PEDIATRICS Vol. 109 No. 1 January 2002, pp. 34-39
Epidemiological, Clinical, and Microbiological Characteristics of Late-Onset Sepsis Among Very Low Birth Weight Infants in Israel: A National Survey
* Department of Neonatology, Rambam Medical Center and Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
Department of Health Services Research Unit, Ministry of Health, Gertner Institute, Tel-Hashomer, Israel
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIXREFERENCES |
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Objective. Nosocomial infections are a serious problem among very low birth weight (VLBW) infants. We studied the association between late-onset sepsis (LOS) and mortality and morbidity in VLBW infants.
Methods. From a national cohort of 5555 VLBW infants born in Israel during 1995 through 1998, 4829 survived at least 3 days and composed the study population. Maternal, perinatal, or postnatal variables that showed a significant association with LOS in a univariate analysis were tested in a bivariate analysis (adjusted for gestational age). Variables with P 
.1 were then tested by a multiple logistic regression for assessing the net effect of each variable on the risk for LOS.
Results. One or more episodes of bloodstream-proven LOS occurred in 1453 infants (30%). Gram-positive and Gram-negative bacteria accounted for 55.4% and 31.2% of microbes, respectively, mainly coagulase-negative Staphylococci and Klebsiella. Compared with those without LOS, infants with LOS had a significantly higher mortality rate (16.9% vs 8.6%). Mortality after Gram-negative LOS (26.2%) and Candida LOS (27.6%) was similar and significantly higher than with Gram-positive LOS (8.7%). Significant independent predictors of LOS were decreasing gestational age, cesarean section, mechanical ventilation, patent ductus arteriosus, necrotizing enterocolitis, and bronchopulmonary dysplasia.
Conclusions. LOS occurred in 30% of Israeli VLBW infants. Six strong independent predictors for LOS were identified. Recognition and awareness of the epidemiologic, clinical, and microbiologic characteristics of LOS remain the keystones for management of this nosocomial infection.
Key Words: sepsis • premature infant • very low birth weight infant • morbidity • mortality
Abbreviations: LOS, late-onset sepsis • VLBW, very low birth weight • SCN, Staphylococcus-coagulase-negative • RDS, respiratory distress syndrome • PDA, patent ductus arteriosus • IVH, intraventricular hemorrhage • NEC, necrotizing enterocolitis • BPD, bronchopulmonary dysplasia • GA, gestational age
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIXREFERENCES |
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Late-onset sepsis (LOS) remains a frequent and significant cause of morbidity and mortality among very low birth weight (VLBW;
1500 g) premature infants.1 In the United States, Stoll et al2 reviewed 6911 VLBW infants who survived beyond 3 days and found that 25% of these infants had 1 or more events of bloodstream culture-proven LOS with coagulase-negative staphylococci (SCN) accounting for 55% of all infections. The risk of LOS increased with decreasing birth weight and gestational age, with respiratory distress syndrome (RDS), patent ductus arteriosus (PDA), severe intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD).2 LOS was associated with prolonged duration of mechanical ventilation and intravascular catheterization and hospitalization,2–6 and VLBW infants who developed LOS were significantly more likely to die than those who were not infected (17% vs 7%).2 To determine the incidence of LOS in Israel, the causative pathogens, the risk factors associated with sepsis, and the association of LOS with various morbidities and mortality, we reviewed the results of the Israel VLBW Database, which comprises a national cohort of 5555 VLBW infants cared for in all Israeli neonatal departments.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIXREFERENCES |
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This study is based on analysis of data from the Israel Neonatal Network collected on VLBW newborn infants born in Israel. All 28 neonatal departments in Israel participate in the data collection, which composes the Israel National VLBW Infant Database (Appendix). All live-born infants in Israel receive a unique identification number at birth. Patient information received by the database coordinator is cross-checked with the national birth registry, and data from any missing infants are requested from the birth hospital. Patient identification and birth hospital subsequently remain confidential by consensus agreement of all participating centers.
For each infant, a prestructured form was filled in. The data collected include parental demographic details, maternal pregnancy history and antenatal care, details of the delivery, the infant’s status at delivery, diagnoses, procedures and complications during hospitalization, and outcome at discharge. An operating manual and standard definitions are used by all departments. From January 1995 through December 1998, 5555 VLBW infants were registered in the database, accounting for >98% of all live-born VLBW infants in Israel. A total of 726 infants died in the first 3 days of life, and the remaining 4829 infants who survived at least 3 days composed the study population.
