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• W4207054385 abstract "Neonatal septicemia (sepsis) remains a major cause of worldwide morbidity and mortality among term and preterm infants. The term “sepsis” originates from the Greek meaning “to rot.” The modern term came into use in 1914 and meant a change in symptomatology caused by infection and identified by a set of subjective and objective factors.1Gyawali B. Ramakrishna K. Dhamoon A.S. Sepsis: the evolution in definition, pathophysiology, and management.SAGE Open Med. 2019; 7 (2050312119835043)Crossref PubMed Google Scholar In the 21st century, the generally accepted criterion is organ dysfunction accompanying infection. The consensus definition for sepsis has continued to evolve but remains difficult to define, particularly in the neonatal intensive care unit (NICU).2Fleiss N. Coggins S.A. Lewis A.N. Zeigler A. Cooksey K.E. Walker L.A. et al.Evaluation of the neonatal sequential organ failure assessment and mortality risk in preterm infants with late-onset infection.JAMA Netw Open. 2021; 4: e2036518Crossref PubMed Scopus (17) Google Scholar Formal definitions, such as proposed in the Third International Consensus Definitions for Sepsis and Septic Shock, rely on evidence of end-organ dysfunction.3Matics T.J. Sanchez-Pinto L.N. Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the sepsis-3 definitions in critically ill children.JAMA Pediatr. 2017; 171: e172352Crossref PubMed Scopus (204) Google Scholar Neonatal adaptations of these formal definitions can predict mortality from neonatal sepsis.2Fleiss N. Coggins S.A. Lewis A.N. Zeigler A. Cooksey K.E. Walker L.A. et al.Evaluation of the neonatal sequential organ failure assessment and mortality risk in preterm infants with late-onset infection.JAMA Netw Open. 2021; 4: e2036518Crossref PubMed Scopus (17) Google Scholar,4Zeigler A.C. Ainsworth J.E. Fairchild K.D. Wynn J.L. Sullivan B.A. Sepsis and mortality prediction in very low birth weight infants: analysis of HeRO and nSOFA.Am J Perinatol. 2021; : 1-8Google Scholar, 5Wynn J.L. Polin R.A. A neonatal sequential organ failure assessment score predicts mortality to late-onset sepsis in preterm very low birth weight infants.Pediatr Res. 2020; 88: 85-90Crossref PubMed Scopus (37) Google Scholar, 6Singer M. Deutschman C.S. Seymour C.W. Shankar-Hari M. Annane D. Bauer M. et al.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).JAMA. 2016; 315: 801-810Crossref PubMed Scopus (9719) Google Scholar However, the commonly used, colloquial definition of neonatal sepsis is an infant who has clinical or laboratory signs of infection, a positive bacterial culture usually from a sterile site such as blood or cerebrospinal fluid, and who would benefit from appropriate antibacterial treatment.2Fleiss N. Coggins S.A. Lewis A.N. Zeigler A. Cooksey K.E. Walker L.A. et al.Evaluation of the neonatal sequential organ failure assessment and mortality risk in preterm infants with late-onset infection.JAMA Netw Open. 2021; 4: e2036518Crossref PubMed Scopus (17) Google Scholar,7Shane A.L. Sanchez P.J. Stoll B.J. Neonatal sepsis.Lancet. 2017; 390: 1770-1780Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar Ancillary biomarkers such as complete blood count (CBC) with differential count of leukocytes, C-reactive protein, or procalcitonin are frequently used to guide the diagnosis of sepsis, although none has been proven to be highly reliable.8Hornik C.P. Benjamin D.K. Becker K.C. Benjamin Jr., D.K. Li J. Clark R.H. et al.Use of the complete blood cell count in late-onset neonatal sepsis.Pediatr Infect Dis J. 2012; 31: 803-807Crossref PubMed Scopus (58) Google Scholar, 9Brown J.V.E. Meader N. Wright K. Cleminson J. McGuire W. Assessment of C-reactive protein diagnostic test accuracy for late-onset infection in newborn infants: a systematic review and meta-analysis.JAMA Pediatr. 2020; 174: 260-268Crossref PubMed Scopus (27) Google Scholar, 10Pontrelli G. De Crescenzo F. Buzzetti R. Jenkner A. Balduzzi S. Calò Carducci F. et al.Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis.BMC Infect Dis. 2017; 17: 302Crossref PubMed Scopus (50) Google Scholar A common clinical scenario is an infant evaluated for sepsis whose bacterial cultures are sterile—but who has/has had symptoms or ancillary laboratory values that are concerning for infection. If the clinician decides that the infant would benefit from a full treatment course of empiric antibacterial therapy, the infant is treated for “culture-negative” sepsis.11Cantey J.B. Baird S.D. Ending the culture of culture-negative sepsis in the neonatal ICU.Pediatrics. 2017; 140: e20170044Crossref PubMed Scopus (67) Google Scholar This phenomenon occurs frequently; studies suggest that the diagnosis of culture-negative sepsis exceeds the incidence of proven sepsis by up to 16-fold in the US and up to 50-fold in low-to-middle income countries.12Turner C. Turner P. Hoogenboom G. Aye Mya Thein N. McGready R. Phakaudom K. et al.A three-year descriptive study of early onset neonatal sepsis in a refugee population on the Thailand Myanmar border.BMC Infect Dis. 2013; 13: 601Crossref PubMed Scopus (0) Google Scholar,13Klingenberg C. Kornelisse R.F. Buonocore G. Maier R.F. Stocker M. Culture-negative early-onset neonatal sepsis—at the crossroad between efficient sepsis care and antimicrobial stewardship.Front Pediatr. 2018; 6: 285Crossref PubMed Scopus (75) Google Scholar As a result, culture-negative sepsis represents a major proportion of antibiotic use, accounting for 10%-20% of all antibiotic use in the NICU.13Klingenberg C. Kornelisse R.F. Buonocore G. Maier R.F. Stocker M. Culture-negative early-onset neonatal sepsis—at the crossroad between efficient sepsis care and antimicrobial stewardship.Front Pediatr. 2018; 6: 285Crossref PubMed Scopus (75) Google Scholar, 14Prusakov P. Goff D.A. Wozniak P.S. Cassim A. Scipion C.E.A. Urzúa S. et al.A global point prevalence survey of antimicrobial use in neonatal intensive care units: the no-more-antibiotics and resistance (NO-MAS-R) study.E Clin Med. 2021; 32: 100727Google Scholar, 15Cantey J.B. Wozniak P.S. Pruszynski J.E. Sánchez P.J. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study.Lancet Infect Dis. 2016; 16: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar The implications (ie, outcomes) of neonatal culture-negative sepsis are unclear. Unquestionably, culture-proven sepsis in neonates is associated with mortality.2Fleiss N. Coggins S.A. Lewis A.N. Zeigler A. Cooksey K.E. Walker L.A. et al.Evaluation of the neonatal sequential organ failure assessment and mortality risk in preterm infants with late-onset infection.JAMA Netw Open. 2021; 4: e2036518Crossref PubMed Scopus (17) Google Scholar,4Zeigler A.C. Ainsworth J.E. Fairchild K.D. Wynn J.L. Sullivan B.A. Sepsis and mortality prediction in very low birth weight infants: analysis of HeRO and nSOFA.Am J Perinatol. 2021; : 1-8Google Scholar,5Wynn J.L. Polin R.A. A neonatal sequential organ failure assessment score predicts mortality to late-onset sepsis in preterm very low birth weight infants.Pediatr Res. 2020; 88: 85-90Crossref PubMed Scopus (37) Google Scholar However, limited data suggest that culture-negative sepsis may not be associated with increased risk for death.16Jiang S. Yang Z. Shan R. Zhang Y. Yan W. Yang Y. et al.Neonatal outcomes following culture-negative late-onset sepsis among preterm infants.Pediatr Infect Dis J. 2020; 39: 232-238Crossref PubMed Scopus (6) Google Scholar,17Mukhopadhyay S. Puopolo K.M. Hansen N.I. Lorch S.A. DeMauro S.B. Greenberg R.G. et al.Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions.Arch Dis Child Fetal Neonatal Ed. 2021; 106: 467-473Crossref PubMed Scopus (1) Google Scholar The impact of culture-negative sepsis on neurodevelopmental outcome is unclear. Some studies have found that infants with culture-negative sepsis compared with uninfected infants are at increased risk for adverse neurodevelopmental outcomes.16Jiang S. Yang Z. Shan R. Zhang Y. Yan W. Yang Y. et al.Neonatal outcomes following culture-negative late-onset sepsis among preterm infants.Pediatr Infect Dis J. 2020; 39: 232-238Crossref PubMed Scopus (6) Google Scholar In a large retrospective cohort of extremely low birthweight (<1000 g) infants, Mukhopadhyay et al found a 17% increase in neurodevelopmental impairment at age 2 years in those with culture-negative sepsis compared with unaffected infants (relative risk 1.17 [95% CI 1.04-1.31]).17Mukhopadhyay S. Puopolo K.M. Hansen N.I. Lorch S.A. DeMauro S.B. Greenberg R.G. et al.Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions.Arch Dis Child Fetal Neonatal Ed. 2021; 106: 467-473Crossref PubMed Scopus (1) Google Scholar Other studies have not found an association between culture-negative sepsis and neurodevelopmental impairment in extremely preterm infants.18Schlapbach L.J. Aebischer M. Adams M. Natalucci G. Bonhoeffer J. Latzin P. et al.Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants.Pediatrics. 2011; 128: e348-e357Crossref PubMed Scopus (237) Google Scholar It is noteworthy that the duration of antibiotic treatment for culture-negative sepsis is not associated with NICU length of stay or mortality.15Cantey J.B. Wozniak P.S. Pruszynski J.E. Sánchez P.J. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study.Lancet Infect Dis. 2016; 16: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,19Songer C.N. Calip G.S. Srinivasan N. Barbosa V.M. Pham J.T. Factors influencing antibiotic duration in culture-negative neonatal early-onset sepsis.Pharmacotherapy. 2021; 41: 148-161Crossref PubMed Scopus (1) Google Scholar For these reasons, reducing duration of therapy has become a high-yield target for antibiotic stewardship programs.15Cantey J.B. Wozniak P.S. Pruszynski J.E. Sánchez P.J. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study.Lancet Infect Dis. 2016; 16: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,20Kopsidas I. Tsopela G.C. Molocha N.M. Bouza E. Chorafa E. Chorianopoulou E. et al.Reducing duration of antibiotic use for presumed neonatal early-onset sepsis in Greek NICUs. A “low-hanging fruit” approach.Antibiotics (Basel). 2021; 10: 275Crossref PubMed Scopus (0) Google Scholar,21McCarthy K.N. Hawke A. Dempsey E.M. Antimicrobial stewardship in the neonatal unit reduces antibiotic exposure.Acta Paediatr. 2018; 107: 1716-1721Crossref PubMed Scopus (18) Google Scholar There are 2 significant negative effects associated with the overdiagnosis of culture-negative sepsis. The first is that infants without bacterial infection accrue only the adverse effects of prolonged antibiotic use without any benefit. These adverse effects include short-term complications (increased risk for late-onset sepsis, necrotizing enterocolitis, and mortality)22Cotten C.M. Taylor S. Stoll B. Goldberg R.N. Hansen N.I. Sánchez P.J. et al.Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants.Pediatrics. 2009; 123: 58-66Crossref PubMed Scopus (592) Google Scholar, 23Kuppala V.S. Meinzen-Derr J. Morrow A.L. Schibler K.R. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants.J Pediatr. 2011; 159: 720-725Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 24Abdel Ghany E.A. Ali A.A. Empirical antibiotic treatment and the risk of necrotizing enterocolitis and death in very low birth weight neonates.Ann Saudi Med. 2012; 32: 521-526Crossref PubMed Scopus (26) Google Scholar, 25Alexander V.N. Northrup V. Bizzarro M.J. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis.J Pediatr. 2011; 159: 392-397Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar and long-term complications (increased risk for colonization with drug-resistant bacteria,26Iosifidis E. Evdoridou I. Agakidou E. Chochliourou E. Protonotariou E. Karakoula K. et al.Vancomycin-resistant Enterococcus outbreak in a neonatal intensive care unit: epidemiology, molecular analysis and risk factors.Am J Infect Control. 