.1% in early surgery and 19.2% in late surgery group, P = .328; adjusted hazard ratio, 1.138; 95% CI, .802-1.650). CONCLUSIONS: There is no apparent survival benefit in delaying surgery when indicated in IE patients after ischemic stroke. Further observational analyses that include detailed pre- and postoperative clinical neurologic findings and advanced imaging data (eg, ischemic stroke size), may allow for more refined recommendations on the optimal timing of valvular surgery in patients with IE and recent stroke syndromes.

tert-Butyl 4-{[2-amino-4-(2-hy-droxy-phen-yl)pyrimidin-5-yl]meth-yl}piperazine-1-carboxyl-ate.

In the title compound, C20H27N5O3, the central piperazine ring adopts a chair conformation, with the N-bound carboxyl-ate and methyl-ene substituents occupying bis-ectional and equatorial orientations, respectively. A twist is evident between the aromatic rings [dihedral angle = 25.61 (9)°] but an intra-molecular O-H⋯N hydrogen bond persists between these. Supra-molecular tapes along [1-10] are formed in the crystal packing through N(amino)-H⋯O(hydrox-yl) and N(amino)-H⋯N(pyrimidin-yl) hydrogen bonds, and these are linked into layers in the ab plane by π-π inter-actions [inter-centroid distance between pyrimidinyl rings = 3.5919 (9) Å].

4-(2H-1,3-Benzodioxol-5-yl)-1-(4-methyl-phenyl)-1H-pyrazol-5-amine.

In the title compound, C17H15N3O2, two independent mol-ecules (A and B) comprise the asymmetric unit. The major conformational difference arises in the relative orientation of the pyrazole ring amine and dioxole substituents which are anti in A and syn in B. The five-membered dioxole ring in each mol-ecule has an envelope conformation with the methyl-ene C atom as the flap. The mean plane through the benzodioxole and benzene groups make dihedral angles of 31.67 (8) and 68.22 (9)°, respectively, with the pyrazole ring in A; the equivalent values for B are 47.18 (7) and 49.08 (9)°. In the crystal, supra-molecular zigzag chains along the b-axis direction arise as a result of N-H⋯N hydrogen bonding. These are consolidated into supra-molecular double chains via C-H⋯O and C-H⋯π inter-actions.

Morpho-biochemical characterization and molecular marker based genetic diversity of pearl millet (Pennisetum glaucum (L.) R. Br.).

Pearl millet is a key food for millions living in semi-arid and arid regions and is a main diet for poorer populations. The genetic diversity existing in the pearl millet germplasm can be used to improve the micronutrient content and grain yield. Effective and organized exploitation of diversity at morphological and DNA levels is the strategy for any crop improvement program. In this study, the genetic diversity of 48 pearl millet genotypes was evaluated for eight morphological traits and eleven biochemical characters. All genotypes were also characterized using twelve SSR and six SRAP markers to evaluate genetic diversity. The significant mean difference between morphological and biochemical traits were detected. The productive tillers per plant varied from 2.65 to 7.60 with a mean of 4.80. The grain yield of genotypes varied more than 3× from 15.85 g (ICMR 07222) to 56.75 g (Nandi 75) with an average of 29.54 g per plant. Higher levels of protein, iron, and zinc contents were found to be present in ICMR 12555 (20.6%), ICMR 08666 (77.38 ppm), and IC 139900 (55.48 ppm), respectively, during the experiment. Substantial variability was observed for grain calcium as it ranged from 100.00 ppm (ICMR 10222) to 256.00 ppm (ICMR 12888). The top eight nutrient-dense genotypes flowered in 34-74 days and had 5.71-9.39 g 1,000 grain weight. Genotype ICMR 08666 was superior for Fe, Zn, K and P. The inter-genotype similarity coefficient at the genetic level, generated using DNA markers, ranged from 0.616 to 0.877 with a mean of 0.743. A combination of morpho-biochemical traits and DNA markers based diversity may help to differentiate the genotypes and diverse genotypes can be used in breeding programs to improve the mineral content in pearl millet.

