Abstract
Background
Skin and soft tissue infections (SSTIs) are a key antimicrobial stewardship target because they are a common infection in hospitalized patients, and non-guideline-concordant antibiotic use is frequent. To inform antimicrobial stewardship interventions, we evaluated the proportion of veterans hospitalized with SSTIs who received guideline-concordant empiric antibiotics or an appropriate total duration of antibiotics.
Methods
A retrospective medication use evaluation was performed in 34 Veterans Affairs Medical Centers between 2016 and 2017. Hospitalized patients who received antibiotics for uncomplicated SSTI were included. Exclusion criteria were complicated SSTI, severe immunosuppression, and antibiotics for any non-SSTI indication. Data were collected by manual chart review. The primary outcome was the proportion of patients receiving both guideline-concordant empiric antibiotics and appropriate treatment duration, defined as 5–10 days of antibiotics. Data were analyzed and reported using descriptive statistics.
Results
Of the 3890 patients manually evaluated for inclusion, 1828 patients met inclusion criteria. There were 1299 nonpurulent (71%) and 529 purulent SSTIs (29%). Overall, 250 patients (14%) received guideline-concordant empiric therapy and an appropriate duration. The most common reason for non-guideline-concordance was receipt of antibiotics targeting methicillin-resistant Staphylococcus aureus (MRSA) in 906 patients (70%) with a nonpurulent SSTI. Additionally, 819 patients (45%) received broad-spectrum Gram-negative coverage, and 860 patients (48%) received an antibiotic duration >10 days.
Conclusions
We identified 3 common opportunities to improve antibiotic use for patients hospitalized with uncomplicated SSTIs: use of anti-MRSA antibiotics in patients with nonpurulent SSTIs, use of broad-spectrum Gram-negative antibiotics, and prolonged durations of therapy.
Keywords: abscess, cellulitis, antibiotic stewardship, skin and soft tissue infections
Skin and soft tissue infections (SSTIs) are 1 of the 3 most common infectious diseases–related diagnoses leading to hospitalizations and antibiotic use in both Veterans Affairs Medical Centers (VAMCs) and non-VA medical centers [1–3]. Antibiotics are a necessary treatment for many SSTIs but also carry the risk of adverse effects such as organ dysfunction, allergic reactions, and Clostridioides difficile infection [4, 5]. Additionally, the effectiveness of antibiotics has waned over time due to the development of resistance [6, 7]. Therefore, it is essential to use antibiotics for treatment of SSTI in a manner that optimizes cure but also minimizes the risk of adverse effects and development of antibiotic resistance.
The Infectious Diseases Society of America (IDSA) has published guidelines for the treatment of SSTIs since 2005 [8–10]. Despite the availability of these guidelines, guideline-discordant antibiotic use for SSTI treatment in hospitalized patients is commonly reported [11–13]. In light of frequent SSTI-related hospitalizations and previously reported suboptimal antibiotic use, a work group of the VA Antimicrobial Stewardship Task Force (ASTF) and VA Pharmacy Benefits Management Services Center for Medication Safety (VA MedSAFE) performed a medication use evaluation (MUE) of inpatient antibiotic use for uncomplicated SSTIs in hospitalized veterans. In an effort to inform antimicrobial stewardship interventions, we assessed the proportion of patients who received empiric antibiotics concordant with the current guidelines at the time of evaluation and an appropriate duration of total antibiotic therapy.
METHODS
We retrospectively evaluated uncomplicated SSTI management in patients hospitalized at 34 VAMCs. The evaluation period was from June 1, 2016, to May 31, 2017. Inclusion criteria were age 18 years and older; hospitalization in an acute care unit on at least 1 calendar day; presence of at least 1 SSTI-related International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis code during hospitalization (ie, L02, L03); and receipt of at least 1 SSTI-targeted antibiotic initiated within 2 calendar days of hospitalization. Only the first VAMC hospitalization per patient within the evaluation period was included. Exclusion criteria were complicated SSTI, receipt of empiric antibiotics for a non-SSTI indication, inpatient SSTI treatment in the previous 28 days at a non-VAMC, transfer in or out of the VAMC during SSTI treatment, death in the 5 days after the start of SSTI treatment, or severe immunosuppression. Complicated SSTI was defined as infected chronic wounds or ulcers (ie, present ≥28 days or unknown duration); SSTI involving the facial, rectal, or genital areas; human or animal bite–related SSTIs; necrotizing SSTIs; SSTIs involving deeper structures such as tendon, fascia, or bone; and surgical site infections. Patients with wound or ulcer infections reported to be present <28 days were included and not evaluated differently than other SSTIs. Severe immunosuppression was defined as an absolute neutrophil count <500 cells/mm3 any time during hospitalization, history of hematopoietic stem cell or solid organ transplant any time before admission, or receipt of an immunosuppressive medication. Immunosuppressive medications were high-dose steroids for at least 2 of the previous 4 weeks, chemotherapy in the previous 6 weeks, or other immunosuppressive medication in the previous 3 months.
