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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