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sPART 2 Postnatal Bacterial Infections Martin: Fanaroff and Martin's NeonatalPerinatal Medicine, 8th ed., Co !ri"ht # 2$$% Mos&!

, An I' rint of (lse)ier Mor)en *. (d+ards N(,NATA- *(P*I* .es ite the de)elo 'ent of ne+er, 'ore otent anti'icro&ial a"ents, infections are still an i' ortant ca/se of neonatal 'or&idit! and 'ortalit!. This cha ter art foc/ses on &acterial infections, &/t )iral, f/n"al, and arasitic infections '/st &e considered in the differential dia"nosis of neonatal se sis. Incidence and Mortalit! *e sis neonator/' is the ter' /sed to descri&e an! s!ste'ic &acterial infection doc/'ented &! a ositi)e &lood c/lt/re in the first 'onth of life. Neonatal se sis can &e classified into t+o relati)el! distinct illnesses &ased on the ostnatal a"e at onset 0 Ta&le 12344 5: earl!-onset se sis occ/rs in the first 2 da!s of life6 is /s/all! a f/l'inant, '/ltis!ste' infection ac7/ired &! )ertical trans'ission fro' the 'other6 and has a hi"her case fatalit! rate than late-onset se sis 0see Cha ter 22 5. -ate-onset se sis is /s/all! 'ore insidio/s &/t 'a! ha)e an ac/te onset. Another t! e of se sis has &een reco"ni8ed, )er!-late-onset se sis, +hich occ/rs after 1 'onths of life and affects re'at/re infants +ho are of )er! lo+ &irth+ei"ht 09-B:5 in the neonatal intensi)e care /nit. 9er!-late-onset se sis is often ca/sed &! Candida s ecies or &! co''ensal or"anis's s/ch as coa"/lasene"ati)e sta h!lococci 0C,N*5. This infection has /s/all! &een associated +ith rolon"ed instr/'entation, s/ch as ind+ellin" intra)asc/lar lines and endotracheal int/&ation.;<%= The incidence of neonatal se sis )aries fro' 4 to < cases er 4$$$ li)e &irths. In the reanti&iotic era, it +as al'ost al+a!s fatal. Mortalit! rates decreased dra'aticall! after the introd/ction of anti'icro&ial a"ents and +ith technolo"ical ad)ances in neonatal care. *ince 4>>$, the case fatalit! rate for infectio/s neonatal illnesses has contin/ed to decline and no+ is <? to 2$? for earl!-onset se sis and <? for late-onset se sis. Ta&le 12-44 -- Characteristics of Neonatal *e sis -AT( ,N*(T 0B2 (AR-@ ,N*(T 0A2 .A@*5 .A@* T, 1 M,NTC*5 Intra art/' co' lications 9(R@ -AT( ,N*(T 0D1 M,NTC*5 9aries Es/all! ostnatal en)iron'ent Insidio/s

,ften resent 9ertical6 or"anis' often ac7/ired fro' 'otherFs "enital tract F/l'inant co/rse,

Es/all! a&sent 9ertical or thro/"h ostnatal en)iron'ent Insidio/s or ac/te,

Trans'ission

Clinical

-AT( ,N*(T 0B2 (AR-@ ,N*(T 0A2 .A@*5 .A@* T, 1 M,NTC*5 '/ltis!ste' focal infection, 'anifestations in)ol)e'ent, ne/'onia 'enin"itis co''on co''on Case-fatalit! rate <?32$? <?

9(R@ -AT( ,N*(T 0D1 M,NTC*5

-o+

Micro&iolo"! The &acterial atho"ens res onsi&le for se sis neonator/' tend to chan"e o)er ti'e. In the Enited *tates, "ra'- ositi)e cocci, incl/din" "ro/ A stre tococci, +ere the 'ost co''on atho"ens &efore the introd/ction of anti&iotics, &/t this redo'inance shifted to "ra'-ne"ati)e enteric &acilli after anti'icro&ial a"ents ca'e into co''on /se. In the 4><$s and earl! 4>%$s, *ta h!lococc/s a/re/s and (scherichia coli +ere the 'ost co''on or"anis's isolated. In the late 4>%$s, the "ro/ B stre tococc/s 0GB*5 e'er"ed as a erinatal atho"en and contin/es to &e an i' ortant or"anis' in ne+&orn infections, as is (. coli. This is reflected in the distri&/tion of &acteria ca/sin" earl!-onset neonatal se sis in acti)e s/r)eillance cond/cted o)er a '/ltistate area d/rin" 4>>8 thro/"h 2$$$;%2= 0 Ta&le 12342 , art I5. In neonates of 9-B: +ith earl!-onset se sis, GB* +as the 'ost fre7/ent atho"en, follo+ed &! (. coli and Cae'o hil/s infl/en8ae.;>8= An increase in the incidence of (. coli and a decrease in GB* has recentl! &een noted.;>2= ,ther atho"ens, incl/din" C,N*, Candida s ecies, and *. a/re/s, are 'ore co''onl! etiolo"ic a"ents in late-onset infection, as sho+n &! data fro' a '/lticenter ros ecti)e re"istr! in neonates +ith 9-B:;>>= 0see Ta&le 12342 , art II5. As histor! s/""ests, f/rther chan"es in the etiolo"ic a"ents of neonatal se sis are liHel! and +arrant contin/ed o&ser)ation. Ta&le 12-42 -- (tiolo"ic A"ents in Neonatal *e sis ,RGANI*M NEMB(R 0?5

Bacteria Ca/sin" (arl!-,nset Neonatal *e sis I Gro/ B *tre tococc/s 4%% 0J45

,RGANI*M (scherichia coli 9iridans stre tococci (nterococc/s s ecies *ta h!lococc/s a/re/s Gro/ . *tre tococc/s Pse/do'onas s ecies

NEMB(R 0?5 2$ 0425 %2 04%5 4% 0J5 4< 0J5 42 015 > 025

,ther "ra'-ne"ati)e enteric 4% 0J5 &acilli ,ther T,TA12 0>5 J$8 04$$5

(tiolo"ic A"ents in -ate-,nset Neonatal *e sis K Coa"/lase-ne"ati)e *ta h!lococc/s *ta h!lococc/s a/re/s Candida al&icans (scherichia coli Lle&siella Candida ara silosis (nterococc/s s ecies Pse/do'onas Gro/ B *tre tococc/s ,ther &acteria ,ther f/n"i %2> 0J85 4$1 085 2% 0%5 %J 0<5 <2 0J5 <J 0J5 J1 015 1< 015 1$ 025 4>2 04<5 1$ 025

,RGANI*M

NEMB(R 0?5

T,TA-

4141 04$$5

I (arl! onset, A2 da!s of a"e. Ada ted fro' C!de TB et al:Trends in incidence and anti'icro&ial resistance of earl!-onset se sis: Po /lation-&ased s/r)eillance in *an Francisco and Atlanta. Pediatrics 44$:%>$, 2$$2. K Infants +ere all )er! lo+ &irth +ei"ht 0A4<$$ "5. Blood c/lt/res +ere o&tained after 22 ho/rs of life. Ada ted fro' *toll BM et al: -ate-onset se sis in )er! lo+ &irth +ei"ht neonates: The eN erience of the NICC. Neonatal Research Net+orH. Pediatrics 44$:28<, 2$$2.

Trans'ission There are 'an! +a!s that infectio/s a"ents can &e trans'itted to the neonate. Trans lacental trans'ission is +ell doc/'ented for con"enital )iral infections &/t not for erinatal &acterial infections, +ith the eNce tions of those ca/sed &! Tre one'a allid/' and -isteria 'onoc!to"enes. Ascendin" intra-a'niotic infection follo+ed &! as iration of infected a'niotic fl/id can res/lt in s!ste'ic neonatal infection, es eciall! in the settin" of r/ t/re of 'e'&ranes 0R,M5 lastin" lon"er than 2J ho/rs. A roNi'atel! 4? to J? of neonates &orn to 'others +ith intra-a'niotic infection de)elo s!ste'ic infection. Neonatal infection can also &e ac7/ired d/rin" )a"inal deli)er! fro' &acteria coloni8in" the 'otherFs lo+er "enital tract. Inade7/ate hand+ashin" &! the n/rser! staff can ro'ote the s read of 'icroor"anis's fro' an infected to an /ninfected infant or fro' the hands of coloni8ed care"i)ers to the ne+&orn. The /se of instr/'entation, incl/din" endotracheal t/&es, naso"astric feedin" t/&es, /'&ilical catheters, central )eno/s catheters, and Fole! catheters, also increases the risH of neonatal infection. (arl!-onset infection is 'ost often trans'itted )erticall! &! ascendin" a'niotic fl/id infection and &! deli)er! thro/"h an infected or coloni8ed &irth canal. The atho"ens that ca/se later-onset disease 'a! &e ac7/ired )erticall! in the eri art/' eriod or hori8ontall! fro' fo'ites in the en)iron'ent or fro' coloni8ed care"i)ers after deli)er!. RisH Factors MAT(RNA- RI*L FACT,R* 0*ee also Cha ter 22 .5

Maternal factors 'a! infl/ence the de)elo 'ent of s!ste'ic &acterial infection in the neonate. For reasons that re'ain /nclear, the rates of in)asi)e earl!-onset GB* infection are hi"her a'on" &lacHs than in other racial "ro/ s.;88= Maternal factors s/ch as 'aln/trition and recentl! ac7/ired seN/all! trans'itted diseases can also increase the risH of infection. The rates of re'at/rit! and lo+ &irth+ei"ht, +hich &oth redis ose to neonatal infection, are in)ersel! related to socioecono'ic stat/s. Maternal coloni8ation +ith GB* has &een +ell doc/'ented as a risH factor for neonatal se sis. Coloni8ation d/rin" the third tri'ester +itho/t an! co' lications of re"nanc! carries a roNi'atel! a 4? risH of infection6 this risH is increased if coloni8ation is associated +ith re'at/rit!, 'aternal fe)er, or rolon"ed R,M. As!' to'atic &acteri/ria has &een associated +ith re'at/re &irth. Coloni8ation +ith "enital '!co las'as has &een associated +ith lo+ &irth+ei"ht.;<1= P(RIPARTEM RI*L FACT,R* 0*ee also Cha ter 22 .5 *o'e of the eri art/' factors associated +ith an increased risH of neonatal infection are /ntreated or inco' letel! treated focal infections of the 'other 0incl/din" /rinar! tract, )a"inal, or cer)ical infections5, as +ell as s!ste'ic infections, s/ch as 'aternal se tice'ia or 'aternal fe)er +itho/t a foc/s. Enco' licated R,M lastin" lon"er than 2J ho/rs has &een associated +ith a 4? incidence of neonatal se sis a&o)e the &aseline rate of $.4? to $.<?. The risH of infection increases fo/rfold if chorioa'nionitis and rolon"ed R,M coeNist. Pre'at/rit! and lo+ &irth+ei"ht ha)e &een associated +ith an increased incidence of se sis. In a o /lation-&ased cohort st/d! of neonatal GB* disease in Atlanta, *ch/chat and others;8>= noted attacH rates of <.>> er 4$$$, 2.<4 er 4$$$, and $.8> er 4$$$ li)e-&orn infants +ith &irth+ei"hts of less than 4<$$ ", 4<$$ to 2<$$ ", and 'ore than 2<$$ ", res ecti)el!. Rates of first e isode of late-onset infection er 4$$$ hos ital da!s also decreased +ith increasin" &irth+ei"ht and "estational a"e, so that infants +ith a &irth+ei"ht of 2<$ " or less had a fo/rfold hi"her rate than those +ith a &irth+ei"ht of 4$$$ " or 'ore. ;>>= Another eri art/' risH factor is the /se of fetal scal electrodes. As '/ch as J.<? of deli)eries /sin" electronic fetal 'onitorin" ha)e &een associated +ith s/&se7/ent de)elo 'ent of neonatal scal a&scesses.;J1= Ce halhe'ato'as rarel! 'a! &e co' licated &! se sis, 'enin"itis, and osteo'!elitis. Perinatal as h!Nia, defined as a <-'in/te A "ar score of less than %, in the resence of rolon"ed R,M has &een associated +ith an increased incidence of se sis. N(,NATA- RI*L FACT,R* Altho/"h no si"nificant seN difference has &een doc/'ented for infections ac7/ired in /tero, it +as noted in the 4>%$s that 'ale infants had a hi"her incidence of neonatal se sis than fe'ale infants. Possi&l!, this is related to OlinHed i''/nore"/lator! "enes. I''at/rit! of the i''/ne s!ste' of the ne+&orn host, as sho+n in Ta&le 12341 , can also ha)e a role in the redis osition to infection 0see Part ,ne of this cha ter5. Meta&olic disorders 'a! redis ose to infection.;28= A'on" neonates of 9-B: +ith late-onset

se sis, co' lications of re'at/rit! associated +ith an increased rate of infection incl/ded 'echanical )entilation, /'&ilical )essel catheteri8ation, other )asc/lar catheters, h! erali'entation, and d/ration of hos ital sta!.;>>= Ta&le 12-41 -- Cost Res onses to Bacterial Infection in the Neonate C,MP,N( FENCTI,N NT *TATE* IN N(,NAT( C-INICA- *IGNIFICANC( .ecreased rod/ction of che'otactic factors, decreased o soni8ation of &acteria -acH of anti&od! to s ecific atho"ens res/lts in increased risH of infection Increased risH of '/cosal coloni8ation +ith otential atho"ens .ecreased infla''ator! res onse, ina&ilit! to locali8e infection

, soni8ation, .ecreased co' le'ent Co' le'e che'oattractio co' onents, es eciall! nt n in reter' infants I"G concentration decreased in reter' infants, ter' infants ha)e hi"her concentration than ad/lts6 I"A a&sent fro' secretions I' aired 'i"ration, i' aired &indin" to che'otactic factors Nor'al +ith s/fficient 7/antities of o sonin

Anti&od!

, soni8ation, co' le'ent acti)ation

Ne/tro hil Che'otaNis

Pha"oc!tosis

Nor'al in health! Bacterial Hillin" neonates, di'inished in stressed neonates Monoc!te Che'otaNis Pha"oc!tosis .ecreased Contro)ersial .ecreased infla''ator! res onse Encertain Encertain

Bacterial Hillin" Contro)ersial

I", i''/no"lo&/lin. Ada ted fro' Polin RA et al: Neonatal se sis. Ad) Pediatr Infect .is 2:2<, 4>>2.