Potential patients were extracted from the Corporate Data Warehouse using relevant SSTI ICD-10-CM coded discharge diagnoses. Each of the 34 participating VAMCs were then provided with up to 150 of their own patients to manually screen for inclusion and exclusion criteria using the electronic medical record. The actual number of patients provided to each facility for manual screening ranged from 58 to 150 patients depending on the number of qualifying SSTI cases at the facility during the evaluation period. A full manual chart review was conducted for included patients using standardized Microsoft InfoPath forms, which were stored in a secure central database. Additionally, standardized instructions were provided to chart abstractors, and a monthly webinar was provided to address MUE logistics, education on key areas for data collection, provide an update of progress to sites, and to answer questions. Questions not addressed by the pre-established, standardized data collection instructions were adjudicated by 4 infectious diseases–trained pharmacists or physicians (E.S., J.S., M.G., M.N.). No further validation of manually collected data was performed. Manually collected data included patient characteristics, antibiotic allergies, antibiotics for the SSTI episode of interest and 14 days before the SSTI episode of interest, incision and drainage for the SSTI episode of interest and 14 days prior, cutaneous cultures within 1 calendar day of antibiotic initiation, SSTI location(s), vital signs within 1 calendar day of antibiotic initiation, laboratory results within 1 calendar day of antibiotic initiation, vasopressor receipt within 1 calendar day of antibiotic initiation, imaging obtained on the day before through 4 days after antibiotic initiation, and SSTI retreatment within 28 days of discharge. Electronically extracted data included comorbidities, blood cultures within 1 calendar day of antibiotic initiation, mortality within 28 days after antibiotic initiation, and readmissions within 28 days after discharge.
The primary objective was to assess the proportion of patients who received both empiric antibiotics concordant with the current guidelines at the time of evaluation and an appropriate duration of total antibiotic therapy [10]. For purulent SSTIs, guideline-concordant empiric therapy was defined as receipt of only methicillin-resistant Staphylococcus aureus (MRSA)–targeted antibiotics. MRSA-targeted antibiotics included the following antibiotics or antibiotic classes administered by any systemic route of administration: ceftaroline, daptomycin, lipoglycopeptides, oxazolidinones, tetracyclines, trimethoprim-sulfamethoxazole, vancomycin. Clindamycin was not considered an MRSA-targeted antibiotic because it is not recommended as empiric therapy in IDSA guidelines [10]. For nonpurulent SSTIs, guideline-concordant empiric therapy was defined as receipt of only streptococci-targeted antibiotics. Streptococci-targeted antibiotics included nonantipseudomonal penicillins, nonantipseudomonal cephalosporins except ceftaroline and cephamycins, or clindamycin by any systemic route of administration. An appropriate antibiotic duration was defined as 5–10 total calendar days of antibiotics. Current SSTI guidelines recommend a minimum of 5 days extended until improvement for cellulitis, but a specific upper range is not provided [10]. Therefore, we selected 10 days as the upper range to define appropriate duration based on previous guidelines and studies suggesting that longer durations would rarely be necessary in the included population [9, 14–18]. Patients with bacteremia were not included in the duration assessment but were included in the empiric antibiotic selection assessment.
Purulence was assessed by manual chart review at the time of empiric antibiotic selection, not based on the final diagnosis, because the goal of the MUE was to evaluate prescribing behaviors, not clinical outcomes. Purulence was defined as the presence of terms consistent with purulence (ie, abscess, carbuncle, felon, fluid collection or accumulation, furuncle, purulent, pus, pustule). Empiric antibiotic therapy was defined as any antibiotic received in the emergency department or on the earliest calendar day of hospitalization. Unnecessary empiric MRSA coverage was defined as receipt of 1 or more MRSA-targeted empiric antibiotics in a patient with a nonpurulent SSTI. Unnecessary empiric broad-spectrum coverage was defined as receipt of any systemic beta-lactam/beta-lactamase inhibitor, antipseudomonal cephalosporin, carbapenem, aminoglycoside, polymyxin, aztreonam, or tigecycline. Missed streptococci coverage was considered receipt of only empiric antibiotics traditionally considered to have suboptimal streptococci coverage (ie, aztreonam, macrolides, metronidazole, rifampin, tetracyclines, trimethoprim-sulfamethoxazole). SSTI retreatment in the 28 days after hospital discharge was defined as any systemic antibiotic or incision and drainage in addition to or beyond that planned at the time of hospital discharge (ie, additional treatment days with the same or a different antibiotic for SSTI independent of the initial course being completed).
The MUE was developed and coordinated by VA MedSAFE and the ASTF work group. VA Salt Lake City Informatics Decision-Enhancement and Analytic Sciences Center (IDEAS 2.0) performed electronic data extraction. VA MedSAFE performed electronic data extraction and all data analysis. All data were analyzed descriptively, as this was a noncomparative evaluation. Data were analyzed using SAS Software, version 9.3 (SAS Institute). The Hines VHA Institutional Review Board reviewed this MUE and deemed it quality improvement per the VHA Policy Handbook 1058.05, and it was therefore exempt from VHA Human Subjects Research requirements.
