YJINF3311_proof ■ 15 May 2014 ■ 1/2 Journal of Infection (2014) xx, 1e2

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LETTER TO THE EDITOR Procalcitonin guided antibiotic therapy in patients presenting with fever in the emergency department

To the editor, In this journal, Tromp et al. reported on the biomarker procalcitonin (PCT), a precursor protein of calcitonin, in the diagnosis of bacterial infections. The study compared the accuracy of PCT, interleukin-6 (IL-6), lipopolysaccharidebinding protein (LBP), C-reactive protein (CRP) in diagnosing bacterial infections. PCT was tested the best single biomarker for the prediction of bacteraemia in septic patients in the emergency department (ED).1 We describe our findings of a study using PCT guided antibiotic therapy to reduce antibiotics prescription in the ED. We show a trend toward significance in reducing antibiotic prescription using a single PCT measurement, in undifferentiated febrile patients visiting the ED. The surviving sepsis campaign states that broadspectrum antibiotics have to be administered within one hour, when patients have a suspected infection with systemic inflammatory response syndrome (SIRS).2 This increases the rate of antibiotic prescriptions in the emergency department (ED),3 and may contribute to further resistance for antibiotics. Antimicrobial stewardship stands for targeted and effective antibacterial therapy, with special attention for the initiation and timely ending of antibiotics use. The goal of antimicrobial stewardship is to contain the increasing resistance of microorganisms.4 The aim of this study was to reduce the unnecessary antibiotics prescription by introducing a PCT guided therapy algorithm. Undifferentiated febrile ED patients were randomized to either PCT guided therapy or standard-ofcare. In both groups routine blood testing was performed, including CRP. Only in the PCT guided therapy group, a PCT value was reported to the physicians. The PCT results were appraised using cut-off points as found by other research groups, in which a PCT level of PCT > 0.5 mg/L was associated with bacterial infection.5 Samples for bacterial and viral cultures and polymerase chain reaction (PCR) were taken from the suspected focus of infection, to confirm a definitive diagnosis. Although PCT guided antibiotic prescription advice was given, the treating physician

was free at all times to ignore the advice based on clinical judgement. The study was performed in the Slotervaart hospital in Amsterdam, a 420-beds general teaching hospital in the Netherlands, between May 2010 and March 2012. The study included 107 patients with fever, including the following diagnoses: Respiratory infections 49(46%), urinary tract infections 19(18%), skin and soft tissue infections 10(9%), bloodstream infections 6(6%), digestive tract infections 4(4%), meningo-encephalic infections 2(2%), other febrile disease, including thyrotoxicosis, malignant neuroleptic syndrome and polymyalgia rheumatica 17(15%). Fewer antibiotics were prescribed in the PCT guided therapy group (80% vs 92% (p Z 0.08)). Differences were observed in ICU admittance (14(24%) vs 4 (8%) (p Z 0.03)); mortality (0 (0%) vs 2 (4%) (p Z 0.12)); temperature (median 38.8 (IQR 38.2e39.2) vs median 39.0 (IQR 38.7e39.5)) (p Z 0.03)) and CRP level (mean 138 mg/L (SD 120) vs 179 mg/L (SD 146) (p Z 0.02)) between PCT guided therapy and standard-of-care, respectively. Mean length of hospital stay was 8 days in both groups. In multivariate logistic regression analysis, PCT guided therapy resulted in a trend towards reduction of the number of patients who received antibiotics (OR 0.47 (95%CI 0.13e1.66)). In this randomized controlled trial, we show that PCT guided antibiotic therapy for undifferentiated febrile patients in the ED results in a trend toward reduction of the initiation of unnecessary antibiotic therapy. A review by Schuetz et al.6 showed that the PCT intervention studies in primary care, ED and ICU settings use only subgroups of patients. These studies mainly focus on respiratory tract infections and sepsis. Our study is the first study on PCT guided antibiotic therapy to include an adult ED population with fever, irrelevant of suspected underlying pathology. Because no selection of patients was made, besides fever, the use of PCT guided therapy may be expanded beyond patients with specific suspected pathology in the ED. We demonstrated a trend toward reduction of the initiation of unnecessary antibiotic therapy. Larger studies are necessary to prove significant differences. Reduction in number of antibiotic prescriptions with PCT guided therapy has been reported for specific patient populations in the ED.7,8 In the proHOSP study,8 the authors reported a significant reduction in the prescription of antibiotics in patients with lower respiratory tract infections. Likewise, there were similar rates for adverse events in mortality and ICU admittance.

