sepsis - fanarof n avery

8/13/2019 Sepsis - Fanarof n Avery

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sPART 2 Postnatal Bacterial Infections Martin: Fanaroff and Martin's Neonatal-Perinatal Medicine, 8th ed., Co!ri"ht # 2$$% Mos&!, An Irint of (lse)ier

Mor)en *. (d+ards

N(NATA *(P*I*esite the de)eloent of ne+er, ore otent antiicro&ial a"ents, infectionsare still an iortant ca/se of neonatal or&idit! and ortalit!. This chaterart foc/ses on &acterial infections, &/t )iral, f/n"al, and arasitic infections/st &e considered in the differential dia"nosis of neonatal sesis.

Incidence and Mortalit!

*esis neonator/ is the ter /sed to descri&e an! s!steic &acterial infectiondoc/ented &! a ositi)e &lood c/lt/re in the first onth of life. Neonatal sesiscan &e classified into t+o relati)el! distinct illnesses &ased on the ostnatal a"eat onset 0Ta&le 13445: earl!-onset sesis occ/rs in the first da!s of life6 is/s/all! a f/linant, /ltis!ste infection ac7/ired &! )ertical transission frothe other6 and has a hi"her case fatalit! rate than late-onset sesis 0seeChater 225. ate-onset sesis is /s/all! ore insidio/s &/t a! ha)e an ac/teonset. Another t!e of sesis has &een reco"nied, )er!-late-onset sesis, +hichocc/rs after 1 onths of life and affects reat/re infants +ho are of )er! lo+&irth+ei"ht 09B5 in the neonatal intensi)e care /nit. 9er!-late-onset sesis isoften ca/sed &! Candida secies or &! coensal or"aniss s/ch as coa"/lase-ne"ati)e stah!lococci 0CN*5. This infection has /s/all! &een associated +ithrolon"ed instr/entation, s/ch as ind+ellin" intra)asc/lar lines andendotracheal int/&ation.;>$, the casefatalit! rate for infectio/s neonatal illnesses has contin/ed to decline and no+ is


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(AR@ N*(T 0 A@*5AT( N*(T 0A@* T 1 MNT*5

9(R@ AT(N*(T 0D1MNT*5

anifestations/ltis!stein)ol)eent, ne/oniacoon

focal infection,enin"itis coon

Case-fatalit!rate


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RGANI*MNEMB(R0?5

(scherichia coli $ 045

9iridans stretococci % 04%5

(nterococc/s secies 4% 0J5

*tah!lococc/s a/re/s 4< 0J5

Gro/ *tretococc/s 42 015

Pse/doonas secies > 025

ther "ra-ne"ati)e enteric&acilli

4% 0J5

ther 1 0>5

TTA J$8 04$$5

(tiolo"ic A"ents in ate-nset Neonatal*esis K

Coa"/lase-ne"ati)e*tah!lococc/s

%2> 0J85

*tah!lococc/s a/re/s 4$1 085

Candida al&icans % 0%5

(scherichia coli %J 0


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RGANI*MNEMB(R0?5

TTA414104$$5

(arl! onset, da!s of a"e. Adated fro !de TB et al:Trends in incidenceand antiicro&ial resistance of earl!-onset sesis: Po/lation-&aseds/r)eillance in *an Francisco and Atlanta. Pediatrics 44$:%>$, 2$$2.

K Infants +ere all )er! lo+ &irth +ei"ht 04


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Maternal factors a! infl/ence the de)eloent of s!steic &acterial infectionin the neonate. For reasons that reain /nclear, the rates of in)asi)e earl!-onsetGB* infection are hi"her aon" &lacHs than in other racial "ro/s.;88= Maternalfactors s/ch as aln/trition and recentl! ac7/ired se/all! transitted diseasescan also increase the risH of infection. The rates of reat/rit! and lo+

&irth+ei"ht, +hich &oth redisose to neonatal infection, are in)ersel! related tosocioeconoic stat/s. Maternal coloniation +ith GB* has &een +ell doc/entedas a risH factor for neonatal sesis. Coloniation d/rin" the third triester+itho/t an! colications of re"nanc! carries aroiatel! a 4? risH ofinfection6 this risH is increased if coloniation is associated +ith reat/rit!,aternal fe)er, or rolon"ed RM. As!toatic &acteri/ria has &eenassociated +ith reat/re &irth. Coloniation +ith "enital !colasas has&een associated +ith lo+ &irth+ei"ht.;


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sesis, colications of reat/rit! associated +ith an increased rate ofinfection incl/ded echanical )entilation, /&ilical )essel catheteriation, other)asc/lar catheters, h!eralientation, and d/ration of hosital sta!.;>>=

Ta&le 1-41 -- ost Resonses to Bacterial Infection in the Neonate

CMPN(NT

FENCTIN *TATE* IN N(NAT( CINICA *IGNIFICANC(

Coleent

soniation,cheoattraction

ecreased coleentcoonents, eseciall!in reter infants

ecreased rod/ction ofcheotactic factors,decreased osoniation of&acteria

Anti&od!soniation,coleentacti)ation

I"G concentrationdecreased in reterinfants, ter infantsha)e hi"herconcentration thanad/lts6 I"A a&sent frosecretions

acH of anti&od! tosecific atho"ens res/ltsin increased risH ofinfection Increased risH of/cosal coloniation +ithotential atho"ens

Ne/trohil CheotaisIaired i"ration,iaired &indin" to

cheotactic factors

ecreased inflaator!resonse, ina&ilit! to

localie infection

Pha"oc!tosisNoral +ith s/fficient7/antities of osonin

Bacterial Hillin"Noral in health!neonates, diinished instressed neonates

Monoc!te Cheotais ecreasedecreased inflaator!resonse

Pha"oc!tosis Contro)ersial Encertain

Bacterial Hillin" Contro)ersial Encertain

I", i/no"lo&/lin.

Adated fro Polin RA et al: Neonatal sesis. Ad) Pediatr Infect is :2>2.


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T(R RI*L FACTR*

It has &een s/""ested that &ottle feedin" a! redisose to infection. Prearedfor/la does not contain se)eral iortant &iolo"ic factors fo/nd in colostr/,s/ch as &acterial a""l/tinins and iron-&indin" roteins, +hich ha)e a local"astrointestinal rotecti)e effect a"ainst "ra-ne"ati)e enteric &acilli. BreastilH also contains i/no"lo&/lins, acroha"es, and l!hoc!tes, all of +hichla! a role in i/nolo"ic defense. Factors that a! affect late-onset neonatalinfection incl/de rior antiicro&ial /se6 reat/rit!6 a hi"h infant-to-n/rse ratioin the neonatal intensi)e care /nit6 and the resence of forei"n aterials s/ch asendotracheal t/&es and )entric/loeritoneal sh/nts. Containated arenteralfl/ids, incl/din" liid e/lsions, also ha)e &een associated +ith s!steic

infections.

Infants +ho ac7/ire earl!-onset disease often ha)e at least one aor risH factorassociated +ith re"nanc! and deli)er!, s/ch as rolon"ed RM, reterdeli)er!, lo+ &irth+ei"ht, erinatal ash!ia, or aternal eriart/ infection.B! contrast, late-onset disease is seldo associated +ith o&stetric colications.

Patholo"!

istolo"ic findin"s a! &e inial in f/linant cases of neonatal sesis.;>4=hen findin"s are resent, the! often reflect coeistin" setic shocH. */ch

findin"s a! incl/de renal ed/llar! heorrha"e, renal cortical necrosis orac/te t/&/lar necrosis, adrenal cortical and ed/llar! heorrha"e and necrosis,heatic necrosis, intra)entric/lar heorrha"e, and eri)entric/lar le/Hoalacia.()idence of disseinated intra)asc/lar coa"/lation a! &e o&ser)ed as +ell. Inlate-onset disease, atholo"ic chan"es consistent +ith the artic/lar focalinfection can &e deonstrated, incl/din" enin"itis, ne/onia, heatica&scesses, and arthritis or osteo!elitis. 0*ecific or"an s!ste infections aredisc/ssed later in the chater.5

ia"nosis

*@MPTM* AN *IGN*

The si"ns and s!tos of neonatal sesis often are nonsecific. Theteerat/re of the infant +ith sesis a! &e ele)ated, deressed, or noral.;%


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redicti)e )al/e in distin"/ishin" infectio/s fro noninfectio/s illness. The)aria&les eained +ere affect, feedin" attern, le)el of acti)it!, le)el ofalertness, resirator! stat/s or effort, /scle tone, and eriheral erf/sion.Incl/sion criteria re7/ired that the infants had a rectal teerat/re of 18QC04$$.JQF5 or hi"her and had recei)ed no anti&iotics +ithin the re)io/s 2 ho/rs.

