Subscribe to RSS
DOI: 10.1055/s-0032-1333413
Recent Developments and Current Issues in the Epidemiology, Diagnosis, and Management of Bacterial and Fungal Neonatal Sepsis
Publication History
23 August 2012
07 December 2012
Publication Date:
07 January 2013 (online)
![](https://www.thieme-connect.de/media/ajp/201302/lookinside/thumbnails/10.1055-s-0032-1333413-1.jpg)
Abstract
Identifying neonates with sepsis is complicated by variability in clinical presentation. The incidence of early onset sepsis (EOS) resulting from invasive group B streptococcal (GBS) infections has been notably reduced by the widespread delivery of intrapartum antibiotic prophylaxis. Rates of EOS attributable to non-GBS etiologies have remained constant, and ampicillin-resistant Escherichia coli has become more prevalent. Late-onset sepsis (LOS) attributable to gram-positive organisms including coagulase-negative Staphylococci and Staphylococcus aureus is associated with increased morbidity and mortality among premature infants. Invasive candidiasis is an emerging cause of LOS, especially among infants who receive broad-spectrum antimicrobial agents. Prophylactic fluconazole administration to very low-birth-weight (VLBW) neonates during the first 6 weeks of life prevents invasive candidiasis in neonatal intensive care units (NICU) with high rates of fungal infections. Targeted fluconazole prophylaxis may be beneficial in VLBW neonates who receive care in NICUs with lower rates of invasive fungal infections. Assessment of immune function, neutrophil markers, acute phase reactants, and utilization of sepsis screening scores may contribute to the management of sepsis. Maternal decolonization, antimicrobial stewardship, early enteral feeding, and optimal infection control practices are potential practical strategies for reducing the burden of neonatal sepsis.
-
References
- 1 Tissières P, Ochoda A, Dunn-Siegrist I , et al. Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ. PLoS ONE 2012; 7: e32863
- 2 Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin Perinatol 2010; 37: 307-337
- 3 Schrag SJ, Stoll BJ. Early-onset neonatal sepsis in the era of widespread intrapartum chemoprophylaxis. Pediatr Infect Dis J 2006; 25: 939-940
- 4 Schuchat A, Zywicki SS, Dinsmoor MJ , et al. Risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case-control study. Pediatrics 2000; 105 (1 Pt 1) 21-26
- 5 Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol 2010; 37: 339-354
- 6 Alexander JM. Epidural analgesia for labor pain and its relationship to fever. Clin Perinatol 2005; 32: 777-787
- 7 Stoll BJ, Hansen NI, Bell EF , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010; 126: 443-456
- 8 Gibbs RS, Duff P. Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol 1991; 164 (5 Pt 1) 1317-1326
- 9 Romero R, Quintero R, Oyarzun E , et al. Intraamniotic infection and the onset of labor in preterm premature rupture of the membranes. Am J Obstet Gynecol 1988; 159: 661-666
- 10 Goldenberg RL, Andrews WW, Goepfert AR , et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 2008; 198: e1-e5
- 11 Weston EJ, Pondo T, Lewis MM , et al. The burden of invasive early-onset neonatal sepsis in the United States, 2005–2008. Pediatr Infect Dis J 2011; 30: 937-941
- 12 Stoll BJ, Hansen NI, Sánchez PJ , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics 2011; 127: 817-826
- 13 Hornik CP, Fort P, Clark RH , et al. Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. Early Hum Dev 2012; 88 (Suppl. 02) S69-S74
- 14 Lim DV, Morales WJ, Walsh AF, Kazanis D. Reduction of morbidity and mortality rates for neonatal group B streptococcal disease through early diagnosis and chemoprophylaxis. J Clin Microbiol 1986; 23: 489-492
