Narrowing performance gap between rural and urban hospitals for acute myocardial infarction care.

BACKGROUND: Rural communities experience significant barriers to quality healthcare, including disparities in medical care following acute myocardial infarctions (AMI). This study sought to determine if the population density of the county where Medicare patients were hospitalized following AMI predicted short-term outcomes and to quantify longitudinal changes in hospital performance on quality of care metrics. METHODS: Hospital-level data was queried from the 2012 and 2018 Centers for Medicare & Medicaid Services archives. Each hospital was classified based on residing county using the National Center for Health Statistics Rural-Urban Continuum Codes (RUCC). Variations and longitudinal changes in risk-adjusted outcomes and quality of care metrics were stratified by RUCC classification and analyzed. RESULTS: Among the 4798 hospitals identified, rural hospitals had significantly higher risk-adjusted 30-day mortality (rs = 0.095, p < 0.001) and decreased statin prescribed at discharge (rs = -0.066, p = 0.004). Only aspirin (R2 = 0.003, p = 0.024) and statin (R2 = 0.006, p = 0.001) prescribed at discharge were correlated with improved 30-day mortality. Despite these differences, from 2012 to 2018 the performance gap between rural and urban hospitals narrowed for all but one quality of care metric, with concurrent 1.83% [95% CI 1.76-1.90] and 3.37% [95% CI 3.30-3.44] reductions in mortality and hospital readmissions, respectively. CONCLUSIONS: In the United States, only modest variations currently exist between rural and urban hospitals in the medical care of AMI. Although the performance gap has narrowed, new strategies to improve timely and effective care are necessary to alleviate residual cardiovascular healthcare disparities in rural communities.

Assessing a Novel Method of Calculation of the Cobb Angle for Scoliosis: Interexaminer Reliability and Student Satisfaction.

OBJECTIVE: The objectives of this pilot study were to compare the interexaminer reliability of 2 different methods of Cobb angle measurement and to determine whether the participants considered 1 of the 2 methods easier to learn, understand, and apply. METHODS: Entry-level anatomy students who have familiarity with vertebral column anatomy but have not had previous radiology training were instructed on how to measure a Cobb angle. Each student measured 2 curves (thoracic and lumbar) on a single radiograph, first with the traditional method of Cobb angle measurement and second with a novel method of Cobb angle measurement using a digital level. RESULTS: The variance of measurements decreased by using the novel method from thoracic to lumbar measurements and for the moderate and severe scoliosis films. All decreases in variance were statistically significant except for the lumbar measurement variance for the severe scoliosis film. The novel method of Cobb angle measurement with these same participants showed interexaminer reliability. More than 78% of naive participants considered the proposed method easier to learn, understand, and apply when compared with the traditional method. CONCLUSION: In this group of naive students, there was improved interrater reliability, greater satisfaction, and reduced measurement variances in some cases, with a novel method using a digital level to measure the Cobb angle compared with the traditional method of measurement.

Synergistic effect of age and body mass index on mortality and morbidity in general surgery.

BACKGROUND: The elderly population (aged 65 y and older) is expected to be the dominant age group in the United States by 2030. In addition, the prevalence of obesity in the United States is growing exponentially. Obese elderly patients are increasingly undergoing elective or emergent general surgery. There are few, if any, studies highlighting the combined effect of age and body mass index (BMI) on surgical outcomes. We hypothesize that increasing age and BMI synergistically impact morbidity and mortality in general surgery. MATERIALS AND METHODS: We collected individual-level, de-identified patient data from the Michigan Surgical Quality Collaborative. Subjects underwent general surgery with general anesthetic, were >18 y, and had a BMI between 19 and 60. Primary and secondary outcomes were 30-d "Any morbidity" and mortality (from wound, respiratory, genitourinary, central nervous system, and cardiac systems), respectively. Preoperative risk variables included diabetes, dialysis, steroid use, cardiac risk, wound classification, American Society of Anesthesiology class, emergent cases, and 13 other variables. We conducted binary logistic regression models for 30-d morbidity and mortality to determine independent effects of age, BMI, interaction between both age and BMI, and a saturated model for all independent variables. RESULTS: We identified 149,853 patients. The average age was 54.6 y, and the average BMI was 30.9. Overall 30-d mortality was 2%, and morbidity was 6.7%. Age was a positive predictor for mortality and morbidity, and BMI was negatively associated with mortality and not significantly associated with morbidity. Age combined with higher BMI was positively associated with morbidity and mortality when the higher age groups were analyzed. Saturated models revealed age and American Society of Anesthesiology class as highest predictors of poor outcomes. CONCLUSIONS: Although BMI itself was not a major independent factor predicting 30-d major morbidity or mortality, the morbidly obese, elderly (>50 and 70 y, respectively) subgroup may have an increased morbidity and mortality after general surgery. This information, along with patient-specific factors and their comorbidities, may allow us to better take care of our patients perioperatively and better inform our patients about their risk of surgical procedures.

