A prospective, multicenter, observational study of complicated skin and soft tissue infections in hospitalized patients: clinical characteristics, medical treatment, and outcomes

Skin and soft tissue infections (SSTIs) encompass a variety of conditions, are associated with substantial morbidity, and account for a large percentage of infections requiring hospitalization [1, 2]. Infections have generally been considered as complicated (cSSTIs) if they required surgical procedures (in addition to antibiotic therapy) or if they involved deeper subcutaneous tissue (e.g., fascia or muscle) [1, 2]. Recently, the U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research introduced a new terminology for acute bacterial skin and skin structure infections [3], but because this was after we had completed our study we have retained the earlier classification for this report. CSSTIs are now more challenging to manage, as the spectrum of causative pathogens is more complex and the prevalence of antibiotic resistant microorganisms, especially methicillin-resistant Staphylococcus aureus (MRSA), has increased [4, 5]. While there is currently no clear consensus on how to manage these infections, treatment virtually always includes administering antibiotic therapy and often requires concomitant drainage and debridement procedures. The management approach depends on many factors, including the infection type and severity, epidemiologic setting, likely causative pathogens, and local antibiotic resistance patterns [2, 6–8]. Despite the frequent occurrence of cSSTIs, our current understanding is limited about their clinical characteristics at presentation, how they are treated in actual clinical settings, and what the outcomes are of treatment.

Previously published controlled clinical studies of cSSTIs have enrolled relatively homogeneous patient populations, had strict inclusion and exclusion criteria and protocol-defined treatment algorithms [9–13]. They are efficacy trials, designed to determine whether an intervention produces the expected result under ideal circumstances. On the other hand, most published “real-world” studies of cSSTIs are based on retrospective data sources which often do not provide detailed information on patient presentations, approaches to treatment or clinical outcomes [14, 15]. Observational studies are designed to examine usual treatment patterns and everyday practices, optimally across a broad spectrum of patients and health care settings, to provide complementary data to those obtained in other study types.

The goal of this prospective observational study of patients with cSSTIs was to explore the current epidemiology, treatment, and resulting clinical outcomes of these infections. A clearer understanding of the current practice patterns in managing patients with cSSTIs in usual clinical settings should help in the development of strategies to improve the treatment of these common and potentially severe infections.

We enrolled patients hospitalized between June 2008 and December 2009 in 56 U.S. hospitals that we selected to include those of varying size, ownership status, academic affiliation, and geographic regions. We selected investigators based on their experience working on the inpatient service at each of these hospitals. An Institutional Review Board approved the protocol for each site; 9 sites used a central ethical review board (Quorum Review, Seattle, WA), while the rest used their local Institutional Review Board and all enrolled patients provided informed consent.

We initiated this multicenter, prospective observational study to learn about the current epidemiology, clinical presentation, treatment and outcomes for patients with cSSTIs. The study protocol did not recommend or mandate any initial or subsequent interventions, but CRFs recorded each of the local physicians’ management decisions. The prospective design of the study made it possible to capture a more comprehensive patient profile, including data on risk factors for healthcare-associated infections, wound measurements, and infection parameters. These enabled us to score wound severity, to clinically assess the infection, to note the reasons investigators initiated and discontinued each agent, and to evaluate quality of life measures. Furthermore, we enrolled a large number of patients with varied types of infections admitted to hospitals representing a wide-range of types of institutions and geographic regions. Thus, these data are likely to reflect usual current clinical practice for managing cSSTIs in hospitalized patients in the US.

Our study showed that, among the 1,033 patients enrolled, 73.5% had a healthcare-associated infection. This is nearly identical to the 73.6% reported in a single-center retrospective cohort study of patients hospitalized with cSSTIs [15]. Compared to our study, their criteria for defining healthcare-associated infection used a longer time frame for previous hospitalization (1 year versus 6 months) and previous antibiotic use (90 days versus 30 days) and did not include immunosuppressed state as a criterion. This rate of healthcare associated infection is considerably higher, however, than the 27% reported in a recent retrospective cohort study of more than 12,000 patients hospitalized with skin, soft-tissue, bone or joint infection [24]. This difference could be attributed to that study including bone and joint infections, and using a definition of healthcare associated infection with a substantially shorter timeframe for previous hospitalization compared with ours (30 days versus 180 days) and that did not include previous antibiotic treatment, a criterion met by 47.6% of our patients. Physicians treating patients with cSSTI may find the high prevalence rate of healthcare-associated infections noted in this study to be clinically important, as previous studies [15, 24] have reported that these patients had longer lengths of stay, higher mortality, and higher hospital costs.

