Skin, Soft Tissue, Bone, and Joint Infections in Hospitalized Patients: Epidemiology and Microbiological, Clinical, and Economic Outcomes
Background. Infections involving skin, soft tissue, bone, or joint (SSTBJ) are common and often require hospitalization. There are currently few published studies on the epidemiology and clinical and economic outcomes of these infections, whether acquired in the community or healthcare setting, in a large population.
Objective. To characterize outcomes of culture‐proven SSTBJ infection in hospitalized patients, using information from a large database.
Design. We identified patients hospitalized in 134 institutions during 2002‐2003 for whom specific International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes and a culture‐positive SSTBJ specimen were recorded. Patients were classified into 4 clinical groups based on the type and clinical severity of infection. Patients in each group were further classified on the basis of whether their infection was community acquired or healthcare associated and whether it was complicated or uncomplicated.
Results. We identified 12,506 patients with culture‐positive infections and categorized them as having cellulitis (37.3%), osteomyelitis or septic arthritis (22.4%), surgical wound infection (26.1%), device‐associated or prosthesis infection (7.2%), or other SSTBJ infection (6.9%). Monomicrobial infection was reported for 59% of patients, 54.6% of whom had Staphylococcus aureus as the etiologic agent. Of all S. aureus isolates recovered, 1,121 (28.0%) of 4,007 were resistant to methicillin. Healthcare‐associated infections accounted for 27.2% of cases and were associated with a significantly greater mortality rate, a longer length of stay, and greater hospital charges, compared with community‐acquired infections. Patients with a complicated infection (78.4%) had a significantly greater mortality rate, a longer length of stay, and greater hospital charges, compared with patients with an uncomplicated infection.
Conclusions. SSTBJ infections are frequent among hospitalized patients. S. aureus caused infection in more than 50% of the patients studied, and 28.0% of the S. aureus isolates recovered were resistant to methicillin. Healthcare‐associated and complicated infections are associated with a significantly higher mortality rate and more prolonged and expensive hospitalizations. These findings could assist in projects to revise current management strategies in order to optimize outcomes while restraining costs.
Received February 20, 2007; accepted June 5, 2007; electronically published October 3, 2007.
Infections involving skin, soft tissue, bone, or joint (SSTBJ) occur frequently.1,2 Deeper tissue infections may be caused by the spread of superficial infections to contiguous underlying tissues or by the direct inoculation or hematogenous spread of pathogens. Although many patients with SSTBJ infections can be treated as outpatients, patients with more‐severe infections usually require hospitalization.2 SSTBJ infection is an increasingly common reason for hospitalization in the United States, especially among certain high‐risk populations.3 These infections are associated with considerable morbidity, occasional mortality, and substantial hospital charges.4
SSTBJ infection may be acquired in the community, typically as a result of some type of trauma, or in a healthcare‐related setting, usually following an invasive procedure. Many types of organisms can cause SSTBJ infection, often as part of a polymicrobial infection, but the predominant pathogens are aerobic gram‐positive cocci. Staphylococcus aureus, alone or in combination with other pathogens, is the most common etiologic agent. It is responsible for 30%‐50% of diabetic foot infections,5 skin and soft‐tissue infections,6‐8 and bone or joint infections.9,10 The increasing prevalence of methicillin resistance among healthcare‐acquired and community‐acquired S. aureus isolates11‐15 is associated with worse outcomes, more‐challenging decisions regarding the choice of antibiotic therapy, and greater financial costs for persons with SSTBJ infection.11,13,16
Despite the frequency of SSTBJ infections, much about them remains unknown, including the effect of the infecting pathogen(s), site of acquisition (ie, community or healthcare facility), and infection type on the clinical outcome. Similarly, we know of no prospective studies of the financial burden of these types of infections on the healthcare system. Understanding the current epidemiology and microbiological characteristics of SSTBJ infection might help clinicians select appropriate empirical antibiotic regimens to optimize outcomes while restraining costs. We designed this study to elucidate these issues and to examine their effect on clinical and financial outcomes for hospitalized patients with culture‐proven SSTBJ infection.