LOS was defined as positive microbial growth on 1 or more bloodstream cultures obtained after 72 hours of life with accompanying clinical signs of sepsis. All microbial growths in bloodstream cultures were reported. The number of episodes of LOS, the age at infection(s), and organisms were recorded. The diagnosis of sepsis caused by SCN was determined according to the criteria of the Vermont Oxford Network Database7,8 and required 1) clinical signs of sepsis, 2) positive bloodstream culture for SCN, and 3) intravenous antibacterial therapy for at least 5 days after obtaining blood culture or until death, should that occur within 5 days after obtaining blood culture. Whenever SCN and another pathogen were identified in the same bloodstream culture, only the other pathogen was recorded in the database.
Statistical Analysis
Differences between the groups of infants with and without LOS regarding the mean duration of mechanical ventilation, oxygen supplementation, and hospital stay were compared by 2-sample t test. The association between potential risk factors and the incidence of LOS was tested by a 
2 test for contingency tables. Considering the strong correlation between birth weight and gestational age (r = 0.7, P < .001), birth weight was excluded from the bivariate and multivariate analyses. Because gestational age (GA) showed the strongest association with the incidence of LOS, the adjusted (for GA) effect on LOS of each risk factor found to be associated with LOS in the univariate analysis was tested using bivariate logistic regression analyses. Variables showing an association with LOS at P .1 in the bivariate analysis were then included in the multivariate logistic regression model, to assess the net effect of each independent variable on the risk of developing LOS.9 Results are presented as odds ratios with the appropriate 95% confidence intervals. Statistical analysis was performed using the SAS statistical software (version 8.0; SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIXREFERENCES |
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Epidemiology of LOS
From 1995 through 1998, 4829 VLBW infants survived at least 3 full days and composed the study population. One or more episodes of bloodstream culture-proven sepsis occurred in 1453 (30%) of these survivors. A total of 1880 episodes of LOS were reported (Table 1), and 263 (18.1%) and 82 (5.6%) infants experienced 2 or 3 episodes of LOS, respectively. Gram-positive bacteria accounted for 55.4% of LOS episodes, and SCN was the leading causal microbe, composing 47.3% of all episodes of LOS. The most common Gram-negative bacteria that caused LOS were Klebsiella (14.7%), Pseudomonas (4.2%), and Enterobacter species (3.8%). LOS caused by Candida infections accounted for 11.1% of infections.
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The recurrence rate of LOS was inversely related to birth weight and GA. Whereas 15.2% and 14.2% of neonates who weighed <1000 g or were born before 29 weeks of gestation, respectively, had multiple episodes of LOS, only 2.2% and 1.6% of neonates who weighed >1250 g or were born after 32 weeks of gestation, respectively, had more than 1 episode of LOS (P < .0001). Infants with recurrent episodes of LOS had higher rates of fungal infection, which occurred in 8.8% of infants as a primary infection and in 31.4% and 55.4% of neonates who had 2 or 3 episodes of LOS, respectively (P < .001).
Demographic, Gestational, and Labor Characteristics
In the univariate analysis, antepartum hemorrhage, prolonged rupture of membranes (>6 hours), and chorioamnionitis were associated with significantly higher risk for LOS, whereas multiple births and pregnancy-induced or chronic hypertension were associated with a significantly lower risk for LOS. However, in the multivariate analysis, only cesarean delivery was found to be significantly associated with LOS (P = .03; odds ratio: 1.17; 95% confidence interval: 1.01–1.36; Table 2).
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Neonatal Characteristics
Decreasing gestational age and birth weight were associated with a marked and significant increase in the rate of LOS. More than half of neonates born before 28 weeks of gestation had at least 1 episode of LOS (56% and 50.9% at 24–25 weeks and 26–27 weeks, respectively) compared with only 15% and 9.3% among infants born at 32–33 weeks or after 34 weeks of gestation, respectively (P < .001). The rate of LOS decreased with increasing birth weight from 53% of neonates with a birth weight of <750 g, 46.4% for infants who weighed 750 g to 999 g at birth, 30.6% for neonates at 1000 g to 1249 g, and 16.8% for those at 1250 g to 1500 g (Table 3).
