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Review

Clinical Microbiology of Bacterial and Fungal Sepsis in Very-Low-Birth-Weight Infants

David Kaufman, Karen D. Fairchild
David Kaufman
1Department of Pediatrics, Division of Neonatology, University of Virginia Health System, Charlottesville, Virginia
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  • For correspondence: davidkaufman@virginia.edu
Karen D. Fairchild
2Department of Pediatrics, Division of Neonatology, University of Maryland School of Medicine, Baltimore, Maryland
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DOI: 10.1128/CMR.17.3.638-680.2004
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  • FIG. 1.
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    FIG. 1.

    Timing of bacterial and fungal sepsis in VLBW infants. Percentages indicate the approximate number of VLBW infants with septicemia. EONS usually occurs via ascent of organisms from the birth canal to the amniotic fluid, with or without rupture of amniotic membranes. LONS occurs with vertical and horizontal spread of organisms. While the vast majority of cases of sepsis in VLBW infants occur in the first 30 days of life, VLBW infants requiring prolonged intensive care are at risk for VLONS beyond 2 months of age.

  • FIG. 2.
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    FIG. 2.

    Pathogenesis of fungal colonization and infection.

Tables

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  • TABLE 1.

    Susceptibility of preterm infants to sepsis

    Antimicrobial defensePreterm infant compromised defenses
    Epidermal and epithelial barriersImmature skin (3-6-cell stratum corneum and thin keratin layer)
    Insensible water loss from skin and humidification systems, creating moist skin that favors the growth of microorganisms
    Skin trauma from intensive care interventions
    Adherence of Candida to exposed intermediate epithelial cells, favoring colonization
    Enhanced adherence of Candida and GBS to buccal epithelial cells of preterm versus term infants, facilitating oral colonization
    Invasive catheters and tubes
        Surface for colonization provided by intravascular catheters breaching intact epidermis
        Proliferation due to parenteral nutrition and biofilms on plastic catheters
        Colonization of endotracheal and nasogastric tubes
        Trauma from endotracheal, suctioning, and nasogastric tubes
    Intact endothelial tissuesTrauma to endothelium and endocardium from central vascular catheters
    Injury from hyperosmolar nutrition solutions and medications
    Gastrointestinal mucosaDecreased acid production
    Immature peristalsis and reduced absorption, favoring microorganism overgrowth
    Thin mucin layer, leading to decreased barrier function and secretory IgA binding
    Diminished number of intraepithelial lymphocytes
    FIP
    NEC
    MicrofloraCompetitive bacterial microflora diminished by broad-spectrum antibiotics, favoring growth of resistant bacterial and fungal organisms
    More commensal gram-positive organisms selected for by human milk
    ComplementLower levels with decreasing gestational age
    CytokinesDecreased production of IL-1, IL-8, gamma interferon, TNF-α, G-CSF, and GM-CSF
    DefensinsDiminished with decreasing gestational age
    NeutrophilsDecreased bone marrow storage pools and G-CSF levels
    Immature neutrophil oxidative burst
    Decreased numbers of azurophilic granules
    Diminished granular contents (lactoferrin, defensins, lysozyme, myeloperoxidase, proteases, and cathepsin G)
    Possible impairment of function by medications (steroids, H2 antagonists, lipid emulsions)
    MonocytesDiminished number and function
    Decreased adherence at sites of infection
    Decreased opsonization and phagocytosis
    Diminished gamma interferon, IL-3, and G-CSF release
    T-cells, B-cells, and antibodiesDecreased numbers of lymphocytes in gastrointestinal tract
    Majority of transfer of maternal IgGs after 32 weeks' gestation
    Decreased production of antibodies by preterm lymphocytes
  • TABLE 2.

    Organisms and death rates associated with bloodstream infections in VLBW (<1,500 g) neonatesa

    OrganismEONSLONS
    No. of infections (% of total)Mortality (%)bNo. of infections (% of total)Mortality (%)b
    Gram-positive bacteria (total)31 (36.9)26922 (70.2)11.2
        GBS9 (10.7)30 (2.3)21.9
        Viridans streptococcus3 (3.6)
        Other streptococci4 (4.8)
        Listeria monocytogenes2 (2.4)
        Coagulase-negative Staphylococcus9 (10.7)629 (47.9)9.1
        Staphylococcus aureus1 (1.2)103 (7.8)17.2
        Enterococcus species43 (3.3)
        Other3 (3.6)117 (8.9)
    Gram-negative bacteria (total)51 (60.7)41231 (17.6)36.2
        Escherichia coli37 (44.0)64 (4.9)34.0
        Haemophilus influenzae7 (8.3)
        Citrobacter2 (2.4)
        Bacteroides2 (2.4)
        Klebsiella1 (1.2)52 (4.0)22.6
        Pseudomonas35 (2.7)74.4
        Enterobacter33 (2.5)26.8
        Serratia29 (2.2)35.9
        Other2 (2.4)18 (1.4)
    Fungi (total)2 (2.4)160 (12.2)31.8
        Candida albicans2 (2.4)76 (5.8)43.9
        Candida parapsilosis54 (4.1)15.9
        Other30 (2.3)
    • ↵ a NICHD Neonatal Network Survey, 1998 to 2000 (453, 454). A total of 5,447 patients with EONS and 6,215 patients with LONS were studied. There were a total of 84 bloodstream infections in the EONS patients (1.5% of the total) and 1,313 bloodstream infections in the LONS patients (21.1% of the total).

