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PEDIATRICS Vol. 104 No. 3 September 1999, pp. 447-453
,
From the * Department of Pediatrics, Division of Neonatology and
Pediatric Critical Care, the Department of Clinical Chemistry, and
the § Department of Biometry and Medical Documentation, University of
Ulm, Ulm, Germany.
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ABSTRACT |
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Top
Abstract
Results
Discussion
Conclusion
References
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Objective. To examine whether the determination of interleukin 8 (IL-8) and C-reactive protein (CRP) in neonates with suspected nosocomial bacterial infection (NBI) is feasible and cost-effective in reducing antibiotic therapy.
Methods. Between April 1996 and May 1997, IL-8 was measured 260 times along with blood cultures, CRP, and immature-to-total-neutrophil (IT) ratio for suspected NBI in term and preterm neonates. All infants were retrospectively analyzed for NBI. Sensitivity, specificity, positive and negative predictive values, and 95% confidence intervals were calculated for IL-8, CRP, and IT ratio. Receiver-operating characteristic curves were analyzed to determine optimal thresholds. Between June 1997 and June 1998, IL-8 was measured 215 times in newborn infants with suspected NBI and the decision to start antibiotic therapy was based on increased IL-8 and/or CRP values. A cost-effectiveness analysis was performed and sensitivity, specificity, and receiver-operating characteristic curves were reevaluated.
Results. At the first suspicion of NBI, the combination of
IL-8 
53 pg/mL and/or CRP >10 mg/L detected culture-proven NBI
with 96% sensitivity. The combined culture-proven and clinical NBI
were detected with 93% sensitivity and 80% specificity. The use of IL-8 reduced unnecessary antibiotic therapy for suspected NBI by 73%
and was cost-effective when compared with initiating antibiotic therapy
based on clinical signs alone or based on clinical signs and an
increased IT ratio and/or CRP.
Conclusions. The combination of IL-8 and/or CRP is a reliable and early test for the diagnosis of NBI in newborn infants. Using the combination of IL-8 and/or CRP to restrict antibiotic therapy to truly infected infants reduces unnecessary antibiotic therapy and is cost-effective. Key words: newborn infant, term, preterm, sepsis, nosocomial bacterial infection, interleukin 8, C-reactive protein, immature-to-total-neutrophil ratio, blood culture, costs.
Culture-proven nosocomial bacterial infections (NBI) are
found in up to 25% of very low birth weight infants and are associated with substantial morbidity and mortality.1 Because
clinical signs of bacterial infections are unspecific in newborn
infants, the common approach is to initiate antibiotic therapy in all
infants with clinically suspected bacterial infection, and to
discontinue treatment if blood cultures remain sterile and clinical
signs disappear.2,3 As a result, most infants receive antibiotics unnecessarily if analyzed retrospectively.2,3 The development of multiple drug-resistant bacteria makes the restriction of antibiotic therapy to truly infected patients
mandatory.4,5
Well-known laboratory parameters indicating infection such as white
blood count, white cell indices, and C-reactive protein (CRP) are
either unspecific or not useful for the early diagnosis and therefore
cannot be recommended to guide the initiation of antibiotic
therapy.6,13 In recent years, several new markers of
infection have been investigated, such as tumor necrosis factor
A proinflammatory cytokine with similar kinetics as
IL-6,32,33 IL-8 is produced predominantly by monocytes, macrophages, and endothelial cells in response to various stimuli such
as lipopolysaccharide and tumor necrosis factor This is the first study investigating: 1) IL-8 as an early marker for
the diagnosis of NBI in a large population of mostly preterm infants;
and 2) whether the use of IL-8 in combination with CRP within the
work-up for suspected NBI is feasible and cost-effective in restricting
antibiotic therapy to truly infected infants.
The first part of the study is a retrospective analysis of the
first 12 months of routine IL-8 measurements, the second part of the
study is a prospective evaluation of a new treatment protocol based on
previously published evidence.14,35 Neither investigation
required approval of the institutional review board.
Study Population
One thousand three hundred eighty-six newborn infants admitted
to the neonatal intensive care unit and step-down-unit at the University Children's Hospital in Ulm between April 1996 and June 1998, including 223 preterm infants with a gestational age <30 weeks.
