As IRB members are no doubt aware, public health officials are warning that the overuse and misuse of antibiotics has selected out resistant strains of bacteria all over the globe. As the drugs kill off susceptible strains, those with innate or acquired resistance emerge and proliferate.
As a result, the short-lived miracle of the antibiotic era — which essentially began with the use of penicillin in WWII — is at risk of coming to an end. Once-treatable infections are progressing to severe illness, and the use of antibiotics preventively prior to medical care is imperiled. Thus, clinical trials are examining whether antibiotics can be used less often for shorter durations without sacrificing clinical effect.
For example, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) is sponsoring a clinical trial at five medical centers, enrolling some 400 children to determine whether the standard 10-day course of antibiotics for community-acquired pneumonia (CAP) could be reduced to five days but still provide effective treatment. One of the safeguards in place is that the duration would be shortened only for those showing improvement after the first few days of treatment. Most frequently caused by Streptococcus pneumoniae, CAP typically is treated with a 10-day regimen of amoxicillin.
Children age six months to six years will be studied in the Short Course vs. Standard Course Outpatient Therapy of CAP in Children (SCOUT-CAP) trial. As an additional safeguard, participants in the study must have been initially treated in outpatient clinics, urgent care facilities, and EDs for CAP and have clinically improved prior to enrollment. The trial is being conducted in part through the NIAID-funded Antibacterial Resistance Leadership Group (ARLG), which is targeting a broad array of clinical research to preserve antibiotic efficacy. Participating research institutions include Duke University, Vanderbilt University, Cincinnati Children’s Hospital Medical Center, Children’s Hospital of Philadelphia, and Children’s Hospital of Pittsburgh.
Estimated to run through March 2019, the clinical trial will evaluate short courses of the oral antibiotics amoxicillin, amoxicillin-clavulanate combination, and cefdinir. The research subjects will be split into equal groups undergoing five-day and 10-day treatment. C. Buddy Creech, MD, MPH, one of the principal investigators and a pediatric infectious diseases physician at Vanderbilt, agreed to field a few questions on the SCOUT-CAP trial for IRB Advisor.
IRB Advisor: Can you comment on the primary ethical issues raised by this type of study — for example, obtaining informed consent to treat the five-day group that will receive only half the currently recommended antibiotic duration?
Creech: The most important ethical portion of this study is that the children who will be enrolled must already be showing signs of recovery, including no fever for at least 24 hours before they switch to potentially receiving placebo. Realistically, new data from a large CDC-sponsored study1 suggest that the vast majority of community-acquired pneumonia in children is actually due to viruses. Therefore, the antibiotics they are receiving may not have much of an impact at all. The other important consideration is that if we can shorten therapy, and therefore decrease the likelihood of rash, diarrhea, and stomach upset that comes with antibiotic use, we would make a significant impact on medical care for pneumonia.
IRB Advisor: Can you comment more on the safeguards in place to ensure longer treatment for those in this group that do not clear the infection after five days?
Creech: The first safeguard is that if children are not better by day five when we seek to enroll them, they simply will not be in the study. Therefore, all children must be significantly improved — including no fever — before they can even be considered for the study. Second, we are asking parents to keep a daily diary that will help them gauge symptoms such as cough, fever, and fussiness. If any of these increase or if any children appear to get worse, we have created ways to get them back to their pediatrician to consider other treatments. We’ve also built safeguards into the study so that if multiple children seem to get worse during day 5-10, we can ask an independent group of physicians to review their records to see if we need to change, or even stop, the study.
IRB Advisor: Related to that question, can you elaborate on the provision that calls for enrolling research subjects who were initially treated in outpatient clinics and other settings?
Creech: For children, one of the most reliable signs of ongoing infection is fever. Therefore, fever must be gone for at least 24 hours or we will not enroll the child. The child must also have a normal rate of breathing and look well overall.
IRB Advisor: Did the IRB(s) involved comment on or stipulate that these types of measures must be place for the trial to proceed?
Creech: The IRBs at five institutions, the NIH, the FDA, and an independent Safety Monitoring Committee (SMC) reviewed the protocol. Each of the measures we instituted were decided upon upfront and no additional modifications were needed before proceeding with the trial.
IRB Advisor: Will the use of previously treated patients make it more difficult to ultimately extrapolate your findings to inform antibiotic therapy for untreated cases of CAP in pediatric patients?
Creech: This study will be the first of hopefully many studies evaluating the best management of children with pneumonia. We hope to develop robust prediction models to help determine, at the time of diagnosis, which children are more likely to have bacterial versus viral pneumonia — and, therefore, who needs antibiotics and who does not.
IRB Advisor: Stepping back for a second, we know antibiotic resistance has become a major public health threat, but can you comment generally on why this particular area of research is important?
Creech: For years, we have given strict instructions to parents, “make sure your child takes all of the prescription,” and yet for many infections we don’t actually know the precise length of treatment needed to make sure children recover well. Many are based on years of experience; others are based on ensuring that we treat until the child is better, and then for a short period after.
Over time, though, we have learned that even short courses of antibiotics can have important effects on the types of germs that children carry on their skin, in their noses and throats, and in their GI tract. As a result, the field is moving toward making certain that we treat children with the most precise antibiotic for the shortest amount of time. This study will help us make certain that shorter duration of therapy — only five days for children that are already getting better — will be just as good as a full 10 days.
IRB Advisor: It seems you will need to draw a bright line marking when it is safe to end therapy if the traditional patterns of antibiotic overkill are to be reversed. Is there a gray area there that might end up showing, for example, seven days of therapy gives you the most bang for the buck in terms of balancing patient safety versus antibiotic resistance?
Creech: We deliberately chose five days for a couple of reasons. First, it usually takes children a few days to recover from pneumonia, so anything shorter than five days might be a bit too short. Second, shortening to only seven days is already done by some pediatricians with good results. Therefore, we thought this study would be a good chance to move that to five days. [Previous research] suggests that in this age group, five days of amoxicillin is just as good as 10 days, while three days was not. We wanted to extend those observations to the United States by enrolling children receiving other antibiotics, and enrolling a much larger number of children.
- Jain S, Williams DJ, Arnold SR, et al, for the CDC EPIC Study Team. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Children. N Engl J Med 2015;372:835-845.