Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
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Antibiotic development has decreased significantly, in part because of recent changes in regulatory requirements in the United States. These changes both decrease the probability of technical and regulatory success for a new antibiotic for which marketing approval is sought and motivate the pharmaceutical industry to focus its research efforts on other therapeutic areas. ⋯ The answers to important questions about the benefit of antibacterial treatment for community-acquired pneumonia and the publication of clear guidance for future clinical studies will support future investments. We discuss the underlying issues and offer some alternative strategies to enable improvements in clinical trial design for community-acquired pneumonia.
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Clinical features such as cough, sputum production, fever, and the presence of a new lung infiltrate seen on radiograph are not specific to respiratory tract infection, nor do they define the need for antibiotic therapy. Therefore, investigators have looked for biological markers that can supplement clinical information to determine whether the etiology of the infection is more likely bacterial, needing antibiotic therapy, or viral. There are studies of a number of biological markers in serum and bronchoalveolar lavage fluid, including cytokines, acute-phase reactants, and immunoglobulins. ⋯ In addition, serial measurements of PCT have been reported to correlate with clinical response to therapy and may be able to guide short durations of therapy. In the future design of trials for community-acquired pneumonia, we may want to exclude patients with low PCT levels, because they are unlikely to benefit from antibiotic therapy. On the other hand, inclusion of patients with low PCT values creates heterogeneity in the study population and confounds the interpretation of clinical trial end points.
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The "atypical pathogens" reviewed include Legionella pneumophila, Chlamydophilia pneumoniae, and Mycoplasma pneumoniae. Urinary antigen tests are the most frequently used tests for Legionella species and show good specificity and reasonable sensitivity. For M. pneumoniae, detection of immunoglobulin M, used for the past decade, has substantially improved diagnostic specificity and has simplified testing. ⋯ With regard to future studies, it is noted that the standard of care in the United States, Canada, and some other countries is routine use of agents to treat infection with atypical pathogens, which makes the conduct of controlled trials to address these issues ethically difficult and practically impossible. Additional limitations are the difficulty in diagnostic testing for C. pneumoniae and the importance of rapid institution of therapy for patients severely ill enough to require hospitalization. These observations introduce substantial ethical and logistical barriers to studies of specific agents, except by retrospective analyses.
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Initial antibiotic selection and patient outcomes: observations from the National Pneumonia Project.
Guidelines for empirical treatment of hospitalized patients with pneumonia provide specific recommendations for antibiotic selection that are primarily based on findings from observational studies. ⋯ Initial antimicrobial treatment with the combination of a second- or third-generation cephalosporin and a macrolide or initial treatment with a fluoroquinolone was associated with a reduced 30-day mortality rate, compared with treatment with third-generation cephalosporin monotherapy, among non-intensive care unit patients. Although our results are consistent with other observational studies, controversy continues to exist about the use of nonexperimental cohort studies to demonstrate associations between processes of care, such as antibiotic selection, and patient outcomes.
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Comparative Study
Contemporary epidemiology and prognosis of health care-associated infective endocarditis.
The aim of this study was to describe the characteristics of health care-associated infective endocarditis (HAIE) and to establish the risk factors for mortality. ⋯ HAIE is an important health problem associated with considerable mortality. New strategies to prevent HAIE should be assessed.