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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. · 3.10 Impact Factor
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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.
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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.
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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.
Clinical Infectious Diseases 01/2009; 47 Suppl 3:S157-65. · 9.15 Impact Factor
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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. · 4.13 Impact Factor
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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
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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. · 4.13 Impact Factor
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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. · 2.46 Impact Factor
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Clinical Infectious Diseases 03/2008; 46(4):505-6. · 9.15 Impact Factor
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Antimicrobial Agents and Chemotherapy 02/2008; 52(1):24-36. · 4.84 Impact Factor
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ABSTRACT: There are few data on macrolide pharmacodynamics in pneumococcal infections. We evaluated pneumococcal area under the inhibitory concentration-time curve (AUIC) values at the point of hospital admission in 59 bacteraemic patients failing in the community and in 98 bacteraemic controls without macrolide exposure. The area under the 24-h concentration-time curve (AUC24) was calculated for each patient using age, weight and daily dose; using minimum inhibitory concentrations (MICs), the values of AUIC (i.e. AUC24/MIC) were then computed. Clinical and outcome information was also collected in hospital. Five of six patients who died of pneumococcal bacteraemia in hospital received azithromycin, with a mean AUIC of 8.1 prior to hospital admission. Resistant isolates were recovered in 35 (59%) macrolide failures and in only 28 (29%) controls (P=0.001). Azithromycin AUICs averaged 10 in failure patients and 17 in controls. For clarithromycin and erythromycin, the mean AUIC values in failures were 31 and 53, respectively, and the AUIC in controls was >100. Low AUIC values against Streptococcus pneumoniae precede macrolide failures in the community. Patient factors do not predict these outcomes and thus the most likely explanation for macrolide failure in the community is inadequate macrolide activity in patients who receive these antibiotics for treatment of organisms that are not sufficiently susceptible.
International Journal of Antimicrobial Agents 10/2007; 30(3):264-9. · 4.13 Impact Factor
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ABSTRACT: Current knowledge and policies regarding vancomycin use and the clinical performance of vancomycin in U.S. hospitals were assessed.
A questionnaire was sent to interested hospital pharmacists. An observational study of hospitalized adults who received at least 72 hours of i.v. vancomycin for a culture-confirmed gram-positive infection followed. Hospital antibiograms were obtained for gram-positive susceptibility data.
A total of 59 respondents completed the survey. Survey results revealed that vancomycin is rarely restricted. Investigators from 24 hospitals, 16 (67%) of which were teaching facilities, collected retrospective data from the records of 200 patients. Infection sites included blood, lower respiratory tract, and skin and soft tissue. Staphylococcus aureus was isolated from 52% of positive cultures; 75% of these were methicillin-resistant S. aureus (MRSA). Serum vancomycin concentrations were monitored in 95% of patients; results from 22 hospitals were evaluable. Trough serum vancomycin concentrations were higher in teaching versus nonteaching hospitals (p < 0.001). Peak serum vancomycin concentrations were also higher in teaching versus nonteaching hospitals (p < 0.05). Clinical responses from 22 hospitals were evaluable; the mean success rate of 82% did not significantly differ between teaching and nonteaching hospitals. Vancomycin- associated adverse events occurred in 13 patients (6.5%) and were reported more frequently for patients in teaching versus nonteaching hospitals (p = 0.02).
Observational data suggest that vancomycin remains an effective antibiotic with infrequent discontinuations due to adverse events, and trough serum vancomycin concentrations are monitored routinely. Antibiogram data revealed that the prevalence of MRSA continues to increase.
