Publications

Community-acquired pneumonia remains the primary infectious cause of death in the United States. At current levels of antimicrobial resistance, conventional agents are at risk of becoming less effective, and the need for new agents is pressing. Cethromycin is a new ketolide antibiotic being investigated for use in respiratory tract infections. To review its pharmacology, in vitro susceptibilities, pharmacokinetics, efficacy, safety, and drug interactions, we conducted a MEDLINE search restricted to English-language articles citing cethromycin or ABT-773 (its original designation) from 1990-May 2009. Additional data sources were identified from the references of selected articles. All published trials and available poster data citing cethromycin were selected for review. In vitro, cethromycin displays more potent antibacterial effects than its predecessor telithromycin. Cethromycin exhibits potent inhibition of both gram-positive and gram-negative respiratory pathogens. A new drug application for cethromycin was submitted to the United States Food and Drug Administration in 2008 for the treatment of community-acquired pneumonia. Clinical trial data in the treatment of respiratory tract infections support cethromycin's efficacy. The limited safety data have not included any reports of hepatotoxicity. If cethromycin proves to be safe with regard to hepatotoxicity, it has great promise as an alternative to current standard therapy for community-acquired respiratory infections, especially pneumonia. Given current resistance levels, cethromycin could provide more reliable coverage against common respiratory pathogens than traditional agents in the beta-lactam and macrolide classes.

BACKGROUND

Psychological functioning is an important determinant of health outcomes in chronic lung disease. To better define the role of anxiety in chronic obstructive pulmonary disease (COPD), a study was conducted of the inter-relations between anxiety and COPD in a large cohort of subjects with COPD and a matched control group.

METHODS

Data were used from the FLOW (Function, Living, Outcomes, and Work) cohort of patients with COPD (n=1202) and matched controls without COPD (n=302). Anxiety was measured using the Anxiety subscale of the Hospital Anxiety and Depression Scale.

RESULTS

COPD was associated with a greater risk of anxiety in multivariable analysis (OR 1.85; 95% CI 1.072 to 3.18). Among patients with COPD, anxiety was related to poorer health outcomes including worse submaximal exercise performance (less distance walked during the 6-min walk test: -66.3 feet for anxious vs non-anxious groups; 95% CI -127.3 to -5.36) and a greater risk of self-reported functional limitations (OR 2.41; 95% CI 1.71 to 3.41). Subjects with COPD with anxiety had a higher longitudinal risk of COPD exacerbation in Cox proportional hazards analysis after controlling for covariates (HR 1.39; 95% CI 1.007 to 1.90).

CONCLUSION

COPD is associated with a higher risk of anxiety. Once anxiety develops among patients with COPD, it is related to poorer health outcomes. Further research is needed to determine whether systematic screening and treatment of anxiety in COPD will improve health outcomes and prevent functional decline and disability.

PURPOSE

The purpose of this study was to delineate the effect of chronic obstructive pulmonary disease (COPD) on a broad range of valued life activities (VLAs) and make comparisons to effects of other airways conditions.

METHODS

We used cross-sectional data from a population-based, longitudinal study of US adults with airways disease. Data were collected by telephone interview. VLA disability was compared among 3 groups defined by reported physician diagnoses: COPD/emphysema, chronic bronchitis, and asthma. Multiple regression analyses were conducted to identify independent predictors of VLA disability.

RESULTS

About half of individuals with COPD were unable to perform at least 1 VLA; almost all reported at least 1 VLA affected. The impact among individuals with chronic bronchitis and asthma was less but still notable: 74%-84% reported at least 1 activity affected, and about 15% were unable to perform at least 1 activity. In general, obligatory activities were the least affected. Symptom measures and functional limitations were the strongest predictors of disability, independent of respiratory condition.

CONCLUSION

VLA disability is common among individuals with COPD. Obligatory activities are less affected than committed and discretionary activities. A focus on obligatory activities, as is common in disability studies, would miss a great deal of the impact of these conditions. Because individuals are often referred to pulmonary rehabilitation as a result of dissatisfaction with ability to perform daily activities, VLA disability may be an especially relevant outcome for rehabilitation.

OBJECTIVE

In recent years hydroxychloroquine (HCQ) has emerged as a key therapy in systemic lupus erythematosus (SLE). We determined the rates of HCQ use in a diverse, community-based cohort of patients with SLE and identified predictors of current HCQ use.

METHODS

Patients were participants in the University of California San Francisco Lupus Outcomes Study, an ongoing longitudinal study of patients with confirmed SLE. We examined the prevalence of HCQ use per person-year and compared baseline characteristics of users and nonusers, including demographic, socioeconomic, clinical, and health system use variables. Multiple logistic regression with generalized estimating equations was used to evaluate predictors of HCQ use.

