Unique Considerations in the Evaluation of Antibacterials in Clinical Trials for Pediatric Community‐Acquired Pneumonia

Abstract

There are few placebo-controlled, randomized, prospective clinical trials of antibiotic therapy for community-acquired pneumonia (CAP) in children. The reduction in mortality seen in early trials of antibacterials for treatment of bacterial CAP in adults and children was dramatic and led to the adoption of antibacterial therapy as the standard of care for CAP in both adults and children. Because of the efficacy of antibacterials for treatment of CAP in adults and the reluctance of society to place children at risk of adverse outcomes in placebo-controlled clinical trials, pediatric investigations of this type were not performed after 1940. Instead, comparative trials were subsequently conducted and reported. More recently, comparative trials using a noninferiority trial design have been used by regulatory agencies to grant approval of antibiotic therapy for pediatric CAP. We cannot reliably distinguish between pneumonia cases caused by bacterial, viral, or atypical pathogens among the relatively homogeneous population of children with CAP who are enrolled into clinical trials. Patient- or parent-reported outcomes represent an option for appropriate, defined clinical trial outcomes for pediatric CAP, because the disease in children has a relatively short and potentially self-resolving clinical course. Clinical trials that require invasive techniques for diagnosis and placebo-controlled randomized trials are not acceptable for children, who are considered to be a vulnerable population.

Design of clinical trials of antibacterial agents for community-acquired bacterial pneumonia

“…Despite the lack of randomized, placebo-controlled trials, more than a dozen clinical studies using historical or concurrent controls have unanimously demonstrated a substantial mortality benefit of antibacterial agents for the treatment of CABP in both children and adults [16,24,25]. In historically controlled studies of patients with confirmed S. pneumoniae CABP, mortality rates in the pre- versus immediate post-antibiotic era were 38% versus 12%, respectively, for a 26% (95% CI: 24–28%) absolute reduction in mortality with antibacterial treatment (number needed to treat (NNT) to save a life of ∼4) [16].…”

Quality of Care for Common Pediatric Respiratory Infections: Shortfalls and Improvements

“…The quality shortfalls are added costs and lack of specificity in making a timely, efficient diagnosis [46,47].…”

“…Although current techniques have reasonable sensitivity and specificity for viral pathogens, bacterial pathogen identifica tion is poor and mixed viralbacterial infections complicate interpretation [46]. Less than 10% of children hospitalized for CAP have positive blood cultures [47].…”

“…are not sufficiently developed for widespread use [47]. The urine antigen test for pneumococcal infection used for adults has poor sensitivity and specificity among children [46]. Transtracheal aspirates, bronchial lavages and lung punctures are too invasive for routine diagnostic use and sputum cultures are difficult to obtain in children.…”

How long should we treat this infection for?: Table 1

“…Despite the existence of multiple guidelines for most common childhood infections, many of the recommendations on duration of treatment are based more on expert opinion than strong scientific evidence. There are few infections for which trials demonstrating optimal duration of antimicrobial therapy exist; those that do exist are subject to design flaws and contradictory conclusions 2. Well-designed randomised controlled trials (RCTs) of treatment duration for paediatric infections are rare 3 4…”