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Nosocomial Infection in the NICU: A Medical Complication or Unavoidable Problem?

From The Pediatrix-Obstetrix Center for Research and Education.

Disclosures: None.

Reese Clark MD1,2, Richard Powers MD3, Robert White MD4, Barry Bloom MD1,5, Pablo Sanchez MD6
and Daniel K Benjamin Jr MD, MPH, PhD2

1. 1Pediatrix Medical Group, Inc. (R.C., B.B.), Sunrise, FL, USA

2. 2Duke University Medical Center (R.C., D.K.B.), Durham, NC, USA

3. 3Children's Mercy Hospital (R.P.), Oakland, CA, USA

4. 4Memorial Hospital of South Bend (R.W.), South Bend, IN, USA

5. 5Wesley Medical Center (B.B.), Wichita, KS, USA

6. 6University of Texas Southwestern Medical Center (P.S.), Dallas, TX, USA.

Correspondence: Reese H. Clark, MD, Director of Research, Pediatrix Medical Group, Inc., 1301 Concord
Terrace, Sunrise, FL 33323-2825, USA.

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Abstract

Nosocomial sepsis is a serious problem for neonates who are admitted for intensive care. As it is
associated with increases in mortality, morbidity, and prolonged length of hospital stay, both the human
and fiscal costs of these infections are high. Although the rate of nosocomial sepsis increases with the
degree of both prematurity and low birth weight, no specific lab test has been shown to be very useful
in improving our ability to predict who has a "real" blood-stream infection and, therefore, who needs to
be treated with a full course of antibiotics. As a result, antibiotic use is double the rate of "proven"
sepsis and we are facilitating the growth of resistant organisms in the neonatal intensive care unit. The
purpose of this article is to review the topic of nosocomial infections in neonates.
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INTRODUCTION

Definition

The US Department of Health and Human Services Centers for Disease Control and Prevention defines
nosocomial infection as an infection during hospitalization that was not present or incubating at the
time of admission.1 Most authors describing neonatal infection find it convenient to use the terms
"early-onset" and "late-onset" infection. Early-onset infections are confirmed infections in the first three
days of life, whereas late-onset infections occur after the third day. Nosocomial infection is equivalent
to late-onset, or infection after the first 72 hours of life.2 Infection rates may be stated as percent of
admissions, percent of liveborns, or by number of infections per 1000 patient days. As 20 to 30% of
preterm neonates may have two or more nosocomial infection episodes, infection rates per patient day
probably gives a more accurate idea of magnitude, whereas rates per patient group (admissions,
liveborns, birth-weight range, gestational age range) give a good idea of attack or incidence rates.

It is also important to distinguish nosocomial infection, which usually means any infection (blood
stream, pneumonia, central nervous system, or urinary tract), from nosocomial sepsis, which usually
relates primarily to blood-stream infection. Another challenge is the definition of what constitutes
infection. Most reports define confirmed nosocomial infection as a positive blood, spinal fluid, or urine
culture. A few reports make the distinction between a positive culture with clinical signs of infection, a
positive culture with no signs of infection, or signs of infection with a negative culture.

While pneumonia, urinary tract infections, meningitis, and sepsis are all important causes of nosocomial
infection, sepsis is the most commonly reported. Additionally, sepsis frequently accompanies
pneumonia, urinary tract infections, and meningitis. Therefore, the goal of this paper is to review the
topic of nosocomial sepsis (clinical presentation, diagnosis, and pre-disposing factors).

Incidence

The neonatal intensive care unit (NICU) nosocomial infection rate has increased over the past
decade.2,3 The total number of neonates who develop nosocomial infection per admission varies from
6.24 to 33%5 or, when reported as total infections per 1000 patient days, the rate varies from 4.84 to
22.6 Blood-stream infections (nosocomial sepsis) vary from 3 to 28% of admissions.4,5,7,8,9 The
variability in infection rates depends on the gestational age, distribution of the infants surveyed for the
report, and on the specific environment and care practices.10 Even when statistical correction has been
made for case mix, the variability between centers generally remains.5,11

While "confirmed" nosocomial infection occurs in approximately 30% of very-low-birth-weight


neonates, antibiotic use (especially vancomycin) is much more common (see Figure 1). This suggests
that suspected nosocomial infection is a much more frequent occurrence than "confirmed" nosocomial
infection. Suspected nosocomial infection often drives the use of broad-spectrum antibiotics, which may
predispose patients to more serious infections like candidemia and Gram-negative sepsis. The real
problem is that we have a very limited gold standard in diagnosing true sepsis; no lab test identifies all
the patients that need to be treated and some degree of "overtreatment" is unavoidable, even if risky,
in terms of subsequent infections.

Figure 1.

Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require
assistance to access this image, please contact help@nature.com or the author

The gestational age-specific rates of reported use of vancomycin and blood cultures from Pediatrix
Medical Group, Inc.

Full figure and legend (78K)

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CLINICAL PRESENTATION, ORGANISMS, AND OUTCOMES

The presentations and outcomes of neonates with specific organisms as the cause for their sepsis are
unique to the organism.