Definition of Bacterial Infection
NBI was defined as clinical signs combined with laboratory
changes suggesting bacterial infection after the third day of
life,1 in contrast to early-onset infections starting
within the first 72 hours of life.
Suspected NBI required one or more clinical signs suggesting infection.
The diagnosis of culture-proven NBI was based on one or more clinical
signs of NBI and a positive blood or cerebrospinal fluid culture.
Clinical NBI was diagnosed if there were one or more signs of infection
and a CRP >10 mg/L at 12 to 60 hours after the first blood sample was
taken.6,7,14,18 All patients who did not fulfill our
criteria for culture-proven or clinical infections were considered
not-infected.
In patients who received antibiotics, two normal CRP values were
required before they were classified as not-infected and antibiotic
therapy was discontinued.7 In patients, who did not
receive antibiotics and recovered from clinical signs of infection
without antibiotics, a single negative CRP was considered to be
sufficient for classification as not-infected.
The clinical signs of neonatal bacterial infection are pallor, grayish
skin color, and poor perfusion (capillary refill >2 seconds);
increasing incidence of bradycardia and/or apnea; tach-ypnea (>60/min), dyspnea (grunting, nasal flaring, retractions), rising fraction of inspired oxygen in previously stable infants, and worsening respiratory failure; muscular hypotonia, muscular hypertonia, hyperexcitability, irritability, lethargy, and fever.36,37
Standard Biochemical and Hematologic Determinations
CRP and blood counts were prospectively measured along with IL-8
at any time in hospitalized patients at the onset of clinical signs
suggesting infection, ie, when a NBI was first suspected. CRP
measurements were repeated at least once 12 to 60 hours after the
initial evaluation. Healthy infants were not evaluated in this study.
CRP was measured by rate nephelometry (Beckmann Array, Beckmann
Instruments, Munich, Germany). Inter- and intraassay variations were
<5% and <4% at 15 mg/mL. The threshold was set to 10 mg/L.6
Complete blood counts were done on a cell counter (Abbott CD3500,
Abbott, Wiesbaden, Germany). Leukocytes were differentiated with
microscopy by a small pool of experienced technicians. A segmented
neutrophil granulocyte was defined by at least one indentation of the
nucleus to less than a third of the maximal nuclear
diameter.9,38 The immature-to-total-neutrophil (IT) ratio
was calculated as the sum of the immature granulocytes divided by the
sum of all neutrophil granulocytes. The IT ratio was considered to be
elevated if >0.20.2,9,10,39
IL-8 Measurements
IL-8 was measured by a chemiluminescence immunoassay (Immulite,
DPC-Biermann, Bad Nauheim, Germany). The threshold for IL-8 was set to
70 pg/mL during the first study period (recommended by the manufacturer
for adults) and to 53 pg/mL during the second study period (according
to the analysis of the receiver-operating characteristic [ROC]
curve). The IL-8 assay had a lower limit of detection of 20 pg/mL and
was calibrated up to 10 000 pg/mL. Inter- and intraassay variations
were <5% and <2% at 95 pg/mL. IL-8 values were available within 90 minutes after blood sampling.
To evaluate IL-8 as an early marker of bacterial infections, only IL-8
values obtained at the time when a NBI was first suspected in a
hospitalized infant (n = 260 [April 1996-May
1997] and n = 215 [June 1997-June 1998])
were analyzed.
IL-8 was measured 516 times after the third day of life. Forty-one
measurements were excluded from the evaluation, because these
measurements were conducted as repeated tests (23), the indication for
the determination of IL-8 was not obvious or the data were incomplete
(9), IL-8 had been measured after surgery (4), or in patients with
chromosomal abnormalities (5).