Leveraging Technology and Gamification to Engage Learners in a Microbiology Curriculum in Undergraduate Medical Education.

Background: Microbiology is a critical and expansive topic that many medical schools' curriculum must teach in a constrained time frame. We implemented a microbiology question bank smart phone app enhanced with game elements and clinical pearls during a microbiology course for first-year medical students. We hypothesized that these enhancements and clinical pearls would engage the students meaningfully and increase their knowledge base. Methods: Though use was optional, students' game play was recorded through the app, which was compared to test grades retrospectively. A player efficiency rating (PER) was calculated as a function of question response, accuracy, and engagement. Students were separated into tertiles of PER and median exam grades were compared using a non-parametric Kruskal-Wallis (KW) test. An anonymous satisfaction and usability feedback survey was also administered. Results: One hundred eighty-one of the 189 students (96%) answered at least one question, and 165 (87%) completed all 56 questions. The average PER was 84.75. We received feedback surveys from 61 (34%) students in the course, with positive responses regarding the perceived impact on learning microbiology. The KW test found a positive correlation for median exam scores of the player groups when divided into tertiles by PER (p = 0.0002). Conclusions: We leveraged gamification and clinical pearls to design a supplemental microbiology question bank. We found high engagement overall and higher class exam scores associated with greater use of the question bank.

Esophageal Cancer Complicated by a Distal Acquired Esophagopulmonary Fistula.

Description Esophageal respiratory fistulas, commonly found as a tracheoesophageal fistula (TEF), are abnormal connections between the esophagus and trachea. These can be congenital (infants) or acquired (malignancy). A more rare form of an esophageal respiratory fistula is an abnormal connection between the esophagus and the lung parenchyma-also known as an esophagopulmonary fistula. In our case, we present a middle-aged male with a history of esophageal cancer undergoing chemotherapy and radiation presenting into the intensive care unit for increasing shortness of breath and vomiting after eating found to have a rare form of a TEF causing his symptoms.

Developing structure-activity relationships for the prediction of hepatotoxicity.

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Assessment of genetic fidelity of micropropagated date palm (Phoenix dactylifera L.) plants by RAPD and ISSR markers assay.

RAPD (Random Amplified Polymorphic DNA) and ISSR (Inter-Simple Sequence Repeats) markers assay were employed to validate the genetic stability of date palm (Phoenix dactylifera L.) plants multiplied through somatic embryogenesis with upto forty two in vitro subcultures. Out of the 160 RAPD and 21 ISSR primers screened, 30 RAPD and 12 ISSR primers produced a total of 347 (246 RAPDs + 101 ISSRs) clear, distinct and reproducible amplicons, which were monomorphic across all micropropagated plants (27) studied. Thus, a total 8592 bands (number of plants analysed x number of amplicons with all the primers) were generated which exhibited homogeneous banding patterns with both RAPD and ISSR markers. These results indicate that the micropropagation protocol developed by us for rapid in vitro multiplication is appropriate and suitable for clonal propagation of date palm and corroborated the fact that somatic embryogenesis can also be used as one of the safest modes for production of true-to-type plants.

Safety and efficacy of tocilizumab in the treatment of severe acute respiratory syndrome coronavirus-2 pneumonia: A retrospective cohort study.

Background: Cytokine release storm (CRS) in severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is thought to be the cause for organ damage and death which is independent of the actual viral burden. Tocilizumab (TCZ), an interleukin-6 receptor antagonist, is approved for the treatment of CRS. We describe the efficacy and safety of TCZ in SARS CoV-2 pneumonia. Methods: This retrospective study was conducted at a tertiary care hospital from April 20 2020 to May 21 2020. The primary endpoint was the cumulative incidence of a composite of either need for admission to the intensive care unit (ICU) with invasive mechanical ventilation or death. Safety outcomes included an increase in liver transaminases and/or evidence of infection. Results: A total of 20 patients received TCZ during the study period. The median age was 54 years (95% confidence interval [CI] 47-63). About 85% of the patients were male. Nearly 70% of the patients had at least one comorbidity. About 55% required ICU admission. The median duration of ICU stay was 11 days (95% CI: 3-13 days). The cumulative incidence of the requirement for mechanical ventilation, clinical improvement and mortality was 11% (95% CI: 0.03%-1%), 74% (95% CI 37%-89%) and 25% (95% CI: 11%-63%), respectively. There was no difference in outcomes according to age, gender or computed tomography severity score. Asymptomatic transaminitis was the most common drug reaction (55%), and one patient developed bacteraemia. Conclusions: TCZ is likely a safe and effective modality of treatment for improving clinical and laboratory parameters of SARS CoV-2 patients with a reduction in ICU stay and ventilatory care need.