Access to care by Medicare beneficiaries in the U.S. with diabetes and multiple chronic conditions during the COVID-19 pandemic.

OBJECTIVE: Determine characteristics of Medicare beneficiaries with diabetes and multiple chronic conditions (MCC) associated with being unable to obtain medical services during COVID-19. RESEARCH DESIGN AND METHODS: Retrospective cohort study of data from COVID-19 Supplements of Medicare Current Beneficiary Surveys administered in Summer (N = 11,114, unweighted) and Fall (N = 9686, unweighted) 2020, and Winter 2021 (N = 11,107, unweighted). Binary logistic regression was used to model for adjusted odds of self-reports of being unable to access different types of care. RESULTS: In three time periods from March 2020 through March/April 2021 beneficiaries with diabetes plus MCC combinations reported being unable to get medical care, compared to beneficiaries with diabetes alone. Notably, patterns persisted at the 12-month mark with beneficiaries with diabetes plus cancer (OR = 1.24), and diabetes plus cancer/stroke (OR = 2.53) experiencing increased odds of being unable to get care because of COVID-19, compared to beneficiaries with diabetes alone. By March/April 2021 beneficiaries with diabetes plus COPD (OR = 1.08), diabetes plus stroke (OR = 1.49), and diabetes plus Alzheimer's (OR = 1.09) experienced increased odds of being unable to get treatment for ongoing conditions. Beneficiaries with diabetes plus Alzheimer's (OR = 1.40) also experienced increased odds of being unable to get a regular check-up 12 months into the pandemic. Finally, members of racial/ethnic minority groups experienced increased odds of being unable to obtain services at various times during the pandemic compared to non-Hispanic Whites, with increased odds persisting at 12 months for non-Hispanic Blacks and Hispanics. CONCLUSIONS: Beneficiaries with MCC, and minorities, experienced increased odds of being unable to obtain some services during COVID-19, even when controlling for similar diabetes and MCC combinations. Work remains for providers and public health systems to dismantle and reimagine systems to provide equitable access to care.

Knowledge and Behaviors Toward COVID-19 Among US Residents During the Early Days of the Pandemic: Cross-Sectional Online Questionnaire.

BACKGROUND: The early days of the coronavirus disease (COVID-19) pandemic in the United States brought uncertainty in the knowledge about COVID-19 and what to do about it. It is necessary to understand public knowledge and behaviors if we are to effectively address the pandemic. OBJECTIVE: The aim of this study is to test the hypothesis that knowledge about COVID-19 influences participation in different behaviors including self-reports of purchasing more goods than usual, attending large gatherings, and using medical masks. METHODS: This study was funded and approved by the Institutional Review Board on March 17, 2020. The cross-sectional online survey of 1034 US residents aged 18 years or older was conducted on March 17, 2020. RESULTS: For every point increase in knowledge, the odds of participation in purchasing more goods (odds ratio [OR] 0.88, 95% CI 0.81-0.95), attending large gatherings (OR 0.87, 95% CI 0.81-0.93), and using medical masks (OR 0.56, 95% CI 0.50-0.62) decreased by 12%, 13%, and 44%, respectively. Gen X and millennial participants had 56% and 76% higher odds, respectively, of increased purchasing behavior compared to baby boomers. The results suggest that there is a politicization of response recommendations. Democrats had 30% lower odds of attending large gatherings (OR 0.70, 95% CI 0.50-0.97) and 48% lower odds of using medical masks (OR 0.52, 95% CI 0.34-0.78) compared to Republicans. CONCLUSIONS: This survey is one of the first attempts to study determinants of knowledge and behaviors in response to the COVID-19 pandemic in the United States. A national, coordinated effort toward a pandemic response may ensure better compliance with behavioral recommendations to address this public health emergency.

