Cellulitis in adult patients: A large, multicenter, observational, prospective study of 606 episodes and analysis of the factors related to the response to treatment (2024)

John Conly, Editor

Associated Data

Data Availability Statement

Abstract

Introduction

Cellulitis [a common type of skin and soft tissue infection] is a frequent bacterial infection of the skin and subcutaneous tissues, whose incidence is rising, and that results in substantial economic and healthcare burdens [1–7]. In fact, although mild cellulitis can be managed in the ambulatory setting by family doctors, more serious cases represent a common and progressively increasing cause of hospital admissions in developed countries, particularly among the elderly and individuals with predisposing factors or comorbidities [1–4].

In the hospital setting, patients are usually treated with intravenous (IV) antibiotics for 5–7 days, although IV or oral therapy may be prolonged up to 14 days or longer in immunosuppressed or in complex cases, depending on the response [4–6, 8]. The causative microorganism is not identified in most cases of cellulitis, but Streptococcus pyogenes, other streptococci and Staphylococcus aureus account for about three-fourths of those cases in which an agent is recovered, although the relative proportion may differ depending on the type cellulitis and the individual characteristics of the patients [3–7, 9, 10]. However, cellulitis management may be complicated if it is caused by certain agents, such as methicillin-resistant S. aureus (MRSA), a difficult-to-treat and potentially deadly microorganism requiring specific antimicrobials for its cure [6, 7, 9, 11]. Furthermore, healthcare costs are increased because of frequent hospital readmissions due to the high recurrence rate of cellulitis, which is favored by diverse local and systemic factors [3–5].

All these clinical and healthcare circ*mstances emphasize the value of identifying the factors leading to cellulitis for prevention purposes. In this regard, a number of predisposing factors have been described, involving mainly skin integrity, immunity or vasculature [3–5, 12–16]. Likewise, the identification of the factors related to the response to therapy would be highly desirable, in order to improve the management and outcome of these infections.

Despite its frequency, few large series of cellulitis have been published and few studies, mostly with relatively reduced sample sizes, have analyzed the interactions of the multiple potential causes leading to cellulitis, the clinical, microbiological and therapeutic aspects and the outcome. In addition, the published studies may be difficult to compare because of the variety in designs, objectives, settings, criteria, endpoints, nature and management of the infection, and type of data recorded. Finally, the vast majority of the studies are retrospective, with information obtained from medical charts or computerized databases, and their analyses have been restricted to the relatively few data gathered, obviating the confounding effect of other covariates not recorded.

Therefore large, comprehensive, prospective studies evaluating the multiplicity of factors involved in the diverse aspects of cellulitis are necessary. To this end, we have carried out a large, prospective and observational study of adult patients with cellulitis admitted to the Internal Medicine wards of several Spanish hospitals. A number of parameters, including demography, topography, predisposing factors, comorbidities, microbiological, clinical, laboratory, imaging, outcome and treatment data were recorded and analyzed, in order to identify the factors associated with poor responses to therapy.

Patients and methods

Patients older than 18 years with cellulitis admitted to the Internal Medicine wards of Hospital Universitario Central de Asturias (HUCA), Oviedo, Hospital de Cabueñes, Gijón, Hospital Dr Peset, Valencia, Hospital de Povisa, Vigo, Complejo Hospitalario de León, and Hospital La Fe, Valencia, all in Spain, between January 1^st 2016 and June 30^th 2017 were included in the study. The diagnosis of cellulitis was primarily based on history and physical examination [3–6, 8], regardless of the use of other microbiological or imaging diagnostic procedures, and the patients were followed-up for one month after hospital discharge.The response to treatment was evaluated by the physician in charge. Good cellulitis response implied cure with absence of relapses or hospital re-admissions. Poor cellulitis response implied failure to cure, or initial response but relapse within 30 days of hospital discharge. Patients were considered as septic if fulfilled the diagnostic criteria of the Third International Consensus Definitions for Sepsis and Septic shock [17].