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In-Hospital Morbidity and Interventions
After adjustment for GA, RDS, mechanical ventilation, PDA, NEC, and BPD were found to be associated with an increased rate of LOS (P < .001). Infants with LOS had longer duration (mean ± standard deviation) of mechanical ventilation and of oxygen supplementation (19.8 ± 29.3 vs 9.6 ± 15.4 days and 35.7 ± 49 vs 16.4 ± 28.7 days, respectively; P < .001). Furthermore, infants who had LOS and survived had lengthier hospitalizations compared with infants without LOS (81 ± 45 vs 54 ± 28 days; P < .001; Table 3).
Regression Analysis of Variables Associated With Sepsis
Logistic regression analysis, which included all of the potential risk factors for LOS that were significant in the bivariate analysis, revealed that the following factors were independently associated with increased risk of LOS: a 1-week decrease in GA, delivery by cesarean section, mechanical ventilation, PDA, NEC, and BPD (Table 4).
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LOS and Mortality
VLBW neonates with LOS had a significantly higher mortality than those without LOS (16.9% vs 8.6%; P < .001). The pathogen-specific death rate was calculated per infant with LOS (n = 1453), and not per LOS episode (n = 1880). For the analysis, mortality was ascribed to the last infecting organism before death. The mortality among infants whose last episode of sepsis was attributable to Gram-positive organisms was 8.7% compared with 26.2% among infants with LOS caused by Gram-negative organisms, and 27.6% in infants with candidal infections. Infants with Gram-negative sepsis caused by Pseudomonas and Klebsiella had mortality rates of 47% and 27.9%, respectively (Table 5).
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The mortality rates within 3 days and 6 days of last episodes of LOS, as well as the total mortality rates associated with selected pathogens, are shown in Fig 1. Mortality within 3 days occurred especially among infants with Pseudomonas (27.3%) and Klebsiella (12.4%) sepsis, as compared with 3.5% among infants with fungal organisms and 1.5% among infants with sepsis caused by Gram-positive organisms. Infants whose LOS was caused by Pseudomonas, Klebsiella, or Escherichia coli and who did not die within 3 days of infection were unlikely to die within the following 3 days. Conversely, infants whose LOS was caused by Enterobacter, Acinetobacter, or Candida species and who survived up to 3 days postinfection still had a high risk for dying within the following 3 days.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIXREFERENCES |
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The present report evaluated a national cohort of neonates, representing almost all live-born VLBW infants born in Israel during the study period. LOS among VLBW infants in Israel proved to be frequent and was significantly associated with various neonatal conditions, longer hospitalization, and higher death rates. The incidence of LOS in VLBW infants is high: 25%2 and 16%10 in the United States and 30% in Israel. In the 2 US studies2,10 and in our study, mortality rates were 2-fold or above in infants with LOS as compared with those without LOS (17%–21% vs 7%–9%).
The higher incidence of LOS in Israel may reflect differences in study populations. Our study comprised a national cohort of infants as compared with VLBW infants treated in selected units in the United States and Australia.2,6,10 Variations in staffing policies may result in a difference in the rates of LOS, and the current understaffing of Israeli neonatal units might have increased the risk of cross-infection11 and thus could explain an increased incidence of LOS in our series.
The distribution of pathogens between our data and those of Stoll et al2 is different. Overall, we had a higher percentage of Gram-negative and fungal organisms and fewer Gram-positive organisms. Specifically, we found more Klebsiella and Pseudomonas but less SCN, Staphylococcus aureus, and group B streptococcus. The lower proportion of SCN infections in our population compared with the US data of Stoll et al2 reflects a different distribution of organisms, predominantly the higher proportion of Gram-negative infections in Israel. The definition of sepsis caused by SCN is often problematic, and it is possible that some of our reported infections reflect contaminated specimens. Although our database protocol chose the Vermont Oxford definition,7 our results may overestimate the true infection rate.
Mortality after fungal sepsis and Gram-negative sepsis was 3- to 4-fold higher than after Gram-positive sepsis. Pseudomonas, Klebsiella, and Candida species were the leading pathogens associated with death after LOS episodes. To attribute mortality to specific organisms, Stoll et al2 undertook a clinical and autopsy chart review of infants who died after LOS; however, our data do not enable us to ascribe further attributable mortality to specific pathogens. Once LOS develops, mortality is expected earlier with Gram-negative pathogens than with Gram-positive pathogens or Candida.