,TC(R RI*L FACT,R* It has &een s/""ested that &ottle feedin" 'a! redis ose to infection. Pre ared for'/la does not contain se)eral i' ortant &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. Breast 'ilH also contains i''/no"lo&/lins, 'acro ha"es, and l!' hoc!tes, all of +hich la! a role in i''/nolo"ic defense. Factors that 'a! affect late-onset neonatal infection incl/de rior anti'icro&ial /se6 re'at/rit!6 a hi"h infant-to-n/rse ratio in the neonatal intensi)e care /nit6 and the resence of forei"n 'aterials s/ch as endotracheal t/&es and )entric/lo eritoneal sh/nts. Conta'inated arenteral fl/ids, incl/din" li id e'/lsions, also ha)e &een associated +ith s!ste'ic infections. Infants +ho ac7/ire earl!-onset disease often ha)e at least one 'aPor risH factor associated +ith re"nanc! and deli)er!, s/ch as rolon"ed R,M, reter' deli)er!, lo+ &irth+ei"ht, erinatal as h!Nia, or 'aternal eri art/' infection. B! contrast, late-onset disease is seldo' associated +ith o&stetric co' lications. Patholo"! Cistolo"ic findin"s 'a! &e 'ini'al in f/l'inant cases of neonatal se sis.;>4= :hen findin"s are resent, the! often reflect coeNistin" se tic shocH. */ch findin"s 'a! incl/de renal 'ed/llar! he'orrha"e, renal cortical necrosis or ac/te t/&/lar necrosis, adrenal cortical and 'ed/llar! he'orrha"e and necrosis, he atic necrosis, intra)entric/lar he'orrha"e, and eri)entric/lar le/Ho'alacia. ()idence of disse'inated intra)asc/lar coa"/lation 'a! &e o&ser)ed as +ell. In late-onset disease, atholo"ic chan"es consistent +ith the artic/lar focal infection can &e de'onstrated, incl/din" 'enin"itis, ne/'onia, he atic a&scesses, and arthritis or osteo'!elitis. 0* ecific or"an s!ste' infections are disc/ssed later in the cha ter.5 .ia"nosis *@MPT,M* AN. *IGN* The si"ns and s!' to's of neonatal se sis often are nons ecific. The te' erat/re of the infant +ith se sis 'a! &e ele)ated, de ressed, or nor'al. ;%<= Most, &/t not all, infants +ith se sis ha)e res irator! si"ns, incl/din" c!anosis or a nea. ,ther si"ns s/ch as feedin" diffic/lties or lethar"! are nons ecific and 'a! &e s/&tle or insidio/s. Th/s, a hi"h indeN of s/s icion is re7/ired to identif! and e)al/ate at-risH infants. C-INICA- MANIF(*TATI,N* Bonadio and collea"/es;J4= e)al/ated ros ecti)el! a clinical o&ser)ation scorin" 'ethod for fe&rile infants !o/n"er than 2 'onths of a"e to deter'ine its

redicti)e )al/e in distin"/ishin" infectio/s fro' noninfectio/s illness. The )aria&les eNa'ined +ere affect, feedin" attern, le)el of acti)it!, le)el of alertness, res irator! stat/s or effort, '/scle tone, and eri heral erf/sion. Incl/sion criteria re7/ired that the infants had a rectal te' erat/re of 18QC 04$$.JQF5 or hi"her and had recei)ed no anti&iotics +ithin the re)io/s 22 ho/rs. All 211 infants in the st/d! /nder+ent a co' lete se sis e)al/ation, incl/din" l/'&ar /nct/re for &lood cell co/nt, "l/cose and rotein deter'inations, Gra' stain and c/lt/re, &lood and /rine c/lt/res, and /rinal!sis fro' a catheteri8ed sa' le. The a/thors fo/nd that the 'ean score for infants +ith serio/s &acterial infection 0'enin"itis, se sis, or /rinar! tract infection5 +as si"nificantl! hi"her than that for infants +ith ase tic 'enin"itis or for those +ith ne"ati)e c/lt/res and nor'al cere&ros inal fl/id 0C*F5. Affect, eri heral erf/sion, and res irator! stat/s +ere the )aria&les that &est differentiated infected fro' noninfected fe&rile infants. T+o of the 2> infants +ith serio/s &acterial infections did ha)e nor'al o&ser)ation scores6 ho+e)er, &oth had a&nor'al clinical or la&orator! findin"s s/""esti)e of infection. The ne"ati)e redicti)e )al/e 0NP96 see Ta&le 12342 5 of this scorin" s!ste' +as >%?. Th/s, altho/"h o&ser)ational findin"s alone cannot re lace the h!sical eNa'ination and la&orator! st/dies, the! are an i' ortant as ect of the e)al/ation of the fe&rile neonate. Ta&le 12-42 -- Ter's /sed for Anal!8in" Acc/rac! and Relia&ilit! of Tests T(RM *ensiti)it! .(FINITI,N Percenta"e of atients +ith infection +ho ha)e an a&nor'al test res/lt Percenta"e of atients +itho/t infection +ho ha)e a nor'al test res/lt If test res/lt is a&nor'al, ercenta"e of atients +ith infection

* ecificit! Positi)e redicti)e )al/e

Ne"ati)e redicti)e If test res/lt is nor'al, ercenta"e of atients +ith no )al/e infection

Fro' :ein&er" GA et al: -a&orator! aids for dia"nosis of neonatal se sis. In Re'in"ton M* et al 0eds5: Infectio/s .iseases of the Fet/s and Ne+&orn Infant, <th ed. Philadel hia, :B *a/nders, 2$$4, 4128 .

Fe)er is a co''on reason +h! a arent 'i"ht seeH 'edical attention6 ho+e)er, fe)er is an insensiti)e and nons ecific findin". Man! noninfectio/s illnesses can

res/lt in !reNia, incl/din" deh!dration, dr/" +ithdra+al, and eNtensi)e he'ato'as. Llein and associates;%<= ca'e to the follo+in" concl/sions: Te' erat/re ele)ation in f/ll-ter' infants is /nco''on. Te' erat/re ele)ation is infre7/entl! associated +ith s!ste'ic infection +hen onl! a sin"le ele)ated te' erat/re occ/rs. Te' erat/re ele)ation that is s/stained lon"er than an ho/r is fre7/entl! associated +ith infection. Te' erat/re ele)ation +itho/t other si"ns of infection is infre7/ent. The infantFs te' erat/re 'a! &e hel f/l in s/""estin" an infectio/s or noninfectio/s rocess if the trend of te' erat/res and the ne+&ornFs clinical stat/s is considered, &/t a sin"le readin" sho/ld not &e taHen alone as an indication of infection. *e tic infants can resent +ith ne/rolo"ic findin"s s/ch as sei8/res and f/ll fontanelle e)en in the a&sence of 'enin"itis. Gastrointestinal s!' to's can incl/de he ato'e"al!, a&do'inal distention, )o'itin", diarrhea, "astric as irates, "/aiac- ositi)e stools, and Pa/ndice. (Ncl/din" Pa/ndice, c/taneo/s 'anifestations 'a! &e resent &/t are not co''on findin"s in neonatal se sis. Focal infections 'a! recede or acco' an! neonatal se sis6 these can incl/de cell/litis, i' eti"o, soft tiss/e a&scesses, o' halitis, conP/ncti)itis, otitis 'edia, 'enin"itis, and osteo'!elitis. The resence of certain focal infections can s/""est the ca/sati)e a"ent, s/ch as stre tococci +ith cell/litis, sta h!lococci +ith a&scesses, and Pse/do'onas aer/"inosa +ith necrotic sHin lesions. Co' lications of neonatal se sis incl/de 'etastatic foci of infection, disse'inated intra)asc/lar coa"/lation, con"esti)e heart fail/re, and shocH. .IFF(R(NTIA- .IAGN,*I* Beca/se the si"ns and s!' to's of neonatal se sis are nons ecific, noninfectio/s etiolo"ies sho/ld &e considered in the differential. *e sis +ith or +itho/t ne/'onia can resent as res irator! distress, transient tach! nea of the ne+&orn, and 'econi/' as iration. Central ner)o/s s!ste' 0CN*5 s!' to's can &e ca/sed &! intracranial he'orrha"e, dr/" +ithdra+al, and in&orn errors of 'eta&olis', as +ell as &! se sis and 'enin"itis. Intestinal o&str/ction, "astric erforation, and necroti8in" enterocolitis can resent +ith so'e of the "astrointestinal si"ns and s!' to's seen +ith se sis. *o'e non&acterial infections, s/ch as disse'inated her es si' leN )ir/s 0C*95 infection, can &e indistin"/isha&le fro' &acterial se sis and '/st &e considered in the differential dia"nosis. MICR,BI,-,GIC T(*T*

C/lt/res A definiti)e dia"nosis of neonatal se sis can &e 'ade onl! +ith a ositi)e &lood c/lt/re. Blood, /rine, and C*F sho/ld &e o&tained fro' all infants s/s ected of ha)in" se sis. The o ti'/' 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 &lood c/lt/re can &e hel f/l in distin"/ishin" &lood c/lt/re conta'inants fro' tr/e atho"ens. A 'ini'/' of $.< '- of &lood er &ottle is reco''ended. To a)oid conta'ination, &lood sho/ld not &e o&tained fro' a ca illar! sticH or fro' /'&ilical catheters, eNce t erha s i''ediatel! after insertion. There are se)eral 'an/al and a/to'ated 'ethods a)aila&le for detectin" "ro+th in the &lood c/lt/re 'edi/'. Man! of the ne+ a/to'ated radio'etric techni7/es can detect "ro+th as earl! as 8 ho/rs and al'ost al+a!s +ithin 2J to J8 ho/rs after collection. Erine sho/ld &e o&tained in a sterile 'anner, s/ch as &! catheteri8ation or s/ ra /&ic &ladder as iration, and sent for che'ical and 'icrosco ic anal!ses and c/lt/re &efore anti'icro&ial thera ! is started. Erine c/lt/res can &e ositi)e in infants +ith se sis in the a&sence of ri'ar! /rinar! tract infection, &/t "enerall! the !ield for ositi)e /rine c/lt/res is lo+, es eciall! in earl!-onset disease.;J2= Co+e)er, &eca/se the /rine c/lt/re 'a! &e ositi)e +ith ne"ati)e &lood c/lt/res in older ne+&orns +ith ri'ar! /rinar! tract disease, it is r/dent to o&tain /rine +hene)er ossi&le. C*F sho/ld &e o&tained &efore anti&iotic ad'inistration and sent for &lood cell co/nt, differential, and che'istr! deter'inations, as +ell as for Gra' stain and c/lt/re 0see RMenin"itis,S later, as +ell as A endiN B, for nor'al C*F indices5. Altho/"h contro)ersial, so'e &elie)e that l/'&ar /nct/re 'a! &e ost oned or eNcl/ded fro' the e)al/ation of an infant +ith s/s ected earl!-onset disease 'anifested &! ne/'onia. Co+e)er, 'enin"itis acco' anies se sis in a roNi'atel! 4$? of infants +ith earl!-onset disease and 'ore often +ith lateonset disease6 it cannot &e dia"nosed or eNcl/ded solel! on the &asis of the s!' to'atolo"!6 and &lood c/lt/res can &e sterile in 4$? to 4<? of infants +ith earl!-onset and in one third of infants of 9-B: +ith late-onset 'enin"itis.;4$$= ,ther c/lt/res sho/ld &e o&tained as indicated &! clinical findin"s. C/lt/res of tracheal as irates sho/ld &e o&tained in int/&ated neonates +ith a clinical ict/re s/""esti)e of ne/'onia or +hen the 7/alit! and )ol/'e of the secretions chan"e s/&stantiall!. Indiscri'inate c/lt/res of tracheal secretions, ho+e)er, can often &e diffic/lt to inter ret. As irates or &io sies of sHin and soft tiss/e lesions can &e sent for stains and c/lt/res. If a Point infection is s/s ected, e)al/ation of the Point as irate is hel f/l. *tool c/lt/res assist in the dia"nosis of neonatal se tice'ia ca/sed &! enteric atho"ens s/ch as *hi"ella, *al'onella, and Ca' !lo&acter, &/t 'ost often the &acteria reco)ered fro' stool c/lt/res reflect "astrointestinal coloni8ation rather than infection. C/lt/res of "astric as irates o&tained on the first da! of life reflect a'niotic fl/id infection and do not redict the de)elo 'ent of neonatal infection. B/ff! Coat (Na'ination

-e/Hoc!te s'ears '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 acridine oran"e, then eNa'ined 'icrosco icall! for intracell/lar &acteria. A ositi)e &/ff! coat s'ear s/ orts the dia"nosis of se sis and identifies the 'or holo"ic and Gra' stain characteristics of the or"anis', &/t does not identif! the infectio/s a"ent or incl/de or eNcl/de other foci of infection. Anti"en .etection Assa!s I''/noassa!s that detect &acterial cell +all or ca s/le car&oh!drate anti"ens in &od! fl/ids are an adP/nct to dia"nosis. M/lti le st/dies ha)e sho+n that anti"en tests are not an a ro riate s/&stit/te for ro erl! erfor'ed &acterial c/lt/res in the dia"nosis of neonatal se sis. :ith the a)aila&le radio'etric &lood c/lt/re technolo"!, ra id anti"en testin" is no+ infre7/entl! re7/ired or indicated. In addition, these tests 'a! ro)ide res/lts that are 'isleadin". The onl! s eci'ens reco''ended for testin" +ith these de)ices are ser/' or C*F. A ositi)e res/lt sho/ld &e taHen to indicate the resence of anti"en and not necessaril! the resence of )ia&le or"anis's. ,TC(R -AB,RAT,R@ T(*T* -e/Hoc!te Co/nts Man! different as ects of the le/Hoc!te co/nt ha)e &een eNa'ined for their redicti)e )al/e in dia"nosin" se sis. -e/Hoc!tosis or le/Ho enia, defined as 'ore than 2$,$$$T''1 and fe+er than <$$$T''1, res ecti)el!, +ere &elie)ed to &e relia&le indicators of infection &/t no+ are Hno+n to &e insensiti)e and nons ecific. F/rther'ore, a sin"le le/Hoc!te co/nt o&tained shortl! after &irth is not ade7/atel! sensiti)e for dia"nosin" se sis. Manroe and collea"/es;24= esta&lished reference ran"es for the a&sol/te total ne/tro hil co/nt, a&sol/te total i''at/re ne/tro hil co/nt, and the ratio of i''at/re to total ne/tro hils 0I:T5 for neonates d/rin" t+o ti'e eriods: the first %$ ho/rs of life and fro' %$ ho/rs to 28 da!s of life 0 Ta&le 1234J 5. Researchers fro' the sa'e instit/tion, led &! Mo/8inho and associates,;2J= o&ser)ed that neonates +ith 9-B: 0those +ei"hin" less than 4<$$ " and of 1$ +eeHsF "estation or less5 often had ne/tro hil indices that did not fall +ithin these ran"es. Based on the res/lts of co'&ined retros ecti)e and ros ecti)e st/d! of infants +ith 9-B:, the )al/es for a&sol/te total i''at/re ne/tro hil co/nt and I:T +ere not si"nificantl! different fro' Manroe and collea"/esF ran"es, &/t ne+ a&sol/te total ne/tro hil co/nt ran"es for infants +ith 9-B: +ere ro osed 0 Ta&le 1234< 5. These ne+ ran"es +ere &ased on s'all n/'&ers of Rnor'al, /ninfectedS neonates +ith 9-B:, and therefore ros ecti)e trials to confir' these ran"es and to deter'ine their /sef/lness in redictin" se sis '/st &e erfor'ed. Ta&le 12-4J -- Reference Ran"es for Ne/tro hil 0 er ''15 IndeNes in the Neonate

IN.(O BIRTC 48$$3 <J$$ U442$ A$.4%

42 C,ER* 28$$3 4J,J$$ U4JJ$ A$.4%

2J C,ER* 22$$3 42,%$$ U428$ A$.41

J8 C,ER* 22 C,ER*

B42$ C,ER*

ANC INC I:T

J2$$3>$$$ 48$$32$$$ 48$$3<J$$ A8$$ A$.41 A<$$ A$.41 A<$$ A$.42

ANC, a&sol/te ne/tro hil co/nt 0'at/re and i''at/re for's56 INC, i''at/re ne/tro hil co/nt 0all ne/tro hils eNce t se"'ented ones56 I:T, ratio of INC di)ided &! ANC.

Ada ted fro' Manroe B- et al: The neonatal &lood co/nt in health and disease: I. Reference )al/es for ne/tro hilic cells. M Pediatr ><:8>, 4>2>.

Ta&le 12-4< -- Pro osed Reference Ran"e for A&sol/te Total Ne/tro hil Co/nt in Infants +ith 9er! -o+ Birth+ei"ht I AG( A&sol/te Total Ne/tro hil Co/nt K MINIMEM Birth <$$ 48 h 22$$ %$ h 44$$ 42$ 44$$ h MAOIMEM %$$$ 4J,$$$ 88$$ <%$$

Ada ted fro' Mo/8inho A et al: Re)ised reference ran"es for circ/latin" ne/tro hils in )er!-lo+-&irth-+ei"ht infants. Pediatrics >J:2%, 4>>J. I .efined as U4<$$ ".

K Ne/tro hilsT'' 1.

The total ne/tro hil co/nt has &een /sed to hel redict the resence of infection. Ne/tro enia, es eciall! if it occ/rs in the first ho/rs of life and is associated +ith res irator! distress, can &e +orriso'e &eca/se of a stron" association +ith earl!-onset GB* se sis. Co+e)er, 'an! noninfectio/s rocesses are associated +ith &oth ne/tro enia and ne/tro hilia;4$J=0 Ta&le 1234% and BoN 1231 5. ,n the other hand, 'an! infants +ith doc/'ented se sis ha)e nor'al total ne/tro hil co/nts at the ti'e of the initial e)al/ation. Therefore, the a&sol/te total ne/tro hil co/nt has not &een fo/nd hel f/l in dia"nosin" or eNcl/din" neonatal se sis. Ta&le 12-4% -- Clinical Factors Affectin" Ne/tro hil Co/nts Total Total Ne/tro hils I''at/re Ne/tro hils .ecreas Increas Increased ed ed Maternal h! ertension Maternal fe)er, health! neonate B% Co/rs of intra art/' oN!tocin *tressf/l la&or K As h!Nia 0<-'in A "ar score A<5 Meconi/' as iration s!ndro'e Pne/'othoraN +ith /nco' licated res irator! distress s!ndro'e VVVV$ $ VV V VVV I:T Ratio I Increas .ERATI,N ed 0ho/rs5 V VVV V VVV V VVV V VVV 22 2J

VV

VV

42$

VVV

VVVV

2J

VV VVV V VVV V

VV

2J3%$

VVV

VV

22

VVVV

VVV V

2J

Total Total Ne/tro hils I''at/re Ne/tro hils .ecreas Increas Increased ed ed Peri)entric/lar he'orrha"e VVV W *ei8/res X $ V VV

I:T Ratio I Increas .ERATI,N ed 0ho/rs5 VVV V VVV V VVV V VVV VV VVV 42$

VVV VVV V VV VV VVV V VVV V

VVV

2J

Prolon"ed cr!in" 0BJ 'in5

VVVV

As!' to'atic $ h! o"l!ce'ia 0U1$ '"Td-5 Ce'ol!tic disease */r"er! VV $

VVV VVV VVVV

2J 2328 da!s 2J

Ci"h altit/de

VVVV

%Y

V, $?32<?6 V V, 2<?3<$?6 V V V, <$?32<?6 V V V V, 2<?34$$?.

