Prevention of Nosocomial Infections in Neonatal Intensive ... · Prevention of Nosocomial Infections in Neonatal Intensive ... of ventilator-associated pneumonia ... 82 Prevention

Prevention of Nosocomial Infections in NeonatalIntensive Care UnitsPaolo Manzoni, MD1 Daniele De Luca, MD2 Mauro Stronati, MD3 Evelyne Jacqz-Aigrain, MD, PhD4

Giulia Ruffinazzi, MD3 Martina Luparia, MD1 Elena Tavella, MD1 Elena Boano, RN1

Elio Castagnola, MD5 Michael Mostert, MD6 Daniele Farina, MD1

1Neonatology and NICU, “S. Anna” Hospital, Turin, Italy2 Laboratory of Clinical Molecular Biology and Pediatric Intensive CareUnit, University Hospital “A. Gemelli,” Catholic University of theSacred Heart, Rome, Italy

3Neonatology, IRCCS S. Matteo, Pavia, Italy4Department of Paediatric Pharmacology and Pharmacogenetics,Clinical Investigation Center, Hopital “R. Debré,” Paris, France

5 Infectious Disease Unit, “G. Gaslini” Children’s Hospital, Genoa, Italy6Department of Paediatrics, University of Torino, Torino, Italy

Am J Perinatol 2013;30:81–88.

Address for correspondence and reprint requests Paolo Manzoni, MD,Neonatology and NICU, S. Anna Hospital, Azienda Ospedaliera ReginaMargherita–S. Anna, C.so Spezia 60, 10126 Torino, Italy(e-mail: [email protected]).

Sepsis-related morbidity and mortality is an increasing con-cern in all neonatal intensive care units (NICUs), and thereported incidences are dramatically high regardless of theimprovements in the quality of neonatal assistance.1

Neonatal sepsis includes bloodstream, urine, cerebrospi-nal, peritoneal, and lung infections, as well as infections

starting from burns and wounds or from any other usuallysterile site. It is associated with cytokine- and biomediator-induced disorders of respiratory, hemodynamic, and meta-bolic processes that are triggered by infections.

Many specific risk factors account for the increased risk ofbacterial and fungal sepsis in such patients, including the use

Keywords

► neonate► fluconazole► lactoferrin► sepsis► candida► infection► probiotics

Abstract Neonatal sepsis causes a huge burden of morbidity and mortality and includesbloodstream, urine, cerebrospinal, peritoneal, and lung infections as well as infectionsstarting from burns and wounds, or from any other usually sterile sites. It is associatedwith cytokine - and biomediator-induced disorders of respiratory, hemodynamic, andmetabolic processes. Neonates in the neonatal intensive care unit feature many specificrisk factors for bacterial and fungal sepsis. Loss of gut commensals such as Bifidobacteriaand Lactobacilli spp., as occurs with prolonged antibiotic treatments, delayed enteralfeeding, or nursing in incubators, translates into proliferation of pathogenic microfloraand abnormal gut colonization. Prompt diagnosis and effective treatment do notprotect septic neonates form the risk of late neurodevelopmental impairment in thesurvivors. Thus prevention of bacterial and fungal infection is crucial in these settings ofunique patients. In this view, improving neonatal management is a key step, and thisincludes promotion of breast-feeding and hygiene measures, adoption of a cautiouscentral venous catheter policy, enhancement of the enteric microbiota compositionwith the supplementation of probiotics, and medical stewardship concerning H2blockers with restriction of their use. Additional measures may include the use oflactoferrin, fluconazole, and nystatin and specific measures to prevent ventilatorassociated pneumonia.

receivedJuly 25, 2012accepted after revisionNovember 1, 2012published onlineDecember 29, 2012

Copyright © 2013 by Thieme MedicalPublishers, Inc., 333 Seventh Avenue,New York, NY 10001, USA.Tel: +1(212) 584-4662.

DOI http://dx.doi.org/10.1055/s-0032-1333131.ISSN 0735-1631.

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of broad-spectrum antimicrobial drugs, parenteral nutrition,acid inhibitors, and steroids, as well as the systematic andlong-lasting use of invasive devices such as central venouscatheter (CVC) and endotracheal tube.