All 211 infants in the st/d! /nder+ent a colete sesis e)al/ation, incl/din"l/&ar /nct/re for &lood cell co/nt, "l/cose and rotein deterinations, Grastain and c/lt/re, &lood and /rine c/lt/res, and /rinal!sis fro a catheteriedsale. The a/thors fo/nd that the ean score for infants +ith serio/s &acterialinfection 0enin"itis, sesis, or /rinar! tract infection5 +as si"nificantl! hi"herthan that for infants +ith asetic enin"itis or for those +ith ne"ati)e c/lt/resand noral cere&rosinal fl/id 0C*F5. Affect, eriheral erf/sion, andresirator! stat/s +ere the )aria&les that &est differentiated infected frononinfected fe&rile infants. T+o of the 2> infants +ith serio/s &acterial infectionsdid ha)e noral o&ser)ation scores6 ho+e)er, &oth had a&noral clinical or

la&orator! findin"s s/""esti)e of infection. The ne"ati)e redicti)e )al/e 0NP96seeTa&le 1345 of this scorin" s!ste +as >%?. Th/s, altho/"h o&ser)ationalfindin"s alone cannot relace the h!sical eaination and la&orator! st/dies,the! are an iortant asect of the e)al/ation of the fe&rile neonate.

Ta&le 1-4 -- Ters /sed for Anal!in" Acc/rac! and Relia&ilit! of Tests

T(RM (FINITIN

*ensiti)it! Percenta"e of atients +ith infection +ho ha)e ana&noral test res/lt

*ecificit!Percenta"e of atients +itho/t infection +ho ha)e anoral test res/lt

Positi)e redicti)e)al/e

If test res/lt is a&noral, ercenta"e of atients +ithinfection

Ne"ati)e redicti)e)al/e

If test res/lt is noral, ercenta"e of atients +ith noinfection

Fro ein&er" GA et al: a&orator! aids for dia"nosis of neonatal sesis. InRein"ton * et al 0eds5: Infectio/s iseases of the Fet/s and Ne+&orn Infant,


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res/lt in !reia, incl/din" deh!dration, dr/" +ithdra+al, and etensi)eheatoas. Llein and associates;%


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C/lt/res

A definiti)e dia"nosis of neonatal sesis can &e ade onl! +ith a ositi)e &loodc/lt/re. Blood, /rine, and C*F sho/ld &e o&tained fro all infants s/sected ofha)in" sesis. The oti/ n/&er of &lood c/lt/res and )ol/e of &lood er

c/lt/re ha)e not &een esta&lished for neonates. &tainin" ore than one &loodc/lt/re can &e helf/l in distin"/ishin" &lood c/lt/re containants fro tr/eatho"ens. A ini/ of $.< of &lood er &ottle is recoended. To a)oidcontaination, &lood sho/ld not &e o&tained fro a caillar! sticH or fro/&ilical catheters, ecet erhas iediatel! after insertion. There arese)eral an/al and a/toated ethods a)aila&le for detectin" "ro+th in the&lood c/lt/re edi/. Man! of the ne+ a/toated radioetric techni7/es candetect "ro+th as earl! as 8 ho/rs and alost al+a!s +ithin 2J to J8 ho/rs aftercollection.

Erine sho/ld &e o&tained in a sterile anner, s/ch as &! catheteriation ors/ra/&ic &ladder asiration, and sent for cheical and icroscoic anal!sesand c/lt/re &efore antiicro&ial thera! is started. Erine c/lt/res can &e ositi)ein infants +ith sesis in the a&sence of riar! /rinar! tract infection, &/t"enerall! the !ield for ositi)e /rine c/lt/res is lo+, eseciall! in earl!-onsetdisease.;J= o+e)er, &eca/se the /rine c/lt/re a! &e ositi)e +ith ne"ati)e&lood c/lt/res in older ne+&orns +ith riar! /rinar! tract disease, it is r/dentto o&tain /rine +hene)er ossi&le.

C*F sho/ld &e o&tained &efore anti&iotic adinistration and sent for &lood cellco/nt, differential, and cheistr! deterinations, as +ell as for Gra stain and

c/lt/re 0see Menin"itis,S later, as +ell as Aendi B, for noral C*F indices5.Altho/"h contro)ersial, soe &elie)e that l/&ar /nct/re a! &e ostoned orecl/ded fro the e)al/ation of an infant +ith s/sected earl!-onset diseaseanifested &! ne/onia. o+e)er, enin"itis accoanies sesis inaroiatel! 4$? of infants +ith earl!-onset disease and ore often +ith late-onset disease6 it cannot &e dia"nosed or ecl/ded solel! on the &asis of thes!toatolo"!6 and &lood c/lt/res can &e sterile in 4$? to 4


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e/Hoc!te sears ade fro the &/ff! coat la!er of centrif/"ed, anticoa"/lated&lood can &e stained +ith Gra stain and eth!lene &l/e or +ith acridineoran"e, then eained icroscoicall! for intracell/lar &acteria. A ositi)e &/ff!coat sear s/orts the dia"nosis of sesis and identifies the orholo"ic andGra stain characteristics of the or"anis, &/t does not identif! the infectio/s

a"ent or incl/de or ecl/de other foci of infection.

Anti"en etection Assa!s

I/noassa!s that detect &acterial cell +all or cas/le car&oh!drate anti"ens in&od! fl/ids are an ad/nct to dia"nosis. M/ltile st/dies ha)e sho+n that anti"entests are not an aroriate s/&stit/te for roerl! erfored &acterial c/lt/resin the dia"nosis of neonatal sesis. ith the a)aila&le radioetric &lood c/lt/retechnolo"!, raid anti"en testin" is no+ infre7/entl! re7/ired or indicated. Inaddition, these tests a! ro)ide res/lts that are isleadin". The onl!seciens recoended for testin" +ith these de)ices are ser/ or C*F. Aositi)e res/lt sho/ld &e taHen to indicate the resence of anti"en and notnecessaril! the resence of )ia&le or"aniss.

T(R ABRATR@ T(*T*

e/Hoc!te Co/nts

Man! different asects of the le/Hoc!te co/nt ha)e &een eained for theirredicti)e )al/e in dia"nosin" sesis. e/Hoc!tosis or le/Hoenia, defined asore than 2$,$$$1 and fe+er than


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IN(O BIRT 42 ER* 2J ER* J8 ER* 2 ER*42$ER*

ANC48$$3$$$ 48$$3$$$ 48$$3J:%, 4>>J.

efined as

U4


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K Ne/trohils1.

The total ne/trohil co/nt has &een /sed to hel redict the resence ofinfection. Ne/troenia, eseciall! if it occ/rs in the first ho/rs of life and isassociated +ith resirator! distress, can &e +orrisoe &eca/se of a stron"association +ith earl!-onset GB* sesis. o+e)er, an! noninfectio/s rocessesare associated +ith &oth ne/troenia and ne/trohilia;4$J=0Ta&le 134%andBo 1315. n the other hand, an! infants +ith doc/ented sesis ha)enoral total ne/trohil co/nts at the tie of the initial e)al/ation. Therefore, thea&sol/te total ne/trohil co/nt has not &een fo/nd helf/l in dia"nosin" orecl/din" neonatal sesis.

Ta&le 1-4% -- Clinical Factors Affectin" Ne/trohil Co/nts

Total Ne/trohilsTotalIat/reNe/trohils

I:TRatio

ERATIN0ho/rs5

ecreased

Increased

IncreasedIncreased

Maternal h!ertension V V V V $ V V 2

Maternal fe)er, health!neonate

$ V V V V VV V VV

2J

% o/rs of intraart/o!tocin

$ V V V VV V VV

42$

*tressf/l la&or K $ V V V V V V VV V VV

2J

Ash!ia 0


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Total Ne/trohils

TotalIat/reNe/trohils

I:TRatio

ERATIN0ho/rs5

ecreased

Increased Increased

Increased

Peri)entric/lar heorrha"eW

V V V V V VV V VV

42$

*ei/res X $ V V V V V VV V VV

2J

Prolon"ed cr!in" 0J in5 $V V VV

V V V VV V VV

4

As!toatich!o"l!ceia 0U1$ "d5

$ V V V V V V V V 2J

eol!tic disease V V V V V V V V V 328 da!s

*/r"er! $V V VV

V V V V V V V 2J

i"h altit/de $

V V V

V V V V V $ % Y

V, $?32


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Clinical Neonatal Factors a)in" No (ffect on Ne/trohil Co/nts

Race

*e

Maternal dia&etes ellit/s

Ro/te of deli)er!

Preat/re aniorrheis, other afe&rile

Meconi/ stainin", no l/n" disease

Encolicated resirator! distresss!ndroe

Encolicated transient tach!nea of thene+&orn

!er&ilir/&ineia, h!siolo"ic,/nelained

Photothera!

Brief 0U1 in/tes5 cr!in"

i/rnal )ariation

Fro ein&er" GA, Po+ell LR: a&orator! aids for dia"nosis of neonatal sesis.In Rein"ton * et al 0eds5: Infectio/s iseases of the Fet/s and Ne+&ornInfant, , 4>>.

The total ne/trohil co/nt of the cord &lood of infants deli)ered )a"inall! or&! cesarean section after la&or 0234J ho/rs5 is t+ice that of infants deli)ered &!cesarean section +itho/t la&or.