Fro' :ein&er" GA et al: -a&orator! aids for dia"nosis of neonatal se sis. In Re'in"ton M* et al 0eds5: Infectio/s .iseases of the Fet/s and Ne+&orn Infants, <th ed. Philadel hia, :B *a/nders 2$$4, 411$ . I I:T, i''at/re ne/tro hilsTtotal ne/tro hils. K ./ration B48 ho/rs, 'idforce s rotation, &reech eNtraction, 4$-'in/te second sta"e of la&or. W No sei8/res associated +ith eri)entric/lar he'orrha"e. X *ei8/res in the a&sence of h! o"l!ce'ia, as h!Nia, or central ner)o/s s!ste' he'orrha"e. Y Not tested after % ho/rs.

BoN 12-1

Clinical Neonatal Factors Ca)in" No (ffect on Ne/tro hil Co/nts Race *eN Maternal dia&etes 'ellit/s Ro/te of deli)er! I Pre'at/re a'niorrheNis, 'other afe&rile Meconi/' stainin", no l/n" disease Enco' licated res irator! distress s!ndro'e Enco' licated transient tach! nea of the ne+&orn C! er&ilir/&ine'ia, h!siolo"ic, /neN lained 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 se sis. In Re'in"ton M* et al 0eds5: Infectio/s .iseases of the Fet/s and Ne+&orn Infant, <th ed. Philadel hia, :B *a/nders, 2$$4, 4122 6 and data ada ted fro' Manroe B- et al: The neonatal &lood co/nt in health and disease: I. Reference )al/es for ne/tro hilic cells. M Pediatr ><:8>, 4>2>. I The total ne/tro hil 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 i''at/re ne/tro hil co/nt, defined as the a&sol/te n/'&er of all ne/tro hils eNcl/din" the se"'ented ne/tro hils, has also &een eNtensi)el! st/died. All ne+&orns, &/t es eciall! re'at/re ones, ha)e a relati)el! lar"e n/'&er of i''at/re ne/tro hils in the first fe+ da!s of life. Infected neonates 'a! ha)e an increase a&o)e the / er li'its of nor'al in i''at/re cells released fro' the &one 'arro+ in res onse to infection, &/t this res onse is inconsistent and so'eti'es dela!ed and therefore an insensiti)e 'arHer for the earl! dia"nosis of infection. Co+e)er, it is /n/s/al for /ninfected infants to ha)e an ele)ated a&sol/te total i''at/re ne/tro hil co/nt a&o)e the reference ran"es6 therefore, if s/ch a findin" is resent, f/rther e)al/ation for occ/lt infection sho/ld &e considered.

The I:T ratio has &een in)esti"ated as an earl! redictor of se sis. The 'aNi'al I:T ratio in /ninfected neonates is $.4% in the first 2J ho/rs, decreasin" to $.42 &! %$ ho/rs. The / er li'it of nor'al for neonates of 12 +eeHsF "estation or less is sli"htl! hi"her, at $.2. Beca/se 'ost infected neonates ha)e an ele)ated I:T ratio so'e ti'e d/rin" the infection, re eatedl! nor'al I:T ratios can &e reass/rin". The /sef/lness of this test is li'ited &eca/se 'an! noninfectio/s rocesses, incl/din" rolon"ed ind/ction +ith oN!tocin, stressf/l la&or, and e)en rolon"ed cr!in", are associated +ith increased I:T ratios. Ac/te-Phase Reactants The ac/te- hase res onse is a res onse of the &od! to infection or tra/'a clinicall! 'anifested &! 'alaise, anoreNia, fe)er, le/Hoc!tosis, ne"ati)e nitro"en &alance, and he atic rod/ction of ac/te- hase roteins 0APRs5. APRs are roteins rod/ced &! he atoc!tes in res onse to infla''ation. The infla''ation 'a! &e secondar! to infection, tra/'a, or other rocesses of cell/lar destr/ction. There are 'an! different APRs, incl/din" C-reacti)e rotein 0CRP5, fi&rino"en, C1 co' le'ent, Z4-acid "l!co rotein, Z4-antitr! sin, and elastase Z4- roteinase inhi&itor 0(Z4-PI5.;81= These APRs ha)e different las'a half-li)es and different incre'ental res onses to infla''ation. The 'ethodolo"! for the detection of APRs has i' ro)ed +ith the de)elo 'ent of ra id, a/to'ated, 7/antitati)e s ecific i''/noassa!s. There ha)e &een n/'ero/s st/dies e)al/atin" APRs as earl! indicators of neonatal se tice'ia6 /nfort/natel!, an ele)ated APR does not distin"/ish &et+een infectio/s and noninfectio/s ca/ses of infla''ation. C-Reacti)e Protein CRP is a "lo&/lin so na'ed &eca/se it for's a reci itate in the resence of the C- ol!saccharide of *tre tococc/s ne/'oniae. Its f/nction is not entirel! clear, &/t it is &elie)ed to &e a carrier rotein in)ol)ed in re'o)in" otentiall! toNic 'aterial. There are se)eral 'ethods a)aila&le for 'eas/rin" CRP. *o'e are f/ll! a/to'ated and 7/antitati)e, +hereas others are se'i7/antitati)e or 7/alitati)e and 'an/al. There is 'ini'al, if an!, trans lacental assa"e of 'aternal CRP, and concentrations are /naffected &! "estational a"e. Nor'al concentrations in neonates are 4 '"Td- 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 the infla''ator! rocess. The ser/' half-life is < to 2 ho/rs. Altho/"h the CRP decreases ro' tl! in the resence of a ro riate thera !, fe+ clinical st/dies ha)e &een erfor'ed e)al/atin" discontin/ation of thera ! &ased on CRP nor'ali8ation. CRP is si"nificantl! ele)ated at the ti'e of the initial e)al/ation in <$? to >$? of infants +ith s!ste'ic &acterial infections. *erial deter'inations of CRP at 42-ho/r inter)als after the onset of si"ns of se sis increased the sensiti)it! of CRP in detectin" se sis.;8$= It has &een o&ser)ed, ho+e)er, that infants +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 elicit a )aria&le CRP res onse, +ith nor'al )al/es in c/lt/re- ositi)e )iral 'enin"itis and increased )al/es in 'inor )iral infections. Noninfectio/s rocesses, incl/din"

'econi/' as iration ne/'onitis, can ha)e an ele)ated CRP / to 4$ ti'es the nor'al concentration. CRP has a lo+ ositi)e redicti)e )al/e and sho/ld not &e /sed alone to dia"nose se sis. (r!throc!te *edi'entation Rate The er!throc!te sedi'entation rate 0(*R5 is not a direct 'eas/re of an APR &/t rather reflects chan"es in 'an! ser/' rotein APRs. A 'icro-(*R has &een de)elo ed for /se in infants. An a roNi'ation of the 'aNi'al nor'al rate in the first 2 +eeHs of life can &e o&tained &! addin" 1 to the a"e of the ne+&orn in da!s. Be!ond 2 +eeHs of life, the 'aNi'al rate )aries &et+een 4$ and 2$ '' er ho/r. ,+in" to interla&orator! )ariation, each la&orator! '/st de)elo its o+n reference ran"e. The (*R is li'ited in that other factors /nrelated to infla''ation 0ane'ia, h! er"lo&/line'ia5 can affect the rate. Micro-(*R )al/es )ar! in)ersel! +ith the he'atocrit &/t are affected little, if at all, &! &irth+ei"ht or "estational a"e. Clinicall!, sli"htl! ele)ated 'icro-(*Rs ha)e &een noted +ith s/ erficial infections and +ith noninfectio/s rocesses, incl/din" as h!Nia, as iration ne/'onia, and res irator! distress s!ndro'e. MarHedl! ele)ated )al/es in the a&sence of infection are /n/s/al &/t ha)e &een o&ser)ed +ith Coo'&s- ositi)e he'ol!tic disease and h!siolo"ic h! er&ilir/&ine'ia. The Hinetic descri tion of the (*R re)eals a lon" dela! after onset of the infla''ator! rocess &efore the eaH rate is reached and a lon" half-life. Altho/"h the (*R is /s/all! ele)ated at so'e oint in s!ste'ic &acterial infections, it is fre7/entl! nor'al on initial e)al/ation. Fi&rino"en Plas'a fi&rino"en concentrations are Hno+n to increase in association +ith infection, altho/"h so'e factors can res/lt in a lo+ fi&rino"en le)el des ite se)ere infection, incl/din" disse'inated intra)asc/lar coa"/lation, eNchan"e transf/sion, and res irator! distress s!ndro'e. Meas/re'ent of fi&rino"en concentrations is not /sef/l in the earl! dia"nosis of infection &eca/se there is a lar"e o)erla in )al/es &et+een infected and health! infants. Fi&ronectin Fi&ronectin 0Fn5 is a '/ltif/nctional, hi"h3'olec/lar-+ei"ht "l!co rotein rod/ced ri'aril! &! the li)er and endothelial cells and +idel! distri&/ted in the &od!, incl/din" in las'a and &od! fl/ids, on cell s/rfaces, and in the eNtracell/lar 'atriN. Fn is in)ol)ed in he'ostasis, )asc/lar inte"rit!, and +o/nd healin". It is i' ortant in e'&r!o"enesis, directin" cell 'i"ration, roliferation, and differentiation. Fn aids in the i''/ne res onse &! a/"'entin" 'acro ha"e and ne/tro hil ha"oc!tosis and actin" as a nons ecific o sonin for the retic/loendothelial s!ste'. The las'a Fn concentration )aries +ith a"e. In health! neonates it is a roNi'atel! half that fo/nd in ad/lts, +hereas health! re'at/re infants ha)e a roNi'atel! one third of the a'o/nt in nor'al ad/lts. After &irth the las'a 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

infection and also in neonates +ith as h!Nia, res irator! distress s!ndro'e, and &roncho /l'onar! d!s lasia. C!toHines Altho/"h c!toHine Hinetics ha)e not &een thoro/"hl! in)esti"ated in neonates, it is &elie)ed &! 'an! that 'eas/rin" c!toHine concentrations can &e hel f/l in the earl! dia"nosis of neonatal se sis. In a st/d! &! Girardin and collea"/es,;<<= 8 of > infants +ith s!ste'ic infection had ele)ated ser/' t/'or necrosis factor-Z, +hereas onl! 4 of %$ noninfected infants had an ele)ated )al/e. B/cH and co+orHers;JJ= e)al/ated ros ecti)el! the /se of interle/Hin 0I-5-% and CRP 'eas/re'ents in the dia"nosis of earl!-onset se sis in 222 neonates. (le)ated I--% concentrations +ere o&ser)ed in 21? of ne+&orns +ith c/lt/re- ositi)e infection and in 82? of infants +ith a clinical dia"nosis of se sis &/t ne"ati)e c/lt/res. *e)ent!-ei"ht ercent of ne+&orns +itho/t e)idence of infection had nor'al a'o/nts of I--%. Fift!-fi)e ercent of the infected ne+&orns +ith nor'al I--% concentrations had ele)ated CRP 'eas/re'ents, s/""estin" that the eaH I--% concentration +as 'issed &eca/se of its short half-life. The co'&ination of I--% and CRP deter'inations 'a! &e hel f/l in the earl! dia"nosis of se sis +hile a+aitin" c/lt/re res/lts.;JJ=;%8= Groll and collea"/es;<2= cond/cted a st/d! of I--% concentrations in 2$ neonates, 4$ +ith ro)ed nosoco'ial se sis and 4$ +itho/t infection6 8 of the infected ne+&orns had ele)ated I--% deter'inations, +hereas onl! 4 of the 4$ /ninfected infants had an a&nor'al )al/e, and that infant +ent on to de)elo clinical se sis +ith ne"ati)e c/lt/res +ithin the follo+in" 1% ho/rs. Man! in)esti"ators ha)e e)al/ated colon!-sti'/latin" factors in the neonatal eriod. .ata are conflictin" &/t s/""est that concentrations of "ran/loc!te colon!-sti'/latin" factors )ar! +ith "estational a"e and are infl/enced &! 'ode of deli)er!, n/tritional stat/s, 'aternal h! ertension, 'aternal "l/cocorticoid thera !, and infection.;1>= A eaH in "ran/loc!te colon!-sti'/latin" factor concentration +as o&ser)ed a roNi'atel! 2 ho/rs after &irth in health! ne+&orns, +ith a corres ondin" increase in the total ne/tro hil co/nt 2 to 42 ho/rs after &irth. Infected ne+&orns had a '/ch hi"her eaH concentration at 2 ho/rs than did /ninfected infants. *creenin" Panels (Ncl/din" c/lt/res, none of the re)io/sl! 'entioned tests, +hen /sed alone, is sensiti)e or s ecific eno/"h relia&l! to dia"nose or eNcl/de neonatal se sis. Man! in)esti"ators ha)e e)al/ated the redicti)e )al/es of anels of tests for dia"nosin" se sis. 0 Ta&le 12342 resents definitions of ter's /sed in e)al/atin" s/ch tests.5 Lrediet and collea"/es;%2= 'eas/red dail! CRPs and I:T ratios in all ne+&orns ad'itted to the n/rser!, 48< atients d/rin" the first J da!s of life and 4$2 infants after the fo/rth da! of life. A se sis +orH/ , incl/din" c/lt/res, co' lete &lood co/nt, and radiolo"ic st/dies, +as erfor'ed onl! as clinicall! indicated. For earl!-onset disease, the ositi)e redicti)e )al/e 0PP95 of either test alone

