Open Forum Infectious Diseases BRIEF REPORT infection or sepsis, PCT-guided prescribing algorithms have Time Course of C-Reactive Protein been shown to safely reduce antibiotic therapy and may improve and Procalcitonin Levels During the clinical outcomes [4, 5]. Treatment of Acute Bacterial Skin e o Th bjectives of this pilot study were to (1) describe the time course of CRP and PCT during the treatment of acute bac- Infections terial skin infections and (2) evaluate appropriate time points 1,2,3,6,7 4,8 9 Timothy C. Jenkins, Jason S. Haukoos, Eleanor Cotton, 9 7 1,2,5,6,7 to obtain biomarker specimens in future studies of biomark- David Weitzenkamp, Daniel N. Frank, and William J. Burman 1 2 3 er-guided treatment strategies. We hypothesized that CRP and Department of Medicine, Division of Infectious Diseases, Department of Patient Safety and 4 5 Quality, Department of Emergency Medicine, and Denver Public Health, Denver Health, Denver, PCT levels would be elevated at presentation and would decline 6 7 8 Colorado; Department of Medicine, Division of Infectious Diseases, and Department of by day 3 of treatment. Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado; Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado METHODS In a pilot study of 22 patients with an acute bacterial skin infec- Study Design tion, serum levels of C-reactive protein and procalcitonin tended This was a prospective observational pilot study of patients to be elevated at presentation and declined within 3–5 days of treated at Denver Health for an acute bacterial skin infection treatment. Further study of a biomarker-guided treatment strat- between February 28, 2014, and March 9, 2017. egy to reduce antibiotic overuse in skin infections is warranted. Keywords. acute bacterial skin and skin structure infec- Study Setting and Population tion; antibiotic stewardship; biomarker; C-reactive protein; Patients ≥18 years of age with cellulitis, cutaneous abscess, procalcitonin; skin and soft tissue infection. wound infection, or an infected ulcer were eligible. Key exclu- sion criteria were initiation of antibiotic therapy >2 hours prior to enrollment, suspected or confirmed deep tissue infection, Antibiotic overuse in the treatment of skin infections—both in presence of a co-existing infection requiring antibacterial ther- ambulatory and inpatient settings—is problematic. Nearly half apy, neutropenia, malignancy, and use of immunosuppressing of patients receive antibiotic regimens with an unnecessarily medications. The study was approved by the Colorado Multiple broad spectrum of activity , and 70%–80% are prescribed Institutional Review Board, and all patients provided written a treatment duration that is longer than recommended [1, 2]. informed consent. Measurement of serum biomarkers as an adjunct to the clin- ical evaluation may reduce such antibiotic overuse by helping Study Visits and Biomarker Measurements clinicians determine whether a patient is responding appropri- Clinical assessments were performed at enrollment and 24 ately to therapy and to determine when an infection has been (±8) hours, 3 (±1) days, 5 (-1/+3) days, and 28 (±4) days later. adequately treated. Despite these potential clinical utilities, Infection type was classified according to Food and Drug there have been few studies of biomarkers in patients with acute Administration (FDA) definitions . Blood specimens for bacterial skin infections. CRP, PCT, and white blood cell (WBC) measurement were In other types of infections, C-reactive protein (CRP) and obtained prior to or within 2 hours of the start of antibiotics, procalcitonin (PCT) have demonstrated promise as biomarkers 4–6 hours later (optional), and at the 24-hour, day 3, and day to optimize antibiotic use. For example, in patients with sepsis, 5 visits. Biomarker measurements were performed only after persistently elevated levels can identify patients not responding completion of all study visits. CRP, PCT, and WBC values to therapy . In critically ill patients with acute