2013; 41: 857-861Abstract Full Text Full Text PDF PubMed Google Scholar atopic diseases,27Mubanga M. Lundholm C. D'Onofrio B.M. Stratmann M. Hedman A. Almqvist C. Association of early life exposure to antibiotics with risk of atopic dermatitis in Sweden.JAMA Network open. 2021; 4: e215245Crossref PubMed Scopus (4) Google Scholar,28Zou Z. Liu W. Huang C. Sun C. Zhang J. First-year antibiotics exposure in relation to childhood asthma, allergies, and airway illnesses.Int J Environ Res Public Health. 2020; 17: 5700Crossref Scopus (5) Google Scholar and obesity29Chelimo C. Camargo Jr., C.A. Morton S.M.B. Grant C.C. Association of repeated antibiotic exposure up to age 4 years with body mass at age 4.5 years.JAMA Network Open. 2020; 3: e1917577Crossref PubMed Scopus (14) Google Scholar,30Leong K.S.W. McLay J. Derraik J.G.B. Gibb S. Shackleton N. Taylor R.W. et al.Associations of Prenatal and childhood antibiotic exposure with obesity at age 4 years.JAMA Network Open. 2020; 3: e1919681Crossref PubMed Scopus (11) Google Scholar). The second is that the diagnosis of culture-negative sepsis may be incorrect, potentially leading to failure to diagnose and manage a different, clinically relevant condition. Infants with culture-negative sepsis have real clinical and/or laboratory changes and lead to their evaluation and empiric treatment. A phenomenon is defined as a situation that is reliably observed, but whose cause or explanation is in question.31Phenomenon. Merriam-Webster Dictionary. 1st ed. Merriam-Webster, Springfield, MA2016Google Scholar It is impossible to dismiss out of hand the frequent observation of sepsis-like events in neonates who have sterile blood cultures, but how do we investigate this phenomenon to improve our understanding and management? The purpose of this review is to provide a framework for understanding the differential diagnosis and pragmatic management of culture-negative sepsis in NICU. The first step to creating a framework for better understanding and management of potential culture-negative sepsis is to define and explore the differential diagnosis (Table I). Infectious considerations include localized bacterial infection without bacteremia; bacterial sepsis in which the blood cultures are falsely negative due to poor blood culture technique, pre-event blood collection, pretreatment with antimicrobial therapy; sepsis caused by bacteria that do not readily grow in standard media; and sepsis caused by a pathogen other than bacteria or yeast. Most importantly, the differential diagnosis includes conditions that are not related to infection. These conditions are discussed in more detail below.Table IClinical scenarios that can be diagnosed as “culture-negative” sepsisNoninfectious sepsis-like syndromePhysiologic instability due to prematurityFocal bacterial infection without bacteremiaViral sepsisFungal sepsisParasitic sepsisProbable bacterial sepsis, insufficient volumeProbable bacterial sepsis, pretreatedProbable bacterial sepsis, premature cultureProbable bacterial sepsis, anaerobicProbable bacterial sepsis, fastidiousProbable bacterial sepsis, unculturableProbable bacterial sepsis, ultra-low bacterial concentration Open table in a new tab There are myriad noninfectious causes of sepsis-like illness in neonates. Neonates and young infants have an extremely limited repertoire of clinical signs of unwellness. Therefore, many different etiologies can result in a phenotype that is consistent with—but not specific for—sepsis. Prematurity itself can cause sepsis-like physiologic changes. Prematurity can cause hypotension in the first few days of life due to decreased peripheral vascular resistance, low cardiac output, and the presence of patent ductus arteriosus; respiratory distress due to surfactant deficiency and increased chest wall compliance; apnea due to immature central respiratory centers; temperature instability due to low body weight, high body surface area, and immature skin; and more.32Aldana-Aguirre J.C. Deshpande P. Jain A. Weisz D.E. Physiology of low blood pressure during the first day after birth among extremely preterm neonates.J Pediatr. 2021; 236: 40-46.e3Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 33Owen L.S. Manley B.J. Davis P.G. Doyle L.W. The evolution of modern respiratory care for preterm infants.Lancet. 