+as 48? to 21?, and the ne"ati)e redicti)e )al/e 0NP95 +as ><? to >8?. :hen the tests +ere /sed to"ether, the PP9 increased to 12? and the NP9 decreased to ><?. For late-onset se sis, the PP9 and NP9 for the tests, +hen /sed alone, ran"ed fro' <>? to %1? and >$? to >J?, res ecti)el!. :hen the tests +ere /sed to"ether to screen for late-onset infection, the PP9 increased to %<? and the NP9 decreased to 88?. These researchers concl/ded that a screenin" anel co' risin" CRP and the I:T ratio had li'ited )al/e. Te"t'e!er and others;4$2= assessed a screenin" anel in 2J infected neonates. Their anel co' rised CRP, I:T ratio, "ran/loc!te co/nt, and (Z4-PI. The sensiti)it! of each test alone ran"ed fro' 1%? to 2$?, eNce t for (Z4-PI, +hich ran"ed fro' 82? 0earl!-onset se sis5 to 4$$? 0late-onset disease5. :hen all the tests +ere /sed to"ether, the sensiti)it! increased to 4$$?. Beca/se the a/thors assessed onl! infected infants, the! +ere /na&le to deter'ine the s ecificit! or redicti)e acc/rac! of their screenin" anel. Phili and collea"/es;22= e)al/ated the redicti)e acc/rac! of a three- art screen 0(Z4-PI, I:T ratio, and CRP5 in 'ore than 1$$ infected and /ninfected infants ad'itted to the neonatal intensi)e care /nit. :hen /sed alone, (Z4-PI +as 'ore sensiti)e than the other t+o tests for dia"nosin" se sis, &/t had a lo+er PP9. :hen the three tests +ere /sed as a anel, the sensiti)it! +as 21?, the s ecificit! +as >>.2?, the PP9 +as 82.%?, and the NP9 +as >>.2?. In s/''ar!, the /se of screenin" anels does not si"nificantl! i' ro)e the ositi)e redicti)e acc/rac!6 ho+e)er, the redicti)e acc/rac! of a ne"ati)e anel often increases to >8? to 4$$?. Treat'ent (MPIRICA- ANTIMICR,BIA- TC(RAP@ Altho/"h si"ns and s!' to's of neonatal se sis are often s/&tle and nons ecific, once the clinical dia"nosis is o&)io/s, the infant is often criticall! ill. (' irical anti'icro&ial thera ! sho/ld &e instit/ted i''ediatel! after o&tainin" sa' les for c/lt/re rather than +aitin" for the c/lt/re res/lts. The choice of e' irical thera ! sho/ld &e &ased on se)eral factors: the ti'in" and settin" of the disease 0e."., earl! onset, late onset co''/nit! ac7/ired, health care associated late or )er! late onset5, the 'icroor"anis's 'ost fre7/entl! enco/ntered, the s/sce ti&ilit! rofiles for those or"anis's, the site of the s/s ected infection and the enetration of the s ecific anti&iotic to that site, and the safet! of the anti&iotic. Care"i)ers sho/ld &e a+are of the s/sce ti&ilit! rofiles for the 'ost co''on neonatal atho"ens isolated in their co''/nit! and in their neonatal /nit. Non&acterial infectio/s etiolo"ies '/st &e considered in the differential and, if dee'ed a si"nificant ossi&ilit!, a ro riate anti)iral or antif/n"al thera ! '/st &e started in addition to anti&iotic thera !. For earl!-onset disease in the Enited *tates, the anti'icro&ial re"i'en sho/ld ro)ide co)era"e a"ainst GB*, (. coli and other "ra'-ne"ati)e enteric &acilli,

and -. 'onoc!to"enes. The co'&ination of a' icillin and an a'ino"l!coside is fre7/entl! /sed. -isteria or"anis's and GB* are /nifor'l! s/sce ti&le to a' icillin, +hereas the s/sce ti&ilit! of (. coli to a' icillin is less relia&le. The a'ino"l!coside ro)ides co)era"e a"ainst 'ost "ra'-ne"ati)e enteric &acilli and, +ith "enta'icin s ecificall!, has &een fo/nd to act s!ner"isticall! +ith a' icillin a"ainst GB* and -isteria or"anis's in )itro and in ani'al 'odels. The choice of a'ino"l!coside sho/ld &e &ased on s/sce ti&ilit! atterns for "ra'ne"ati)e enteric &acilli in the co''/nit!. Genta'icin is /sed 'ost fre7/entl!, +ith to&ra'!cin and a'iHacin reser)ed for treat'ent of '/ltidr/"-resistant &acteria. If 'enin"itis is s/s ected, es eciall! "ra'-ne"ati)e &acillar! 'enin"itis, 'an! add or re lace the a'ino"l!coside +ith the third-"eneration ce halos orin, cefotaNi'e, for &etter CN* enetration. (' irical thera ! for late-onset disease ac7/ired in the co''/nit! sho/ld ro)ide co)era"e for the sa'e neonatal atho"ens as disc/ssed earlier and also for otential co''/nit!-ac7/ired atho"ens, s/ch as *. ne/'oniae and Neisseria 'enin"itidis. Beca/se 'enin"itis fre7/entl! is a co' onent of lateonset se sis, anti&iotics +ith "ood CN* enetration sho/ld &e selected. A' icillin and a third-"eneration ce halos orin 0e."., cefotaNi'e5 are co''onl! reco''ended. Cealth care-associated late-onset disease can &e ca/sed &! the /s/al neonatal atho"ens &/t also &! C,N*, enterococci, "ra'-ne"ati)e enteric &acilli 0incl/din" dr/"-resistant strains5, and f/n"i. (' irical thera ! de ends on the resence of risH factors for co''ensal or"anis's s/ch as C,N* 0/se of catheters or sh/nts5 and the s/sce ti&ilit! rofiles for co''on nosoco'ial atho"ens isolated fro' the n/rser!. 9irt/all! all sta h!lococci rod/ce enicillinase and therefore are resistant to a' icillin and enicillin. 9anco'!cin and "enta'icin are co''onl! /sed for initial thera !. 9anco'!cin "enerall! is acti)e a"ainst all sta h!lococcal s ecies, stre tococci, and 'ost enterococci, +hereas the s ectr/' of acti)it! of a enicillinase-resistant enicillin incl/des stre tococci and onl! the 'ethicillin-s/sce ti&le strains of C,N* and *. a/re/s. CefotaNi'e or ceftriaNone 'a! &e incl/ded +hen "ra'-ne"ati)e 'enin"itis is a concern. CefotaNi'e does not ha)e acti)it! a"ainst -. 'onoc!to"enes, enterococci or Pse/do'onas s ecies. Cefta8idi'e +ith an a'ino"l!coside sho/ld &e /sed if Pse/do'onas infection is s/s ected. Man! other co'&inations of anti'icro&ial a"ents 'a! &e effecti)e thera ! for nosoco'ial late-onset se sis6 ho+e)er, it is r/dent to /se those a"ents that ha)e ro)en +ith eN erience to &e safe. The risHs and &enefits sho/ld &e considered thoro/"hl! if ro/tine /se of third"eneration ce halos orins for late-onset disease is conte' lated. ,ne disad)anta"e is an increased risH for de)elo 'ent of "astrointestinal coloni8ation and erha s s/&se7/ent infection +ith f/n"i and dr/"-resistant &acteria. :ith ceftriaNone, in artic/lar, there is a theoretical risH of &ilir/&in dis lace'ent fro' al&/'in &eca/se of the dr/"Fs hi"h rotein-&indin" ca acit!. There are no clinical data to s/&stantiate this effect in neonates. ,n the other hand, these ce halos orins are safe and effecti)e a"ainst 'an! of the co''on

neonatal atho"ens, and there is eNtensi)e eN erience +ith cefotaNi'e /se d/rin" the neonatal eriod. Beca/se the third-"eneration ce halos orins do not ca/se the dose-related toNicities seen +ith a"ents s/ch as the a'ino"l!cosides, 'onitorin" of ser/' concentrations is not necessar!. (' irical thera ! /s/all! 'a! &e narro+ed to one dr/" once final c/lt/re identification and s/sce ti&ilit! res/lts are a)aila&le. The dosa"e and fre7/enc! of ad'inistration of anti'icro&ial a"ents )ar! +ith the ne+&ornFs "estational a"e, ostnatal a"e, &irth+ei"ht, and stat/s of he atic and renal f/nction. Reco''endations for anti&iotic /se in neonates are "i)en in Ta&les 12348 , 1234> , 1232$ and in A endiN A. These are "/idelines onl!6 s ecific doses and inter)als 'a! chan"e fre7/entl!, es eciall! in the criticall! ill infant. Ideall!, ser/' concentrations of so'e anti&iotics 0a'ino"l!cosides, )anco'!cin5 sho/ld &e 'onitored to ens/re thera e/tic efficac! +hile 'ini'i8in" toNicit!. The d/ration of thera ! de ends on the site of infection 0see later5. Ta&le 12-48 -- Reco''ended .osa"e *ched/le for Anti'icro&ial A"ents Fre7/entl! Esed to Treat Neonatal *e sis .osa"e 0'"TH" er da!5 and Inter)als of Ad'inistration Bod! :ei"ht U2$$$ " Bod! :ei"ht D2$$$ " ANTIBI,TIC A' icillin R,ET( $32 .a!s I9, IM 4$$ di) 7 42h %$ di) 7 42h 4$$ di) 7 42h 4$$ di) 7 42h <$ once dail! 8328 .a!s $32 .a!s 4<$ di) 7 8h 4<$ di) 7 8h 8328 .a!s D28 .a!s 2$$ di) 7 %h 42$ di) 7 %h 4<$ di) 7 8h 4<$ di) 7 8h 2< once dail! 2$$ di) 7 %h 42$ di) 7 %h 4<$ di) 7 %h 4<$ di) 7 8h 4$$ once dail!

A8treona'

I9

>$ di) 7 8h >$ di) 7 8h 4<$ di) 7 8h 4<$ di) 7 8h <$ once dail! 4$$ di) 7 42h 4$$ di) 7 8h <$ once dail!

CefotaNi'e

I9, IM

Cefta8idi'e

I9, IM

CeftriaNone

I9, IM

Clinda'!cin (r!thro'!cin

I9, IM, 4$ di) 7 P, 42h I9, P, 2$ di) 7

4< di) 7 8h 4< di) 7 8h 2$ di) 7 %h 1$ di) 7 %h 1$ di) 7 8h 2$ di) 7 J$ di) 7 8h J$ di) 7 %h

.osa"e 0'"TH" er da!5 and Inter)als of Ad'inistration Bod! :ei"ht U2$$$ " Bod! :ei"ht D2$$$ " ANTIBI,TIC R,ET( $32 .a!s 42h Metronida8ole I9, P, 4< di) 7 42h 4<$ di) 7 42h <$ di) 7 42h 4< di) 7 42h 22< di) 7 8h 8328 .a!s $32 .a!s 42h 4< di) 7 42h 4<$ di) 7 42h 1$ di) 7 42h 22< di) 7 8h 4<$ di) 7 %h 1$ di) 7 %h 1$$ di) 7 %h 4<$ di) 7 %h 8328 .a!s D28 .a!s

Me8locillin

I9, IM

Nafcillin

I9

2< di) 7 8h 2< di) 7 8h

Penicillin G Ben8athine enicillin G Procaine enicillin G Ticarcillin .i), di)ided.

I9

4$$,$$$ E 2$$,$$$ E 4<$,$$$ E 2$$,$$$ E 2$$,$$$ E di) 7 42h di) 7 8h di) 7 8h di) 7 %h di) 7 %h <$,$$$ E <$,$$$ E <$,$$$ E <$,$$$ E <$,$$$ E 0one dose5 0one dose5 0one dose5 0one dose5 0one dose5 <$,$$$ E 7 <$,$$$ E 7 <$,$$$ E 7 <$,$$$ E 7 <$,$$$ E 7 2Jh 2Jh 2Jh 2Jh 2Jh 4<$ di) 7 42h 22< di) 7 8h 22< di) 7 8h 1$$ di) 7 %h 1$$ di) 7 %h

IM

IM

I9, IM

Ada ted fro' Nelson M.: Anti&iotic thera ! for ne+&orns. In PocHet&ooH of Pediatric Anti'icro&ial Thera !. Balti'ore, :illia's [ :ilHins, 4>>8.

Ta&le 12-4> -- Reco''ended .osa"e *ched/le for A'ino"l!cosides and 9anco'!cin in the Treat'ent of Neonatal *e sis

.osa"e for :eeHsF Gestation or Postconce tional A"e ANTIBI,T R,ET IC ( A1$ A'iHacin I U2 da!s I9, IM 4< '"TH" 7 2Jh 4< '"TH" 7 48h 4< '"TH" 7 48h 4< '"TH" 7 42h 4< '"TH" 7 42h 4< '"TH" 7 8h 1$312 D12

D2 da!s

Genta'icin or to&ra'!cin K U2 da!s I9, IM 1 '"TH" 7 2Jh 1 '"TH" 7 48h 1 '"TH" 7 48h 2.< '"TH" 7 42h 2.< '"TH" 7 42h 2.< '"TH" 7 8h

D2 da!s 9anco'!cin W U2 da!s I9

2$ '"TH" 7 2Jh 2$ '"TH" 7 48h

4< '"TH" 7 48h 4< '"TH" 7 42h

4< '"TH" 7 42h 4< '"TH" 7 8h

D2 da!s

I .esired ser/' concentrations: eaH 2$3J$ \"T'-, tro/"h A4$ \"T'-. K .esired ser/' concentrations: eaH <342 \"T'-, tro/"h U2 \"T'-. W .esired ser/' concentrations: eaH 2$3J$ \"T'-, tro/"h A4< \"T'-.

Ta&le 12-2$ -- Indications, Phar'acolo"!, and ToNicit! of Anti&iotics Co''onl! Esed in Ne+&orn Infants

ANTIBI,TIC

IN.ICATI,N* Aero&ic "ra'ne"ati)e infections6 /se sho/ld &e li'ited to treat'ent of "enta'icinresistant or"anis's

PCARMAC,-,G T,OICIT@ @

C,MM(NT*

A'iHacin

Renal eNcretion6 acti)it! in C*F lo+6 not a&sor&ed fro' GI tract

Possi&le ototoNicit!, ne hrotoNicit!, and ne/ro'/sc/lar &locHade

ToNicit! rare if a ro riate dosa"e is /sed and &lood concentration is 'onitored

A' icillin

Initial treat'ent of se sis and 'enin"itis6 "ra'- ositi)e or"anis's eNce t *ei8/res +hen sta h!lococci6 Renal eNcretion hi"h dosa"es are "ra'-ne"ati)e "i)en or"anis's if s/sce ti&le 0*al'onella, *hi"ella, Ce'o hil/s, (scherichia coli5 Acti)e a"ainst stre tococci6 ro/tine /se can res/lt in e'er"ence of resistant "ra'ne"ati)e or"anis's

CefotaNi'e

*e sis, 'enin"itis ca/sed &! s/sce ti&le "ra'-ne"ati)e or"anis's

Pri'aril! renal eNcretion6 "ood enetration into C*F

Cefta8idi'e

Can &e /sed in co'&ination +ith an a'ino"l!coside for treat'ent of Pse/do'onas infection *e sis,

Renal eNcretion6 enetrates &lood-&rain &arrier

CeftriaNone

1$?3%<?

Potential

Ma! dis lace

ANTIBI,TIC

IN.ICATI,N* 'enin"itis, soft tiss/e and &oneTPoint infections ca/sed &! s/sce ti&le or"anis's6 not effecti)e a"ainst sta h!lococci, -isteria s , enterococci, or Pse/do'onas s Treat'ent of s/sce ti&le anaero&ic infections

PCARMAC,-,G T,OICIT@ @

C,MM(NT*

eNcreted &! the Hidne!s, the re'ainder "all&ladder eNcreted in sl/d"in" &ile6 enetrates &lood-&rain &arrier

&ilir/&in fro' al&/'in&indin" sites in neonates

Clinda'!cin

Pse/do'e'&rano /s colitis in older children &/t rare in neonates .ose-related re)ersi&le &one 'arro+ s/ ression6 idio athic irre)ersi&le a lastic ane'ia 0rare56 'onitorin" of &lood concentration 'andator!

Treat'ent of infections ca/sed &! Chlora' heni &acteria col resistant to all other anti&iotics 0e."., *al'onella s 5

Meta&oli8ed &! the li)er, s'all a'o/nt eNcreted /nchan"ed in the /rine6 "ood enetration thro/"h &lood&rain &arrier

Gra! &a&! s!ndro'e 0)aso'otor colla se5 related to i''at/re he atic f/nction and associated +ith ele)ated concentrations of /nconP/"ated chlora' henicol

Chla'!dia, Pert/ssis s , 'inor (r!thro'!cin sta h!lococcal or stre tococcal sHin infections Genta'icin Can &e /sed for initial treat'ent of neonatal se sis6 not

(Ncreted in /rine, stool, and &iliar! No si"nificant s!ste'6 toNicit! crosses &lood&rain &arrier oorl! Renal eNcretion6 acti)it! lo+ in C*F6 not Possi&le ototoNicit!, ne hrotoNicit!, and ToNicit! rare if the a ro riate dosa"e is

ANTIBI,TIC

IN.ICATI,N*

PCARMAC,-,G T,OICIT@ @

C,MM(NT*

effecti)e alone &/t can &e s!ner"istic +hen /sed +ith a&sor&ed fro' ne/ro'/sc/lar a' icillin GI tract in &locHade a"ainst "ro/ B nor'al host stre tococci, enterococci, and -isteria s Penicillinresistant *ta h!lococc/s a/re/s infections6 acti)e a"ainst stre tococci, &/t not a first-line a"ent (Ncretion is renal and he atic for nafcillin and oNacillin6 nafcillin and oNacillin are hi"hl! rotein &o/nd ,totoNic, ne hrotoNic if a&sor&ed

/sed and &lood concentration s are 'onitored

Nafcillin, oNacillin

Neo'!cin

Bacterial diarrhea, Not a&sor&ed entero atho"eni &! GI tract c (. coli Most stre tococci, Tre one'a allid/', Bacteroides s 0eNce t Bacteroides fra"ilis5, Neisseria 'enin"itidis

.o not /se arenterall!

Penicillin G

Renal eNcretion6 fair enetration of infla'ed 'enin"es

Can &e /sed to treat infections ca/sed &! s/sce ti&le or"anis's

M!co&acteri/' *tre to'!cin t/&erc/losis Ticarcillin

9esti&/lar and M/st &e "i)en Renal eNcretion a/ditor! da'a"e, IM ne hrotoNicit! Can &e associated +ith h! ernatre'i

(N anded "ra'- Renal eNcretion Platelet ne"ati)e d!sf/nction acti)it!6 can &e /sed to treat

ANTIBI,TIC

IN.ICATI,N*

PCARMAC,-,G T,OICIT@ @

C,MM(NT* a and h! oHale'ia6 electrol!tes are 'onitored

s/sce ti&le Pse/do'onas infections Broad co)era"e Renal of "ra'eNcretion6 lo+ ne"ati)e acti)it! in C*F or"anis's

To&ra'!cin

Possi&le ototoNicit! and ne hrotoNicit!