The a&sol/te total iat/re ne/trohil co/nt, defined as the a&sol/te n/&er ofall ne/trohils ecl/din" the se"ented ne/trohils, has also &een etensi)el!st/died. All ne+&orns, &/t eseciall! reat/re ones, ha)e a relati)el! lar"en/&er of iat/re ne/trohils in the first fe+ da!s of life. Infected neonatesa! ha)e an increase a&o)e the /er liits of noral in iat/re cellsreleased fro the &one arro+ in resonse to infection, &/t this resonse isinconsistent and soeties dela!ed and therefore an insensiti)e arHer for theearl! dia"nosis of infection. o+e)er, it is /n/s/al for /ninfected infants to ha)ean ele)ated a&sol/te total iat/re ne/trohil co/nt a&o)e the referenceran"es6 therefore, if s/ch a findin" is resent, f/rther e)al/ation for occ/lt

infection sho/ld &e considered.


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The I:T ratio has &een in)esti"ated as an earl! redictor of sesis. The aialI:T ratio in /ninfected neonates is $.4% in the first 2J ho/rs, decreasin" to $.42&! %$ ho/rs. The /er liit of noral for neonates of 12 +eeHs "estation orless is sli"htl! hi"her, at $.2. Beca/se ost infected neonates ha)e an ele)atedI:T ratio soe tie d/rin" the infection, reeatedl! noral I:T ratios can &e

reass/rin". The /sef/lness of this test is liited &eca/se an! noninfectio/srocesses, incl/din" rolon"ed ind/ction +ith o!tocin, stressf/l la&or, and e)enrolon"ed cr!in", are associated +ith increased I:T ratios.

Ac/te-Phase Reactants

The ac/te-hase resonse is a resonse of the &od! to infection or tra/aclinicall! anifested &! alaise, anoreia, fe)er, le/Hoc!tosis, ne"ati)e nitro"en&alance, and heatic rod/ction of ac/te-hase roteins 0APRs5. APRs areroteins rod/ced &! heatoc!tes in resonse to inflaation. The inflaationa! &e secondar! to infection, tra/a, or other rocesses of cell/lardestr/ction. There are an! different APRs, incl/din" C-reacti)e rotein 0CRP5,fi&rino"en, C1 coleent, Z4-acid "l!corotein, Z4-antitr!sin, and elastaseZ4-roteinase inhi&itor 0(Z4-PI5.;81= These APRs ha)e different lasa half-li)esand different increental resonses to inflaation. The ethodolo"! for thedetection of APRs has iro)ed +ith the de)eloent of raid, a/toated,7/antitati)e secific i/noassa!s. There ha)e &een n/ero/s st/diese)al/atin" APRs as earl! indicators of neonatal seticeia6 /nfort/natel!, anele)ated APR does not distin"/ish &et+een infectio/s and noninfectio/s ca/sesof inflaation.

C-Reacti)e Protein

CRP is a "lo&/lin so naed &eca/se it fors a reciitate in the resence of theC-ol!saccharide of *tretococc/s ne/oniae. Its f/nction is not entirel! clear,&/t it is &elie)ed to &e a carrier rotein in)ol)ed in reo)in" otentiall! toicaterial. There are se)eral ethods a)aila&le for eas/rin" CRP. *oe are f/ll!a/toated and 7/antitati)e, +hereas others are sei7/antitati)e or 7/alitati)eand an/al. There is inial, if an!, translacental assa"e of aternal CRP,and concentrations are /naffected &! "estational a"e. Noral concentrations inneonates are 4 "d or lo+er. An increasin" CRP )al/e is /s/all! detecta&le

+ithin % to 48 ho/rs, and the eaH CRP is seen at 8 to %$ ho/rs after onset of theinflaator! rocess. The ser/ half-life is < to ho/rs. Altho/"h the CRPdecreases rotl! in the resence of aroriate thera!, fe+ clinical st/diesha)e &een erfored e)al/atin" discontin/ation of thera! &ased on CRPnoraliation. CRP is si"nificantl! ele)ated at the tie of the initial e)al/ation in$? of infants +ith s!steic &acterial infections. *erial deterinations ofCRP at 42-ho/r inter)als after the onset of si"ns of sesis increased thesensiti)it! of CRP in detectin" sesis.;8$= It has &een o&ser)ed, ho+e)er, thatinfants +ith onset of infection in the first 42 ho/rs of life and infants +ith GB*infection a! not ha)e an ele)ated CRP )al/e. Non&acterial infections can elicita )aria&le CRP resonse, +ith noral )al/es in c/lt/re-ositi)e )iral enin"itisand increased )al/es in inor )iral infections. Noninfectio/s rocesses, incl/din"


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econi/ asiration ne/onitis, can ha)e an ele)ated CRP / to 4$ ties thenoral concentration. CRP has a lo+ ositi)e redicti)e )al/e and sho/ld not &e/sed alone to dia"nose sesis.

(r!throc!te *edientation Rate

The er!throc!te sedientation rate 0(*R5 is not a direct eas/re of an APR &/trather reflects chan"es in an! ser/ rotein APRs. A icro-(*R has &eende)eloed for /se in infants. An aroiation of the aial noral rate in thefirst 2 +eeHs of life can &e o&tained &! addin" 1 to the a"e of the ne+&orn inda!s. Be!ond 2 +eeHs of life, the aial rate )aries &et+een 4$ and 2$ er ho/r. +in" to interla&orator! )ariation, each la&orator! /st de)elo itso+n reference ran"e. The (*R is liited in that other factors /nrelated toinflaation 0aneia, h!er"lo&/lineia5 can affect the rate. Micro-(*R )al/es)ar! in)ersel! +ith the heatocrit &/t are affected little, if at all, &! &irth+ei"htor "estational a"e. Clinicall!, sli"htl! ele)ated icro-(*Rs ha)e &een noted +iths/erficial infections and +ith noninfectio/s rocesses, incl/din" ash!ia,asiration ne/onia, and resirator! distress s!ndroe. MarHedl! ele)ated)al/es in the a&sence of infection are /n/s/al &/t ha)e &een o&ser)ed +ithCoo&s-ositi)e heol!tic disease and h!siolo"ic h!er&ilir/&ineia. TheHinetic descrition of the (*R re)eals a lon" dela! after onset of theinflaator! rocess &efore the eaH rate is reached and a lon" half-life.Altho/"h the (*R is /s/all! ele)ated at soe oint in s!steic &acterialinfections, it is fre7/entl! noral on initial e)al/ation.

Fi&rino"en

Plasa fi&rino"en concentrations are Hno+n to increase in association +ithinfection, altho/"h soe factors can res/lt in a lo+ fi&rino"en le)el desitese)ere infection, incl/din" disseinated intra)asc/lar coa"/lation, echan"etransf/sion, and resirator! distress s!ndroe. Meas/reent of fi&rino"enconcentrations is not /sef/l in the earl! dia"nosis of infection &eca/se there is alar"e o)erla in )al/es &et+een infected and health! infants.

Fi&ronectin

Fi&ronectin 0Fn5 is a /ltif/nctional, hi"h3olec/lar-+ei"ht "l!corotein

rod/ced riaril! &! the li)er and endothelial cells and +idel! distri&/ted in the&od!, incl/din" in lasa and &od! fl/ids, on cell s/rfaces, and in theetracell/lar atri. Fn is in)ol)ed in heostasis, )asc/lar inte"rit!, and +o/ndhealin". It is iortant in e&r!o"enesis, directin" cell i"ration, roliferation,and differentiation. Fn aids in the i/ne resonse &! a/"entin" acroha"eand ne/trohil ha"oc!tosis and actin" as a nonsecific osonin for theretic/loendothelial s!ste. The lasa Fn concentration )aries +ith a"e. Inhealth! neonates it is aroiatel! half that fo/nd in ad/lts, +hereas health!reat/re infants ha)e aroiatel! one third of the ao/nt in noral ad/lts.After &irth the lasa concentration "rad/all! increases, reachin" ad/lt )al/es

&! 2 onths of a"e. Fn has &een fo/nd to &e decreased in neonates +ith


18/56

infection and also in neonates +ith ash!ia, resirator! distress s!ndroe, and&roncho/lonar! d!slasia.

C!toHines

Altho/"h c!toHine Hinetics ha)e not &een thoro/"hl! in)esti"ated in neonates, itis &elie)ed &! an! that eas/rin" c!toHine concentrations can &e helf/l in theearl! dia"nosis of neonatal sesis. In a st/d! &! Girardin and collea"/es,;


19/56

+as 48? to 21?, and the ne"ati)e redicti)e )al/e 0NP95 +as >


20/56

and . onoc!to"enes. The co&ination of aicillin and an aino"l!coside isfre7/entl! /sed. isteria or"aniss and GB* are /niforl! s/sceti&le toaicillin, +hereas the s/sceti&ilit! of (. coli to aicillin is less relia&le. Theaino"l!coside ro)ides co)era"e a"ainst ost "ra-ne"ati)e enteric &acilliand, +ith "entaicin secificall!, has &een fo/nd to act s!ner"isticall! +ith

aicillin a"ainst GB* and isteria or"aniss in )itro and in anial odels. Thechoice of aino"l!coside sho/ld &e &ased on s/sceti&ilit! atterns for "ra-ne"ati)e enteric &acilli in the co/nit!. Gentaicin is /sed ost fre7/entl!,+ith to&ra!cin and aiHacin reser)ed for treatent of /ltidr/"-resistant&acteria. If enin"itis is s/sected, eseciall! "ra-ne"ati)e &acillar!enin"itis, an! add or relace the aino"l!coside +ith the third-"enerationcehalosorin, cefotaie, for &etter CN* enetration.