American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 09/2007; 64(15):1633-41. · 2.10 Impact Factor
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ABSTRACT: We examined the relationship between the time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia while patients were receiving vancomycin therapy and the in vitro bactericidal activity of vancomycin. Vancomycin killing assays were performed with 34 MRSA bloodstream isolates (17 accessory gene regulator group II [agr-II] and 17 non-agr-II isolates) from 34 different patients with MRSA bacteremia for whom clinical and microbiological outcomes data were available. Vancomycin doses were prospectively adjusted to achieve peak plasma concentrations of 28 to 32 mug/ml and trough concentrations of 8 to 12 microg/ml. Bactericidal assays were performed over 24 h with approximately 10(7) to 10(8) CFU/ml in broth containing 16 microg/ml vancomycin. The median time to clearance of bacteremia was 6.5 days for patients with MRSA isolates demonstrating > or =2.5 reductions in log(10) CFU/ml at 24 h and >10.5 days for patients with MRSA isolates demonstrating <2.5 log(10) CFU/ml by 24 h (P = 0.025). The median time to clearance was significantly longer with MRSA isolates with vancomycin MICs of 2.0 microg/ml compared to that with MRSA isolates with MICs of < or =1.0 microg/ml (P = 0.019). The bacteremia caused by MRSA isolates with absent or severely reduced delta-hemolysin expression was of a longer duration of bacteremia (10 days and 6.5 days, respectively; P = 0.27) and had a decreased probability of eradication (44% and 78%, respectively; P = 0.086). We conclude that strain-specific microbiological features of MRSA, such as increased vancomycin MICs and decreased killing by vancomycin, appear to be predictive of prolonged MRSA bacteremia while patients are receiving vancomycin therapy. Prolonged bacteremia and decreased delta-hemolysin expression may also be related. Evaluation of these properties may be useful in the consideration of antimicrobial therapies that can be used as alternatives to vancomycin for the treatment of MRSA bacteremia.
Antimicrobial Agents and Chemotherapy 07/2007; 51(7):2582-6. · 4.84 Impact Factor
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ABSTRACT: The pharmacokinetics of oseltamivir and oseltamivir carboxylate in healthy Japanese (n = 14) and Caucasian (n = 14) males were compared. Subjects in each ethnic group were randomized to twice-daily oral oseltamivir 75 mg, 150 mg, or placebo for 13 doses. Oseltamivir was well tolerated across doses and ethnic groups. Oseltamivir was rapidly absorbed and hydrolyzed to oseltamivir carboxylate in all subjects. The mean plasma concentration-time profiles for oseltamivir and oseltamivir carboxylate were similar in Japanese and Caucasian subjects. At steady state, there was no evidence of any ethnic difference in the individual AUC(0-12) values for oseltamivir or oseltamivir carboxylate. Despite a significant difference in group mean body weight (approximately 20 kg) between the Japanese and Caucasian subjects, there was no evidence that dose-adjusted AUC(0-12) and C(max) for oseltamivir carboxylate were affected by body weight or ethnicity. Day 7 trough concentrations (C(min)) for oseltamivir carboxylate markedly exceeded the IC(50) (50% inhibitory concentration) against influenza A and B isolates. In conclusion, the results of this study support the use of the same dose regimens of oseltamivir in both Caucasian and Japanese subjects because of similarity in pharmacokinetics.
The Journal of Clinical Pharmacology 07/2007; 47(6):689-96. · 2.91 Impact Factor
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ABSTRACT: To compare once-daily intramuscular cefepime with ceftriaxone controls.
Double-blind study.
Six skilled nursing facilities.
Residents aged 60 and older with nursing home-acquired pneumonia.
Cultures were obtained, and patients were randomized to cefepime or ceftriaxone 1 g intramuscularly every 24 hours.
Clinical success: cure or improvement. Cure was defined as complete resolution of all symptoms and signs of pneumonia or a return to the patient's baseline state. Improvement was defined as clear improvement but incomplete resolution of all pretherapy symptoms or signs or incomplete return to the patient's usual baseline status. Safety and pharmacoeconomics were also assessed.