RESULTS
There were 10 276 adult patients who were hospitalized at participating facilities during the evaluation period and had an SSTI discharge diagnosis. Five thousand one hundred sixty-five patients were electronically excluded based on presence of an exclusionary diagnosis code, as detailed in Figure 1. Of the remaining 5111 patients, 3890 patients were manually reviewed. Two thousand sixty-two patients were not included based on manual chart review. The evaluable cohort consisted of 1828 included patients.
Figure 1.
Flowchart describing selection of patients with SSTI. aExclusionary diagnosis for the current admission or a procedure code in the previous 30 days included any of the following: surgical site infection, facial SSTI, perirectal/genital SSTI, bite-related SSTI, deep tissue infection, chronic ulcer, amputation, vascular surgery. bPatients met multiple exclusion criteria. Abbreviation: SSTI, skin and soft tissue infection.
A nonpurulent SSTI was identified in 1299 patients (71%), and a purulent SSTI was identified in 529 patients (29%). The population was predominantly male, and comorbidities were common (Table 1). Older age, greater body size, lower-extremity SSTI, and comorbidities such as diabetes mellitus, heart failure, or peripheral vascular impairment were more common in patients with a nonpurulent compared with a purulent SSTI. In contrast, upper extremity SSTI, MRSA colonization, and injection drug use were more common in patients with a purulent vs nonpurulent SSTI. Although all patients were hospitalized, acute severity of illness was low based on the low proportion of patients (n = 55, 3%) with an elevated quick sequential organ failure score (qSOFA) or on vasopressors. Additional factors that may have influenced empiric antibiotic selection were receipt of outpatient antibiotics for SSTI before admission in 488 patients overall (25%), documented penicillin allergy in 170 patients (13%) with a nonpurulent SSTI, and positive MRSA nasal screen in 160 patients (13%) with a nonpurulent SSTI.
Table 1.
Demographics and Other Characteristics of Skin and Soft Tissue Infection Cohort
| Nonpurulent SSTI (n = 1299) | Purulent SSTI (n = 529) | |
|---|---|---|
| Age, median (IQR), y | 67 (59–74) | 61 (52–69) |
| Male gender | 1260 (97) | 490 (93) |
| Antibiotic allergy | ||
| Penicillin | 170 (13) | 68 (13) |
| Cephalosporin | 23 (2) | 9 (2) |
| Comorbidities | ||
| Diabetes mellitus | 664 (51) | 236 (45) |
| Heart failure | 322 (25) | 77 (15) |
| Chronic ischemic heart disease | 283 (22) | 74 (14) |
| Peripheral vascular impairment | 412 (32) | 83 (16) |
| Chronic kidney disease | 298 (23) | 85 (16) |
| End-stage renal disease or hemodialysis | 49 (4) | 13 (3) |
| Cirrhosis | 54 (4) | 20 (4) |
| Injection drug use | 55 (4) | 60 (11) |
| SSTI-specific characteristics | ||
| Body mass index, median (IQR), kg/m2 | 32 (27–38) | 30 (25–35) |
| Weight, median (IQR), kg | 100 (82–123) | 94.5 (79–113) |
| MRSA history (previous year) | 92 (7) | 52 (10) |
| Current positive MRSA screena | 160/1232 (13) | 131/510 (26) |
| SSTI treatment previous 14 d | 273 (21) | 175 (33) |
| Any antibacterial previous 14 d | 306 (24) | 185 (35) |
| Incision & drainage previous 14 d | 10 (0.8) | 56 (11) |
| Incision & drainage (current hospitalization)b | 35 (3) | 321 (61) |
| Primary SSTI locationc | ||
| Lower extremity | 891 (69) | 198 (37) |
| Foot | 243 (19) | 60 (11) |
| Upper extremity | 136 (10) | 107 (20) |
| Hand | 97 (7) | 81 (15) |
| Trunk | 39 (3) | 101 (19) |
| Neck | 10 (0.7) | 24 (5) |
| Other | 3 (0.2) | 2 (0.4) |
| Bilateral SSTI (nonpurulent only) | 343 (26) | - |
| Acute severity of illness measuresd | ||
| Temperature >38°C (100.4°F) | 171 (13) | 80 (15) |
| qSOFA ≥2 | 41 (3) | 11 (2) |
| Vasopressors | 4 (0.3) | 1 (0.2) |
| qSOFA ≥2 OR vasopressors | 43 (3) | 12 (2) |
| Lactate >2 mmol/L | 140 (11) | 40 (8) |
| WBC >12×103/µL | 397 (31) | 189 (36) |
| Erythrocyte sedimentation rate obtainede | 475 (37) | 191 (36) |
| C-reactive protein obtainede | 511 (39) | 209 (40) |
| Imaging obtainede | 859 (66) | 354 (67) |
| Ultrasound | 417 (32) | 131 (25) |
| X-ray | 501 (39) | 225 (43) |
| Computed tomography | 115 (9) | 89 (17) |
| Magnetic resonance imaging | 38 (3) | 33 (6) |
| Radionuclide imaging | 6 (0.5) | 2 (0.4) |
Data expressed as No. (%) unless specified otherwise.