Many demographic, epidemiological, topographic, microbiological, clinical, laboratory, imaging, prognostic, hospitalization, and therapeutic (both surgical and antibiotic) data were collected and analyzed according to the cellulitis response to therapy. Regarding the diverse microbiological features, only positive cultures obtained from blood or drained pus collections were considered. Positive swab cultures from skin ulcers or exudates were disregarded because the risk of obtaining spurious microbiological results due to contamination.

This was an observational study, using anonymized data, in which the patients underwent routine clinical care for cellulitis, without any change in its management or specific determinations or procedures. Therefore, no formal written informed consent was obtained from the patients. The Research Ethics Committee of the Principality of Asturias granted a formal waiver of ethical approval for this study.

Results

Discussion

In our large series of 606 adult patients, we found poor responses to treatment in 14.2% of the patients, a proportion similar to that found in some studies [5, 7], and lower than in others [18, 19]. We also found that prior episodes of cellulitis, venous insufficiency, immunosuppression and sepsis were independently associated with poorer outcomes of cellulitis, whereas recent non-surgical trauma was predictive of better outcomes, after adjusting for covariates. Interestingly neither the type of microorganism nor the number of antimicrobials administered or its duration associated with different response to therapy.

Although the history of prior episodes of cellulitis itself appears to be deleterious for the outcome of the infection, the number of such episodes seems to be critical. Thus, patients with one or two prior episodes had similar responses to treatment, whereas the outcome of patients with three or more episodes was clearly worse. Taking into account that 95.1% of recurrent cellulitis in the poor response group occurred in the same location, it can be derived that successive episodes of cellulitis could lead to residual lymphatic and/ or microvascular damage, probably accentuated by sustained inflammation or fibrosis. Consequently, the treatment of further episodes would be less successful. Our findings of poorer outcomes associated with venous insufficiency would also support this explanation.

A history of one or more episodes of cellulitis was observed in 25.7% of our patients, a proportion concordant with the 18% to 49% reported in several studies [3–5, 20, 21]. Although the convenience of chronic administration of antibiotics to prevent recurrences is controversial [3–5], some studies, including a meta-analysis, found that regimens composed of daily oral penicillin or monthly intramuscular benzathine penicillin were efficacious to reduce the recurrence rate or the time to recurrence under certain circ*mstances [15, 22–24]. Therefore, this option should be considered in patients with multiple episodes of cellulitis.

In fact, the 2014 guidelines from the Infectious Diseases Society of America indicate that treatment with oral penicillin or erythromycin or intramuscular benzathine penicillin should be considered in patients who have 3–4 episodes of cellulitis per year, despite attempts to treat or control predisposing factors, although the strength for this recommendation was weak and the quality of evidence only moderate [8]. However, in some cases cellulitis might recur, even with antibiotics prophylaxis, and the protective effect diminished progressively once the prophylaxis was stopped [22, 24].

Our results suggest an additional perspective for the convenience of preventive treatment in patients with highly recurrent cellulitis, as the response to treatment seems to be somewhat impaired in these cases, and poor cellulitis responses were strongly related to poor vital outcomes in the univariate and multivariate analyses. From this perspective, the best benefits would be expected if antimicrobial prophylaxis prevented the development of more than two recurrent episodes in the same location.

Venous insufficiency leading to lower limbs edema, chronic lymphedema and chronic obstructive venous disease are well-known vascular factors favoring cellulitis [3, 5, 14, 16]. The presence of edema/lymphedema and venous insufficiency were significantly associated with poor responses to cellulitis therapy in our study. However, only the latter was independently predictive of such outcome, suggesting that the vascular component, rather than the edema itself, was responsible for the worse response to treatment.

Not surprisingly, the other predisposing factor independently associated with poor cellulitis outcome in the multivariate analysis was immunosuppression. On the contrary, non-surgical trauma was the only factor significantly predictive of better cellulitis outcomes, a finding that could be explained by the lower presence of underlying conditions, predisposing factors (especially edema/lymphedema), and comorbidities observed in the patients with this particular type of cellulitis.