- 15 Boyer KM, Gotoff SP. Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. N Engl J Med 1986; 314: 1665-1669
- 16 Centers for Disease Control and Prevention. Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC, 2010. MMWR 2010; 1-36
- 17 Moore MR, Schrag SJ, Schuchat A. Effects of intrapartum antimicrobial prophylaxis for prevention of group-B-streptococcal disease on the incidence and ecology of early-onset neonatal sepsis. Lancet Infect Dis 2003; 3: 201-213
- 18 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 (2 Pt 1) 285-291
- 19 Glasgow TS, Young PC, Wallin J , et al. Association of intrapartum antibiotic exposure and late-onset serious bacterial infections in infants. Pediatrics 2005; 116: 696-702
- 20 Cohen-Wolkowiez M, Moran C, Benjamin DK , et al. Early and late onset sepsis in late preterm infants. Pediatr Infect Dis J 2009; 28: 1052-1056
- 21 Healy CM, Baker CJ, Palazzi DL, Campbell JR, Edwards MS. Distinguishing true coagulase-negative Staphylococcus infections from contaminants in the neonatal intensive care unit. J Perinatol 2012;
- 22 Shane AL, Hansen NI, Stoll BJ , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Methicillin-resistant and susceptible Staphylococcus aureus bacteremia and meningitis in preterm infants. Pediatrics 2012; 129: e914-e922
- 23 Leibovitz E. Strategies for the prevention of neonatal candidiasis. Pediatr Neonatol 2012; 53: 83-89
- 24 Benjamin Jr DK, Stoll BJ, Fanaroff AA , et al; National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006; 117: 84-92
- 25 Kaufman DA. Challenging issues in neonatal candidiasis. Curr Med Res Opin 2010; 26: 1769-1778
- 26 Benjamin Jr DK, Poole C, Steinbach WJ, Rowen JL, Walsh TJ. Neonatal candidemia and end-organ damage: a critical appraisal of the literature using meta-analytic techniques. Pediatrics 2003; 112 (3 Pt 1) 634-640
- 27 Benjamin Jr DK, Stoll BJ, Gantz MG , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics 2010; 126: e865-e873
- 28 Ascher SB, Smith PB, Watt K , et al. Antifungal therapy and outcomes in infants with invasive Candida infections. Pediatr Infect Dis J 2012; 31: 439-443
- 29 Stoll BJ, Hansen NI, Adams-Chapman I , et al; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292: 2357-2365
- 30 Ascher SB, Smith PB, Clark RH , et al. Sepsis in young infants with congenital heart disease. Early Hum Dev 2012; 88 (Suppl. 02) S92-S97
- 31 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: 275-278
- 32 Neal PR, Kleiman MB, Reynolds JK, Allen SD, Lemons JA, Yu PL. Volume of blood submitted for culture from neonates. J Clin Microbiol 1986; 24: 353-356
- 33 Connell TG, Rele M, Cowley D, Buttery JP, Curtis N. How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children's hospital. Pediatrics 2007; 119: 891-896
- 34 Isaacs D, Barfield CP, Grimwood K, McPhee AJ, Minutillo C, Tudehope DI. Australian Study Group for Neonatal Infections. Systemic bacterial and fungal infections in infants in Australian neonatal units. Med J Aust 1995; 162: 198-201
- 35 May M, Daley AJ, Donath S, Isaacs D. Australasian Study Group for Neonatal Infections. Early onset neonatal meningitis in Australia and New Zealand, 1992–2002. Arch Dis Child Fetal Neonatal Ed 2005; 90: F324-F327
- 36 Stoll BJ, Hansen N, Fanaroff AA , et al. To tap or not to tap: high likelihood of meningitis without sepsis among very low birth weight infants. Pediatrics 2004; 113: 1181-1186
- 37 Garges HP, Moody MA, Cotten CM , et al. Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters?. Pediatrics 2006; 117: 1094-1100