Indication for and Duration of Antibiotic Therapy
During the first study period, antibiotics were started in all
infants with a suspected bacterial infection and either a CRP >10 mg/L
and/or an IT ratio >0.20. During the second study period, antibiotics
were only started in infants with suspected infection if the CRP was
increased to >10 mg/L and/or the IL-8-level was According to institutional guidelines, all antibiotics had to be
discontinued at 48 to 72 hours in not-infected infants.40
Statistical Analysis
Sensitivity, specificity, and positive and negative predictive
values were calculated for IL-8, CRP, and IT ratio measured at the
first suspicion of infection, ie, at 0 hours (Table
1). Sensitivity was calculated for
culture-proven infections and the combination of culture-proven and
clinical infections. Specificity and positive and negative predictive
value were calculated for the combination of culture-proven and
clinical infections. Exact 95% confidence intervals were calculated
for all the parameters.
TABLE 1
,11,12 soluble tumor necrosis factor
receptor,13 interleukin
(IL)-6,11,1214-19 IL-1
,17 IL-8
(IL-8),12,16 IL-1 receptor antagonist,20
soluble intercellular adhesion molecule,12,16,21
granulocyte colony-stimulating factor,22 soluble IL-2
receptor and neopterin,23 markers of
complement-activation,24-26 procalcitonin,27,28 leukocyte elastase,29 elastase-1-proteinase inhibitor,30 and most recently CD11b as a cell surface marker.31 None of these markers has yet made the progress from the laboratory to clinical application. And so far, only IL-6, tumor necrosis factor , and IL-1 have been
investigated for NBI.17,19
.34 Based on our previous study on IL-6,14 IL-8 was introduced as a routine diagnostic tool at our institution in 1996, as soon as it
became available on a random-access automated assay suitable for
24-hour emergency laboratories.
PATIENTS AND METHODS
53 pg/mL. Exceptions
were allowed if the condition of an infant was considered to be
life-threatening and withholding antibiotic therapy while waiting for
laboratory results would have been inappropriate.
Statistical Analysis*
Graphs of ROC curves were plotted for visual analysis and the determination of thresholds for combined patients with culture-proven or clinical infections versus not-infected patients.
Sample Size Calculation and Length of the Second Study Period
The sample size calculation for the second study period was based on the results of the first study period (Table 2). To prove with McNemar's Test at a one-sided significance level of 5% and a power of 90% that using IL-8 and CRP instead of IT ratio and CRP results in a reduction of antibiotic therapy, only 31 patients with suspected NBI have to be examined. However, to further increase the power of the study and to detect false-negative IL-8 values, the length of the second study period was arbitrarily set to 12 months.
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Cost-effectiveness Analysis
Hospital costs (money spent by the Department of Pediatrics) were calculated including manpower in the laboratory and costs for materials (ie, laboratory costs for IL-8, CRP, differential white blood cell count and blood cultures, costs for antibiotics at special hospital rates treating 2 infants with each unit, and materials to place and maintain intravenous access).
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RESULTS |
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Top
Abstract
Results
Discussion
Conclusion
References
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First Study Period (April 1996-March 1997)
On 260 occasions IL-8 was measured at the first suspicion of NBI. Thereof, IL-8 was measured 162 times in infants with a gestational age of <30 weeks.
Culture-proven infections were diagnosed in 26 of the 260 cases of suspected NBI, and clinical infections in 32 (Table 3). Median IL-8 values and ranges for patient groups are also shown in Table 3. Isolated bacteria are listed along with laboratory results in Table 4.
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The ROC curve suggested a threshold of 53 pg/mL as being more suitable for the diagnosis of NBI (Fig 1).
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In infants with culture-proven NBI, the sensitivity of IL-8 (70
pg/mL) was 77% (20 out of 26) and increased to 88% (23 out of 26)
when the threshold of IL-8 was set to 53 pg/mL. CRP was increased to
>10 mg/L in only 15 (58%) infants with culture-proven NBI. The best
sensitivity for culture-proven NBI (96%) was achieved by the
combination of IL-8 and/or CRP. Sensitivities of IL-8, CRP, and IT
ratio for blood and cerebrospinal fluid culture-proven NBI are
displayed in Table 5, including values
categorized according to isolated pathogens.
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In infants with clinical infection, the sensitivity of IL-8 (70
pg/mL) was 63% (20 out of 32) and increased to 81% (26 out of 32)
when the threshold of IL-8 was set to 53 pg/mL.