Presentation

The dominant presenting features of septicemia or sepsis include: increasing apnea (55%); feeding
intolerance, abdominal distension, or guaiac-positive stools (43%); need for increased respiratory
support (29%); and lethargy and hypotonia (23%).12 An abnormal white blood-cell count (46%),
unexplained metabolic acidosis (11%) or hyperglycemia (10%) are the most common laboratory
indicators.12 Gram-negative nosocomial sepsis often presents with a more rapid clinical deterioration
and is commonly associated with shock and coagulation problems.13 In addition, the pathogens
associated with fulminant (lethal within 48 hours) late-onset sepsis are most often Gram-negative
organisms. The frequency of fulminant sepsis is the highest for Pseudomonas sp, 20 of 36 (56%; 95% CI:
38 to 72%), and lowest for coagulase-negative Staphylococci, four of 277 (1%; 95% CI: 0 to 4%).13

A set of clinical signs (apnea, bradycardia, etc.) and laboratory values (leukocytosis, immature white
blood cells, neutropenia, and elevated c-reactive protein or interleukins) suggest the diagnosis of sepsis,
but they have poor positive predictive value.12 Despite these limitations, the combination of clinical
signs and laboratory findings has been used to define "clinical sepsis" and is often used to decide whom
to treat and when to stop treatment. The uncertainty generated by the absence of good predictors for
nosocomial sepsis is one of the causes for the overuse of antibiotics.14

Organisms

Gram-positive and Gram-negative bacteria account for 55.4 and 31.2% of microbes, respectively.15 The
most common organisms are Staphylococci, Escherichia coli and Klebsiella, and Candida (Figure 2).1,15
In addition to the pathogens that are easily grown in blood-culture media, other organisms that are
fastidious organisms (e.g., Mycoplasma and Ureaplasma species) may be missed.

Figure 2.

Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require
assistance to access this image, please contact help@nature.com or the author

The organisms reported in neonates with nosocomial sepsis (adapted from Stoll et al.).

Full figure and legend (98K)

Outcomes

Mortality after Gram-negative sepsis (26.2%) and Candida sepsis (27.6%) is similar and significantly
higher than with Gram-positive sepsis (8.7%).15 However, the virulence of organisms like coagulase-
negative Staphylococci may be underestimated because many cultures that grow Gram-positive bacteria
represent skin contaminants rather than true blood-stream infections.
Fungal sepsis is more indolent than Gram-negative sepsis and more fulminant than coagulase-negative
Staphylococci. It is commonly associated with thrombocytopenia and occurs more often in neonates
with a birth weight <0.750 kg and those who are very premature (estimated gestational age <26
weeks).16 Acquired nosocomial Candida sepsis is associated with significant morbidity.17 Data on 27
Candida-infected survivors showed that all of them developed chronic lung disease compared with 33%
in the control cases (p<0.01). The survivors also had a higher incidence of periventricular leukomalacia
(26 vs 12%, p=0.06); an increase in severe retinopathy of prematurity (22 vs 9%, p=0.04); and adverse
neurological outcomes (60 vs 35%) compared to neonates in the control group.17

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DIAGNOSIS OF NOSOCOMIAL SEPSIS

The gold standard for the diagnosis of nosocomial sepsis remains the finding of a positive blood culture
for a known pathogen. There are two common errors that are made in evaluating neonates with
possible sepsis. The reduction of both types of these errors is important.

Type I Errors (False Positive, Contaminant)

A type I error (false positive, contaminant) is accepting a positive culture as real when the patient is not
truly bacteremic. Type I errors lead to the overuse of antibiotics and can subsequently increase the risks
for more serious infections.

The best way to avoid type I errors is to prevent coagulase-negative Staphylococci contamination of
blood cultures. Prepping the skin prior to puncture requires broad-spectrum site antisepsis; however,
the skin of the neonate, especially the preterm neonate, is more susceptible to damage from antiseptic
agents. Additionally, the thinner layers of epidermis in premature neonates also contribute to the
enhanced absorption of disinfectants.18,19,20

Four agents have been shown to be effective at disinfecting the skin: povidone-iodine, tincture of iodine,
70% isopropyl alcohol, and chlorhexidine gluconate.21,22,23 Of these, chlorhexidine gluconate and
povidone-iodine appear to be the best agents after taking into account the risks of systemic absorption
and local skin irritation. A 30-second exposure time is recommended, followed by removal with sterile
water or saline.24,25,26
It is equally important to avoid contamination of the culture from a deep-line hub. Use of microbiologic
techniques to differentiate a contaminated specimen from a real specimen includes colony counts and
time to detection, both of which can help differentiate true sepsis from line contamination.27,28,29 It is
also possible to reduce the risk of a type I error by limiting the number of personnel who draw cultures,
needle sticks, and times that the deep-line hub is entered.

Type II Errors (False Negative, Inadequate Culture)

Type II errors (false negative, inadequate culture) occur when a negative blood culture result is accepted
as proof that the patient is not infected when, in fact, the patient has true bacteremia that has not been
detected by the blood culture. Consequently, type II errors can lead to undertreatment of neonates with
life-threatening sepsis.