- 38 Wynn JL, Tan S, Gantz MG , et al; NICHD Neonatal Research Network. Outcomes following candiduria in extremely low birth weight infants. Clin Infect Dis 2012; 54: 331-339
- 39 Polin RA. Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics 2012; 129: 1006-1015
- 40 Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Immune status in very preterm neonates. Pediatrics 2012; 129: e967-e974
- 41 Newman TB, Puopolo KM, Wi S, Draper D, Escobar GJ. Interpreting complete blood counts soon after birth in newborns at risk for sepsis. Pediatrics 2010; 126: 903-909
- 42 Rozycki HJ, Stahl GE, Baumgart S. Impaired sensitivity of a single early leukocyte count in screening for neonatal sepsis. Pediatr Infect Dis J 1987; 6: 440-442
- 43 Hornik CP, Benjamin DK, Becker KC , et al. Use of the complete blood cell count in early-onset neonatal sepsis. Pediatr Infect Dis J 2012; 31: 799-802
- 44 Hornik CP, Benjamin DK, Becker KC , et al. Use of the complete blood cell count in late-onset neonatal sepsis. Pediatr Infect Dis J 2012; 31: 803-807
- 45 Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clin Perinatol 1991; 18: 361-381
- 46 Lloyd BW, Oto A. Normal values for mature and immature neutrophils in very preterm babies. Arch Dis Child 1982; 57: 233-235
- 47 Gerdes JS, Polin RA. Sepsis screen in neonates with evaluation of plasma fibronectin. Pediatr Infect Dis J 1987; 6: 443-446
- 48 Bhandari V, Wang C, Rinder C, Rinder H. Hematologic profile of sepsis in neonates: neutrophil CD64 as a diagnostic marker. Pediatrics 2008; 121: 129-134
- 49 Streimish I, Bizzarro M, Northrup V , et al. Neutrophil CD64 as a diagnostic marker in neonatal sepsis. Pediatr Infect Dis J 2012; 31: 777-781
- 50 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 (6 Pt 1) 1411-1415
- 51 Manzoni P, Mostert M, Galletto P , et al. Is thrombocytopenia suggestive of organism-specific response in neonatal sepsis?. Pediatr Int 2009; 51: 206-210
- 52 Byington CL, Kendrick J, Sheng X. Normative cerebrospinal fluid profiles in febrile infants. J Pediatr 2011; 158: 130-134
- 53 Kestenbaum LA, Ebberson J, Zorc JJ, Hodinka RL, Shah SS. Defining cerebrospinal fluid white blood cell count reference values in neonates and young infants. Pediatrics 2010; 125: 257-264
- 54 Kanegaye JT, Nigrovic LE, Malley R , et al; American Academy of Pediatrics, Pediatric Emergency Medicine Collaborative Research Committee. Diagnostic value of immature neutrophils (bands) in the cerebrospinal fluid of children with cerebrospinal fluid pleocytosis. Pediatrics 2009; 123: e967-e971
- 55 Smith PB, Cotten CM, Garges HP , et al. A comparison of neonatal Gram-negative rod and Gram-positive cocci meningitis. J Perinatol 2006; 26: 111-114
- 56 Shah SS, Ebberson J, Kestenbaum LA, Hodinka RL, Zorc JJ. Age-specific reference values for cerebrospinal fluid protein concentration in neonates and young infants. J Hosp Med 2011; 6: 22-27
- 57 Smith PB, Garges HP, Cotton CM, Walsh TJ, Clark RH, Benjamin Jr DK. Meningitis in preterm neonates: importance of cerebrospinal fluid parameters. Am J Perinatol 2008; 25: 421-426
- 58 Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340: 448-454
- 59 Philip AG. Response of C-reactive protein in neonatal group B streptococcal infection. Pediatr Infect Dis 1985; 4: 145-148
- 60 Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998; 102: E41
- 61 Hofer N, Zacharias E, Müller W, Resch B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012; 102: 25-36
- 62 Benitz WE. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin Perinatol 2010; 37: 421-438
- 63 Dandona P, Nix D, Wilson MF , et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab 1994; 79: 1605-1608
