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Original Paper

Neonatology 2010;97:165174

DOI: 10.1159/000241296

Use of Procalcitonin-Guided Decision-Making toShorten Antibiotic Therapy in Suspected NeonatalEarly-Onset Sepsis: Prospective RandomizedIntervention Trial

Martin Stockera Matteo Fontanaa Salhab el Heloua Karl Wegscheiderb

Thomas M. Bergera

aNeonatal and Pediatric Intensive Care Unit, Childrens Hospital of Lucerne, Switzerland, and bDepartment ofMedical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Germany

tors for early-onset sepsis, likelihood of infection as assessed

by the attending physician and early conventional labora-

tory findings. There was a significant difference in the pro-

portion of newborns treated with antibiotics672 h between

the standard group (82%) and the PCT group (55%) (absolute

risk reduction 27%; odds ratio 0.27 (95% CI 0.120.62), p =

0.002). On average, PCT-guided decision-making resulted in

a shortening of 22.4 h of antibiotic therapy. Clinical outcomewas similar and favorable in both groups but sample size was

insufficient to exclude rare adverse events. Conclusion:Se-

rial PCT determinations allow to shorten the duration of an-

tibiotic therapy in term and near-term infants with suspect-

ed early-onset sepsis. Before this PCT-guided strategy can

be recommended, its safety has to be confirmed in a larger

cohort of neonates. Copyright 2009 S. Karger AG, Basel

Introduction

In neonates, clinical signs and symptoms associatedwith early-onset sepsis are non-specific and currentlyavailable laboratory tests have poor positive and negativepredictive values. Delay in antibiotic treatment of infect-ed neonates carries a substantial risk, both in terms ofmortality and morbidity. Therefore, newborns with sus-pected sepsis (based on clinical signs and/or perinatal/

Key Words

Antibiotic therapy Early-onset sepsis Intervention study

Procalcitonin Term and near-term neonates

Abstract

Background:Diagnosis of neonatal early-onset sepsis is dif-

ficult because clinical signs and laboratory tests are non-specific. Early antibiotic therapy is crucial for treatment suc-

cess. Objective: To evaluate the effect of procalcitonin

(PCT)-guided decision-making on duration of antibiotic

therapy in suspected neonatal early-onset sepsis. Methods:

This single-center, prospective, randomized intervention

study was conducted in a tertiary neonatal and pediatric in-

tensive care unit in the Childrens Hospital of Lucerne, Swit-

zerland, between June 1, 2005 and December 31, 2006. All

term and near-term infants (gestational age 634 weeks)

with suspected early-onset sepsis were randomly assigned

either to standard treatment based on conventional labora-

tory parameters (standard group) or to PCT-guided treat-ment (PCT group). Minimum duration of antibiotic therapy

was 4872 h in the standard group, whereas in the PCT group

antibiotic therapy was discontinued when two consecutive

PCT values were below predefined age-adjusted cut-off val-

ues. Results:121 newborns were randomly assigned either

to the standard group (n = 61) or the PCT group (n = 60). The

two groups were similar for baseline demographics, risk fac-

Received: July 24, 2008

Accepted after revision: February 9, 2009

Published online: September 24, 2009

formerly Biology of the Neonate

Martin Stocker, MDPediatric Intensive Care UnitRoyal Brompton Hospital, Sydney Street

London SW3 6NP (UK)Tel. +41 79 373 67 19, E-Mail [email protected]

2009 S. Karger AG, Basel16617800/10/09720165$26.00/0

Accessible online at:www.karger.com/neo
http://dx.doi.org/10.1159%2F000241296http://dx.doi.org/10.1159%2F000241296

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Stocker /Fontana /el Helou /Wegscheider /Berger

Neonatology 2010;97:165174166

neonatal risk factors) are commonly treated with broad-spectrum antibiotics (usually ampicillin and an amino-glycoside) until infection can be safely excluded [1]. Ruleout sepsis is one of the most common discharge diagno-ses in near-term and term infants admitted to the neona-tal intensive care unit [2]. Unnecessary long-term use of

broad-spectrum antibiotics is a serious concern becauseit can promote the development of resistant bacteria, pro-long hospitalization and increase costs.