The best way to reduce type II errors is to obtain adequate blood culture specimens. Two variables
determine the volume of blood necessary for an adequate sample: the sensitivity of the detection
system and the probability of finding at least one microorganism in the blood culture bottle (density of
bacteremia or fungemia in the blood sample).30 Obtaining small volumes of blood in the face of low-
density bacteremia or fungemia runs an appreciable risk of not finding an organism in the culture
bottle.30,31 In neonatal and pediatric case control studies, as many as 60% of culture results will be
falsely negative if only 0.5 ml of blood is obtained in low-colony-count sepsis.30,32,33 Obtaining 1 ml of
blood for culture improves culture yields in neonates, but this can represent a significant blood-volume
loss for very-low-birth-weight neonates.30,32,33

The use of ancillary tests (C-reactive protein,34,35 white blood count,36 interleukin-6,37,38 etc.) may
increase the odds of correctly identifying those patients who are septic, but who have negative culture
results due to problems with blood sampling. Unfortunately, these ancillary tests may have a good
negative predictive value (i.e., normal values are reassuring that blood-stream infection is not present)
but low positive predictive value.39 The sensitivity, specificity, and negative and positive predictive
values are all dependent on serum levels used to define abnormal and the number of times the test is
repeated.34,35,36,40,41 High levels of all of these tests can be seen in neonates who do not have a
blood-stream infection.

Serial C-reactive protein measurements are more valuable than single measurements, and, in patients
who are suspected of having sepsis, may be useful in conjunction with leukocyte counts in making the
decision to withhold or stop treatment after negative blood cultures, but they should not be used, in
isolation, to decide who should receive a full course of antibiotics.35,42,43,44,45 In very-low-birth-
weight infants, fungal and Gram-negative pathogens are associated with a lower platelet count and
more prolonged thrombocytopenia compared with Gram-positive pathogens; therefore, changes in
platelet counts may be useful as a marker for these more serious infections.16,46

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PREDISPOSING FACTORS ASSOCIATED WITH NOSOCOMIAL SEPSIS

Host-related

Premature and very-low-birth-weight infants appear to be particularly vulnerable to nosocomial sepsis


due to their relative immune deficiency (e.g., poor phagocytosis, hypogammaglobinemia, etc.).15
Numerous other factors associated with an increased risk of nosocomial infection include: neutropenia
associated with hypertensive mother,47,48 degree of prematurity,1,7,15,49 prolonged rupture of
membranes,50 and maternal disease or infection.50 Male gender and decreased baseline serum
immunoglobulin G concentrations were also associated with an increased risk of blood culture proven
sepsis.12

Clinical practice-related

Clinical practices can also be associated with an increased risk of acquiring an infection. Empirical or
prior antibiotic use51,52 and history of treatment with dexamethasone increases the risk by as much as
60%.53 Analysis of bacteremia/sepsis and meningitis among infants enrolled in a clinical trial evaluating
the efficacy of postnatal steroids showed that infants randomly assigned to treatment with
dexamethasone (started at 2 weeks after birth at 0.25 mg/kg/dose every 12 hours, then tapered over 2
weeks) were significantly more likely than neonates assigned to placebo to have a positive blood culture
result (48 vs 30%, RR 1.62; 95% CI=1.20 to 2.18) and definite bacteremia/sepsis/meningitis (22 vs 14%,
RR 1.60; 95% CI=1.02 to 2.51).53 H2 blocker therapy (before study entry) was also associated with a
significantly increased risk of definite infection (adjusted OR=3.19, 95% CI=1.38 to 7.38).53 In addition,
cesarean-section delivery has been reported to be associated with a significantly decreased risk of
nosocomial sepsis (adjusted OR=0.56, 95% CI=0.33 to 0.93).53

Clinical practice factors associated with an increased likelihood that the neonate has nosocomial fungal
sepsis include: need for mechanical ventilation,1,7,15,49 exposure to a central venous catheter,54,55
catheter hub manipulation and colonization,56,57,58 prolonged exposure to total parenteral nutrition
and/or intravenous lipids,54,59 delayed enteral feedings,54 multiple blood cultures in the preceding 14
days, and exposure to broad-spectrum antibiotics (especially third-generation
cephalosporins).60,61,62,63,64,65,66,67,68 In addition, heparin may elicit a superantigen response
(toxic shock) from Candida albicans and increase the virulence of Candida.69
Understanding these risk factors and adjusting clinical practice to reduce the risk may reduce the
incidence of nosocomial infection and improve outcomes.

Environmental Factors

In the 1970 s, most NICUs maintained near-operating-room conditions based on the concept that the
greatest infection risk comes from the outside. In the 1980 s, recognition that most infection comes
from within the NICU led to relaxation of parental visiting limitations. It was also in the 1980 s that
cramped conditions were recognized as fostering infection, resulting in an increase in floor space
allocation. In the 1990 s, there was increased recognition of parental needs for space and privacy at the
bedside and studies have shown that parental contact was not harmful, even when it is skin-to-skin.

Today, justified concerns remain about infection entering the NICU from the community (primarily viral-
respiratory syncytial virus, Rotavirus, "colds and flu", and varicella) and there are major concerns for
cross-contamination (e.g., methicillin-resistant Staph aureus) and colonizing organisms becoming
invasive (e.g., Staph epidermidis, Candida), especially among very premature and extremely-low-birth-
weight neonates.

