Neonatal sepsioutcomes

Andi L. Shane a,b,c,*,

aDivision of Infectious Disease, EAtlanta, GA 30322, USAbDepartment of Pediatrics, Emory30322, USAcChildrens Healthcare of Atlanta

32013

KEYWORDSNeonatal sepsis;

rolonged rupture oficrobial prophylaxisssociated with earlygative pathogens asonatal sepsis (LOS)Staphylococci and

Staphylococcus aureus, is associated with increased morbidity and mortality among prematureinfants. Invasive candidiasis is an emerging cause of late-onset sepsis, especially among infants

le administration touces invasive candi-

diasis in neonatal intensive care units with high rates of fungal infection. Prevention of health-steroid use, earlyeter care practices,es for reducing the

hts reserved.

* Corresponding author. Division of Infectious Disease, Emory University School of Medicine, 2015 Uppergate Drive NE, Atlanta, GA 30322,USA. Tel.: 1 404 727 5642; fax: 1 404 727 9223.

E-mail addresses: ashane@emory.edu (A.L. Shane), barbara_stoll@oz.ped.emory.edu (B.J. Stoll).d Tel.: 1 404 727 2456; fax: 1 404 727 5737.

0163-4453/$36 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.jinf.2013.09.011

www.elsevierhealth.com/journals/jinf

Journal of Infection (2014) 68, S24eS32care associated infections through antimicrobial stewardship, limitedenteral feeding, limited use of invasive devices and standardization of cathand meticulous hand hygiene are important and cost-effective strategiburden of late-onset neonatal sepsis. 2013 The British Infection Association. Published by Elsevier Ltd. All rigwho receive broad spectrum antimicrobial agents. Prophylactic fluconazovery low birthweight (VLBW) neonates during the first 6 weeks of life redimmunologic immaturity, maternal Group B streptococcal colonization, pmembranes, and maternal intra-amniotic infection. Intrapartum antimadministered to GBS-colonized women has reduced the burden of disease aonset GBS invasive infections. Active surveillance has identified Gram-nean emerging etiology of early-onset invasive infections. Late-onset neattributable to Gram-positive organisms, including coagulase negativeBurden;Management;Prevention

neonatal infections varies by geographic region and maternal and neonatal risk factors. World-wide, it is estimated that more than 1.4 million neonatal deaths annually are the consequenceof invasive infections. Risk factors for early-onset neonatal sepsis (EOS) include prematurity,Accepted 20 September 201Available online 18 Octobers: Progress towards improved

Barbara J. Stoll b,c,d

mory University School of Medicine, 2015 Uppergate Drive NE,

University School of Medicine, 2015 Uppergate Drive NE, Atlanta, GA

, 2015 Uppergate Drive NE, Atlanta, GA 30322, USA

Summary Neonates are predisposed to infections during the perinatal period due to multipleexposures and a relatively compromised immune system. The burden of disease attributed to

Neonatal sepsis S25period. Risk factors for EOS include prematurity and rity, low birth weight, prolonged rupture of membranesIntroduction

The perinatal period is hazardous with multiple opportu-nities for exposures to virulent organisms. Potential sites ofexposure include the uterus, the birth canal, the neonatalcare unit, invasive procedures and devices, healthcareproviders, family and visitors, and the community. Inaddition to these multiple sites of exposure and diversemodes of infection transmission, neonates are relativelyimmunocompromised. The impaired innate immune func-tion of premature infants predisposes them to invasiveinfections. Because the fetal immune response begins atabout 24 weeks of age and development occurs until term,premature neonates do not benefit from complete immunesystem development, making them more susceptible toinfection with organisms that term infants may be able tosuppress.1 Prolonged hospitalization, invasive proceduresand devices, lack of enteral feeding, and the utilizationof broad spectrum antibiotics, due to increased risk of in-fections with multi-resistant pathogens, increase risk toalready vulnerable neonates.

The recognition of neonatal sepsis is complicated bythe frequent presence of non-infectious conditions thatresemble those of sepsis, especially in very low birthweight(VLBW) preterm infants, and by the absence of optimaldiagnostic tests. While the laboratory identification of anorganism from a sterile site is optimal for definitivediagnosis, it is not always possible to isolate a causativepathogen. Invasive infections can also occur in seeminglyasymptomatic neonates. Therefore assessment of historyand risk factors in combination with diagnostic tests areused to identify neonates who are more likely to beinfected.

Burden of disease and characterization

Worldwide, invasive neonatal infections are estimated tocause approximately 36% of the estimated 4 millionneonatal deaths annually. Rates of infection vary bygeographic region, resource endowment, maternal andinfant risk factors. Early and late-onset neonatal sepsis isdifferentiated by timing of symptom onset, virulence of theinfecting organism(s) and associated pathogenesis. Early-onset sepsis (EOS) is defined by infection in the first week oflife. Many investigators, including those who participate inthe Eunice Kennedy Shriver National Institute of ChildHealth and Human Development (NICHD) Neonatal Networkand the Vermont Oxford Network, define EOS by the onsetof signs or symptoms and an associated positive culture ator before 72 h of life. Late-onset sepsis (LOS) is character-ized by the onset of symptoms consistent with sepsis atgreater than 72 h of life. These classifications of EOS andLOS reflect the differing etiologies and proposed patho-physiology of pathogens commonly associated with thetiming of onset of these conditions.

