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Pattern and etiology of culture-proven early-onset neonatal sepsis: a five-year prospective study

Open ArchivePublished:June 29, 2011DOI:https://doi.org/10.1016/j.ijid.2011.05.004

      Summary

      Objectives

      To investigate the incidence of early-onset neonatal sepsis and identify the main pathogens over a 5-year period in Kuwait.

      Methods

      Blood samples were collected from all infants with any clinical or laboratory feature suggestive of sepsis, at the main maternity hospital in Kuwait. Cases of early-onset neonatal infection were defined as culture of a single potentially pathogenic organism from blood or cerebrospinal fluid from infants younger than 7 days of age, in association with clinical or laboratory findings consistent with infection.

      Results

      The overall incidence of early-onset neonatal infection was 2.7 (95% confidence interval (CI) 2.3–3.2) episodes per 1000 live-births. The case-fatality was 13.1% (95% CI 8.6–18.9%). Group B Streptococcus (GBS) accounted for 17.6% of infections among infants younger than 7 days (incidence 0.48 per 1000 live-births), but 38.1% of infections in the first 2 days of life. Neither the incidence of early-onset infection by GBS nor by Escherichia coli changed significantly over the study period.

      Conclusions

      Although the incidence of GBS infections was relatively low, GBS accounted for most early-onset infections. Intrapartum antibiotic prophylaxis against GBS should be strengthened. There was no evidence to suggest that early-onset infection due to non-GBS organisms such E. coli has increased in the last 5 years.

      Keywords

      1. Introduction

      Neonatal deaths account for one third of global child mortality and infection is the leading cause of death in the neonatal period.
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      but the impact on other non-GBS infections remains unclear. Concern has arisen about the possibility that intrapartum antibiotic prophylaxis may lead to an increase in the incidence of infections by non-GBS organisms or provoke antibiotic resistance.
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      Studies that have investigated this issue have reported conflicting findings. While some studies found no evidence that early-onset neonatal infections caused by non-GBS are increasing,
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      No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis over 18 years.
      others have reported an increase in Escherichia coli infections among low and very low birth weight infants.
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      Some reports have also suggested an increase in the resistance of E. coli to ampicillin, particularly among premature infants.
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      Neonatal early onset Escherichia coli sepsis: trends in incidence and antimicrobial resistance in the era of intrapartum antimicrobial prophylaxis.
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      Early-onset neonatal sepsis in the era of group B streptococcal prevention.
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      • Schuchat A.
      Trends in incidence and antimicrobial resistance of early-onset sepsis: population-based surveillance in San Francisco and Atlanta.
      Several studies have investigated early-onset neonatal infection in developing and developed countries. However, few studies have attempted to describe the pattern of neonatal infection in oil-rich countries in the Gulf region.
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      The pattern of organisms causing neonatal infections changes in the same place over a period of time.
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      Early onset neonatal sepsis.
      The incidence, the main pathogens, and the current trends in early-onset neonatal infection remain mostly unknown in this area. This study aimed to determine the incidence of early-onset neonatal sepsis and to identify the main pathogens and the trends over a 5-year period in Kuwait.

