A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials.

Introduction: There is a great need to find alternative treatments for chronic pain which have become a healthcare problem. We discuss current therapeutic targeting Nav1.7. Areas Covered: Nav1.7 is a sodium ion channel protein that is associated with several human pain genetic syndromes. It has been found that mutations associated with Nav1.7 lead to the loss of the ability to perceive pain in individuals that are otherwise normal. Several therapeutic interventions are presently undergoing preclinical and research using the methodology of damping Nav1.7 expressions as a methodology to decrease the sensation of pain leading to analgesia. Expert Opinion: It is our strong belief that there is a viable future in the targeting of protein of Nav1.7 for the relief of chronic pain in humans. The review will look at the genomics associated with SCN1A and proteomic of Nav1.7 as a foundation to explain the mechanism of the therapeutic interventions targeting Nav1.7, the human disease that are associated with Nav1.7, and the current development of treatment for chronic pain whether in preclinical or clinical trials targeting Nav1.7 expressions. The development of therapeutic antagonists targeting Nav1.7 could be a viable alternative to the current treatments which have led to the opioid crisis. Therefore, Nav1.7 targeted treatment has a major clinical significance that will have positive consequences as it relates to chronic pain interventions.

Neural Net Modeling of Checkpoint Inhibitor Related Myocarditis and Steroid Response.

Background: Serious but rare side effects associated with immunotherapy pose a difficult problem for regulators and practitioners. Immune checkpoint inhibitors (ICIs) have come into widespread use in oncology in recent years and are associated with rare cardiotoxicity, including potentially fatal myocarditis. To date, no comprehensive model of myocarditis progression and outcomes integrating time-series based laboratory and clinical signals has been constructed. In this paper, we describe a time-series neural net (NN) model of ICI-related myocarditis derived using supervised machine learning. Methods: We extracted and modeled data from electronic medical records of ICI-treated patients who had an elevation in their troponin. All data collection was performed using an electronic case report form, with approximately 300 variables collected on as many occasions as available, yielding 6000 data elements per patient over their clinical course. Key variables were scored 0-5 and sequential assessments were used to construct the model. The NN model was developed in MatLab and applied to analyze the time course and outcomes of treatments. Results: We identified 23 patients who had troponin elevations related to their ICI therapy, 15 of whom had ICI-related myocarditis, while the remaining 8 patients on ICIs had other causes for troponin elevation, such as myocardial infarction. Our model showed that troponin was the most predictive biomarker of myocarditis, in line with prior studies. Our model also identified early and aggressive use of steroid treatment as a major determinant of survival for cases of grade 3 or 4 ICI-related myocarditis. Conclusion: Our study shows that a supervised learning NN can be used to model rare events such as ICI-related myocarditis and thus provide clinical insight into drivers of progression and treatment outcomes. These findings direct attention to early detection biomarkers and clinical symptoms as the best means of implementing early and potentially life-saving steroid treatment.

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs. METHODS: We retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors. RESULTS: Among patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes. CONCLUSIONS: Routine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

An integrated epidemiological and neural net model of the warfarin effect in managed care patients.

INTRODUCTION: Risk assessment tools are utilized to estimate the risk for stroke and need of anticoagulation therapy for patients with atrial fibrillation (AF). These risk stratification scores are limited by the information inputted into them and a reliance on time-independent variables. The objective of this study was to develop a time-dependent neural net model to identify AF populations at high risk of poor clinical outcomes and evaluate the discriminatory ability of the model in a managed care population. METHODS: We performed a longitudinal, cohort study within a health-maintenance organization from 1997 to 2008. Participants were identified with incident AF irrespective of warfarin status and followed through their duration within the database. Three clinical outcome measures were evaluated including stroke, myocardial infarction, and hemorrhage. A neural net model was developed to identify patients at high risk of clinical events and defined to be an "enriched" patient. The model defines the enrichment based on the top 10 minimum mean square error output parameters that describe the three clinical outcomes. Cox proportional hazard models were utilized to evaluate the outcome measures. RESULTS: Among 285 patients, the mean age was 74±12 years with a mean follow-up of 4.3±2.6 years, and 154 (54%) were treated with warfarin. After propensity score adjustment, warfarin use was associated with a slightly increased risk of adverse outcomes (including stroke, myocardial infarction, and hemorrhage), though it did not attain statistical significance (adjusted hazard ratio [aHR] =1.22; 95% confidence interval [CI] 0.75-1.97; p=0.42). Within the neural net model, subjects at high risk of adverse outcomes were identified and labeled as "enriched." Following propensity score adjustment, enriched subjects were associated with an 81% higher risk of adverse outcomes as compared to nonenriched subjects (aHR=1.81; 95% CI, 1.15-2.88; p=0.01). CONCLUSION: Enrichment methodology improves the statistical discrimination of meaningful endpoints when used in a health records-based analysis.

Population pharmacokinetics of levofloxacin in Korean patients.

Levofloxacin (LVFX) has different effects depending on the area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ratio. While AUC can be expressed as dose/clearance (CL), we measured serial concentrations of LVFX in Koreans and tried to set a Korean-specific equation, estimating the CL of the antibiotic. In total, 38 patients, aged 18-87 years, received once daily intravenous LVFX doses of 500 mg or 250 mg, depending on their renal function. Four plasma samples were obtained according to a D optimal sampling design. The population pharmacokinetic (PK) parameters of LVFX were estimated using non-linear mixed-effect modeling (NONMEM, ver. 7.2). The CL of LVFX was dependent on creatinine clearance (CLCR) as a covariate. The mean population PK parameters of LVFX in Koreans were as follows: CL (l/hour) = 6.19 × (CLCR/75)(1.32). The CL of LVFX in Koreans is expected to be lower than that in Western people.

Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations.

Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2-4 µg/mL). This multicentre, retrospective, case-control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs ≥ 2 µg/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3-15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3-7.5 days) vs. 8 days (IQR, 5.8-19.5 days); P=0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P=0.06) and 6% vs. 38% (P=0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections.

Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions.

Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.

Increase in the mediators of asthma in obesity and obesity with type 2 diabetes: reduction with weight loss.

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 falls significantly.

Interpretation of Epithelial Lining Fluid Concentrations of Antibiotics against Methicillin Resistant Staphylococcus aureus.

Although antibiotics whose epithelial lining fluid (ELF) concentrations are reported high tend to be preferred in treatment of pneumonia, measurement of ELF concentrations of antibiotics could be misled by contamination from lysis of ELF cells and technical errors of bronchoalveolar lavage (BAL). In this review, ELF concentrations of anti-methicillin resistant Staphylococcus aureus (MRSA) antibiotics were interpreted considering above confounding factors. An equation used to explain antibiotic diffusion into CSF (cerebrospinal fluid) was adopted: ELF/free serum concentration ratio = 0.96 + 0.091 × ln (partition coefficient / molecular weight(1/2)). Seven anti-MRSA antibiotics with reported ELF concentrations were fitted to this equation to see if their ELF concentrations were explainable by the penetration capacity only. Then, outliers were modeled under the assumption of varying contamination from lysed ELF cells (test range 0-10% of ELF volume). ELF concentrations of oritavancin, telavancin, tigecycline, and vancomycin were well described by the diffusion equation, with or without additional impact from cell lysis. For modestly high ELF/free serum concentration ratio of linezolid, technical errors of BAL should be excluded. Although teicoplanin and iclaprim showed high ELF/free serum ratios also, their protein binding levels need to be cleared for proper interpretation. At the moment, it appears very premature to use ELF concentrations of anti-MRSA antibiotics as a relevant guide for treatment of lung infections by MRSA.

Correlations between Microbiological Outcomes and Clinical Responses in Patients with Severe Pneumonia.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Roux-en-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Efficacy of a methylphenidate transdermal system versus t.i.d. methylphenidate in a laboratory setting.

OBJECTIVE: To test the efficacy and tolerability of the methylphenidate transdermal formulation (MTS) against immediate-release methylphenidate (IR MPH) and placebo in a 12-hr analog classroom setting. METHOD: A total of nine boys ages 6 to 9 years, medicated with MPH for ADHD, complete a within-subject, double-blind study. For the purpose of the study, the boys are administered a dose of 20 cm(2) MTS, a matched dose of IR MPH 10 mg TID, and placebo. ADHD symptoms and frequency counts of classroom rule violations and the number of math problems completed are assessed hourly, during three consecutive analog classroom sessions. RESULTS: Findings show that, across measures and throughout the day, both treatments significantly differentiated from placebo (p < .05) but not from each other. It is also observed that the MTS produced more consistent results across the day but had a delayed onset versus IR MPH. Both medications are well tolerated with only mild reductions in sleep onset. CONCLUSION: The MTS demonstrates comparable efficacy and tolerability to TID IR MPH.

Drug delivery to the posterior segment of the eye through hydrogel contact lenses.

PURPOSE: Despite pharmacological advances, delivery of drugs to the posterior segment of the eye remains problematic. We investigated the ability of hydrogel contact lenses to deliver small-molecule steroids, as well as larger biological molecules to the posterior segment. METHODS: Release characteristics of steroid-instilled lenses were studied in vitro. Drug delivery to the posterior segment of the eye was evaluated in a rabbit model, in which hydrogel contact lenses treated with diluted steroids (prednisolone or beclomethasone) were placed on rabbit corneas for four hours on days 1, 2, 5, 8 and 10. The amount of drug in plasma, posterior segment tissue and vitreous humour was measured with high-performance liquid chromatography-tandem mass spectrometry. In a further preliminary investigation, two rabbits were treated with ranibizumab. RESULTS: The lenses released prednisolone and beclomethasone in saline over a six-hour period at a declining rate. Prednisolone was found in posterior segment tissue from six of six rabbits at concentrations ranging from 26.8 to 166 ng/g and in vitreous humour from two of six rabbits. Beclomethasone was detected in posterior segment tissue from three rabbits but was not found in the vitreous humour. Ranibizumab was detected in posterior segment tissue in a range from 0.19 ng/mL to 0.5183 ng/mL. CONCLUSIONS: Hydrogel contact lenses are a non-invasive, periocular drug delivery device capable of achieving measurable drug levels in posterior segment tissue.

Glucose supply and insulin demand dynamics of antidiabetic agents.

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Characterization of cardiovascular outcomes in a type 2 diabetes glucose supply and insulin demand model.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

A disease model descriptive of progression between chronic obstructive pulmonary disease exacerbations and community-acquired pneumonia: roles for underlying lung disease and the pharmacokinetics/pharmacodynamics of the antibiotic.

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.

What can we learn from the time course of untreated and partially treated community-onset Streptococcus pneumoniae pneumonia? A clinical perspective on superiority and noninferiority trial designs for mild community-acquired pneumonia.

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.

Influence of extended-spectrum beta-lactams on gram-negative bacterial resistance.

PURPOSE: The influence of extended- spectrum beta-lactams on gram-negative bacterial resistance was studied. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Costs of treating lower respiratory tract infections.

OBJECTIVE: To determine the direct medical costs of treating lower respiratory tract infections (LRTIs) in a managed care organization (MCO). STUDY DESIGN: Retrospective analysis of a regional MCO identifying adults diagnosed with acute exacerbation of chronic bronchitis (AECB) or community- acquired pneumonia (CAP). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

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%.