Early onset sepsis (EOS)

EOS remains a serious complication of the post-partumassociated immunologic immaturity,2 maternal Group Bstreptococcal (GBS) colonization, rupture of membranesgreater than 18 h, and maternal intra-amniotic infection.3,4

In the 1970s, Group B streptococci (GBS) emerged as theleading cause of neonatal meningitis and bacteremia inthe United States. The association between maternal GBScolonization and neonatal infection resulted in the devel-opment of guidelines to administer intrapartum antimicro-bials to GBS-colonized women in the United States toreduce invasive GBS in the newborn. Widespread imple-mentation of these guidelines has resulted in substantialreduction in early-onset GBS disease. However, burden ofdisease continue and GBS remains the most frequently iso-lated EOS pathogen in the United States, particularlyamong term infants.

Epidemiologic surveillance has noted the emergence ofEscherichia coli (E. coli) as an important pathogen associ-ated with EOS, especially among VLBW infants. Increasedrates of severe disease and death with Gram-negative EOShave been reported in some studies. To monitor changesover time, it remains important to continue active surveil-lance for rates of EOS and pathogens associated withinfection.

Burden of EOS

The burden of EOS in the United States, assessed by theCenters for Disease Control and Prevention (CDC) throughtheir Active Bacterial Core Surveillance (ABCs) in 4 statesfrom 2005 to 2008 yielded an overall rate of EOS of 0.77 per1000 live births and a case fatality rate of 10.9%. In the ABCsurveillance, GBS was responsible for 0.29 infections per1000 live births with a case fatality rate of 7% and E. coliwas responsible for 0.19 infections per 1000 live birthswith a case fatality rate of 25%.5 In comparison, the Na-tional Institutes for Child Health and Development (NICHD)Neonatal Research Network (NRN) assessed all live birthsfrom 16 university neonatal care units from 2006 to 2009.This evaluation resulted in an overall rate of EOS of 0.98per 1000 live births with a case fatality rate of 16%; arate of GBS infections of 0.41 per 1000 live births andcase fatality rate of 9% and 0.28 E. coli infections per1000 live births with a case fatality rate of 33%.6 In boththe CDC ABCs and NICHD NRN studies, rates of infectionand case fatality increased with decreasing gestationalage and birthweight. In both studies, the estimated burdenof EOS in the United States was approximately 3300 casesand 400 deaths annually.

Group B streptococci (GBS)

The central challenge with the management of EOS GBS isidentifying the 2% of infants born to GBS colonized womenwho will develop invasive disease (EOS, pneumonia, and/ormeningitis). One-half of infants born to GBS colonizedwomen will themselves be colonized.7,8 Of these, 98% willbe asymptomatic while 2% will have evidence of invasivedisease. Studies in the United States have elucidated anumber of risk factors for early onset (EO) GBS diseaseincluding maternal GBS carriage, GBS bacteriuria, prematu-

cologists continued to support the 2003 recommendations

S26 A.L. Shane, B.J. Stoll(ROM) 18 h, intrapartum fever, young maternal age, Blackrace, a previous infant with invasive GBS disease, and lowlevels of anti-capsular antibody. A case-control study inthe United Kingdom (UK) found that maternal GBS carriage,GBS bacteriuria, prolonged ROM, and intrapartum feverwere significantly associated with GBS EOS. Young maternalage, Black race, and a previous infant with invasive diseasewere not found to be risk factors for EO GBS; prematurityand low levels of anti-capsular antibody were not evaluatedin the UK studies.9

Recommendations for intrapartum antibiotic prophylaxis(IAP) in women who are colonized with GBS or have otherrisk factors for EO GBS have been instrumental in reducingthe rates of EO GBS disease in the United States.10 Despitethe benefit of IAP, rates of uptake are limited by inade-quate screening practices and missed opportunities toadminister IAP.6 The revised guidelines from the CDC pub-lished in 2010 specify situations when IAP is indicated.The most challenging situations are when GBS status atthe onset of labor is unknown. The guidelines advise thatif a woman delivers an infant at 37 weeks, has ROM18 h, has an intrapartum temperature 38 C, or an intra-partum nucleic acid amplification test detects GBS, thenIAP should be administered.10

Of note, not all countries have adopted policies foruniversal GBS screening of pregnant women and provisionof intrapartum antibiotic prophylaxis to colonized women.Multinational studies have demonstrated variability inmaternal recto-vaginal GBS colonization from 7 to 22%.Several countries including the United States, Canada,Australia, Spain, and Belgium experienced rates of EOGBS of 1 in 1000 live births before the institution of IAP,while other countries including England, Sweden, andFinland reported lower baseline rates. Surveillance for EOGBS in the United Kingdom (UK) revealed an incidence of0.5 cases of EO GBS per 1000 live births and a case fatalityrate of 10.6%. In 2001, the burden of disease was estimatedat 376 cases with 39 deaths and in 2004 as 326 cases with 41deaths.11,12 A recent meta-analysis of studies from allWorld Health Organization (WHO) regions including 56studies with incidence data, 29 with case fatality rates(CFR), and 19 with serotyping, demonstrated a mean inci-dence of EO GBS of 0.43 per 1000 live births and a CFR of12.1%. The most common serotypes were 111 (49%), 1a(23%), V (9%), 1b (7%), 11 (6%). Studies that reported anyuse of IAP had a comparatively decreased incidence of EOGBS of 0.23 per 1000 live births versus 0.75 per 1000 livebirths when IAP was not reported.13

