In a fascinating article recently accepted for publication in the highly impactful journal Clinical Infectious Diseases, Bart and colleagues from the Office of Infectious Diseases, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, explore geographic shifts in enrollment in ABSSSI (among other infections) treatment trials since 2001. The concern is that as sites of enrollment change over time, results might be less generalizable across specific geographic areas.
The authors reviewed Phase 3 trials submitted to the Food and Drug Administration after 2001 for ABSSSI (n=29,282 subjects), seeking to identify temporal and geographic trends in enrollment, demographics, clinical characteristics and comorbidities, and microbiological data. North American enrollment in ABSSSI trials increased over time from 42.6% to 63.3%, driven mainly by increasing US subject recruitment, which, in turn, and unfortunately, was driven by increasing rates of intravenous drug use (IVDU) among patients with ABSSSI. Eastern European enrollment declined over the same interval.
Interestingly, looking globally, there were no regional differences between North American patients and others in terms of BMI; we know that obesity can be an important contributor to ABSSSI development,1 and we often think of the US (i.e., North America) as having more of a population-level problem with obesity than do other countries. Patients enrolled from North America were less likely to have a positive primary outcome than Eastern European patients with ABSSSI, but degree of differences observed did not appear sufficiently substantial to significantly impact trial generalizability.
For ABSSSI trials, North American sites recruited more subjects than other regions, enrolling a median of 9 subjects per site compared to 6 in Eastern Europe. In exploring possible explanations for this difference, the authors were able to exclude length of IV drug administration (typically mandated in such trials, and often longer than usual practice) as having impacted recruitment. North American recruitment for ABSSSI trials was high, despite having more subjects that received prior antibacterial drug therapy (this is not uncommon in the ED setting, where many patients we see with ABSSSI have “failed outpatient therapy”—whether that failure is due to poor compliance or suboptimal prescribing. As mentioned above, there was an unusually high prevalence of IVDU among North American subjects.
In most other global regions, reported IVDU was very low and similar to levels estimated for the general population of that region.2 In fact, 40.6% of North American subjects in ABSSSI trials indicated current or recent IVDU, far exceeding the estimated regional IVDU prevalence of around 1%. North American subject reports of IVDU increased over time from 13.5% in 2001-2009 trials to 49.8% in 2010-2017 trials. Interestingly, prior antimicarobial drug therapy was less common among North American subjects reporting IVDU drug use than those who did not; this may be attributable to the observation that the typical IVDU-related ABSSSI needs definitive therapy and is not trialed on an oral antimicrobial drug first.
It is worthwhile to note that In a secondary analysis of the SOAR data, our group showed that the efficacy and safety of a single 1200 mg dose of oritavancin was similar to 7-10 days of vancomycin for the treatment of ABSSSI specifically in a US intravenous drug user population, including infections caused by MRSA.3 Similarly, we looked at a subset of IV drug abusers in the OASIS studies and found that S. aureus was the most commonly isolated pathogen in IVDU and non-IVDU patients, and that about 50% of S. aureus pathogens in the population were MRSA . In these cohorts, omadacycline showed similar efficacy and safety, compared with linezolid, in IVDU and non-IVDU patients.4
Among patients enrolled in ABSSSI treatment trials globally, the vast majority of bacterial isolates were Gram-positive, though isolates from Eastern Europe were less likely to be S. aureus (43.7%) that those from North America (61.9%). Methicillin resistance among S. aureus isolates was highest in North America (53.9% vs 5.3% for Eastern Europe). Among North American isolates, the microbiology was similar in IVDU and non-IVDU cohorts, although IVDU ABSSSI isolates were less commonly S. aureus than non-IV drug user isolates (53.5% vs 61.7%). In addition, oral Streptococcus spp, including S. intermedius and S. constellatus, were some four times more common among IVDU isolates, potentially reflecting the habit of licking needles prior to injection.5
The authors’ conclusion to this very fine work is that “The regional prevalence of different pathogens was also broadly similar with several noted differences. Overall, we conclude that observed differences across regions do not appear to be a significant source of concern when considering generalizability of trial results across regions. However, the enrollment of subjects from a range of regions remains important to account for potential regional differences, as the increasing convergence toward North American or Eastern European sites may mask potential cultural or clinical care differences that are more difficult to assess than demographic or microbiological differences.”6
The bottom line for us “empiric prescribers” in the community, urgent, and emergent care spaces is that the clinical trial data support coverage against MRSA in ABSSSI treated in the US.
1. Narayanan N, Adams CD, Kubiak DW, et al. Evaluation of treatment options for methicillin-resistant Staphylococcus aureus infections in the obese patient. Infect Drug Resist. 2019;12:877-891. doi:10.2147/IDR.S196264
2. Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review – The Lancet Global Health. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(17)30375-3/fulltext. Accessed March 19, 2020.
3. Pollack CV, Good S, Wikler M. 3 Single-Dose Oritavancin Treatment of Acute Bacterial Skin and Skin Structure Infections in Intravenous Drug Users: Results from SOLO Trials. Annals of Emergency Medicine. 2015;66(4):S2. doi:10.1016/j.annemergmed.2015.07.032
4. SAEM Annual Meeting Abstracts. Academic Emergency Medicine. 2019;26(S1):S9-S304. doi:10.1111/acem.13756
5. Binswanger IA, Kral AH, Bluthenthal RN, Rybold DJ, Edlin BR. High prevalence of abscesses and cellulitis among community-recruited injection drug users in San Francisco. Clin Infect Dis. 2000;30(3):579-581. doi:10.1086/313703
6. Bart SM, Farley JJ, Bala S, Amini T, Cox E. Geographic shifts in antibacterial drug clinical trial enrollment: implications for generalizability. Clin Infect Dis. doi:10.1093/cid/ciaa246