A retrospective study on 106 evaluable cases found that inappropriate antimicrobial selection and dosing, prior antibiotic treatment and marked obesity were associated with poorer outcomes [19]. Another retrospective study used ICD-9 codes to identify 293 outpatients with uncomplicated cellulitis and found obesity and heart failure to be associated with treatment failure [18]. Our prospective study that evaluated a large number of variables of 606 hospitalized patients failed to confirm such associations. However, the comparison among studies may be difficult because of different designs, settings, statistical power, covariates analyzed and criteria for failure. In fact, the failure rates in these studies (32.1% and 24%, respectively) were appreciably higher than in ours (14.2%) and the degree of obesity associated with failure in the two studies, as evaluated by the body mass index, was considerably higher than in our series.

Regarding microbiological issues, the causing microorganisms are rarely identified in cellulitis, with rates of about 15–30% [4, 5]. We found positive pus cultures in 19.5% of the patients as a whole (78.7% of the 150 patients with available culture). Most of the positive cultures were monomicrobial (78.0%), and S. aureus was the most commonly isolated pathogen (37.3% of all cultures). Although streptococci are usually considered to be somewhat more common than S. aureus [4, 8], the etiology may vary depending on diverse circ*mstances [3–6], and S. aureus is recovered with higher frequency from purulent collections [4, 9]. Our results support this statement and, in fact, we found streptococci to be somewhat more common than S. aureus in blood cultures.

The yield of blood cultures is considerably lower, with values of about 2–8% [4–6, 10, 25, 26] and, therefore, they are not routinely recommended in recent guidelines, except for certain specific groups [5, 8]. We found positive results in 18.3% of patients with blood culture available (7.6% of the patients as a whole), all of them monomicrobial. Like ours, other studies found streptococci to be more common than S. aureus in blood cultures [10, 26].

Overall, the causing microorganism was identified, either in pus or blood, in about one-fourth of the patients in our study, without any difference regarding the type of response to treatment. Community-acquired MRSA infection rate is increasing. A study from Hawaii, one of the world places with higher MRSA prevalence, reported 62% of MRSA isolates in patients with abscesses or skin ulcers [27]. In two studies of skin and soft tissue infections in adults from Spain, S. aureus was isolated in 35.1% and MRSA in 12.9% of patients [13], whereas in other smaller study MRSA reached 22% [28]. In our multicenter series, MRSA represented 24.6% of all pure or mixed isolates of S. aureus in blood or pus (9.8% of all patients with positive cultures), without any significant difference in the response to treatment as compared with methicillin-sensitive S. aureus (P = 0.8).

Of note, none of the multiple microbiological items studied had any significant association with the response to treatment. Similarly, none of the diverse parameters analyzed related to treatment, including the number, duration or administration route of the antibiotics, as well as the surgical treatment, had any significant impact on the cellulitis outcome in the univariate or multivariate analyses.

Likewise, none of the clinical, laboratory, imaging or hospitalization parameters were associated with the response to therapy in the multivariate analysis, with the exception of sepsis, which was marginally associated with this outcome (P = 0.05), but was excluded (P = 0.6) when a stronger and related variable, the vital outcome, was entered into the model (P<0.0001).

The main strengths of our study are the large number of patients included, its prospective nature and the large number of parameters evaluated, which allowed to adjust for and minimize the effect of confounding variables. Limitations include the lack of a unified treatment protocol, to evaluate the responses to the same drugs, and the variability inherent to multicenter studies, particularly regarding procedural and management issues. However, no unified treatment protocol exists currently [3–6, 8], given the diversity of clinical and microbiological circ*mstances inherent to cellulitis, and the multicenter nature of the study allows to evaluate the real clinical practice across our country, minimizing potential biases from a single institution.Finally, given the setting of our study, these results may only be generalizable to hospitalized patients and not to a community based or outpatient population.

From our large study, we conclude that three or more episodes of prior cellulitis, venous insufficiency, immunosuppression, and the development of sepsis are independently associated with poorer cellulitis outcomes, whereas microbiological, clinical and therapeutic aspects were not. Beyond the possible role of antibiotic prophylaxis for the prevention of recurrences, its use could also be useful to improve the response to treatment in patients with previous multiple episodes of cellulitis that develop new events.

Acknowledgments

Funding Statement

The authors thank the Infectious Diseases Working Group of the Spanish Society of Internal Medicine (SEMI) for funding this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability

All relevant data are within the manuscript.

References