Preterm neonates in NICU are at high risk of intestinaldisorders with proliferation of a pathogenic microflora, be-cause treatment with antibiotics, total parenteral nutrition(TPN), or nursing in incubators may delay or impair theintestinal colonization process. Loss of gut commensalssuch as Bifidobacteria spp. and Lactobacilli spp., due to thedifficulties in oral feeding or a slower acquisition of them inpreterm neonates, translates into an increased susceptibilityto abnormal gut colonization. For all these reasons, thedigestive tract is regarded as an important reservoir andsite for colonization by all kinds of pathogens and subsequentsepsis in preterm infants.

Immature or injured skin and impaired gut barriers allowdissemination of many organisms (among them, Staphylococ-ci and Candida spp.) from various colonizing sites.

Infants with complicated gastrointestinal diseases are atincreased risk due to abdominal surgery and prolongedperiods of TPN and ileus. In addition, many critically illinfants subjected to mechanical ventilation are at high riskof ventilator-associated pneumonia (VAP) that may inturn determine sepsis and other long-term negativeoutcomes.

Due to the high incidence of negative outcomes in sepsissurvivors,2 prevention of bacterial and fungal colonizationand infection is the key in these settings.

In this article, the currently available strategies to pre-vent infections in NICU patients will be reviewed(►Table 1).

Prevention of Sepsis: What Does Not Work

In the last years, several promising strategies have beenassessed and have been ineffective in preventing sepsis.

Recent evidence provided by large, multicenter trialsshowed that the administration of glutamine, immunoglo-bulins (either pooled immunoglobulins or specific antista-phylococcal enriched donor’s immunoglobulins, or themonoclonal antibody pagibaximab) had no benefits in pre-venting the incidence and severity of neonatal late-onsetsepsis. As a result, these potential approaches are not cur-rently recommended.

Glutamine is one of themost abundant amino acids in bothplasma and human milk, with trophic actions on enterocytesand gut integrity,3 but it is still not routinely included instandard amino acid solutions. Some studies suggested thatparenteral nutrition supplemented with glutamine may re-duce sepsis andmortality in critically ill adults.4 Some reportsadvocated a similar benefit also in extremely low-birth-weight (ELBW) infants.5 A multicenter, randomized, dou-ble-masked, clinical trial was thus conducted to reveal possi-ble beneficial effects of glutamine in preterm infants.6 ELBWinfants (weighing between 401 and 1000 g) were randomizedto receive within 72 hours of birth either a usual amino acidsolution with no glutamine (control) or an isonitrogenousamino acid solution with 20% glutamine whenever theyreceived TPN. Primary outcome was death or late-onsetsepsis. Of the 721 infants who were assigned to glutaminesupplementation, 370 (51%) died or developed late-onsetsepsis, as compared with 343 of the 712 infants (48%)assigned to control (relative risk: 1.07; 95% confidence inter-val: 0.97 to 1.17). Glutamine had no effect on tolerance ofenteral feeds, necrotizing enterocolitis, or growth. No signifi-cant adverse events were observed with glutamine supple-mentation. The conclusion was that parenteral glutaminesupplementation did not decrease mortality or the incidenceof late-onset sepsis in ELBW infants. Similar results have beenobtained byother two trials of glutamine supplementation.7,8

Consequently, routine use of parenteral glutamine supple-mentation cannot be recommended in this population.

Also therapy with intravenous immune globulins (eitherpooled or specifically enriched against some pathogen) hasproved to be not effective both in prevention and on theoutcomes of suspected or proven neonatal sepsis.

The Immunoglobulin Neonatal International Study (INIS)Collaborative group conducted an International Multicentertrial involving 113 hospitals in 9 countries.9 In all, 3,493infants were randomized to receive two infusions of eitherpolyvalent immunoglobulin G (IgG) immune globulin (at adose of 500 mg/kg) or a matching placebo 48 hours apart. Noeffect, in terms of death or major disability at the age of twoyears, could be demonstrated.

