Randomized controlled trials of acute bacterial skin and skin structure infections often omit patients with obesity, who are at high risk for such infections.
“We, as a society, expect FDA-approved medications to be safe and effective in people receiving treatment with these approved agents,” Ronald Hall, PharmD, notes. “Unfortunately, we don’t have data on treatments for acute bacterial skin and skin structure infections (ABSSSIs) in people with obesity, despite their increased risk for developing ABSSSIs. Some retrospective studies have suggested higher treatment failure rates in people with obesity. However, few randomized, controlled trials include detailed information about their representation, much less their outcomes.”
For a study published in Open Forum Infectious Diseases, Dr. Hall and colleagues examined randomized controlled trials (RCTs) published between 2000 and 2022 to determine how often body size measures were included. “We also evaluated the FDA-approved prescribing information and FDA approval packages, as well as pharmacokinetic studies and non-randomized data, for antibiotics approved for ABSSSIs from 2000-2022,” Dr. Hall says.
The percentage of people with obesity included in the RCTs served as the study’s primary endpoint, and the researchers examined the inclusion of a patient’s weight, BMI, and weight and/or BMI in a trial’s baseline characteristics. They defined obesity as a BMI of 30 kg/m² or higher, as it is also defined by the CDC.
Exclusion of Patients With Obesity from ABSSSI RCTs
The review included 69 studies, and the study team examined package inserts for 10 antibiotics with an ABSSSI indication that were approved from 2000 to2022. Dr. Hall and colleagues found that only about 50% of the RCTs included weight and/or BMI, and the average weights and/or BMIs that were reported were lower than US averages. No RCTs included in the review assessed the effect of body size on outcomes, according to the study results.
“Over time, improvements in reporting BMI in RCTs of ABSSSIs are occurring,” Dr. Hall says (Figure). “However, this is not happening for body weight, despite weight being necessary to calculate BMI. This discrepancy in reporting is likely due to the focus on the obesity pandemic despite the fact that many pharmacokinetic studies have associated drug concentrations best being related to patient weight.”
In their review of the package inserts, the investigators found that only three of the 10 approved agents mentioned people with obesity. There was a “clear increase” in the number of people with obesity represented in the approval trials over time, according to the study results, and three of the 10 new antibiotics recognized significant changes in the drug’s pharmacokinetics when used in patients with obesity.
“Using antibiotics that have efficacy and safety data in people with obesity can provide a better idea of the likely outcomes than other agents with missing data for this population,” Dr. Hall says. “Unfortunately, the biggest takeaway is that RCTs, often referred to as the gold standard of evidence-based medicine, frequently fail to include the patients in whom the intervention(s) will ultimately be used.”
Directions for Future Research & A Call to Action
The findings indicate that many patients with ABSSSIs are receiving antibiotics that have not been extensively evaluated in people with obesity, Dr. Hall continues.
Future research that involves “well-designed pharmacokinetic or retrospective trials for FDA-approved agents lacking information in these areas” is necessary, he says. Though it would likely be too expensive to conduct such trials without funding, RCTs of antibiotics for ABSSSIs in people with obesity “would answer these questions best.”
Dr. Hall also addressed the role of the FDA in this process. “We are calling on the FDA to extend its requirement for equitable, representative participant enrollment to people with obesity,” he says. “Other options present include the stratification of enrollment in RCTs by obesity status or reporting of univariable results for the obesity subgroup in the original RCT publication, followed by the publication of a more detailed multivariable analysis of the impact of obesity on patient outcomes.”
