[show abstract][hide abstract] ABSTRACT: In treatment of pneumonia, microorganisms sometimes persist, appear or reappear despite good clinical responses. On the other hand, recent increasing antibiotic resistance emphases the goal of rapid eradication of pathogen in severe infection. This study was planned to evaluate the correlations between microbiological outcomes and clinical responses in severe pneumonia.
Data was gathered from 3 clinical trials regarding severe pneumonia. Microbiological outcomes, determined by serial culture of respiratory tract samples,were compared with clinical outcomes.
In total, 146 bacterial strains from 76 patients were analyzed. While clinical success was generally related to total or partial eradication of isolated organisms, Acinetobacter, Enterobacter, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia were often not eradicated and yet were observed in 56% of cases considered clinically successful at the end of antibiotic treatment. Most of the non-eradicated strains (71%) already had or developed resistance against the antibiotics used for treatment. Ten patients relapsed during the follow-up period; 7 of these relapses were associated with 10 non-eradicated organisms.
These data raise concern about the pathogenicity of bacteria that persist in the respiratory tract even though good clinical outcomes of pneumonia are achieved, especially when Acinetobacter, Enterobacter, P. aeruginosa, or S. maltophilia were involved. Thus, clinical relapse and development of drug resistance by non-eradicated organisms may be raised.
[show abstract][hide abstract] ABSTRACT: Objective: To determine whether the expression of key asthma related genes, IL-4, LIGHT, LTBR, MMP-9, CCR-2 and ADAM-33 in mononuclear cells and the plasma concentration of nitric oxide metabolites (NOM) and MMP-9 are increased in the obese, obese type 2 diabetics (T2DM) and in morbidly obese patients prior to and after gastric bypass surgery (RYGB). Design and Methods: The expression of these genes in MNC and plasma concentrations of these indices was measured in healthy lean and in obese with and without T2DM and following RYGB in obese T2DM. Results: The expression of IL-4, MMP-9, LIGHT and CCR-2 and plasma NOM concentrations was significantly higher in the obese subjects and in obese T2DM patients than in normal subjects. The expression of IL-4, LIGHT, MMP-9 and CCR-2 expression was related to BMI and HOMA-IR. The expression of IL-4, LIGHT, LTBR, ADAM-33, MMP-9 and CCR-2 fell after RYGB surgery as did plasma concentrations of MMP-9 and NOM. Conclusions: Obesity with and without T2DM is associated with an increase in the expression of IL-4, LIGHT, MMP-9 and CCR-2; plasma NOM and MMP-9 concentrations are also increased. Following RYGB surgery and weight loss, the expression of these factors in MNC and plasma concentrations fall significantly.
[show abstract][hide abstract] ABSTRACT: Roux-en-Y gastric bypass (RYGB) results in profound weight loss and resolution of type 2 diabetes mellitus (T2DM). The mechanism of this remarkable transition remains poorly defined. It has been proposed that endotoxin (lipopolysaccharide [LPS]) sets inflammatory tone, triggers weight gain, and initiates T2DM. Because RYGB may diminish LPS from endogenous and exogenous sources, we hypothesized that LPS and the associated cascade of oxidative and inflammatory stress would diminish after RYGB.
Fifteen adults with morbid obesity and T2DM undergoing RYGB were studied. After an overnight fast, a baseline blood sample was collected the morning of surgery and at 180 days to assess changes in glycemia, insulin resistance, LPS, mononuclear cell nuclear factor (NF)-κB binding and mRNA expression of CD14, TLR-2, TLR-4, and markers of inflammatory stress.
At 180 days after RYGB, subjects had a significant decrease in body mass index (52.1 ± 13.0 to 40.4 ± 11.1), plasma glucose (148 ± 8 to 101 ± 4 mg/dL), insulin (18.5 ± 2.2 mμU/mL to 8.6 ± 1.0 mμU/mL) and HOMA-IR (7.1 ± 1.1 to 2.1 ± 0.3). Plasma LPS significantly reduced by 20 ± 5% (0.567 ± 0.033 U/mL to 0.443 ± 0.022 E U/mL). NF-κB DNA binding decreased significantly by 21 ± 8%, whereas TLR-4, TLR-2, and CD-14 expression decreased significantly by 25 ± 9%, 42 ± 8%, and 27 ± 10%, respectively. Inflammatory mediators CRP, MMP-9, and MCP-1 decreased significantly by 47 ± 7% (10.7 ± 1.6 mg/L to 5.8 ± 1.0 mg/L), 15 ± 6% (492 ± 42 ng/mL to 356 ± 26 ng/mL) and 11 ± 4% (522 ± 35 ng/mL to 466 ± 35 ng/mL), respectively.