Abbreviations: IQR, interquartile range; qSOFA, quick sequential organ failure score; SSTI, skin and soft tissue infection; WBC, white blood cell count.
aReported as No. positive/No. obtained.
bAny time during current hospitalization.
cMultiple responses allowed.
dWithin 1 calendar day of antibacterial initiation unless specified otherwise.
eAntibiotic days 1–5.
Overall, the majority of patients (n = 1348, 74%) did not have a culture obtained or pathogen identified (Table 2). Gram-positive organisms were the most commonly identified organisms (n = 390, 81%). Gram-negative organisms were identified in 18% (n = 73) of patients with a culture obtained (4% of patients in the overall population). When identified, Gram-negatives were more common in lower-quality wound cultures (53/254, 21%) rather than abscess aspirate or tissue cultures (20/156, 13%). Blood cultures, which were obtained in 1442 patients (79%) overall, were positive for a pathogen in 58 patients (3%) and for a contaminant in 41 patients (2%).
Table 2.
Microbiology
| Nonpurulent SSTI (n = 1299) | Purulent SSTI (n = 529) | |
|---|---|---|
| Cutaneous culture obtaineda | 137 (11) | 343 (65) |
| Abscess or tissueb | 18 (1) | 166 (31) |
| Wound/swabb | 117 (9) | 195 (37) |
| Unknownb | 5 (0.4) | 3 (0.6) |
| Cutaneous culture resultsc | Nonpurulent SSTI (n = 137) | Purulent SSTI (n = 343) |
| Aerobic Gram-positive | 99 (72) | 291 (85) |
| Staphylococcus aureus | 50 (36) | 216 (63) |
| MSSA | 29 (21) | 84 (24) |
| MRSA | 21 (15) | 132 (38) |
| Streptococcus spp. | 29 (21) | 54 (16) |
| Enterococcus spp. | 10 (7) | 9 (3) |
| Other Gram-positive (not specified) | 42 (31) | 57 (17) |
| Aerobic Gram-negative | 31 (23) | 45 (13) |
| Aeromonas spp. or Vibrio spp. | 0 (0) | 0 (0) |
| Enterobacteriaceae | 6 (4) | 17 (5) |
| Pseudomonas spp. or Acinetobacter spp. | 9 (6) | 6 (2) |
| Other Gram-negative (not specified) | 18 (13) | 22 (6) |
| Anaerobic organism | 5 (4) | 20 (6) |
| No growth | 27 (20) | 39 (11) |
| Polymicrobiald | 41 (3) | 76 (14) |
| Blood cultures | Nonpurulent SSTI (n = 1299) | Purulent SSTI (n = 529) |
| Blood culture obtained | 1038 (80) | 404 (76) |
| Contaminante,f | 27 (2) | 14 (3) |
| Positive blood culturee | 30 (2) | 18 (3) |
| MRSA | 0 (0) | 3 (0.6) |
| MSSA | 1 (0.1) | 3 (0.6) |
| Streptococcus spp. | 17 (1) | 5 (1) |
| Other Gram-positive | 11 (0.8) | 5 (1) |
| Pseudomonas spp. or Acinetobacter spp. | 0 (0) | 1 (0.2) |
| Anaerobic organism | 1 (0.1) | 1 (0.2) |
Patients could have multiple cultures obtained.
Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; SSTI, skin and soft tissue infection.
aPatients with cutaneous culture obtained/total patients.
bPatients with culture type/total patients.
cPatients with organisms isolated from any cutaneous culture/patients with a cutaneous culture.
dPolymicrobial is defined as any patient with more than 1 unique organism isolated in any culture(s). Unique organisms could be isolated in the same or different cultures.
ePatients with specified criteria/total patients.
fDefined as 1 positive blood culture set with an organism that rarely represents true bacteremia [40].
Only 14% of patients (n = 250) received guideline-concordant empiric antibiotics and an appropriate duration (Table 3). Breaking the primary measure into specific elements, guideline-concordant empiric therapy was given to 283 patients (22%). Overall, 914 patients (52%) with an evaluable duration received 5–10 days total of antibiotics.
Table 3.
