Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
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Clinical trials evaluating antimicrobial therapy for nosocomial pneumonia face many hurdles in terms of producing data that are widely applicable, supportive of safe medical practices, and able to demonstrate distinct advantages of one form of therapy over the other. Adherence to strict performance measures in conducting such trials should improve their overall quality. Such measures include enrollment of clearly defined patient populations who have a high likelihood of nosocomial pneumonia, use of diagnostic measures to confirm the presence of lower respiratory tract infection, and inclusion of broad-based pathogen distributions to ensure that the trial is applicable to the majority of patients developing nosocomial pneumonia.
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Lower respiratory tract infections in intubated patients include ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP). These infections are increasingly caused by multidrug-resistant bacteria, which colonize the patient's oropharynx and enter the lower respiratory tract around the endotracheal tube cuff or through the lumen. Progression of colonization to VAT and, in some patients, to VAP is related to the quantity, types, and virulence of invading bacteria versus containment by host defenses. ⋯ In addition, the diagnosis of VAP requires a new and persistent infiltrate on a chest radiograph, which may be difficult to assess in critically ill patients, and a significant bacterial culture of a endtotracheal aspirate or bronchoalveolar lavage specimen. Current guidelines for the management of VAP strongly recommend the use of early, appropriate empirical antibiotic therapy based on patient risk factors for multidrug-resistant pathogens. An alternative model focused on VAT, using serial surveillance of endotracheal aspirate specimens to identify multidrug-resistant pathogens and their antibiotic susceptibilities, would allow earlier, targeted antibiotic treatment that could improve outcomes in patients, prevent VAP, and provide an attractive model for clinical research trials.
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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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Appropriate end points are crucial for the successful interpretation of clinical trials. Choosing end points for therapeutic trials of ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) requires careful consideration, because they are complications of critical illness. It may be difficult to distinguish the consequences of VAP and HAP from manifestations of the underlying illnesses, and it is important to determine their incremental magnitude, to plan for possible treatment effects and, thus, sample size calculations. ⋯ Because of these findings, superiority trials of VAP treatment that use mortality as a primary end point are not possible. Equivalency studies are possible, but there are sample size implications. The use of time to clinical event end points, especially when combined with mortality, may be the best option for trial in the future.