The US CDC recommends universal screening for recto-vaginal colonization in pregnancy at 35e37 weeks gesta-tion. Selective IAP is recommended for all colonized womenor for those with unknown colonization status at onset oflabor and risk factors including delivery 18 h, intrapartum temperature 38 C or an intrapartumrapid screen positive for GBS.10 In contrast, in the UK, ante-natal GBS screening in pregnancy is not recommended bythe National Screening Committee, with the most recentreview in 2008e9 supporting this stance. In 2003, the RoyalCollege of Obstetricians and Gynaecologists recommendeda risk-based approach for identifying women who maybenefit from IAP for EO GBS prevention. Based on existingevidence and expert consensus, a recent external reviewfor risk-based screening. The 2012 guidelines recommendedIAP for women with a history of an infant with invasive GBSinfection, GBS bacteriuria in the current pregnancy, avaginal swab positive for GBS in the current pregnancy, py-rexia in labor and chorioamnionitis. For pyrexia and cho-rioamnionitis, the panel recommended broad-spectrumtherapy that included coverage for GBS. IAP for GBS wasnot felt to be necessary if the woman was delivering via acaesarean section with intact membranes.15

Although randomized controlled trials have not beenconducted to compare the efficacy of a risk based versus ascreening based strategy to reduce vertical transmission ofGBS, international observational studies suggest that bothstrategies reduce rates of invasive disease in the newborn.Theoretically, universal screening would provide greaterprotection by capturing women with unrecognized riskfactors and therefore may be more effective in preventingEO GBS.

With increasing use of IAP, concerns have been raisedabout an increase in non-GBS EOS and increasing antimi-crobial resistance. Most population-based studies reportstable rates of EOS caused by non-GBS pathogens.16 Howev-er, several studies have suggested that ampicillin-resistantE. coli may be emerging, especially among VLBWinfants.17,18

The future of the prevention of perinatal GBS likely liesin rapid testing to detect GBS colonization and to target atrisk women. A safe and effective vaccine would provideprotection against both EO and LO GBS and may be a moresuitable intervention in resource-poor settings wherescreening and IAP may not be feasible. Maintenance ofsurveillance systems to monitor rates of infection andassociated pathogens will be instrumental in optimizingthe allocation of resources.

Late onset sepsis (LOS)

Surveillance of neonates from 2006 to 2008 by the UKNeonIN Surveillance Network demonstrated that Gram-positive organisms comprised 70% of infections, Gram-negative organisms 25% and fungi 5%. Of the Gram-positive pathogens, CoNS was responsible for 42%, Staphy-lococcus aureus for 10%, Enterococci for 9%, GBS for 5%,with others contributing the remaining 4%. Of the Gram-negative pathogens, E. coli contributed 8%, Klebsiellaspp. 5%, Enterobacter spp. 5% Pseudomonas spp. 3% andother organisms responsible for 4%. Candida spp. werecompleted in July 2012 by the UK National Screening Com-mittee recommended the continuation of risk-based ante-natal GBS screening. The panel was unable to weigh thebenefits and harms of antenatal GBS screening, based onan incidence of 0.5 per 1000 live births in the UK and a mor-tality rate of 0.05 per 1000 live births. The panel estimatedthat they would have to provide IAP to 210 women per 1000pregnancies if universal screening were instituted. Aconcern for antimicrobial resistance as a consequence ofuniversal screening provided additional evidence to thepanel to support risk-based screening and IAP.14 A July2012 update to the 2003 guideline for the prevention ofEO GBS from the Royal College of Obstetricians and Gynae-

Neonatal sepsis S27responsible for all of the fungal infections.12 The majorityof bacterial isolates from blood cultures of neonates aged2e28 days in England and Wales during the same timeperiod were Gram-positive (81%); CoNS (45%), Staphylo-coccus aureus (13%), GBS (7%), non-pyogenic streptococci(7%), and other (9%). Of the 19% of Gram-negative isolates,Enterobacteriacae (9%) were most common followed by, E.coli (7%), Pseudomonas spp. (2%), and other (1%).19 Surveil-lance for this study included pathogens isolated fromneonates from 2 days of age, which may include presenta-tions of EOS as well as LOS. In both of these studies, Gram-positive organisms were isolated from septic neonates morecommonly than Gram-negative organisms. The later studyfrom England and Wales did not report the prevalence offungal isolates.