Outcomes
| Nonpurulent SSTI (n = 1299) | Purulent SSTI (n = 529) | |
|---|---|---|
| Guideline-concordant empiric therapy & appropriate total duration of therapy (composite) | 188 (14) | 62 (12) |
| Guideline-concordant empiric therapy | 283 (22) | 141 (27) |
| Guideline-concordant empiric therapy w/ clindamycin as adequate MRSA | N/A | 203 (38) |
| Non-guideline-concordant therapy description | ||
| Unnecessary empiric MRSA coverage | 906 (70) | N/A |
| Missed empiric MRSA coverage | N/A | 83 (16) |
| Missed/suboptimal empiric streptococci coverage | 39 (3) | N/A |
| Unnecessary empiric broad-spectrum | 558 (43) | 261 (49) |
| Unnecessary empiric broad-spectrum (excludes patients with qSOFA score ≥2 OR on vasopressors)a | 451/1256 (36) | 222/517 (43) |
| Antibiotic durationb | ||
| Antibiotic duration ≤5 d | 73 (6) | 27 (5) |
| Antibiotic duration 6–10 d | 629 (50) | 185 (36) |
| Antibiotic duration >10 d | 562 (44) | 298 (58) |
| Total antibiotic duration, median (IQR) , d | 10 (8–13) | 11 (9–14) |
| Inpatient duration, median (IQR), d | 4 (3–6) | 4 (3–6) |
| Outpatient duration, median (IQR), d | 7 (6–10) | 8 (6–11) |
| Other outcomes | ||
| Outpatient parenteral antibiotic therapy at discharge | 36 (3) | 17 (3) |
| Length of stay, median (IQR), d | 4 (3–6) | 4 (3–6) |
| SSTI retreatment within 28 d | 172 (13) | 67 (13) |
| Readmission within 28 d | 28 (2) | 9 (2) |
| All-cause mortality within 28 d | 17 (1) | 3 (0.6) |
| Clostridioides difficile infection within 28 d | 6 (0.5) | 4 (0.8) |
Data are expressed as No. (%) unless otherwise specified.
Abbreviations: IQR, interquartile range; MRSA, methicillin-resistant Staphylococcus aureus; qSOFA, quick sequential organ failure score; SSTI, skin and soft tissue infection.
aDoes not include amoxicillin-clavulanate or ampicillin-sulbactam.
bDuration of therapy statistics only account for patients who were not bacteremic (nonpurulent n = 1264; purulent n = 510).
The most common type of non-guideline-concordant empiric therapy was MRSA coverage in nonpurulent SSTI, which occurred in 906 patients (70%) (Table 3). Vancomycin was the most common anti-MRSA antibiotic and was given to 733 patients (56%). One hundred eighty-four patients (14%) were given oral doxycycline or minocycline. All other anti-MRSA antibiotics accounted for <5% of anti-MRSA antibiotics in patients with a nonpurulent SSTI.
The second most common type of non-guideline-concordant therapy was empiric broad-spectrum coverage, which occurred in 819 patients (Table 3). Piperacillin-tazobactam was the most common broad-spectrum antibiotic and was given to 497 patients (27%). Ampicillin-sulbactam (n = 116, 6%) and amoxicillin-clavulanate (n = 117, 6%) were the second most common broad-spectrum antibiotics. All other antibiotics accounted for <5% of unnecessary broad-spectrum antibiotics.
The third most common area of potentially suboptimal prescribing was excessive duration of therapy. The median duration (IQR) was 10 (8–13) days in the nonpurulent group and 11 (9–14) days in the purulent group (Table 3). The majority of the course was outpatient antibiotics after discharge (median, 7–8 days). Eight hundred sixty (48%) of the 1774 nonbacteremic patients received >10 days of antibiotics, with 562 (44%) in the nonpurulent group and 298 (58%) in the purulent group.
There was variability in guideline concordance between sites (Figure 2). Comparing results across the 34 sites, the median percentage of patients who received guideline-concordant empiric therapy (IQR) was 22% (16%–27%). The median percentage of empiric MRSA coverage in nonpurulent SSTI cases (IQR) was 72% (63%–85%). The median percentage of empiric broad-spectrum Gram-negative coverage in all SSTI cases (IQR) was 46% (34%–57%). The median percentage of treatment >10 days in all SSTI cases was 50% (37%–53%).
Figure 2.
Non-guideline-concordant therapy results by participating site This plot displays the percentage of cases at each of the 34 participating sites (y-axis) that met the specified criteria (x-axis). Boxes: median and IQR. Whiskers: lower bound = (quartile 1–1.5 * IQR) and upper bound = (quartile 3 + 1.5 * IQR). Circles = outliers. Empiric nonconcordant = non-guideline-concordant empiric antibiotic selection in all patients. Empiric MRSA (nonpurulent) = empiric therapy with a MRSA-targeted antibiotic in patients with a nonpurulent skin and soft tissue infection. Empiric broad-spectrum = empiric therapy with a broad-spectrum Gram-negative antibiotic in all patients. Duration >10 days = total antibiotic duration was >10 days in all patients. Abbreviations: IQR, interquartile range; MRSA, methicillin-resistant Staphylococcus aureus.
