Skin and Soft Tissue Infections: Modern Evolution of an Ancient Problem

Skin and soft tissue infections (SSTI) were described several thousand years ago in ancient Chinese, Egyptian, and Greek writings [1-4]. In the modern era, SSTIs were the focus of one of the first ever published clinical studies of an antibacterial agent [5], as well as one of the first active-controlled studies demonstrating the superiority of an antibacterial agent versus background medical therapy [6]. Given such a venerable and well documented history, perhaps it is surprising that SSTI have become such a dynamic--even contentious--contemporary topic.

Just in the last decade, the remarkable spread of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of community acquired infections has resulted in substantial changes in the epidemiology and treatment of SSTI [7-11]. As a result, the frequency of health care visits and antibacterial prescriptions for such infections has markedly increased [12]. Meanwhile, considerable controversy has arisen regarding the need to treat skin abscesses (including those caused by MRSA) with adjunctive antibacterial therapy, in addition to incision and drainage [13, 14]. Such controversy has been exacerbated by the fact that most investigations exploring this issue have been highly underpowered and yet still often have shown trends to benefit of antibacterial therapy [14]. Furthermore, patients with complicated abscesses (e.g., those accompanied by systemic signs of illness) have been excluded from such studies.

Another recent controversy has developed regarding the precise magnitude of the therapeutic benefit of antibacterial therapy for other forms of SSTI, such as cellulitis and wound/ulcer infections [1, 15, 16]. This new controversy has resulted in a complete re-think of regulatory standards governing conduct of clinical trials of new antibacterial agents for the treatment of complicated SSTI (referred to as complicated skin and skin structure infections in regulatory parlance) [16]. In the face of such dramatically changing clinical, scientific, and regulatory landscapes, new research in SSTI is clearly needed to guide clinical practice, resolve scientific controversies, and create a framework for rational regulatory standards.

It is in the above context that the importance of the study by Jenkins et al. [17] should be appreciated. They systematically described presentation, treatment, and outcomes of 322 cases of SSTI at a comprehensive urban health care system in the United States (US) during the year 2007. The high frequency of SSTI seen during the year of study underscores the magnitude of the global societal problem. Furthermore, the authors described a general overuse of radiographic procedures (X rays, computerized tomography, and magnetic resonance imaging scans) and laboratory testing (erythrocyte sedimentation rate and C reactive protein) in patients with SSTI. These tests resulted in very low diagnostic yields, and thus likely substantially contributed to unnecessary health care expenditures related to SSTIs.

Another factor impacting health care resources was selection of antimicrobial therapy. Appropriately, empiric treatment against MRSA was administered to most patients. Of great concern, however, is that a high percentage of patients received treatment with broad spectrum antibacterial agents which had activity against gram negative bacilli (GNB) and anaerobes. Such patients also often received combinations of three or more antibacterial agents. The vast majority of intact skin SSTI (including cellulitis and abscess) are caused by streptococci and staphylococci [17, 18]. Treatment of infections caused by such a narrow spectrum of etiologic microbes with combinations of multiple agents, including those with broad activity against GNB and anaerobes, is antithetical to critically needed antibacterial stewardship. Hence, there is much work to be done to improve antibacterial prescribing behaviors for SSTI.

In previous years, cellulitis was considered by US Food and Drug Administration (FDA) guidance to be indicative of an uncomplicated skin infection [19]. However, analysis of historical data has demonstrated that the mortality rate of cellulitis (or “erysipelas” as it was called prior to the 1950s) was ~11% in the pre-antibiotic era, underscoring that cellulitis is a complicated infection which is made relatively benign only in the context of effective antibacterial therapy [15]. Furthermore, while historical data do demonstrate a substantial effect of antibacterial therapy for wound infections and carbuncles/major abscesses, much of the available data are from historically-controlled studies or a systematic review of single armed cohort studies [15]. Therefore, the US FDA will likely only allow patients with cellulitis to be considered evaluable for primary efficacy analysis in future antibacterial clinical trials of complicated SSTI, and patients with complicated abscesses or wound/ulcer infections are likely to be excluded from such studies [16]. However, Jenkins et al classified only 20% of SSTI as cellulitis. Some additional cases of cellulitis were probably classified as “SSTI with additional complicating factors” due to the presence of other co-factors, such as health-care contact, bacteremia, and significant comorbidities. Nevertheless, the overall proportion of SSTI which was identified as cellulitis was low, and the majority of patients seen had other skin infections. Therefore, insistence that only patients with cellulitis be enrolled in future clinical trials of SSTI will make completion of enrollment of such studies very difficult, and will leave clinicians in the unacceptable position of not knowing the efficacy of new antibacterial agents for complicated abscesses and wound and ulcer infections—regulatory thinking on this matter should be re-addressed.

The severity of the infections seen was also of crucial importance. For example, nearly 10% (10/103) of patients with abscesses as their SSTI manifestation were bacteremic. This finding puts into sharp relief the debate regarding whether patients with cutaneous abscesses require adjunctive antibacterial therapy in addition to incision and drainage. Adjunctive antibacterial therapy must not be withheld from patients who are potentially bacteremic. Furthermore, the high rate of concomitant bacteremia in patients with abscesses in the current study, and the 6% mortality rate of complex abscesses in the pre-antibiotic era (which was largely due to sequelae from concomitant bacteremia) [15], underscore that these infections indeed can be “complicated.” Finally, the lack of mortality seen in the antibiotic era, including in the current study, underscores that antibacterial therapy is very effective in the treatment of complicated abscesses, and that patients with these infections should be included in non-inferiority studies of antibacterial therapy for SSTI [15].

Limitations to the study by Jenkins et al. include the retrospective design, the lack of data capture on wound infections due to the search criteria used, the comingling of severe SSTI of several types within the broad category of “SSTI with additional complicating factors,” and the exclusion of pediatric data collection. Important information might have been gleaned by separately capturing data on cellulitis, wounds, ulcers, and abscesses, and by analyzing these categories stratified by disease severity. Further study of SSTI, including in children, is greatly needed to advance clinical care, improve antibacterial stewardship, help reduce overuse of imaging and laboratory medical resources, and establish critical parameters in support of conduct of antibacterial clinical trials for these infections. Foci of study necessary to facilitate future antibacterial clinical trials include: quantification of the efficacy of active versus inactive antibacterial therapy for SSTI subtypes, establishment of a severity of illness scoring system for SSTI, and identification of appropriate clinical endpoints for efficacy analysis.

Skin infections have been around ever since the invention of skin, have been written about by Homo sapiens for more than 2,500 years, and have been studied in the context of antibacterial therapy since the discovery of antibacterial therapy. But these infections are ever evolving, and our understanding must evolve with them to facilitate optimal clinical care and rational investigation and use of antibacterial therapy for SSTIs.