For over a decade, the NICHD Neonatal ResearchNetwork, http://neonatal.rti.org has studied the epidemi-ology of neonatal infections among thousands of VLBW ne-onates. Gram-positive organisms are most commonlyassociated with LOS among VLBW infants, although mortal-ity is two to three times greater among infants with invasivecandidiasis and Gram-negative infections than in those withGram-positive infections.17,20,21 In the NRN cohort, 70% in-fections were associated with Gram-positive organisms;coagulase-negative staphylococci (CoNS) contributed 48%,Gram-negative 18% and fungal 12%. In some evaluations,more than one organism was isolated.17 The predominanceof Gram-positive organisms among VLBW infants was alsoseen in a large study of community based NICUs over a 14year period. Among 12,204 cases of LOS, Gram-positive or-ganisms were most frequent.21 Several studies have notedan increased risk of mortality among infants with LOScompared to those who are uninfected.17,21,22

Coagulase negative staphyloccci (CoNS)

In a large retrospective cohort study conducted in 248NICUs in the US from 1997 to 2009, 17,624 episodes of CoNSsepsis were identified among 16,629 VLBW infants; mostepisodes were classified as possible infections. Infants withlower birth weights and gestational age (GA) were morelikely to have a CoNS isolated during an episode of sepsis. ACoNS infection was characterized as isolation of the organ-ism from 2 or more blood cultures, one blood culture andone other sterile site, or one blood culture with a significantinfection. The number of central lines, clinical presentationof lethargy, and gastric acid residuals, but not central lineduration was risk factors for a CoNS infection.23 As CoNS arefrequently isolated from neonates with clinical sepsis, it isimportant to understand risk factors for their recovery andstrategies to decrease their prevalence.

Staphylococcus aureus

A retrospective evaluation of NICHD NRN sites from 2007 to2009 identified 8444 VLBW neonates who survived greaterthan 3 days. Among these infants, 316 (3.7%) had Staphylo-coccus aureus (SA) bacteremia or meningitis; 88 infants hadmethicillin-resistant Staphylococcus aureus (MRSA) infec-tions, 228 infants had methicillin-susceptible Staphylo-coccus aureus (MSSA) infections, and there were nocoinfections. Almost all of the infants who had MRSA infec-tions had manifestations after 7 days of age. Nine of twentyparticipating centers had no cases of MRSA. Morbidities didnot differ between neonates with MRSA and MSSA infec-tions. Although SA infections comprised only 1% of all causebacteremia and meningitis; mortality rates of neonateswith both MRSA and MSSA infections were high (26% and24%, respectively) and comparable.24

Candidiasis

Although less frequent than Gram-positive or Gram-negative infections, invasive infections with fungal organ-isms, primarily Candida spp. result in substantial morbidityand mortality, with a 13% mortality rate among a cohortstudy of 128 US NICUs and 130,523 neonates.25e27 Overall,between 1.5% and 2.5% of all BSI in VLBW neonates are esti-mated to be due to fungal etiologies, the most common ofwhich are Candida albicans and C. parapsilosis.27,28 Therisk for fungal sepsis is increased by colonization acquiredvertically from maternal sources as well as horizontallyfrom the NICU environment. A positive correlation existsbetween multiple sites of colonization and risk for invasivecandidiasis.25 Risk factors supporting the use of empiricantifungal therapy in a neonate exhibiting signs and symp-toms of sepsis include GA, exposure to third generationcephalosporin antibiotics in the 7 days prior to symptomonset, and thrombocytopenia.29 Invasive candidiasisoccurred in 137 of 1515 (9%) of neonates less than 1000 gbirthweight in a prospective observational cohort studyconducted in 19 NICHD NRN sites. Incidence of invasiveinfection varied from 2 to 28% among the sites that enrolledmore than 50 neonates.30 Overall mortality in a cohort of730 infants with invasive candidiasis from 192 US NICUsenrolled between 1997 and 2003 was 19%.31 Among infantsweighing between 401 and 1000 g at birth born between1993 and 2001, who had an invasive fungal infection, 31(30%) had a head circumference less than the 10th percen-tile at 18e22 months of corrected gestational age; a statis-tically significant (p < 0.05) difference compared touninfected neonates and comparable to neonates with ahistory of Gram-negative invasive infections.32

Prevention of candidiasisDue to the burden and severity of disease associated withneonatal candidiasis, prevention of colonization and inva-sive infections would be beneficial. Oral nystatin and oraland intravenous fluconazole have been evaluated inseveral studies as prophylactic agents. Five internationalevaluations have demonstrated reduced rates of coloniza-tion, cessation of an outbreak33 and reduction in diseaseincidence.34,35

Prophylactic administration of fluconazole during thefirst six weeks of life reduces fungal colonization andinvasive fungal infection in extremely low birthweightinfantsdthose with birthweights

S28 A.L. Shane, B.J. Stollto high risk neonates.37 Results from over 14 trials at multi-ple institutions with 3100 neonates suggests that flucona-zole prophylaxis decreases colonization of the urine,gastrointestinal tract, and integument, without promotingthe development of resistance and without adverseeffects.28,36e42 A meta-analysis published in 2009 of 5 trialsenrolling 656 neonates

Neonatal sepsis S29(TNF)-alpha levels associated with sepsis, involving 140neonates suggested potential improved survival among theinfants who had culture confirmed sepsis and who receivedpentoxifylline.58 Additional large scale trials will be neededto reproduce this potential benefit.

Antimicrobial utilization practices

Antimicrobial utilization practices in NICUs influence thetypes of microorganisms responsible for neonatal sepsis andtheir resistance patterns. The US Centers for DiseaseControl and Prevention (CDC) has initiated a campaign toprevent antimicrobial resistance in healthcare settingshttp://www.cdc.gov/getsmart/healthcare/. This effort isdesigned to increase clinician awareness and to improvediagnosis and appropriate treatment of infection. Thecampaign supports involving infectious disease and phar-macy consultants, treating infections with an antimicrobialwith the narrowest spectra and discontinuing therapy whenadequate therapy has been administered. Prevention of in-fections through optimizing infection control and enhancedsurveillance are additional components of the campaign.