Blood concentration s are 'onitored

9anco'!cin

(ffecti)e a"ainst coa"/lasene"ati)e Possi&le sta h!lococci, ototoNicit!6 'ethicillinre)io/s resistant *. Renal eNcretion re arations a/re/s6 'ost associated +ith "ra'- ositi)e ne hrotoNicit! aero&ic or"anis's are s/sce ti&le Contraindicated in ne+&orns .is laces &ilir/&in fro' al&/'in&indin" sites Per'anent discoloration of teeth, ena'el h! o lasia6 inhi&its &one "ro+th in re'at/re infants

Fl/shin" or h! otension 'a! res/lt fro' ra id inf/sion

*/lfona'ides

Tetrac!clines

Contraindicated in ne+&orns

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

*EPP,RTI9( TC(RAP@

Altho/"h a ro riate anti'icro&ial thera ! is cr/cial, s/ orti)e care is e7/all! i' ortant. 9entilator! s/ ort 'a! &e necessar!, artic/larl! for infants +ith f/l'inant earl!-onset disease. I9 h!dration and erha s arenteral n/trition, +ith close 'onitorin" of electrol!tes and "l/cose, sho/ld &e considered. *e tic shocH, if resent, sho/ld &e treated a ro riatel! +ith fl/ids and inotro es as indicated &! the clinical sit/ation. IMMEN,TC(RAP@ The ne+&ornFs i''/ne s!ste' is co' ro'ised in 'an! as ects, incl/din" the ne/tro hilFs che'otactic res onse to atho"ens, T cell rod/ction of roinfla''ator! c!toHines, and f/nctional co' le'ent acti)it! 0see Part 4 of this cha ter5. Preter' infants are f/rther co' ro'ised &! h! o"a''a"lo&/line'ia &eca/se si"nificant transfer of 'aternal i''/no"lo&/lin 0I"5 G does not &e"in /ntil 12 to 1J +eeHsF "estation. ()en ter' infants 'a! lacH s ecific anti&odies to the 'ost co''on atho"ens in earl!onset neonatal infections &eca/se 'ost ad/lts ha)e lo+ concentrations of anti&od! a"ainst GB* and (. coli. :ith the increased risH of o)er+hel'in" &acterial infection in the reter' neonate, researchers ha)e st/died the effect of I9 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 treat'ent of infected neonates. A &eneficial effect fro' I9IG and a ro riate anti&iotics +as o&ser)ed in se)eral st/dies co' ared +ith anti&iotics /sed alone for the treat'ent of se sis. Co+e)er, these +ere li'ited &! s'all n/'&ers of atients, non&linded in)esti"ators, lacH of a lace&o control, or lacH of &acteria-s ecific anal!sis of the I9IG re aration /sed. Meta-anal!sis of st/dies of I9IG for the treat'ent of neonates +ith se sis sho+ed a si"nificant decrease in the 'ortalit! rate co' ared +ith standard thera ies.;%J= F/rther st/dies are +arranted &efore I9IG /se in infections can &e reco''ended as ro/tine thera !. ,ther A"ents in .e)elo 'ent ,ther a"ents that 'a! &e &eneficial in the treat'ent of neonatal infections incl/de h/'an 'onoclonal I"M anti&od! and h! eri''/ne "lo&/lin s ecific for the infectin" atho"en. Preli'inar! in )itro and ani'al st/dies looH ro'isin", &/t f/rther in)esti"ation is needed. Fn ad'inistration 'a! &e of /se in the re)ention and treat'ent of neonatal se sis &eca/se of its '/ltif/nctional roles, incl/din" nons ecific o soni8ation that aids in clearin" de&ris in the retic/loendothelial s!ste', a/"'entation of ha"oc!tic acti)it!, and he'ostasis. Fn has &een /sed in ad/lts as a to ical a"ent to i' ro)e +o/nd healin" +ith ersistent corneal /lcerations and I9 in /ncontrolled st/dies of atients +ith '/ltior"an s!ste' fail/re. Preli'inar! res/lts a ear enco/ra"in", &/t lar"e, ros ecti)e, controlled st/dies are re7/ired &efore an! reco''endations a&o/t its /se can &e 'ade. The /se of "ran/loc!te transf/sions as adP/ncti)e thera ! in neonates +ith o)er+hel'in" se sis and ne/tro enia +as considered, &/t this 'ode of thera ! is infre7/entl! /sed &eca/se of the need to ad'inister forei"n

rotein. More recentl!, the /se of reco'&inant h/'an "ran/loc!te colon!sti'/latin" factors or "ran/loc!te-'acro ha"e colon!-sti'/latin" factors as an adP/ncti)e thera ! in the treat'ent of se tic ne/tro enic neonates has &een considered. Preli'inar! data fro' case re orts and fro' a s'all trial see' ro'isin", &/t a lar"e, rando'i8ed, controlled trial is needed to )alidate the &eneficial effects o&ser)ed.;<J=;%%= PR(9(NTI,N Intra art/' anti&iotic ro h!laNis 0IAP5 for re)ention of earl!-onset GB* disease has &een in +ides read /se since 4>>%. The "/idelines iss/ed in 4>>% reco''ended screenin" of re"nant +o'en for GB* coloni8ation either &! 'eans of lo+er )a"inal and rectal c/lt/res o&tained at 1< to 12 +eeHsF "estation or &! assessin" clinical risH factors to identif! candidates for IAP. Both strate"ies also tar"eted +o'en +ith &acteri/ria d/rin" re"nanc! and those +ith a re)io/sl! affected infant +ith GB* infection. *ince the i' le'entation of IAP, the incidence of earl!-onset GB* infections has decreased &! %<?, fro' 4.2 er 4$$$ li)e &irths in 4>>1 to $.% er 4$$$ in 4>>8.;88= For the !ears 4>>8 to 4>>>, an esti'ated 1>$$ to J<$$ earl!-onset infections and 2$$ to 22< neonatal deaths +ere re)ented ann/all! &! the /se of IAP. In contrast, the incidence of late-onset disease has re'ained constant at a roNi'atel! $.< er 4$$$ li)e &irths thro/"ho/t the 4>>$s and into the 24st cent/r!. A direct co' arison of the t+o re)ention strate"ies no+ has de'onstrated that c/lt/re-&ased screenin" is <$? 'ore effecti)e than a risH-&ased strate"! in re)entin" earl!-onset disease in neonates.;82= The 2$$2 re)ised "/idelines fro' the Centers for .isease Control and Pre)ention 0C.C5 reco''end that all re"nant +o'en &e screened d/rin" each re"nanc! for GB* carria"e. The lo+er )a"inal and rectal c/lt/res o&tained at 1< to 12 +eeHsF "estation sho/ld &e laced in a non-n/triti)e trans ort 'edi/', inc/&ated in selecti)e &roth 'edi/', and s/&c/lt/red into <? shee &lood a"ar for isolation of GB*. All re"nant +o'en identified as GB* carriers sho/ld recei)e IAP at the ti'e of la&or or R,M. Penicillin 0< 'illion /nits initiall! and then 2.< 'illion /nits e)er! J ho/rs /ntil deli)er!5 is reco''ended.;J%= A' icillin 02 " initiall! and then 4 " e)er! J ho/rs /ntil deli)er!5 is an acce ta&le alternati)e. Penicillin-aller"ic +o'en +ho are not at hi"h risH for ana h!laNis sho/ld recei)e cefa8olin 02 " initiall! and 4 " e)er! 8 ho/rs /ntil deli)er!5. Beca/se of increasin" rates of resistance, clinda'!cin and er!thro'!cin are less effecti)e as alternati)e a"ents. These sho/ld &e reser)ed for +o'en +ith risH of ana h!laNis in +ho' testin" has indicated that the isolates are s/sce ti&le. .eli)er! of a re)io/s infant +ith in)asi)e disease and GB* &acteri/ria is al+a!s an indication for IAP. IAP is not indicated for lanned cesarean section &efore R,M and onset of la&or. RisH factors 0la&or onset or R,M &efore 12 +eeHsF "estation, R,M 48 ho/rs or 'ore &efore deli)er!, or intra art/' fe)er5 sho/ld &e /sed onl! +hen the res/lts of c/lt/res are not Hno+n at the onset of la&or. An al"orith' for IAP for +o'en +ith threatened reter' deli)er! is incl/ded in the c/rrent reco''endations.;J%=

The 'ana"e'ent of infants &orn to +o'en recei)in" intra art/' che'o ro h!laNis de ends on the infantFs stat/s at &irth, the d/ration of ro h!laNis, and the "estational a"e of the infant. If a +o'an recei)es IAP for s/s ected chorioa'nionitis, her infant sho/ld ha)e a f/ll dia"nostic e)al/ation and e' irical thera ! endin" c/lt/re res/lts &ased on the infantFs eN os/re to esta&lished infection. *!' to'atic infants sho/ld /nder"o f/ll dia"nostic e)al/ation and e' irical thera !. A l/'&ar /nct/re, if feasi&le, sho/ld &e erfor'ed. -i'ited e)al/ation consistin" of co' lete &lood co/nt +ith differential and &lood c/lt/re and o&ser)ation for at least J8 ho/rs is indicated for as!' to'atic infants of less than 1< +eeHsF "estation and for those +hose 'others recei)ed che'o ro h!laNis for less than J ho/rs &efore deli)er!. ,&ser)ation is a ro riate for as!' to'atic infants of at least 1< +eeHsF "estation +hose 'others recei)ed che'o ro h!laNis at least J ho/rs &efore deli)er!. (N os/re to anti&iotics d/rin" re"nanc! has not chan"ed the clinical s ectr/' of GB* disease or the onset of clinical si"ns of infection +ithin 2J ho/rs of &irth for ter' infants +ith earl!-onset GB* infection.;J2= In re orts that doc/'ent increases in non-GB* se sis, the increase has occ/rred onl! in infants &orn re'at/rel! or +ith lo+ &irth+ei"ht. A'on" '/lticenter st/dies of the incidence of non-GB* se sis, the onl! one that identified a si"nificant increase in the rate of (. coli earl!-onset disease e)al/ated onl! infants +ith 9-B:.;>%= */r)eillance in t+o cities fo/nd sta&le rates of se sis ca/sed &! other or"anis's &/t an increase in a' icillin-resistant (. coli a'on" reter' &/t not ter' infants.;%2= These trends are reass/rin" &/t indicate the i' ortance of on"oin" s/r)eillance. A co' rehensi)e ro"ra' for re)ention of neonatal &acterial infections a+aits the de)elo 'ent and licens/re of )accines, so'e of +hich are no+ /nder testin", and of strate"ies to re)ent re'at/re deli)er!.

(ditors: Mac.onald, Mhairi G.6 *eshia, Mar! M. L.6 M/llett, Martha .. Title: A)er!'s Neonatolo"!, %th (dition Co !ri"ht ]#2$$< -i incott :illia's [ :ilHins

D Ta&le of Contents D Part 9 - The Ne+&orn Infant D Cha ter J2 - Bacterial and F/n"al Infections Cha ter J2 Bacterial and F/n"al Infections Ro&ert -. *chelonHa

Bishara M. FreiP Geor"e C. McCracHen Mr. Infections ca/se si"nificant 'ortalit! and lon"-ter' 'or&idit! in neonates, es eciall! for re'at/re infants of )er! lo+ &irth +ei"ht 04,2,1,J,<,%5. Te' oral and "eo"ra hic differences in the relati)e fre7/encies of )ario/s neonatal atho"ens are +ell reco"ni8ed 02,8,>,4$,445. In North A'erica in the 4>1$s and 4>J$s, "ra'- ositi)e cocci s/ch as "ro/ A ^_-he'ol!tic stre tococci and *ta h!lococc/s a/re/s +ere the 'ost co''on &acterial isolates fro' neonates +ith se sis, +ith (scherichia coli acco/ntin" for 'ost of the re'ainin" cases. *. a/re/s and (. coli &eca'e the 'aPor atho"ens in the 4><$s, &/t since the late 4>%$s, "ro/ B ^_-he'ol!tic stre tococci and (. coli ha)e redo'inated. Coa"/lase-ne"ati)e sta h!lococci e'er"ed in the 4>8$s and ha)e s/r assed *. a/re/s and "ra'-ne"ati)e enteric &acilli as the &acteria 'ost fre7/entl! associated +ith nosoco'ial infections in 'an! neonatal intensi)e care /nits 0NICEs5, and se)eral Candida s ecies ha)e increased in fre7/enc! to &eco'e 'aPor neonatal atho"ens in the 4>>$s. This has lar"el! &een a conse7/ence of the s/r)i)al of )er!-lo+-&irth-+ei"ht 09-B:5 infants +ho re7/ire len"th! hos itali8ations and considera&le 'echanical and n/tritional s/ ort 042,415. *ince the 4>>$s there has &een an e'er"in" ro&le' of '/lti le-dr/"-resistant "ra'- ositi)e and "ra'-ne"ati)e enteric &acilli in NICEs 04J,4<,4%,425. The o/tco'e of neonatal infections 'a! &e i' ro)ed if illness is reco"ni8ed earl! and a ro riate anti'icro&ial a"ents are ad'inistered ro' tl!. This cha ter resents ertinent e ide'iolo"ic and atho"enetic conce ts of s ecific infections, clinical 'anifestations, and dia"nostic e)al/ations of atients +ith these diseases, +ith a rational a roach to thera ! of neonatal infections. (PI.(MI,-,G@ The t+o rinci al so/rces of ne+&orn infection are the 'other and the n/rser! en)iron'ent. Infection is ac7/ired fro' the 'other trans lacentall!, at the ti'e of deli)er!, or in the ostnatal eriod. The infant 'a! ac7/ire infection ostnatall! fro' en)iron'ental so/rces, s/ch as n/rser! ersonnel, res irator! e7/i 'ent, sinHs, conta'inated total arenteral n/trition sol/tions or 'edication )ials, and inc/&ators. Infections 'anifestin" +ithin the first +eeH of life are /s/all! the res/lt of eN os/re to 'icroor"anis's of 'aternal ori"in, &/t infections resentin" later can ha)e a 'aternal or en)iron'ental so/rce. M!riad aero&ic and anaero&ic &acteria, '!co las'as, chla'!diae, f/n"i, )ir/ses, and roto8oa can &e fo/nd in the 'aternal "enital tract. *o'e of these or"anis's ose little threat to the ne+&orn infant 0e."., -acto&acill/s, ahe'ol!tic stre tococci, 9eillonella5, and others are infre7/ent ca/ses of neonatal disease 0e."., *tre tococc/s ne/'oniae, Neisseria 'enin"itidis5 048,4>,2$5. More co''onl!, or"anis's s/ch as "ro/ s A and B ^`-he'ol!tic stre tococci, (. coli, -isteria 'onoc!to"enes, Cae'o hil/s infl/en8ae, Neisseria "onorrhoeae, c!to'e"alo)ir/s, and her es si' leN )ir/s are res onsi&le for serio/s neonatal infections 01,J5.