(irical thera! for late-onset disease ac7/ired in the co/nit! sho/ldro)ide co)era"e for the sae neonatal atho"ens as disc/ssed earlier and also

for otential co/nit!-ac7/ired atho"ens, s/ch as *. ne/oniae andNeisseria enin"itidis. Beca/se enin"itis fre7/entl! is a coonent of late-onset sesis, anti&iotics +ith "ood CN* enetration sho/ld &e selected.Aicillin and a third-"eneration cehalosorin 0e."., cefotaie5 are coonl!recoended.

ealth care-associated late-onset disease can &e ca/sed &! the /s/al neonatalatho"ens &/t also &! CN*, enterococci, "ra-ne"ati)e enteric &acilli0incl/din" dr/"-resistant strains5, and f/n"i. (irical thera! deends on theresence of risH factors for coensal or"aniss s/ch as CN* 0/se ofcatheters or sh/nts5 and the s/sceti&ilit! rofiles for coon nosocoial

atho"ens isolated fro the n/rser!. 9irt/all! all stah!lococci rod/ceenicillinase and therefore are resistant to aicillin and enicillin. 9anco!cinand "entaicin are coonl! /sed for initial thera!. 9anco!cin "enerall! isacti)e a"ainst all stah!lococcal secies, stretococci, and ost enterococci,+hereas the sectr/ of acti)it! of a enicillinase-resistant enicillin incl/desstretococci and onl! the ethicillin-s/sceti&le strains of CN* and *. a/re/s.Cefotaie or ceftriaone a! &e incl/ded +hen "ra-ne"ati)e enin"itis is aconcern. Cefotaie does not ha)e acti)it! a"ainst . onoc!to"enes,enterococci or Pse/doonas secies. Ceftaidie +ith an aino"l!coside sho/ld&e /sed if Pse/doonas infection is s/sected. Man! other co&inations of

antiicro&ial a"ents a! &e effecti)e thera! for nosocoial late-onset sesis6ho+e)er, it is r/dent to /se those a"ents that ha)e ro)en +ith eerience to&e safe.

The risHs and &enefits sho/ld &e considered thoro/"hl! if ro/tine /se of third-"eneration cehalosorins for late-onset disease is contelated. nedisad)anta"e is an increased risH for de)eloent of "astrointestinalcoloniation and erhas s/&se7/ent infection +ith f/n"i and dr/"-resistant&acteria. ith ceftriaone, in artic/lar, there is a theoretical risH of &ilir/&indislaceent fro al&/in &eca/se of the dr/"s hi"h rotein-&indin" caacit!.

There are no clinical data to s/&stantiate this effect in neonates. n the otherhand, these cehalosorins are safe and effecti)e a"ainst an! of the coon


21/56

neonatal atho"ens, and there is etensi)e eerience +ith cefotaie /sed/rin" the neonatal eriod. Beca/se the third-"eneration cehalosorins do notca/se the dose-related toicities seen +ith a"ents s/ch as the aino"l!cosides,onitorin" of ser/ concentrations is not necessar!.

(irical thera! /s/all! a! &e narro+ed to one dr/" once final c/lt/reidentification and s/sceti&ilit! res/lts are a)aila&le.

The dosa"e and fre7/enc! of adinistration of antiicro&ial a"ents )ar! +iththe ne+&orns "estational a"e, ostnatal a"e, &irth+ei"ht, and stat/s of heaticand renal f/nction. Recoendations for anti&iotic /se in neonates are "i)en in

Ta&les 1348, 134>, 132$and in Aendi A. These are "/idelines onl!6secific doses and inter)als a! chan"e fre7/entl!, eseciall! in the criticall! illinfant. Ideall!, ser/ concentrations of soe anti&iotics 0aino"l!cosides,)anco!cin5 sho/ld &e onitored to ens/re therae/tic efficac! +hileiniiin" toicit!. The d/ration of thera! deends on the site of infection 0seelater5.

Ta&le 1-48 -- Recoended osa"e *ched/le for Antiicro&ial A"entsFre7/entl! Esed to Treat Neonatal *esis

ANTIBITIC

osa"e 0"H" er da!5 and Inter)als of Adinistration

RET(

Bod! ei"ht U2$$$ " Bod! ei"ht D2$$$ "

$3 a!s 8328 a!s $3 a!s 8328 a!s D28 a!s

Aicillin I9, IM4$$ di) 742h

4$ di) 7 8h42$ di) 7%h

42$ di) 7%h

Cefotaie I9, IM4$$ di) 742h

4


22/56

ANTIBITIC

osa"e 0"H" er da!5 and Inter)als of Adinistration

RET(

Bod! ei"ht U2$$$ " Bod! ei"ht D2$$$ "

$3 a!s 8328 a!s $3 a!s 8328 a!s D28 a!s

42h 42h

Metronidaole I9, P4< di) 742h

4< di) 742h

4< di) 742h

1$ di) 742h

1$ di) 7 %h

Melocillin I9, IM4


23/56

ANTIBITIC

RET(

osa"e for eeHs Gestation orPostconcetional A"e

1$ 1$31 D1

AiHacin

U da!sI9, IM 4< "H" 7

2Jh4< "H" 748h

4< "H" 742h

D da!s4< "H" 748h

4< "H" 742h

4< "H" 7 8h

Gentaicin or to&ra!cin K

U da!s I9, IM 1 "H" 72Jh

1 "H" 748h

2.< "H" 742h

D da!s1 "H" 748h

2.< "H" 742h

2.< "H" 78h

9anco!cin W

U da!sI9 2$ "H" 7

2Jh4< "H" 748h

4< "H" 742h

D da!s2$ "H" 748h

4< "H" 742h

4< "H" 7 8h

esired ser/ concentrations: eaH 2$3J$ \",tro/"h 4$ \".

K esired ser/ concentrations: eaH


24/56

ANTIBITIC INICATIN*PARMACG

@TOICIT@ CMM(NT*

AiHacin

Aero&ic "ra-ne"ati)einfections6 /sesho/ld &eliited totreatent of"entaicin-resistantor"aniss

Renalecretion6acti)it! in C*Flo+6 nota&sor&ed froGI tract

Possi&leototoicit!,nehrotoicit!,andne/ro/sc/lar&locHade

Toicit! rareif aroriatedosa"e is/sed and&loodconcentrationis onitored

Aicillin

Initial treatentof sesis andenin"itis6"ra-ositi)eor"anissecetstah!lococci6"ra-ne"ati)eor"aniss ifs/sceti&le0*alonella,*hi"ella,

eohil/s,(scherichia coli5

Renal ecretion*ei/res +henhi"h dosa"es are"i)en

Cefotaie

*esis,enin"itisca/sed &!s/sceti&le"ra-ne"ati)e

or"aniss

Priaril! renalecretion6 "oodenetrationinto C*F

Acti)e a"ainststretococci6ro/tine /secan res/lt ineer"ence ofresistant"ra-

ne"ati)eor"aniss

Ceftaidie

Can &e /sed inco&ination+ith anaino"l!cosidefor treatent ofPse/doonasinfection

Renalecretion6enetrates&lood-&rain&arrier

Ceftriaone *esis, 1$?3%


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@TOICIT@ CMM(NT*

enin"itis, softtiss/e and&oneointinfectionsca/sed &!s/sceti&leor"aniss6 noteffecti)e a"ainststah!lococci,isteria s,enterococci, orPse/doonas s

ecreted &!the Hidne!s,the reainderecreted in&ile6 enetrates&lood-&rain&arrier

"all&laddersl/d"in"

&ilir/&in froal&/in-&indin" sitesin neonates

Clinda!cin

Treatent ofs/sceti&leanaero&icinfections

Pse/doe&rano/s colitis in olderchildren &/t rarein neonates

Chlorahenicol

Treatent of

infectionsca/sed &!&acteriaresistant to allother anti&iotics0e."., *alonellas5

Meta&olied &!the li)er, sall

ao/ntecreted/nchan"ed inthe /rine6 "oodenetrationthro/"h &lood-&rain &arrier

Gra! &a&!s!ndroe0)asootor

collase5 relatedto iat/reheatic f/nctionand associated+ith ele)atedconcentrations of/ncon/"atedchlorahenicol

ose-relatedre)ersi&le&one arro+s/ression6

idioathicirre)ersi&lealasticaneia0rare56onitorin" of&loodconcentrationandator!

