Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
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Background. A need exists for new antimicrobial agents to treat neonates, infants, and children for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by nosocomial antibiotic-resistant pathogens. Current and clear guidance on approval of new agents for all pediatric age groups is lacking. ⋯ Conclusions. Investigation and approval of new agents for HAP and VAP in all pediatric age groups is needed. A uniform definition of HAP and VAP is required that is relevant for clinical trials and balances the risks of experimental therapy and sampling procedures for study patients with potential benefits for both the patient under investigation and the hospitalized children who may develop nosocomial pneumonia.
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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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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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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.
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Clinical trials of nosocomial pneumonia can include patients with hospital-acquired pneumonia, ventilator-associated pneumonia, and health care-associated pneumonia. All study participants should meet a clinical definition of infection and have some microbiologic confirmation of infection and its etiology. If the trial is to reflect clinical practice and to be practical to conduct, insistence that all patients have bronchoscopic quantitative cultures performed may not be practical. ⋯ All trials should include a protocol to control for standards of care, including timing of initial therapy, recent antibiotic use, local microbiology patterns, duration of therapy, and the use of a de-escalation therapy strategy. Blinding of a trial may not be required if studying a new agent that is more active against multidrug-resistant pathogens than against currently available comparators. Any new agent should meet a noninferiority end point for 30-day mortality, but if superiority is a goal of trial design, end points could be microbiologic eradication, time to microbiologic eradication, prolonged duration of therapy, need to modify initial therapy, and serial evaluation of the arterial oxygen tension to fractional inspired oxygen ratio.