Community-associated meticillin-resistant Staphylococcus aureus infections: epidemiology, recognition and management.

Meticillin-resistant Staphylococcus aureus (MRSA) is an important cause of infection, particularly in hospitalized patients and those with significant healthcare exposure. In recent years, epidemic community-associated MRSA (CA-MRSA) infections occurring in patients without healthcare risk factors have become more frequent. The most common manifestation of CA-MRSA infection is skin and soft tissue infection, although necrotizing pneumonia, sepsis and osteoarticular infections can occur. CA-MRSA strains have become endemic in many communities and are genetically distinct from previously identified MRSA strains. CA-MRSA may be more capable colonizers of humans and more virulent than other S. aureus strains. Specific mechanisms of pathogenicity have not been elucidated, but several factors have been proposed as responsible for the virulence of CA-MRSA, including the Panton-Valentine leukocidin, phenol-soluble modulins and type I arginine catabolic mobile element. The movement of CA-MRSA strains into the nosocomial setting limits the utility of using clinical risk factors alone to designate community- or healthcare-associated status. Identification of unique genetic characteristics and genotyping are valuable tools for MRSA epidemiological studies. Although the optimum pharmacological therapy for CA-MRSA infections has not been determined, many CA-MRSA strains remain broadly susceptible to several non-beta-lactam antibacterial agents. Empirical antibacterial therapy should include an MRSA-active agent, particularly in areas where CA-MRSA is endemic.

An expert system approach to the assessment of hepatotoxic potential.

Hepatotoxicity is a major cause of pharmaceutical drug attrition and is also a concern within other chemical industries. In silico approaches to the prediction of hepatotoxicity are an important tool in the early identification of adverse effects in the liver associated with exposure to a chemical. Here, we describe work in progress to develop an expert system approach to the prediction of hepatotoxicity, focussing particularly on the identification of structural alerts associated with its occurrence. The development of 74 such structural alerts based on public-domain literature and proprietary data sets is described. Evaluation results indicate that, whilst these structural alerts are effective in identifying the hepatotoxicity of many chemicals, further research is needed to develop additional structural alerts to account for the hepatotoxicity of a number of chemicals which is not currently predicted. Preliminary results also suggest that the specificity of the structural alerts may be improved by the combined use of applicability domains based on physicochemical properties such as log P and molecular weight. In the longer term, the performance of predictive models is likely to benefit from the further integration of diverse data and prediction model types.

Association of fluconazole pharmacodynamics with mortality in patients with candidemia.

Recent studies of nonneutropenic patients with candidemia or candidiasis suggest that fluconazole pharmacodynamic parameters correlate with clinical outcomes; however, additional data of correlation to mortality in patients with candidemia would be valuable. We assessed the impact of MICs for Candida, fluconazole pharmacodynamics, and patient characteristics on all-cause mortality with use of a prospective cohort of 96 hospitalized patients with candidemia. Among 84 patients for whom Candida isolates were available for testing, the most frequent Candida species isolated were Candida albicans (44%), followed by Candida parapsilosis (20.2%), and Candida glabrata (20.2%). Fluconazole resistance (MIC of >or=64 microg/ml) was present in 7 (8.3%) to 10 (11.9%) of 84 isolates, depending on the MIC endpoint determination method (50% or 80% inhibition read at 24 or 48 h). Overall mortality occurred in 27 (28.1%) of 96 patients, and nonsurvivors were more likely to have fluconazole-resistant isolates (25% versus 6.7%; P = 0.02). Multivariable analysis demonstrated an association between fluconazole resistance and mortality, but it did not reach statistical significance (odds ratio, 5.3; 95% confidence interval, 0.8 to 33.4; P = 0.08). By pharmacodynamic analysis, a fluconazole area under the concentration-time curve/MIC of <11.5 or MIC of >or=64 was associated with increased patient mortality (P