Numerous NICU outbreaks of infection have been reported. The vast majority of clustered cases for any
pathogen have been found to be genetically similar strains with transmission due to cross-
contamination from a small number of health care workers. Clusters of cases with cytomegalovirus and
coagulase-negative Staphylococci may also originate from multiple strains.70 Reservoirs for transmission
are numerous: laundry,71 soap bottles and sinks,72,73 hand lotion,74 pet dog,75 bed toys,76 blood gas
analyzer,25,77 ventilator circuits,78 multi-use vials,79 sibling-to-mother-to-patient,80 water tap,81
hands,82,83 suction equipment,84 air conditioner,85 wooden tongue depressors,86 water bath for
blood products,87 expressed mother's milk,88,89 powdered milk,90,91,92 latex gloves,93
resuscitator,94 and saline for heparin dilution.95 About 85% of all NICU surfaces will grow nosocomial
pathogens, with over half contaminated by two or more pathogenic organisms.96

Central line-related factors

Gaynes et al.10 reported a median of 5.1 blood stream infections per 1000 umbilical- or central-catheter
days for the 1500-g-or-more birth-weight group and 14.6 blood stream infections per 1000 umbilical- or
central-catheter days for the less-than-1500-g birth-weight group. Both hyperalimentation fluids and
intralipids can serve as culture media for bacteria and fungus.97,98,99,100 In a retrospective analysis of
the relationship between lipids and sepsis in very low-birth-weight infants, two factors were shown to
be independent of gestational age and birth weight in increasing the risk of line infection intravenous
lipid use and any surgically or percutaneous placed central catheter.99 Infants with coagulase-negative
Staphylococci bacteremia are five times as likely as controls to have received intravenous lipid emulsion
before the onset of bacteremia and 56% of all cases of nosocomial bacteremia could be associated with
lipid administration.100

As lipids are a critical part of parenteral nutrition in premature infants, they remain an essential part of
early management. Clinicians must balance the risk of infection vs the benefit of enhanced caloric intake
when deciding how early to curtail the use of intravenous lipids. Malnutrition also increases the risk of
opportunistic infections.

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CONCLUSIONS

Nosocomial sepsis is a serious problem for neonates who are admitted for intensive care. Since it is
associated with increases in mortality, morbidity, and prolonged length of hospital stay, both the human
and fiscal costs of these infections are high. Although the rate of nosocomial sepsis increases with the
degree of both prematurity and low birth weight, no specific lab test has been shown to be very useful
in improving our ability to predict who has a "real" blood-stream infection and, therefore, who needs to
be treated with a full course of antibiotics. As a result, antibiotic use is double the rate of "proven"
sepsis and we are facilitating the growth of resistant organisms in the neonatal intensive care unit. The
purpose of this article is to review the topic of nosocomial infections in neonates. This paper represents
the first in a two-part series. In our next paper, we will review strategies for the prevention and
treatment of nosocomial infection.

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References

1. Lopez Sastre JB, Coto CD, Fernandez CB. Neonatal sepsis of nosocomial origin: an epidemiological
study from the "Grupo de Hospitales Castrillo". J Perinat Med 2002;30:149157. | PubMed |

2. Craft A, Finer N. Nosocomial coagulase negative staphylococcal (CoNS) catheter-related sepsis in


preterm infants: definition, diagnosis, prophylaxis, and prevention. J Perinatol 2001;21:186192. |
Article | PubMed |
3. Zafar N, Wallace CM, Kieffer P, Schroeder P, Schootman M, Hamvas A. Improving survival of
vulnerable infants increases neonatal intensive care unit nosocomial infection rate. Arch Pediatr Adolesc
Med 2001;155:10981104. | PubMed |

4. Ferguson JK, Gill A. Risk-stratified nosocomial infection surveillance in a neonatal intensive care unit:
report on 24 months of surveillance. J Paediatr Child Health 1996;32:525531. | PubMed |

5. Hentschel J, de Veer I, Gastmeier P, Ruden H, Obladen M. Neonatal nosocomial infection


surveillance: incidences by site and a cluster of necrotizing enterocolitis. Infection 1999;27:234238. |
PubMed |

6. Drews MB, Ludwig AC, Leititis JU, Daschner FD. Low birth weight and nosocomial infection of
neonates in a neonatal intensive care unit. J Hosp Infect 1995;30:6572. | Article | PubMed |

7. Nagata E, Brito AS, Matsuo T. Nosocomial infections in a neonatal intensive care unit: incidence and
risk factors. Am J Infect Control 2002;30:2631. | Article | PubMed |

8. Horbar JD, Rogowski J, Plsek PE, et al. Collaborative quality improvement for neonatal intensive
care. NIC/Q Project Investigators of the Vermont Oxford Network. Pediatrics 2001;107:1422. | Article |
PubMed | ISI | ChemPort |

9. Berger A, Salzer HR, Weninger M, Sageder B, Aspock C. Septicaemia in an Austrian neonatal


intensive care unit: a 7-year analysis. Acta Paediatr 1998;87:10661069. | Article | PubMed |

10. Gaynes RP, Edwards JR, Jarvis WR, Culver DH, Tolson JS, Martone WJ. Nosocomial infections among
neonates in high-risk nurseries in the United States. National Nosocomial Infections Surveillance System.
Pediatrics 1996;98:357361. | PubMed | ChemPort |

11. Sohn AH, Garrett DO, Sinkowitz-Cochran RL, et al. Prevalence of nosocomial infections in neonatal
intensive care unit patients: Results from the first national point-prevalence survey. J Pediatr
2001;139:821827. | Article | PubMed | ChemPort |

