Health care–associated infections in the neonatal intensive care unit
2005; Elsevier BV; Volume: 33; Issue: 5 Linguagem: Inglês
10.1016/j.ajic.2004.11.006
ISSN1527-3296
Autores Tópico(s)Nosocomial Infections in ICU
ResumoNeonates represent a unique and highly vulnerable patient population. Advances in medical technology that have occurred over the last few decades have improved the survival and quality of life for neonates, particularly those infants born with extreme prematurity or with congenital defects. Although immunologic immaturity and altered cutaneous barriers play some role in the vulnerability of neonates to nosocomial infections, clearly, therapeutic interventions that have proven to be lifesaving for these fragile infants also appear to be associated with the majority of infectious complications resulting in neonatal morbidity and mortality. Rates of infections in neonatal intensive care units (NICUs) have varied from 6% to 40% of neonatal patients, with the highest rates in those facilities having larger proportions of very low-birth-weight infants (birthweight ≤1000 grams) or neonates requiring surgery. Efforts to protect the vulnerable NICU infants include the following: (1) optimal infection control practices, especially good hand hygiene and good nursery design; (2) prudent use of invasive interventions with particular attention to early removal of invasive devices after they are no longer essential; and (3) judicious use of antimicrobial agents, with an emphasis on targeted (narrow spectrum) rather than broad-spectrum antibiotics and appropriate indications (proven or suspected bacterial infections). Neonates represent a unique and highly vulnerable patient population. Advances in medical technology that have occurred over the last few decades have improved the survival and quality of life for neonates, particularly those infants born with extreme prematurity or with congenital defects. Although immunologic immaturity and altered cutaneous barriers play some role in the vulnerability of neonates to nosocomial infections, clearly, therapeutic interventions that have proven to be lifesaving for these fragile infants also appear to be associated with the majority of infectious complications resulting in neonatal morbidity and mortality. Rates of infections in neonatal intensive care units (NICUs) have varied from 6% to 40% of neonatal patients, with the highest rates in those facilities having larger proportions of very low-birth-weight infants (birthweight ≤1000 grams) or neonates requiring surgery. Efforts to protect the vulnerable NICU infants include the following: (1) optimal infection control practices, especially good hand hygiene and good nursery design; (2) prudent use of invasive interventions with particular attention to early removal of invasive devices after they are no longer essential; and (3) judicious use of antimicrobial agents, with an emphasis on targeted (narrow spectrum) rather than broad-spectrum antibiotics and appropriate indications (proven or suspected bacterial infections). As with other settings in which critically ill patients receive care, infants hospitalized in neonatal intensive care units (NICU) are at risk for health care-associated infections because of their profound physiologic instability and exposure to invasive devices and broad-spectrum antibiotics.1Sohn A.H. Garrett D.O. Sinkowitz-Cochran R.L. Grohskopf L.A. Levine G.L. Stover B.H. et al.Prevalence of nosocomial infections in neonatal intensive care unit patients: results from the first national point-prevalence survey.J Pediatr. 2001; 139: 821-827Abstract Full Text PDF PubMed Scopus (327) Google Scholar, 2Sinh N. Large infection problems in small patients merit renewed emphasis on prevention.Infect Control Hosp Epidemiol. 2004; 25: 714-716Crossref PubMed Scopus (11) Google Scholar, 3National Nosocomial Infections Surveillance System National Nosocomial Infection Surveillance (NNIS) System Report, data summary from January 1992 through June 2003, issued August 2003.Am J Infect Control. 