2017; 389: 1649-1659Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 34Erickson G. Dobson N.R. Hunt C.E. Immature control of breathing and apnea of prematurity: the known and unknown.J Perinatol. 2021; 41: 2111-2123Crossref PubMed Scopus (3) Google Scholar Adrenal insufficiency occurs in a plurality of extremely preterm infants and causes hypotension and poor perfusion.35Aucott S.W. The challenge of defining relative adrenal insufficiency.J Perinatol. 2012; 32: 397-398Crossref PubMed Scopus (7) Google Scholar Each of these conditions is associated with negative outcomes, but none is caused by infection. These conditions of prematurity are far more common than sepsis; almost every extremely preterm infant will experience surfactant deficiency and temperature instability, and hypotension is 50-100 times more common than early-onset sepsis.36Dempsey E.M. Barrington K.J. Evaluation and treatment of hypotension in the preterm infant.Clin Perinatol. 2009; 36: 75-85Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Although respiratory distress is a common finding in infected infants, it is nonspecific, also occurring in infants with surfactant deficiency as well as retained lung fluid, meconium aspiration, pneumothorax, and congenital malformations, to name a few. 37Weintraub A.S. Cadet C.T. Perez R. DeLorenzo E. Holzman I.R. Stroustrup A. Antibiotic use in newborns with transient tachypnea of the newborn.Neonatology. 2013; 103: 235-240Crossref PubMed Scopus (29) Google Scholar,38Shani L. Weitzman D. Melamed R. Zmora E. Marks K. Risk factors for early sepsis in very low birth weight neonates with respiratory distress syndrome.Acta Paediatr. 2008; 97: 12-15Crossref PubMed Scopus (10) Google Scholar Respiratory distress syndrome is managed with exogenous surfactant administration and positive pressure ventilation; rapid improvement with these interventions excludes the need for prolonged antimicrobial therapy if blood culture is negative. Retained lung fluid causes transient tachypnea of the newborn and resolves over time unrelated to antibiotic therapy. The role for antibiotic therapy in meconium aspiration syndrome is unclear; limited trial data have not shown benefit.39Natarajan C.K. Sankar M.J. Jain K. Agarwal R. Paul V.K. Surfactant therapy and antibiotics in neonates with meconium aspiration syndrome: a systematic review and meta-analysis.J Perinatol. 2016; 36: S49-S54Crossref PubMed Scopus (27) Google Scholar Antibiotic therapy does not directly impact congenital malformations or air leak syndromes. Sometimes, sepsis-like episodes occur due to use of certain medications. For example, administration of prostaglandins to manage patent ductus arteriosus-dependent heart lesions can lead to apnea and temperature instability, and opiates used for pain relief can lead to respiratory depression or hypotension.40Meckler G.D. Lowe C. To intubate or not to intubate? Transporting infants on prostaglandin E1.Pediatrics. 2009; 123: e25-e30Crossref PubMed Scopus (41) Google Scholar, 41Siljehav V. Hofstetter A.M. Leifsdottir K. Herlenius E. Prostaglandin E2 mediates cardiorespiratory disturbances during infection in neonates.J Pediatr. 2015; 167: 1207-1213.e3Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 42Anand K.J. Hall R.W. Desai N. Shephard B. Bergqvist L.L. Young T.E. et al.Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.Lancet. 2004; 363: 1673-1682Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar Immunization of preterm infants often results in 1-3 days of increased clinical instability, including respiratory decompensation, apnea, bradycardia, or desaturation episodes, which may be mistaken for sepsis.43Montague E.C. Hilinski J.A. Williams H.O. McCracken C.E. Giannopoulos H.T. Piazza A.J. Respiratory decompensation and immunization of preterm infants.Pediatrics. 2016; 137: e20154225Crossref PubMed Scopus (7) Google Scholar,44Lee J. Robinson J.L. Spady D.W. Frequency of apnea, bradycardia, and desaturations following first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B immunization in hospitalized preterm infants.BMC Pediatr. 