12. Fanaroff AA, Korones SB, Wright LL, et al. Incidence, presenting features, risk factors and
significance of late onset septicemia in very low birth weight infants. The National Institute of Child
Health and Human Development Neonatal Research Network. Pediatr Infect Dis J 1998;17:593598. |
Article | PubMed | ISI | ChemPort |

13. Karlowicz MG, Buescher ES, Surka AE. Fulminant late-onset sepsis in a neonatal intensive care unit,
1988-1997, and the impact of avoiding empiric vancomycin therapy. Pediatrics 2000;106:13871390. |
Article | PubMed | ChemPort |

14. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the
experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285291. | Article | PubMed
| ISI |
15. Makhoul IR, Sujov P, Smolkin T, Lusky A, Reichman B. Epidemiological, clinical, and microbiological
characteristics of late-onset sepsis among very low birth weight infants in Israel: a national survey.
Pediatrics 2002;109:3439. | Article | PubMed |

16. Benjamin Jr DK, DeLong ER, Steinbach WJ, Cotton CM, Walsh TJ, Clark RH. Empirical therapy for
neonatal candidemia in very low birth weight infants. Pediatrics 2003;112:543547. | Article | PubMed
| ISI |

17. Friedman S, Richardson SE, Jacobs SE, O'Brien K. Systemic Candida infection in extremely low birth
weight infants: short term morbidity and long term neurodevelopmental outcome. Pediatr Infect Dis J
2000;19:499504. | Article | PubMed | ChemPort |

18. Darmstadt GL, Dinulos JG. Neonatal skin care. Pediatr Clin North Am 2000;47:757782. | PubMed |
ChemPort |

19. Lund C, Kuller J, Lane A, Lott JW, Raines DA. Neonatal skin care: the scientific basis for practice. J
Obstet Gynecol Neonatal Nurs 1999;28:241254. | PubMed | ChemPort |

20. Lund C, Kuller J, Lane A, Lott JW, Raines DA. Neonatal skin care: the scientific basis for practice.
Neonatal Netw 1999;18:1527. | PubMed |

21. Calfee DP, Farr BM. Comparison of four antiseptic preparations for skin in the prevention of
contamination of percutaneously drawn blood cultures: a randomized trial. J Clin Microbiol
2002;40:16601665. | Article | PubMed |

22. Trautner BW, Clarridge JE, Darouiche RO. Skin antisepsis kits containing alcohol and chlorhexidine
gluconate or tincture of iodine are associated with low rates of blood culture contamination. Infect
Control Hosp Epidemiol 2002;23:397401. | PubMed |

23. Humar A, Ostromecki A, Direnfeld J, et al. Prospective randomized trial of 10% povidone-iodine
versus 0.5% tincture of chlorhexidine as cutaneous antisepsis for prevention of central venous catheter
infection. Clin Infect Dis 2000;31:10011007. | Article | PubMed |

24. Mimoz O, Karim A, Mercat A, et al. Chlorhexidine compared with povidone-iodine as skin
preparation before blood culture. A randomized, controlled trial. Ann Intern Med 1999;131:834837. |
PubMed |

25. Garland SM, Mackay S, Tabrizi S, Jacobs S. Pseudomonas aeruginosa outbreak associated with a
contaminated blood-gas analyser in a neonatal intensive care unit. J Hosp Infect 1996;33:145151. |
PubMed |

26. Malathi I, Millar MR, Leeming JP, Hedges A, Marlow N. Skin disinfection in preterm infants. Arch Dis
Child 1993;69:312316. | PubMed | ISI | ChemPort |
27. Garland JS, Henrickson K, Maki DG. The 2002 Hospital Infection Control Practices Advisory
Committee Centers for Disease Control and Prevention guideline for prevention of intravascular device-
related infection. Pediatrics 2002;110:10091013. | Article | PubMed |

28. Kilbride HW, Powers R, Wirtschafter DD, et al. Evaluation and development of potentially better
practices to prevent neonatal nosocomial bacteremia. Pediatrics 2003;111:e50418. | PubMed |

29. Benjamin Jr DK, Miller W, Garges H, et al. Bacteremia, central catheters, and neonates: when to pull
the line. Pediatrics 2001;107:12721276. | PubMed |

30. Schelonka RL, Chai MK, Yoder BA, Hensley D, Brockett RM, Ascher DP. Volume of blood required to
detect common neonatal pathogens. J Pediatr 1996;129:275278. | Article | PubMed | ChemPort |

31. Kellogg JA, Ferrentino FL, Goodstein MH, Liss J, Shapiro SL, Bankert DA. Frequency of low level
bacteremia in infants from birth to two months of age. Pediatr Infect Dis J 1997;16:381385. | Article |
PubMed | ChemPort |

32. Kennaugh JK, Gregory WW, Powell KR, Hendley JO. The effect of dilution during culture on
detection of low concentrations of bacteria in blood. Pediatr Infect Dis 1984;3:317318. | PubMed |

33. Brown DR, Kutler D, Rai B, Chan T, Cohen M. Bacterial concentration and blood volume required for
a positive blood culture. J Perinatol 1995;15:157159. | PubMed |