LPS, NF-κB DNA binding, TLR-4, TLR-2, and CD14 expression, CRP, MMP-9, and MCP-1 decreased significantly after RYGB. The mechanism underlying resolution of insulin resistance and T2DM after RYGB may be attributable, at least in part, to the reduction of endotoxemia and associated proinflammatory mediators.
Surgery 11/2011; 151(4):587-93. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: The nonsignificant reduction in macrovascular outcomes observed in Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; and the Veterans Affairs Diabetes Trial have collectively created uncertainty with respect toward the proper extent of blood glucose reduction and also the optimal therapeutic choice to attain the reduction. In the article entitled "Glucose Supply and Insulin Demand Dynamics of Antidiabetic Agents" in this issue of Journal of Diabetes Science and Technology, we presented data for a pharmacokinetic/pharmacodynamic model that characterizes the effect of conventional antidiabetic therapies on the glucose supply and insulin demand dynamic. Here, it is our objective to test the hypothesis that, in conjunction with hemoglobin A1c (HbA1c), patients managed on the glucose supply side of the model would have fewer cardiovascular events versus those managed on the insulin demand side.
To test this hypothesis, the electronic medical records of a group model health maintenance organization were queried to compile a population of patients meeting the following inclusion criteria: (1) type 2 diabetes mellitus (T2DM), (2) known date of T2DM diagnosis; (3) ICD-9 or CPT code identification and chart review confirmation of a first major cardiovascular event (myocardial infarction, coronary artery bypass graft, or angioplasty),(4) five years of continuous eligibility, and (5) on antidiabetic therapy at the beginning of the 5-year observation period. These patients were subsequently matched (1:1) to T2DM patients meeting the same criteria who had not experienced an event and were analyzed for differences in glucose control (HbA1C), the glucose supply:insulin demand dynamic (SD ratio), and categorical combinations of both parameters.
Fifty cardiovascular event patients met inclusion criteria and were matched to controls. No difference was observed for the average HbA1c or SD ratio between patients experiencing an event and controls (7.5 +/- 1.0% versus 7.3 +/- 0.9%, p = .275, and 1.2 +/- 0.3 versus 1.3 +/- 0.3, p = .205, respectively). Likewise, for categorical representations, there were no differences in event rate at the pre-identified breakpoints (HbA1c >or=7% versus <7%; 72% versus 64%, p = .391, and SD ratio >or=1 versus <1; 68% versus 76%, p = .373, >or=1.25 versus <1.25; 42% versus 56%, p = .161, >or=1.5 versus <1.5; 22% versus 30%, p = .362, respectively). Analyzing the combined effect of glucose control and the SD dynamic, patients managed at higher glucose values and on the insulin demand side of the model (HbA1c >or=7% and SD ratio <1.25) tended to have greater cardiovascular risk than those managed at an HbA1c <7%, or HbA1c >or=7% with an SD ratio >or=1.25 (61% versus 39%; p = .096).
Independently, more aggressive HbA1c reduction and higher SD ratio values were not independently associated with a reduction in cardiovascular outcomes. Combining the parameters, it would appear that patients managed at higher glucose values and on the insulin demand side of the model may have increased cardiovascular risk. Based on these findings, it is pertinent to conduct subsequent works to refine SD ratio estimates and apply the model to larger, long-term T2DM cardiovascular outcome trials. J Diabetes Sci Technol 2010;4(2):382-390.
Journal of diabetes science and technology 01/2010; 4(2):382-90.
[show abstract][hide abstract] ABSTRACT: For microvascular outcomes, there is compelling historical and contemporary evidence for intensive blood glucose reduction in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). There is also strong evidence to support macrovascular benefit with intensive blood glucose reduction in T1DM. Similar evidence remains elusive for T2DM. Because cardiovascular outcome trials utilizing conventional algorithms to attain intensive blood glucose reduction have not demonstrated superiority to less aggressive blood glucose reduction (Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; and Veterans Affairs Diabetes Trial), it should be considered that the means by which the blood glucose is reduced may be as important as the actual blood glucose.
By identifying quantitative differences between antidiabetic agents on carbohydrate exposure (CE), hepatic glucose uptake (HGU), hepatic gluconeogenesis (GNG), insulin resistance (IR), peripheral glucose uptake (PGU), and peripheral insulin exposure (PIE), we created a pharmacokinetic/pharmacodynamic model to characterize the effect of the agents on the glucose supply and insulin demand dynamic. Glucose supply was defined as the cumulative percentage decrease in CE, increase in HGU, decrease in GNG, and decrease in IR, while insulin demand was defined as the cumulative percentage increase in PIE and PGU. With the glucose supply and insulin demand effects of each antidiabetic agent summated, the glucose supply (numerator) was divided by the insulin demand (denominator) to create a value representative of the glucose supply and insulin demand dynamic (SD ratio).