VLBW infants who weigh <1000 g at birth are at the greatest risk for LOS and recurrent LOS. In the present study and in the report of Stoll et al,2 between one third and one half of such infants developed LOS. Multiple logistic regression analysis showed that significant independent predictors of LOS in Israeli VLBW infants included decreasing GA, cesarean delivery, mechanical ventilation, PDA, NEC, and BPD. The excess LOS observed among VLBW infants delivered by cesarean section might reflect the lower mortality in those infants (8.6%), as compared with infants delivered vaginally (16.7%) in our study population. Furthermore, the cesarean section rates are higher in pregnancies associated with a variety of obstetric complications,12 which may influence the infants’ subsequent outcome. Mechanical ventilation significantly increases the rate of acquired pneumonia and LOS in VLBW infants.13 PDA, NEC, and BPD mandate more neonatal interventions, including mechanical ventilation, indwelling lines, and prolonged parenteral nutrition, thus imposing additional risks for development of LOS. A vicious cycle becomes apparent: As more aggressive management is provided after birth, more VLBW infants survive, more interventions are performed, longer duration of mechanical ventilation and hospitalization is required, and a higher incidence of LOS and other complications occurs. Consequently, more interventions and therapies are applied and recurrent episodes of sepsis are likely to occur.
When LOS is suspected, empirical antimicrobial therapy should be targeted against Pseudomonas, Klebsiella, E coli, and Enterobacter, because the present study and the report of Karlowicz et al14 demonstrated these to be the most frequent causes of mortality within 48 to 72 hours of development of LOS. In addition, whenever fungal sepsis is suspected in a VLBW infant, empirical antifungal therapy should be considered,15 as it was shown recently by Makhoul et al16 to reduce morbidity and mortality from fungal LOS. In established LOS, the administration of intravenous immunoglobulin might be of benefit,17 whereas pathogen-specific monoclonal antibody preparations against pathogens that cause high mortality might further improve the outcome of infants with LOS.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIXREFERENCES |
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LOS remains a frequent and major problem among VLBW infants. Gestational age, cesarean section, mechanical ventilation, PDA, NEC, and BPD seem to be the strongest predictors for LOS. There are some intercountry differences as to the association of some maternal and neonatal variables with LOS and as to the distribution of pathogens that cause LOS. Identification of VLBW infants who are at high risk for LOS and early detection of LOS remain the keys to successful management of this condition.
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APPENDIX |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIXREFERENCES |
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The Israel Neonatal Network, which compiles the Israel National VLBW Infant Database, consists of the following participating centers: Assaf Harofeh Medical Center, Rishon Le Zion; Barzilay Medical Center, Ashkelon; Bikur Holim Hospital, Jerusalem; Bnei Zion Medical Center, Haifa; Carmel Medical Center, Haifa; English (Scottish) Hospital, Nazareth; French Hospital, Nazareth; Hadassa University Hospital Ein-Karem, Jerusalem; Hadassa University Hospital Har Hazofim, Jerusalem; Haemek Medical Center, Afula; Hillel Yafe Medical Center, Hadera; Italian Hospital, Nazareth; Kaplan Hospital, Rehovot; Laniado Hospital, Netanya; Maayanei Hayeshua Medical Center, Bnei-Brak; Meir Medical Center, Kefar Saba; Misgav Ladach Hospital, Jerusalem; Poriah Hospital, Tiberias; Rambam Medical Center, Haifa; Rivka Ziv Hospital, Zefat; Schneider Children’s Medical Center of Israel and Rabin Medical center (Beilinson Campus), Petach-Tikva; Shaare-Zedek Hospital, Jerusalem; Sheba Medical Center, Tel-Hashomer; Soroka Medical Center, Beer-Sheva; Sourasky Medical Center, Tel-Aviv; Western Galilee Medical Center; Nahariya; Wolfson Medical Center, Holon; Yoseftal Hospital, Eilat.
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ACKNOWLEDGMENTS |
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The Israel National VLBW database is partially funded by the Israel Center for Disease Control and the Ministry of Health.
We thank Professor Moshe Berant for helpful assistance in the preparation of this manuscript.
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FOOTNOTES |
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Received for publication May 2, 2001; Accepted Aug 15, 2001.
Reprint requests to (I.R.M.) Department of Neonatology, Rambam Medical Center, Bat-Galim, Haifa, 31096, Israel. E-mail: makhoul{at}rambam.health.gov.il.
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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