Methods
Study Design
For this retrospective cohort analysis, we collected data from all patients with a culture‐positive skin specimen, soft‐tissue specimen, bone specimen, joint specimen, surgical device, or prosthesis who were inpatients at one of 134 US acute care hospitals between January 1, 2002, and December 31, 2003. Most participating institutions were located in northeastern states. This study was conducted in compliance with the New England Institutional Review Board–Human Subjects Research Committee (Wellesley), federal regulations, and the Health Insurance Portability and Accountability Act. All data were deidentified so that patient specific information could not be identified directly or indirectly through linked identifiers.
Data Source
We obtained data from a large, multi‐institutional database (Cardinal Health Research Database) of US acute care hospitals, the details of which have been published previously.17‐21 For each patient, the database includes demographic characteristics, location before admission, hospital site of admission (including type of intensive care unit [ICU]), documented procedures and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) diagnosis codes, admission and discharge dates for each ICU admission, total length of hospital stay (LOS), total and ancillary hospital charges billed, discharge disposition, therapeutic and diagnostic interventions, and up to 400 or more key clinical findings,19 including patient history and physician assessments, select physiological findings, and results of chemistry, hematologic, and microbiology laboratory tests. These data also are used to calculate clinical severity scores, which are based on the probability of in‐hospital mortality, using disease‐specific logistic regression models.19,21
Patient Classification
We classified eligible patients as having a healthcare‐associated infection if their first culture‐positive wound specimen was obtained within 1 day of (ie, on the day before, of, or after) admission to a study hospital and if they had transferred to the study hospital from another healthcare facility, were receiving long‐term hemodialysis, were hospitalized during the previous 30 days, or had evidence of receiving chemotherapy for a malignancy. We classified patients as having a community‐acquired infection if their infection did not meet the healthcare‐associated definition and if their first culture‐positive SSTBJ specimen was obtained within 2 days of admission.
We further classified patients hierarchically into mutually exclusive groups based on the type and clinical severity of infection, using the source of their culture‐positive specimen and the following ICD‐9‐CM diagnosis code(s): 680/681, 686, 707, 711, 713, 730‐1, and 996‐9 (Table 1). Group 1 comprised patients with osteomyelitis or septic arthritis; group 2 comprised patients with surgical site infections, including surgical wound infection (group 2a) and surgical device–associated or prosthesis infection (group 2b); group 3 comprised patients with cellulitis; and group 4 comprised patients with any other type of SSTBJ infection. We assumed this simple clinical hierarchical grouping would correlate with the severity of infection and thus with the clinical outcome. Patients with more than 1 infection were categorized on the basis of their most‐severe infection. We also stratified patients as having either a complicated or uncomplicated infection, using US Food and Drug Administration criteria.22 Patients were stratified as having a complicated infection if they had (1) a documented skin, soft tissue, bone, or joint (musculoskeletal)–related procedure code within 2 days of admission; (2) autoimmune disease, chronic liver disease, chronic renal disease, diabetes mellitus, human immunodeficiency virus infection, an immunocompromised status (including receipt of current immunosuppressive agents), peripheral vascular disease, and/or a current diagnosis of systemic (including metastatic) cancer; or (3) a hemogram with a peripheral white blood cell count less than 1,000 cells/mm3 recorded within 2 days of admission.
Microbiological Analysis
We documented the causative pathogens from wound specimen cultures for each patient. In addition to classifying the infection as monomicrobial or polymicrobial, we identified the specific pathogen(s) isolated.
Clinical and Economic Outcomes
Our primary end points were in‐hospital mortality, LOS, and billed hospital charges. Each institution calculated its own hospital charges, and we aggregated the results and calculated the mean, median, and SD.
Data Analysis
We used the χ2 test for univariate analyses of between‐group differences in mortality and the Wilcoxon rank sum nonparametric test with linear regression models for comparison of LOS and total charges. To adjust for potential confounding variables in the multivariate analyses, we used logistic regression models for mortality comparisons. To assess discrimination and calibration of the logistic model, we used the C statistic and calculated an approximate χ2 statistic by means of the Hosmer‐Lemeshow goodness‐of‐fit test. We considered a P value of .05 or less to be statistically significant. We used SAS statistical software, version 8.2 (SAS Institute), for all statistical analyses.