The sensitivity, specificity, and the negative and positive predictive values for IL-8 to detect both culture-proven and clinical infection at thresholds of 53 pg/mL and 70 pg/mL are shown in Table 6 in comparison with CRP and IT ratio. Again, the best sensitivity (93%) was achieved by the combination of IL-8 and/or CRP.
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One premature infant (gestational age of 24 weeks) died from culture-proven NBI. IL-8 was >10 000 pg/mL at initial evaluation.
Second Study Period (June 1997-June 1998): Using IL-8 and CRP to Decide on Antibiotic Therapy in Infants With Clinical Signs of NBI
Two hundred fifteen IL-8 measurements were conducted at the first suspicion of NBI, thereof 147 infants with a gestational age of <30 weeks. Sensitivity, specificity, and positive and negative predictive values for all parameters and ROC curves were recalculated and confirmed the results from the first study period (Tables 5 and 6 and Fig 2).
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All culture-proven and clinical NBI were detected at the first suspicion of infection. No deaths as a result of NBI occurred. No infected infant received antibiotics because of perceived life-threatening condition before laboratory results were available.
Of the 149 infants who were retrospectively considered to be not-infected, 26 (17%) had an increased IL-8 and/or CRP and 20 (13%) had received antibiotics for 48 hours. Three of the unnecessarily treated infants had IL-8 and CRP values within the normal range, but antibiotics were started while laboratory results had been pending because of perceived life-threatening condition. In 9 not-infected infants, antibiotics were withheld despite marginally elevated IL-8 because they rapidly recovered from signs after other interventions.
Eighty (54%) of the 149 not-infected patients had an increased IT ratio or CRP. If antibiotics had been started based on an IT ratio >0.20 and/or a CRP >10 mg/L, 75 (50%) of the 149 not-infected infants would have been treated for 48 hours, 5 would have recovered rapidly from clinical signs after other interventions.
The use of IL-8 therefore resulted in a reduction of unnecessary antibiotic therapy by 73%, ie, only 20 instead of 75 not-infected infants received antibiotics. IL-8 needed to be determined in 4 patients with suspected nosocomial infection to save 1 patient from unnecessary antibiotic therapy.
On this basis, the cost-effectiveness analysis was performed and showed that the determination of IL-8 for suspected NBI was cost-effective (Table 7). Despite markedly increased laboratory costs, the total hospital costs were not changed owing to the 73% reduction of unnecessary antibiotic therapy.
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In 7 of the 33 clinically infected infants, histologically proven necrotizing enterocolitis or peritonitis was diagnosed. IL-8, measured when necrotizing enterocolitis was first suspected because of abdominal distension and biliary reflux combined with signs of NBI, ranged between 364 pg/mL and 4676 pg/mL.
A separate analysis of ROC curves for infants with a gestational age <30 weeks showed that there was no difference compared with the whole study population (not shown).
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DISCUSSION |
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Top
Abstract
Results
Discussion
Conclusion
References
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The analysis of 475 IL-8 values showed that term and preterm infants increased serum levels of IL-8 in response to NBI. One of the highest values (>10 000 pg/mL) was found in a very prematurely born infant who succumbed to a blood culture-proven septicemia. The study showed that using IL-8 in combination with CRP resulted in a reduction of unnecessary antibiotic therapy and was feasible and cost-effective.
Until this study we tried to limit antibiotic therapy of infants with suspected bacterial infection to those who had either an IT ratio of >0.20 or a CRP >10 mg/L in addition to clinical signs of infection. Thereby antibiotic therapy was reduced to 71% of infants with clinical signs of NBI, but it was still initiated in 58% of cases unnecessarily according to our definitions (Table 6, first study period). After the introduction of IL-8 we were able to further reduce antibiotic therapy to 40% of infants with suspected NBI and antibiotic therapy was retrospectively considered unnecessary in only 23% of treated infants.
Although this study was not conducted as a randomized trial, the observed reduction of antibiotic therapy in not-infected infants is certainly based on the excellent predictive accuracy of IL-8. Instead of randomizing infants to either IL-8 or IT ratio, this study was designed that every infant served as his own control: both IL-8 and IT ratio were measured in all infants who had clinical signs of infection and were strongly considered for antibiotic treatment.