Sixty-nine patients were randomized; 61 were evaluable: (32 to cefepime, 29 ceftriaxone). Patients were predominately female (76%). They had a mean age+/-standard deviation of 85+/-6, with a mean 5.8+/-1.9 comorbidities; they had age-appropriate renal dysfunction, with a mean estimated creatinine clearance of 35+/-7 mL/min. Clinical success occurred in 78% of cefepime- and 66% of ceftriaxone-treated patients (P=.39). Fifty-seven patients (93%) were switched to oral antibiotics after 3 days. Antibiotic-related adverse events occurred in 5% of patients. Seven patients (11.5%) were hospitalized. The overall mortality rate was 8%. Mean antibiotic costs were 117+/-40 dollars for cefepime- and 215+/-68 dollars for ceftriaxone-treated patients (P<.001). Cost-effectiveness analysis of total costs showed that cefepime would cost 597 dollars and ceftriaxone 1,709 dollars per expected successfully treated patient. One- and two-way sensitivity analyses using a generic price for ceftriaxone and improving its comparative efficacy revealed that the results were robust.
Once-daily cefepime was a cost-effective alternative to ceftriaxone for the treatment of elderly nursing home residents who developed pneumonia and did not require hospitalization.
Journal of the American Geriatrics Society 05/2007; 55(5):651-7. · 3.74 Impact Factor
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ABSTRACT: Antibacterial cost-containment programmes emphasise the use of narrow-spectrum generic agents whenever possible. The use of these agents is driven by their lower purchase prices; the consequences of treatment failure are rarely considered. This study was conducted to identify the costs of treating patients hospitalised with community-acquired pneumonia (CAP) associated with Streptococcus pneumoniae following failure to respond to outpatient treatment with macrolide antibacterials.
A multicentre, retrospective, observational study was performed in patients with CAP due to S. pneumoniae who were admitted to 31 North American hospitals following a lack of response to >or=2 days of outpatient treatment with a macrolide antibacterial. Direct medical costs (year 2004 values) of infection-related hospital resources, including antibacterials (purchase, preparation, dispensing, administration and monitoring), diagnostic tests, therapeutic procedures, treatment of adverse events and therapeutic failures, and hospitalisation per diem (ward, critical care and ventilator days), were analysed. Total hospital costs were then compared with standard diagnosis-related group (DRG) reimbursement.
A total of 122 patients were enrolled. Patients were frequently bacteraemic (52%) and infected with macrolide-resistant strains of S. pneumoniae (71%). Initial inpatient antibacterial treatment was not successful in 17 patients (14%) and seven patients (5.7%) died. The mean length of stay was 8.7 days (SD 7) including 1.3 days (SD 2.9) in a critical care unit and 1.4 days (SD 4.4) of mechanical ventilation. The mean cost of hospitalisation was US dollars 12,678 (SD 13 346) but standard DRG reimbursement averaged only US dollars 8,634.
Patients who do not respond to outpatient treatment with a macrolide antibacterial and who are subsequently hospitalised with CAP caused by S. pneumoniae are likely to be infected with a non-susceptible strain, are frequently bacteraemic, are at an increased risk for mortality compared with previously published estimates in patients with CAP due to S. pneumoniae, and incur hospital costs that far exceed standard DRG reimbursement for CAP.
PharmacoEconomics 02/2007; 25(8):677-83. · 2.66 Impact Factor
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ABSTRACT: The pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors (ACE) in elderly patients and patients with renal and hepatic impairment were examined, and a role for an AUC/EC50 ratio to guide dosing was evaluated. A Medline and International Pharmaceutical Abstracts search was used to identify human studies and abstracts. Relevant data were evaluated and summarized. Dosing regimens were compared using an AUC/EC50 ratio. Most studies evaluating ACE inhibitors in renal impairment report a strong linear correlation between creatine clearance and drug elimination. AUC and EC50 values for these drugs in elderly subjects appear similar to younger and hypertensive patients. There is increased AUC in some patients with hepatic impairment. Pharmacodynamic data are conflicting. Prolonged ACE inhibition is evident in renal impairment but not necessarily other disease states. ACE inhibitor dosing for hypertension is reasonable based on pharmacokinetics and EC50 values. Further individualization of therapy may improve outcomes, and using the threshold AUC/EC50 ratio may help guide appropriate dosing.