Prevention of healthcare associated infections(HAI)

Strategies to prevent hospital acquired late-onset infectioninclude improved hand hygiene, early human milk feeding,meticulous skin care, limited use of invasive devices andinfrequent manipulation of devices when they are essential,and uniform practices related to catheter insertion and care.Environmental design that optimizes access to hygiene andpersonal protective equipment as well as increased staffingreduces opportunities for HAI. Ongoing surveillance is essen-tial to monitor rates of infection and emerging pathogens tooptimally allocate resources. At our institution, we havedevelopeda campaign, One isNot Zero todrawattention toinfection control strategies. This campaign reinforces theconcept that even one hospital acquired infection is consid-ered unacceptable; our aim is to have zero hospital acquiredinfections. The success of the One is Not Zero philosophyrequires the support of providers, staff, and administrators.Hand hygiene before and after contact with patients andequipment is essential and compliance should be routinelyassessed. Standardization of processes related to centralvenous and arterial catheter insertion and maintenance,termed bundles, include the use of dedicated teams withexpertise related to the selection of optimal insertion sites,the meticulous application of antisepsis, and the utilizationof maximal barrier precautions for insertion and manipula-tion. Minimizing the numbers of ports, management of thecatheter insertion site, timely removal when access is nolonger needed and monitoring and reviewing local BSI dataregularly facilitates reductions in rates of HAIs.59,60 A legalmandate passed in 2007 in New York state required surveil-lance and reporting of central line associated BSIs in all inten-sive care units. Participating hospitals joined the CDCNational Healthcare Safety Network to standardize surveil-lance and reporting. In collaboration with the QualityImprovement Network formed by representation from all ofthe18 state-designated regional perinatal centers, thesenet-worksevaluatedbest practices andagreed tobundlingof careelements for insertion and maintenance of central cathetersand to utilize checklists to monitor adherence to thebundle activities.60 A comparison of the pre- and post-intervention period did not reveal that central catheter usedeclined, however overall statewide catheter-associatedBSIs decreased 67% from 6.4 catheter-associated infectionsper 1000 line days to 2.2 catheter-associated infections per1000 line days (p < 0.005). With a change in definition of acatheter associated BSI to a requirement for 2 or more iso-lates of potential skin contaminants (for example coagulasenegative Staphylococci (CoNS), statewide rates decreased40% from 3.5 catheter-associated infections per 1000 linedays to 2.1 catheter-associated infections per 1000 linedays (p < 0.005). Overall, there was no change in pathogendistribution; CoNS remained the most commonly isolatedorganism.

New strategies to prevent hospital associatedinfections

Due to the burden of disease ensuing from hospitalassociated infections, additional strategies including lacto-ferrin and probiotic supplementation as well as anti-staphylococcal monoclonal antibodies have been exploredas strategies to prevent nosocomial infections. While anti-staphylococcal monoclonal antibodies have not proven tobe of benefit, preliminary data suggest that bovine lacto-ferrin (BLF) supplementation alone and in combination withprobiotics may reduce LOS. A prospective, multicenter,double-blind, randomized placebo-controlled trial in 11tertiary care NICUs compared bovine lactoferrin alone orin combination with the probiotic Lactobacillus rhamnosusGG (LGG). Over a 9 month period during 2007e2008, 472VLBW neonates received placebo, LGG and BLF, or BLFonly, daily from birth through 30 days of life or 45 days.Compared with placebo, BLF supplementation with andwithout LGG reduced the incidence of the first LOS episodein VLBW neonates. Further studies of lactoferrin, with andwithout probiotics, to reduce risk of neonatal sepsis areindicated.61,62

Longer term risks of neonatal sepsis

Although rates and mortality as a consequence of neonatalsepsis are declining in some settings, several studies sug-gest that survivors or neonatal sepsis are at increased riskfor adverse neurodevelopmental sequelae. Brain imagingreveals white matter injury (WMI) in survivors that may beassociated with neurodevelopmental delay. In a retrospec-tive review of 133 neonates with GA

mental impairment, including cerebral palsy, was signifi-

S30 A.L. Shane, B.J. Stollcantly more likely in one quarter of 541 extremelypremature infants who had a neonatal infection than inthe neonates who did not experience an infection.65 Neuro-developmental impairment was noted to be present duringlong term follow up at school age entry among former VLBWinfants who experienced LOS.66 These studies underscorethe importance of neurodevelopmental follow-up of survi-vors of neonatal sepsis, especially those who are pretermand are of low birthweight.

Conclusions

Rates of early-onset sepsis, particularly due to GBS, havedeclined, but the burden of disease remains significant dueto missed opportunities for prevention. In some settings,rates of late-onset catheter associated bloodstream in-fections have declined. However, late-onset hospital ac-quired infections among premature and low birthweightinfants continue to be associated with substantial morbidityand mortality, including long term neurodevelopmentalconsequences. Strategies to prevent late-onset infectionsrequire vigilance and attention to practices including handhygiene, early human milk supplementation, the use ofcentral line bundles, the limitation of indwelling devices,and antibiotic stewardship. Additional prevention strate-gies with potential benefit include immune modulators andimmunizations. Our greatest advances in improving out-comes have been achieved through research; each patientcan be studied to contribute to evidence-based medicineand improved care.