    • ↵ b All-cause mortality.

  • TABLE 3.

    Diagnostic utility of CRP and cytokine measurements in predicting sepsis in VLBW infantsa

    StudyInfant populationNo. of patientsNo. of culture- proven sepsis eventsTime of testingTestSensitivity (%)Specificity (%)PPV (%)NPV (%)
    Franz et al., 2001 (145)Preterm and term709 (387 preterm)14BirthIL-8NRNR
        22-26 wk93 (a)55 (a)
        27-29 wk89 (a)56 (a)
        30-32 wk83 (a)77 (a)
    Kuster et al., 1998 (272)VLBW12521>2 daysIL-1ra100 (a)92 (a)NRNR
    IL-689 (b)83 (b)
    CRP50 (b)93 (b)
    Ng et al., 1997 (340)VLBW6845>3 daysCRP + IL-698 (c)91 (c)90 (c)98 (c)
    Chan and Ho, 1997 (77)VLBW7030>3 daysCRP48 (d)79 (d)74 (d)55 (d)
    Wagle et al., 1994 (487)<29 wk gestation123361-87 daysCRP90 (a)81 (a)48 (a)98 (a)
    Seibert et al., 1990 (426)23-31 wk gestation1258BirthCRP63 (a)70 (a)13 (a)96 (a)
    67 (b)82 (b)60 (b)86 (b)
    8523>3 daysCRP57 (a)61 (a)30 (a)82 (a)
    58 (b)90 (b)93 (b)49 (b)
    • ↵ a Selected studies are summarized with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) calculated for CRP and cytokine levels in VLBW infants. Tests were compared to different definitions of infection, which included culture-proven plus clinical sepsis (a), culture-proven sepsis (b), septicemia plus NEC plus microbiologically confirmed focal infection (c) or sepsis-like syndrome with positive blood, CSF, or joint fluid culture (d). Serial testing was performed in all studies except one (Chan et al.), but the number and timing of tests varied for the other studies. Positive values were defined as CRP ≥ 1.0 to 1.5 mg/dl, IL-6 ≥ 25 to 31 pg/ml, IL-8 ≥ 70 pg/ml, and IL-1 receptor antagonist (IL-1ra) ≥ 12,000 pg/ml. NR, not reported.

  • TABLE 4.

    Fungal colonization in VLBW and ELBW infantsa

    CharacteristicResults for study (study period)
    Baley et al. (30) (1983)Hageman et al. (183) (1985)Pappu-Katikaneni et al. (362) (1991)Rowen et al. (395) (1992)Saiman et al. (402) (1993-1995)Huang et al. (215) (1996)Kicklighter et al. (255) (1998-1999)bKaufman et al. (246) (1998-2000)b
    Birth wt (gr)<1,500<1,500<1,500<1,500<1,500<1,500<1,500<1,000
    No. of patients146384011678011652b50b
    % of patients with colonization2747633431224660
    % of patients colonized with:
        C. albicans1624402618134444
        C. papapsilosis5241041363745
        C. glabrata0003<143
        C. guilliermondii0000<103
        C. lusitaniae0000011.15.1
        C. tropicalis2.102.51.703.70
    Other3.40002.7c0.801.1
    % of total no. of patients colonized by site:
        Skin
            Groin or axilla13.712.9048
            Umbilicus8
        Gastrointestinal tract
            Rectal19.233.63112.94554
            Stool62.5
        Respiratory tract
            Oropharyngeal1111.2d6
            Endotracheal4.811.2d2.642
        Urine8.37.7
    % of total no. of patients with fungal sepsis2.17.912.56.03.12.63.916
    • ↵ a Summary of eight studies (30, 183, 215, 246, 255, 362, 395, 402).

    • ↵ b Analysis of the control patients in these randomized trials.

    • ↵ c Includes non-albicans and non-parapsilosis species.

    • ↵ d Nasopharyngeal and endotracheal cultures did not correlate with one another.

  • TABLE 5.