Alpha-glucosidase inhibitors (1.25), metformin (2.20), and thiazolidinediones (TZDs; 1.25-1.32) demonstrate a greater effect on glucose supply (SD ratio >1), while secretagogues (0.69-0.81), basal insulins (0.77-0.79), and bolus insulins (0.62-0.67) demonstrate a greater effect on insulin demand (SD ratio <1).
Alpha-glucosidase inhibitors, metformin, and TZDs demonstrate a greater effect on glucose supply, while secretagogues, basal insulin, and bolus insulin demonstrate a greater effect on insulin demand. Because T2DM cardiovascular outcome trials have not demonstrated macrovascular benefit with more aggressive blood glucose reduction when using conventional algorithms that predominantly focus on insulin demand, it would appear logical to consider a model that incorporates both the extent of blood glucose lowering (hemoglobin A1c) and the means by which the blood glucose was reduced (SD ratio) when considering macrovascular outcomes.
Journal of diabetes science and technology 01/2010; 4(2):365-81.
[show abstract][hide abstract] ABSTRACT: There are no well-designed placebo-controlled clinical trials in the recent era that precisely define the magnitude of the drug effect of antimicrobial therapy for mild community-acquired pneumonia (CAP). However, there is evidence that ineffective therapies, selected on the basis of the ratio of 24-h area under the concentration curve to minimum inhibitory concentration, associated with a discordant (nonsusceptible in vitro) specific agent (or no therapy) for mild CAP due to Streptococcus pneumoniae are associated with increased risk of progression to serious CAP. The relatively high rate of clinical success associated with appropriate antimicrobial treatment of mild CAP renders a standard outcome measure of clinical success an unlikely way to differentiate new agents. However, there may be an advantage in composite outcome assessments for mild CAP. Composite-outcomes end points that include time to resolution of morbidity, the use of patient reported-outcomes instruments, and biomarkers are recommended for future studies. Because the composite rate of success in recent randomized clinical trials exceeds 90%, it would seem that a noninferiority margin of 10% is reasonable for trials for mild CAP.
[show abstract][hide abstract] ABSTRACT: Patients with chronic obstructive pulmonary disease (COPD) may progress to community-acquired pneumonia (CAP), but there has been no formal study of the factors responsible. We studied the influence of severity of underlying lung disease, pathogen characteristics and the ratio of the area under the concentration-time curve from 0-24h to minimum inhibitory concentration (AUC24/MIC), i.e. the area under the inhibitory curve (AUIC), during the progression from acute exacerbation of chronic bronchitis (AECB) in COPD to CAP. The model parameters were derived from a multinational database of 3885 patients with AECB or CAP (April 1996 to July 2006). Patients with underlying COPD were evaluated in two separate analyses: infection progression between COPD and CAP within Global Initiative for Chronic Obstructive Lung Disease (GOLD)-like grouping (GLG); and distribution of pathogen by GLG, CAP and AECB. Secondary analyses examined the impact of target AUIC attainment on progression to CAP for Streptococcus pneumoniae. The relative impact of GLG and AUIC were modelled in multivariate logistic regression for S. pneumoniae. Progression to CAP linked directly with GLG I/II, III and IV (18.3%, 31.7% and 48.9%, respectively; P < 0.001). Progression to CAP was strongly associated with S. pneumoniae (57.3%), whilst other pathogens were predominant in AECB that did not progress to CAP (61.7%) (P = 0.002). AUIC > or = 100 was associated with AECB (65.1%) and AUIC < 100 with CAP (91.7%) (P < 0.001). In conclusion, the frequency of progression to CAP increases directly with GLG. For S. pneumoniae, achieving an AUIC > or =100 can attenuate progression, regardless of GLG. Thus, AUIC > or = 100 appears to be a viable antibiotic selection strategy to protect patients with S. pneumoniae from developing CAP.
International Journal of Antimicrobial Agents 09/2008; 33(1):58-64. · 4.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: The influence of extended- spectrum beta-lactams on gram-negative bacterial resistance was studied.
Hospital pharmacists were asked to provide data on antimicrobial use and bacterial susceptibilities. Defined daily doses per 1000 patient-days of cefepime, ceftazidime, ceftriaxone, and piperacillin-tazobactam were assessed for significant associations with gram-negative susceptibility. To account for midyear changes in usage patterns and the lag between changes in usage and resistance, susceptibility over two-year periods was evaluated.