Overall, unadjusted outcomes were not different in the 238 patients who met the composite criteria for guideline-concordant therapy and appropriate duration compared with the 1590 patients who did not meet criteria. SSTI retreatment occurred in 24 patients (10%) in the guideline-concordant therapy group and 215 (14%) in the non-guideline-concordant therapy group. Hospital length of stay (IQR) was 4 (3–5) days in the guideline-concordant group compared with 4 (3–6) days in the non-guideline-concordant group.
DISCUSSION
We identified a high rate of non-guideline-concordant antibiotic use and prolonged antibiotic durations in the 1828 evaluated patients hospitalized with uncomplicated SSTI. The 3 most commonly identified opportunities to improve antibiotic use were empiric anti-MRSA antibiotics for nonpurulent SSTIs, empiric broad-spectrum Gram-negative antibiotics, and duration of therapy >10 days. The suboptimal antibiotic use patterns reported in this evaluation were similar to evaluations performed outside VAMCs [11–13, 19].
We found little justification for the frequency of guideline-discordant therapy. We excluded patients who received antibiotics for non-SSTI indications and patients with more complicated SSTIs such as necrotizing infections or chronic wound infections, for which broad-spectrum empiric antibiotics are often recommended. The acute severity of illness was low based on the proportion of patients requiring vasopressors (0.3%) or having elevated qSOFA scores (3%). Isolation of Gram-negative (4%) or anaerobic organisms (1%) not covered by guideline-recommended antibiotics was infrequent and most often occurred in lower-quality wound swab cultures. Lastly, outcomes, such as SSTI retreatment and length of stay, were not numerically different in patients receiving non-guideline-concordant therapies or prolonged durations in unadjusted analysis.
Although the primary focus of the evaluation was to identify prescribing behaviors to target for antimicrobial stewardship interventions, the results also highlight several opportunities to improve diagnostic elements related to SSTI, specifically related to misdiagnosis and overuse of diagnostic tests. Fourteen percent (n = 555) of the 3890 initially evaluated patients were excluded due to receipt of antibiotics for an indication in addition to SSTI, suggesting that diagnostic uncertainty may impact initial antibiotic selection. Bilateral lower-extremity cellulitis, which is uncommon in the literature and indicates potential misdiagnosis, and comorbidities complicating SSTI diagnosis, such as peripheral vascular impairment and lymphedema, were identified in a quarter of patients with nonpurulent SSTI [20, 21]. Additionally, a quarter of all patients were treated for an SSTI as an outpatient in the 14 days before hospitalization. Previous outpatient antibiotic treatment is likely related to not only true outpatient antibiotic failures but also misdiagnosis and misinterpretation of natural SSTI course [22–24]. Collectively, the number of exclusions due to treatment of other infections, patients with bilateral lower-extremity involvement, and comorbidities complicating SSTI diagnosis suggest diagnostic uncertainty, and alternative diagnoses may be drivers of unnecessary antibiotic use for SSTI. This observation is consistent with studies reporting that alternative diagnoses were common in patients hospitalized for SSTIs when evaluated by dermatology [24, 25].
With regard to diagnostic testing, imaging was performed in two-thirds of patients, with x-ray and ultrasound being the most common. Previous studies suggest that these tests are low yield for identifying an additional or alternate diagnosis in the setting of suspected SSTI; therefore, they are not recommended for uncomplicated cellulitis and cutaneous abscess [10, 26–28]. Additionally, labs such as erythrocyte sedimentation rate and C-reactive protein were obtained in approximately a third of patients but are not specifically recommended in the diagnosis of SSTI [10]. Lastly, routine blood cultures were of low value on the population level based on the low rate of positivity (3%) relative to contamination (2%) and low acute severity of illness [26, 29]. Although no official blood culture recommendation is provided for nonimmunocompromised patients, IDSA guidelines state that blood cultures are low yield and should be considered only in patients with severe systemic features [10]. These results suggest that there is opportunity to optimize diagnostic testing related to SSTI.