2006; 6: 20Crossref PubMed Scopus (26) Google Scholar Feeding intolerance, environmental hypo- or hyperthermia, milk protein allergy, anemia, and numerous other noninfectious conditions also may raise suspicion for sepsis. Many of these infants receive empiric antibiotics and unfortunately, some infants receive prolonged therapy despite sterile cultures. Neonates with localized infection can exhibit the same systemic signs and laboratory findings as sepsis. Feeding intolerance, abdominal distension, lethargy, temperature instability, tachypnea, desaturation, apnea, and bradycardia have been associated with neonatal pneumonia, urinary tract infection, meningitis, and other infections without bacteremia.45Levy I. Comarsca J. Davidovits M. Klinger G. Sirota L. Linder N. 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Neonatal omphalitis: a review of its serious complications.Acta Paediatrica. 2006; 95: 519-522Crossref PubMed Scopus (28) Google Scholar, 50Arshad M. Seed P.C. Urinary tract infections in the infant.Clin Perinatol. 2015; 42 (vii): 17-28Abstract Full Text Full Text PDF PubMed Google Scholar One of the most challenging neonatal infections to diagnose is pneumonia. Chest radiographs in neonates can be nonspecifically abnormal, and may be the only factor used to differentiate culture-negative sepsis from pneumonia.51Tusor N. De Cunto A. Basma Y. Klein J.L. Meau-Petit V. Ventilator-associated pneumonia in neonates: the role of point of care lung ultrasound.Eur J Pediatr. 2021; 180: 137-146Crossref PubMed Scopus (0) Google Scholar Therefore, it is essential to exclude noninfectious causes of respiratory distress first. However, if pneumonia cannot be excluded, empiric therapy usually is similar to that for culture-negative sepsis. Duration should be limited to 4-5 days.15Cantey J.B. Wozniak P.S. Pruszynski J.E. Sánchez P.J. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study.Lancet Infect Dis. 2016; 16: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,47Mathur N.B. Murugesan A. Comparison of four days versus seven days duration of antibiotic therapy for neonatal pneumonia: a randomized controlled trial.Indian J Pediatr. 2018; 85: 963-967Crossref PubMed Scopus (0) Google Scholar,52Engle W.D. Jackson G.L. Sendelbach D. Ford D. Olesen B. Burton K.M. et al.Neonatal pneumonia: comparison of 4 vs 7 days of antibiotic therapy in term and near-term infants.J Perinatol. 2000; 20: 421-426Crossref PubMed Scopus (31) Google Scholar Reported incidence of urina minimize contamination.50Arshad M. Seed P.C. Urinary tract infections in the infant.Clin Perinatol. 2015; 42 (vii): 17-28Abstract Full Text Full Text PDF PubMed Google Scholar Diagnosis by combining pyuria (white blood cell count ≥10/mm3) with quantification of specific organism (≥10 000-50 000 colony forming units per mL [CFU/mL]) would allow clinicians to narrow antibiotic therapy to a single agent.53Tamim M.M. Alesseh H. Aziz H. Analysis of the efficacy of urine culture as part of sepsis evaluation in the premature infant.Pediatr Infect Dis J. 2003; 22: 805-808Crossref PubMed Scopus (39) Google Scholar,54Magers J.P.P. Speaks S. Sanchez P.J. Short-course antibiotic therapy for urinary tract infection (UTI) in the NICU: it's safe and effective! Poster presented at IDWeek; September 29, 2021; San Diego, CA.https://idweekorgGoogle Scholar Administration of antibiotics prior to attainment of a urine sample for culture will result in false-negative result. Limited observational data support 5-10 days of therapy for urinary tract infection.45Levy I. Comarsca J. Davidovits M. Klinger G. Sirota L. Linder N. Urinary tract infection in preterm infants: the protective role of breastfeeding.Pediatr Nephrol (Berlin, Germany). 