respiratory were classified as elevated when >10.0 mg/L, ≥0.05 ng/mL, or >10.0 K/µL, respectively. The PCT cutoff of ≥0.05 ng/mL was used because values from 0.05–0.5 ng/mL may be observed Received 18 October 2017; editorial decision 18 January 2018; accepted 25 January 2018. with localized bacterial infections . Correspondence: T. C. Jenkins, MD, 601 Broadway, Denver, CO 80204 (timothy.jenkins@ dhha.org). Clinical Outcomes Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases On day 3, treatment success was defined according to FDA Society of America. This is an Open Access article distributed under the terms of the Creative guidance as a 20% reduction in lesion size at 48–72 hours com- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any pared with baseline and absence of need for rescue antibiotic medium, provided the original work is not altered or transformed in any way, and that the work therapy . On day 5, as no standardized definition of treat- is properly cited. For commercial re-use, please contact email@example.com ment success exists for this time point, we defined success as a DOI: 10.1093/ofid/ofy029 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy029/4830034 by Ed 'DeepDyve' Gillespie user on 16 March 2018 50% reduction in lesion size compared with baseline, absence of (Table 1). By day 3 and day 5, the mean CRP levels (SD) need for rescue therapy, absence of purulent drainage, and no had decreased to 63.0 (74.5) mg/L (P = .028) and 22.7 (31.8) new sites of skin infection. mg/L (P < .001), respectively, and the mean WBC level (SD) had decreased to 9.3 (3.9) K/µL (P < .001) and 8.5 (3.1) K/µL Statistical Analysis (P < .001), respectively. The mean PCT level (SD) had decreased Results were presented for the overall cohort and stratified to 0.34 (0.99) ng/mL (P = .21) and 0.14 (0.4) ng/mL (P = .095), by abscess vs nonabscess infections. For the overall cohort, respectively; however, these declines were not statistically sig- the change in mean CRP, PCT, and WBC level from baseline nificant. Individual-patient CRP, PCT, and WBC levels aer ft (enrollment) to day 3 and from baseline to day 5 was evaluated the start of antibiotic therapy are displayed in Supplementary by paired t test. As this was a pilot study, no formal sample size Figure 1. calculation was performed. R (Version 3.3.1) was used for data Supplementary Figure 2 shows the change in CRP, PCT, and analysis. WBC levels between baseline and day 3 stratified by the classifi- cation of treatment success or failure. Biomarker levels declined RESULTS by day 3 in most cases of successful treatment; however, CRP Twenty-two patients were included: 15 with a cutaneous and PCT levels remained stable or increased slightly in several abscess, 5 with cellulitis, 1 with a wound infection, and 1 with cases. In the 3 cases classified as treatment failure, CRP and an infected ulcer. The most common reasons for exclusion were PCT levels increased by day 3 in 1 patient, declined in 1, and inability to complete the serial visits or phlebotomy (n = 143), were undetectable in 1. initiation of antibiotic therapy >2 hours prior to enrollment Baseline CRP, PCT, and WBC levels were generally higher (n = 133), perirectal or perineal infection (n = 77), and sus- among patients with nonabscess infections as compared with pected or confirmed deep tissue infection (n = 68). abscesses (Supplementary Figure 3); however, levels tended to Characteristics of the cohort are shown in Supplementary decline by day 3 and day 5 in both groups. In addition, base- Table 1. Half of the patients were hospitalized for treatment. line levels were higher, and the declines by day 3 and day 5 e m Th ean age was 46 years; 20 (91%) were male. All patients appeared to be more precipitous among hospitalized patients received systemic antibiotic therapy, and all with an abscess as compared with those treated as outpatients (Supplementary underwent incision and drainage. At the day 3 and day 5 visits, Figure 4). 