      2. Materials and methods

      Kuwait is a small country with a population of 3.5 million. Almost all deliveries occur in health facilities, and neonatal and infant mortality is around 5.6 and 9 per 1000 live-births, respectively, which is comparable to most developed countries.
      The study was conducted at the Kuwait Maternity Hospital, a major tertiary hospital where approximately one third of all deliveries in the country occur. There are approximately 12 000 deliveries per year at this hospital. Around 2.5% of all live births are very low birth weight (≤1500 g). Since 2005, mothers who are at risk of GBS infection have received ampicillin as intrapartum prophylaxis against GBS infection using a risk-based approach. Antibiotic treatment is initiated immediately among infants with suspected infection, particularly with the presence of risk factors such as premature rupture of membranes or maternal fever. Empirical antibiotic treatment usually starts with ampicillin and amikacin, but later on the treatment is guided by clinical and laboratory findings.
      For five consecutive years, from January 2005 to December 2009, blood samples were collected from all infants with any clinical or laboratory features suggestive of sepsis. Blood samples were obtained from a peripheral vein after skin disinfection with povidone iodine. Blood was cultured using the fully automated BACTEC blood culture system. Cerebrospinal fluid (CSF) samples were collected from all infants with culture-proven sepsis or before the initiation of antimicrobial therapy for clinically suspected infections.
      Data were collected prospectively on sex of the infant, gestational age, birth weight, age at which the positive blood culture was obtained, and clinical outcome, using a standard data collection form. Resistance or susceptibility of the isolated organisms to various antibiotics was recorded based on the routine laboratory testing in the hospital.
      Cases of early-onset neonatal infection were defined as the isolation of a single potentially pathogenic organism (bacterium or fungus) cultured from blood and/or CSF from infants who were younger than 7 days of age, in association with clinical and/or laboratory findings consistent with infection. Cases of meningitis were defined as CSF culture-positive or blood culture-positive plus pleocytosis. Likely contaminants were excluded based on the clinical judgment of the attending neonatologist. Coagulase-negative staphylococci (CoNS) were considered pathogenic only if blood culture was positive within 48 h of collection in an infant with clinical symptoms suggestive of sepsis.
      The cumulative incidence per year was calculated by dividing the number of infections by the number of live births at the hospital, excluding cases of early-onset infection among infants admitted from other hospitals (14 infections). Poisson distribution was used to calculate 95% confidence intervals (95% CI). Chi-square tests were used to evaluate the differences in proportions for categorical variables and the Mann–Whitney test was used to test the difference in medians for continuous variables. Chi-square for trends was used to test for linear trends in the incidence of early-onset neonatal infections over the study period. The study was approved by the ethics committee at the Faculty of Medicine, Kuwait University.

      3. Results

      During the 5-year study period, there were 56 134 live births and a total of 153 episodes of early-onset sepsis were identified, of which seven (4.6%) infections were identified in both blood and CSF. Of 153 early-onset infections, 83 (54.2%) occurred in males. The overall incidence in the study period was 2.7 (95% CI 2.3–3.2) infections per 1000 live-births, with a case-fatality of 13.1% (95% CI 8.6–18.9%). The incidence of early-onset neonatal infections during the study period is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Incidence of early-onset neonatal infections among infants aged younger than 7 days between 2005 and 2009.