There are a few notable distinctions between definitions used in this evaluation compared with current guidelines [10]. We did not factor each patient’s drug allergies, MRSA colonization, or preceding outpatient treatment with an oral antibiotic into our guideline-concordant empiric antibiotic assessment [10]. The presence of a positive MRSA nasal screen (13%) or documented penicillin allergy (13%) may have contributed to avoidance of beta-lactams in patients with a nonpurulent SSTI. The negative consequences of unnecessary beta-lactam avoidance in patients with reported penicillin allergies have been well described elsewhere [30]. MRSA nasal screening was systematically performed, primarily by polymerase chain reaction, at the time of admission throughout the VA during the evaluation period [31]. MRSA screen results are reported in the medical record within ~1 calendar day of admission, which would have often been within the time frame of our empiric therapy definition, so they may have influenced empiric antibiotic selection. Guidelines do recommend use of anti-MRSA antibiotics for nonpurulent SSTIs in patients with known MRSA colonization [10]. However, several studies in MRSA-endemic areas suggest that the addition of anti-MRSA antibiotics in patients with nonpurulent cellulitis does not improve outcomes, but the absolute number of patients with a history of MRSA or documented current MRSA colonization was small [32–35]. The relatively high proportion of patients (25%) treated for an SSTI as an outpatient in the 14 days before hospitalization, which was similar to other evaluations, may have driven non-guideline-concordant antibiotic use [19, 26]. We did not track if previous antibiotics were for treatment of an acute SSTI episode or recurrent cellulitis prophylaxis. A previous evaluation reported that <5% of patients had a recurrent infection, so most use was likely for treatment of an acute SSTI episode, which would indicate suboptimal response to outpatient oral antibiotics before admission [11]. Strictly following IDSA SSTI guidelines, failure to respond to oral therapy is considered a severe SSTI for which broad-spectrum antibiotics are recommended in patients with nonpurulent SSTI [10]. However, studies suggest that patients admitted after not responding to outpatient antibiotics are not more likely to have a nontraditional pathogen compared with patients who were not previously treated [22, 23]. Additionally, lack of response to empiric antibiotics and recurrent SSTIs are often due to a combination of predisposing patient factors, misdiagnosis, or misinterpretation of natural SSTI course rather than failure of antibiotic therapy [16, 19, 23–25, 36–39].
Additional limitations include the retrospective categorization of purulent or nonpurulent SSTI, which was dependent on the quality of provider assessment and documentation. We were not able to retrospectively assess SSTI lesion size or response to treatment based on physical exam due to the heterogeneity in documentation. Lesion size may impact both empiric antibiotic selection and duration of therapy, prompting providers to prescribe broader-spectrum antibiotics or longer antibiotic durations for larger or slow-to-respond lesions [10]. We were also unable to operationally categorize SSTI severity as recommended in guidelines due to overlap in the moderate and severe classifications [10]. Instead, we used extensive exclusion criteria to develop a population of primarily uncomplicated SSTIs. These exclusion criteria strengthen our assessment of prescribing behavior but result in a population not representative of the diverse classifications of SSTIs admitted to hospitals based on ICD-10-CM diagnosis codes. The patients in our evaluation may have limited generalizability given the high proportion of males with diabetes, low proportion of injection drug users, and low acute severity of illness. We did include patients with wound infections (eg, diabetic foot infections) reported to be present <28 days, but we did not specifically track management in this subset of patients. We did not quantitatively evaluate factors associated with non-guideline-concordant therapy or the impact of non-guideline-concordant therapy on clinical outcomes. Lastly, our evaluation was intended as a high-level assessment of prescribing behaviors relative to guidelines. There are likely instances where patients receiving non-guideline-concordant therapy by our definitions were still managed effectively based on individual patient-specific (eg, patients with purulent SSTI treated with antibiotics active against methicillin-susceptible Staphylococcus aureus based on previous history) or institution-specific information (eg, high rate of clindamycin susceptibility vs MRSA at a given institution).
In conclusion, we found a high rate of non-guideline-concordant empiric antibiotic therapy and prolonged total duration of therapy for patients hospitalized with SSTI. Based on our evaluation, the VA ASTF provided an educational webinar on the diagnosis and management of SSTIs, a template for the creation of electronic antibiotic order sets for SSTI treatment, tools for performing prospective audit and feedback specific to SSTI, and an antibiotic use dashboard specific to SSTI. Although not addressed by our intervention, we would highlight the 7-day median duration of antibiotics at discharge as an important antimicrobial stewardship target. Additionally, our evaluation highlights several potential diagnostic targets likely contributing to suboptimal or unnecessary use of antibiotics and other health care resources. Further study is needed to understand the factors driving non-guideline-concordant antibiotic use, interfacility variation, the impact of non-guideline-concordant therapy on outcomes and unintended consequences, and effective interventions to optimize antibiotic use for SSTIs.
Acknowledgments
The authors acknowledge Kenneth Bukowski for assisting with development of data collection tools and data management and members of the Antimicrobial Stewardship Task Force and Antimicrobial Stewardship Taskforce Implementation Work Group.
Availability of data. The data are not publicly available. Data collection forms and instructions are available upon request.