The observed reduction of unnecessary antibiotic therapy for suspected NBI occurred in long-term hospitalized infants, who are prone to infections with multiple drug-resistant bacteria. Although the cost-effectiveness analysis suggested no difference in total hospital costs, the potential long-term effect of this reduction on the development and spread of antibiotic-resistant bacteria may eventually far outweigh the increase in laboratory costs.
In the presence of clinical signs of a bacterial infection, a positive blood culture result is widely accepted as proof of a bacterial infection. However, it is known that clinically sick infants with laboratory indications of infection (ie, elevated IT ratio; CRP; leuko-, neutro-, or thrombocytopenia), who clinically respond to antibiotic therapy, frequently do not have positive blood cultures.611-1416-18,40,41 Therefore, clin-ical bacterial infection was defined in this study as a combination of clinical signs and laboratory changes, as has been done previously by us6,14,40 and others.11-13,16,18 CRP, the second constituent for the diagnosis of bacterial infection in this study, is a useful marker for bacterial infections in newborn infants.6-8 To eliminate potentially false-positive CRP values, the 5 infants in whom IL-8 was measured after surgery were not evaluated.
Coagulase-negative staphylococci growing in blood cultures of preterm infants may be of equivocal significance, reflecting either contamination or true bacteremia. Because 47 of the 49 episodes with blood cultures growing coagulase-negative staphylococci were accompanied by an increase of CRP to >10 mg/L within 60 hours after initial evaluation, the predominance of coagulase-negative staphylococci in this study is probably true and not caused by contamination. Of the 2 patients who did not have an increased CRP at 12 to 60 hours, 1 had a definite ventriculoperitoneal shunt infection with marked new cerebrospinal fluid granulocytosis and the other an increased CRP at 72 hours. In only 2 further patients coagulase-negative staphylococci were recovered from blood cultures without additional laboratory signs of infection: these patients were classified as not-infected.
According to a recent large survey in preterm infants, ~55% of culture-proven NBI are caused by coagulase-negative staphylococci.1 In our study, with 83%, this organism was even more frequently recovered. With this predominance of coagulase-negative staphylococci, our data and conclusion are primarily based on NBI caused by this organism.
There is a trend to lower IL-8 values in patients with culture-proven NBI from coagulase-negative staphylococci (median, 96 pg/mL; range, <20-5698 pg/mL) compared with culture-proven NBI from other organisms (median, 318 pg/mL; range, 56-10 000 pg/mL). With the predominance of coagulase-negative staphylococci in our study, we may therefore have underestimated the sensitivity of IL-8.
We predominantly observed increased serum levels of IL-8 before there was a detectable increase of CRP, but IL-8 was occasionally normal in the presence of an (already) elevated CRP, suggesting that more time had already elapsed in the course of the infection. The combination of IL-8 with CRP detected those infants without substantially decreasing specificity (Table 6).
During the first study period we have seen that a single negative IL-8 does not rule out bacterial infection (negative predictive value 98%). We therefore repeated IL-8 and CRP determinations at least once if symptoms persisted or new signs of infection occurred in infants with initially negative IL-8 and CRP. However, during the second study period no further cases of NBI were detected by repeated measurements corresponding to a negative predictive value of 100%. All culture-proven and clinically infected infants received antibiotics as soon as the initial laboratory results were available, ie, within 90 minutes after the first blood sample was taken.
Throughout the 2-year study period 1 of 59 infants with culture-proven NBI and 3 of 65 clinically infected infants were not detected by IL-8 or CRP at the first suspicion of NBI, resulting in an overall false-negative rate of 3%. We have not observed any adverse outcome when antibiotic therapy was withheld based on normal IL-8 and CRP, but we cannot provide data to prove that this strategy will not result in an adverse outcome in initially missed infants. In contrast, we indeed fear that if antibiotic therapy is withheld by inexperienced physicians based on negative laboratory results this may be harmful. We also strongly discourage to withhold antibiotic therapy and to wait for laboratory results in an infant with suspected septic shock (ie, requiring urgent intubation, volume resuscitation and/or inotropic support), despite the excellent predictive accuracy of IL-8. The strategy outlined in this study is primarily intended for the many deteriorations observed in the long-term care of preterm infants.