Similar disappointing findings were so far obtained bystudies addressing the potential benefit of antistaphylococcalimmunoglobulins for the prevention of staphylococcal infec-tion in very low-birth-weight (VLBW) infants. A recent Co-chrane review analyzed all eligible randomized and quasi-randomized studies in this area.10 Three eligible studies were

Table 1 Overview of Preventive Measures to Reduce Risk forSepsis in NICU

Neonatal management

• Breast-feeding with fresh human milk• Promotion of enteral feeding• Hygiene measures• CVC management policies• CVC bundles• In-line filters• Enteric microbiota composition enhancement with the

use of probiotics• H2 blockers and steroids restrictions• Antibiotic stewardship• Stewardship in TPN use• Prevention of VAP

Pharmacological prophylactic interventions

• General anti-infective prophylaxis: bioactive substances,probiotics, lactoferrin

• Specific antifungal prophylaxis: fluconazole, nystatin• Specific anti-RSV prophylaxis: palivizumab

Abbreviations: CVC, central venous catheter; NICU, neonatal intensivecare unit; RSV, Respiratory Syncitial Virus; TPN, total parenteral nutrition;VAP, ventilator-associated pneumonia.

American Journal of Perinatology Vol. 30 No. 2/2013

Prevention of Infections in Neonatal Intensive Care Units Manzoni et al.82

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included involving a total of 2,701 VLBW neonates. Nosignificant differences in the risk of staphylococcal infectionbetween two antistaphylococcal studied drugs (INH A-21Veronate,11 Inhibitex Inc., Alpharetta, GA, USA and alsoAltastaph, Nabi Biopharmaceuticals Inc., Rockville, MD,USA) versus placebo could be demonstrated. The authorsconcluded that both types of antistaphylococcal immunoglo-bulins are not recommended for prevention of staphylococcalinfections in preterm or VLBW neonates and that furtherresearch to investigate the efficacy and the impact on long-termneurodevelopmental outcome of other products, such aspagibaximab, was needed.

Pagibaximab is a recently developed chimeric monoclonalantibody against lipoteichoic acid, a component of the cellmembrane of many gram-positive organisms, particularlyrepresented in all Staphylococcus spp. It reacts with coagu-lase-negative staphylococci and Staphylococcus aureus isolatestrains and was granted “orphan drug status” in 2000. Aninvestigational pipeline has been developed over the lastdecade to provide evidence supporting the claim of preven-tion of staphylococcal sepsis in VLBW infants.

In a preliminary phase I study, the safety, pharmacokinet-ics, and pharmacodynamics of pagibaximab were assessedand no major adverse effects were noticed.12 The antibodywas effective against staphylococci preclinically and seemedsafe and well tolerated.

A phase IIa, randomized, double-blind, placebo-controlledtrial was therefore conducted evaluating also the effects onstaphylococcal sepsis. Some dozens of VLBW neonates wererandomized to receive once-a-weekpagibaximab (90or60mg/kg) or placebo infusions since the early days of life. The resultsshowed that infantswho received 90mg/kgdid not feature anystaphylococcal sepsis episode. Pagibaximab had a linear phar-macokinetic trendwith a 14.5-day half-life andwas not immu-nogenic. However, the target protective levels < 500 μg/mLwere only consistently achieved after two to three doses.13

These promising findings prompted the organization of alarge phase IIb, multicenter, randomized, double-blind, con-trolled trial that was performed in 100 NICUs across NorthAmerica and Europe, enrolling 1,579 VLBW infants weighing600 to 1200 g at birth. The protocol and the preliminary resultsare described and accessible at www.clinicaltrials.gov.14

The primary endpoint was the incidence of infections byStaphylococcus spp. from study days 0 to 35. The report postedat www.clinicaltrials.gov states that no significantly differentadverse events occurred in the two groups and that no safetyconcerns arose. The same report declares that out of 1579infants analyzed (792 in the pagibaximab and 787 in theplacebo groups), 85 in the pagibaximab groupversus 79 in theplacebo group had staphylococcal sepsis in the first 35 days ofstudy, thus nearly the same.14

These findings seem to be consistent with the alreadyreported lack of effectiveness of other strategies based onadministration of specific antistaphylococcal immunoglobu-lins, either pooled from donors or enriched,9,12 and seemconfirming that administration of specific antistaphylococcalantibodies, whichever the type, is not effective in preventingneonatal late-onset sepsis by Staphylococcus spp. in thenursery.

Prevention of Sepsis—What Does Work

Nutrition: Human MilkAvailability of essential nutrients is critical for a properdevelopment and maturation of all organs, both in the fetusand in the neonate. Several nutrients play both direct andindirect roles in conditioning the onset of sepsis and infectionduring the neonatal period. For some nutrients, there isevidence of a protective role against infections also in earlyinfancy (i.e., after the neonatal period).