:ithin a fe+ da!s after &irth, a-he'ol!tic stre tococci, *. e ider'idis, and "ra'ne"ati)e enteric &acilli coloni8e the throat, nose, /'&ilic/s, and stool 024,22,215. The "astrointestinal 0GI5 tract of ne+&orns &eco'es hea)il! coloni8ed &! lacto&acilli. Infants in NICEs tend to ha)e dela!ed coloni8ation, +hich ro&a&l! is related to earl! anti'icro&ial thera ! for ossi&le se sis, and are 'ore liHel! to ac7/ire nosoco'ial strains of "ra'-ne"ati)e &acilli s/ch as Lle&siella, (ntero&acter, Citro&acter, and (. coli 02J,2<,2%5. Coloni8ation of the scal , aNilla, and "roin &! coa"/lase-ne"ati)e sta h!lococci is /ni)ersal &! J8 ho/rs of a"e 0425. In a ros ecti)e st/d! of 48 re'at/re infants ad'itted to a NICE, *. e ider'idis as the onl! coa"/lase-ne"ati)e sta h!lococcal s ecies isolated fro' the aNilla, ear, naso har!nN, and rect/' +as fo/nd in a&o/t 44? of infants d/rin" their first ostnatal da!6 this increased to 4$$? &! J +eeHs of a"e. None of these infants had a P.421% redo'inant *. e ider'idis &iot! e on the first da! co' ared +ith 8>? &! J +eeHs of a"e. The re)alence of sli'e rod/ction and '/lti-dr/" resistance a'on" isolates rose fro' %8? to ><? and fro' 12? to 82?, res ecti)el!, d/rin" the J-+eeH st/d! eriod 0225. Postnatal f/n"al coloni8ation is 'ore liHel! to occ/r in lo+-&irth-+ei"ht 0-B:5 infants. An esti'ated 4$? of ter' infants ha)e GI Candida coloni8ation +ithin the first < da!s of life6 infants +ei"hin" less than 4,<$$ " ha)e coloni8ation rates of a&o/t %$? 0285. (arl! coloni8ation 0less than 2 +eeHs of a"e5 is 'ore co''on, in)ol)es the GI and res irator! tracts, and is +ith Candida al&icans or C. tro icalis, /nliHe late coloni8ation 0abc2 +eeHs of a"e5, +hich /s/all! in)ol)es the sHin and is 'ore liHel! to &e +ith C. ara silosis 02>5. C. al&icans coloni8ation of infants is /s/all! of 'aternal ori"in, +hereas C. ara silosis coloni8ation is ac7/ired fro' eNo"eno/s so/rces s/ch as the hands of n/rser! ersonnel 01$5. C/taneo/s coloni8ation +ith Malasse8ia 0Pit!ros or/'5 f/rf/r, a li o hilic !east &est Hno+n as the ca/se of tinea )ersicolor, is co''on and is fo/nd in as 'an! as t+o-thirds of all criticall! ill ne+&orns6 fe+er than 1? of health! ne+&orns and !o/n" infants ha)e sHin coloni8ation &! this f/n"/s 014,12,115. The /se of +ater-in-oil e'ollient crea's 0e."., (/cerin Cre'e5 as a 'oist/ri8er for re'at/re infants does not a ear to alter coloni8ation atterns &! &acteria or f/n"i 01J5, &/t in a rando'i8ed controlled trial of to ical e'ollient crea' there +as an <? a&sol/te increased risH 02<.8? )s. 2$.J?6 RR: 4.2%6 ><? CI: 4.$2,4.<J5 of ac7/irin" nosoco'ial &acterial se sis. This increase in infection rates d/e 'ostl! to an increase in the n/'&er of coa"/lase-ne"ati)e sta h!lococci infection 01<5. The )a"ina or cer)iN of as!' to'atic, seN/all! acti)e +o'en is coloni8ed &! Erea las'a /real!tic/' in J$? to 8$? and &! M!co las'a ho'inis in 24? to <1?. 9ertical trans'ission rates fro' J<? to %%? for reter' and ter' neonates ha)e &een re orted for E. /real!tic/' 01%5. B! 1 'onths of a"e, a&o/t 11? to %8? of these infants contin/e to ha)e detecta&le har!n"eal, oc/lar, or )a"inal coloni8ation 0125. 9ertical trans'ission rates for infants &orn to +o'en +ith cer)ical Chla'!dia tracho'atis infections

ha)e &een esti'ated at J$? to 2$?6 a&o/t 1<? of /ntreated infants contin/e to &e infected at one or 'ore sites 0e."., conP/ncti)a, naso har!nN, oro har!nN, rect/', )a"ina5 at 42 'onths of a"e 018,1>,J$5. In the Enited *tates, &acterial se sis affects / to 12,$$$ infants ann/all!, and the incidence of neonatal se sis is fro' 4 to 8 cases er 4,$$$ li)e &irths 0J4,J2,J15. The a)era"e national incidence rate for n/rser!-ac7/ired infections is a&o/t 4.J?, &/t fi"/res re orted for NICEs are considera&l! hi"her and ran"e fro' <? to 1$? 01,JJ,J<,J%,J25. The 'ost i' ortant risH factors for ac7/irin" a nosoco'ial infection are lo+ &irth +ei"ht and "estational a"e6 others incl/de rolon"ed hos itali8ation, in)asi)e roced/res, lace'ent of ind+ellin" de)ices s/ch as central )eno/s catheters or )entric/lo eritoneal sh/nts, &acterial or f/n"al coloni8ation, and o)ercro+ded n/rseries. PCARMAC,-,GIC BA*I* ,F ANTIMICR,BIA- TC(RAP@ *election of anti'icro&ial thera ! for neonatal infections '/st &e &ased on har'acoHinetic ro erties of anti&iotics in ne+&orn infants of different "estational and ostnatal a"es, anti'icro&ial s/sce ti&ilities of co''onl! enco/ntered atho"ens +ithin each n/rser!, and the nat/ral histor! of the infectio/s disease &ein" treated 0J85. Co'&inin" t+o or 'ore anti&iotics is the /s/al clinical ractice +hen initiatin" thera ! for res/'ed s!ste'ic &acterial disease 0e."., a' icillin and an a'ino"l!coside are co'&ined to treat s/s ected earl! onset se tice'ia or 'enin"itis &efore identification of the atho"en5. After a &acteri/' has &een identified and its s/sce ti&ilit! to )ario/s anti'icro&ial a"ents is deter'ined, a sin"le a ro riate anti&iotic /s/all! is satisfactor! for treatin" 'ost infections. Altho/"h anti&iotics are /sed co''onl! to re)ent infection, the! are effecti)e ro h!lacticall! onl! if directed a"ainst a sin"le atho"en. For eNa' le, a sin"le dose of enicillin G "i)en intra'/sc/larl! at &irth red/ces the coloni8ation rate and incidence of earl!- onset "ro/ B stre tococcal 0GB*5 disease, eNce t in infants +ho ac7/ire the infection in /tero 0J>5. Co+e)er, if anti&iotics are /sed as &road-s ectr/' co)era"e a"ainst 'an! otential atho"ens, the! rarel! are effecti)e. This /'&rella 'ethod of che'o ro h!laNis enco/ra"es the e'er"ence of resistant strains a'on" re)io/sl! s/sce ti&le &acteria and alters the nor'al flora of the GI and res irator! tracts +ith o)er"ro+th of otentiall! )ir/lent or"anis's. Broad-co)era"e ro h!laNis 'a! artiall! s/ ress a &acteri/', 'asHin" the de)elo 'ent of clinical disease and ca/sin" ne"lect of i' ortant s/r"ical 'eas/res or serio/s dela! in ad'inisterin" 'ore effecti)e thera !. *(P*I* N(,NAT,REM The ter' se sis neonator/' descri&es a disease of infants +ho are !o/n"er than 4 'onth of a"e, are clinicall! ill, and ha)e ositi)e &lood c/lt/res. The resence of clinical 'anifestations differentiates this condition fro' the transient &actere'ia o&ser)ed in so'e health! neonates.

The &acteria res onsi&le for neonatal se sis )ar! "eo"ra hicall!. GB* and (. coli redo'inate in the Enited *tates, +hereas *. a/re/s and "ra'-ne"ati)e &acilli are '/ch 'ore co''on in de)elo in" co/ntries 085. The &acterial etiolo"! of se sis also )aries &! the ostnatal a"e of the infant. In a st/d! of a cohort of %,><% 9-B: infants 0J$4 to 4,<$$ "5 ad'itted to 4< 'edical centers in the Enited *tates d/rin" a 12-'onth eriod &et+een 4>>8 and 2$$$, the incidence of earl!- onset se sis 0occ/rrin" d/rin" the first 22 ho/rs of life5 +as 4.<? and that of late-onset se sis 0occ/rrin" after 1 da!s of a"e5 +as 2<?. The nat/re of the atho"ens associated +ith the earl!-onset and late-onset infections differed 'arHedl!, +ith (. coli redo'inatin" 0JJ? of cases5 in the for'er and coa"/lasene"ati)e sta h!lococci 0J8? of cases5 in the latter 0Ta&le J2-45 01,J5. TAB-( J2-4 .I*TRIBETI,N ,F PATC,G(N* IN A C,C,RT ,F <,JJ2 0(AR-@,N*(T5 AN. %,><% 0-AT(-,N*(T5 9(R@--,:-BIRTC-:(IGCT INFANT* 0J$4-4,<$$ G5 IN TC( ENIT(. *TAT(* FR,M *(PT(MB(R 4,4>>8 T, AEGE*T 4, 2$$$. ,r"anis' Gra'- osti)e &acteria Gro/ B stre tococci *tre tococc/s )iridans ,ther stre tococci (nterococc/sT"ro/ . stre tococci Coa"/lase-ne"ati)e sta h!lococci *ta h!lococc/s a/rer/s ,ther Gra'-ne"ati)e &acteria (scherichia coli Cae'o hil/s infl/en8ae Lle&siella Pse/do'onas (ntero&acter ,ther F/n"i Candida al&icans Candida ara silosis 2 025 $ 0$5 2% 0%5 <J 0J5 12 0JJ5 2 085 N* N* N* 2 085 %J 0<5 N* <2 0J5 1< 015 11 015 48 045 > 0445 1 0J5 J 0<5 N* > 0445 4 045 1 0J5 1$ 025 N* N* J1 015 %2> 0J85 4$1 085 442 0>5 (arl!-,nset *e sis 0N -ate-,nset *e sis 0N d d 8J5 4,1415

,ther

$ 0$5

1$ 025

9al/es are "i)en as n/'&er 0 ercent5. N*, not s ecified P.4212

Patho"enesis Maternal, en)iron'ental, and host factors deter'ine +hich infants eN osed to a otentiall! atho"enic or"anis' +ill de)elo se sis, 'enin"itis, or other serio/s in)asi)e infections. Man! re art/' and intra art/' o&stetric co' lications ha)e &een associated +ith increased risH of infection in the ne+&orn, the 'ost si"nificant of +hich are re'at/re onset of la&or, rolon"ed r/ t/re of fetal 'e'&ranes, chorioa'nionitis, and 'aternal fe)er. In one st/d! of >%1 re"nancies co' licated &! re'at/re r/ t/re of 'e'&ranes, the incidence of clinical se sis increased fro' 2? a'on" infants &orn +ithin 21 ho/rs of 'e'&rane r/ t/re to 2? and 44? a'on" those deli)ered 2J to J2 ho/rs and J8 to 24 ho/rs after r/ t/re, res ecti)el!. The risH +as hi"hest for the re'at/re, -B: infants 0<$5. The incidence of infection has &een esti'ated at 8.2? for infants &orn to 'others +ith rolon"ed r/ t/re of 'e'&ranes 0abc2J ho/rs5 and clinical chorioa'nionitis 0<45. Intraa'niotic infection is associated +ith a hi"her incidence of se sis a'on" infants +ei"hin" less than 2,<$$ " at &irth co' ared +ith those +ei"hin" 2,<$$ " or 'ore 04%? and J?, res ecti)el!5. .eath fro' se sis is "reater in the -B: "ro/ 044? and $?, res ecti)el!5 0<25. Isolation of &acteria fro' the chorioa'nion has &een associated +ith an increased risH of neonatal death a'on" reter' infants 0<15. Maternal /rinar! tract infections, lo+ arit!, and the /se of internal 'onitorin" de)ices are risH factors for chorioa'nionitis 0<J5. Conc/rrent 'aternal and neonatal &actere'ia has &een doc/'ented for 'an! 'icroor"anis's 0<<,<%,<25. :ith i' ro)ed s/ orti)e care of the sicH neonate has co'e increased o ort/nit! for 'icroor"anis's of relati)el! lo+ )ir/lence to ca/se s!ste'ic disease. The /se of arterial and )eno/s /'&ilical catheters, central )eno/s catheters, ind+ellin" /rinar! catheters, and endotracheal t/&es ro)ides access to the de&ilitated infant for or"anis's in the res irator!, GI, or "enito/rinar! tract, on the sHin, or in res irator! s/ ort e7/i 'ent. Bacterial coloni8ation of the sHin and '/cosal s/rfaces recedes in)asi)e disease in 'ost infants +ith se sis. T! e III strains of GB*, the ones 'ost co''onl! associated +ith earl!-onset se tice'ia and +ith 'enin"itis at an! a"e in earl! infanc!, adhere &etter to )a"inal and neonatal &/ccal e ithelial cells in )itro than do other GB* strains 0<8,<>5. Bloodstrea' in)asion "enerall! follo+s

local '/lti lication of the or"anis' at sites of coloni8ation. As iration of infected a'niotic fl/id is another ro osed ro/te for fetal infection a'on" infants &orn to 'others +ith chorioa'nionitis. Ani'als ha)e &een /sed to define the host-&acteria interactions that deter'ine 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 &! retreat'ent +ith t! e-s ecific ca s/lar ol!saccharide anti&od! 0%$,%45. The oro"astric ro/te for (. coli L4 in the infant rat and the intratracheal installation of GB* in the P.4218 rhes/s 'onHe! or rat rod/ce illnesses that closel! arallel the h/'an s!ndro'es 0%2,%1,%J5. *e)eral in)esti"ations of the host- arasite association of h/'ans +ith GB* ha)e foc/sed on 'eas/re'ent of s ecific anti&od! in the ser/' of infected and coloni8ed ersons. Protecti)e concentrations of anti&od! to GB* serot! e III +ere fo/nd in 21? of +o'en +hose ne+&orn infants +ere +ell &/t in onl! 42? of +o'en +hose neonates de)elo ed se sis or 'enin"itis ca/sed &! this or"anis' 0%<5. The a'o/nt of anti&od! to GB* serot! e III +as considera&l! lo+er in ill infants than in health! neonates &orn to 'others +ith )a"inal coloni8ation 0%<5. -e)els of GB* serot! e III anti&odies correlate +ith in )itro o sonic acti)it! and in )i)o rotection of ani'als eN eri'entall! infected +ith these strains 0%%,%25. The ad'inistration of standard intra)eno/s i''/no"lo&/lin re arations +ith acti)ities a"ainst GB*, of h/'an GB* 'onoclonal anti&odies, or of GB* h! eri''/ne ol!clonal anti&odies ro)ides si"nificant rotection to ani'als eN eri'entall! infected +ith this atho"en 0%8,%>5. As!' to'atic coloni8ation also is associated +ith anti&od! for'ation 02$,245. Altho/"h less eNtensi)el! st/died, si'ilar o&ser)ations ha)e &een 'ade for other GB* serot! es 0%>,22,21,2J,2<5. ()idence s/""ests that anti&odies to the L4 (. coli anti"en are rotecti)e a"ainst infection &! this or"anis', &/t this is not fir'l! esta&lished 02%5. Neonatal ser/' has &een sho+n to &e inefficient in Hillin" (. coli &eca/se of a deficienc! of noni''/no"lo&/lin G ser/' co' onents, s/ch as co' le'ent factor > 022,285. Ph!siolo"ic deficiencies of the classic and alternati)e ath+a!s of co' le'ent acti)ation in neonates contri&/te to inefficient &acterial o soni8ation 02>,8$5. ,r"anis's s/ch as GB* and (. coli that ha)e hi"h ca s/lar sialic acid content tend to &e oor acti)ators of the alternati)e co' le'ent ath+a! 0845. Fi&ronectin is a '/ltif/nctional "l!co rotein fo/nd in the las'a and on the s/rface of certain e ithelial cells, &ase'ent 'e'&ranes, and connecti)e tiss/es. In las'a, fi&ronectin acts as a nons ecific o sonin that enhances clearance of in)adin" &acteria 0825. Fi&ronectin is deficient in neonatal las'a, and its concentration )aries in)ersel! +ith "estational a"e 082,815. *e tic infants ha)e &een sho+n to ha)e si"nificantl! lo+er las'a concentrations of this

