Impact of antibiotic timing on mortality from Gram-negative bacteraemia in an English district general hospital: the importance of getting it right every time.

OBJECTIVES: There is limited evidence that empirical antimicrobials affect patient-oriented outcomes in Gram-negative bacteraemia. We aimed to establish the impact of effective antibiotics at four consecutive timepoints on 30 day all-cause mortality and length of stay in hospital. METHODS: We performed a multivariable survival analysis on 789 patients with Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa bacteraemias. Antibiotic choices at the time of the blood culture (BC), the time of medical clerking and 24 and 48 h post-BC were reviewed. RESULTS: Patients that received ineffective empirical antibiotics at the time of the BC had higher risk of mortality before 30 days (HR = 1.68, 95% CI = 1.19-2.38, P = 0.004). Mortality was higher if an ineffective antimicrobial was continued by the clerking doctor (HR = 2.73, 95% CI = 1.58-4.73, P < 0.001) or at 24 h from the BC (HR = 1.83, 95% CI = 1.05-3.20, P = 0.033) when compared with patients who received effective therapy throughout. Hospital-onset infections, 'high inoculum' infections and elevated C-reactive protein, lactate and Charlson comorbidity index were independent predictors of mortality. Effective initial antibiotics did not statistically significantly reduce length of stay in hospital (-2.98 days, 95% CI = -6.08-0.11, P = 0.058). The primary reasons for incorrect treatment were in vitro antimicrobial resistance (48.6%), initial misdiagnosis of infection source (22.7%) and non-adherence to hospital guidelines (15.7%). CONCLUSIONS: Consecutive prescribing decisions affect mortality from Gram-negative bacteraemia.

Impressions and attitudes of adult residents of Karachi towards a possible public health insurance scheme.

OBJECTIVE: To gauge the general population's knowledge and attitude towards a possible public health insurance scheme. METHODS: This descriptive, cross-sectional study was conducted at the Aga Khan University Hospital, Karachi, from April to May 2015, and comprised permanent residents of the city. Convenience sampling was used. Data was collected via questionnaires. SPSS 22 was used for data analysis. RESULTS: There were 340 participants in the study with an overall mean age of 32.9±12.4 years. Besides, 159(46.8%) participants were aware of the concept of medical insurance while the correct definition was identified by 160(50.5%) respondents. Overall, 256(75.3%) participants were willing to join a theoretical public health insurance scheme. Of all the respondents, 107(31.5%) had faced a catastrophic event in the past and consequently were more willing to join. Of those unsure or not willing to join, 33(37.9%) respondents identified lack of trust in government programmes as the main reason for their choice. CONCLUSIONS: A large majority of adults had a favourable attitude towards the implementation of a possible public health insurance scheme.

Cytotoxic effects of aflatoxin B1 on human brain microvascular endothelial cells of the blood-brain barrier.

Aflatoxins are mycotoxins produced by Aspergillus spp. Although AFB1 is implicated as a carcinogen in hepatocellular carcinoma, brain autopsies in affected areas have revealed its presence in 81% of cases. Given its haematogenous spread, here we determined the cytotoxic effects of AFB1 on primary human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier, human umbilical vein endothelial cells (HUVEC) as well as immortalized epithelial cells of human hepatocellular carcinoma (Huh7). The cell types were exposed to AFB1 (3-32 nM) for 24 h and release of lactate dehydrogenase was measured as cell cytotoxicity marker. Furthermore, DNA was collected from both cell types and DNA adduct formation was determined by immunoblot using anti-AFB1-DNA adduct antibody. At 32 nM, AFB1 killed >85% HBMEC, while controls showed minimal effects (P < .05). Similar concentrations of AFB1 showed 22% cell death of HUVEC, while the same concentration did not kill Huh7. At low concentrations, in other words, 3.2 nM, AFB1 produced DNA adduct formation in HBMEC, while high concentration (32 nM) did not form DNA adducts. For HUVEC, 16 nM and 32 nM exhibited DNA adduct formation. For Huh7, 3.2 nM did not form DNA adducts, while 32 nM exhibited DNA adduct formation. For the first time, we report that AFB1 affected the viability of primary endothelial cells but not immortalized Huh7 cells. Cytotoxicity of brain endothelial cells suggests extra-hepatic complications post-AFB1 exposure.