(r!thro!cin

Chla!dia,Pert/ssis s,inorstah!lococcalor stretococcalsHin infections

(creted in/rine, stool,and &iliar!s!ste6crosses &lood-&rain &arrieroorl!

No si"nificanttoicit!

Gentaicin Can &e /sed forinitial treatent

of neonatalsesis6 not

Renalecretion6

acti)it! lo+ inC*F6 not

Possi&leototoicit!,

nehrotoicit!,and

Toicit! rareif the

aroriatedosa"e is


26/56


@TOICIT@ CMM(NT*

effecti)e alone&/t can &es!ner"istic +hen/sed +ithaicillina"ainst "ro/ Bstretococci,enterococci, andisteria s

a&sor&ed froGI tract innoral host

ne/ro/sc/lar&locHade

/sed and&loodconcentrations areonitored

Nafcillin,oacillin

Penicillin-resistant*tah!lococc/sa/re/sinfections6acti)e a"ainststretococci, &/tnot a first-linea"ent

(cretion isrenal andheatic fornafcillin andoacillin6nafcillin andoacillin arehi"hl! rotein&o/nd

Neo!cin

Bacterialdiarrhea,

enteroatho"enic (. coli

Not a&sor&ed

&! GI tract

totoic,

nehrotoic ifa&sor&ed

o not /se

arenterall!

Penicillin G

Moststretococci,

Treoneaallid/,Bacteroides s0ecetBacteroides

fra"ilis5,Neisseriaenin"itidis

Renalecretion6 fairenetration ofinflaed

enin"es

Can &e /sedto treatinfectionsca/sed &!s/sceti&le

or"aniss

*treto!cinM!co&acteri/t/&erc/losis

Renal ecretion9esti&/lar anda/ditor! daa"e,nehrotoicit!

M/st &e "i)enIM

Ticarcillin (anded "ra-ne"ati)e

acti)it!6 can &e/sed to treat

Renal ecretion Plateletd!sf/nction

Can &eassociated

+ithh!ernatrei


27/56


@TOICIT@ CMM(NT*

s/sceti&le

Pse/doonasinfections

a andh!oHaleia6electrol!tesare onitored

To&ra!cin

Broad co)era"eof "ra-ne"ati)eor"aniss

Renalecretion6 lo+acti)it! in C*F

Possi&leototoicit! andnehrotoicit!

Bloodconcentrations areonitored

9anco!cin

(ffecti)e a"ainstcoa"/lase-

ne"ati)estah!lococci,ethicillin-resistant *.a/re/s6 ost"ra-ositi)eaero&icor"aniss ares/sceti&le

Renal ecretion

Possi&leototoicit!6re)io/srearationsassociated +ithnehrotoicit!

Fl/shin" orh!otensiona! res/ltfro raidinf/sion

*/lfonaidesContraindicatedin ne+&orns

islaces &ilir/&infro al&/in-&indin" sites

Tetrac!clinesContraindicatedin ne+&orns

Peranentdiscoloration ofteeth, enaelh!olasia6inhi&its &one"ro+th in

reat/re infants

C*F, cere&rosinal fl/id6 GI, "astrointestinal.

*EPPRTI9( T(RAP@


28/56

Altho/"h aroriate antiicro&ial thera! is cr/cial, s/orti)e care is e7/all!iortant. 9entilator! s/ort a! &e necessar!, artic/larl! for infants +ithf/linant earl!-onset disease. I9 h!dration and erhas arenteral n/trition,+ith close onitorin" of electrol!tes and "l/cose, sho/ld &e considered. *eticshocH, if resent, sho/ld &e treated aroriatel! +ith fl/ids and inotroes as

indicated &! the clinical sit/ation.

IMMENT(RAP@

The ne+&orns i/ne s!ste is coroised in an! asects, incl/din" thene/trohils cheotactic resonse to atho"ens, T cell rod/ction ofroinflaator! c!toHines, and f/nctional coleent acti)it! 0see Part 4 ofthis chater5. Preter infants are f/rther coroised &!h!o"aa"lo&/lineia &eca/se si"nificant transfer of aternali/no"lo&/lin 0I"5 G does not &e"in /ntil 12 to 1J +eeHs "estation. ()en terinfants a! lacH secific anti&odies to the ost coon atho"ens in earl!-onset neonatal infections &eca/se ost ad/lts ha)e lo+ concentrations ofanti&od! a"ainst GB* and (. coli. ith the increased risH of o)er+helin"&acterial infection in the reter neonate, researchers ha)e st/died the effect ofI9 i/ne "lo&/lin 0I9IG5 in re)entin" and treatin" neonatal infections.

Intra)eno/s I/ne Glo&/lin

There ha)e &een a n/&er of st/dies e)al/atin" I9IG for treatent of infectedneonates. A &eneficial effect fro I9IG and aroriate anti&iotics +as o&ser)edin se)eral st/dies coared +ith anti&iotics /sed alone for the treatent of

sesis. o+e)er, these +ere liited &! sall n/&ers of atients, non&lindedin)esti"ators, lacH of a lace&o control, or lacH of &acteria-secific anal!sis of theI9IG rearation /sed. Meta-anal!sis of st/dies of I9IG for the treatent ofneonates +ith sesis sho+ed a si"nificant decrease in the ortalit! ratecoared +ith standard theraies.;%J= F/rther st/dies are +arranted &efore I9IG/se in infections can &e recoended as ro/tine thera!.

ther A"ents in e)eloent

ther a"ents that a! &e &eneficial in the treatent of neonatal infectionsincl/de h/an onoclonal I"M anti&od! and h!eri/ne "lo&/lin secific for

the infectin" atho"en. Preliinar! in )itro and anial st/dies looH roisin",&/t f/rther in)esti"ation is needed. Fn adinistration a! &e of /se in there)ention and treatent of neonatal sesis &eca/se of its /ltif/nctional roles,incl/din" nonsecific osoniation that aids in clearin" de&ris in theretic/loendothelial s!ste, a/"entation of ha"oc!tic acti)it!, and heostasis.Fn has &een /sed in ad/lts as a toical a"ent to iro)e +o/nd healin" +ithersistent corneal /lcerations and I9 in /ncontrolled st/dies of atients +ith/ltior"an s!ste fail/re. Preliinar! res/lts aear enco/ra"in", &/t lar"e,rosecti)e, controlled st/dies are re7/ired &efore an! recoendations a&o/tits /se can &e ade. The /se of "ran/loc!te transf/sions as ad/ncti)e thera!

in neonates +ith o)er+helin" sesis and ne/troenia +as considered, &/t thisode of thera! is infre7/entl! /sed &eca/se of the need to adinister forei"n


29/56

rotein. More recentl!, the /se of reco&inant h/an "ran/loc!te colon!-sti/latin" factors or "ran/loc!te-acroha"e colon!-sti/latin" factors as anad/ncti)e thera! in the treatent of setic ne/troenic neonates has &eenconsidered. Preliinar! data fro case reorts and fro a sall trial seeroisin", &/t a lar"e, randoied, controlled trial is needed to )alidate the

&eneficial effects o&ser)ed.;>%. The "/idelines iss/ed in 4>>%recoended screenin" of re"nant +oen for GB* coloniation either &!eans of lo+er )a"inal and rectal c/lt/res o&tained at 1< to 1 +eeHs "estationor &! assessin" clinical risH factors to identif! candidates for IAP. Both strate"iesalso tar"eted +oen +ith &acteri/ria d/rin" re"nanc! and those +ith are)io/sl! affected infant +ith GB* infection. *ince the ileentation of IAP,the incidence of earl!-onset GB* infections has decreased &! %


30/56

The ana"eent of infants &orn to +oen recei)in" intraart/cheoroh!lais deends on the infants stat/s at &irth, the d/ration ofroh!lais, and the "estational a"e of the infant. If a +oan recei)es IAP fors/sected chorioanionitis, her infant sho/ld ha)e a f/ll dia"nostic e)al/ationand eirical thera! endin" c/lt/re res/lts &ased on the infants eos/re to

esta&lished infection. *!toatic infants sho/ld /nder"o f/ll dia"nostice)al/ation and eirical thera!. A l/&ar /nct/re, if feasi&le, sho/ld &eerfored. iited e)al/ation consistin" of colete &lood co/nt +ithdifferential and &lood c/lt/re and o&ser)ation for at least J8 ho/rs is indicatedfor as!toatic infants of less than 1< +eeHs "estation and for those +hoseothers recei)ed cheoroh!lais for less than J ho/rs &efore deli)er!.&ser)ation is aroriate for as!toatic infants of at least 1< +eeHs"estation +hose others recei)ed cheoroh!lais at least J ho/rs &eforedeli)er!.