"l!co rotein than health!, a"e-'atched controls 08J5. The sol/&le for' of fi&ronectin &inds oorl! to GB* 08<5. Fi&ronectin enhances ha"oc!te f/nction in )itro and in )i)o 0825. e/antitati)e and 7/alitati)e deficiencies in neonatal ne/tro hils contri&/te to the i''at/rit! of the i''/ne s!ste' of ne+&orns. The a&nor'alities &eco'e 'ost rono/nced at ti'es of stress or d/rin" infections and incl/de i' aired che'otaNis, decreased defor'a&ilit!, red/ced C1&i rece tor eN ression, de ressed &acterial Hillin" &! ha"oc!tes, and oNidati)e 'eta&olic a&nor'alities. The ne/tro hil stora"e ool of neonates is 'arHedl! de leted co' ared +ith that of ad/lts 08%5. *te' cell roliferati)e rates are at near 'aNi'al ca acit! and cannot increase a recia&l! in res onse to infection 0825. Clinical Manifestations Most infants +ith se tice'ia resent +ith nons ecific si"ns that are /s/all! o&ser)ed first &! the n/rse or 'other rather than &! the h!sician. The 'ost co''on of these )a"/e si"ns are te' erat/re insta&ilit!, lethar"!, a nea, and oor feedin" 0885. Altho/"h h! other'ia is 'ore co''on, a te' erat/re ele)ation a&o)e 12.8]Q]QC is si"nificant in the neonate and fre7/entl! associated +ith &acterial infections, es eciall! +ith te' erat/res hi"her than 1>]QC 08>5. The clinical si"ns in so'e infants 'a! s/""est res irator! or GI disease 0e."., tach! nea and c!anosis or )o'itin", diarrhea, and a&do'inal distention5. *e tice'ia '/st al+a!s &e incl/ded in the differential dia"nosis +hen e)al/atin" an infant +ith these findin"s 0885. Clinical 'anifestations of se sis in )er!-lo+-&irth +ei"ht infants 0<$4-4,<$$ "5 incl/de increasin" a nea 0<<?5, feedin" intolerance, a&do'inal distension, or he'e- ositi)e stools 0J1?5, increased res irator! s/ ort 02>?5, and lethar"! and h! otonia 021?5. A&nor'al +hite &lood cell co/nt, /neN lained 'eta&olic acidosis, and h! er"l!ce'ia are noted in J%?, 44?, and 4$?, res ecti)el! 0J25. Altho/"h it is te' tin" to reco''end an e)al/ation for se tice'ia in all infants +ith nons ecific clinical 'anifestations, this is i' ractical and /nnecessar! in 'an! cases. A co' lete histor! and h!sical eNa'ination, co/ led +ith clinical eN erience, are the &est "/ides to deter'ine the eNtent of the e)al/ation. If se tice'ia cannot &e reasona&l! eNcl/ded on clinical "ro/nds, a &lood c/lt/re sho/ld &e o&tained and e' iric anti&iotics ad'inistered. Ce atos leno'e"al!, Pa/ndice, and etechiae are classic si"ns of neonatal infection &/t re resent late 'anifestations. *tre tococcal .isease In the 4>2$s, Gro/ B ^`-he'ol!tic stre tococci infections e'er"ed a leadin" infectio/s ca/se of 'or&idit! and 'ortalit! in the Enited *tates 0>$,>45. B! the 4>8$s, GB* +ere the 'ost co''on "ra'- ositi)e &acteria isolated fro' &lood of infants +ith se tice'ia in North A'erica 0>25. Altho/"h control 'eas/res s/ch as intra art/' anti&iotic thera ! +hich +ere in +ides read ractice in the 4>>$s ha)e red/ced the incidence of earl! onset Gro/ B stre to-coccal 0GB*5 disease,

GB* re'ains an i' ortant ca/se of neonatal se sis. GB* acco/nts for 4$? to J$? of se sis cases occ/rrin" in the first +eeH of life 01,>1,>J5. In the 'id 4>8$s, clinical trials de'onstrated that ad'inisterin" intra art/' intra)eno/s anti&iotics co/ld re)ent earl! onset neonatal GB* se sis 0><5. In res onse to these findin"s, the A'erican Acade'! of Pediatrics in 4>>2 ro)ided "/idelines reco''endin" intra art/' anti&iotic ro h!laNis 0IAP5 of selected GB* carriers 0>%5. In 4>>%, +ith additional data and the colla&orati)e efforts of clinicians, researchers, rofessional or"ani8ations and the /&lic health co''/nit!, the Centers for .isease Control and Pre)ention 0C.C5 iss/ed consens/s "/idelines reco''endin" IAP to re)ent GB* 'aternal-infant trans'ission P.421> 0>2,>85. The 4>>% national "/idelines reco''ended that +o'en coloni8ed +ith GB* at 1< +eeHs or 'ore of "estation or +o'en +ith intra art/' risH factors 0deli)er! A12 +eeHs "estation, intra art/' te' erat/re abc4$$.J]Q]QF or r/ t/re of 'e'&ranes abc48 h5 sho/ld &e offered intra art/' che'o ro h!laNis. Additionall!, +o'en ha)in" a re)io/s infant +ith in)asi)e GB* disease or +o'en +ith GB* &acteri/ria d/rin" re"nanc! sho/ld also &e offered intra art/' che'o ro h!laNis. Beca/se of the ro/tine i' le'entation of IAP, the incidence of earl! onset neonatal infections decreased &! %< ercent, fro' 4.2 er 4$$$ li)e &irths in 4>>1 to $.% er 4$$$ in 4>>8 0>>5. :ith the decline in earl! onset GB* disease, there has &een a conco'itant rise in (. coli and a' icillin-resistant (. coli se sis in )er! lo+ &irth +ei"ht and reter' infants 0J5. The C.C and the A'erican Colle"e of ,&stetricians and G!necolo"ists ha)e reco''ended /ni)ersal screenin" at 1< or 'ore +eeHs of "estation and IAP for GB*-coloni8ed +o'en 04$$,4$45. The e ide'iolo"!, atho"enesis, and clinical feat/res of GB* disease ha)e &een defined 04$25. The or"anis' is a co''on inha&itant of the fe'ale "enital tract and can &e isolated fro' )a"inal and anorectal c/lt/res of as 'an! as 1<? of as!' to'atic re"nant +o'en 04$2,4$1,4$J,4$<5. RisH factors for 'aternal GB* coloni8ation incl/de lo+er arit!, hi"her fre7/enc! of interco/rse, '/lti le seN/al artners, and conc/rrent coloni8ation +ith Candida s 04$J5. Peri art/' GB * coloni8ation of the lo+er /ro"enital tract has &een associated +ith se)eral 'aternal co' lications incl/din" reter' la&or, re'at/re r/ t/re of 'e'&ranes, endo'etritis, chorioa'nionitis, /rinar! tract infection, intra art/' or ost art/' fe)er, late a&ortions, and in)asi)e infections, s/ch as &actere'ia or 'enin"itis 0<2,4$%5. The identical serot! e can &e isolated fre7/entl! fro' /rethral c/lt/res of the seN/al artners of these c/lt/re- ositi)e +o'en 04$25. Altho/"h 'ost infected re"nant +o'en ha)e nor'al, health! infants, 4? to 2? of re"nancies in)ol)in" 'aternal infection res/lt in still&irths or infants +ith neonatal disease. 9ertical trans'ission of "ro/ B *tre tococci occ/rs in a roNi'atel! <$? to 2$? of 'other-infant airs, res/ltin" in neonatal coloni8ation rates of fro' 8? to 2<?. Trans'ission is 'ost liHel! to occ/r a'on"

infants &orn to hea)il! coloni8ed 'others 04$85. The earl!-onset GB* s!ndro'e occ/rs +ithin the first 22 ho/rs of life 0'ean a"e of onset 2$ ho/rs5, and %<? of re orted cases in)ol)e re'at/re infants. There is often a histor! of other 'aternal o&stetric co' lications 0Ta&le J2-25 04$%5. ,nset is s/dden and follo+s a f/l'inant co/rse, +ith the ri'ar! foc/s of infla''ation in the l/n"s, altho/"h 'enin"itis can de)elo . Res irator! distress is the 'ost co''on initial si"n a'on" infants +ith earl! onset 'enin"itis 04$>5. A nea, h! otension, and disse'inated intra)asc/lar coa"/lation ca/se ra id deterioration and often lead to the atient's de'ise +ithin 2J ho/rs. It is diffic/lt to identif! the infant +ith res irator! distress ca/sed &! GB* infection, &eca/se in %$? of infected atients, the chest radio"ra h sho+s a retic/lo"ran/lar attern +ith air &roncho"ra's indistin"/isha&le fro' that seen +ith /nco' licated h!aline 'e'&rane disease. The 'ortalit! rate is a roNi'atel! %? and is in)ersel! correlated +ith &irth +ei"ht 044$,4445. All fi)e GB* serot! es ha)e &een incri'inated in earl!-onset disease in ro/"hl! si'ilar ro ortions. A si'ilar s!ndro'e has &een associated +ith "ro/ s . and G stre tococci 0442,4415. TAB-( J2-2 RisH factors for earl!-onset "ro/ B stre tococcal disease Pre'at/re .eli)er! -o+ Birth :ei"ht Increased inter)al &et+een 'e'&rane r/ t/re and deli)er! R/ t/re of 'e'&ranes &efore la&or onset A'nionitis and intra art/' fe)er Maternal "ro/ B stre tococcal recto)a"inal coloni8ation 0es eciall! hea)! coloni8ation5 African A'erican race @o/n" 0A2$ !r5 'aternal a"e Gro/ B stre tococcal &acteri/ria d/rin" c/rrent re"nanc! -o+ le)el of ca s/lar ol!saccharide t! e-s ecific anti&odies Pre)io/s still&irth or s ontaneo/s a&ortion M/lti le "estation Pre)io/s deli)er! of infant +ith "ro/ B stre tococcal disease Prolon"ed d/ration of intra/terine 'onitorin" Ada ted fro' *ch/chat A. ( ide'iolo"! of "ro/ B *tre tococcal disease in the Enited *tates: *hiftin" aradi"'s. Clin Micro&ial Re) 4>>86 44:J>2. A late-onset s!ndro'e ca/sed &! GB* or -. 'onoc!to"enes occ/rs 'ost fre7/entl! at 2 to J +eeHs of a"e, &/t it 'a! &e seen as late as 4% +eeHs. The onset is insidio/s6 oor feedin" and fe)er are the 'ost fre7/ent resentin" si"ns. A f/l'inant illness +ith ra id onset and ro"ressi)e deterioration occasionall! is enco/ntered 044J5. Menin"itis is seen in a roNi'atel! %$? of infants +ith the late-onset s!ndro'e, and GB* serot! e III acco/nts for a&o/t ><? of these cases 04$25. Rarel!, infants +ith late-onset 'enin"itis ca/sed &! GB* resent +ith h!droce hal/s. These infants 'a! a ear to ha)e /nco' licated h!droce hal/s +ith nor'al l/'&ar cere&ros inal fl/id 0C*F5. (Na'ination of )entric/lar fl/id re)eals leoc!tosis, and the or"anis' is reco)ered on c/lt/re. * inal fl/id c/lt/res of infants +ith 'enin"itis ca/sed &! "ra'- ositi)e or"anis's /s/all!

are sterile +ithin 2J to 1% ho/rs of thera !, and the 'ortalit! rate is 4$? to 4<?. A roNi'atel! 2$? of neonatal infections ca/sed &! GB* do not fit into the earl!- or late-onset s!ndro'es and eNtend o)er a &road clinical s ectr/' in)ol)in" 'an! different or"an s!ste's. *e)eral 'anifestations ha)e &een o&ser)ed 04$2,44<,44%5: Cell/litis *cal a&scess I' eti"o Fasciitis Breast a&scess Adenitis */ ra"lottitis ConP/ncti)itis ,r&ital cell/litis P.42J$

(th'oiditis ,titis 'edia Pne/'onia co' licated &! e' !e'a M!ocarditis (ndocarditis Ce atitis *e tic arthritis ,steo'!elitis B/rsitis Erinar! tract infection ,' halitis Peritonitis

As!' to'atic transient &actere'ia. The transient &actere'ia is re'arHa&le &eca/se these infants a ear clinicall! +ell and are c/lt/red &eca/se of a histor! of 'aternal o&stetric co' lications. A re eat &lood c/lt/re &efore the instit/tion of anti&iotic thera ! fre7/entl! is sterile. Both rela ses and reinfections can occ/r after in)asi)e GB* infections 04$25. Reasons for rela se 'a! incl/de an inade7/ate enicillin dose, a short d/ration of thera ! of the initial e isode, or /nreco"ni8ed foci of infection 0e."., endocarditis, &rain a&scess5. Reinfection can occ/r &eca/se of 'aternal GB* 'astitis 04425. Rifa' in 02$ '"TH"Td for J-2 da!s5 has &een /sed to eradicate GB* carria"e in infants +ith rec/rrent disease and is "i)en after co' letion of s!ste'ic enicillin thera ! 04425. Coa"/lase-Positi)e *ta h!lococcal .isease The ha"e "ro/ I *. a/re/s, +hich +as co''on in the late 4><$s, still eNists in so'e n/rseries and occasionall! ca/ses serio/s s!ste'ic neonatal disease. The atho"enicit! of this or"anis' is &ased on its a&ilit! to in)ade the sHin and '/sc/losHeletal s!ste', rod/cin" f/r/ncles, &reast a&scesses, adenitis, and osteo'!elitis. *e tice'ia /s/all! is secondar! to local in)asion. After *. a/re/s is reco)ered fro' &lood c/lt/res of neonates, a caref/l search sho/ld &e 'ade for a ri'ar! foc/s. *o'e "ro/ I *. a/re/s strains rod/ce toNic shocH s!ndro'e toNin-4, for'erl! Hno+n as enterotoNin F or !ro"enic toNin C, and ha)e ca/sed toNic shocH s!ndro'e in older neonates 0448,44>5. Clinical characteristics of this disease incl/de the s/dden onset of fe)er, diarrhea, shocH, '/co/s 'e'&rane h! ere'ia, and a diff/se er!the'ato/s 'ac/lar rash +ith s/&se7/ent des7/a'ation of the hands and feet, co''encin" on a&o/t the fifth or siNth da! of illness. In the earl! 4>2$s, ha"e "ro/ II coa"/lase- ositi)e sta h!lococci e'er"ed as a co''on ca/se of neonatal infection. Altho/"h this or"anis' 'a! &e in)asi)e, atho"enicit! de ends rinci all! on rod/ction of eNotoNins 0e."., eNfolatiati)e or e ider'ol!tic toNins A and B5. Co''on areas of ri'ar! infection incl/de the /'&ilical st/' , conP/ncti)a, and throat6 infection of a s/r"ical +o/nd has &een descri&ed 042$5. The eNfoliati)e toNins act on the 8ona "ran/losa of the e ider'is and ca/se e ider'al s littin" thro/"h acti)it! of the toNins on the des'oso'es 04245. Clinical disease 'a! taHe one of se)eral for's, incl/din" &/llo/s i' eti"o, toNic e ider'al necrol!sis 0Ritter disease5, and nonstre tococcal scarlatina. Collecti)el!, these diseases ha)e &een referred to as the eN anded scalded sHin s!ndro'e 0Fi". J2-45 04225.

