Journal of Infection (2014) xx, 1e2

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LETTER TO THE EDITOR 757677787980

Procalcitonin guided antibiotic therapy inpatients presenting with fever in theemergency department

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To the editor,

In this journal, Tromp et al. reported on the biomarkerprocalcitonin (PCT), a precursor protein of calcitonin, in thediagnosis of bacterial infections. The study compared theaccuracy of PCT, interleukin-6 (IL-6), lipopolysaccharide-binding protein (LBP), C-reactive protein (CRP) in diagnosingbacterial infections. PCT was tested the best singlebiomarker for the prediction of bacteraemia in septicpatients in the emergency department (ED).1 We describeour findings of a study using PCT guided antibiotic therapyto reduce antibiotics prescription in the ED. We show a trendtoward significance in reducing antibiotic prescription usinga single PCT measurement, in undifferentiated febrile pa-tients visiting the ED.

The surviving sepsis campaign states that broad-spectrum antibiotics have to be administered within onehour, when patients have a suspected infection withsystemic inflammatory response syndrome (SIRS).2 This in-creases the rate of antibiotic prescriptions in the emer-gency department (ED),3 and may contribute to furtherresistance for antibiotics. Antimicrobial stewardship standsfor targeted and effective antibacterial therapy, with spe-cial attention for the initiation and timely ending of antibi-otics use. The goal of antimicrobial stewardship is tocontain the increasing resistance of microorganisms.4

The aim of this study was to reduce the unnecessaryantibiotics prescription by introducing a PCT guided ther-apy algorithm. Undifferentiated febrile ED patients wererandomized to either PCT guided therapy or standard-of-care. In both groups routine blood testing was performed,including CRP. Only in the PCT guided therapy group, a PCTvalue was reported to the physicians. The PCT results wereappraised using cut-off points as found by other researchgroups, in which a PCT level of PCT > 0.5 mg/L wasassociated with bacterial infection.5 Samples for bacterialand viral cultures and polymerase chain reaction (PCR)were taken from the suspected focus of infection, toconfirm a definitive diagnosis. Although PCT guided antibi-otic prescription advice was given, the treating physician

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Please cite this article in press as: Limper M, Procalcitonin guided antdepartment, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.04

was free at all times to ignore the advice based on clinicaljudgement.

The study was performed in the Slotervaart hospital inAmsterdam, a 420-beds general teaching hospital in theNetherlands, between May 2010 and March 2012. The studyincluded 107 patients with fever, including the followingdiagnoses: Respiratory infections 49(46%), urinary tractinfections 19(18%), skin and soft tissue infections 10(9%),bloodstream infections 6(6%), digestive tract infections4(4%), meningo-encephalic infections 2(2%), other febriledisease, including thyrotoxicosis, malignant neurolepticsyndrome and polymyalgia rheumatica 17(15%). Fewerantibiotics were prescribed in the PCT guided therapygroup (80% vs 92% (p Z 0.08)). Differences were observedin 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) vs179 mg/L (SD 146) (p Z 0.02)) between PCT guided therapyand standard-of-care, respectively. Mean length of hospitalstay was 8 days in both groups. In multivariate logisticregression analysis, PCT guided therapy resulted in a trendtowards reduction of the number of patients who receivedantibiotics (OR 0.47 (95%CI 0.13e1.66)).

In this randomized controlled trial, we show that PCTguided antibiotic therapy for undifferentiated febrile pa-tients in the ED results in a trend toward reduction of theinitiation of unnecessary antibiotic therapy. A review bySchuetz et al.6 showed that the PCT intervention studies inprimary care, ED and ICU settings use only subgroups of pa-tients. These studies mainly focus on respiratory tract in-fections and sepsis. Our study is the first study on PCTguided antibiotic therapy to include an adult ED populationwith 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 pa-tients with specific suspected pathology in the ED.

We demonstrated a trend toward reduction of the initia-tion of unnecessary antibiotic therapy. Larger studies arenecessary to prove significant differences. Reduction in num-ber of antibiotic prescriptions with PCT guided therapy hasbeen reported for specific patient populations in the ED.7,8 Inthe proHOSP study,8 the authors reported a significant reduc-tion in the prescription of antibiotics in patients with lowerrespiratory tract infections. Likewise, thereweresimilar ratesfor adverse events in mortality and ICU admittance.