Collaborators in the Skin and Soft Tissue Infection Medication Use Evaluation Group. Atlanta VA Health Care System: Tiffany Goolsby, PharmD, Lucy Witt, MD; Bay Pines VA Healthcare System: Joseph Hong, PharmD, Patrick Landayan, PharmD, Katelyn Shatz, PharmD, MBA; Boise VA Medical Center: Benjamin Pontefract, PharmD, Kaysie Murdock, PharmD; VA Boston Healthcare System: Jaime Gallegos-Salazar, MD, Judith Strymish, MD; James J. Peters VA Medical Center (Bronx): Mei Chang, PharmD, Henry Poon, PharmD, Kirsten Vest, PharmD; Central Arkansas Veterans Healthcare System: Nicholas Tinsley, PharmD, MS; VA Central Iowa Health Care System: Gregory Bockenstedt, PharmD, Darshan Patel, PharmD, John Message, PharmD; Central Texas Veterans Health Care System: Gordon Ang, PharmD, Archana Banerjee, PharmD, Sarah Fry, PharmD, Michael Rose, PharmD; Cincinnati VA Medical Center: Jason Hiett, PharmD, Victoria Tate, PharmD; VA Connecticut Healthcare System: Ann Fisher, MD, Brian Kotansky, PharmD, Van Vu, PharmD; John D. Dingell VA Medical Center (Detroit): Sorabh Dhar, MD, Ryan Kuhn, PharmD, Sandra Willis, PharmD, MBA; Durham VA Health Care System: Rachel Britt, PharmD, Mary Townsend, PharmD; Malcom Randall VA Medical Center (Gainesville); Edward Hines, Jr. VA Hospital (Chicago): Erica Little, PharmD; Jack C. Montgomery VA Medical Center (Muskogee): Lisa Williams, DPh; Kansas City VA Medical Center: Elizabeth Ficek, PharmD, Renae Tell, PharmD; Captain James A. Lovell Federal Health Care Center (North Chicago): Xuxuan Liu, PharmD, John Pasciak, PharmD; VA Maryland Health Care System: Ruth Iliuta, RN, CWCN, COCN; Memphis VA Medical Center: Jessica Bennett, PharmD, Victoria Germinario, PharmD; James H. Quillen VA Medical Center (Mountain Home): Elizabeth Jacobs, PharmD, Justin Spivey, PharmD, Marty Vannoy, PharmD; VA Nebraska-Western Iowa Health Care System: Pamela Foral, PharmD; VA Northern California Health Care System: Christine Feller, RD, CCRP, Hien Nguyen, MD, Shu Lu, PharmD; VA North Texas Health Care System: Tim Burns, PharmD, Paris Khan, PharmD, Marcus Kouma, PharmD; VA Pittsburg Healthcare System: Deanna Buehrle, PharmD, Nicholas Ruzzi, PharmD; Portland VA Medical Center: Kimberly MacKay, PharmD, Lisa Tran, PharmD; Richmond VA Medical Center: Jennifer Emberger, MD, Khine Sann, MD, Daniel Tassone, PharmD; Salt Lake City VA Medical Center: Emily Spivak, MD, MHS, Jesse Sutton, PharmD; San Diego VA Medical Center: Sean Chow, PharmD; Ariel Ma, PharmD; San Juan VA Medical Center: Edmarielis Gonzalez-Gonzalez, PharmD, Hector Cintron, PharmD; Sioux Falls VA Health Care System: Andrea Aylward, PharmD, K. Taylor Daniel, PharmD, Jenna Welu, PharmD; South Texas Veterans Health Care System: Cameron Pickard, PharmD, Chelsea Sanchez, PharmD; VA Southern Nevada Healthcare System: Ashfaq Shafiq, PharmD; VA St. Louis Health Care System: Danielle Skouby, PharmD; Wilkes Barre VA Medical Center: Jill O’Donnell, PharmD, Michael Surdy, PharmD. Collaborators are listed by VA membership at the time of MUE participation, and some collaborators may no longer be practicing at affiliated locations.
Disclaimer. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.
Financial support. There was no financial support for this project.
Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Contributor Information
Skin and Soft Tissue Infection Medication Use Evaluation Group:
Tiffany Goolsby, Lucy Witt, Joseph Hong, Patrick Landayan, Katelyn Shatz, Benjamin Pontefract, Kaysie Murdock, Jaime Gallegos-Salazar, Judith Strymish, Mei Chang, Henry Poon, Kirsten Vest, Nicholas Tinsley, Gregory Bockenstedt, Darshan Patel, John Message, Gordon Ang, Archana Banerjee, Sarah Fry, Michael Rose, Jason Hiett, Victoria Tate, Ann Fisher, Brian Kotansky, Van Vu, Sorabh Dhar, Ryan Kuhn, Sandra Willis, Rachel Britt, Mary Townsend, Erica Little, Lisa Williams, Elizabeth Ficek, Renae Tell, Xuxuan Liu, John Pasciak, Ruth Iliuta, Jessica Bennett, Victoria Germinario, Elizabeth Jacobs, Justin Spivey, Marty Vannoy, Pamela Foral, Christine Feller, Hien Nguyen, Shu Lu, Tim Burns, Paris Khan, Marcus Kouma, Deanna Buehrle, Nicholas Ruzzi, Kimberly MacKay, Lisa Tran, Jennifer Emberger, Khine Sann, Daniel Tassone, Emily Spivak, Jesse Sutton, Sean Chow, Ariel Ma, Edmarielis Gonzalez-Gonzalez, Hector Cintron, Andrea Aylward, K Taylor Daniel, Jenna Welu, Cameron Pickard, Chelsea Sanchez, Ashfaq Shafiq, Danielle Skouby, Jill O’Donnell, and Michael Surdy
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