Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS).

BACKGROUND: Sepsis is a major contributor to neonatal mortality, particularly in low-income and middle-income countries (LMICs). WHO advocates ampicillin-gentamicin as first-line therapy for the management of neonatal sepsis. In the BARNARDS observational cohort study of neonatal sepsis and antimicrobial resistance in LMICs, common sepsis pathogens were characterised via whole genome sequencing (WGS) and antimicrobial resistance profiles. In this substudy of BARNARDS, we aimed to assess the use and efficacy of empirical antibiotic therapies commonly used in LMICs for neonatal sepsis. METHODS: In BARNARDS, consenting mother-neonates aged 0-60 days dyads were enrolled on delivery or neonatal presentation with suspected sepsis at 12 BARNARDS clinical sites in Bangladesh, Ethiopia, India, Pakistan, Nigeria, Rwanda, and South Africa. Stillborn babies were excluded from the study. Blood samples were collected from neonates presenting with clinical signs of sepsis, and WGS and minimum inhibitory concentrations for antibiotic treatment were determined for bacterial isolates from culture-confirmed sepsis. Neonatal outcome data were collected following enrolment until 60 days of life. Antibiotic usage and neonatal outcome data were assessed. Survival analyses were adjusted to take into account potential clinical confounding variables related to the birth and pathogen. Additionally, resistance profiles, pharmacokinetic-pharmacodynamic probability of target attainment, and frequency of resistance (ie, resistance defined by in-vitro growth of isolates when challenged by antibiotics) were assessed. Questionnaires on health structures and antibiotic costs evaluated accessibility and affordability. FINDINGS: Between Nov 12, 2015, and Feb 1, 2018, 36 285 neonates were enrolled into the main BARNARDS study, of whom 9874 had clinically diagnosed sepsis and 5749 had available antibiotic data. The four most commonly prescribed antibiotic combinations given to 4451 neonates (77·42%) of 5749 were ampicillin-gentamicin, ceftazidime-amikacin, piperacillin-tazobactam-amikacin, and amoxicillin clavulanate-amikacin. This dataset assessed 476 prescriptions for 442 neonates treated with one of these antibiotic combinations with WGS data (all BARNARDS countries were represented in this subset except India). Multiple pathogens were isolated, totalling 457 isolates. Reported mortality was lower for neonates treated with ceftazidime-amikacin than for neonates treated with ampicillin-gentamicin (hazard ratio [adjusted for clinical variables considered potential confounders to outcomes] 0·32, 95% CI 0·14-0·72; p=0·0060). Of 390 Gram-negative isolates, 379 (97·2%) were resistant to ampicillin and 274 (70·3%) were resistant to gentamicin. Susceptibility of Gram-negative isolates to at least one antibiotic in a treatment combination was noted in 111 (28·5%) to ampicillin-gentamicin; 286 (73·3%) to amoxicillin clavulanate-amikacin; 301 (77·2%) to ceftazidime-amikacin; and 312 (80·0%) to piperacillin-tazobactam-amikacin. A probability of target attainment of 80% or more was noted in 26 neonates (33·7% [SD 0·59]) of 78 with ampicillin-gentamicin; 15 (68·0% [3·84]) of 27 with amoxicillin clavulanate-amikacin; 93 (92·7% [0·24]) of 109 with ceftazidime-amikacin; and 70 (85·3% [0·47]) of 76 with piperacillin-tazobactam-amikacin. However, antibiotic and country effects could not be distinguished. Frequency of resistance was recorded most frequently with fosfomycin (in 78 isolates [68·4%] of 114), followed by colistin (55 isolates [57·3%] of 96), and gentamicin (62 isolates [53·0%] of 117). Sites in six of the seven countries (excluding South Africa) stated that the cost of antibiotics would influence treatment of neonatal sepsis. INTERPRETATION: Our data raise questions about the empirical use of combined ampicillin-gentamicin for neonatal sepsis in LMICs because of its high resistance and high rates of frequency of resistance and low probability of target attainment. Accessibility and affordability need to be considered when advocating antibiotic treatments with variance in economic health structures across LMICs. FUNDING: The Bill & Melinda Gates Foundation.

Twenty-year survival after coronary artery surgery: an institutional perspective from Emory University.