Results
Patient Characteristics
Of 1,335,164 eligible patients admitted during the study period, 12,506 had a culture‐positive specimen that indicated SSTBJ infection (Table 2). A total of 22.5% had osteomyelitis or septic arthritis (group 1), 33.3% had surgical wound infection (groups 2a and 2b), 37.3% had cellulitis (group 3), and 6.9% had other SSTBJ infections (group 4). The median age of patients included in the study was 61 years, and approximately 75% were white. Diabetes mellitus, the most common comorbidity, was present in nearly 50% of patients and was especially common among patients with bone or joint infection (group 1). Peripheral vascular disease, the second most common comorbidity, was present in almost 22% of patients and in more than 30% of patients with bone or joint infection (group 1). More than 75% of patients met criteria for a complicated infection. Approximately 50% of patients had been hospitalized in the previous year, and approximately 25% required some type of surgical intervention during the index admission. Fewer than 1% of patients were neutropenic or required mechanical ventilation.
Pathogen Distribution
Infection was monomicrobial in 7,329 patients (59%); in 5,334 (72.8%), infection was community acquired; and in 1,995 (27.2%), infection was healthcare associated. Gram‐positive organisms were recovered from 86.9% and gram‐negative organisms from 10.1% of patients with monomicrobial infection (Table 3). Of 5,177 patients with polymicrobial infection, 96.1% had aerobic gram‐positive organisms, 53.1% had aerobic gram‐negatives organisms, and 12.3% had obligate anaerobes. S. aureus was recovered from 52.1% of patients; 28.1% of isolates were methicillin resistant.
S. aureus was the pathogen most frequently recovered from patients with monomicrobial infection, accounting for 54.6% of the etiologic agents; 28.0% of these isolates were resistant to methicillin. Overall, methicillin‐resistant S. aureus (MRSA) was recovered from 15.3% of patients. Methicillin resistance was more prevalent among S. aureus isolates from patients with healthcare‐associated infection (36.1%) than among isolates from patients with community‐acquired infection (25.1%) (
).
Of the 7,329 patients with monomicrobial infection, coagulase‐negative staphylococci were recovered from 18.2% overall and from 32.9% of patients with a device‐associated or prosthesis infection; Streptococcus species (recovered from 13.0% of patients) and Enterococcus species (recovered from 3.5% of patients) were found relatively infrequently. A total of 738 (10.1%) of these patients had a gram‐negative bacterial infection, with Pseudomonas aeruginosa recovered most often (from 3.1% of patients). Other pathogens, including obligate anaerobic bacteria and fungi, were rarely isolated from patients with monomicrobial infection. Blood cultures were performed for 3,660 patients (50%), and a pathogen was recovered from 729 (20%) patients. Of these 729 patients, 65.2% had the same organism recovered from blood and the SSTBJ specimen. Of patients with a monomicrobial surgical device–associated or prosthesis infection (group 2b) who had a blood culture performed, positive findings were reported for 36.8%, which is the highest such percentage among the groups.
Clinical and Economic Outcomes
Mortality. The overall in‐hospital mortality rate for study patients was only 1.1%. The mortality rate was highest (3.0%) among patients with other infections (group 4) and lowest (0.7%) among patients with cellulitis (group 3). Bacteremic patients had a mortality rate that was significantly higher than that for patients without bacteremia (3.1% vs 1.0%; 
); the difference remained statistically significant for patients with polymicrobial infection (3.8% vs 1.2%; 
) and patients with monomicrobial infection (2.7% vs 0.8%; 
) (Table 4). The mortality rate was significantly higher for patients with complicated infection, compared with those with uncomplicated infection (1.2% vs 0.6%; 
) and for patients with healthcare‐associated infection compared with those with community‐acquired infection (1.6% vs 0.7%; 
) (Table 5). By multiple logistic regression analysis, significant independent risk factors for increased mortality were identified as healthcare‐associated infection (odds ratio [OR], 1.9 [95% confidence interval {CI}, 1.2‐3.1]; 
), Proteus infection (OR, 7.1 [95% CI, 3.1‐16.1]; 
), and bacteremia (OR, 3.1 [95% CI, 1.7‐5.8]; 
). Patients with cellulitis had a significantly decreased risk of mortality (OR, 0.5 [95% CI, 0.3‐0.9]; 
).