Procalcitonin (PCT) is a precursor peptide of the hor-mone calcitonin. The physiological function of PCT isunknown. In bacterial infections, plasma PCT concen-trations increase from 0.0010.01 ng/ml (baseline range)to values ranging from 1 to 1,000 ng/ml. After injectionof endotoxins, PCT concentrations rise within 68 h andreach a plateau after approximately 12 h. This is a fasterresponse than that seen in C-reactive protein (CRP)which reaches maximal values after approximately 48 h

[3]. Because of its kinetics, we hypothesize that PCT couldbe a better parameter than CRP to guide duration of an-tibiotic therapy.

In healthy adults, plasma PCT concentrations are verylow, mostly !0.01 ng/ml. Normal birth and extrauterineadaptation stimulate an acute phase reaction in the new-born infant with release of PCT and other acute phaseproteins [4]. In healthy neonates, plasma PCT concentra-tions increase gradually after birth, reach peak values atabout 24 h of age (mean 1.52.5 ng/ml, range 0.120 ng/ml) and then decrease to normal values below 0.5 ng/mlby 4872 h of age [46]. In newborns admitted to the neo-

natal intensive care unit with clinical signs of respiratorydistress without infection, peak plasma PCT concentra-tions at 48 h of age have been reported to be higher (mean34 ng/ml) with large interindividual variations (range0.220 ng/ml) [5, 710].

Previous studies on the use of PCT as a marker of neo-natal sepsis suggested that PCT could be useful. However,the results of several observational studies are contradic-tory [5, 7, 8, 1119]. With our prospective interventionstudy, we wanted to test the efficacy of PCT-guided deci-sion-making on the duration of antibiotic therapy andoutcome in neonatal early-onset sepsis.

Methods

Study Design and SettingThis study was designed as a single-center, prospective, ran-

domized intervention study. The study was approved by the localethics committee for human studies. Parental informed consentwas obtained for all study neonates. BRAHMS Diagnostica (Ber-

lin, Germany) provided the testing kits for PCT determinationsbut was not involved in any other aspects of the study and manu-script preparation. The study has been registered at ClinicalTrial.gov.

We hypothesized that PCT-guided decision-making al lows toshorten the duration of empiric antibiotic therapy in suspectedneonatal early-onset sepsis with unchanged outcome. The pri-

mary endpoint was the proportion of infants treated with antibi-otics for 672 h (efficacy of study intervention). The co-primaryendpoint was the absolute reduction of the duration of antibiotictherapy (quantitative version of the primary endpoint for est ima-tion of effect size). Safety endpoints were survival and recurrenceof infection requiring additional courses of antibiotic therapy inthe first month of life. For comparison of recurrence of infection,the proportion of infants treated with antibiotics6120 h was cal-culated (non-inferiority test of the PCT group). Regardless oftreatment duration, observation periods were the same in bothgroups with a minimum of 3 days of hospitalization and a follow-up interview after 1 month (telephone interview about intercur-rent illness, physician visits, medications and hospitalizations).

PatientsBetween June 1, 2005 and December 31, 2006, term and near-

term infants with a gestational age 634 weeks admitted to theChildrens Hospital of Lucerne (tertiary center adjacent to a ma-ternity hospital) with suspected early-onset sepsis in the first 3days of life requiring empiric antibiotic therapy (ampicillin andgentamicin) were eligible for the study and randomly assignedeither to standard care (standard group) or PCT-guided decision-making (PCT group). Randomization was accomplished by draw-ing group assignment cards in opaque-sealed envelopes. Exclu-sion criteria were severe congenital malformations, chromosom-al abnormalities and surgery in the first 3 days of life.

Laboratory ExaminationsThe laboratory examinations were performed according to the

schedule shown in figure 1. White blood count (WBC) with im-mature to total neutrophil ratio (I:T ratio) and CRP concentra-tions were obtained in all patients. Serial PCT measurements wereonly performed in patients assigned to the PCT group. PlasmaPCT concentrations were measured using a time-resolved ampli-fied cryptate emission (TRACE) technology assay (KryptorPCT, BRAHMS, Henningsdorf, Germany). Assay time is 19 min,and in the clinical setting, results can be obtained within 1 h with2050 l of plasma or serum [20].

We defined age-adjusted PCT cut-off values according to theresults of previous studies (fig. 2a) [5, 710]. To provide a marginof safety, the normal upper value of PCT at 1836 h of age wasdefined as 10 ng/ml which is about 50% of the highest PCT con-centrations measured in neonates with respiratory distress not

related to infection (approx. 20 ng/ml) [5].