2009; 24: 527-531Crossref PubMed Scopus (0) Google Scholar,54Magers J.P.P. Speaks S. Sanchez P.J. Short-course antibiotic therapy for urinary tract infection (UTI) in the NICU: it's safe and effective! Poster presented at IDWeek; September 29, 2021; San Diego, CA.https://idweekorgGoogle Scholar The least common but most severe localized infection, particularly when undiagnosed, is meningitis. As many as 34%-69% of neonates with meningitis do not have concomitant bacteremia.55El-Naggar W. Afifi J. McMillan D. Toye J. Ting J. Yoon E.W. et al.Epidemiology of meningitis in Canadian neonatal intensive care units.Pediatr Infect Dis J. 2019; 38: 476-480Crossref PubMed Scopus (0) Google Scholar Missing meningitis in a neonate can result in incorrect antibiotic prescribing, including antibiotic selection, dose, and duration, predisposing the infant to poor neurodevelopmental outcome. Unlike in cases of isolated bloodstream infection, the minimum treatment duration for meningitis is at least 14-21 days depending on etiology but could be significantly longer if a suppurative intracranial complication develops.56Kimberlin D.W. Barnett E.D. Lynfield R. Sawyer M.H. Committee on Infectious Diseases AAoPGroup B Streptococcal Infections. Red Book: 2021-2024 Report of the Committee on Infectious Diseases. American Academy of Pediatrics, 2021: 0Google Scholar,57Kimberlin D.W. Barnett E.D. Lynfield R. Sawyer M.H. Committee on Infectious Diseases AAoPSerious Neonatal Bacterial Infections Caused by Enterobacteriaceae (Including Septicemia and Meningitis). Red Book: 2021-2024 Report of the Committee on Infectious Diseases. American Academy of Pediatrics, 2021: 0Google Scholar Other localized infections, such as necrotizing enterocolitis, cellulitis, peritonitis, etc, rarely are associated with a positive blood culture. Even infants with osteomyelitis, which is usually assumed to be the result of hematogenous spread of bacteria, can have a sterile blood culture at the time of diagnosis.58Zhan C. Zhou B. Du J. Chen L. Clinical analysis of 17 cases of neonatal osteomyelitis: a retrospective study.Medicine (Baltimore). 2019; 98: e14129Crossref PubMed Scopus (4) Google Scholar Physical examination remains invaluable in identifying the likely cause and site of infection, to further guide additional diagnostic procedures required, and to arrive at the correct final diagnosis. Properly obtained blood cultures have excellent sensitivity and specificity for neonatal sepsis.59Schelonka R.L. Chai M.K. Yoder B.A. Hensley D. Brockett R.M. Ascher D.P. Volume of blood required to detect common neonatal pathogens.J Pediatr. 1996; 129: 275-278Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar,60Lamy B. Roy P. Carret G. Flandrois J.-P. Delignette-Muller M.L. What Is the relevance of obtaining multiple blood samples for culture? a comprehensive model to optimize the strategy for diagnosing bacteremia.Clin Infect Dis. 2002; 35: 842-850Crossref PubMed Scopus (58) Google Scholar However, blood culture handling is a complex and error-prone process. Contamination with skin or enteric flora leads to false-positive cultures and frequent unnecessary therapy. When evaluating culture-negative sepsis, however, a clinician's primary concern is not contamination but rather false-negative blood cultures. False-negative cultures are seen with inadequate volume of blood collected and inoculated, pretreatment with antibacterial agents, and premature (ie, pre-event sampling of blood). The American Academy of Pediatrics guidelines for evaluation of early- and late-onset sepsis recommend obtaining a minimum blood sample of 1 mL, as there is a direct correlation between the volume of blood obtained and the sensitivity of blood culture.61Garcia-Prats J.A. Cooper T.R. Schneider V.F. Stager C.E. Hansen T.N. Rapid detection of microorganisms in blood cultures of newborn infants utilizing an automated blood culture system.Pedi" @default.
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• W4207054385 date "2022-05-01" @default.
• W4207054385 modified "2023-10-16" @default.
• W4207054385 title "A Proposed Framework for the Clinical Management of Neonatal “Culture-Negative” Sepsis" @default.
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