Active surveillance to determine the impact of methicillin-resistant Staphylococcus aureus colonization on patients in intensive care units of a Veterans Affairs Medical Center.

OBJECTIVE: The impact of methicillin-resistant Staphylococcus aureus (MRSA) colonization on mortality has not been well characterized. We sought to describe the impact of MRSA colonization on patients admitted to intensive care units (ICUs) in the Birmingham Veterans Affairs Medical Center (VAMC). METHODS: We conducted a retrospective cohort study of ICU patients at the Birmingham VAMC during 2005 to evaluate the predictors of MRSA colonization and determine its effect on clinical outcomes. Surveillance cultures for MRSA were performed on admission to the ICU and weekly thereafter. Clinical findings, the incidence of MRSA infection, and mortality within 3 months after ICU admission were recorded. Predictors of mortality and S. aureus colonization were determined using multivariable models. RESULTS: S. aureus colonization was present in 97 (23.3%) of 416 patients screened, of whom 67 (16.1%) were colonized with methicillin-susceptible S. aureus (MSSA) and 30 (7.2%) with MRSA. All-cause mortality at 3 months among MRSA-colonized patients was significantly greater than that among MSSA-colonized patients (46.7% vs 19.4%; P = .009). MRSA colonization was an independent predictor of death (adjusted odds ratio [OR], 3.7 [95% confidence interval [CI], 1.5-8.9]; P = .003) and onset of MRSA infection after hospital discharge (adjusted OR, 7.6 [95% CI, 2.48-23.2]; P < .001). Risk factors for MRSA colonization included recent antibiotic use (adjusted OR, 4.8 [95% CI, 1.9-12.2]; P = .001) and dialysis (adjusted OR, 18.9 [95% CI, 2.1-167.8]; P = .008). CONCLUSIONS: Among ICU patients, MRSA colonization is associated with subsequent MRSA infection and an all-cause mortality that is greater than that for MSSA colonization. Active surveillance for MRSA colonization may identify individuals at risk for these adverse outcomes. Prospective studies of outcomes in MRSA-colonized patients may better define the role of programs for active MRSA surveillance.

Dissemination of community-associated methicillin-resistant Staphylococcus aureus in a tertiary care hospital.

BACKGROUND: The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) was investigated at a tertiary care hospital, and relationship was made between the clinical and genetic definitions of community- and healthcare-associated MRSA. METHODS: Nonduplicate isolates of S. aureus were collected during 2004. Isolates were classified clinically as community-associated (CA) or healthcare-associated (HA). Molecular typing studies were performed on the isolates. RESULTS: Four hundred and two S. aureus isolates were collected, of which 281 (70%) were MRSA. By clinical definition, 58 (21%) were classified as CA-MRSA and 215 (77%) as HA-MRSA. Among CA-MRSA, 36 (62%) harbored a SCCmec type IV gene. None of the SCCmec type IV CA-MRSA expressed inducible clindamycin resistance (MLSBi). Among 57 HA-MRSA isolates, 31 (54.4%) harbored a SCCmec type IV gene; MLSBi present in 5 (16%). Type IV SCCmec MRSA were most often associated with skin and soft tissue infections (RR 3.34 95% CI 1.43, 7.8). USA300 was the most common genotype among both CA- and HA-MRSA. CONCLUSIONS: Community-associated MRSA is a prominent pathogen with its most common genotype, USA300, representing a significant proportion of CA- and HA-MRSA infections in our institution. Clinical definitions of CA- and HA- status do not correlate well with the genetic definitions, particularly for HA-MRSA.