Our evaluation of initial antibiotic treatment revealed that vancomycin was used considerably more often (in 61.0%) than has been reported in previous studies. Two retrospective multicenter studies performed in the past decade, both of which used an inpatient claims database, eported initial treatment with vancomycin in 17.6% and 27.8% of cSSTI patients, respectively [14, 25]. The much higher use of vancomycin in our study is likely attributable to the steep rise in the prevalence of MRSA as a pathogen in cSSTIs over the past several years [26]. It is noteworthy that the initial intravenous therapy selected was discontinued in over a fifth of patients because it was either not needed or inappropriate. Also of note is that a substantial percentage of patients were treated with relatively broad-spectrum agents that are typically used to cover gram-negative bacilli (e.g., fluoroquinolones, 3^rd generation cephalosporins, aminoglycosides), which is probably unnecessary in most cases of cSSTI.

The mean LOS we observed in this study is longer than might be observed in some practices; this is probably related to the fact that we enrolled patients with more severe infections as they needed to be hospitalized for at least 48 h. Our LOS is, however, similar to those previously reported in patients hospitalized for cSSTIs [15, 24, 27]. Despite differences in patient population, the overall mean LOS in our study (7.1 days, ranging from 5.8 to 8.1 days) was similar to that reported by Lipsky et al. (7.3 days, ranging from 5.1 to 8.9 days depending on infection type and whether or not the infection was complicated) [24]. The LOS for patients with cellulitis or SSI, the two infection types examined in our study that were also included individually in the Lipsky study [24], were slightly higher in our study, probably because many of our patients would have been considered to have a complicated infection. The LOS found in our study is also similar to that found by Zilberberg et al. [15], (9.4 days for patients with healthcare associated infection and 5.5 days for community associated infection) and Edelsberg et al. [14] (5.2 days for those successfully treated and 10.6 days for those who failed treatment). The in-hospital mortality rate in the overall cohort in this study (0.4%) is, however, considerably lower than the rates reported in the literature (0.8%-5.2%) [14, 15, 24, 27, 28]. This could be related to differences in patient populations, infection types or severity, or how the infections were managed.

Our study has several limitations. First, there is a possibility of selection bias in the patients enrolled or hospitals selected, notwithstanding our considerable efforts to minimize this by establishing a priori definitions and standardized data collection procedures. Secondly, we did not recognize the need to provide the investigators with specific enough criteria to identify DFI or SSI until after patient enrollment had begun. Initially, we intended for the investigators to use their discretion when enrolling patients. While using this method would have added to the naturalistic design of the study and resulted in enrollment of a more heterogeneous population, several sites asked us questions about what constituted a DFI or SSI. Thus, we sent out clarification to all the sites on how to define these infection types (see the appendix). Third, although the data from this study underwent a rigorous review and query process, the data accuracy and completeness ultimately depended on the investigators at the study sites. To minimize this problem, we made efforts to sign up experienced clinicians and trained them on data collection in advance of the study. Fourth, clinical outcome was based on the investigators’ subjective assessment and not on a change in the wound score or microbiological response at the end of therapy. This was necessary, as there are no agreed upon criteria for the wound score and the presence and resolution of cSSTIs are based on clinical (not microbiological) criteria. Finally, our findings may not be generalizable to non-hospitalized patients, to patients hospitalized in other countries, to other types of cSSTIs not included in our study, or to patients who had conditions that were excluded from our study.

Strengths of this study include the prospective observational design, the variety of hospital types, the training of the investigating clinicians, the attempt to define types of cSSTIs, the development of standardized CRFs, the use of a validated wound scoring system and the large number of patients enrolled.

This multicenter, prospective observational study of patients with cSSTIs was designed to explore the current epidemiology, treatment, and resulting clinical outcomes of patients hospitalized with these infections. During an 18 month period we enrolled 1033 patients. Almost 3/4ths of patients had at least one healthcare associated risk factor. Infections of the lower extremity comprised over half the cases and two-thirds has an open wound. In almost 90% of cases antibiotic therapy was initially an empiric intravenous agent, the most common of which was vancomycin. A substantial percentage of the patients were treated with unnecessarily broad-spectrum agents. Empiric antibiotics were discontinued in about 1/5th of patients because culture results indicated they were not needed or the pathogen was not susceptible to the selected agent. Over 40% of patients underwent some form of surgical treatment. At the end of therapy infection was improved or resolved in almost 90% of patients. Because of the study design these data likely reflect usual current clinical practice for managing cSSTIs in hospitalized patients in the US. This study provides useful information on the current epidemiology and clinical management practices and outcomes of hospitalized patients with cSSTIs.

The work was supported by Janssen Scientific Affairs, LLC, Raritan, NJ, USA.