Human milk contains several substances with putativeanti-infective actions, such as lactoferrin (LF), lactoperoxi-dase, lysozyme, immunoglobulin A (IgA), IgG, immunoglobu-lin M (IgM), cytokines, interferon, oligosaccharides,bifidogenic factors, platelet-activating factor acetylhydrolase,vitamin E, beta carotene, ascorbic acid.

Also the mucosal trophic effect of human milk on the gutcan be seen as an anti-infective mechanism because humanmilk has a known impact on gut permeability, which changesas a function of age and type of feeding.15 The feeding ofhuman milk is associated with decreased gut permeability at28 days of age,16meaning that humanmilk-fed neonates havea more rapid maturation of intestinal epithelium, leading tolower intestinal permeability. This might cause less trans-locations of pathogens from the gut and ultimately lessinfections and necrotizing enterocolitis (NEC).

Which factors in maternal milk could account for this? LFpossibly plays a major role. Experimental data obtained inhuman gut cell lines showed that enterocytes exposed to highLF concentrations respondwith a potent and rapid increase incell proliferation, whereas the same cells when exposed tolow LF concentrations show enhancement and stimulation ofintestinal differentiation. These experiments also reportedthat bovine LF has the same extent of activity as human LF.17

LF is thus a key modulator of intestinal epithelium develop-ment, and the speculation is that the higher concentrations ofLF in colostrum contribute to the early proliferation ofintestinal cells, which then differentiate as a result of itsdecreased concentrations in mature milk.

Of importance, beneficial effects of breast milk in preven-tion of infections depend on the amounts of human milkingested. Only average intakes higher than 50 mL/kg/d havebeen associated with a protective effect,18 as well as onlyfresh (and not donor) milk has been found to be protective.Pasteurization at 62.5°C for 30 minutes (Holder method)decreases many anti-infective milk substances, and thismight explain why in a recent randomized trial of donorhuman versus preterm formula, the two different types ofmilk were shown to have the same lackof effect on preventionof sepsis.19

CVC PolicyStrict policies in the management of the CVC are mandatoryto prevent or reduce line-associated infections. The durationof a CVC should be correctly monitored as it impacts on theoccurrence of a line-associated infection. After 15 days ofmaintenance, the odds of developing a bloodstream infectionincrease abruptly.20 Therefore, scheduled removal of


Prevention of Infections in Neonatal Intensive Care Units Manzoni et al. 83

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percutaneously inserted CVC should be considered, at least inat-risk ELBW neonates, even in absence of signs of suspectedsepsis. This recommendation is different from the usualpractice in adult and pediatric critical care, and the differencein patient populations (the need for a long-term Total Paren-teral Nutrition (TPN) in preemies) may explain this situation.Anyway, further, more robust evidence has to be produced toreally clarify this issue.

In terms of best use of human resources, “proactive”management of percutaneously inserted central cathetersresults in decreased incidence of infection in the ELBW popu-lation. In a single NICU study, the creation of a dedicated taskforce for the CVCmanagement produced a two-third reductionin the incidence of line-associated infections (from 15.8 in-fections/1000 catheters per day to only 5.1 infections/1000catheters per day).21 Additionally, recent evidence confirmedthat standardization of CVC placement and maintenance canreduce the risk for bloodstream infection by 50%.22

The use of “in-line filters” is also a promising approach.Particulate contamination due to infusion therapy carries apotential health risk, in terms of occurrence of systemicinflammatory response syndrome, organ failure, thrombosis,and ultimately sepsis. A recent single-center, prospective,randomized controlled trial conducted in a pediatric inten-sive care unit assessed the effects of filtration of intravenousfluids on the reduction of complications in critically illchildren.23 The authors demonstrated a significant reductionin the overall complication rate (40.9% versus 30.9%;p ¼ 0.003) for the filter group. In detail, the incidence ofsystemic inflammatory response syndrome was significantlylower (30.3% versus 22.4%; p ¼ 0.01). Pediatric intensive careunit stay and duration of mechanical ventilation were alsosignificantly reduced. However, no significant impact couldbe shown on the incidence of sepsis. This strategy needsfurther evaluation specifically designed for sepsis preventionand neonatal settings.