LOS and hospital charges. The mean LOS (±SD) was 
days per patient. Patients with osteomyelitis had the longest LOS (
days), whereas those with cellulitis had the shortest (
days). The LOS was significantly longer for patients with complicated infections than for patients with uncomplicated infections (
vs 
days; 
) (Table 5). The mean total hospital charges (±SD) were 
per patient. Charges were highest for patients with a surgical device–associated or prosthesis infection ($29,632), followed by patients with osteomyelitis or septic arthritis ($26,399), patients with surgical wound infection ($22,863), and patients with other SSTBJ infections ($20,838); charges were lowest for patients with cellulitis ($14,798).
Among patients with healthcare‐associated infection, the mean LOS (±SD) was significantly longer (
vs 
days; 
) and the mean total charges (±SD) were significantly greater (
vs 
; 
) than those for patients with community‐acquired infection (Table 6). By linear regression analysis, significant independent predictors of an LOS longer than the overall mean value were identified as higher probability of death (increase of 2.5 days; 
),21 complicated infection (1.1 days; 
), MRSA infection (1.0 days; 
), healthcare‐associated infection (1.4 days; 
), P. aeruginosa infection (0.9 days; 
), Proteus infection (2.4 days; 
), other gram‐negative bacterial infection (1.9 days; 
), and bacteremia (3.1 days; 
). An LOS shorter than the overall mean value was observed for patients with cellulitis (decrease of 2.3 days; 
) and patients with a surgical infection (decrease of 1.2 days; 
).
Discussion
SSTBJ infection is a common reason for hospitalization. During a 2‐year period involving 134 hospitals, we found 12,506 patients with culture‐proven SSTBJ infection. Categorizing these patients into 4 groups (ie, osteomyelitis or septic arthritis, surgical wound infection or device‐associated or prosthesis infection, cellulitis, and other infections) on the basis of the tissues and structures infected and the patient’s surgical status proved to be easy and clinically sensible and allowed for useful comparisons of groups of relatively similar sizes. We also categorized patients on the basis of whether the infection was complicated or uncomplicated (the majority had complicated infections) and whether the infection was community acquired or healthcare associated (the majority had community‐acquired infections). One of our important findings was that, overall, patients with infections that developed in a healthcare setting were associated with a significantly higher mortality rate, longer LOS, and greater financial cost than patients with infections acquired in the community; these differences were also observed for patients with healthcare‐associated infections caused by MRSA or by methicillin‐susceptible S. aureus. These findings may be related to the fact that our patients were relatively old and that most had at least 1 major comorbidity, characteristics that are relatively typical for patients with SSTBJ infection. Methicillin resistance was more prevalent among S. aureus isolates recovered from patients with healthcare‐associated infection than it was among isolates recovered from patients with community‐acquired infection (36.1% vs 25.1%; 
).