Conflict of interest

All authors, no pertinent conflicts of interest. A. Shane isthe recipient of a research grant from the Gerber Founda-tion with funds provided to her institution.

References

1. Tissieres P, Ochoda A, Dunn-Siegrist I, Drifte G, Morales M,Pfister R, et al. Innate immune deficiency of extremely pre-mature neonates can be reversed by interferon-g. PLoS One2012;7:e32863.

2. Wynn JL, Levy O. Role of innate host defenses in susceptibilityto early-onset neonatal sepsis. Clin Perinatol 2010;37:307e37.

3. Schrag SJ, Stoll BJ. Early-onset neonatal sepsis in the era ofwidespread intrapartum chemoprophylaxis. Pediatr InfectDis J 2006;25:939e40.associated with necrotizing enterocolitis were significantlymore likely to have mild WMI (78%) than uninfected infants(57%), p < 0.01.64 Among a cohort of 6093 VLBW infants,those with a history of infection were significantly morelikely to develop cerebral palsy, to have lower scores onBayley scales of neurodevelopment, to have visual impair-ment, and to experience poor growth.32 Of 320 VLBW in-fants who developed invasive candidiasis, 73% had died orhad manifestations of neurodevelopmental impairmentwhen assessed at 18e22 months of age.26 Neurodevelop-4. Schuchat A, Zywicki S, Dinsmoor M, Mercer B, Romaguera J,OSullivan M, et al. Risk factors and opportunities for preven-tion of early-onset neonatal sepsis: a multicenter case-control study. Pediatrics 2000;105:21e6.

5. Weston EJ, Pondo T, Lewis MM, Martell-Cleary P, Morin C,Jewell B, et al. The burden of invasive early-onset neonatalsepsis in the United States, 2005e2008. Pediatr Infect Dis J2011;30:937e41.

6. Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, VanMeurs KP, et al. Early onset neonatal sepsis: the burden ofgroup B Streptococcal and E. coli disease continues. Pediat-rics 2011;127:817e26.

7. Lim DV, Morales WJ, Walsh AF, Kazanis D. Reduction ofmorbidity and mortality rates for neonatal group B strepto-coccal disease through early diagnosis and chemoprophylaxis.J Clin Microbiol 1986;23:489e92.

8. Boyer KM, Gotoff SP. Prevention of early-onset neonatal groupB streptococcal disease with selective intrapartum chemopro-phylaxis. N Engl J Med 1986;314:1665e9.

9. Heath PT, Balfour GF, Tighe H, Verlander NQ, Lamagni TL,Efstratiou A, et al. Group B streptococcal disease in infants:a case control study. Arch Dis Child 2009;94:674e80.

10. Centers for Disease Control and Prevention. Prevention ofperinatal Group B streptococcal disease: revised guidelinesfrom CDC; 2010. p. 1e36. MMWR2010.

11. Vergnano S, Embleton N, Collinson A, Menson E, Russell AB,Heath P. Missed opportunities for preventing group B strepto-coccus infection. Arch Dis Child Fetal Neonatal Ed 2010;95:F72e3.

12. Vergnano S, Menson E, Kennea N, Embleton N, Russell AB,Watts T, et al. Neonatal infections in England: the NeonIN sur-veillance network. Arch Dis Child Fetal Neonatal Ed 2011;96:F9e14.

13. Edmond KM, Kortsalioudaki C, Scott S, Schrag SJ, Zaidi AK,Cousens S, et al. Group B streptococcal disease in infantsaged younger than 3 months: systematic review and meta-analysis. Lancet 2012;379:547e56.

14. UK National Screening Committee. Screening for Group BStreptococcal infection in pregnancy: external review againstprogramme appraisal criteria for the UK National ScreeningCommittee (UK NSC); 2012.

15. Royal College of Gynaecologists. The prevention of early-onset neonatal Group B streptococcal disease. Green-topguideline No36. 2nd ed.; 2012.

16. Moore MR, Schrag SJ, Schuchat A. Effects of intrapartum anti-microbial prophylaxis for prevention of group-B-streptococcaldisease on the incidence and ecology of early-onset neonatalsepsis. Lancet Infect Dis 2003;3:201e13.

17. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA,Ehrenkranz RA, et al. Late-onset sepsis in very low birthweight neonates: the experience of the NICHD NeonatalResearch Network. Pediatrics 2002;110:285e91.

18. Glasgow TS, Young PC, Wallin J, Kwok C, Stoddard G, Firth S,et al. Association of intrapartum antibiotic exposure and late-onset serious bacterial infections in infants. Pediatrics 2005;116:696e702.

19. Muller-Pebody B, Johnson AP, Heath PT, Gilbert RE,Henderson KL, Sharland M, et al. Empirical treatment ofneonatal sepsis: are the current guidelines adequate? ArchDis Child Fetal Neonatal Ed 2011;96:F4e8.

20. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA,Ehrenkranz RA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med2002;347:240e7.

21. Hornik CP, Fort P, Clark RH, Watt K, Benjamin DK, Smith PB,et al. Early and late onset sepsis in very-low-birth-weight in-fants from a large group of neonatal intensive care units.Early Hum Dev 2012;88(Suppl. 2):S69e74.