Another option to consider is an “intraremoval” prophy-lactic strategy. In a recent trial, the administration of twodoses of cefazolin during CVC removal and change reducedfrom 11 to 0% the incidence of coagulase-negative staphylo-coccal sepsis (number needed to treat: 9).24 These data mighthave limited generalizability due to the fact that in manyNICUs the proportion of coagulase-negative staphylococciresistant to cefazolin is high. Nevertheless, this is interestinginformation and deserves further confirmation addressingalso the possible differences in risk between various types ofcatheters: in fact, umbilical central catheter seems at muchlower risk than peripherally inserted CVC.25

Restriction of H2-BlockersUse of H2 blockers is associated with increased rates ofinfections in preterm neonates in NICU and should thereforebe limited or avoided. The acid gastric barrier is the mostprimitiveway of contrasting pathogens, and its impairment isobviously detrimental for the preterm host.

In a retrospective study of 569 infants in NICU over 3 years,Bianconi et al examined the effect of ranitidine on theincidence of late-onset sepsis and concluded that after con-

trolling for all possible confounding factors, infants receivingranitidine were at approximately 7 times greater risk of late-onset sepsis (odds ratio [OR] 6.99; 95% confidence interval[CI]: 3.78 to 12.94; p < 0.0001).26 More recently, other re-ports confirmed these findings, suggesting that the use ofranitidine or other H2 blockers in the nursery should beavoided.27,28 In this view, no data are currently available onthe impact of proton pump inhibitors (e.g., omeprazole). Thisclass of antacid drugs operate by a different pharmacologicalmechanism but still result in increased gastric pH and proba-ble altered gastrointestinal flora, thus—at least in theory—itsuse should be carefully considered in neonates at high risk forsepsis.

ProbioticsProbiotics colonize the neonate since the early moments oflife, starting from labor when the offspring ingests micro-organisms belonging to the normal commensal flora of thematernal genitourinary tract. Should thebaby be prematurelyborn, or through cesarean section, or exposed to antibioticssince the early moments of life, this natural process may notoccur or be impaired.

Probiotics have known immunomodulating and anti-infec-tive activities, as they produce substances with bacteriostatic/bactericidal actions (e.g., the Lactobacillus reuterii produce theso-called reutericyclin, an antibiotic peptide29), compete foradhesion to gut cells displacing the pathogens,30 and finallyinfluence intestinal permeability.31

The impact of healthy gut colonization has been confirmedby studies that showed how colonization with Bacteroidesspp. increases the number of gut cells producing IgA, IgG, andIgM in the first months of life.32

Probiotics have a known effect in the prevention of NEC,which is often related to sepsis.33 A recent Cochrane reviewstated that enteral supplementation of probiotics preventssevere NEC (risk ratio 0.35), sepsis (risk ratio 0.9), and all-cause mortality (risk ratio 0.4) in preterm infants.34

Moreover, Lactobacillus rhamnosus GG and L. reuteriiproved effective in preventing gut colonization byCandida spp.,35 a process that often precedes fungalsepsis. ►Table 236,37,63–71 summarizes the results from themain trials of probiotics for prevention of Candida coloniza-tion. The safety of probiotics has been recently confirmed in aretrospective, two-center study reporting on the absence ofany adverse effect or microbiologic issue over 6 years ofroutine L. rhamnosus LGG. administration in VLBW neonatesadmitted in two large Italian NICUs.36

Despite the important available evidence, major areas arestill in need of further studies and clarifications before pro-biotics can be more broadly embraced, including the scat-tered availability of well-defined pharmacological-gradeproducts (as opposed to nutritional supplement grade) inmany countries/settings, the lack of data on long-term neuro-developmental follow-up in infants fed probiotics since birth,and the identification of which species of probiotics ispreferable for each different clinical purpose, given thatthat different probiotic species may have different actionsand targets.