Probability of Infection and Duration of Antibiotic TherapyThe probability of infection was assessed by the attending

physician during the hospitalization. Assessments according topredefined guidelines were not the results of a single evaluationbut based on maternal risk factors (group B Streptococcus(GBS)positivity, prolonged rupture of membranes (PROM)118 h, cho-rioamnionitis), the evolution of the patients clinical symptoms (6predefined groups of clinical symptoms: (1) respiratory distress/

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PCT and Antibiotic Therapy in Neonates Neonatology 2010;97:165174 167

apnea, (2) tachycardia/bradycardia, (3) arterial hypotension/poorperfusion, (4) seizures/floppy infant, (5) irritability/lethargy/poorfeeding, (6) vomiting/feeding intolerance/ileus) and the results ofserial conventional laboratory examinations (cut-off values: I:Tratio10.2, CRP15 mg/l) but independent of plasma PCT concen-trations although physicians in the PCT group could not be blind-ed to these results. Four different degrees of likelihood of infec-tion were defined. Group 1: Infection was proven when bloodand/or cerebrospinal f luid cultures were positive. Group 2: Infec-tion was considered to be probable when cultures were negativebut there was strong evidence of sepsis based on the presence ofrisk factors, the clinical picture (including clinical symptoms of63 groups) and positive conventional laboratory f indings. Group3: In these patients, infection was considered to be possible based

on milder clinical signs and symptoms (including symptoms of!3 groups), abnormal conventional laboratory findings and un-clear situation after 3 days of antibiotic therapy. Group 4: Infec-tion was retrospectively considered to be unlikely after 23 days.Because blood culture results are commonly unreliable (frequentuse of intrapartum antibiotics, insufficient amounts of blood),groups 1 and 2 were combined for analysis [21].

The duration of antibiotic therapy (12-hourly ampicillin and12- to 24-hourly gentamicin) in the standard group was based onthe attending physicians assessment of the probability of infec-

tion (fig. 1): in group 1/2, antibiotics were given for 721 days, ingroup 3 for 45 days and in group 4 for 23 days. In the PCTgroup, if infection was considered to be unlikely or possible(groups 3 and 4), antibiotic therapy was discontinued when twoconsecutive PCT values were below the predefined age-adjustedcut-off values (fig. 2a). Antibiotic therapy could be prolonged de-spite fulfilled PCT criteria at the discretion of the attending phy-sician.

Statistical AnalysesProportions were compared using Fishers exact test. Continu-

ous baseline variables were compared using the exact Mann-Whitney U test. For dichotomous endpoints, absolute risk reduc-tions as well as odds ratios (ORs) were calculated. To test for in-

teraction effects between a dichotomous endpoint and theprobability of infection/CRP elevations, logistic regression mod-els were used. For continuous endpoints, differences of groupmeans were calculated. To test for interaction effects between acontinuous endpoint and the probability of infection/CRP eleva-tions, two-way analysis of variance models were used. All testswere performed two-sided. p values !0.05 were considered sig-nificant. The trial was designed to obtain a power of 90% to detecta 30% difference between the two groups in the duration of anti-biotic therapy with an estimated standard deviation of 50%.

12 h

PCT

24 h

Group

3 / 4

WBC

CRP

PCT

12 h 24 h

7 d 21 d

Group

1 / 2

7 d 21 d

96 h 120 h48 h 72 hpoint 0Schedule

(h = hours; d = days)

Group 3

Group 3Group 4

WBC

CRP

WBC

CRP

PCT

WBC

CRP

96 h 120 h

WBC

CRP

PCT

WBC

CRP

48 h 72 h

WBC

CRP

PCT

WBC

CRP

point 0

Standard group

PCT group

Schedule

(h = hours; d = days)

Fig. 1.Schedule of laboratory examinations (WBC: white blood count (including I:T ratio), CRP: C-reactiveprotein, PCT: procalcitonin). Light gray boxes: predefined duration of antibiotic therapy based on probabilityof infection (all patients in standard group, all patients in PCT group who did not fulfill PCT criteria for earlydiscontinuation of therapy). Dark gray boxes: patients in PCT group who fulfilled PCT criteria for early dis-continuation of therapy. Group 1/2 = Infection proven/probable, group 3 = infection possible, group 4 = infec-tion unlikely, point 0 = beginning of antibiotic therapy (time axis indicates hours after initiation of antibiotictherapy).