2003; 31: 481-498Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar However, this group of infants has some unique host risk factors that make them particularly vulnerable for acquiring health care-associated infections, as well as experiencing more severe illness as a result of these infections. Whether the infant is born prematurely or at full term, many components of the immune system exhibit diminished functional capacity (quantitative and qualitative) when compared with older children and adults4Wilson C.B. Lewis D.B. Basis and implications of selectively diminished cytokine production in neonatal susceptibility to infection.Rev Infect Dis. 1990; 12: S410-S420Crossref PubMed Scopus (86) Google Scholar (Table 1). Most of the differences are based merely on an age-related intrinsic immaturity, which is more profound the earlier during gestation that the infant is born. In addition, the protected environment of intrauterine life prevents any significant immunologic exposure that would be necessary to prime many valuable protective immune responses. For these reasons, the newborn infant depends heavily on passively acquired maternal antibodies received from their mother by transplacental passage.5Lewis D.B. Wilson C.B. Developmental immunology and the role of host defenses in neonatal susceptibility to infection.in: Remington J.S. Klein J.O. Infectious diseases of the fetus and newborn infant. WB Saunders, Philadelphia, PA2001: 25-38Google Scholar These passively acquired antibodies are primarily immunoglobulin G (IgG). Transmission of the antibodies to the fetus begins approximately midgestation (24-26 weeks gestation), with levels of IgG antibodies in the fetus not reaching adult levels until near full term. Infants born prematurely will have IgG antibody levels that are significantly lower than older children and adults.5Lewis D.B. Wilson C.B. Developmental immunology and the role of host defenses in neonatal susceptibility to infection.in: Remington J.S. Klein J.O. Infectious diseases of the fetus and newborn infant. WB Saunders, Philadelphia, PA2001: 25-38Google Scholar These passively acquired antibodies represent the mother's prior experience and therefore may not always provide adequate protection against microorganisms to which the infant will be exposed in the NICU. The sick premature infant as well as full-term neonate may exhibit an iatrogenic hypogammaglobulinemia as a result of frequent blood drawing, which removes available maternally derived antibodies before the infant is capable of producing adequate antibodies for immunologic protection.Table 1Quantitative and qualitative immune deficiencies noted in newborn infants5Lewis D.B. Wilson C.B. Developmental immunology and the role of host defenses in neonatal susceptibility to infection.in: Remington J.S. Klein J.O. Infectious diseases of the fetus and newborn infant. WB Saunders, Philadelphia, PA2001: 25-38Google Scholar, 6Bektas S. Goetz B. Speer C.P. Decreased adherence, chemotaxis and phagocytic activities of neutrophils from preterm neonates.Acta Paediatr Scand. 1990; 79: 1031-1038Crossref PubMed Scopus (101) Google Scholar, 7Kallman J. Schollin J. Schalen C. Erlandsson A. Kihlstrom E. Impaired phagocytosis and opsonization towards group B streptococci in preterm neonates.Arch Dis Child Fetal Neonatal Ed. 1998; 78: F46-F50Crossref PubMed Scopus (83) Google ScholarComponent of the immune systemDefectPhagocytic cells (PMNs and monocytes)Decreased migration/chemotaxisDecreased phagocytic activityDecreased bone marrow storage pool of PMNsB-cells/immunoglobulinsIgM synthesis delayed until 30 weeks gestationDependence on maternally derived IgGPoor response to polysaccharide antigensT lymphocytesDiminished T-cell-mediated cytotoxicityDiminished participation in delayed-type hypersensitivityDiminished potentiation of B-cell differentiationComplement/opsonizationDecreases in both classic and alternate pathwaysDecreased fibronectin (50% of adult levels)Natural killer cellsDecreased numberDecreased cytotoxicityReticuloendotheliumDecreased antigen removal Open table in a new tab The sterile environment of the uterus results in the delivery of an infant devoid of protective endogenous microbial flora. Colonization of mucous membranes and skin occurs rapidly after birth. In healthy newborns, the majority of microbial flora that colonizes the mucosal surfaces and the skin is acquired from the infants' mother and other family members. However, neonates hospitalized within a NICU setting are likely to have their endogenous microbial flora result from endemic microorganisms present in the NICU and modified by frequent exposure to antibiotics8Singh N. Patel K.L. Leger M.