Procedural outcomes of deep brain stimulation (DBS) surgery in rural and urban patient population settings.

Presently, disparities exist between race, sex, socioeconomic status, hospitals, income, comorbidities, and insurance profiles of patients undergoing DBS surgery. Here, we aim to highlight several variables and their predictive powers of DBS surgery outcomes as measured by dischargelocation, length of hospital stays, and total hospital charges. A retrospective cohort study using discharge data from NIS and HCUP for analyses and regression model statistics is performed. Comparative analyses demonstrate urban patients were more often non-routinely discharged, possessed private insurance, and accrued greater hospital costs compared to rural patients. Moreover, regression analyses predicts urban patients have 70% lower odds of routine discharge while those with a major loss of function prior to surgery also have 81% lower odds of routine discharge compared to those with minor loss of function. Ultimately, our study found urban patients or patients with major illnesses have higher hospital charges, longer hospitalization, and more often non-routinely discharged.

Disparities in diabetes-related multiple chronic conditions and mortality: The influence of race.

AIMS: The aims of this study are to confirm disparities in diabetes mortality rates based on race, determine if race predicts combinations of diabetes and multiple chronic conditions (MCC) that are leading causes of death (LCD), and determine if combinations of diabetes plus MCC mediate the relationship between race and mortality. METHODS: We performed a retrospective cohort study of 443,932 Medicare beneficiaries in the State of Michigan with type 2 diabetes mellitus and MCC. We applied Cox proportional hazards regression to determine predictors of mortality. We applied multinomial logistic regression to determine predictors of MCC combinations. RESULTS: We found that race influences mortality in Medicare beneficiaries with Type 2 diabetes mellitus and MCC. Prior to adjusting for MCC combinations, we observed that Blacks and American Indian/Alaska Natives have increased risk of mortality compared to Whites, while there is no difference in mortality between Hispanics and Whites. Regarding MCC combinations, Black/African American beneficiaries experience increased odds for most MCC combinations while Asian/Pacific Islanders and Hispanics experience lower odds for MCC combinations, compared to Whites. When adjusting for MCC, mortality disparities observed between Whites, Black/African Americans, and American Indians/Alaska Natives persist. CONCLUSIONS: Compared to Whites, Black/African Americans in our cohort had increased odds of most MCC combinations, and an increased risk of mortality that persisted even after adjusting for MCC combinations.

Rural, urban, and teaching hospital differences in hip fracture mortality.

INTRODUCTION: Hip fractures remain one of the most prevalent and deadly conditions afflicting those 65 years and older. For other health conditions (e.g. myocardial infarction), hospital location is associated with poorer health outcomes. To our knowledge, no study has investigated the relationship between hip fracture morality rate in the United States between urban and rural hospital settings. METHODS: A retrospective cohort study was conducted to examine differences in in-hospital mortality between groups treated in rural, urban-teaching, and urban-non-teaching hospitals, as well as public and private hospitals. Mortality rates were also compared for variances between surgical treatment, sex, insurance, patient location, race, and income. Discharge data was collected for 256,240 inpatient stays from the 2012 National Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality. RESULTS: Odds of mortality were 14.6% greater in rural hospital hip fracture patients compared to Urban/Non-Teaching centers (p < 0.05). CONCLUSIONS: Results from this study lend support to necessitate further research investigating prospective barriers to care of those in rural settings. This may point to limitations in resources and trained medical and surgical specialists in rural hospitals and need for continued research to mitigate such findings.

Differences in spending for diabetes and multiple chronic conditions in Michigan Medicare beneficiaries.

OBJECTIVES: To determine which combinations of type 2 diabetes (T2D) and multiple chronic conditions (MCC) contribute to total spending and differences in spending between groups based on sex, race/ethnicity, and rural residency. STUDY DESIGN: Retrospective cohort study using 2012 Medicare claims data from beneficiaries in Michigan with T2D. METHODS: Zero-inflated Poisson regression models to estimate relationships of demographic characteristics and MCC combinations on hospital outpatient, acute inpatient, skilled nursing, hospice, and Part D drug spending. RESULTS: Across most MCC combinations, there are lower odds of no spending, with a concurrent increase in the expected mean of actual spending when payments are made, except for hospital outpatient costs. For hospital outpatient services, we observed lower spending across all MCC combinations. When controlling for MCC, we generally found that compared with White beneficiaries, Black, Asian/Pacific Islander, and Hispanic beneficiaries experience increased odds of no spending, but when payments were made, payments generally increased. American Indian/Alaska Native beneficiaries are the exception; they experience decreased odds of no payments for hospital outpatient and acute inpatient services, with a concurrent decrease in mean expected payments. CONCLUSIONS: When considering a range of MCC combinations, we observed differences in total payments between racial/ethnic minority groups and White beneficiaries. Our results highlight the ongoing need to make changes in the health care system to make the system more accessible to racial/ethnic minority groups.