BACKGROUND: Coronary artery bypass graft (CABG) surgery has been performed frequently for symptomatic coronary atherosclerotic heart disease for more than 30 years. However, uncertainty exists regarding the relationship between long-term survival after CABG and readily available clinical correlates of mortality. METHODS AND RESULTS: We studied outcome at 20 years by age, sex, and other variables in 3939 patients who had CABG surgery from 1973 to 1979 in the Emory University System of Healthcare. Twenty-year survival, freedom from myocardial infarction, and freedom from repeat CABG were 35.6% (95% confidence interval [CI], 33.9% to 37.3%), 66.6% (95% CI, 64.6% to 68.6%), and 59.1% (95% CI, 56.9% to 61.5%). Multivariate correlates of late mortality were age (hazard ratio [HR], 1.46 per 10 years), female sex (HR, 1.21), hypertension (HR, 1.44), angina class (HR, 1.07 per class increase of 1), prior CABG (HR, 1.72), ejection fraction (HR, 1.07 per 10-point decrease), number of vessels diseased (HR, 1.11 per 1-vessel increase), and weight (HR, 1.04 per 10 kg). Twenty-year survival by age was 55%, 38%, 22%, and 11% for age <50, 50 to 59, 60 to 69, and >70 years at the time of initial surgery. Survival at 20 years after surgery with and without hypertension was 27% and 41%, respectively. Similarly, 20-year survival was 37% and 29% for men and women. CONCLUSIONS: Symptomatic coronary atherosclerotic heart disease requiring surgical revascularization is progressive with continuing events and mortality. Clinical correlates of mortality significantly impact survival over time and may help identify long-term benefits after CABG.

Outcomes and long-term survival for patients undergoing mitral valve repair versus replacement: effect of age and concomitant coronary artery bypass grafting.

BACKGROUND: A paucity of literature is available on the effects of age and coronary artery bypass grafting (CABG) on the outcomes of patients undergoing mitral valve (MV) repair versus replacement. METHODS AND RESULTS: A matched study was performed using prospectively collected data from the Emory cardiovascular database from 1984 to 1997 comparing 625 MV repair patients with 625 MV replacement patients. Mean age was significantly higher in the replacement group (56+/-14 versus 55+/-14 years). Preoperative demographics and postoperative outcomes were similar between groups. Length of stay (LOS) was significantly less in the repair group (9.5+/-9.4 versus 12.3+/-13.1 days). In-hospital mortality was significantly less in the repair group (4.3% versus 6.9%), and overall 10-year survival was significantly higher in the repair group (62% versus 46%). Ten-year survival of patients <60 years of age was significantly higher in repair patients (81% versus 55%) but similar in patients > or =60 years of age (33% versus 36%, respectively). Ten-year survival of MV repair without CABG was significantly higher compared with MV replacement patients (74% versus 51%) but similar to patients with concomitant CABG (28% versus 34%, respectively). Independent predictors of long-term mortality included increasing age, urgent/emergent status, female sex, diabetes mellitus, increasing weight, heart failure, decreasing ejection fraction, concomitant CABG, and MV replacement. CONCLUSIONS: Mitral valve repair has reduced LOS and improved in-hospital and 10-year survival. However, in the present series, MV repair does not provide significant long-term survival benefit over MV replacement in patients older than 60 years of age or those requiring concomitant CABG.

Outcomes of repeat revascularization in diabetic patients with prior coronary surgery.

OBJECTIVES: This study evaluated both short- and long-term outcomes of diabetic patients who underwent repeat coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) after initial CABG. BACKGROUND: Although diabetic patients who have multivessel coronary disease and require initial revascularization may benefit from CABG as compared with PCI, the uncertainty concerning the choice of revascularization may be greater for diabetic patients who have had previous CABG. METHODS: Data were obtained over 15 years for diabetic patients undergoing PCI procedures or repeat CABG after previous coronary surgery. Baseline characteristics were compared between groups, and in-hospital, 5-year, and 10-year mortality rates were calculated. Multivariate correlates of in-hospital and long-term mortality were determined. RESULTS: Both PCI (n = 1,123) and CABG (n = 598) patients were similar in age, gender, years of diabetes, and insulin dependence, but they varied in presence of hypertension, prior myocardial infarction, angina severity, heart failure, ejection fraction, and left main disease. In-hospital mortality was greater for CABG, but differences in long-term mortality were not significant (10 year mortality, 68% PCI vs. 74% CABG, p = 0.14). Multivariate correlates of long-term mortality were older age, hypertension, low ejection fraction, and an interaction between heart failure and choice of PCI. The PCI itself did not correlate with mortality. CONCLUSIONS: The increased initial risk of redo CABG in diabetic patients and the comparable high long-term mortality regardless of type of intervention suggest that, except for patients with severe heart failure, PCI be strongly considered in all patients for whom there is a percutaneous alternative.

Routine measurement of outcomes in Australia's public sector mental health services.

OBJECTIVE: This paper describes the Australian experience to date with a national 'roll out' of routine outcome measurement in public sector mental health services. METHODS: Consultations were held with 123 stakeholders representing a range of roles. RESULTS: Australia has made an impressive start to nationally implementing routine outcome measurement in mental health services, although it still has a long way to go. All States/Territories have established data collection systems, although some are more streamlined than others. Significant numbers of clinicians and managers have been trained in the use of routine outcome measures, and thought is now being given to ongoing training strategies. Outcome measurement is now occurring 'on the ground'; all States/Territories will be reporting data for 2003-04, and a number have been doing so for several years. Having said this, there is considerable variability regarding data coverage, completeness and compliance. Some States/Territories have gone to considerable lengths to 'embed' outcome measurement in day-to-day practice. To date, reporting of outcome data has largely been limited to reports profiling individual consumers and/or aggregate reports that focus on compliance and data quality issues, although a few States/Territories have begun to turn their attention to producing aggregate reports of consumers by clinician, team or service. CONCLUSION: Routine outcome measurement is possible if it is supported by a co-ordinated, strategic approach and strong leadership, and there is commitment from clinicians and managers. The Australian experience can provide lessons for other countries.