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Neonatology 2010;97:165174168

Results

Between June 1, 2005 and December 31, 2006, a totalof 126 term and near-term infants were admitted to theNeonatal and Pediatric Intensive Care Unit of the Chil-drens Hospital of Lucerne because of suspected early-on-set sepsis in the first 3 days of life and treated with em-piric antibiotic therapy. Of these, 5 were excluded becauseof missing parental consent (n = 2), protocol errors (n =2) and surgery during the first 3 days (n = 1). Therefore,

121 patients were randomly assigned either to the stan-dard group (n = 61) or the PCT group (n = 60). The two

groups were similar for baseline demographics and riskfactors for early-onset sepsis without statistically signifi-cant differences (table 1). Similarly, results of convention-al laboratory examinations and the proportions of in-fants belonging to groups 14 were comparable in thestandard and the PCT group (table 2).

6 12 18 24 30 36 42 48 54 60 66 72 96 120

Hours of age

0.5

0.2

1.0

2.0

5.0

10.0

PCT(ng/ml)semiloggraph 20.0

50.0

100.0Age-adjusted PCT cutoff values

a

6 12 18 24 30 36 42 48 54 60 66 72 96 120

Hours of age

0.5

0.2

1.0

2.0

5.0

10.0


50.0

100.0Infection proven/probable (n = 9)

b

Fig. 2.aAge-adjusted PCT cut-off values(gray boxes = predefined safety range;semilog graph). bPCT values of group 1/2patients.

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Primary EndpointThere was a significant difference in the proportion of

newborns treated with antibiotics 672 h between thestandard group (82%) and the PCT group (55%) (absoluterisk reduction 27%; OR 0.27, 95% CI 0.12/0.62, Fishersexact test (two-tailed) p = 0.002). The effect of PCT-guid-ed decision-making was dependent on the probability ofinfection (interaction p = 0.022) with the most pro-nounced effect in group 3 patients (table 3).

Co-Primary EndpointOverall, PCT-guided decision-making resulted in a

shortening of antibiotic therapy by an average of 22.4 h(exact Mann-Whitney U test p = 0.004; t test p = 0.012).This effect was also dependent on the probability of in-fection (interaction p = 0.024) (table 4). For validation ofthese results, we also evaluated the doses of 12-hourlyamoxicillin. The results were similar and showed anoverall reduction of 1.8 doses of 12-hourly amoxicillin(exact Mann-Whitney U test p = 0.004; t test p = 0.013).

6 12 18 24 30 36 42 48 54 60 66 72 96 120

Hours of age

0.5

0.2

1.0

2.0

5.0

10.0

PCT(ng/ml)semilo

ggraph 20.0

50.0

100.0Infection possible (n = 21)

c

6 12 18 24 30 36 42 48 54 60 66 72 96 120

Hours of age

0.5

0.2

1.0

2.0

5.0

10.0


50.0

100.0Infection unlikely (n = 30)

d

Fig. 2. cPCT values of group 3 patients.d PCT values of group 4 patients (box-whisker plot: median, box marked by thefirst and third quartile, whiskers extendedto the range, time axis indicates postnatalage in hours).

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Neonatology 2010;97:165174170

Table 1.Baseline demographics and risk factors for early-onset sepsis

Standard group(n = 61)

PCT group(n = 60)

p value

Gestational age, weeks, median (range)Birth weight, g, median (range)

Female infantsSpontaneous vaginal deliveryVacuum/forceps deliveryPrimary C-sectionSecondary C-sectionArterial cord pH, median (range)Apgar scores, median

1 min5 min

10 minGBS positivePROM >18 hChorioamnionitsNo risk factorsIntrapartum antibioticsAge at initiation of antibiotic therapy, h

median (range)

39.7 (34.041.7)3,330 (1,8004,900)

21 (35)31 (51)

4 (7)10 (16)16 (26)

7.25 (6.957.37)

899

19 (31)6 (10)2 (3)

36 (59)22 (36)

7 (268)

39.4 (34.442.0)3,200 (2,0004,640)

25 (42)36 (60)

7 (12)6 (10)

11 (18)7.22 (6.977.37)

89

1017 (28)12 (20)

3 (5)31 (52)24 (40)

10 (160)

0.810.89

0.340.360.360.420.380.22

ns

0.840.130.680.470.81

0.23

Values are numbers with percentages in parentheses unless otherwise indicated.GBS = Group B Streptococcus ; PROM = prolonged rupture of membranes.p values of two-sided Mann-Whitney U test (p < 0.05 = significant, ns = not significant).