0163-4453/$36 ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association. http://dx.doi.org/10.1016/j.jinf.2014.04.009 Please cite this article in press as: Limper M, Procalcitonin guided antibiotic therapy in patients presenting with fever in the emergency department, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.04.009

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In the PCT guided therapy group, we observed significantly more ICU admittances, and patients had a higher temperature. Because the patients were randomized, these differences were due to chance. However, this means that the PCT guided therapy group may have consisted of generally sicker patients. We performed a statistical correction for this difference; however, the differences between groups may have influenced the results. In a similar population, PCT could therefore reduce the proportion of antibiotic prescriptions even more. There were some limitations in this study. First of all, the sample size was relatively small. A number of 221 patients were not included because of logistical problems in the ED, such as lack of time of physician to include patients, unawareness of study protocol and missing data. In the PCT guided therapy group, there was a 25% rate of antibiotic prescription with a low PCT level. Patients with a low PCT result were still prescribed antibiotics. This may be attributable to either the unfamiliarity of PCT as an accurate diagnostic marker, or a lack of confidence in the new diagnostic instrument.9 In conclusion, this first study evaluating PCT guided antibiotic therapy in an undifferentiated adult ED population, suggests that PCT guided therapy results in a reduction of antibiotics prescription in febrile patients, without an increase in hospital admittance or mortality. Larger trials may strengthen the role of PCT in the ED. PCT may be an important tool in antimicrobial stewardship.

References 1. Tromp M, Lansdorp B, Bleeker-Rovers CP, Gunnewiek JM, Kullberg BJ, Pickkers P. Serial and panel analyses of biomarkers do not improve the prediction of bacteremia compared to one procalcitonin measurement. J Infect 2012; 65(4):292e301. 2. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39(2):165e228. 3. Hitti EA, Lewin 3rd JJ, Lopez J, Hansen J, Pipkin M, Itani T, et al. Improving door-to-antibiotic time in severely septic emergency department patients. J Emerg Med 2012;42(4): 462e9. 4. Lesprit P, Brun-Buisson C. Hospital antibiotic stewardship. Curr Opin Infect Dis 2008;21(4):344e9. 5. Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial):

Letter to the Editor

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a multicentre randomised controlled trial. Lancet 2010; 375(9713):463e74. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171(15):1322e31. Albrich WC, Dusemund F, Bucher B, Meyer S, Thomann R, Kuhn F, et al. Effectiveness and safety of procalcitoninguided antibiotic therapy in lower respiratory tract infections in “real life”: an international, multicenter poststudy survey (ProREAL). Arch Intern Med 2012;172(9):715e22. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059e66. Gilbert D. Serum procalcitonin levels: comment on “Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in ‘real life’”. Arch Intern Med 2012;172(9):722e3.

M. Limper Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

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Y. van der Does* Department of Emergency Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands D.P.M. Brandjes Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands M.D. De Kruif Department of Pulmonary Medicine, Academic Medical Center, Amsterdam, The Netherlands P.P.M. Rood Department of Emergency Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands E.C.M. van Gorp Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands E-mail addresses: [email protected], [email protected] (Y. van der Does) Accepted 30 April 2014

* Corresponding author. Department of Emergency Medicine, Erasmus University Medical Center, ’s-Gravendijkwal 230, 3015CE Rotterdam, The Netherlands. Tel.: þ31 (0) 10 704 0 704. a Contributed equally. Please cite this article in press as: Limper M, Procalcitonin guided antibiotic therapy in patients presenting with fever in the emergency department, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.04.009

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Procalcitonin guided antibiotic therapy in patients presenting with fever in the emergency department.

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