-M. et al.Risk of resistant infections with enterobacteriaceae in hospitalized neonates.Pediatr Infect Dis J. 2002; 21: 1029-1033Crossref PubMed Scopus (93) Google Scholar, 9Nambiar S. Singh N. Change in epidemiology of health-care associated infections in the neonatal intensive care unit.Pediatr Infect Dis J. 2002; 21: 839-842Crossref PubMed Scopus (77) Google Scholar and contacts with health care workers.10Waters V. Larson E. Wu F. San Gabriel P. Haas J. Cimiotti J. et al.Molecular epidemiology of gram-negative bacilli from infected neonates and health care worker's hands in neonatal intensive care units.Clin Infect Dis. 2004; 38: 1688-1689Crossref PubMed Scopus (61) Google Scholar There is a higher frequency of colonization by NICU patients with antibiotic-resistant bacteria (gram-negative enteric rods and staphylococci), Enterococcus, and Candida species. The stratum cornium of the fetus develops poorly before 26-weeks gestation. In the significantly premature infant (24 weeks through 30 weeks), the skin is less thick (only a few cell layers) and poorly keratinized.11Harpin V.A. Rutter N. Barrier properties of the newborn infant's skin.J Pediatr. 1993; 102: 419-425Abstract Full Text PDF Scopus (260) Google Scholar Skin and mucous membranes in premature neonates are more permeable to exogenous antigens. The inherent immaturity of the neonate's skin enhances susceptibility to microorganisms exposed to the infant's skin. This increases the risk for development of dermatitis and cellulitis and is a portal for invasive bacteria to enter deeper tissues or even the vascular space. Regardless of gestational age, the skin matures, and the stratum cornium develops to more mature levels by 2 weeks of age.11Harpin V.A. Rutter N. Barrier properties of the newborn infant's skin.J Pediatr. 1993; 102: 419-425Abstract Full Text PDF Scopus (260) Google Scholar Infants hospitalized within the NICU can be exposed and acquire health care-associated infections from both human and inanimate sources. A mode of nosocomial transmission that is unique to neonates is natal or intrapartum transmission of microorganisms from mother to infant derived from the maternal birth canal. Any microorganism found in the maternal birth canal can result in infection of the newborn based on the pathogenicity of the microorganism and the susceptibility of the infant (Table 2). NICU residents can also become infected with health care-associated infections through horizontal transmission of microorganisms spread by aerosol or contact (direct or indirect) transmission. Despite the enhanced safety of blood products administered in hospitals at the present time, the frequent utilization of blood products in the stabilization of critically ill newborns allows for the potential transmission of bloodborne pathogens, currently identified and those yet to be identified.12Yeager A.S. Transfusion-acquired cytomegalovirus infection in newborn infants.Am J Dis Child. 1974; 128: 478-483PubMed Google Scholar, 13Azimi P.H. Roberto R.R. Guralnik J. Livermore T. Hoag S. Hagens S. et al.Transfusión-acquired hepatitis A in a premature infant with secondary nosocomial spread in an intensive care nursery.Am J Dis Child. 1986; 140: 23-27PubMed Google Scholar, 14King E.A. Alter A.A. Schwartz O. Fishman S.A. Postexchange transfusion hepatitis in the newborn infant.J Pediatr. 1973; 83: 341-342Abstract Full Text PDF PubMed Scopus (6) Google Scholar, 15Saulsbury F.T. Wykoff R.F. Boyle R.J. Transfusion-acquired human immunodeficiency virus in twelve neonates: epidemiologic, clinical and immunological features.Pediatr Infect Dis J. 1987; 6: 544-549Crossref PubMed Scopus (20) Google ScholarTable 2Common vertically/natally acquired infectionsBacteriaVirusesOtherGroup B StreptococcusHerpes simplexCandida speciesListeria monocytogenesCytomegalovirusChlamydia trachomatisGram-negative enteric rodsHIVUreaplasma urealyticumNeisseria gonorrhoeaeHepatitis BMycoplasma hominisStaphylococcus aureus Open table in a new tab Administration of breast milk from either the infant's mother or donor-bank breast milk provides an opportunity for the transmission of agents found in breast milk and skin of the breast milk donor15Saulsbury F.T. Wykoff R.F. Boyle R.J. Transfusion-acquired human immunodeficiency virus in twelve neonates: epidemiologic, clinical and immunological features.Pediatr Infect Dis J. 1987; 6: 544-549Crossref PubMed Scopus (20) Google Scholar, 16Oxtoby M.J. Human immunodeficiency virus and other viruses inhuman milk: placing the issues in a broader perspective.Pediatr Infect Dis J. 1988; 7: 825-835Crossref PubMed Scopus (109) Google Scholar, 17American Academy of Pediatrics Human milk.in: Pickering L.K. 2003 Red Book: report of the Committee on Infectious Diseases. 