Type 2 Diabetes and Chronic Conditions Disparities in Medicare Beneficiaries in the State of Michigan.

BACKGROUND: This study aimed to describe the prevalence of type 2 diabetes and combinations of multiple chronic conditions (MCCs) that are leading causes of death (LCD) and confirm that disparities exist between groups based on race and sex. MATERIALS AND METHODS: We conducted a retrospective cohort study using 2012 Medicare claims data from beneficiaries with type 2 diabetes over the age of 65 in the state of Michigan. RESULTS: Female beneficiaries have type 2 diabetes and 1 or more MCCs that are LCD more often than males. Most type 2 diabetes patients have diabetes alone without MCCs, while a large proportion have at least 1 additional chronic condition that is a LCD. One in 3 patients have 3 or more chronic conditions. The most prevalent type 2 diabetes coexisting MCCs are congestive heart failure (CHF), chronic obstructive pulmonary disease and chronic kidney disease. Asian/Pacific Islanders have the highest prevalence of type 2 diabetes without MCCs, and the highest prevalence of diabetes plus CHF. While fewer black beneficiaries have diabetes alone or 1 additional MCC, the prevalence of 3 or more MCCs in blacks generally exceeds the prevalence in other races. In beneficiaries with newly diagnosed type 2 diabetes, chronic obstructive pulmonary disease and CHF are the first new chronic conditions to be diagnosed after an initial type 2 diabetes diagnosis. CONCLUSIONS: Race and sex disparities occur in the prevalence of type 2 diabetes and MCCs that are LCD in Medicare beneficiaries in the state of Michigan.

In-hospital Mortality, Length of Stay, and Discharge Disposition in a Cohort of Rural and Urban American Indians and Alaska Natives.

This study uses data from the 2012 National Inpatient Sample to determine if mortality, length of stay, and discharge disposition are different between rural and urban American Indians and Alaska Natives (AI/ANs) with alcohol abuse, depression, diabetes, and post-traumatic stress disorder. Results show no difference in mortality between groups. Alcohol abuse, depression, and diabetes are less prevalent in rural AI/ANs, and rural patients have shorter lengths of stay and fewer chronic conditions, diagnoses, and procedures. Finally, urban patients are discharged to short-term hospitals or skilled nursing facilities at higher rates. Rural diabetes patients exhibit increased mortality, but there is little evidence that rurality adversely affects the AI/AN population for the conditions we studied.

Treatment and prevention practices in postmenopausal women after bone mineral density screening at a community-based osteoporosis project.

OBJECTIVE: To determine the use of treatment and prevention practices in postmenopausal women who have received the results of an osteoporosis screening. METHODS: Telephone survey to follow-up with women who underwent dual-energy x-ray absorptiometry scanning at a community-wide osteoporosis screening project. Participants categorized by their scan results as having normal bone mineral density or low bone mineral density were asked about their osteoporosis treatment and prevention practices since receiving their scan results. RESULTS: Two hundred nineteen women were interviewed. Calcium supplement use increased significantly in both groups (P=.002). There was no significant difference in the number of women using alendronate sodium, calcitonin, and selective estrogen receptor modulators before and after screening. Both groups reported increases in exercise levels and dairy intake, but the difference was not statistically significant. CONCLUSIONS: Our results indicate that the use of over-the-counter calcium supplements increases after osteoporosis screening. However, the use of treatments that require a physician prescription does not increase after screening regardless of the patient's bone mineral density status.

From Introduction to Integration: Providing Community-Engaged Structure for Interprofessional Education.