RESULTS

A total of 881 patients contributed 3,095 person-years of data over 4 interview cycles. The prevalence of HCQ use was 55 per 100 person-years and was constant throughout the observation period. In multivariate models, the odds of HCQ use were nearly doubled among patients receiving their SLE care from a rheumatologist compared with those identifying generalists or nephrologists as their primary sources of SLE care. In addition, patients with shorter disease duration were more likely to use HCQ, even after adjusting for age and other covariates.

CONCLUSION

In this community-based cohort of patients, HCQ use was suboptimal. Physician specialty and disease duration were the strongest predictors of HCQ use. Patients who are not using HCQ, those with longer disease duration, and those who see nonrheumatologists for their SLE care should be targeted for quality improvement.

OBJECTIVE

To describe characteristics of systemic lupus erythematosus (SLE) patients who are frequent users of the emergency department and to identify predictors of frequent emergency department use.

METHODS

Data for this study were derived from the University of California, San Francisco Lupus Outcomes Study, a large cohort of persons with SLE who undergo annual structured interviews. Participants were categorized into 1 of 3 levels of emergency department utilization: nonusers (no visits in the preceding year), occasional users, (1-2 visits), and frequent users (> or =3 visits). We compared characteristics of the 3 groups and determined predictors of frequent emergency department use (> or =3 visits) using multivariate logistic regression, adjusting for a variety of potential confounding covariates.

RESULTS

Of 807 study participants, 499 (62%) had no emergency department visits; 230 (28%) had occasional emergency department visits (1-2 visits); and 78 (10%) had frequent (> or =3 visits) emergency department visits. Frequent users were younger, less likely to be employed, and less likely to have completed college. They also had greater disease activity, worse general health status, and more depressive symptoms. Frequent emergency department users were more likely to have Medicaid as their principal insurance. In multivariate logistic regression, older age predicted a lower likelihood of frequent emergency department visits, whereas greater disease activity and having Medicaid insurance predicted a higher likelihood of frequent emergency department visits.

CONCLUSION

In persons with SLE, greater disease activity and Medicaid insurance are associated with more frequent emergency department use.

PURPOSE OF REVIEW

The purpose of this review is to discuss the apparent impact of persistent-immune activation and inflammation on morbidity and mortality among treated HIV-infected individuals, to explore the potential role of Th17 T-cell depletion in this process, and to discuss potential-therapeutic implications.

RECENT FINDINGS

Although the vast majority of HIV-infected individuals can now achieve and maintain viral suppression with modern-antiretroviral therapy (ART), their life expectancy remains much shorter than the general population and they continue to be at much higher risk for non-AIDS-associated diseases commonly associated with aging (non-AIDS-associated cancer, cardiovascular disease, etc). Abnormal levels of immune activation and inflammation persist despite sustained viral suppression and may drive these clinical events. Although the causes of persistent-immune activation remain incompletely characterized, persistent low-level HIV replication and/or release from latently infected cells in gut-associated lymphoid tissue (GALT) and microbial translocation probably play a major role. Failure to restore Th17 cells in GALT during ART might impair both the recovery of the gut mucosal barrier and the clearance of microbial products.

SUMMARY

Insights from recent-pathogenesis studies might suggest novel-therapeutic approaches designed to restore Th17 cells in GALT, thereby decreasing microbial translocation, immune activation, and ultimately morbidity and mortality during treated HIV infection.

BACKGROUND

Due to the emergence of community-associated strains, the prevalence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections has increased substantially in pediatric patients. A vancomycin AUC(0-24)/MIC index >400 best predicts treatment outcomes for invasive MRSA infection in adults. Data on whether recommended vancomycin doses in children achieve this break point are lacking.

OBJECTIVE

This study aimed to assess the likelihood that currently recommended vancomycin doses in children achieve AUC(0-24)/MIC >400.

METHODS

Vancomycin AUC(0-24)/MIC predictions were conducted across a range of dosages (40-70 mg/kg/d) using a Monte Carlo simulation (n = 5000). AUC(0-24) was calculated as daily dose divided by vancomycin clearance, and daily dose was fixed for a given simulation. Three literature-reported estimates in children were used to define vancomycin clearance and its variance. For the MIC distribution of MRSA isolates, susceptibility data were obtained from the University of California, San Francisco Children's Hospital, San Francisco, California (n = 180; 40% < or =0.5 mg/L; 59% = 1 mg/L; and 1% = 2 mg/L).

RESULTS

Using the recommended empiric dosage of 40 mg/kg/d, 58% to 66% of children were predicted to achieve AUC(0-24)/MIC >400. Increasing the vancomycin dosage to 60 mg/kg/d substantially increased the likelihood (88%-98%) of achieving this pharmacodynamic target. On sensitivity analysis, a dosage of 40 mg/kg/d was more strongly influenced by small changes in MIC compared with 60 mg/kg/d.

CONCLUSIONS

Recommended empiric vancomycin dosing in children (40 mg/kg/d) was not predicted to consistently achieve the pharmacodynamic target of AUC(0-24)/MIC >400 for invasive MRSA infections. A vancomycin dosage of 60 mg/kg/d was predicted to optimize achievement of this target in children.

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.