Valve replacement in patients on chronic renal dialysis: implications for valve prosthesis selection.

BACKGROUND: Reports are sparse describing heart valve replacement in patients with end-stage renal disease. This review assesses a 15-year experience and outcomes after valve replacement in patients on chronic preoperative renal dialysis. METHODS: A computerized database, hospital records, and telephone contact provided outcome data for patients on chronic dialysis undergoing valve replacement between March 22, 1985, and October 13, 2000, in two hospitals. RESULTS: Seventy-two patients underwent 95 valve procedures (74 operations). Ages ranged from 23 years to 84 years (mean, 57 years). Fifty-five aortic, 30 mitral, and 3 tricuspid valve replacements and 7 valvuloplasties were performed. Six of the 74 procedures were reoperative valve replacements. In the 46 patients with reliable long-term (greater than 30 days) follow-up data, significant bleeding or stroke was documented in 17 of 34 patients with a mechanical valve and 1 of 12 patients with a bioprosthetic valve. Overall survival (including two operative deaths) was 72.8% at 3 months, 65.4% at 6 months, 60.5% at 1 year, 39.8% at 2 years, 28.5% at 3 years, and 15.9% at 6 years (Kaplan-Meier). Type of valve implanted did not influence early and late survival. CONCLUSIONS: In this series of patients on chronic dialysis, survival appears to justify valve replacement. However, the sixfold higher incidence of late bleeding or stroke in patients on dialysis with a mechanical valve requiring warfarin suggests that bioprosthetic valves are the valve substitute of choice in patients on chronic dialysis.

The negative event scale: measuring frequency and intensity of adult hassles.

This study examined the structure, concurrent validity, and reliability of a hassle measure for middle-aged adults in both event frequency and intensity recordings. The measure included a range of interpersonal day-to-day events and re-examined aspects of the primary appraisal confounding debate between Lazarus and colleagues (Lazarus, Delongis, Folkman, & Gruen, 1985) and Dohrenwend and Shrout (1985). Of the 373 participants, 73% were female, 72% were in paid work, 69% were in permanent relationships and 62% had children. Principal component analyses of separate hassle frequency and intensity scores highlighted components consistent with previous research. There were seven interpersonal and four non-interpersonal subscales associated with negative events with family and friends, work, health, money, and household. The subscales had very good reliability and concurrent validity and there were generally strong correlations (i.e. up .84) between frequency and intensity scores for each subscale. Given some important sampling limitations (e.g. female overrepresentation) the findings show a psychometrically sound hassle scale for adults.

Emergency coronary artery bypass grafting can be performed safely without cardiopulmonary bypass in selected patients.

BACKGROUND: Patients requiring emergency surgical revascularization are often not considered for off-pump coronary artery bypass grafting (OPCAB). METHODS: From 1996 to 2003, 614 patients underwent emergency coronary artery bypass grafting (Society of Thoracic Surgeons definition) at an academic institution. Forty-four (7%) of these procedures were performed without cardiopulmonary bypass, while 570 were conventional coronary artery bypass procedures with cardiopulmonary bypass (CABG/CPB). Data were collected prospectively into a computerized database and reviewed retrospectively. RESULTS: Though a greater proportion of CABG/CPB patients had critical left main stenosis (15.9% vs 38.3%, p = 0.005), other preoperative risk factors were similar between groups. Completeness of revascularization (No. distal anastomoses/No. diseased vessel systems) was significantly greater in the CABG/CPB group (1.51 +/- 0.03 vs 1.25 +/- 0.07, p = 0.003). There were no differences among individual complication rates (death, cardiac reoperation, postoperative myocardial infarction, permanent cerebral vascular accident, deep sternal wound infection, renal failure requiring hemodialysis, and respiratory failure requiring reintubation). However, the combined incidence of these endpoints was significantly lower in the OPCAB group (6.8% vs 21.1%, p = 0.038). OPCAB patients received fewer blood transfusions (65.9% vs 84.9%, p = 0.004) and had a significantly shorter intensive care unit stay (1.47 vs 3.20 days, p = 0.016). In-hospital mortality (0% vs 6.3%, p = 0.168) and mean postoperative length of stay (5.48 vs 7.03 days, p = 0.414) favored OPCAB, but did not reach statistical significance. CONCLUSIONS: Off-pump coronary artery bypass can be performed safely and effectively and should be considered in selected patients with acceptable hemodynamics undergoing emergency coronary revascularization.