BACKGROUND: Training future healthcare profession students using interprofessional education (IPE) is critical to improve quality of health care and patient safety. OBJECTIVE: The objective of this study was to implement an IPE program and determine student satisfaction with each session, including a clinical case requiring teams with members from each profession addressing clinical scenarios. SUBJECTS: The subjects of this study were students from Athletic Training, Medicine, Nursing, Pharmacy, Physical Therapy, Physician Assistant, Social Work, and Speech-Language Pathology. METHODS: Evaluations, administered to all participating students, consisted of Likert-style responses, rating agreement with a series of questions, and space for descriptive comments. Score differences for each question were compared using independent group t-tests with a P-value of 0.05 to determine statistical significance. RESULTS: There were statistically higher satisfaction ratings for the problem-based learning case when compared to less interactive sessions (P < 0.0001). CONCLUSION: Students perceived benefits of the IPE program. Perceptions improved when various students had the opportunity to work together on clinically relevant problems.

Stromelysin-1 (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase-3 are overexpressed in the wall of abdominal aortic aneurysms.

BACKGROUND: Atherosclerosis is implicated in the pathogenesis of abdominal aortic aneurysm (AAA) but more often causes aortic occlusive disease (AOD). The matrix metalloproteinases (MMPs) degrade extracellular matrix and may play a central role in the pathogenesis of AAA. The aim of this study was to examine differences in the patterns of MMP and MMP inhibitor expression between AAA and AOD. METHODS AND RESULTS: The expression of mRNA for 14 MMPs and 4 tissue inhibitors of metalloproteinases (TIMPs) was estimated in samples of aortic wall from 8 patients with AAA and 8 with AOD using the reverse-transcriptase polymerase chain reaction with a synthetic multicompetitor standard. AAA wall expressed significantly more stromelysin-1 (MMP-3) (mean log(10) ratio [copy enzyme cDNA/copy GAPDH cDNA], -1.9; range, -3.3 to -0.7) than the AOD wall (mean, 4; range, -5.7 to -2.4), P<0.005. TIMP-3 expression was significantly higher in AAA (mean, -1.7; range, -2.9 to -1.0) than AOD (mean, -3.6; range, -5.7 to -1.8), P<0.01. Expression of 8 other MMPs (1, 2, 7, 9, 11, 12, 14, and 17) was detected and was similar in AAA and AOD. Expression of the remaining 5 MMPs (-8, -10, -13, -15, and -16) was not detected in any of the samples. CONCLUSIONS: Both AAA and AOD walls express similar levels of a wide range of MMPs, including cell membrane-bound MT-MMPs. Stromelysin-1 (MMP-3) and TIMP-3 were, however, over expressed in the AAA samples and may be involved aneurysm pathogenesis. Stromelysin-1 could provide a target for pharmacological inhibition.

Novel approaches to antimicrobial therapy: peptide deformylase.

Peptide deformylase (PDF) represents one of the most exciting new targets for the development of novel antimicrobial chemotherapies. PDF is an essential bacterial metalloenzyme that deformylates the N-formylmethionine of newly synthesized bacterial polypeptides. Recent progress in understanding the structure and function of PDF has greatly facilitated the drug discovery process. In this article, the potential of PDF as an antimicrobial target is reviewed, and progress in the development of PDF inhibitors (PDFIs) is highlighted. Several structural classes of compounds have been reported as inhibitors of PDF. However, the real challenge has been in obtaining molecules with potent in vivo antibacterial activity against a range of drug-resistant pathogens. One of the more encouraging compounds reported, BB-83698 (British Biotech plc/Genesoft Inc), has shown in vivo efficacy against Streptococcus pneumoniae in both mouse thigh and lung infection models at doses equivalent to existing therapies. The published data suggest that PDFIs are a promising new class of antimicrobial agent best suited to treat respiratory tract infections (RTIs), but with the potential for activity against a variety of other pathogens. It is anticipated that the first PDFI targeting RTIs will enter the clinic soon.

Prevalence of prevention and treatment modalities used in populations at risk of osteoporosis.

STUDY OBJECTIVE: Determine prevalence of osteoporosis screening and prevention and modes of treatment in women older than 65 years at risk of osteoporosis. METHODS: Retrospective chart review of older female patients seeking osteoporosis screening in the community setting. RESULTS: 399 women at risk of low bone mineral density (BMD) underwent dual-energy x-ray absorptiometry scanning. Among participants younger than 65 years (n=52), low BMD was diagnosed in 44.2%; among participants older than 65 years (n=347), low BMD was diagnosed in 70.0%, a statistically significant difference (P=.001). CONCLUSION: From a community-level perspective, the authors have shown that osteoporosis screening at local senior centers, living facilities, and health fairs is an effective tool for identifying low BMD in women at high risk of osteopenia and osteoporosis.