After our initial investigation on IL-6,14 we introduced IL-8 into the routine work-up for bacterial infections in newborn infants as it was first available on a random-access automated assay suitable for 24-hour emergency laboratories and at present requires less serum (50 µL) and less time for measurement (45 minutes) than a similar assay for IL-6. IL-8 has similar kinetics as IL-632,33 and seems to be as useful for the early detection of bacterial infections.
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CONCLUSION |
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Top
Abstract
Results
Discussion
Conclusion
References
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In summary, we conclude that the introduction of the combination of IL-8 and CRP as part of the work-up for bacterial infection judiciously reduces unnecessary antibiotic treatment and therefore unnecessary costs, pain, and possible side effects of antibiotic therapy, and it may help to reduce development and spread of drug-resistant bacteria.
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FOOTNOTES |
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Received for publication Nov 17, 1998; accepted Mar 10, 1999.
Presented in part to the European Society for Pediatric Research Annual Meeting; September 1997; Szeged, Hungary; and to the Society for Pediatric Research Annual Meeting; May 1999; San Francisco, CA.
Address correspondence to Axel R. Franz, MD, Division of Neonatology and Pediatric Critical Care, University Children's Hospital, Prittwitzstr. 43, D-89075 ULM, Germany. E-mail: axel.franz{at}medizin.uni-ulm.de
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ABBREVIATIONS |
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NBI, nosocomial bacterial infection; CRP, C-reactive protein; IL, interleukin; IT, immature-to-total-neutrophil ratio; ROC, receiver-operating characteristic curve.
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REFERENCES |
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Abstract
Results
Discussion
Conclusion
References
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(TNF) and interleukin-6 (IL-6) in newborn sepsis.
Acta Paediatr.
1994;
83:696-699 [Medline]1-proteinase inhibitor in early diagnosis of neonatal septicemia.
J Pediatr.
1986;
108:987-990 [CrossRef][Medline]
8 during the Jarisch-Herxheimer reaction of relapsing fever.
J Exp Med.
1992;
175:1207-1212 This article has been cited by other articles:
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|
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|
  U K Mishra, S E Jacobs, L W Doyle, and S M Garland Newer approaches to the diagnosis of early onset neonatal sepsis. Arch. Dis. Child. Fetal Neonatal Ed., May 1, 2006; 91(3): F208 - F212. [Abstract] [Full Text] [PDF]
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 J.-H. Weitkamp and J. L. Aschner Diagnostic Use of C-Reactive Protein (CRP) in Assessment of Neonatal Sepsis NeoReviews, November 1, 2005; 6(11): e508 - e515. [Full Text] [PDF]
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 |
|
 A. R. Franz, K. Bauer, A. Schalk, S. M. Garland, E. D. Bowman, K. Rex, C. Nyholm, M. Norman, A. Bougatef, M. Kron, et al. Measurement of Interleukin 8 in Combination With C-Reactive Protein Reduced Unnecessary Antibiotic Therapy in Newborn Infants: A Multicenter, Randomized, Controlled Trial Pediatrics, July 1, 2004; 114(1): 1 - 8. [Abstract] [Full Text] [PDF]
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P C Ng Diagnostic markers of infection in neonates Arch. Dis. Child. Fetal Neonatal Ed., May 1, 2004; 89(3): F229 - F235. [Abstract] [Full Text] [PDF]
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 J.-H. Weitkamp, J. Reinsberg, and P. Bartmann Interleukin-8 (IL-8) Preferable to IL-6 as a Marker for Clinical Infection Clin. Vaccine Immunol., November 1, 2002; 9(6): 1401 - 1401. [Full Text] [PDF]
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 Can We Reduce Unnecessary Antibiotic Use in Ill and Preterm Infants? Journal Watch Infectious Diseases, November 1, 1999; 1999(1101): 6 - 6. [Full Text]
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10 mg/L on initial evaluation, showing that the predictive
accuracy of IL-8 is best if measured when CRP is still normal (ie,
early in the course of infection).