34. Hengst JM. The role of C-reactive protein in the evaluation and management of infants with
suspected sepsis. Adv Neonatal Care 2003;3:313. | Article | PubMed |

35. Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the
diagnosis of neonatal infection. Pediatrics 1998;102:E41. | Article | PubMed | ChemPort |

36. Engle WD, Rosenfeld CR, Mouzinho A, Risser RC, Zeray F, Sanchez PJ. Circulating neutrophils in
septic preterm neonates: comparison of two reference ranges. Pediatrics 1997;99:E10. | Article |
PubMed | ChemPort |

37. Resch B, Gusenleitner W, Muller WD. Procalcitonin and interleukin-6 in the diagnosis of early-onset
sepsis of the neonate. Acta Paediatr 2003;92:243245. | PubMed |

38. Gonzalez BE, Mercado CK, Johnson L, Brodsky NL, Bhandari V. Early markers of late-onset sepsis in
premature neonates: clinical, hematological and cytokine profile. J Perinat Med 2003;31:6068. | Article
| PubMed | ISI |

39. Ottolini MC, Lundgren K, Mirkinson LJ, Cason S, Ottolini MG. Utility of complete blood count and
blood culture screening to diagnose neonatal sepsis in the asymptomatic at risk newborn. Pediatr Infect
Dis J 2003;22:430434. | Article | PubMed | ISI |

40. Nuntnarumit P, Pinkaew O, Kitiwanwanich S. Predictive values of serial C-reactive protein in


neonatal sepsis. J Med Assoc Thai 2002;85(Suppl 4):S11518. | PubMed |
41. Greenberg DN, Yoder BA. Changes in the differential white blood cell count in screening for group B
streptococcal sepsis. Pediatr Infect Dis J 1990;9:886889. | PubMed |

42. Chan DK, Ho LY. Usefulness of C-reactive protein in the diagnosis of neonatal sepsis. Singapore Med
J 1997;38:252255. | PubMed |

43. Wagle S, Grauaug A, Kohan R, Evans SF. C-reactive protein as a diagnostic tool of sepsis in very
immature babies. J Paediatr Child Health 1994;30:4044. | PubMed | ISI | ChemPort |

44. Mathers NJ, Pohlandt F. Diagnostic audit of C-reactive protein in neonatal infection. Eur J Pediatr
1987;146:147151. | Article | PubMed | ISI | ChemPort |

45. Pourcyrous M, Bada HS, Korones SB, Baselski V, Wong SP. Significance of serial C-reactive protein
responses in neonatal infection and other disorders. Pediatrics 1993;92:431435. | PubMed | ISI |
ChemPort |

46. Guida JD, Kunig AM, Leef KH, McKenzie SE, Paul DA. Platelet count and sepsis in very low birth
weight neonates: is there an organism-specific response? Pediatrics 2003;111:14111415. | Article |
PubMed | ISI |

47. Gray PH, Rodwell RL. Neonatal neutropenia associated with maternal hypertension poses a risk for
nosocomial infection. Eur J Pediatr 1999;158:7173. | Article | PubMed |

48. Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Effect of maternal hypertension on neonatal
neutropenia and risk of nosocomial infection. Pediatrics 1992;90:430435. | PubMed | ChemPort |

49. Adams-Chapman I, Stoll BJ. Prevention of nosocomial infections in the neonatal intensive care unit.
Curr Opin Pediatr 2002;14:157164. | Article | PubMed |

50. Kawagoe JY, Segre CA, Pereira CR, Cardoso MF, Silva CV, Fukushima JT. Risk factors for nosocomial
infections in critically ill newborns: a 5-year prospective cohort study. Am J Infect Control 2001;29:109
114. | Article | PubMed |

51. Baltimore RS. Neonatal nosocomial infections. Semin Perinatol 1998;22:2532. | PubMed |

52. Villari P, Sarnataro C, Iacuzio L. Molecular epidemiology of Staphylococcus epidermidis in a


neonatal intensive care unit over a three-year period. J Clin Microbiol 2000;38:17401746. | PubMed |

53. Stoll BJ, Temprosa M, Tyson JE, et al. Dexamethasone therapy increases infection in very low birth
weight infants. Pediatrics 1999;104:e63. | PubMed |

54. Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in very low birth weight neonates: a report
from the National Institute of Child Health and Human Development Neonatal Research Network. J
Pediatr 1996;129:6371. | Article | PubMed | ISI | ChemPort |

55. Brodie SB, Sands KE, Gray JE, et al. Occurrence of nosocomial bloodstream infections in six neonatal
intensive care units. Pediatr Infect Dis J 2000;19:5665. | Article | PubMed | ISI | ChemPort |
56. Mahieu LM, De Dooy JJ, De Muynck AO, Van Melckebeke G, Leven MM, Van Reempts PJ.
Microbiology and risk factors for catheter exit-site and -hub colonization in neonatal intensive care unit
patients. Infect Control Hosp Epidemiol 2001;22:357362. | PubMed |

57. Mahieu LM, De Muynck AO, Ieven MM, De Dooy JJ, Goossens HJ, Van Reempts PJ. Risk factors for
central vascular catheter-associated bloodstream infections among patients in a neonatal intensive care
unit. J Hosp Infect 2001;48:108116. | Article | PubMed |