Outcomes of diabetic and nondiabetic patients undergoing general and vascular surgery.

Aims. Preoperative diabetic and glycemic screening may or may not be cost effective. Although hyperglycemia is known to compromise surgical outcomes, the effect of a diabetic diagnosis on outcomes is poorly known. We examine the effect of diabetes on outcomes for general and vascular surgery patients. Methods. Data were collected from the Michigan Surgical Quality Collaborative for general or vascular surgery patients who had diabetes. Primary and secondary outcomes were 30-day mortality and 30-day overall morbidity, respectively. Binary logistic regression analysis was used to identify risk factors. Results. We identified 177,430 (89.9%) general surgery and 34,006 (16.1%) vascular surgery patients. Insulin and noninsulin diabetics accounted for 7.1% and 9.8%, respectively. Insulin and noninsulin dependent diabetics were not at increased risk for mortality. Diabetics are at a slight increased odds than non-diabetics for overall morbidity, and insulin dependent diabetics more so than non-insulin dependent. Ventilator dependence, 10% weight loss, emergent case, and ASA class were most predictive. Conclusions. Diabetics were not at increased risk for postoperative mortality. Insulin-dependent diabetics undergoing general or vascular surgery were at increased risk of overall 30-day morbidity. These data provide insight towards mitigating poor surgical outcomes in diabetic patients and the cost effectiveness of preoperative diabetic screening.

Patient perceptions on the use of advance directives and life prolonging technology.

INTRODUCTION: Use of advance directives is underutilized despite the Patient Self Determination Act of 1990. This study was undertaken to determine use and opinions of advance directives by patients at a multidisciplinary. METHODS: Institutional Review Board-approved prospective survey of patients age 18 and over. RESULTS: Of 306 participants, 77 (25.2%) had a durable power of attorney and 45 (14.7%) had living wills. Of these, 226 (73.9%) responded that it was important to make health care wishes known to their doctor. Only 36 (15.9%) had done so. A total of 266 (86.9%) felt it was important to discuss health care wishes with their family and only 160 (60.1%) had done so. CONCLUSIONS: While adequately describing use and attitudes toward advance directives, it is significant to note that patients believe their wishes for end-of-life care will be honored; however, they fail to take the necessary steps to guarantee this.

In vitro antibacterial activity of the peptide deformylase inhibitor BB-83698.

OBJECTIVES: BB-83698 is a peptide deformylase inhibitor currently in clinical trials in Europe. The purpose of this study was to provide additional susceptibility data from clinical isolates, including drug-resistant strains. METHODS: The in vitro activities of BB-83698 and comparators were determined against 281 streptococci, 154 Staphylococcus aureus, 110 Haemophilus influenzae and 50 Moraxella catarrhalis strains selected for their resistance phenotypes. Broth microdilution MICs and MBCs were determined according to NCCLS guidelines. RESULTS: The MIC90s were 0.25-0.5 mg/L for S. pneumoniae, including penicillin-, erythromycin-, levofloxacin- and multidrug-resistant strains. The MIC90s for Streptococcus pyogenes and Streptococcus agalactiae were 0.12 mg/L and for viridans streptococci, the MIC90 was 0.5 mg/L. Against S. aureus, including oxacillin- and levofloxacin-resistant strains, and vancomycin-intermediate strains, the MIC90 was 8 mg/L. Against beta-lactamase-negative and -positive H. influenzae, the MIC90s were 32 and 64 mg/L, respectively, and against both beta-lactamase-negative and -positive M. catarrhalis the MIC90 was 0.12 mg/L. In MBC studies, the ratio of MBC/MIC was 1:1 or 2:1 against 31% of S. pneumoniae, 33% of S. aureus, 63% of H. influenzae and 9% of M. catarrhalis. CONCLUSIONS: Although BB-83698 has reduced in vitro activity against H. influenzae, it is a potent antimicrobial with excellent activity against streptococci and Moraxella.

Antibacterial activities and characterization of novel inhibitors of LpxC.

Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an Escherichia coli strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the alpha-(R)-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the Enterobacteriaceae, Serratia marcescens, Morganella morganii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia cepacia. BB-78484 was bactericidal against E. coli, achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis. E. coli mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the fabZ or lpxC genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.