Table 2.Assessment of probability of infection*and early conventional laboratory findings

Standard group

(n = 61)

PCT group

(n = 60)

p value

WBC in G/l at time point 0, mean [range]WBC in G/l at time point 24 h, mean [range]I:T ratio 10.2 at time point 0, n (%)I:T ratio 10.2 at time point 24 h, n (%)Platelets in G/l at time point 0, mean [range]Platelets in G/l at time point 24 h, mean [range]CRP 15 mg/l at time point 0, n (%) [range]CRP 15 mg/l at time point 24 h, n (%) [range]Infection probable/proven, n (%)Infection possible, n (%)Infection unlikely, n (%)

17.6 [4.941.0]17.4 [6.135.0]

43 (70)21 (34)

235 [89473]247 [94487]

20 (33) [645]37 (61) [6116]

11/1*(20)19/1 (31)30/1 (49)

16.9 [3.135.0]15.9 [3.241.7]

40 (67)20 (33)

243 [102385]262 [103384]

21 (35) [6180]42 (70) [6159]

9/0 (15)21/ (35)30/ (50)

0.900.130.240.270.230.160.850.340.630.701.0

WBC = White blood cell count; CRP = C-reactive protein; I:T ratio = immature to total neutrophil ratio.

*Infection proven with Staphylococcus hominisin blood culture. p values of two-sided Mann-Whitney U test(p < 0.05 = significant).

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Because gentamicin dosing is gestational age specific, itwas not possible to calculate reductions in gentamicindosing.

Relation of PCT and CRPIn an additional analysis, the clinical judgment of the

likelihood of infection was replaced by the observer-in-dependent 24-hour CRP level. In patients with a CRPconcentration 5 mg/l, the proportion of newbornstreated for 672 h was 63% in the standard group com-pared with 50% in the PCT group (absolute risk reduction13%; OR 0.60, 95% CI 0.17/2.07; Fishers exact test (two-tailed) p = 0.533). In patients with a CRP concentration15 mg/l, significantly more infants were treated with an-tibiotics 672 h in the standard group (95%) than in the

PCT group (57%) (absolute risk reduction 38%; OR 0.076,95% CI 0.016/0.359; Fishers exact test (two-tailed) p !0.001). However, neither the interaction test of CRP con-centrations and the primary endpoint within a logisticregression model nor the corresponding interaction testof CRP concentrations and the co-primary endpoint in atwo-way analysis of variance model were significant (p =0.098 and p = 0.150).

Possible Misclassifications Based on PCTIn the PCT group, 1 near-term infant with a gestation-

al age of 35 6/7 weeks and a birth weight 2,520 g was

treated with a second course of antibiotics. This infantrequired mechanical ventilation on the first day of life.The probability of infection was considered to be unlike-ly and antibiotic therapy was stopped after 24 h when twoconsecutive PCT values had been below the age-adjustedcut-off values. At 72 h of age, empiric antibiotic therapywas restarted because of clinical signs of infection andthe detection of Escherichia coli in tracheal aspirates(blood cultures remained negative). Subsequently, the in-fant recovered rapidly following 7 days of antibiotic ther-apy and the clinical outcome was favorable. In 2 cases,antibiotic therapy was continued beyond 24 h despite ful-

filled PCT criteria based on the attending physicians de-cision. In 1 case, antibiotic therapy was stopped 24 h later,in the other 48 h later. In both cases, infection was ulti-mately considered to be unlikely (group 4).

Safety EndpointsClinical outcome was similar and favorable in both

groups, with all patients surviving and recovering com-

Table 3.Primary endpoint: proportion of infants treated with antibiotics for 72 h (efficacy of study interven-tion)

Standardgroup

PCTgroup

Absoluterisk reduction

p value

All newborns

Infection probable/proven (group 1/2)Infection possible (group 3)Infection unlikely (group 4)

50/61 (82%)

12/12 (100%)19/19 (100%)19/30 (63.3%)

33/60 (55%)

9/9 (100%)13/21 (61.9%)11/30 (36.7%)

27%

0%38.1%26.6%

0.002

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Neonatology 2010;97:165174172

pletely. There was no significant difference in the propor-tion of newborns treated with antibiotics 6120 h (group1/2, patients with recurrence of infection) between thestandard group (39%) and the PCT group (32%) (absoluterisk difference 7%; OR 0.71, 95% CI 0.34/1.51, Fishers ex-act test (two-tailed) p = 0.45: non-inferiority test for the

PCT group).