58. Mahieu LM, De Dooy JJ, Lenaerts AE, Ieven MM, De Muynck AO. Catheter manipulations and the
risk of catheter-associated bloodstream infection in neonatal intensive care unit patients. J Hosp Infect
2001;48:2026. | Article | PubMed | ISI | ChemPort |

59. Mahieu LM, De Muynck AO, De Dooy JJ, Laroche SM, Van Acker KJ. Prediction of nosocomial sepsis
in neonates by means of a computer-weighted bedside scoring system (NOSEP score). Crit Care Med
2000;28:20262033. | Article | PubMed | ISI | ChemPort |

60. Saiman L, Ludington E, Dawson JD, et al. Risk factors for Candida species colonization of neonatal
intensive care unit patients. Pediatr Infect Dis J 2001;20:11191124. | Article | PubMed | ISI | ChemPort
|

61. Saiman L, Ludington E, Pfaller M, et al. Risk factors for candidemia in Neonatal Intensive Care Unit
patients. The National Epidemiology of Mycosis Survey study group. Pediatr Infect Dis J 2000;19:319
324. | Article | PubMed | ISI | ChemPort |

62. Benjamin Jr DK, Ross K, McKinney Jr RE, Benjamin DK, Auten R, Fisher RG. When to suspect fungal
infection in neonates: a clinical comparison of Candida albicans and Candida parapsilosis fungemia with
coagulase-negative staphylococcal bacteremia. Pediatrics 2000;106:712718. | Article | PubMed | ISI |

63. Warris A, Semmekrot BA, Voss A. Candidal and bacterial bloodstream infections in premature
neonates: a case-control study. Med Mycol 2001;39:7579. | PubMed |

64. Rennert G, Rennert HS, Pitlik S, Finkelstein R, Kitzes-Cohen R. Epidemiology of candidemiaa


nationwide survey in Israel. Infection 2000;28:2629. | Article | PubMed |

65. Dyke MP, Ott K. Severe thrombocytopenia in extremely low birthweight infants with systemic
candidiasis. J Paediatr Child Health 1993;29:298301. | PubMed | ISI | ChemPort |

66. Gray PH, Dawson C, Tan W. Severe thrombocytopenia in ELBW infants with systemic candidiasis. J
Paediatr Child Health 1994;30:557. | PubMed | ISI | ChemPort |

67. Faix RG, Kovarik SM, Shaw TR, Johnson RV. Mucocutaneous and invasive candidiasis among very
low birth weight (less than 1,500 grams) infants in intensive care nurseries: a prospective study.
Pediatrics 1989;83:101107. | PubMed |
68. Makhoul IR, Kassis I, Smolkin T, Tamir A, Sujov P. Review of 49 neonates with acquired fungal
sepsis: further characterization. Pediatrics 2001;107:6166. | Article | PubMed | ISI | ChemPort |

69. Stephenson J. Can a common medical practice transform Candida infections from benign to deadly?
JAMA 2001;286:25312532. | Article | PubMed |

70. Nesin M, Projan SJ, Kreiswirth B, Bolt Y, Novick RP. Molecular epidemiology of Staphylococcus
epidermidis blood isolates from neonatal intensive care unit patients. J Hosp Infect 1995;31:111121. |
PubMed |

71. Cairo MS, Agosti J, Ellis R, et al. A randomized, double-blind, placebo-controlled trial of prophylactic
recombinant human granulocyte-macrophage colony-stimulating factor to reduce nosocomial infections
in very low birth weight neonates. J Pediatr 1999;134:6470. | PubMed |

72. Archibald LK, Corl A, Shah B, et al. Serratia marcescens outbreak associated with extrinsic
contamination of 1% chlorxylenol soap. Infect Control Hosp Epidemiol 1997;18:704709. | PubMed |

73. Spainhour S. Serratia marcescens outbreak associated with extrinsic contamination of 1%


chloroxylenol soap. Infect Control Hosp Epidemiol 1998;19:476. | PubMed |

74. Becks VE, Lorenzoni NM. Pseudomonas aeruginosa outbreak in a neonatal intensive care unit: a
possible link to contaminated hand lotion. Am J Infect Control 1995;23:396398. | PubMed |

75. Chang HJ, Miller HL, Watkins N, et al. An epidemic of Malassezia pachydermatis in an intensive care
nursery associated with colonization of health care workers' pet dogs. N Engl J Med 1998;338:706711.
| Article | PubMed | ISI | ChemPort |

76. Davies MW, Mehr S, Garland ST, Morley CJ. Bacterial colonization of toys in neonatal intensive care
cots. Pediatrics 2000;106:E18. | PubMed |

77. Gravel-Tropper D, Sample ML, Oxley C, Toye B, Woods DE, Garber GE. Three-year outbreak of
pseudobacteremia with Burkholderia cepacia traced to a contaminated blood gas analyzer. Infect
Control Hosp Epidemiol 1996;17:737740. | PubMed |

78. Gray J, George RH, Durbin GM, Ewer AK, Hocking MD, Morgan ME. An outbreak of Bacillus cereus
respiratory tract infections on a neonatal unit due to contaminated ventilator circuits. J Hosp Infect
1999;41:1922. | Article | PubMed |

