A comprehensive review of complicated SSSI from the preantibotic era and the immediately postantibiotic era revealed a substantial treatment effect of antimicrobial therapy. Penicillin was more effective than sulfonamides, consistent with both extensive historical experience and the fact that sulfonamide monotherapy has not been used since the advent of combination sulfonamide-dihydrofolate reductase inhibitors 40 years ago. Therefore, systemic penicillin was the clear historical gold standard antimicrobial therapy on which the basis for noninferiority margins should be justified.
ICH E9 and E10 guidances indicate that noninferiority margins should preserve a clinically meaningful fraction of the lower limit of the established efficacy of the comparator drug [22
]. Preservation of 50% of the comparator drug's efficacy relative to placebo or no therapy has been suggested as reasonable when setting noninferiority margins [60
], but others have argued that this method is highly conservative [65
], and this issue has not been clarified [64
]. To preserve one-half of the lower limit of the treatment effects we found, the non-inferiority margin should be 14% for cellulitis/erysipelas, 21% for wound or ulcer infection, and 7% for major abscess. In practice, the noninferiority margin for a specific complicated SSSI trial should be weighted for the proportion of enrolled patients with cellulitis/erysipelas, wound or ulcer infections, and major abscesses. For example, if a 1:1:1 ratio of patients with cellulitis, wound or ulcer infection, or major abscess were enrolled, the noninferiority margin should be 14% (average of 14%, 21%, and 7%). We emphasize that, because of the low mortality of complicated SSSI treated with antibiotics, it may be reasonable to preserve <50% of the gold standard comparator's efficacy, resulting in wider noninferiority margins, especially if the new agent offered other clinical benefits [64
], such as enhanced activity against antimicrobial-resistant bacteria and an enhanced safety profile, compared with currently available agents.
Our calculations for antibiotic efficacy were also conservative in that they were generated by subtracting the upper limit of the 95% CI of no antimicrobial therapy efficacy from the lower limit of the 95% CI of penicillin efficacy. Therefore, our calculations likely resulted in underestimates of the actual efficacy of penicillin relative to no antimicrobial therapy.
] and ICH guidances [22
] also emphasize that the data used to justify a noninferiority margin must be relevant to modern studies (the “Constancy Assumption” standard). Several elements in our analysis support fulfillment of the Constancy Assumption standard for the efficacy of antimicrobial agents for complicated SSSI. First, the efficacy of 2 doses versus 1 dose of dalbavancin in a modern study of complicated SSSI provided an estimate of antibiotic efficacy that was strikingly similar to the historical datasets, and this conclusion was conservative, because 1 dose of dalbavancin was likely more effective than placebo. Second, the microbiology of the historical studies of cellulitis/erysipelas, wound or ulcer infection, and major abscess was similar to the microbiology of such infections in the modern era. Finally, the mortality rates associated with complicated SSSI treated with penicillin were similar to modern mortality rates of complicated SSSI when effective antimicrobial therapy is used.
We emphasize that previous studies evaluating antibiotic efficacy compared with placebo or in the setting of discordant therapy have focused on uncomplicated SSSI rather than complicated SSSI [11
]. In contrast, we specifically excluded analysis of furuncles (ie, uncomplicated abscesses) to focus on complicated SSSI. The 6% mortality rate among patients with a major abscess receiving no antimicrobial therapy reinforces the fact that these infections represented complicated SSSI rather than uncomplicated SSSI.
Because of the low mortality associated with antimicrobial-treated complicated SSSI, mortality is not viable as the only outcome measure for modern complicated SSSI clinical trials. Nevertheless, the historical mortality data underscore the efficacy of antimicrobial agents for treatment of complicated SSSI. Indeed, the fact that cellulitis/erysipelas caused an 11% mortality rate in the preantibiotic era has been largely forgotten in the antibiotic era. The magnitude of that mortality rate is emphasized by its similarity to the 12% mortality rate of myocardial infarction in the placebo arm of a modern, randomized, double-blinded study [69
It is highly unlikely that changes in background medical care affected the mortality rates during the period of our survey, or indeed subsequent to it. For example, during >50 years leading up to 1936, there was no change in the mortality rate of erysipelas () [43
]. Immediately after the availability of sulfonamides, the mortality rate decreased by >3 fold [42
], at a time when no other new medical technology was being introduced. When penicillin became available there was another immediate 10-fold decrease in mortality, to rates comparable to those in the modern era, with no further change during the subsequent >20 years. Published testimonials from physicians caring for patients in the 1930s and 1940s affirm that it was the introduction of antibiotics, and not another change in medical practice, that led to the immediate decrease in mortality attributable to infection [70
The primary limitations of our analysis include heterogeneity, the potential for publication bias, and the large proportion of single-armed, observational studies in the analysis. The heterogeneity of outcomes for patients receiving no antimicrobial therapy was largely accounted for by higher cure rates reported when fewer criteria were used to define treatment failure, and thus, results were likely biased toward a lower efficacy of antimicrobial agents rather than a higher efficacy. For wound or ulcer infections, heterogeneity was driven by inclusion of patients who received topical or local antimicrobial therapy in the analysis. Again, this resulted in a more conservative estimate of antibiotic efficacy, because the efficacy of penicillin relative to no antimicrobial therapy was higher (53%; 95% CI, 44%–62%) in the 7 studies that exclusively evaluated systemic therapy.
We found no statistical evidence of publication bias. However, given the limitations of such analyses [74
], we cannot exclude the possibility that publication bias existed. If publication bias did exist, it likely affected the publication of results for both antimicrobial and nonantimicrobial therapeutic efficacy. For example, published cases in which topical ointments, dye solutions, ultraviolet therapy, or X-ray therapy were used to treat skin infection are likely selected for those cases in which more favorable results were observed.
Ideally, rigorous establishment of the magnitude of efficacy of antimicrobial versus no antimicrobial therapy for complicated SSSI would rely upon contemporary, double-blinded, placebo-controlled trials. However, the clear establishment of efficacy of sulfonamides and penicillin [60
] predated, by several decades, the widespread use of randomized, placebo-controlled trials. Nor can placebo-controlled trials of antimicrobial agents be conducted today for most types of infection [60
]. The limitations of the current analysis must be considered in the context of the public health imperative to develop new antimicrobial agents for resistant infection [1
]. Antimicrobial agents are unique, not just among all drugs, but among all technologies, in that they continually lose efficacy over time in a transmissible manner. Therefore, unlike any other class of drugs, there is a perpetual need to develop new antimicrobial agents to enable treatment of bacteria that are continually becoming resistant to currently available drugs.
The ICH E10 guidance emphasizes that “the determination of the margin in a non-inferiority trial is based on both statistical reasoning and clinical judgment” [23
, p. 9]. Therefore, in light of (1) the critical need for new antimicrobial agents, (2) the robustness of the datasets reviewed, (3) the conservative nature of the calculations, (4) the evidence of a large magnitude of antimicrobial efficacy for treatment of complicated SSSI, and (5) our compliance with critical features of the ICH E9 and E10 and FDA guidances, we believe that the current findings are sufficient to enable a rational justification for noninferiority margins for complicated SSSI clinical trials.