Plausibility of the Constructed Age-Adjusted PCTCut-Off ValuesTo evaluate the plausibility of the constructed age-ad-

justed PCT cut-off values, PCT values of group 1/2, 3 and4 patients were superimposed on the nomogram (fig. 2bd). Median PCT values in group 3 (possible infection:fig. 2c) and group 4 (unlikely infection: fig. 2d) patientswere similar and close to the predefined threshold values.In contrast, median PCT concentrations of group 1/2(probable or proven infection: fig. 2b) patients were sig-

nificantly higher. To evaluate the margin of safety, maxi-mal cut-off values were extended to 20 ng/ml. This wouldhave led to an additional reduction of antibiotic therapyin 7 of 60 infants, but in 2 of these 7 patients infection wasfelt to be probable (group 1/2).

Discussion

In this prospective intervention study, we were able toshow that PCT-guided decision-making significantly re-duces the duration of empiric antibiotic therapy in sus-

pected early-onset sepsis of term and near-term infants.There was a significant difference in the proportion ofnewborns treated with antibiotics 672 h between thestandard group (82%) and the PCT group (55%). On aver-age, PCT-guided decision-making resulted in a shorten-ing of 22.4 h of antibiotic therapy.

Results of previous studies on the use of PCT as anearly marker of neonatal sepsis were contradictory, how-ever most studies were observational studies [5, 7, 8, 1119]. It is essential for observational studies to compare thenew marker with the gold standard. The gold standard forthe diagnosis of neonatal early-onset sepsis, i.e. a positive

blood culture, is often unreliable because of the frequentuse of intrapartum antibiotics or insufficient amounts ofblood available for culture [21]. Therefore, the problem ofall observational studies of neonatal early-onset sepsis isthe definition of sepsis. An intervention study offers avaluable alternative because the calculation of the mainresults is independent of the definition of sepsis. Recently,in an intervention study using serial PCT measurements,

Nobre et al. [22] showed a reduction of the duration of an-tibiotic therapy and intensive care unit stay in adult pa-tients with severe sepsis and septic shock. To the best ofour knowledge, our study is the first PCT-guided inter-vention study in neonatal early-onset sepsis.

In the additional, CRP-stratified analysis, PCT-guid-

ed reduction of the duration of antibiotic therapy wasonly statistically significant in the group with CRP valuesof 15 mg/l 24 h after initiation of antibiotic therapy. Inthese patients, PCT-guided decision-making appearsmost helpful. In contrast, no differences were found forpatients with CRP concentrations 5 mg/l 24 h after an-tibiotics were started. However, these results have to beinterpreted with caution since the differences betweengroups just missed statistical significance. Additionalcalculations of the impact of CRP are not possible be-cause of the study design and the fact that CRP was usedin the assessment of probability of infection (CRP cut-off

value 15 mg/l). The results of previously published stud-ies on the use of CRP as marker of neonatal sepsis arecontradictory. Philip and Mills [23] were able to mini-mize antibiotic therapy using a clinical pathway for neo-natal sepsis. Decisions to start or discontinue of antibiot-ics were predominantly based on CRP determinationswith a cut-off value of 10 mg/l. 216 out of 425 infants weretreated because of risk factors without clinical findingsand the mean duration of antibiotic therapy was 3.1 days.Ehl et al. [24] published an intervention study using CRPto guide duration of antibiotic therapy in suspected neo-natal bacterial infection. Lack of a randomized control

group and false-negative CRP results (CRP !10 mg/l inthe first 2448 h after initiation of antibiotic therapy) in2 out of 15 infants with positive blood cultures were themain limitations of this study. Finally, Benitz et al. [25]calculated and analyzed receiver-operator curves forCRP levels in proven neonatal sepsis and showed poorsensitivity of CRP measurements 24 h after initiation ofantibiotic therapy. Elevated CRP levels were not observedin 18 out of 73 episodes in which blood cultures yieldedpathogenic organisms.

In our study, 3 patients were possibly misclassifiedbased on PCT determinations. In 1 patient, antibiotics

were restarted when cultures of tracheal aspirates of thestill intubated infant were positive for E. coli48 h afterearly discontinuation of empiric antibiotic therapy. It isimpossible to determine whether this was a primary in-fection (pneumonia) with false-negative PCT values or asecondary ventilator-associated nosocomial infection/colonization. The predictive value of PCT for local infec-tions is not conclusive. In a recently published study of

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newborns with suspected pneumonia, Engle et al. [26]detected no additional predictive value of PCT comparedto CRP. In 2 other patients, the attending physician con-tinued antibiotic therapy despite two consecutive normalPCT values based on his clinical assessment. Retrospec-tively, it seems unlikely that the PCT measurements were

truly false-negative since antibiotics were stopped only 24and 48 h later, respectively.