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Table

2MainRrialsof

Prob

iotics

toPrev

entLO

Sor

Colon

izationby

Cand

idaspp.

inPreterm

Infantsin

NICU

Probioticused

Prim

aryoutcome

Inciden

cein

theprobiotic

group(%

)

Inciden

cein

theplace

bo

group(%

)

pva

lue

Man

zoni

etal,20

0635

Lactob

acillus

rham

nosusGG

Cand

idagu

tco

lonization

in<15

00-g

neon

ates

23.1

48.8

0.01

Romeo

etal,20

1137

Lactob

acillus

reuterii

Cand

idagu

tco

lonization

in<25

00-g

neon

ates

7.1

22.9

0.01

Romeo

etal,20

1137

Lactob

acillus

rham

nosusGG

Cand

idagu

tco

lonization

in<25

00-g

neon

ates

10.7

22.9

0.01

Man

zoni

etal,20

0635

Lactob

acillus

rham

nosusGG

LOSin

<15

00-g

neon

ates

48.7

53.6

NS

Kitajim

aet

al,19

9763

Bifid

obacteriu

mbreve

LOSin

<15

00gne

onates

2.2

0NS

Dan

ietal,2

0026

4Lactob

acillus

rham

nosusGG

LOSin

<15

00-g

neon

ates

4.7

4.1

NS

Costaloset

al,20

0365

Saccha

romyces

boulardii

LOSin

<15

00-g

neon

ates

5.8

8.3

NS

Bin-Nun

etal,20

0566

Bifid

obacteriu

minfantis;

Streptococcusthermop

hilus;

Bi-

fido

bacterium

bifid

us

LOSin

<15

00-g

neon

ates

4332

.89

NS

Linet

al,20

0567

Lactob

acillus

acidop

hilus,

Bifid

obacteriu

minfantis

LOSin

<15

00-g

neon

ates

12.2

19.2

NS

Stratiki

etal,2

0076

8Bifid

obacteriu

mlong

umLO

Sin

<15

00-g

neon

ates

09.7

0.09

Linet

al,20

0869

Lactob

acillus

acidop

hilus,

Bifid

obacteriu

mbifidu

sLO

Sin

<15

00-g

neon

ates

19.8

11.5

0.06

Saman

taet

al,20

0970

Bifid

obacteriu

mlactis;

Lactob

acillus

acidop

hilus,

Bifid

obacteriu

mbifidu

s

LOSin

<15

00-g

neon

ates

14.2

29.5

0.02

Roug

éet

al,20

0971

Lactob

acillus

rham

nosusGG

Bifid

obacteriu

mlong

umLO

Sin

<15

00-g

neon

ates

33.3

26.5

NS

Abb

reviations:LO

S,late-ons

etsepsis;NICU,ne

onatal

intensivecare

unit;NS,

notsign

ificant.



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FluconazoleFluconazole prophylaxis is effective in preventing Candidaspp. infection in infants < 1500 g. A recent meta-analysiswith Mantel-Haenszel methods including 10 studies (7 ret-rospective studies and 3 randomized controlled trials)37

shows that fluconazole prophylaxis reduces:

8 the chance of developing invasive fungal infection (IFI) inhigh-risk infants <1000 g (odds ratio (OR) 0.10; 95%confidence interval (CI) 0.05–0.22; p < 0.0001)

8 the chance of developing IFI in all infants <1500 g (OR0.15; 95% CI 0.09–0.26; p < 0.0001)

8 the overall mortality rate (11% versus 16.3%) in all infants<1500 g (OR 0.74; 95% CI 0.58–0.95; p ¼ 0.017)

8 the Candida-related mortality (from 25 non-treatedinfants to 1 fluconazole-treated patient among the4,208 VLBW infants included in the published studiesso far).

Overall, fluconazole prophylaxis decreases invasive fungalinfections by 90% in ELBWand by 85% inVLBW infantswith allcause mortality decreased by 24%. Fluconazole is currentlyrecommended as a strategy in NICU having a high incidenceof fungal infections, and in all those subgroups of neonateswith high odds of developing such a devastating disease.38,39

NystatinNystatin is a nonabsorbed antifungal drug that has beenproposed since the 1990s as a feasible approach for preventionof fungal infections in neonates.38,40–44 The highest-qualityevidence comes from one only recent comparative trial inwhich 278 babies were randomized to three arms receivingnystatin, fluconazole, or placebo. The efficacy of nystatin inpreventing fungal colonization and invasive infections wasdeemed similar to that of fluconazole.45 When groupingtogether all the other nystatin studies, however, the overalllevel of evidence reached is lower, as compared with that offluconazole. However, most data come from retrospective,nonrandomized, or low-quality studies with few of the small-est preterm infants and do not report data onmortality, nor onother major outcomes and on resistances development.