(os/re to anti&iotics d/rin" re"nanc! has not chan"ed the clinical sectr/of GB* disease or the onset of clinical si"ns of infection +ithin 2J ho/rs of &irthfor ter infants +ith earl!-onset GB* infection.;J2= In reorts that doc/entincreases in non-GB* sesis, the increase has occ/rred onl! in infants &ornreat/rel! or +ith lo+ &irth+ei"ht. Aon" /lticenter st/dies of the incidenceof non-GB* sesis, the onl! one that identified a si"nificant increase in the rateof (. coli earl!-onset disease e)al/ated onl! infants +ith 9B.;>%= */r)eillancein t+o cities fo/nd sta&le rates of sesis ca/sed &! other or"aniss &/t anincrease in aicillin-resistant (. coli aon" reter &/t not ter infants.;%2=

These trends are reass/rin" &/t indicate the iortance of on"oin" s/r)eillance.

A corehensi)e ro"ra for re)ention of neonatal &acterial infections a+aitsthe de)eloent and licens/re of )accines, soe of +hich are no+ /ndertestin", and of strate"ies to re)ent reat/re deli)er!.

(ditors: Maconald, Mhairi G.6 *eshia, Mar! M. L.6 M/llett, Martha .

Title: A)er!'s Neonatolo"!, %th (dition

Co!ri"ht ]#2$$< iincott illias [ ilHins

D Ta&le of Contents D Part 9 - The Ne+&orn Infant D Chater J - Bacterial andF/n"al Infections

Chater J

Bacterial and F/n"al Infections

Ro&ert . *chelonHa


31/56

Bishara . Frei

Geor"e . McCracHen r.

Infections ca/se si"nificant ortalit! and lon"-ter or&idit! in neonates,eseciall! for reat/re infants of )er! lo+ &irth +ei"ht 04,2,1,J,,4$,445. In North Aerica in the 4>1$s and4>J$s, "ra-ositi)e cocci s/ch as "ro/ A ^_-heol!tic stretococci and*tah!lococc/s a/re/s +ere the ost coon &acterial isolates fro neonates+ith sesis, +ith (scherichia coli acco/ntin" for ost of the reainin" cases. *.a/re/s and (. coli &ecae the aor atho"ens in the 4>%$s, "ro/ B ^_-heol!tic stretococci and (. coli ha)e redoinated.Coa"/lase-ne"ati)e stah!lococci eer"ed in the 4>8$s and ha)e s/rassed *.a/re/s and "ra-ne"ati)e enteric &acilli as the &acteria ost fre7/entl!associated +ith nosocoial infections in an! neonatal intensi)e care /nits0NICEs5, and se)eral Candida secies ha)e increased in fre7/enc! to &ecoeaor neonatal atho"ens in the 4>>$s. This has lar"el! &een a conse7/ence ofthe s/r)i)al of )er!-lo+-&irth-+ei"ht 09B5 infants +ho re7/ire len"th!hositaliations and considera&le echanical and n/tritional s/ort 042,415.*ince the 4>>$s there has &een an eer"in" ro&le of /ltile-dr/"-resistant"ra-ositi)e and "ra-ne"ati)e enteric &acilli in NICEs 04J,4


32/56


33/56

ha)e &een estiated at J$? to $?6 a&o/t 1


34/56

The &acteria resonsi&le for neonatal sesis )ar! "eo"rahicall!. GB* and (. coliredoinate in the Enited *tates, +hereas *. a/re/s and "ra-ne"ati)e &acilliare /ch ore coon in de)eloin" co/ntries 085. The &acterial etiolo"! ofsesis also )aries &! the ostnatal a"e of the infant. In a st/d! of a cohort of%,>>8 and 2$$$, the incidenceof earl!- onset sesis 0occ/rrin" d/rin" the first 2 ho/rs of life5 +as 4.


35/56

ther $ 0$5 1$ 025

9al/es are "i)en as n/&er 0ercent5.N*, not secified

P.421

Patho"enesis

Maternal, en)ironental, and host factors deterine +hich infants eosed to aotentiall! atho"enic or"anis +ill de)elo sesis, enin"itis, or other serio/sin)asi)e infections.

Man! reart/ and intraart/ o&stetric colications ha)e &een associated+ith increased risH of infection in the ne+&orn, the ost si"nificant of +hich arereat/re onset of la&or, rolon"ed r/t/re of fetal e&ranes,chorioanionitis, and aternal fe)er. In one st/d! of >%1 re"nanciescolicated &! reat/re r/t/re of e&ranes, the incidence of clinical sesisincreased fro 2? aon" infants &orn +ithin 21 ho/rs of e&rane r/t/re to? and 44? aon" those deli)ered 2J to J ho/rs and J8 to 4 ho/rs afterr/t/re, resecti)el!. The risH +as hi"hest for the reat/re, B infants 0


36/56

local /ltilication of the or"anis at sites of coloniation. Asiration of infectedaniotic fl/id is another roosed ro/te for fetal infection aon" infants &orn toothers +ith chorioanionitis.

Anials ha)e &een /sed to define the host-&acteria interactions that deterine

atho"enesis of disease. Bloodstrea infection in infant rats or ice ca/sed &!(. coli L4 or an! of the GB* serot!es can &e re)ented &! retreatent +itht!e-secific cas/lar ol!saccharide anti&od! 0%$,%45. The oro"astric ro/te for(. coli L4 in the infant rat and the intratracheal installation of GB* in the

P.4218

rhes/s onHe! or rat rod/ce illnesses that closel! arallel the h/ans!ndroes 0%2,%1,%J5.

*e)eral in)esti"ations of the host-arasite association of h/ans +ith GB* ha)efoc/sed on eas/reent of secific anti&od! in the ser/ of infected andcolonied ersons. Protecti)e concentrations of anti&od! to GB* serot!e III +erefo/nd in 1? of +oen +hose ne+&orn infants +ere +ell &/t in onl! 4? of+oen +hose neonates de)eloed sesis or enin"itis ca/sed &! this or"anis0%,2,1,J,,8$5.r"aniss s/ch as GB* and (. coli that ha)e hi"h cas/lar sialic acid contenttend to &e oor acti)ators of the alternati)e coleent ath+a! 0845.

Fi&ronectin is a /ltif/nctional "l!corotein fo/nd in the lasa and on thes/rface of certain eithelial cells, &aseent e&ranes, and connecti)e tiss/es.In lasa, fi&ronectin acts as a nonsecific osonin that enhances clearance ofin)adin" &acteria 0825. Fi&ronectin is deficient in neonatal lasa, and itsconcentration )aries in)ersel! +ith "estational a"e 082,815. *etic infants ha)e&een sho+n to ha)e si"nificantl! lo+er lasa concentrations of this


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"l!corotein than health!, a"e-atched controls 08J5. The sol/&le for offi&ronectin &inds oorl! to GB* 08


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GB* reains an iortant ca/se of neonatal sesis. GB* acco/nts for 4$? toJ$? of sesis cases occ/rrin" in the first +eeH of life 01,>1,>J5.

In the id 4>8$s, clinical trials deonstrated that adinisterin" intraart/intra)eno/s anti&iotics co/ld re)ent earl! onset neonatal GB* sesis 0>

0>,>85. The 4>>% national "/idelines recoended that +oen colonied +ithGB* at 1< +eeHs or ore of "estation or +oen +ith intraart/ risH factors0deli)er! 1 +eeHs "estation, intraart/ teerat/re b4$$.J]Q]QF orr/t/re of e&ranes b48 h5 sho/ld &e offered intraart/cheoroh!lais. Additionall!, +oen ha)in" a re)io/s infant +ith in)asi)eGB* disease or +oen +ith GB* &acteri/ria d/rin" re"nanc! sho/ld also &eoffered intraart/ cheoroh!lais. Beca/se of the ro/tine ileentation ofIAP, the incidence of earl! onset neonatal infections decreased &! %< ercent,fro 4. er 4$$$ li)e &irths in 4>>1 to $.% er 4$$$ in 4>>8 0>>5. ith thedecline in earl! onset GB* disease, there has &een a concoitant rise in (. coli

and aicillin-resistant (. coli sesis in )er! lo+ &irth +ei"ht and reter infants0J5. The CC and the Aerican Colle"e of &stetricians and G!necolo"ists ha)erecoended /ni)ersal screenin" at 1< or ore +eeHs of "estation and IAP forGB*-colonied +oen 04$$,4$45.

The eideiolo"!, atho"enesis, and clinical feat/res of GB* disease ha)e &eendefined 04$25. The or"anis is a coon inha&itant of the feale "enital tractand can &e isolated fro )a"inal and anorectal c/lt/res of as an! as 1


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infants &orn to hea)il! colonied others 04$85. The earl!-onset GB* s!ndroeocc/rs +ithin the first 2 ho/rs of life 0ean a"e of onset 2$ ho/rs5, and %


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are sterile +ithin 2J to 1% ho/rs of thera!, and the ortalit! rate is 4$? to4


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As!toatic transient &actereia.

The transient &actereia is rearHa&le &eca/se these infants aear clinicall!+ell and are c/lt/red &eca/se of a histor! of aternal o&stetric colications. Areeat &lood c/lt/re &efore the instit/tion of anti&iotic thera! fre7/entl! is

sterile.