17 of 20 (85%) and 15 of 20 (75%) patients evaluated, respec- tively, were classified as treatment success. DISCUSSION At enrollment, CRP, PCT, and WBC levels were elevated in 20 (91%), 15 (68%), and 16 (73%) patients, respectively. Mean In patients with an acute bacterial skin infection, initial CRP, enrollment CRP, PCT, and WBC levels (SD) were 97.7 (86.7) PCT, and WBC levels were elevated in the majority of cases. mg/L, 0.98 (2.62) ng/mL, and 13.9 (6.6) K/µL, respectively Overall, mean CRP and WBC levels declined significantly by Table 1. Mean Biomarker Levels at Presentation and During Treatment All Subjects Change From Cutaneous Abscess Nonabscess (n = 22) Baseline Level P (n = 15) (n = 7) C-reactive protein, mg/L Baseline level 97.7 ± 86.7 73.9 ± 62.8 148.8 ± 112.5 24 h 89.5 ± 90.7 –8.2 ± 42.2 74.0 ± 82.6 122.7 ± 105.0 Day 3 63.0 ± 74.5 –38.7 ± 70.7 .028 53.1 ± 80.3 80.0 ± 65.6 Day 5 22.7 ± 31.8 –74.4 ± 69.9 <.001 15.1 ± 21.1 37.9 ± 44.7 Procalcitonin, ng/mL Baseline level 0.98 ± 2.62 0.47 ± 1.28 2.08 ± 4.26 24 h 0.65 ± 1.88 –0.33 ± 0.85 0.26 ± 0.6 1.47 ± 3.22 Day 3 0.34 ± 0.99 –0.51 ± 1.74 .21 0.14 ± 0.4 0.69 ± 1.55 Day 5 0.14 ± 0.4 –0.88 ± 2.3 .095 0.05 ± 0.1 0.32 ± 0.68 White blood cells, K/µL Baseline level 13.9 ± 6.6 12.6 ± 5.4 16.6 ± 8.4 24 h 11.5 ± 6.1 –2.4 ± 3.8 10.8 ± 6.3 12.8 ± 6.1 Day 3 9.3 ± 3.9 –5.2 ± 4.5 <.001 8.5 ± 3.0 10.8 ± 5.1 Day 5 8.5 ± 3.1 –4.8 ± 5.0 <.001 7.7 ± 2.9 10.3 ± 2.8 Data presented as mean ± standard deviation. Only prespecified statistical comparisons between baseline and day 3/day 5 levels for the overall cohort were performed to minimize risk of type 1 error. Obtained prior to or within 2 hours of starting antibiotic therapy. 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy029/4830034 by Ed 'DeepDyve' Gillespie user on 16 March 2018 day 3 and day 5 of treatment; although the mean PCT level to clinical decision-making could reduce unnecessarily also declined by days 3 and 5, the trend did not reach statistical broad-spectrum and prolonged antibiotic regimens and war- significance. rants further study. er Th e has been limited research regarding biomarkers in skin Supplementary Data infections to date. In several prior studies, only single CRP or Supplementary materials are available at Open Forum Infectious Diseases PCT levels were obtained at the time patients presented with a online. Consisting of data provided by the authors to benefit the reader, suspected skin infection; therefore, only the diagnostic or prog- the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corre- nostic utility of these biomarkers could be evaluated [8–11]. sponding author. To our knowledge, there has only been 1 study besides ours evaluating the potential utility of serial CRP and PCT levels Acknowledgments in the management of skin infections. In this study, Eder and We are grateful to bioMérieux for providing PCT test kits and Rosse colleagues measured serial CRP and PCT levels in 50 inpa- Rodriguez Perez and Amy Irwin for coordination of the study. tients with heterogeneous skin infections . Similar to our Financial support. This work was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH; TCJ: study, they found initially elevated levels in most patients and K23 AI099082), and NIH/National Center for Advancing Translational observed declines over the first week of treatment. Science Colorado Clinical and Translational Sciences Institute Grant UL1 Analogous to the use of serial PCT levels to guide antibiotic TR001082. Potential conifl cts of interest. bioMérieux provided PCT test kits but prescribing in patients with sepsis or acute respiratory infection was not involved in study design or conduct, data analysis, or manuscript [4, 5], our results and those of Eber and colleagues indicate a preparation. All authors have submitted the ICMJE Form for Disclosure of potential role for serial CRP or PCT levels to guide prescribing Potential Conflicts of Interest. Conflicts that the editors consider relevant to in patients with skin infections. Appropriately declining levels the content of the manuscript have been disclosed. may reassure clinicians about the adequacy of initial therapy, thus preventing unnecessary escalation of antibiotic therapy or References 1. Jenkins TC, Knepper BC, Moore SJ, et al. Antibiotic prescribing practices in a prolonged treatment durations. The time course of CRP and multicenter cohort of patients hospitalized for acute bacterial skin and skin struc- PCT levels we observed suggests that in a future study of a bio- ture infection. Infect Control Hosp Epidemiol 2014; 35:1241–50. 