- 64 Lapillonne A, Basson E, Monneret G, Bienvenu J, Salle BL. Lack of specificity of procalcitonin for sepsis diagnosis in premature infants. Lancet 1998; 351: 1211-1212
- 65 Chiesa C, Natale F, Pascone R , et al. C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period. Clin Chim Acta 2011; 412: 1053-1059
- 66 Raynor LL, Saucerman JJ, Akinola MO, Lake DE, Moorman JR, Fairchild KD. Cytokine screening identifies NICU patients with Gram-negative bacteremia. Pediatr Res 2012; 71: 261-266
- 67 Chiesa C, Panero A, Osborn JF, Simonetti AF, Pacifico L. Diagnosis of neonatal sepsis: a clinical and laboratory challenge. Clin Chem 2004; 50: 279-287
- 68 Lim L, Rozycki HJ. Postnatal SNAP-II scores in neonatal intensive care unit patients: relationship to sepsis, necrotizing enterocolitis, and death. J Matern Fetal Neonatal Med 2008; 21: 415-419
- 69 Bryan CS, John Jr JF, Pai MS, Austin TL. Gentamicin vs cefotaxime for therapy of neonatal sepsis. Relationship to drug resistance. Am J Dis Child 1985; 139: 1086-1089
- 70 Manzoni P, Esposito S, Gallo E, Gastaldo L, Farina D, Principi N. Switch therapy in full-term neonates with presumed or proven bacterial infection. J Chemother 2009; 21: 68-73
- 71 Manzoni P, Rizzollo S, Decembrino L , et al. Recent advances in prevention of sepsis in the premature neonates in NICU. Early Hum Dev 2011; 87 (Suppl. 01) S31-S33
- 72 Bégué P, Floret D, Mallet E , et al. Pharmacokinetics and clinical evaluation of cefotaxime in children suffering with purulent meningitis. J Antimicrob Chemother 1984; 14 (Suppl B): 161-165
- 73 Pickering L , ed. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012
- 74 Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr 2011; 159: 392-397
- 75 Clark RH, Gordon P, Walker WM, Laughon M, Smith PB, Spitzer AR. Characteristics of patients who die of necrotizing enterocolitis. J Perinatol 2012; 32: 199-204
- 76 Cotton CM. Early, prolonged use of postnatal antibiotics increased the risk of necrotising enterocolitis. Arch Dis Child Educ Pract Ed 2010; 95: 94
- 77 Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr 2011; 159: 720-725
- 78 Wade KC, Wu D, Kaufman DA , et al; National Institute of Child Health and Development Pediatric Pharmacology Research Unit Network. Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother 2008; 52: 4043-4049
- 79 Wade KC, Benjamin Jr DK, Kaufman DA , et al. Fluconazole dosing for the prevention or treatment of invasive candidiasis in young infants. Pediatr Infect Dis J 2009; 28: 717-723
- 80 Carver PL. Micafungin. Ann Pharmacother 2004; 38: 1707-1721
- 81 Murdoch D, Plosker GL. Anidulafungin. Drugs 2004; 64: 2249-2258 ; discussion 2259–2260
- 82 Smith PB, Walsh TJ, Hope W , et al. Pharmacokinetics of an elevated dosage of micafungin in premature neonates. Pediatr Infect Dis J 2009; 28: 412-415
- 83 Sáez-Llorens X, Macias M, Maiya P , et al. Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age. Antimicrob Agents Chemother 2009; 53: 869-875
- 84 Natarajan G, Lulic-Botica M, Aranda JV. Refractory neonatal candidemia and high-dose micafungin pharmacotherapy. J Perinatol 2009; 29: 738-743
- 85 Benjamin Jr DK, Smith PB, Arrieta A , et al. Safety and pharmacokinetics of repeat-dose micafungin in young infants. Clin Pharmacol Ther 2010; 87: 93-99
- 86 Chapman RL, Faix RG. Persistently positive cultures and outcome in invasive neonatal candidiasis. Pediatr Infect Dis J 2000; 19: 822-827
- 87 Linder N, Klinger G, Shalit I , et al. Treatment of candidaemia in premature infants: comparison of three amphotericin B preparations. J Antimicrob Chemother 2003; 52: 663-667