Both relases and reinfections can occ/r after in)asi)e GB* infections 04$25.Reasons for relase a! incl/de an inade7/ate enicillin dose, a short d/rationof thera! of the initial eisode, or /nreco"nied foci of infection 0e.".,endocarditis, &rain a&scess5. Reinfection can occ/r &eca/se of aternal GB*astitis 0445. Rifain 02$ "H"d for J- da!s5 has &een /sed to eradicateGB* carria"e in infants +ith rec/rrent disease and is "i)en after coletion ofs!steic enicillin thera! 0445.

Coa"/lase-Positi)e *tah!lococcal isease

The ha"e "ro/ I *. a/re/s, +hich +as coon in the late 4>$s, ha"e "ro/ II coa"/lase-ositi)e stah!lococci eer"ed asa coon ca/se of neonatal infection. Altho/"h this or"anis a! &e in)asi)e,atho"enicit! deends rinciall! on rod/ction of eotoins 0e."., efolatiati)eor eiderol!tic toins A and B5. Coon areas of riar! infection incl/de the/&ilical st/, con/ncti)a, and throat6 infection of a s/r"ical +o/nd has &eendescri&ed 042$5. The efoliati)e toins act on the ona "ran/losa of the

eideris and ca/se eideral slittin" thro/"h acti)it! of the toins on thedesosoes 04245. Clinical disease a! taHe one of se)eral fors, incl/din"&/llo/s ieti"o, toic eideral necrol!sis 0Ritter disease5, andnonstretococcal scarlatina. Collecti)el!, these diseases ha)e &een referred toas the eanded scalded sHin s!ndroe 0Fi". J-45 04225.


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Fi"/re J-4 A 4$-da!-old Ca/casian &o! +ith stah!lococcal scalded sHins!ndroe. e +as treated +ith fl/ids, oral dicloacillin, and +o/nd care. is sHinhealed coletel! and +itho/t scarrin" +ithin 2 +eeHs of this hoto"rah &ein"taHen.

The initial findin" in Ritter disease is "eneralied er!thea associated +ithedea and tenderness on alation, /s/all! noticed &et+een da!s 1 and 4% of

life 04215. After se)eral da!s, a distincti)e des7/aation of lar"e sheets ofeideris occ/rs, +hich is different fro the fine des7/aation o&ser)ed in thesecond and third +eeHs of stretococcal scarlet fe)er. ar"e flaccid &/llaecoonl! o&ser)ed in Ritter disease +ill, on r/t/re, lea)e a tender, +eein"er!theato/s &ase. *oe infants a! aear 7/ite toic +ith the "eneraliedfor of disease. A rare, con"enital for of stah!lococcal scalded sHin s!ndroehas &een descri&ed 042J5. *read +ithin a n/rser! can occ/r, and its reco"nition+arrants the rot instit/tion of infection control eas/res to liit the sreadof the toi"enic strain of *. a/re/s 042


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can &e si"nificant, and these &acteria sho/ld not &e disissed as containants.f the at least 1$ reco"nied coa"/lase-ne"ati)e stah!lococcal secies, *.eideridis is clinicall! the ost si"nificant for neonates 0428,42>,41$5.(erience indicates that these &acteria are resonsi&le for a&o/t 4$? to 2? of

all cases of sesis in NICEs, &/t can acco/nt for as an! as J8? of late-onsetsesis cases in 9B infants 01,>25 Coa"/lase-ne"ati)e stah!lococcal infectionsare nosocoial in ori"in and res/lt in s/&stantiall! lon"er hositaliations foraffected infants 0414,4125. RisH of infection +ith these or"aniss increases +ithdecreasin" "estational a"e and &irth +ei"ht 0411,41J,415.Clinical illnesses incl/de seticeia, enin"itis +ith or +itho/t C*Fa&noralities, necrotiin" enterocolitis, ne/onia, ohalitis, soft tiss/ea&scesses associated +ith ersistent &actereia, endocarditis, and scala&scesses and osteo!elitis at insertion sites of fetal onitorin" electrodes0411,41J,41,4J$,4J4,4J2,4J1,4JJ5.

RisH factors for coa"/lase-ne"ati)e stah!lococcal infections incl/de theresence of forei"n &odies, s/ch as central )eno/s lines, )entric/loeritonealsh/nts, or eritoneal dial!sis catheters, rior anti&iotic thera!, and intra)eno/sinf/sion of liid e/lsions for n/tritional s/ort 042>, 4J5. nce attached, a )isco/s eool!saccharide referred toas slie is fored. *lie co)ers the &acteria to for a s/rface &iofil thatrotects the fro s/ch en)ironental factors as anti&iotics and host defensesaltho/"h allo+in" contin/ed access to n/trition 042>5. The densit! of the &iofila! &e increased if the or"aniss are eosed to s/&inhi&itor! concentrationsof anti&iotics to +hich the! are s/sceti&le 0e."., )anco!cin5 04J5. *lie

aears to inhi&it ne/trohil cheotais and ha"oc!tosis and thel!horoliferati)e resonses of onon/clear cells to ito"ens 04J8,4J>5.*lie-rod/cin" strains acco/nt for ost coa"/lase-ne"ati)e stah!lococciisolated fro infants +ith in)asi)e infections 041


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/cosal necrosis and heorrha"e +hen inected into li"ated infant rat &o+elloos and a! la! a role in the atho"enesis of neonatal necrotiin"enterocolitis 04


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P.42J2

reainin" 2


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045. Nonenterococcal "ro/ stretococci contin/e to &es/sceti&le to enicillin 04%5.

Gra-Ne"ati)e Bacterial Infection

In North Aerica, (. coli is the ost coon "ra-ne"ati)e or"anis ca/sin"seticeia d/rin" the neonatal eriod. Lle&siella and (ntero&acter strains aresecond 01,>25. In contradistinction to illness ca/sed &! GB* and .onoc!to"enes, (. coli infections do not fit into distinct clinical s!ndroes ofearl!- and late-onset disease. Aroiatel! J$? of (. coli strains ca/sin"seticeia ossess L4 cas/lar anti"en, and strains identical +ith those isolatedfro &lood c/lt/res /s/all! can &e identified in the atient's nasohar!n orrectal c/lt/res. The clinical feat/res of (. coli sesis "enerall! are siilar to thoseo&ser)ed in infants +ith disease ca/sed &! other atho"ens. Resirator! distressis noted in a&o/t 1? +ith (. coli sesis occ/rrin" d/rin" the first +eeH of life048$5. ocalied (. coli infections ha)e incl/ded &reast a&scess, cell/litis,ne/onia, l/n" a&scess, e!ea, osteo!elitis, setic arthritis, /rinar! tractinfection, ascendin" cholan"itis, and otitis edia.

An increase in the roortion of neonatal (. coli sesis cases ca/sed &!aicillin-resistant strains has &een noted &! se)eral in)esti"ators 01,48$,4845

This shift occ/rred as aternal intraart/ roh!lais for the re)ention ofearl! onset GB* sesis +as &ein" ileented ore +idel! &! o&stetricians atthese edical centers. Most deaths +ere seen in neonates infected +ithaicillin-resistant (. coli strains.

Pse/doonas seticeia a! resent +ith a characteristic )iolaceo/s a/larlesion or lesions that, after se)eral da!s, de)elo central necrosis. Altho/"hthese sHin lesions ost coonl! are seen in Pse/doonas infection, the!a!&e associated +ith other or"aniss 04825. Pse/doonas t!icall! is enco/nteredin late-onset sesis, altho/"h occasional ne+&orns +ith an earl!-onset for ofthis infection ha)e &een reorted.

Neonatal infections ca/sed &! . infl/enae &iot!e I9 ha)e increased infre7/enc! in the last 2$ !ears and c/rrentl! acco/nt for a&o/t 8? of earl!-onsetsesis in )er! B infants 0J$4-4,


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Petostretococc/s s, 9eillonella s, Proioni&acteri/rn acnes, (/&acteri/rns, and F/so&acteri/ s occ/r relati)el! infre7/entl!. Anaero&es are fo/nd

P.42J1

ied in c/lt/res +ith aero&ic &acteria in a&o/t one-third of cases. Clinicalillnesses incl/de transient &actereia, f/linant seticeia, ostoerati)einfections, and intra/terine death associated +ith setic a&ortion 048


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RisH factors for late-onset s!steic candidiasis incl/de reat/rit!, lo+ &irth+ei"ht, /se of &road-sectr/ antiicro&ial a"ents, 2 &locHer thera!, steroidthera!, central )asc/lar catheters, arenteral h!eralientation, intraliidinf/sions, rolon"ed endotracheal int/&ation, necrotiin" enterocolitis, andi/nolo"ic iat/rit! 02$$,2$4,2$25. The ost iortant of these factors

aears to &e the n/&er of rior anti&iotics and the d/ration of thera!02$1,2$J5. B infants in +ho /coc/taneo/s candidiasis de)elos are atconsidera&le risH of s/&se7/ent in)asi)e disease 02$1,2$J,2$>,2$%5. Clinical anifestations )ar! andare indistin"/isha&le fro those ca/sed &! other atho"ens. A f/n"al ca/se forsesis sho/ld &e considered stron"l! in an infant +ei"hin" less than 4,$s, se)eral screenin" tests and scorin" s!stes ha)e &eendescri&ed that are /rorted to aid the h!sician in aHin" the dia"nosis ofneonatal infection. Altho/"h a fe+ are helf/l in identif!in" the infant at hi"h risHof de)eloin" infection, the dia"nosis of seticeia can &e ade onl! &!reco)er! of the or"anis fro &lood c/lt/res or other norall! sterile &od! fl/ids0224,2225. It is ierati)e that these c/lt/res &e o&tained &! strict asetic

techni7/e. Blood sho/ld &e o&tained fro a eriheral )ein rather than fro the/&ilical )essels, the o/ter se)eral illieters of +hich are containated


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fre7/entl! +ith &acteria. Feoral )ein asiration a! res/lt in c/lt/rescontainated +ith colifor or"aniss fro the erine/. eelsticH salesha)e lo+ sensiti)ities. The sHin

P.42JJ

o)erl!in" the )ein to &e /nct/red sho/ld &e cleansed +ith an antiseticsol/tion, s/ch as an iodohor, and allo+ed to dr! for aial antisetic effect.