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ibiotic therapy in patients presenting with fever in the emergency.009

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In the PCT guided therapy group, we observed signif-icantly more ICU admittances, and patients had a highertemperature. Because the patients were randomized, thesedifferences were due to chance. However, this means thatthe PCT guided therapy group may have consisted ofgenerally sicker patients. We performed a statisticalcorrection for this difference; however, the differencesbetween groups may have influenced the results. In asimilar population, PCT could therefore reduce the propor-tion of antibiotic prescriptions even more.

There were some limitations in this study. First of all,the sample size was relatively small. A number of 221patients were not included because of logistical problemsin the ED, such as lack of time of physician to includepatients, unawareness of study protocol and missing data.

In the PCT guided therapy group, there was a 25% rate ofantibiotic prescription with a low PCT level. Patients with alow PCT result were still prescribed antibiotics. This may beattributable to either the unfamiliarity of PCT as an accu-rate diagnostic marker, or a lack of confidence in the newdiagnostic instrument.9

In conclusion, this first study evaluating PCT guidedantibiotic therapy in an undifferentiated adult ED popula-tion, suggests that PCT guided therapy results in a reduc-tion of antibiotics prescription in febrile patients, withoutan increase in hospital admittance or mortality. Largertrials may strengthen the role of PCT in the ED. PCT may bean 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 bio-markers do not improve the prediction of bacteremiacompared 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 guide-lines 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 septicemergency department patients. J Emerg Med 2012;42(4):462e9.

4. Lesprit P, Brun-Buisson C. Hospital antibiotic stewardship. CurrOpin 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):

Please cite this article in press as: Limper M, Procalcitonin guided antidepartment, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.04

a multicentre randomised controlled trial. Lancet 2010;375(9713):463e74.

6. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin al-gorithms for antibiotic therapy decisions: a systematic reviewof randomized controlled trials and recommendations for clin-ical algorithms. Arch Intern Med 2011;171(15):1322e31.

7. Albrich WC, Dusemund F, Bucher B, Meyer S, Thomann R,Kuhn F, et al. Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infectionsin “real life”: an international, multicenter poststudy survey(ProREAL). Arch Intern Med 2012;172(9):715e22.

8. Schuetz P, Christ-Crain M, Thomann R, Falconnier C,Wolbers M, Widmer I, et al. Effect of procalcitonin-basedguidelines vs standard guidelines on antibiotic use in lower res-piratory tract infections: the ProHOSP randomized controlledtrial. JAMA 2009;302(10):1059e66.

9. Gilbert D. Serum procalcitonin levels: comment on “Effective-ness and safety of procalcitonin-guided antibiotic therapy inlower respiratory tract infections in ‘real life’”. Arch InternMed 2012;172(9):722e3.

QM. LimperDepartment of Internal Medicine, Erasmus University

Medical Center, Rotterdam, The Netherlands

Y. van der Does*Department of Emergency Medicine, Erasmus University

Medical Center, Rotterdam, The Netherlands

D.P.M. BrandjesDepartment of Internal Medicine, Slotervaart Hospital,

Amsterdam, The Netherlands

M.D. De KruifDepartment of Pulmonary Medicine, Academic Medical

Center, Amsterdam, The Netherlands

P.P.M. RoodDepartment of Emergency Medicine, Erasmus University

Medical Center, Rotterdam, The Netherlands

E.C.M. van GorpDepartment of Internal Medicine, Erasmus University

Medical Center, Rotterdam, The Netherlands

Department of Viroscience, Erasmus University MedicalCenter, Rotterdam, The Netherlands Q

E-mail addresses: y.vanderdoes@erasmusmc.nl, y.vander-does@gmail.com (Y. van der Does)

Accepted 30 April 2014

* Corresponding author. Department of Emergency Medicine,Erasmus University Medical Center, ’s-Gravendijkwal 230, 3015CERotterdam, The Netherlands. Tel.: þ31 (0) 10 704 0 704.

a Contributed equally.

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