The Journal of Clinical Pharmacology 10/2006; 46(9):968-80. · 2.91 Impact Factor
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ABSTRACT: Although minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) have been used as the most popular prediction tools for antimicrobial action, they have shortcomings. The MIC and MBC do not consider time-related antimicrobial effects, such as killing rate and postantibiotic effect. In this regard, the concept of pharmacokinetic and pharmacodynamic (PK/PD) modeling has been introduced to help interpret determinations of susceptibility breakpoints. Although area under the inhibitory concentration-time curve (AUIC) can be used as a universal PK/PD parameter, target magnitudes of the parameter have to be high enough to exert rapid bactericidal activity (> 250) and to prevent selection and induction of resistance (> 100). For vancomycin used in treatment of methicillin-resistant Staphylococcus aureus pneumonia, a much higher AUIC (400) is suggested to avoid treatment failure. For resistant gram-negative bacteria, such as Pseudomonas aeruginosa, the usual dosage of fourth-generation cephalosporins, carbapenems, and fluoroquinolones cannot achieve the target AUICs. Either combination therapy or higher dosage should be administered to achieve target AUICs and prevent the potential for failure. Unresolved issues, such as influence of protein binding, PK/PD at tissue sites versus blood, the impact of the immune system, should be addressed to refine the applicability of PK/PD in antibiotic treatment.
Seminars in Respiratory and Critical Care Medicine 03/2006; 27(1):51-67. · 2.43 Impact Factor
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ABSTRACT: We studied methicillin-resistant Staphylococcus aureus (MRSA) isolates to determine if the group II polymorphism at the accessory gene regulator (agr) locus demonstrated any relationship with the clinical efficacy of vancomycin. One hundred twenty-two MRSA isolates from 87 patients treated with vancomycin were evaluated. Forty-five of 87 patients had no clinical or bacteriological response to vancomycin. Among the 36 clinically evaluable patients with the agr group II polymorphism, 31 had an infection that failed to respond to vancomycin, whereas only 5 had an infection that responded successfully to vancomycin. This finding is of interest in light of our previous findings that glycopeptide-intermediately resistant S. aureus (GISA) and hetero-GISA clinical isolates in the United States and Japan are enriched for the agr group II polymorphism, and it suggests a possible intrinsic survival advantage of some S. aureus clones with this genetic marker under vancomycin selective pressure.
Clinical Infectious Diseases 07/2004; 38(12):1700-5. · 9.15 Impact Factor
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ABSTRACT: The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared to that of the immediate-release (IR) product in healthy volunteers. The only significant difference in pharmacokinetic parameters between the two formulations was seen in the rate constant of absorption, which was approximately 50% greater with the IR formulation. The geometric mean plasma ciprofloxacin concentrations were applied to an in vitro pharmacokinetic-pharmacodynamic model exposing three different clinical strains of Escherichia coli (MICs, 0.03, 0.5, and 2.0 mg/liter) to 24 h of simulated concentrations in plasma. A novel mathematical model was derived to describe the time course of bacterial CFU, including capacity-limited replication and first-order rate of bacterial clearance, and to model the effects of ciprofloxacin concentrations on these processes. A "mixture model" was employed which allowed as many as three bacterial subpopulations to describe the total bacterial load at any moment. Comparing the two formulations at equivalent daily doses, the rates and extents of bacterial killing were similar with the IR and XR formulations at MICs of 0.03 and 2.0 mg/liter. At an MIC of 0.5 mg/liter, however, the 1,000-mg/day XR formulation showed a moderate advantage in antibacterial effect: the area under the CFU-time curve was 45% higher for the IR regimen; the nadir log CFU and 24-h log CFU values for the IR regimen were 3.75 and 2.49, respectively; and those for XR were 4.54 and 3.13, respectively. The mathematical model explained the differences in bacterial killing rate for two regimens with identical AUC/MIC ratios.
Antimicrobial Agents and Chemotherapy 07/2004; 48(6):2061-8. · 4.84 Impact Factor