Neonatal sepsis S3122. Cohen-Wolkowiez M, Moran C, Benjamin DK, Cotten CM,Clark RH, Smith PB. Early and late onset sepsis in late preterminfants. Pediatr Infect Dis J 2009;28:1052e6.

23. Healy CM, Baker CJ, Palazzi DL, Campbell JR, Edwards MS. Dis-tinguishing true coagulase-negative Staphylococcus infectionsfrom contaminants in the neonatal intensive care unit. J Peri-natol 2013 Jan;33(1):52e8. http://dx.doi.org/10.1038/jp.2012.36. [Epub 2012 Apr 12].

24. Shane AL, Hansen NI, Stoll BJ, Bell EF, Sanchez PJ,Shankaran S, et al. Methicillin-resistant and susceptibleStaphylococcus aureus bacteremia and meningitis in preterminfants. Pediatrics 2012;129:e914e22.

25. Leibovitz E. Strategies for the prevention of neonatal candidi-asis. Pediatr Neonatol 2012;53:83e9.

26. Benjamin DK, Stoll BJ, Fanaroff AA, McDonald SA, Oh W,Higgins RD, et al. Neonatal candidiasis among extremely lowbirth weight infants: risk factors, mortality rates, and neuro-developmental outcomes at 18 to 22 months. Pediatrics 2006;117:84e92.

27. Fridkin SK, Kaufman D, Edwards JR, Shetty S, Horan T. Chang-ing incidence of Candida bloodstream infections among NICUpatients in the United States: 1995e2004. Pediatrics 2006;117:1680e7.

28. Kaufman DA. Challenging issues in neonatal candidiasis. CurrMed Res Opin 2010;26:1769e78.

29. Benjamin DK, Poole C, Steinbach WJ, Rowen JL, Walsh TJ.Neonatal candidemia and end-organ damage: a criticalappraisal of the literature using meta-analytic techniques.Pediatrics 2003;112:634e40.

30. Benjamin DK, Stoll BJ, Gantz MG, Walsh MC, Sanchez PJ,Das A, et al. Neonatal candidiasis: epidemiology, risk factors,and clinical judgment. Pediatrics 2010;126:e865e73.

31. Ascher SB, Smith PB, Watt K, Benjamin DK, Cohen-Wolkowiez M, Clark RH, et al. Antifungal therapy and out-comes in infants with invasive Candida infections. PediatrInfect Dis J 2012;31:439e43.

32. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR,Vohr B, et al. Neurodevelopmental and growth impairmentamong extremely low-birth-weight infants with neonatalinfection. J Am Med Assoc 2004;292:2357e65.

33. Damjanovic V, Connolly CM, van Saene HK, Cooke RW,Corkill JE, van Belkum A, et al. Selective decontaminationwith nystatin for control of a Candida outbreak in a neonatalintensive care unit. J Hosp Infect 1993;24:245e59.

34. Ozturk MA, Gunes T, Koklu E, Cetin N, Koc N. Oral nystatinprophylaxis to prevent invasive candidiasis in Neonatal Inten-sive Care Unit. Mycoses 2006;49:484e92.

35. Aydemir C, Oguz SS, Dizdar EA, Akar M, Sarikabadayi YU,Saygan S, et al. Randomised controlled trial of prophylacticfluconazole versus nystatin for the prevention of fungal colo-nisation and invasive fungal infection in very low birth weightinfants. Arch Dis Child Fetal Neonatal Ed 2011;96:F164e8.

36. Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M,Donowitz LG. Fluconazole prophylaxis against fungal coloniza-tion and infection in preterm infants. N Engl J Med 2001;345:1660e6.

37. Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazoleprophylaxis in extremely low birth weight neonates reducesinvasive candidiasis mortality rates without emergence offluconazole-resistant Candida species. Pediatrics 2008;121:703e10.

38. Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Flu-conazole prophylaxis prevents invasive fungal infection in high-risk, very low birth weight infants. J Pediatr 2005;147:162e5.

39. Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of flu-conazole prophylaxis on incidence and outcome of invasivecandidiasis in a neonatal intensive care unit. J Pediatr 2005;147:166e71.40. Kaufman D. Fluconazole prophylaxis decreases the com-bined outcome of invasive Candida infections or mortalityin preterm infants. Pediatrics 2008;122:1158e9 [authorreply 9].

41. Manzoni P, Stolfi I, Pugni L, Decembrino L, Magnani C,Vetrano G, et al. A multicenter, randomized trial of prophy-lactic fluconazole in preterm neonates. N Engl J Med 2007;356:2483e95.

42. Uko S, Soghier LM, Vega M, Marsh J, Reinersman GT, Herring L,et al. Targeted short-term fluconazole prophylaxis amongvery low birth weight and extremely low birth weight infants.Pediatrics 2006;117:1243e52.

43. Clerihew L, Austin N, McGuire W. prophylactic systemic anti-fungal agents to prevent mortality and morbidity in very lowbirth weigh infants. Cochrane Database Syst Rev 2007 Oct;17(4):CD003850.

44. Pickering L, American Academy of Pediatrics. Red Book:2012 report of the committee on infectious diseases. 29thed. Elk Grove Village, IL: American Academy of Pediatrics;2012.

45. Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF,Edwards JE, et al. Clinical practice guidelines for the manage-ment of candidiasis: 2009 update by the Infectious DiseasesSociety of America. Clin Infect Dis 2009;48:503e35.

46. Kaufman D, Fairchild KD. Clinical microbiology of bacterialand fungal sepsis in very-low-birth-weight infants. Clin Micro-biol Rev 2004;17:638e80 [table of contents].

47. Noyola DE, Fernandez M, Moylett EH, Baker CJ. Ophthalmo-logic, visceral, and cardiac involvement in neonates with can-didemia. Clin Infect Dis 2001;32:1018e23.

48. Dudeck MA, Horan TC, Peterson KD, Allen-Bridson K,Morrell G, Pollock DA, et al. National Healthcare SafetyNetwork (NHSN) report, data summary for 2010, device-associated module. Am J Infect Control 2011;39:798e816.

49. Sohn AH, Garrett DO, Sinkowitz-Cochran RL, Grohskopf LA,Levine GL, Stover BH, et al. Prevalence of nosocomial infec-tions in neonatal intensive care unit patients: results fromthe first national point-prevalence survey. J Pediatr 2001;139:821e7.

50. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR,Walsh MC, et al. Neonatal outcomes of extremely preterm in-fants from the NICHD Neonatal Research Network. Pediatrics2010;126:443e56.

51. Pammi M, Brocklehurst P. Granulocyte transfusions for neo-nates with confirmed or suspected sepsis and neutropenia.Cochrane Database Syst Rev 2011. CD003956.

52. Del Vecchio A, Christensen RD. Neonatal neutropenia: whatdiagnostic evaluation is needed and when is treatment recom-mended? Early Hum Dev 2012;88(Suppl. 2):S19e24.

53. El-Ganzoury MM, El-Farrash RA, Saad AA, Mohamed AG, El-Sherbini IG. In vivo effect of recombinant human granulocytecolony-stimulating factor on neutrophilic expression of CD11bin septic neonates: a randomized controlled trial. PediatrHematol Oncol 2012;29:272e84.

54. Carr R, Modi N, Dore C. G-CSF and GM-CSF for treating or pre-venting neonatal infections. Cochrane Database Syst Rev2003. CD003066.

55. Napolitano LM. Immune stimulation in sepsis: to be or not tobe? Chest 2005;127:1882e5.

56. Brocklehurst P, Farrell B, King A, Juszczak E, Darlow B,Haque K, et al. Treatment of neonatal sepsis with intravenousimmune globulin. N Engl J Med 2011;365:1201e11.

57. Ohlsson A, Lacy J. Intravenous immunoglobulin for suspectedor subsequently proven infection in neonates. Cochrane Data-base Syst Rev 2010. CD001239.

58. Haque KN, Pammi M. Pentoxifylline for treatment of sepsisand necrotizing enterocolitis in neonates. Cochrane DatabaseSyst Rev 2011. CD004205.

59. Powers RJ, Wirtschafter DW. Decreasing central line associ-ated bloodstream infection in neonatal intensive care. ClinPerinatol 2010;37:247e72.

60. Schulman J, Stricof R, Stevens TP, Horgan M, Gase K,Holzman IR, et al. Statewide NICU central-line-associatedbloodstream infection rates decline after bundles and check-lists. Pediatrics 2011;127:436e44.

61. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG,Messner H, et al. Bovine lactoferrin supplementation forprevention of late-onset sepsis in very low-birth-weight ne-onates: a randomized trial. J Am Med Assoc 2009;302:1421e8.

62. Pammi M, Abrams SA. Oral lactoferrin for the treatment ofsepsis and necrotizing enterocolitis in neonates. CochraneDatabase Syst Rev 2011. CD007138.

63. Glass HC, Bonifacio SL, Chau V, Glidden D, Poskitt K,Barkovich AJ, et al. Recurrent postnatal infections are associ-ated with progressive white matter injury in premature in-fants. Pediatrics 2008;122:299e305.

64. ShahDK, Lavery S, Doyle LW,WongC, McDougall P, Inder TE. Useof2-channel bedsideelectroencephalogrammonitoring in term-born encephalopathic infants related to cerebral injury definedby magnetic resonance imaging. Pediatrics 2006;118:47e55.

65. Schlapbach LJ, Aebischer M, Adams M, Natalucci G,Bonhoeffer J, Latzin P, et al. Impact of sepsis on neurodeve-lopmental outcome in a Swiss National Cohort of extremelypremature infants. Pediatrics 2011;128:e348e57.

66. van der Ree M, Tanis JC, Van Braeckel KN, Bos AF, Roze E.Functional impairments at school age of preterm born chil-dren with late-onset sepsis. Early Hum Dev 2011;87:821e6.

S32 A.L. Shane, B.J. Stoll

Neonatal sepsis: Progress towards improved outcomesIntroductionBurden of disease and characterizationEarly onset sepsis (EOS)Burden of EOSGroup B streptococci (GBS)

Late onset sepsis (LOS)Coagulase negative staphyloccci (CoNS)Staphylococcus aureusCandidiasisPrevention of candidiasis

Other preventive strategies for neonatal sepsisAntimicrobial utilization practicesPrevention of healthcare associated infections (HAI)New strategies to prevent hospital associated infections

Longer term risks of neonatal sepsisConclusionsConflict of interestReferences