Susceptibility data of more than 300,000 gram-negative isolates, representing 10 species of interest, were provided by 82 U.S. hospitals. Two-year periods (n = 45) were evaluable for 25 hospitals, containing 159 hospital-years of data and 204,513 clinical isolates. Use of cefepime increased, while use of ceftazidime, ceftriaxone, and piperacillin-tazobactam decreased. Excluding Pseudomonas aeruginosa, bacteria were most susceptible to cefepime, followed by piperacillin-tazobactam, ceftriaxone, and ceftazidime. Significantly decreased susceptibilities of gram-negative bacteria to the antibiotics themselves were observed with ceftazidime (Enterobacter aerogenes) and ceftriaxone (Escherichia coli). Extended-spectrum beta-lactams associated with significantly decreased susceptibilities of gram-negative bacteria to other beta-lactams included cefepime (E. aerogenes and E. coli susceptibility to ceftazidime), ceftazidime (Enterobacter cloacae susceptibility to cefepime), ceftriaxone (E. cloacae susceptibility to cefepime), piperacillin-tazobactam (E. cloacae, Klebsiella pneumoniae, and P. aeruginosa susceptibility to cefepime). There were insufficient susceptibility data to allow for impact analysis for piperacillin-tazobactam.
Use of cefepime, ceftazidime, ceftriaxone, and piperacillin-tazobactam was associated with variably changing susceptibilities of several key gram-negative bacteria, either to themselves or to each other. Despite the increased use of cefepime, gram-negative bacterial susceptibility to cefepime remained high.
American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 07/2008; 65(12):1154-9. · 2.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: The objective of this study was to evaluate the relationship of the predicted pharmacodynamic parameters 24-h area under the inhibitory curve (AUIC=area under the concentration-time curve for 24h of dosing/minimum inhibitory concentration (AUC0-24/MIC) and time above the minimum inhibitory concentration (T>MIC) with clinical and microbiological outcomes in patients with bacteraemia and sepsis treated with cefepime or ceftazidime. Pharmacokinetic and pharmacodynamic parameters were derived for 76 of 107 patients enrolled in two prospective, randomised, clinical trials comparing cefepime with ceftazidime for the treatment of sepsis with bacteraemia, lower respiratory tract infection or complicated urinary tract infection. The relationships between the pharmacodynamic parameters and outcomes were examined. Whilst no significant differences in clinical outcomes were observed between cefepime and ceftazidime, there were significant differences in the pharmacodynamic analysis. Patients with an AUIC> or =250 had significantly greater clinical cure (79% vs. 33%; P=0.002) and bacteriological eradication (96% vs. 44%; P<0.001) than patients with an AUIC<250. Patients with T>MIC of 100% had significantly greater clinical cure (82% vs. 33%; P=0.002) and bacteriological eradication (97% vs. 44%; P<0.001) than patients with T>MIC of <100%. Both microbiological and clinical cure rates were suboptimal in patients receiving cefepime or ceftazidime for the treatment of serious infections if the AUIC was <250 or T>MIC was <100%.
International Journal of Antimicrobial Agents 04/2008; 31(4):345-51. · 4.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the direct medical costs of treating lower respiratory tract infections (LRTIs) in a managed care organization (MCO).
Retrospective analysis of a regional MCO identifying adults diagnosed with acute exacerbation of chronic bronchitis (AECB) or community- acquired pneumonia (CAP).
A claims database examination of International Classification of Diseases, Ninth Revision, Clinical Modification codes was conducted to identify adults receiving initial outpatient care for an LRTI during 2005-2006. Medical record review then was conducted to verify clinical diagnosis of AECB or CAP. Clinical and demographic data were collected. Outpatient office and clinic visits, hospitalization, and radiology, pathology, and pharmacy records were used to determine treatment costs. Treatment failure was determined by use of a second antibiotic course, follow-up emergency room presentation, or hospitalization for LRTI within 28 days of the index visit. The primary outcome was per-case treatment cost from the payer perspective.
Clinical diagnosis was confirmed for 65 unique coded visits (60 patients; 39 with AECB, 22 with CAP; 1 in both cohorts). Initial visit, initial diagnostic testing, and subsequent hospitalization accounted for the majority (63%) of payer costs. Antibiotics were responsible for 15% of payer costs. Higher initial antibiotic expenditure in the AECB cohort yielded a cost-benefit ratio of 3:1. Mean per-case costs for success and failure were $277 & $372 for AECB, and $493 & $3019 for CAP, respectively.