Of note, although intravenous fluconazole acts on manylevels, oral nystatin may only reduce intestinal colonization.Moreover, nystatin has an extremely high osmolarity (10times higher than fluconazole) and this paradoxically mightbe a relevant risk factor for NEC.46

LactoferrinA new approach toward reduction of sepsis and NEC mightinvolve the use of bioactive substances with known anti-infec-tiveproperties. LF is amammalianmilkglycoprotein involved ininnate immune host defenses and can reduce the incidence oflate-onset sepsis in VLBW infants 47 and of NEC in animalmodels.48 The bovine isoform is nearly homologous to thehumanone. LF targets all pathogens, has bifidogenic properties,and enhances maturation of the nascent gut.49 In a recent trial,bovine LF produced a 65% decrease in late-onset sepsis and asignificant decrease in NEC of any stage of severity.50

Moreover, LF seems to have a strong candidacidal activityand might have a role also specifically for fungal infectionprevention.51,52 In fact, a randomized controlled trial enroll-ing 472 neonates demonstrated a reduction in the risk ofinvasive fungal infection for LF-treated infants (relative riskbetween 3.8 and 11, with a number needed to treat between14 and 17.5).53 As no adverse effects or treatment intoler-ances have been reported to date, the role of LF in themanagement of infections and NEC in NICU looks verypromising and worthy of future, larger-sized trials to confirmthese findings.

The Special Case of VAP

VAP represents a particular challenge because it affects mostcritically ill patients needing mechanical ventilation for theirrespiratory failure, including preterm neonates. VAP is respon-sible for a vicious cycle because it leads to a longer duration ofventilation, and as the additional days of ventilation is inverselyrelated to the birth weight,54,55 this may obviously affect theinsurgence of bronchopulmonary dysplasia and sepsis. Con-versely, a previous episode of sepsis is a significant risk factorfor VAP occurrence in preterm babies.56 It is not surprising thatVAP represents a significant risk factor for death in ELBWbabies (OR: 3.4; 95% CI: 1.20 to 12.31).56 The risk for VAP issignificantly higher below 28 weeks’ gestation,56 thus smallerbabies are at greater risk for concurrent complications. Despiteits importance and the fact that VAP is among the commonestnosocomial infections in pediatric critical care units in Europeand North-America,57,58 few data are available about its occur-rence in NICUs, and a certain degree of variability in VAPdefinitions in the different studies exists. Thus no clear strategyfor its prevention is currently available.

Preventative proposed interventions include early extu-bation strategies and switching to noninvasive respiratorysupport, the reduction of transfers of the babies outside theNICU, and frequent changes of the ventilator circuits; howev-er, more data are needed to properly evaluate the efficacy ofeach intervention.59,60

Very recently, two intriguing new approaches have beenproposed. Ryan et al used an ultraviolet germicidal irradiationin the heating ventilation and air-conditioning system of theirNICU and observed a significantly reduced tracheal microbialcolonization and VAP (from 74 to 39%; p ¼ 0.04; relative risk:1.89; number needed to treat 2.85).61 Christensen et al pro-posed the use of a low sodium saline solution for airway careandbronchoalveolar lavage in intubatedneonates.Thissolutionshoulddecreasethe incidenceofVAPbyreducing thedamagetothe innate antimicrobial system of airways subjected to seriallavages (as happens in long-term ventilated neonates). Theseauthors observed a reduction in VAP incidence from 4.2/1,000episodes in the control group to 1.6 VAPs/1,000 ventilator daysin the treatment arm (p ¼ 0.04) and also a lower incidence ofchronic lung disease (p < 0.001).62

Even though these findings are preliminary and producedby trials that may not be free from biases, they look promisingin identifying new lines of research to prevent VAP andconcurrent complications including neonatal sepsis.



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DisclosuresAuthors P.M. and E.A.J. collaborate in the framework ofseveral EU-funded and endorsed projects in the area ofantifungal safety and treatment in neonates. They repre-sent in these projects the TINN European collaborativegroup. E.A.J. and P.M. are, respectively, coordinator andwork package leader of the FP7 European Project TreatInfections in Neonates (TINN). P.M. and D.F. are, respec-tively, Chairman and Advisor of the Scientific Committeeof the Foundation “Crescere Insieme al S. Anna-ONLUS.”

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