      GBS accounted for 17.6% of all early-onset neonatal infections in infants younger than 7 days (incidence 0.48 per 1000 live-births), while E. coli caused 9.8% (see Table 1). However, GBS contributed to 32.0% of neonatal infections among infants in the first 3 days of life and to 38.1% in the first 2 days of life (see Table 1). Only three infections due to GBS occurred among infants 4–7 days of age. CoNS caused less than 10% of infections in babies less than 2 days of age. All Gram-negative bacillary infections (i.e., Klebsiella spp, E. coli, Acinetobacter spp, Pseudomonas spp, Enterobacter spp, and other Gram-negative bacteria) accounted for 39.2% (n = 60) of infections among infants younger than 7 days, but 33.3% (n = 21) of infections among infants in the first 2 days of life. There were no Candida infections among infants in the first 3 days of life.
      Table 1Organisms causing early-onset infection in the neonatal period in Kuwait, 2005–2009
      OrganismAge ≤2 days, n (%)Age ≤3 days, n (%)Age <7 days, n (%)
      Group B Streptococcus24 (38.1)24 (32.0)27 (17.6)
      Escherichia coli8 (12.7)8 (10.7)15 (9.8)
      Klebsiella4 (6.4)8 (10.7)23 (15.0)
      Coagulase-negative staphylococci5 (7.9)10 (13.3)35 (22.9)
      Pseudomonas2 (3.2)2 (2.7)5 (3.3)
      Acinetobacter1 (1.6)2 (2.7)8 (5.2)
      Enterobacter1 (1.6)2 (2.7)4 (2.6)
      Staphylococcus aureus1 (1.6)1 (1.3)4 (2.6)
      Other Gram-positive bacteria12 (19.0)13 (17.3)20 (13.1)
      Other Gram-negative bacteria5 (7.9)5 (6.7)5 (3.3)
      Candida0 (0)0 (0)7 (4.6)
      Total63 (100)75 (100)153 (100)
      Figure 2 shows the incidence of early-onset neonatal infections caused by GBS and non-GBS bacteria over the 5-year period. While the incidence of non-GBS infection varied from one year to another, the incidence of GBS infection did not change significantly over the study period (Chi square test for linear trend, p = 0.22). There was no clear trend in the early-onset neonatal infections caused by E. coli during the study period. The incidence of early-onset E. coli infection was 0.17, 0.52, 0.0, 0.27, and 0.37 infections per 1000 live-births in years 2005, 2006, 2007, 2008, and 2009, respectively (p = 0.78).
      Figure thumbnail gr2
      Figure 2Incidence of early-onset neonatal infections caused by GBS and non-GBS bacteria among infants aged younger than 7 days between 2005 and 2009.
      Comparison between infants with early-onset neonatal infections caused by GBS and infants with early-onset infections caused by non-GBS is shown in Table 2. Infants with early-onset infections due to GBS were significantly more likely to be born after 37 weeks of gestation and to weigh 2500 g or above when compared to infants with early-onset infections caused by non-GBS. Case-fatality was not significantly different between early-onset infections caused by GBS and those caused by non-GBS (7.4% vs. 13.5%; p = 0.58).
      Table 2Characteristics of infants younger than 7 days of age with early-onset neonatal infections (GBS and non-GBS), Kuwait, 2005–2009
      VariableGBS (n = 27)Non-GBS (n= 126)p-Value
      Sex (male)51.8%54.8%0.800
      Gestational age (weeks)Median (IQR)38.0 (37.0–40.0)35.0 (30.0–38.0)0.002
      ≥3781.5%42.1%0.001
      32–367.4%29.4%
      <3211.1%28.6%
      Birth weight (g)Median (IQR)2900 (2290–3520)2125 (1295–3150)0.008
      ≥250074.1%40.5%0.006
      1500–249914.8%27.0%
      <150011.1%32.5%
      Fatal outcome7.4%13.5%0.58
      GBS, group B Streptococcus; IQR, interquartile range.
      All % are column percents.
      Of 27 GBS infections, 17 (63.0%) were resistant to gentamicin, but all were sensitive to ampicillin and cefotaxime. Of 23 early-onset infections caused by Klebsiella species, two (8.7%) were resistant to cefotaxime and three (13.0%) resistant to gentamicin, but all were resistant to ampicillin. Of 15 early-onset infections caused by E. coli, 14 (93.3%) were resistant to ampicillin, but only one (6.7%) was resistant to gentamicin. Of 60 Gram-negative bacillary infections, 19 (31.6%) were resistant to cefotaxime and six (10%) were resistant to gentamicin.