Initial visit and hospitalization costs contribute the majority of payer expenditure while antibiotic expenditure incurs a nominal burden. Higher expenditure on initial antibiotic therapy in the AECB population appears to be beneficial.
The American journal of managed care 04/2008; 14(4):190-6. · 2.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the economic impact of performing rapid testing for Staphylococcus aureus colonization before admission for all inpatients who are scheduled to undergo elective surgery and providing subsequent decolonization therapy for those patients found to be colonized with S. aureus.
A budget impact model that used probabilistic sensitivity analysis to account for the uncertainties in the input variables was developed. Primary input variables included the marginal effect of S. aureus infection on patient outcomes among patients who underwent elective surgery, patient demographic characteristics, the prevalence of nasal carriage of S. aureus, the sensitivity and specificity of the rapid diagnostic test for S. aureus colonization, the efficacy of decolonization therapy for nasal carriage of S. aureus, and cost data. Data sources for the input variables included the 2003 Nationwide Inpatient Sample data and the published literature.
In 2003, there were an estimated 7,181,484 patients admitted to US hospitals for elective surgery. Our analysis indicated preadmission testing and subsequent decolonization therapy for patients colonized with S. aureus would have produced a mean annual cost savings to US hospitals of $231,538,400 (95% confidence interval [CI], -$300 million to $1.3 billion). The mean annual number of hospital-days that could have been eliminated was estimated at 364,919 days (95% CI, 67,893-926,983 days), and a mean of 935 in-hospital deaths (95% CI, 88-3,691) could have been avoided per year. Sensitivity analysis indicated a 64.5% probability that there would be cost savings to US hospitals as a result of preadmission testing and subsequent decolonization therapy.
The addition of preadmission testing and decolonization therapy to standard care would result in significant cost savings, even after accounting for variations in the model input values.
Infection Control and Hospital Epidemiology 02/2008; 29(1):16-24. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: We evaluated historical trends in the Staphylococcus aureus infection rate, economic burden, and mortality in US hospitals from 1998 through 2003.
The Nationwide Inpatient Sample was used to assess trends over time of S. aureus infection during 1998-2003. Historical trends were determined for 5 strata of hospital stays, including all inpatient stays, surgical procedure stays, invasive cardiovascular surgical stays, invasive orthopedic surgical stays, and invasive neurosurgical stays.
During the 6-year study period from 1998 through 2003, the rate of S. aureus infection increased significantly for all inpatient stays (from 0.74% to 1.0%; annual percentage change (APC), 7.1%; P=.004), surgical stays (from 0.90% to 1.3%; APC, 7.9%; P=.001), and invasive orthopedic surgical stays (from 1.2% to 1.8%; APC, 9.3%; P<.001). For invasive neurosurgical stays, the rate of S. aureus infection did not change from 1998 to 2000 but increased at an annual rate of 11.0% from 2000 to 2003 (from 1.4% to 1.8%; P=.034). The total economic burden of S. aureus infection for hospitals also increased significantly for all stay types, with the annual percentage increase ranging from 9.2% to 17.9% (P<.05 for all). In 2003, the total economic burden of S. aureus infection was estimated to be $14.5 billion for all inpatient stays and $12.3 billion for surgical patient stays. However, there were significant decreases in the risk of S. aureus-related in-hospital mortality from 1998 to 2003 for all inpatient stays (from 7.1% to 5.6%; APC, -4.6%; P=.001) and for surgical stays (from 7.1% to 5.5%; APC, -4.6%; P=.002).
The inpatient S. aureus infection rate and economic burden of S. aureus infections for US hospitals increased substantially from 1998 to 2003, whereas the in-hospital mortality rate decreased.
[show abstract][hide abstract] ABSTRACT: This was a retrospective, multi-center study of patients admitted to hospital with community-acquired pneumonia, caused by Streptococcus pneumoniae, after failing to respond to >2 days of outpatient macrolide therapy. 122 cases, treated between 2000-2004, were enrolled from 31 North American sites between January 2004 - March 2005. Non-susceptible isolates (predominately low-level resistance: erythromycin MICs of 1-16 mcg/ml) were recovered from 87 patients (71%). Bacteremia was present in 63 patients (52%). The in-hospital mortality rate was 5.7 %; all 7 patients who died were bacteremic, 6 had a non-susceptible isolate. We report here the largest series of macrolide failures published to date. The patients were notable for their high rates of macrolide resistance, bacteremia, and mortality. High-level macrolide resistance remains rare among US patients failing outpatient macrolides. The majority of cases and virtually all of the mortality occurred in patients with low-level resistant strains.