The ao/nt of &lood dra+n is critical6 4 to 2 of &lood is re7/ired for otialres/lts 02215. The sensiti)it! of a sin"le &lood c/lt/re in identif!in" seticeia isonl! 8$? 02225. &tainin" &lood c/lt/res fro /ltile sites a! enhance the!ield and aid in identif!in" false-ositi)e res/lts 022J5. /antitati)e &loodc/lt/res, if a)aila&le, are helf/l in differentiatin" tr/e atho"ens fro c/lt/recontainants 022,21$,214,212,211,21J,215.ide interreader differences in &and ne/trohil identification ha)e &eeno&ser)ed, there&! liitin" the /tilit! of the iat/re to total ne/trohil ratio in


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act/al clinical ractice 02J$5. Reeatin" colete &lood co/nts +ithin 2J ho/rsof &irth a! enhance the )al/e of the test as a screen for sesis hi"h-risH infants021>5. In the a&sence of clinical si"ns of sesis, le/Hoc!te )al/es are /nliHel! tor/le o/t infection. In a rosecti)e, o&ser)ational st/d! of 8


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indi)id/al doses of


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"entaicin alone or in co&ination +ith aicillin, or cefotaie alone or inco&ination +ith an aino"l!coside, sho/ld &e /sed for s/sceti&le (. coli,Lle&siella s, and (ntero&acter s6 aiHacin alone or in co&ination +ithcefotaie for "entaicin-resistant colifor &acteria6 ceftaidie, ieracillin,ticarcillin, iercillin-tao&acta, or ticarcillin-cla)/lanate, +ith or +itho/t an

aino"l!coside, for Pse/doonas6 aicillin alone or in co&ination +ith anaino"l!coside for P. ira&ilis, enterococci, and . onoc!to"enes6 andenicillin for other "ra-ositi)e or"aniss, ecet for enicillin-resistant *.a/re/s, for +hich ethicillin or nafcillin is the dr/" of choice. 9anco!cin is /sedfor coa"/lase-ne"ati)e stah!lococci and MR*A. Rarel!, coa"/lase-ne"ati)estah!lococcal strains that are resistant to )anco!cin can eer"e d/rin"treatent +ith this a"ent 02%$5. *. a/re/s strains +ith red/ced s/sceti&ilit! to)anco!cin 0"l!coetide-interediate *. a/re/s ;GI*A=5 ha)e &een isolatedfro a fe+ atients +ith a )ariet! of infections. The first s/ch clinical isolate +asdescri&ed in a J-onth-old aanese infant +ith a nosocoial s/r"ical site

infection 02%4,2%25. No GI*A strains ha)e &een identified in ne+&orns to date.Treatent of GI*A-related infections "enerall! re7/ires the /se of dr/"s s/ch aslineolid. The MIC and inial &actericidal concentration 0MBC5 of enicillin andaicillin sho/ld &e deterined for GB* &eca/se a sall ercenta"e of theseor"aniss are tolerant 0i.e., ha)e an MBC to MIC ratio "reater than 125 to theseanti&iotics 02%15. These strains are &est treated +ith a enicillin-aino"l!cosideco&ination. Penicillin resistant and )anco!cin-tolerant ne/ococci ha)e&een reorted in ne+&orn infants in France &/t not !et in North Aerica 02%J5.

The therae/tic otions for )anco!cin-resistant enterococcal infections inneonates are serio/sl! liited. *oe strains a! &e s/sceti&le to a

co&ination of enicillin or aicillin and an aino"l!coside. Chlora-henicolor tetrac!clines a! &e effecti)e a"ainst soe strains, &/t these dr/"s ha)eserio/s toicities for neonates. Nitrof/rantoin is acti)e a"ainst an!)anco!cin-resistant enterococcal strains and has &een /sed to treatenterococcal /rinar! tract infections in ad/lts. alforistin-7/in/ristin isaro)ed for /se in ad/lts, &/t there are no data on its /se in infants. *e)eralin)esti"ational Hetolides, oaolidinones, "l!c!lc!clines, and e)en ne+erseis!nthetic "l!coetides +ith in )itro acti)ities a"ainst )anco!cin-resistantenterococci are &ein" e)al/ated 02%J,2%5. The half-lifeand ser/ concentrations of ahotericin B are hi"hl! )aria&le d/rin" theneonatal eriod 02%85. The dr/" aears to &e &etter tolerated &! infants thanolder children and ad/lts, &/t renal and heatic f/nctions sho/ld &e onitoredcaref/ll! 04>J,2%>5. The otial dail! dosa"e of ahotericin B is not /ni)ersall!a"reed on. The ost coonl! /sed dosa"e re"ien is to &e"in +ith $.< "H"of the dr/" on the first da! and, if tolerated, to increase the dail! dosa"e to 4.$


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"H" &! the second or third da! of treatent. The c//lati)e dosa"e ofahotericin B needed for the ade7/ate treatent of s!steic Candida infectionis not +ell defined, &/t it is estiated to &e 2$ to 1$ "H" 04>J5. Resistance toahotericin B aon" Candida secies is not a aor clinical ro&le 02$5.Ahotericin B fre7/entl! is co&ined +ith fl/c!tosine for the treatent of

central ner)o/s s!ste f/n"al infection &eca/se of fl/c!tosine's

P.42J%

ecellent C*F enetration and the in )itro s!ner"! of this dr/" co&inationa"ainst Candida. GI intolerance, !elos/ression, and heatotoicit! arecoon side effects of fl/c!tosine 04>J5.

(erience +ith the /se of liosoal ahotericin B rearations in ne+&orns is"ro+in" 024,22,21,2J,2


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their infection. Mild ele)ations of li)er en!e concentrations +ere noted in


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coloniation and treatent of those "ra)idas +ho are ositi)e +ith intraart/anti&iotics 0Ta&le J-15.

Intraart/ anti&iotic roh!lais-related ad)erse effects incl/de the sall &/treal risH of death fro anah!lais for +oen 0estiated risH of $.$$4?5 and an

increase in the roortion of infants +ith sesis ca/sed &! aicillin-resistant&acteria 0J5. A recent st/d! eained the s/sceti&ilit! rofile of 44> coloniin"and 8 in)asi)e GB* strains

P.42J

collected fro t+o hositals in Birin"ha, Ala&aa, &et+een an/ar! 4>>% and*ete&er 4>> fro redoinantl! )a"inall! deli)ered ter ne+&orns andfo/nd that the GB* isolates alost /ni)ersall! +ere enicillin s/sceti&le, +ithonl! a sall inorit! of the strains sho+in" oderate enicillin or aicillin

s/sceti&ilit! 028


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alternati)e re"ien is aicillin, 2 " intra)eno/sl! initial dose, then 4 "intra)eno/sl! e)er! J ho/rs /ntil deli)er!

Intraart/ cheoroh!lais for enicillin-aller"ic +oen &/t not at hi"h risHfor anah!lais sho/ld &e "i)en cefaolin, 2 " intra)eno/sl! initial dose, then 4 "

intra)eno/sl! e)er! 8 ho/rs /ntil deli)er!. oen at hi"h risH for anah!laissho/ld &e "i)en either clinda!cin, >$$ " intra)eno/sl! e)er! 8 ho/rs /ntildeli)er!, R er!thro!cin, ?, 2.>?, and 4.2? +hen aicillin +as "i)en less than 4 ho/r, 4 to 2 ho/rs, 2to J ho/rs, and ore than J ho/rs &efore deli)er!, resecti)el! 02885.

I/nolo"ic aroaches to re)ention incl/de assi)e or acti)e i/niation ofothers, +ith translacental assa"e of rotecti)e anti&odies to the fet/s. An/&er of )accines are c/rrentl! &ein" de)eloent a"ainst Gro/ Bstretococcal cas/lar ol!saccharide anti"ens of serot!es Ia, I&, II, III and 9

sepsis - fanarof n avery

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