Cigarette Smoking, and Blood Monocyte Count Correlate with Chronic Lung Injuries and Mortality.

Background: Cigarette smoking (CS)-related monocytosis contributes to the development of chronic lung injuries via complex mechanisms. We aim to determine correlations between measures of CS and monocytes, their capacities to predict chronic lung diseases, and their associations with mortality. Methods: A single-center retrospective study of patients undergoing surgical resection for suspected lung nodules/masses was performed. CS was quantified as cigarettes smoked per day (CPD), duration of smoking, composite pack years (CPY), current smoking status, and smoking cessation years. A multivariate logistic regression analysis was performed. Results: Of 382 eligible patients, 88% were ever smokers. In this group, 45% were current smokers with mean CPD of 27.2±40.0. CPY and duration of smoking showed positive linear correlations with percentage monocyte count. Physiologically, CPY was associated with progressive obstruction, hyperinflation, and reduced diffusion capacity (DLCO). Across the quartiles of smoking, there was an accumulation of radiologic and histologic abnormalities. Anthracosis and emphysema were associated with CPD, while lung cancer, respiratory bronchiolitis (RB), emphysema, and honeycombing were statistically related to duration of smoking. Analysis using consecutive CPY showed associations with lung cancer (≥10 and <30), fibrosis (≥20 and <40), RB (≥50), anthracosis and emphysema (≥10 and onwards). Percentage monocytes correlated with organizing pneumonia (OP), fibrosis, and emphysema. The greater CPY increased mortality across the groups. Significant predictors of mortality included percentage monocyte, anemia, GERD, and reduced DLCO. Conclusion: Indices of CS and greater monocyte numbers were associated with endpoints of chronic lung disease suggesting a participation in pathogenesis. Application of these easily available metrics may support a chronology of CS-induced chronic lung injuries. While a relative lesser amount of smoking can be associated with lung cancer and fibrosis, greater CPY increases the risk for emphysema. Monocytosis predicted lung fibrosis and mortality. Duration of smoking may serve as a better marker of monocytosis and associated chronic lung diseases.

Long-term outcome and risk factors for late mortality in Gram-negative bacteraemia: a retrospective cohort study.

OBJECTIVES: The long-term outcomes of patients following Gram-negative bacteraemia (GNB) are poorly understood. Here we describe a cohort of patients with GNB over a 2-year period and determine factors associated with late mortality (death between Days 31 and 365 after detection of bacteraemia). METHODS: This was a single-centre, retrospective, observational cohort study of 789 patients with confirmed Escherichia coli, Klebsiella spp. or Pseudomonas aeruginosa bacteraemia with a follow-up of 1 year. Multivariable survival analysis was used to determine risk factors for late mortality in patients who survived the initial 30-day period of infection. RESULTS: Overall, 1-year all-cause mortality was 36.2%, with 18.1% of patients dying within 30 days and 18.1% of patients suffering late mortality. An adverse antimicrobial resistance profile [hazard ratio (HR) = 1.095 per any additional antimicrobial category, 95% confidence interval (CI) 1.018-1.178; P = 0.014] and infection with P. aeruginosa (HR = 2.08, 95% CI 1.11-3.88; P = 0.022) were independent predictors of late mortality. Other significant factors included Charlson comorbidity index and length of hospitalisation after the index blood culture. CONCLUSION: Patients with GNB have a poor long-term prognosis. Risk factors for greater mortality at 1 year include co-morbidity, length of hospitalisation, and infecting organism and its resistance profile.