Clinical outcome (survival, recurrence of infection)was similar (no significant difference in the proportionof infants treated with antibiotics 6120 h: non-inferior-ity test of the PCT group) and favorable in both groupswith no deaths. Power calculation, however, was based onan expected reduction of the duration of antibiotic ther-apy and does not allow to exclude rare adverse events.This would require testing in a much larger patient popu-lation. Therefore, the safety of our PCT-guided strategyremains to be proven.

Several previous studies have described age-depen-dent normal values of PCT in the first 72 h of life [5, 710].Based on these results, we constructed an age-adjustedPCT nomogram for the first 3 days of life and includedan arbitrary margin of safety (fig. 2a) [5, 9]. This nomo-gram seems to be reasonable because median PCT valuesfor patients with possible and unlikely infection (groups3 and 4) were similar and close to the predefined thresh-old values and PCT concentrations for patients withprobable or proven infection (group 1/2) were signifi-cantly higher. Since an extension of the safety cut-off lev-el to 20 ng/ml would have led to additional misclassifica-

tions, a maximum PCT threshold concentration of 10 ng/ml seems to be rational.

There are several limitations to our study. First andmost importantly, the small sample size does not allow to

prove the safety of our PCT-guided strategy. Second, be-cause of the single-center setting, our results cannot eas-ily be extrapolated to centers with different thresholds forinitiation and discontinuation of empiric antibiotic ther-apy in newborns with non-specific signs and symptomscompatible with early-onset sepsis. Third, infection was

proven in only 1 infant (positive blood culture), however,this is not uncommon in neonatal sepsis evaluations be-cause of the frequent use of intrapartum antibiotics orinsufficient amounts of blood available for culture. Fi-nally, because of the study design, we were not able tocalculate the effect for some interesting outcome vari-ables (length of hospitalization, costs, bacterial selec-tion).

Conclusions

PCT analysis is feasible in newborn infants. In our set-ting, serial PCT measurements allowed to significantlyshorten the duration of empiric antibiotic therapy in termand near-term infants with suspected early-onset sepsis.The age-adjusted PCT nomogram with a safety cut-offvalue of 10 ng/ml seems to be reasonable. A multicenterstudy will be required to test the reliability and safety ofa PCT-based strategy in a larger cohort of neonates.

Acknowledgement

BRAHMS Diagnostica (Berlin, Germany) provided the test-ing kits for PCT determinations but was not involved in any oth-er aspects of the study or manuscript preparation.

References

1 Polin RA: The ins and outs of neonatal sep-sis. J Pediatr 2003; 143: 34.

2 Escobar GJ: The neonatal sepsis work-up:personal reflections on the development ofan evidence-based approach toward new-

born infections in a managed care organiza-tion. Pediatrics 1999; 103:e360e373.3 Gendrel D, Bohuon C: Procalcitonin as a

marker of bacterial infection. Pediatr InfectDis J 2000; 19: 679688.

4 Marchini G, Berggren V, Djilali-Merzoug R,Hansson LO: The birth process initiates anacute phase reaction in the fetus-newborninfant. Acta Pediatr 2000; 89: 10821086.

5 Chiesa C, Panero A, Rossi N, Stegagno M,DeGiusti M, Osborn JF, Pacifico L: Reliabil-ity of procalcitonin concentrations for thediagnosis of sepsis in critically ill neonates.Clin Infect Dis 1998; 26: 664672.

6 Assuma M, Signore F, Pacifico L, Rossi N,Osbron JF, Chiesa C: Serum procalcitoninconcentrations in term delivering mothersand their healthy offsprings: A longitudinalstudy. Cl in Chem 2000; 46: 15831587.

7 Guibourdenche J, Bedu A, Petzold L, March-and M, Mariani-Kurdjian P, Hurtaud-RouxM, Aujard Y, Porquet D: Biochemical mark-ers of neonatal sepsis: value of procalcitoninin the emergency setting. Ann Clin Biochem2002; 39: 130135.

8 Monneret G, Labaune JM, Isaac C, BeinvenuF, Puter G, Bienvenu J: Procalcitonin and C-reactive protein levels in neonatal infections.Acta Pediatr 1997; 86: 209212.

