Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
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Overall decisions on the clinical use of new antimicrobials depend on the validity and reliability of the evidence from appropriately designed, conducted, and analyzed clinical trials. Because pneumonia is the sixth leading cause of death in the United States and the leading cause of infectious disease-related death, appropriate design of trials in hospital-acquired pneumonia and ventilator-associated pneumonia are an important public health issue. ⋯ These issues are magnified in the context of noninferiority trials, in which bias can make interventions appear more similar, giving false-positive results of safety and effectiveness. The goal of this article is to provide a scientific basis for improving the validity, reliability, and efficiency of clinical trials in hospital-acquired pneumonia and/or ventilator-associated pneumonia to provide better information for decision making for patients, clinicians, regulators, and other stakeholders.
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Our thesis is a simple one: although a drug can fail in an individual patient for many reasons, appropriately sized and conducted drug-development programs often fail because of insensitive, uninformative end points, and/or poor a priori regimen decisions. The difficulty in successfully developing antimicrobial agents at present is often exacerbated by company decision-makers who are either uninformed or disregard the difference between empirical-based (ie, akin to playing pin-the-tail on the donkey) and quantitative model-based development plans. Frequently, the focus is on Gantt charts (project event schedules) and the on-time submission of a New Drug Application to a regulatory body, such as the US Food and Drug Administration. ⋯ We believe that the goal of drug development is not a New Drug Application submitted on time but, rather, an approved, differentiated, safe, and effective new medicine. Here, we focus on the pharmacokinetic-pharmacodynamic data needed to guide dosing regimen decisions for patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. Early consideration of these data in development programs will reduce risk not only to sponsors but also, most importantly, to the patients enrolled in the clinical trials.
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Hospital-acquired pneumonia and ventilator-associated pneumonia are associated with high rates of morbidity and mortality and are often caused by drug-resistant pathogens. Trials of potential new agents to treat these serious infections are complicated by various factors associated with their design and conduct and the complex underlying conditions of the patients that can potentially obscure determination of treatment benefits. ⋯ Regulatory guidance could help to standardize the design and conduct of trials evaluating potentially efficacious agents. In this article, some of the important challenges that were faced in conducting trials of agents to treat hospital-acquired pneumonia and ventilator-associated pneumonia are described, and areas for which regulatory guidance would be most useful are discussed.
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Recently published guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia are reviewed for recommendations regarding diagnosis and antimicrobial therapy to assess the implications for development of future clinical trials. Despite some differences (mostly related to likely pathogens), there is a general agreement about the recommended approach to management. All of the reviewed guidelines invariably recommend early, appropriate antimicrobial therapy and avoidance of excessive antimicrobials by deescalation of therapy on the basis of microbiological culture results and the clinical response of the patient. Developers of future clinical trials will need to be mindful of these recommendations to maintain best practice care for each investigator.
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Hospital-acquired pneumonia is the second most frequent nosocomial infection and the first in terms of morbidity, mortality, and cost. In recent years, international societies and, most recently, the American Thoracic Society jointly with the Infectious Disease Society of America, have developed guidelines for the management of hospital-acquired pneumonia, health care-associated pneumonia, and ventilator-associated pneumonia. These guidelines include recommendations for risk stratification, initial and definitive antibiotic treatment, and prevention. ⋯ A key issue for these studies is to modify recommendations according to local patterns of microbiology and drug resistance. In summary, implementation of guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia decreases the rate of initial inappropriate antibiotic treatment and decreased 14-day mortality in a study. More clinical studies to validate the influence of guidelines on outcome are warranted.