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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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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Direct delivery of antimicrobial agents to the site of infection via aerosolization may represent a valid option in patients with ventilator-associated pneumonia (VAP). Although promising and supported by the results of several recent investigations, antibiotic aerosolization to treat VAP has not yet entered the armamentarium for daily practice. ⋯ Inclusion criteria should specifically target patients with microbiologically proven VAP caused by potentially multidrug-resistant strains, because a clear benefit of aerosolized antibiotics is awaited in only this subpopulation. Until results of these trials are known, antibiotic aerosolization can be recommended only for treating patients with multidrug-resistant VAP, for which no effective intravenous regimen is available.
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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.