26th ed. American Academy of Pediatrics, Elk Grove Village, IL2003: 117-123Google Scholar (Table 3). However, donor screening and pasteurization of donor breast milk has made this product very safe for use in even the most critically ill neonate.Table 3Microorganisms that may be transmitted through breast milk16Oxtoby M.J. Human immunodeficiency virus and other viruses inhuman milk: placing the issues in a broader perspective.Pediatr Infect Dis J. 1988; 7: 825-835Crossref PubMed Scopus (109) Google Scholar, 17American Academy of Pediatrics Human milk.in: Pickering L.K. 2003 Red Book: report of the Committee on Infectious Diseases. 26th ed. American Academy of Pediatrics, Elk Grove Village, IL2003: 117-123Google ScholarMicroorganism contraindicatedBreastfeedingCytomegalovirusNoHepatitis BNo∗Mothers who are hepatitis B surface antigen positive (newly acquired infection or chronic carriers) may breastfeed after their infant receives hepatitis B immune globulin (HBIG) within 12 hours of birth and initiates the hepatitis B vaccine series.Hepatitis CNoHuman immunodeficiency virus (HIV)Yes†Breastfeeding by HIV-infected mothers should be prohibited, unless a safe alternative is not available.Human T-lymphotrophic virus type I (HTLV-I)YesHuman T-lymphotrophic virus type II (HTLV-II)YesHerpes simplexNo‡Mothers who have after herpetic lesions on their breasts should refrain from breastfeeding until the lesion has resolved.RubellaNo∗ Mothers who are hepatitis B surface antigen positive (newly acquired infection or chronic carriers) may breastfeed after their infant receives hepatitis B immune globulin (HBIG) within 12 hours of birth and initiates the hepatitis B vaccine series.† Breastfeeding by HIV-infected mothers should be prohibited, unless a safe alternative is not available.‡ Mothers who have after herpetic lesions on their breasts should refrain from breastfeeding until the lesion has resolved. Open table in a new tab The rates of health care-associated infections in the NICU are considerably higher than what would be noted in a normal newborn nursery. Rates have varied from 6 to 40 per 100 admissions in the NICU,18Goldmann D.A. Durbin W.A. Freeman J. Nosocomial infections in a neonatal intensive care unit.J Infect Dis. 1981; 141: 149-159Google Scholar, 19Hemming V.G. Overall Jr., J.C. Britt M.R. Nosocomial infections in a newborn intensive care unit: results of forty-one months of surveillance.N Engl J Med. 1976; 294: 1310-1316Crossref PubMed Scopus (226) Google Scholar, 20Welliver R.C. McLaughlin S. Unique epidemiology of nosocomial infection in a children's hospital.Am J Dis Child. 1984; 38: 131-135Google Scholar, 21Hoogkamp-Korstanje J.A. Cats B. Senders R.C. van Ertbruggen I. Analysis of bacterial infections in a neonatal intensive care unit.J Hosp Infect. 1982; 3: 275-284Abstract Full Text PDF PubMed Scopus (49) Google Scholar and this compares with a rate of approximately 0.3 to 1.7 per 100 admissions in normal newborn nursery.20Welliver R.C. McLaughlin S. Unique epidemiology of nosocomial infection in a children's hospital.Am J Dis Child. 1984; 38: 131-135Google Scholar, 22Scheckler W.E. Peterson P.J. Nosocomial infections in 15 rural Wisconsin hospitals-results and conclusions from 6 months of comprehensive surveillance.Infect Control. 1986; 7: 397-402PubMed Google Scholar Rates of health care-associated infections in the NICU are higher in lower birth weight infants, with the rates being nearly 3 times higher in infants whose birth weights are 1500 grams. In addition, health care-associated infection rates are higher in units that include neonatal surgical patients and in units that include nosocomial viral infections20Welliver R.C. McLaughlin S. Unique epidemiology of nosocomial infection in a children's hospital.Am J Dis Child. 1984; 38: 131-135Google Scholar in their surveillance data. Duration of hospitalization, exposure to broad-spectrum antibiotics, and over crowding and poor staffing ratios23Haley R.W. Bregman D.A. The role of understaffing and overcrowding in recurrent outbreaks of staphylococcal infection in a neonatal special-care unit.J Infect Dis. 1982; 145: 875-885Crossref PubMed Scopus (233) Google Scholar, 24Smith P.J. Brookfield D.S. Shaw D.A. Gray J. An outbreak of serratia marcescens infections in a neonatal unit.Lancet. 