2. Hurley HJ, Knepper BC, Price CS, et al. Avoidable antibiotic exposure for uncom- marker-guided prescribing strategy, it would be appropriate to plicated skin and soft tissue infections in the ambulatory care setting. Am J Med obtain levels at presentation, day 3, and day 5. Our data also sug- 2013; 126:1099–106. gest that a biomarker-guided prescribing strategy is most likely 3. Schmit X, Vincent JL. The time course of blood C-reactive protein concentrations in relation to the response to initial antimicrobial therapy in patients with sepsis. to be effective among hospitalized patients where initial levels Infection 2008; 36:213–9. tend to be more highly elevated and decline more precipitously. 4. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treat- ment on mortality in acute respiratory infections: a patient level meta-analysis. This study has important limitations. First, the small sample Lancet Infect Dis 2018; 18:95–107. size and heterogeneous infections limit conclusions that can be 5. Agarwal R, Schwartz DN. Procalcitonin to guide duration of antimicrobial ther- apy in intensive care units: a systematic review. Clin Infect Dis 2011; 53:379–87. drawn; however, this work was largely intended to be hypothe- 6. US Department of Health and Human Services, Food and Drug Administration, sis-generating and to inform the development of future studies. Center for Drug Evaluation and Research (CDER). Guidance for industry. Acute bacterial skin and skin structure infections: Developing drugs for treatment. Second, there are no gold standard criteria for the diagnosis of Updated October 2013. Available at: http://www.fda.gov/downloads/Drugs/…/ skin infections or for treatment outcomes, which may have led Guidances/ucm071185.pdf. Accessed 1 August 2016. to misclassification in some cases. Third, due to the timing of 7. BioMérieux Vidas BRAHMS PCT package insert. Durham, North Carolina: BioMérieux, INC; 2015. biomarker levels obtained in our study, we may not have iden- 8. Noh SH, Park SD, Kim EJ. Serum procalcitonin level reflects the severity of cellu- tified the peak level in any given case. Finally, in the absence of litis. Ann Dermatol 2016; 28:704–10. 9. Pallin DJ, Bry L, Dwyer RC, et al. Toward an objective diagnostic test for bacterial a control group, the specificity of the biomarkers for bacterial cellulitis. PLoS One 2016; 11:e0162947. skin infection could not be evaluated. 10. Jeandrot A, Richard JL, Combescure C, et al. Serum procalcitonin and C-reactive protein concentrations to distinguish mildly infected from non-infected diabetic In summary, this study adds to the sparse literature foot ulcers: a pilot study. Diabetologia 2008; 51:347–52. describing biomarkers in acute bacterial skin infections. Our 11. Mahmood M, Kalatha G, Young J, Jones R. Utility of serum procalcitonin in skin and soft tissue infections: a prospective trial. Infect Dis Clin Pract 2016; 24:39–42. data demonstrate that CRP and PCT are usually elevated 12. Eder J, Hlavin G, Haushofer A, et al. Correlation of serum procalcitonin with the at presentation and decline over 3 to 5 days of treatment. severity of skin and skin structure infections—a pilot study. J Dtsch Dermatol Ges Thus, a biomarker-guided prescribing strategy as an adjunct 2012; 10:564–71. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy029/4830034 by Ed 'DeepDyve' Gillespie user on 16 March 2018
Open Forum Infectious Diseases – Oxford University Press
Published: Mar 1, 2018
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