- 88 Pappas PG, Kauffman CA, Andes D , et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48: 503-535
- 89 Brass EP, Edwards JE. Should the guidelines for management of central venous catheters in patients with candidemia be changed now?. Clin Infect Dis 2010; 51: 304-306
- 90 Vasudevan C, McGuire W. Early removal versus expectant management of central venous catheters in neonates with bloodstream infection. Cochrane Database Syst Rev 2011; (8) CD008436
- 91 Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med 2001; 345: 1660-1666
- 92 Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole-resistant Candida species. Pediatrics 2008; 121: 703-710
- 93 Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Fluconazole prophylaxis prevents invasive fungal infection in high-risk, very low birth weight infants. J Pediatr 2005; 147: 162-165
- 94 Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on incidence and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005; 147: 166-171
- 95 Kaufman D. Fluconazole prophylaxis decreases the combined outcome of invasive Candida infections or mortality in preterm infants. Pediatrics 2008; 122: 1158-1159 ; author reply 1159
- 96 Manzoni P, Stolfi I, Pugni L , et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections; Italian Society of Neonatology. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med 2007; 356: 2483-2495
- 97 Uko S, Soghier LM, Vega M , et al. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants. Pediatrics 2006; 117: 1243-1252
- 98 Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev 2004; 17: 638-680
- 99 Noyola DE, Fernandez M, Moylett EH, Baker CJ. Ophthalmologic, visceral, and cardiac involvement in neonates with candidemia. Clin Infect Dis 2001; 32: 1018-1023
- 100 Schulman J, Stricof R, Stevens TP , et al; New York State Regional Perinatal Care Centers. Statewide NICU central-line-associated bloodstream infection rates decline after bundles and checklists. Pediatrics 2011; 127: 436-444
- 101 Aly H, Herson V, Duncan A , et al. Is bloodstream infection preventable among premature infants? A tale of two cities. Pediatrics 2005; 115: 1513-1518
- 102 Del Vecchio A, Christensen RD. Neonatal neutropenia: what diagnostic evaluation is needed and when is treatment recommended?. Early Hum Dev 2012; 88 (Suppl. 02) S19-S24
- 103 El-Ganzoury MM, El-Farrash RA, Saad AA, Mohamed AG, El-Sherbini IG. In vivo effect of recombinant human granulocyte colony-stimulating factor on neutrophilic expression of CD11b in septic neonates: a randomized controlled trial. Pediatr Hematol Oncol 2012; 29: 272-284
- 104 Carr R, Modi N, Doré CG-CSF. G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Syst Rev 2003; (3) CD003066
- 105 Napolitano LM. Immune stimulation in sepsis: to be or not to be?. Chest 2005; 127: 1882-1885
- 106 Ohlsson A, Lacy J. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev 2010; (3) CD001239
- 107 Brocklehurst P, Farrell B, King A , et al; INIS Collaborative Group. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med 2011; 365: 1201-1211
- 108 Morinis J, Shah J, Murthy P, Fulford M. Horizontal transmission of group B streptococcus in a neonatal intensive care unit. Paediatr Child Health (Oxford) 2011; 16: e48-e50
- 109 Köser CU, Holden MT, Ellington MJ , et al. Rapid whole-genome sequencing for investigation of a neonatal MRSA outbreak. N Engl J Med 2012; 366: 2267-2275
- 110 Manzoni P, Rinaldi M, Cattani S , et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009; 302: 1421-1428
- 111 Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev 2011; (10) CD007138