79. Harbarth S, Sudre P, Dharan S, Cadenas M, Pittet D. Outbreak of Enterobacter cloacae related to
understaffing, overcrowding, and poor hygiene practices. Infect Control Hosp Epidemiol 1999;20:598
603. | PubMed |

80. Hollis RJ, Barr JL, Doebbeling BN, Pfaller MA, Wenzel RP. Familial carriage of methicillin-resistant
Staphylococcus aureus and subsequent infection in a premature neonate. Clin Infect Dis 1995;21:328
332. | PubMed |
81. Hoque SN, Graham J, Kaufmann ME, Tabaqchali S. Chryseobacterium (Flavobacterium)
meningosepticum outbreak associated with colonization of water taps in a neonatal intensive care unit.
J Hosp Infect 2001;47:188192. | Article | PubMed |

82. Huang YC, Lin TY, Leu HS, Peng HL, Wu JH, Chang HY. Outbreak of Candida parapsilosis fungemia in
neonatal intensive care units: clinical implications and genotyping analysis. Infection 1999;27:97102. |
PubMed |

83. Huang YC, Lin TY, Leu HS, Wu JL, Wu JH. Yeast carriage on hands of hospital personnel working in
intensive care units. J Hosp Infect 1998;39:4751. | Article | PubMed |

84. Loiwal V, Kumar A, Gupta P, Gomber S, Ramachandran VG. Enterobacter aerogenes outbreak in a
neonatal intensive care unit. Pediatr Int 1999;41:157161. | Article | PubMed |

85. McDonald LC, Walker M, Carson L, et al. Outbreak of Acinetobacter spp. bloodstream infections in a
nursery associated with contaminated aerosols and air conditioners. Pediatr Infect Dis J 1998;17:716
722. | Article | PubMed |

86. Mitchell SJ, Gray J, Morgan ME, Hocking MD, Durbin GM. Nosocomial infection with Rhizopus
microsporus in preterm infants: association with wooden tongue depressors. Lancet 1996;348:441443.
| Article | PubMed |

87. Muyldermans G, de Smet F, Pierard D, et al. Neonatal infections with Pseudomonas aeruginosa
associated with a water-bath used to thaw fresh frozen plasma. J Hosp Infect 1998;39:309314. |
PubMed |

88. Ng PC, Lewindon PJ, Siu YK, Wong W, Cheung KL, Liu K. Bacterial contaminated breast milk and
necrotizing enterocolitis in preterm twins. J Hosp Infect 1995;31:105110. | PubMed |

89. Drazin PB. Contamination in expressed breast milk. J Hum Lact 1998;14:100. | PubMed |

90. Enterobacter sakazakii infections associated with the use of powdered infant formula Tennessee,
2001. MMWR Morb Mortal Wkly Rep 2002;51:297300.

91. Bar-Oz B, Preminger A, Peleg O, Block C, Arad I. Enterobacter sakazakii infection in the newborn.
Acta Paediatr 2001;90:356358. | Article | PubMed |

92. van Acker J, de Smet F, Muyldermans G, Bougatef A, Naessens A, Lauwers S. Outbreak of


necrotizing enterocolitis associated with Enterobacter sakazakii in powdered milk formula. J Clin
Microbiol 2001;39:293297. | Article | PubMed |

93. Singer S, Singer D, Ruchel R, Mergeryan H, Schmidt U, Harms K. Outbreak of systemic aspergillosis
in a neonatal intensive care unit. Mycoses 1998;41:223227. | PubMed |

94. Umasankar S, Mridha EU, Hannan MM, Fry CM, Azadian BS. An outbreak of Salmonella enteritidis in
a maternity and neonatal intensive care unit. J Hosp Infect 1996;34:117122. | Article | PubMed |
95. Yu WL, Cheng HS, Lin HC, Peng CT, Tsai CH. Outbreak investigation of nosocomial enterobacter
cloacae bacteraemia in a neonatal intensive care unit. Scand J Infect Dis 2000;32:293298. | Article |
PubMed |

96. Chandrashekar MR, Rathish KC, Nagesha CN. Reservoirs of nosocomial pathogens in neonatal
intensive care unit. J Indian Med Assoc 1997;95:7274, 77. | PubMed |

97. Guzman JM, Jaraba MP, De La Torre MJ, Ruiz-Gonzalez MD, Huertas MD, Alvarez R, et al. Parenteral
nutrition and immature neonates. Comparative study of neonates weighing under 1000 and 10001250
g at birth. Early Hum Dev 2001;65Suppl:S133S144. | Article | PubMed |

98. Weese-Mayer DE, Fondriest DW, Brouillette RT, Shulman ST. Risk factors associated with
candidemia in the neonatal intensive care unit: a casecontrol study. Pediatr Infect Dis J 1987;6:190
196. | PubMed |

99. Avila-Figueroa C, Goldmann DA, Richardson DK, Gray JE, Ferrari A, Freeman J. Intravenous lipid
emulsions are the major determinant of coagulase-negative staphylococcal bacteremia in very low birth
weight newborns. Pediatr Infect Dis J 1998;17:1017. | Article | PubMed | ChemPort |

100. Freeman J, Goldmann DA, Smith NE, Sidebottom DG, Epstein MF, Platt R. Association of
intravenous lipid emulsion and coagulase-negative staphylococcal bacteremia in neonatal intensive care
units. N Engl J Med 1990;323:301308. | PubMed |

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