1984; 1: 151-153Abstract PubMed Scopus (45) Google Scholar, 25Van Ogtrop M.L. van Zoeren-Grobben D. Verbakel-Salomons E.M. van Boven C.P. Serratia marcescens infections in neonatal departments: description of an outbreak and review of the literature.J Hosp Infect. 1997; 36: 95-103Abstract Full Text PDF PubMed Scopus (73) Google Scholar are risk factors that have been associated with increased rates of health care-associated infections in the NICU. However, the best markers for the risk of nosocomial infection are birth weight, exposure to invasive devices, and acuity of underlying illness. In any effort to compare infection rates in NICUs, the data need to be stratified by birth weight, device days, and acuity of illness. Bacteremias or bloodstream infections (BSI) are the single most important infections within the NICU because of their frequency and their potential for life-threatening consequences. Infants who develop bacteremia in the first few days of life (early onset sepsis) typically acquire their organism from their mother during the intrapartum period. The microorganisms responsible are found in the maternal birth canal and are transmitted to the infant either through an ascending route immediately prior to labor and delivery (especially in the presence of ruptured amniotic membranes) or through exposure as the infant is delivered. The illness is characterized by a fulminant multisystem disease, with a high mortality rate. Premature birth, low birth weight, maternal fever, premature rupture of membranes, maternal chorioamnionitis, and maternal colonization with group B Streptococcus are specific risk factors for early onset bacteremia and sepsis. Utilization of antimicrobial chemoprophylaxis to prevent early onset group B Streptococcus sepsis has successfully reduced the incidence of early onset group B Streptococcus infections26Schrag S.J. Zell E.R. Lynfield R. Roome A. Arnold K.E. Craig A.S. et al.A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates.N Engl J Med. 2002; 347: 233-239Crossref PubMed Scopus (561) Google Scholar but has been associated with an increase in early onset Escherichia coli infections in very low-birth-weight infants.27Stoll B.J. Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network.Semin Perinatol. 2003; 27: 293-301Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar Late onset bacteremia occurs after 5 to 7 days of age. This may be due to maternally derived microorganisms that colonize the infant in the intrapartum period or can represent infection acquired nosocomially (horizontal transmission). Most episodes of nosocomial bacteremia in the NICU are associated with indwelling vascular catheters.27Stoll B.J. Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network.Semin Perinatol. 2003; 27: 293-301Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, 28Brodie S.B. Sands K.E. Gray J.E. Parker R.A. Goldmann D.A. Davis R.B. et al.Occurrence of nosocomial bloodstream infections in six neonatal intensive care units.Pediatr Infect Dis J. 2000; 19: 56-65Crossref PubMed Scopus (182) Google Scholar Administration of lipids, low birth weight, respiratory tract disease on admission, catheter hub colonization, blood sampling through the central catheter, and treatment with H2 blockers also are independently associated with bloodstream infections.29Freeman J. Goldmann D.A. Smith N.E. Sidebottom D.G. Epstein M.F. Platt Association of intravenous lipid emulsion and coagulase-negative staphylococcal bacteremia in neonatal intensive care units.N Engl J Med. 1990; 323: 301-308Crossref PubMed Scopus (305) Google Scholar, 30Beck-Sague C.M. Azimi P. Fonesca S.N. et al.Bloodstream infections in neonatal intensive care unit patients: results of a multicenter study.Pediatr Infect Dis J. 1994; 13: 1110-1116Crossref PubMed Scopus (178) Google Scholar If the infection occurs in the first 30 days of life, microorganisms most commonly identified are coagulase-negative Staphylococcus (CONS), Staphylococcus aureus, Enterococcus, and gram-negative enteric rods. After 30 days of age, coagulase-negative Staphylococcus is still the most common organism causing nosocomial bacteremia. However, fungi, particularly Candida31Benjamin D.K. Garges H. Steinbach W.J. Candida bloodstream infection in neonates.Semin Perinatol. 