    Comparison of C. albicans, C. parapsilosis, and C. glabrata sepsisa

    CharacteristicResults for:P value
    C. albicansC. parapsilosisC. glabrata
    Baseline characteristics
        No. of patients4189
        Gestational age (wk)26.6 ± 0.527.3 ± 1.329.7 ± 1.20.01
        Birth wt (g) 932 ± 75 965 ± 1941,442 ± 2920.02
        No. (%) of VLBW (<1,500 g) infants38 (93)7 (88)7 (78)NS
        No. (%) born via vaginal delivery26 (63)4 (50)7 (78)NS
    Factors present at the diagnosis of fungemia
        Age at diagnosis (days)17 (11-31)25 (17-87)14 (10-21)NS
        No. (%) on antibiotics12 (38)3 (38)6 (67)NS
        No. (%) with apnea28 (68)4 (50)2 (22)0.01
        Lowest platelet count (103/mm3) 74 ± 9 39 ± 2 124 ± 340.04
        No. of positive blood cultures for fungus2.1 ± 1.11.8 ± 0.712.0 ± 1.3NS
        No. (%) with candiduria15 (37)2 (25)2 (22)NS
        No. (%) with meningitis5 (12)1 (13)1 (11)NS
        No. with renal abscessc/total no. tested (%)5/38 (13)1/7 (14)0/7 (0)NS
        No. with cardiac vegetations/total no. tested (%)2/30 (7)0/6 (0)0/8 (0)NS
        No. (%) with necrotizing enterocolitis6 (15)01 (11)NS
        No. (%) dying of Candida infection000NS
        No. (%) who died, all-cause mortality3 (7)00NS
    • ↵ a Data from reference 131. Plus-minus values are mean ± standard deviation. Median is given as 25th to 75th percentile.

    • b Significant difference between glabrata and non-glabrata groups (P < 0.05). NS, not significant.

    • ↵ c Urinary tract ultrasound and echocardiogram were not performed on every patient.

  • TABLE 6.

    Summary of fluconazole prophylaxis study in ELBW infantsa

    CharacteristicResults for:P
    Fluconazole patients (n = 50)Placebo patients (n = 50)
    No. (%) of patients with fungal infectionb
        Blood, urine, or cerebrospinal fluid infection0 (0)10 (20)0.008
        Bloodstream infection0 (0)8 (16)0.007
    No. (%) of patients with fungal colonization
        One or more sites11 (22)30 (60)0.002
        Two or more sites9 (18)26 (52)0.003
        Skin10 (20)24 (48)0.008
        Gastrointestinal tract9 (18)27 (54)0.003
        Respiratory tract1 (2)21 (42)0.002
    Resistance (MIC50) (μg/ml)
        First 6 mo of study≤2.0≤1.0
        Last 6 mo of study≤2.0≤1.0
    Patient safety (liver function tests, mean ± SD)
        Aspartate aminotransferase (IU/liter)27 ± 1329 ± 160.67
        Alanine aminotransferase (IU/liter)21 ± 1621 ± 190.85
        Direct bilirubin (mg/dl)0.6 ± 1.41.0 ± 1.80.34
        Alkaline phosphatase (IU/liter)305 ± 125318 ± 1820.70
    No. (%) patients who died4 (8)10 (20)0.22
    • ↵ a Data from reference 246.

    • ↵ b Growth of fungus in culture for a patient with symptoms of infection.

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Clinical Microbiology of Bacterial and Fungal Sepsis in Very-Low-Birth-Weight Infants
David Kaufman, Karen D. Fairchild
Clinical Microbiology Reviews Jul 2004, 17 (3) 638-680; DOI: 10.1128/CMR.17.3.638-680.2004

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Clinical Microbiology of Bacterial and Fungal Sepsis in Very-Low-Birth-Weight Infants
David Kaufman, Karen D. Fairchild
Clinical Microbiology Reviews Jul 2004, 17 (3) 638-680; DOI: 10.1128/CMR.17.3.638-680.2004
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  • Top
  • Article
    • SUMMARY
    • INTRODUCTION
    • MICROORGANISMS AND VERY-LOW-BIRTH-WEIGHT INFANTS: SCOPE OF THE PROBLEM
    • DEFINITIONS OF SEPSIS AND FOCAL INFECTIONS IN VERY-LOW-BIRTH-WEIGHT INFANTS
    • DIAGNOSIS OF SEPSIS IN VERY-LOW-BIRTH-WEIGHT INFANTS
    • BACTERIA
    • FUNGAL ORGANISMS
    • PREVENTION OF NOSOCOMIAL SEPSIS IN VERY-LOW-BIRTH-WEIGHT INFANTS
    • CONCLUSION
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

Bacteremia
Fungemia
Infant, Premature, Diseases
Infant, Very Low Birth Weight

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