9 Sachse C, Dressler F, Henkel E: Increased se-

rum procalcitonin in newborn infants with-out infection. Clin Chem 1998; 44: 13431344.

10 Turner D, Hammerman C, Rudensky B,Schlesinger Y, Goia C, Schimmel MS: Pro-calcitonin in preterm infants during the firstfew days of life: introducing an age-relatednomogram. Arch Dis Child Fetal NeonatalEd 2006; 91:F283F286.

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10/10


Neonatology 2010;97:165174174

11 Ballot DE, Perovic O, Galpin J, Cooper PA:Serum procalcitonin as an early marker ofneonatal sepsis. S Afr Med J 2004; 94: 851854.

12 Blommendahl J, Janas M, Laine S, MiettinenA, Ashorn P: Comparison of procalcitoninwith CRP and differential white blood cellcount for diagnosis of culture-proven neona-

tal sepsis. Scand J Infect Dis 2002; 34: 620622.

13 Distefano G, Curreri R, Betta P, Romeo MG,Amato M: Procalcitonin serum levels inperinatal bacterial and fungal infection ofpreterm infants. Acta Paediatr 2004; 93: 216219.

14 Enguix A, Rey C, Concha A, Medina A, CotoD, Dieguez MA: Comparison of procalcito-nin with C-reactive protein and serum amy-loid for the early diagnosis of bacteria l sepsisin critically ill neonates and children. IntCare Med 2001; 27: 211215.

15 Franz AR, Kron M, Pohlandt F, Steinbach G:Comparison of procalcitonin with interleu-kin 8, C-reactive protein and differential

white blood cell count for the early diagnosisof bacterial infections in newborn infants.Pediatr Infect Dis J 1999; 18: 666671.

16 Gendrel D, Assicot M, Raymond J, Moulin F,Francouai C, Badoual J, Bohuon C: Procalci-tonin as a marker for the early diagnosis ofneonatal infection. J Pediatr 1996; 128: 570573.

17 Joram N, Boscher C, Denizot S, Loubersac V,Winer N, Roze JC, Gras-Le Guen C: Umbili-cal cord blood procalcitonin and C-reactive

protein concentrations as markers for earlydiagnosis of very early onset neonatal infec-tion. Arch Dis Child Fetal Neonatal Ed 2006;91:F65F66.

18 Kordek A, Giedrys-Ka lemba S, Pawlus B, Po-draza W, Czajka R: Umbilical cord blood se-rum procalcitonin concentration in the di-agnosis of early neonatal infection. JPerinatol 2003; 23: 148153.

19 Resch B, Gusenleitner W, Mller WD: Pro-calcitonin and interleukin-6 in the diagnosisof early-onset sepsis of the neonate. ActaPaediatr 2003; 92: 243245.

20 Meisner M: Pathobiochemistr y and clinicaluse of procalcitonin. Clin Chim Acta 2002;323: 1729.

21 Connell TG, Rele M, Cowley D, Buttery JP,Curtis N: How reliable is a negative bloodculture result? Volume of blood submittedfor culture in routine practice in a childrenshospital. Pediatrics 2007; 119: 891896.

22 Nobre V, Harbarth S, Graf JD, Rohner P, Pu-gin J: Use of procalcitonin to shorten antibi-otic treatment duration in septic patients.Am J Respir Crit Care Med 2008; 177: 498505.

23 Philip AG, Mills PC: Use of C-reactive pro-tein in minimizing antibiotic exposure: ex-perience with infants initially admitted to a

well-baby nurser y. Pediatrics 2000; 106:e4.24 Ehl S, Gering B, Bartmann P, Hgel J, Poh-

landt F: C-reactive protein is a useful markerfor guiding duration of antibiotic therapy insuspected neonatal bacterial infection. Pedi-atrics 1997; 99: 216221.

25 Benitz WE, Han MY, Madan A, Ramachan-dra P: Serial serum C-reactive protein levelsin the diagnosis of neonatal infection. Pedi-atrics 1998; 102:e41.

26 Engle WD, Jackson GL, Sendelbach DM, Ste-hel EK, Ford DM, McHugh KM, Norris MR,Vedro DA, Velaphi S, Michelow IC, OlsenKD: Pneumonia in term neonates: laborato-ry studies and duration of antibiotic therapy.J Perinatol 2003; 23: 372377.

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