Although many patients had polymicrobial infections, most (59%) had infections caused by a single pathogen. Of the monomicrobial infections, the great majority were caused by aerobic gram‐positive cocci. These findings suggest that many patients can be treated with agents having a relatively narrow spectrum. A positive blood culture result was surprisingly frequent (20% patients with monomicrobial infection for whom blood cultures were performed), suggesting that blood culture may be useful for identifying bacteremia in hospitalized patients with SSTBJ infection, especially those with a surgical device–associated or prosthesis infection. We found that patients with osteomyelitis or septic arthritis, patients with complicated infections, and patients with healthcare‐associated infections had a longer LOS and greater hospital costs, suggesting that targeted efforts to manage these infections could help reduce resource consumption. More than 75% of patients had complicated infection, which probably reflects the fact that our study only included hospitalized patients. The higher morbidity and cost associated with complicated infection suggests that efforts to optimally treat superficial infection, and thereby prevent progression into deeper soft tissues, might reduce costs.5,23,24
S. aureus accounted for more than 50% of all pathogens recovered from patients in this study, confirming that it is the major causative pathogen in a wide range of SSTBJ infections. Furthermore, MRSA was recovered from more than 15% of all patients and more than 25% of patients with monomicrobial S. aureus infection. This is consistent with other reports that, over the past decade, S. aureus comprised a consistent percentage of the pathogens recovered annually from patients with skin and soft‐tissue infections25 and reports that the proportion of S. aureus isolates resistant to methicillin is increasing.26 Traditional risk factors for MRSA infections acquired in healthcare facilities are well defined.11,27 The recent increase in the number of community‐acquired MRSA skin and soft‐tissue infections has increased the overall number and, in many instances, the severity of these difficult infections.28‐30
Infection with antibiotic‐resistant isolates can lead to poor clinical outcomes, prolonged LOS, and increased cost of care.16,31,32 MRSA infections are associated with higher mortality rates and treatment costs, compared with infections caused by methicillin‐susceptible S. aureus.16,33,34 We found that MRSA infection was more frequent among patients with healthcare‐associated infections, which were associated with a higher mortality rate, and that it was an independent risk factor for increased LOS. Thus, our results corroborate those of others and emphasize that clinicians must consider the increasing prevalence of methicillin resistance among S. aureus strains in both the hospital and the community when selecting an antibiotic for treating a patient with SSTBJ infection.
This study provides insights into the epidemiology and the clinical and economic outcomes of the broad range of SSTBJ infections in hospitalized patients, whereas most other studies have exclusively reported on specific types of SSTBJ infection. We found that cellulitis, surgical site infection, and osteomyelitis and septic arthritis require substantial financial resources in terms of LOS‐associated costs and other charges. The Centers for Disease Control and Prevention National Hospital Discharge Survey report showed that 44% of hospitalizations for skin disease were attributable to cellulitis and associated with an average LOS of 5.2 days.35 Surgical site infections, the second most common type of nosocomial infection in the United States, account for 3.7 million excess hospital‐days and more than $1.6 billion in excess hospital charges.4 Osteomyelitis in adults mostly occurs in diabetic patients with a foot ulcer, 15%‐20% of whom develop bone infection.36,37 An analysis of data from the National Inpatient Sample from 1993‐2000 found that osteomyelitis‐related diagnoses were recorded for a mean of 9 of every 10,000 admissions and associated with a median LOS of 7 days.38
Our study was based on a retrospective analysis of infections, and, as such, our analysis was limited by the available data recorded in the multi‐institutional database: the types of specimens obtained for culture, the methods by which specimens were processed and findings reported, and the types of antimicrobial therapy administered were determined by the individual clinicians at the various institutions, and we do not have access to these details. By including patients from many hospitals, however, we were able to collect and analyze data for a large number of patients and elucidate the independent risk factors for mortality. Although we developed our own method of classifying SSTBJ infections, we think the method is clinically sensible and found it easy to use. Combined with classifying patients on the basis of more‐standard criteria, such as the presence of complicating features and the site of infection acquisition, our data revealed which patients have a high likelihood of a complicated, prolonged, or expensive therapy. This information can help administrators and clinicians concentrate efforts on methods that could improve outcomes for these high‐risk patients.
Acknowledgments
We thank the following Cardinal Health Clinical Research Group members for their contributions, including their clinical insights, database management, data analysis, and technical support: R. S. Johannes, MD, MS; Linda Hyde, RHIA; Karen Derby, BA; and Alisa Goetz, PharmD. We also thank Larry Liu, MD, PhD, at Pfizer for his clinical and administrative support. Editorial support was provided by PPSI (Stamford, CT) and funded by Pfizer.
Financial support. This study was funded by Pfizer.
Potential conflicts of interest. B.A.L. reports serving on the advisory board of, receiving research support from, and serving on the speakers bureau of Pfizer. J.A.W. reports serving on the advisory board of, receiving research support from, and serving on the speakers bureau of Pfizer. V.G. reports current employment at Cardinal Health. A.D.K. reports former employment at Cardinal Health. M.M.P. reports current employment at Cardinal Health.
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