2003; 27: 375-383Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar species, and Malassezia furfur become more prominent. Infants whose birth weights are 2500 grams4.13.7NNIS pneumonia rate†Rates are the number of pneumonias per 1000 ventilator days. ≤1000 grams3.43.3 1001-1500 grams2.22.5 1501-2500 grams1.92.1 >2500 grams1.01.4∗ Rates are the number of bacteremias per 1000 catheter days.† Rates are the number of pneumonias per 1000 ventilator days. Open table in a new tab Critically ill neonates frequently have underlying respiratory tract conditions (hyaline membrane disease, bronchopulmonary dysplasia, meconium aspiration syndrome, and others). The respiratory status of the neonate may be further compromised by the development of pneumonia or tracheitis (Table 4). Similar to bacteremia, respiratory tract infections can be divided into groups by time of onset: early onset pneumonia versus late onset pneumonia/tracheitis. In the first few days of life, neonates who develop pneumonia usually have infections with microorganisms acquired natally. Group B Streptococcus, Listeria monocytogenes, and gram-negative enteric rods may result in an overwhelming respiratory tract infection that may be present very shortly after birth.33Webber S. Wilkinson A.R. Lindsell D. Hope P.L. Dobson S.R.M. Isaacs D. Neonatal pneumonia.Arch Dis Child. 1990; 65: 207-211Crossref PubMed Scopus (84) Google Scholar Late onset pneumonia and tracheitis are more commonly because of infection with gram-negative enteric bacilli and Staphylococcus aureus. Endotracheal intubation is the major risk factor.33Webber S. Wilkinson A.R. Lindsell D. Hope P.L. Dobson S.R.M. Isaacs D. Neonatal pneumonia.Arch Dis Child. 1990; 65: 207-211Crossref PubMed Scopus (84) Google Scholar, 34Mas-Muñoz R.L. Udaeta-Mora E. Rivera-Rueda M.A. Morales-Suárez M. Infectión nosocomial en recién nacidos con ventilación mecanica.Bol Med Hosp. Infant Mex. 1992; 49: 839-844PubMed Google Scholar As with other invasive device-related infections, health care-associated pneumonia and tracheitis can be reduced by minimizing intubation days and proper care and maintenance of the ventilator-endotracheal tube circuit. Colonization of the endotracheal tube is virtually inevitable. Lower respiratory tract disease is not established by the mere presence of bacteria isolated from samples of the respiratory tract. Rather, lower respiratory tract disease is diagnosed by changes in respiratory tract signs and symptoms (eg, changes in oxygen requirements, new or changing infiltrates on the chest x-ray, increased volume or change in consistency of secretions suctioned from the endotracheal tube) combined with evidence of an acute inflammatory response, such as fever or polymorphonuclear leukocytes and a predominant bacteria on gram stain of tracheal secretions. Infants in the NICU are particularly vulnerable to community-acquired viruses. Respiratory syncytial virus (RSV), adenovirus, parainfluenza, and influenza can be devastating to the critically ill neonate and may be responsible for nursery-wide outbreaks.35Thwaites R. Piercy J. Nosocomial respiratory syncytial virus infection in neonatal units in the United Kingdom.Acta Paediatr Suppl. 2004; 93: 23-25Crossref PubMed Scopus (15) Google Scholar, 36Gelber S.E. Ratner A.J. Hospital-acquired viral pathogens in the neonatal intensive care unit.Semin Perinatol. 2002; 26: 346-356Abstract Full Text PDF PubMed Scopus (34) Google Scholar, 37Cunney R. Bialachowski A. Thornley D. Smaill F.M. Pennie R.A. An outbreak of influenza A in a neonatal intensive care unit.Infect Control Hosp Epidemiol. 2000; 21: 449-454Crossref PubMed Scopus (155) Google Scholar Immature gastrointestinal immunity, diminished interfering normal microbial flora, higher gastric pH, shorter gastric emptying time, increased permeability of gastrointestinal mucosa, and use of nasogastric tubes place the critically ill neonates at particular risk for acquiring gastrointestinal infections while in the NICU. Specific agents responsible for gastrointestinal disease may vary, based on the geographic location of the nursery, but viruses such as rotavirus,38Sharma R. Hudak M.L. Premachandra B.R. Stevens G. Monteiro C.B. 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