      4. Discussion

      Like other oil-rich countries in the Gulf region, Kuwait has achieved low infant and neonatal mortality rates, comparable to developed nations. This study aimed to describe the pattern and trends of early-onset neonatal infections over a period of 5 years in Kuwait.
      During the study period, the overall incidence of culture-proven early-onset neonatal infection among infants younger than 7 days was 2.7 infections per 1000 live-births. The incidence was 1.3 infections per 1000 live-births in the first 3 days of life and 1.1 per 1000 live-births in the first 2 days of life. This is similar to the incidence reported from developed countries,
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      Long-term epidemiology of neonatal sepsis: benefits and concerns. Commentary on van den Hoogen A, et al.: long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative agents (Neonatology 2010;97:22–28).
      but lower than that reported from developing countries such as India
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      In our setting, GBS was also found to be responsible for the majority of early-onset neonatal infections, particularly those that occurred within the first 2 or 3 days of life. However, the incidence of early-onset neonatal infection due to GBS was comparable to that reported from the USA
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      and was less than 0.5 per 1000 live-births from 2007 onwards (see Figure 2). The incidence of GBS infection did not change significantly between 2005 and 2009. Prior to the implementation of intrapartum antibiotic prophylaxis against GBS in 2005, the incidence of GBS infection was estimated to be 1 per 1000 live-births.
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      With the lack of rigorous assessment of GBS infection before the implementation of prophylaxis against GBS, it is not clear how maternal chemoprophylaxis has affected the burden of GBS infection in Kuwait. Like other settings, it is possible that we have underestimated the actual burden of GBS infection owing to the existence of probable culture-negative GBS sepsis
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      In our study, the overall incidence of early-onset neonatal infection varied from one year to another during the study period, mainly due to changes in the incidence of infection by CoNS and other non-GBS bacteria after the second or third day of life. The increase in the relative importance of CoNS with postnatal age suggests that these infections are due to post-partum exposure in the hospital (nosocomial infection) and this probably supports the definition of early neonatal infection as that occurring in the first 2 days of life.
      There is a consensus that intrapartum antibiotic prophylaxis has reduced the early-onset neonatal infections caused by GBS,
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      • Eberly M.D.
      • Rajnik M.
      The effect of universal maternal screening on the incidence of neonatal early-onset group B streptococcal disease.
      • Puopolo K.
      • Eichenwald E.
      No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis over 18 years.
      but the impact of this intervention on other causes of neonatal infection remains unclear.
      • Alarcon A.
      • Pena P.
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      • Omenaca F.
      Neonatal early onset Escherichia coli sepsis: trends in incidence and antimicrobial resistance in the era of intrapartum antimicrobial prophylaxis.
      One concern is that early-onset neonatal infections caused by non-GBS organisms may increase as a result of intrapartum antibiotic prophylaxis. Similar to other studies,
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      our data do not suggest an increase in the incidence of early neonatal infections due to non-GBS organisms such as E. coli, although calculations are based on small numbers.
      Previous studies have reported an increase in ampicillin-resistant E. coli particularly among preterm infants
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      • Sancha M.
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      • Schuchat A.
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      and where ampicillin is used as intrapartum prophylaxis.
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      In our setting, where ampicillin is used in intrapartum prophylaxis, almost all E. coli infections were resistant to ampicillin. Although we agree with the comment
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      • Pena P.
      • Salas S.
      • Sancha M.
      • Omenaca F.
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      • Hyde T.B.
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      • Reingold A.
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      • O’Brien K.L.
      • Schuchat A.
      Trends in incidence and antimicrobial resistance of early-onset sepsis: population-based surveillance in San Francisco and Atlanta.
      that this may reflect the overall trend for antibiotic resistance in the community as a whole, rather than being a result of using intrapartum antibiotic prophylaxis, we support the recent conclusion that obstetricians should consider preferential use of penicillin G for GBS prophylaxis.
      • Puopolo K.
      • Eichenwald E.
      No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis over 18 years.
      When we compared GBS infections with non-GBS infections, GBS infections tended to occur earlier (first 2 or 3 days of life) than non-GBS infections. Furthermore, infants with early-onset infections caused by non-GBS were more often born before 37 weeks of gestation and were of low birth weight, whereas early-onset infections caused by GBS usually affected full-term babies. This pattern is similar to that reported from other settings.
      • Hyde T.B.
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      • Schuchat A.
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      • O'Sullivan M.J.
      • et al.
      Risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case–control study.
      Unlike India where Klebsiella and Pseudomonas are the most common causes of early-onset neonatal infection,
      • Chacko B.
      • Sohi I.
      Early onset neonatal sepsis.
      • Tallur S.S.
      • Kasturi A.V.
      • Nadgir S.D.
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      Clinico-bacteriological study of neonatal septicemia in Hubli.
      in our study Klebsiella accounted for approximately 15% of early-onset infections among infants younger than 7 days, but 6.4% among infants in the first 2 days of life.
      It has been suggested that studies based in tertiary units usually attract high numbers of preterm infants and urban patients of high socioeconomic status, and are thus not representative of early-onset neonatal illness at the community level.
      • Black R.E.
      • Morris S.S.
      • Bryce J.
      Where and why are 10 million children dying every year?.
      One of the strengths of our study is that the whole population lives in urban settings and 100% of births occur in hospitals, one third of which occur in the study hospital, suggesting high generalizability of the findings to Kuwait. It is known that intrapartum prophylaxis with ampicillin has been recommended since 2005 for all mothers who are at risk of GBS. One of the limitations of this study is the lack of data on the actual extent of use of intrapartum antibiotic prophylaxis during the study period.
      In conclusion, although the incidence of early-onset neonatal infection due to GBS was low in Kuwait and comparable to that in developed countries, GBS accounted for most early-onset infections. The incidence of early-onset neonatal infection due to GBS did not change significantly over the study period. Intrapartum antibiotic prophylaxis against GBS should be audited and possibly strengthened to further reduce the burden of GBS in Kuwait. There was no evidence to suggest that early-onset neonatal infection due to non-GBS organisms such as E. coli has increased in the last 5 years.

      Acknowledgement

      This work was supported by a grant from Kuwait University, Research Department (MK01/10).
      Conflict of interest: No conflict of interest to declare.

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