Fi"/re J2-4 A 4$-da!-old Ca/casian &o! +ith sta h!lococcal scalded sHin s!ndro'e. Ce +as treated +ith fl/ids, oral dicloNacillin, and +o/nd care. Cis sHin healed co' letel! and +itho/t scarrin" +ithin 2 +eeHs of this hoto"ra h &ein" taHen. The initial findin" in Ritter disease is "enerali8ed er!the'a associated +ith ede'a and tenderness on al ation, /s/all! noticed &et+een da!s 1 and 4% of life 04215. After se)eral da!s, a distincti)e des7/a'ation of lar"e sheets of e ider'is occ/rs, +hich is different fro' the fine des7/a'ation o&ser)ed in the second and third +eeHs of stre tococcal scarlet fe)er. -ar"e flaccid &/llae co''onl! o&ser)ed in Ritter disease +ill, on r/ t/re, lea)e a tender, +ee in" er!the'ato/s &ase. *o'e infants 'a! a ear 7/ite toNic +ith the "enerali8ed for' of disease. A rare, con"enital for' of sta h!lococcal scalded sHin s!ndro'e has &een descri&ed 042J5. * read +ithin a n/rser! can occ/r, and its reco"nition +arrants the ro' t instit/tion of infection control 'eas/res to li'it the s read of the toNi"enic strain of *. a/re/s 042<5. E'&ilical )eno/s or arterial catheters and central )eno/s lines are +ellreco"ni8ed risH factors for sta h!lococcal &actere'ia. *. a/re/s is second onl! to coa"/lase-ne"ati)e sta h!lococci as a ca/se of catheter-related infections 042%5. The 'ortalit! rate for neonates +ith *. a/re/s &actere'ia is a&o/t 2$?. -B: infants are at hi"hest risH of death fro' this infection 04225. Coa"/lase-Ne"ati)e *ta h!lococcal .isease The isolation of coa"/lase-ne"ati)e sta h!lococci fro' &lood, C*F, or /rine of ne+&orns +ith clinical si"ns of se sis P.42J4

can &e si"nificant, and these &acteria sho/ld not &e dis'issed as conta'inants. ,f the at least 1$ reco"ni8ed coa"/lase-ne"ati)e sta h!lococcal s ecies, *. e ider'idis is clinicall! the 'ost si"nificant for neonates 0428,42>,41$5. (N erience indicates that these &acteria are res onsi&le for a&o/t 4$? to 22? of all cases of se sis in NICEs, &/t can acco/nt for as 'an! as J8? of late-onset se sis cases in 9-B: infants 01,>25 Coa"/lase-ne"ati)e sta h!lococcal infections are nosoco'ial in ori"in and res/lt in s/&stantiall! lon"er hos itali8ations for affected infants 0414,4125. RisH of infection +ith these or"anis's increases +ith decreasin" "estational a"e and &irth +ei"ht 0411,41J,41<,41%5. Clinical 'anifestations of coa"/lase-ne"ati)e sta h!lococcal infections are si'ilar to those ca/sed &! other atho"ens and incl/de a nea, &rad!cardia, te' erat/re insta&ilit! 0e."., h! other'ia, h! erther'ia5, res irator! distress 0e."., tach! nea, retractions, c!anosis5, GI 'anifestations 0e."., oor feedin", a&do'inal distention, &lood! stools5, lethar"!, and 'eta&olic acidosis 042,42>5. Clinical illnesses incl/de se tice'ia, 'enin"itis +ith or +itho/t C*F a&nor'alities, necroti8in" enterocolitis, ne/'onia, o' halitis, soft tiss/e a&scesses associated +ith ersistent &actere'ia, endocarditis, and scal a&scesses and osteo'!elitis at insertion sites of fetal 'onitorin" electrodes 0411,41J,41<,41%,412,418,41>,4J$,4J4,4J2,4J1,4JJ5. RisH factors for coa"/lase-ne"ati)e sta h!lococcal infections incl/de the resence of forei"n &odies, s/ch as central )eno/s lines, )entric/lo eritoneal sh/nts, or eritoneal dial!sis catheters, rior anti&iotic thera !, and intra)eno/s inf/sion of li id e'/lsions for n/tritional s/ ort 042>, 4J<,4J%5. The or"anis's tra)el alon" catheter tracHs fro' coloni8ation sites. The! e)ent/all! adhere to, and roliferate on, certain &ios!nthetic 'aterials and later ca/se local or s!ste'ic reactions. The 'echanis' &! +hich adherence occ/rs a ears initiall! to in)ol)e h!dro ho&ic and electrostatic interactions &et+een the &acteria and the &io ol!'ers 042>5. ,nce attached, a )isco/s eNo ol!saccharide referred to as sli'e is for'ed. *li'e co)ers the &acteria to for' a s/rface &iofil' that rotects the' fro' s/ch en)iron'ental factors as anti&iotics and host defenses altho/"h allo+in" contin/ed access to n/trition 042>5. The densit! of the &iofil' 'a! &e increased if the or"anis's are eN osed to s/&inhi&itor! concentrations of anti&iotics to +hich the! are s/sce ti&le 0e."., )anco'!cin5 04J25. *li'e a ears to inhi&it ne/tro hil che'otaNis and ha"oc!tosis and the l!' ho roliferati)e res onses of 'onon/clear cells to 'ito"ens 04J8,4J>5. *li'e- rod/cin" strains acco/nt for 'ost coa"/lase-ne"ati)e sta h!lococci isolated fro' infants +ith in)asi)e infections 041<5. Ineffecti)e o sono ha"oc!tosis as a res/lt of intrinsic deficiencies in neonatal host defenses contri&/tes to the increased s/sce ti&ilit! of -B: infants to infection +ith these or"anis's 04<$,4<45. Coa"/lase-ne"ati)e sta h!lococci rod/ce a )ariet! of toNins that 'a! ser)e as )ir/lence factors, incl/din" he'ol!sins, roteases, /rease, and fi&rinol!sin 0425. Most fecal isolates rod/ce a he'ol!sin that f/nctionall! and i''/nolo"icall! is identical to the delta toNin rod/ced &! *. a/re/s 04<25. This toNin ca/ses se)ere

'/cosal necrosis and he'orrha"e +hen inPected into li"ated infant rat &o+el loo s and 'a! la! a role in the atho"enesis of neonatal necroti8in" enterocolitis 04<1,4<J5. -isteria 'onoc!to"enes .isease The incidence of erinatal listeriosis decreased &! a&o/t <4? &et+een 4>8> and 4>>1, fro' 42.J to 8.% er 4$$,$$$ ersons !o/n"er than 4 !ear of a"e 04<<,4<%5. This red/ction +as related te' orall! +ith ind/str!, re"/lator!, and ed/cational efforts to a""ressi)el! enforce food 'onitorin" olicies. The atho"enesis of clinical diseases ca/sed &! -. 'onoc!to"enes is si'ilar to those ca/sed &! GB*. A f/l'inant, disse'inated disease 0"ran/lo'atosis infantise tica5 'a! occ/r d/rin" the first se)eral da!s of life. The atho"en is ac7/ired trans lacentall! or &! as iration at the ti'e of )a"inal deli)er!, and '/lti le or"an s!ste's 0e."., li)er, s leen, Hidne!s, l/n"s, &rain, and sHin5 are in)ol)ed6 1<? to <<? of infants die of their infection 04<2,4<85. The infant fre7/entl! resents +ith h! other'ia, lethar"!, and oor feedin". (arl! assa"e of 'econi/' in a re'at/re infant s/""ests -isteria infection 04<>5. A characteristic rash consistin" of s'all, sal'on-colored a /les scattered ri'aril! on the tr/nH can &e o&ser)ed in so'e infants. The chest roent"eno"ra' sho+s arench!'al infiltrates s/""esti)e of as iration ne/'onitis in 'ost infants. A 'iliar!-t! e of &roncho ne/'onia can &e seen in so'e cases. -isteria serot! es Ia, I&, and I9& rod/ce the earl! onset disease, +hereas serot! e I9& is the redo'inant t! e in late-onset 'enin"itic disease 04%$5. A dela!ed for' of neonatal listeriosis occ/rs d/rin" the second thro/"h fifth +eeHs of life and ri'aril! in)ol)es the 'enin"es 04%$,4%45. The infected infant /s/all! is the f/ll-ter' rod/ct of an /nco' licated la&or and deli)er!. ,nset of s!' to's and si"ns is relati)el! insidio/s and indistin"/isha&le fro' those o&ser)ed +ith 'enin"itis ca/sed &! other atho"ens. The so/rce of the or"anis' in late-onset disease is /nclear. Altho/"h ac7/isition of -isteria 'a! occ/r d/rin" assa"e thro/"h an infected &irth canal, it a ears that 'ost cases res/lt fro' ost art/' hori8ontal s read. In fa)or of the latter ro/te of infection are se)eral re orted cl/sters of neonatal listeriosis and the de'onstration of cross-infections &et+een ne+&orns /sin" en8!'e electro horetic t! in" and .NA fin"er rintin" 04<2,4%2,4%1,4%J5. The eri heral le/Hoc!te co/nt /s/all! sho+s a &risH le/Hoc!tosis, +ith a redo'inance of ol!'or hon/clear le/Hoc!tes in the differential co/nt 04%<5. A si"nificant ele)ation in the n/'&er of 'onoc!tes, to 2? to 24? of the total le/Hoc!te co/nt, has &een doc/'ented on ad'ission la&orator! e)al/ation of infected infants. A 'onoc!tosis of this 'a"nit/de can &e de'onstrated in 'ost re'ainin" infants on re etiti)e testin" of the eri heral le/Hoc!te co/nt, &/t 'onoc!tes t! icall! are not fo/nd in the s inal fl/id of infants infected +ith -. 'onoc!to"enes. Pol!'or hon/clear le/Hoc!tes redo'inate in a&o/t 2<? of cases, +ith a relati)e l!' hoc!tosis in the

P.42J2 re'ainin" 2<?. In contrast, ad/lts +ith -isteria 'enin"oence halitis 'a! ha)e C*F 'onoc!tosis of 8$? to >$? 04<85. As +ith other !o"enic 'enin"itides, h! o"l!corrhachia and ele)ated rotein concentrations are fre7/ent findin"s. (Na'ination of the stained s'ear of s inal fl/id has not &een re+ardin" in 'ore than <$? of cases. This is a reflection of the relati)el! lo+ concentrations of or"anis's in the fl/id. The &acteriolo"! la&orator! sho/ld &e fore+arned of the clinical s/s icion of -isteria 'enin"itis, &eca/se these 'icroor"anis's occasionall! are discarded as conta'inants &eca/se of their tinctorial and 'or holo"ic si'ilarities +ith di htheroids. ,)erni"ht refri"eration of s inal fl/id s eci'ens fre7/entl! enhances "ro+th of this or"anis'. (nterococcal Infection Gro/ . stre tococci +ere for'erl! di)ided into enterococcal and nonenterococcal t! es. The enterococci are no+ incl/ded in the ne+ "en/s (nterococc/s6 'ost neonatal infections are ca/sed &! (nterococc/s faecalis and, to a lesser eNtent, &! (. faeci/' 04%%,4%2,4%85. (arl! onset enterococcal disease 0less than 2 da!s of a"e5 is relati)el! 'ild and resents clinicall! +ith res irator! distress or diarrhea. No associations +ith /nderl!in" conditions, in)asi)e roced/res, or 'aternal o&stetric co' lications ha)e &een o&ser)ed 04%>5. -ate-onset disease 0abc2 da!s of a"e5 'ost co''onl! afflicts lo+-&irth +ei"ht infants +ith co' licated clinical ro&le's that often re7/ire s/r"ical roced/res 0e."., &o+el resection5, central )eno/s catheters, or rior treat'ent +ith anti'icro&ials. Clinical 'anifestations of lateonset disease incl/de a nea, &rad!cardia, circ/lator! fail/re, 'enin"itis, ne/'onia, scal a&scesses, catheter-related &actere'ia, and necroti8in" enterocolitis-associated se tice'ia 04%>5. A&o/t 2$? of enterococcal &lood isolates re resent sHin conta'ination6 clinical correlation is needed to differentiate conta'ination fro' tr/e infection 04%25. (nterococci can s read ra idl! +ithin a n/rser! 042$5. Nosoco'ial o/t&reaHs of enterococcal se tice'ia in NICEs are +ell doc/'ented 04%8,4245. The 'ortalit! rate is esti'ated at %? to 44?, &/t it can &e as hi"h as 42? in infants +ith necroti8in" enterocolitis-associated se tice'ia 04%2,4%>5. The i' ortance of identif!in" (nterococc/s as the etiolo"ic a"ent in se tice'ia ri'aril! relates to selection of ro er anti'icro&ial a"ents. The enterococci are 'oderatel! resistant to enicillin alone, as a res/lt of certain ro erties of their enicillin-&indin" roteins 04%2,4225. *o'e enterococcal strains ha)e ac7/ired ne+ 'echanis's of anti&iotic resistance that incl/de ^`-lacta'ase rod/ction and hi"h-le)el a'ino"l!coside resistance 0'ini'al inhi&itor! concentrations ;MIC= abc2,$$$ ]f"T'-5 042$,421,42J5. *trains resistant to the "l!co e tides )anco'!cin and teico lanin 0"l!co e tide-resistant enterococci5 +ere first descri&ed in 4>82 and since ha)e e'er"ed as 'aPor nosoco'ial atho"ens

042<,42%,422,428,42>5. Nonenterococcal "ro/ . stre tococci contin/e to &e s/sce ti&le to enicillin 04%25. Gra'-Ne"ati)e Bacterial Infection In North A'erica, (. coli is the 'ost co''on "ra'-ne"ati)e or"anis' ca/sin" se tice'ia d/rin" the neonatal eriod. Lle&siella and (ntero&acter strains are second 01,>25. In contradistinction to illness ca/sed &! GB* and -. 'onoc!to"enes, (. coli infections do not fit into distinct clinical s!ndro'es of earl!- and late-onset disease. A roNi'atel! J$? of (. coli strains ca/sin" se tice'ia ossess L4 ca s/lar anti"en, and strains identical +ith those isolated fro' &lood c/lt/res /s/all! can &e identified in the atient's naso har!nN or rectal c/lt/res. The clinical feat/res of (. coli se sis "enerall! are si'ilar to those o&ser)ed in infants +ith disease ca/sed &! other atho"ens. Res irator! distress is noted in a&o/t 21? +ith (. coli se sis occ/rrin" d/rin" the first +eeH of life 048$5. -ocali8ed (. coli infections ha)e incl/ded &reast a&scess, cell/litis, ne/'onia, l/n" a&scess, e' !e'a, osteo'!elitis, se tic arthritis, /rinar! tract infection, ascendin" cholan"itis, and otitis 'edia. An increase in the ro ortion of neonatal (. coli se sis cases ca/sed &! a' icillin-resistant strains has &een noted &! se)eral in)esti"ators 01,48$,4845 This shift occ/rred as 'aternal intra art/' ro h!laNis for the re)ention of earl! onset GB* se sis +as &ein" i' le'ented 'ore +idel! &! o&stetricians at these 'edical centers. Most deaths +ere seen in neonates infected +ith a' icillin-resistant (. coli strains. Pse/do'onas se tice'ia 'a! resent +ith a characteristic )iolaceo/s a /lar lesion or lesions that, after se)eral da!s, de)elo central necrosis. Altho/"h these sHin lesions 'ost co''onl! are seen in Pse/do'onas infection, the!'a! &e associated +ith other or"anis's 04825. Pse/do'onas t! icall! is enco/ntered in late-onset se sis, altho/"h occasional ne+&orns +ith an earl!-onset for' of this infection ha)e &een re orted. Neonatal infections ca/sed &! C. infl/en8ae &iot! e I9 ha)e increased in fre7/enc! in the last 2$ !ears and c/rrentl! acco/nt for a&o/t 8? of earl!-onset se sis in )er! -B: infants 0J$4-4,<$$ "5 01,4815. These strains are nont! ea&le, ha)e a distinct '/ltiloc/s en8!'e "enot! e re)ealed &! clonal anal!sis, eN ress eritricho/s fi'&riae and a )ariant P% o/ter 'e'&rane rotein, and ha)e a characteristic o/ter 'e'&rane electro horetic rofile. Genetic anal!sis s/""ests that these strains re resent a cr! tic "enos ecies onl! distantl! related to C. infl/en8ae or Cae'o hil/s hae'ol!tic/s 0481,48J5. Anaero&ic Infections Anaero&es acco/nt for / to 2<? of all &acteria isolated fro' &lood c/lt/res of neonates +ith s/s ected se tice'ia in )ario/s st/dies 048<,48%,482,4885. A recent retros ecti)e re)ie+ of neonatal &acterial infections s/""ests that the incidence of anaero&ic isolates is a&o/t 4? 048>5. Bacteroides s , ri'aril! Bacteroides fra"ilis, and clostridia are 'ost co''onl! reco)ered 04825.

Pe tostre tococc/s s , 9eillonella s , Pro ioni&acteri/rn acnes, (/&acteri/rn s , and F/so&acteri/' s occ/r relati)el! infre7/entl!. Anaero&es are fo/nd P.42J1 'iNed in c/lt/res +ith aero&ic &acteria in a&o/t one-third of cases. Clinical illnesses incl/de transient &actere'ia, f/l'inant se tice'ia, osto erati)e infections, and intra/terine death associated +ith se tic a&ortion 048<5. -ocali8ed diseases s/ch as o' halitis, cell/litis, and necroti8in" fasciitis are seen co''onl! +ith clostridia 04>$5. Conditions redis osin" to anaero&ic se tice'ia incl/de rolon"ed r/ t/re of 'e'&ranes, chorioa'nionitis, re'at/rit!, and GI disease. Anaero&es isolated fro' &lood +ithin the first 2 da!s of life are /s/all! "ra'ositi)e and enicillin G-s/sce ti&le, &/t those isolated fro' older ne+&orns tend to &e "ra'-ne"ati)e and enicillin G-resistant 048%5. Gra'- ositi)e anaero&es are 'ore liHel! to &e reco)ered fro' &lood of infants +ith se sis associated +ith chorioa'nionitis, +hereas "ra'-ne"ati)e anaero&es redo'inate in necroti8in" enterocolitis-associated &actere'ia 048%5. The 'ortalit! rates for re orted cases of anaero&ic se tice'ia are a&o/t 1<? for illnesses ca/sed &! Bacteroides s and 42? for other anaero&es 04825. Genital M!co las'as M. ho'inis and E. /real!tic/' occasionall! are isolated fro' the &lood of neonates +ith se sis. Cassell and collea"/es 01%5 o&ser)ed conco'itant &actere'ia in J$? and 2%? of reter' infants +ith ositi)e endotracheal c/lt/res for M. ho'inis and E. /real!tic/', res ecti)el!. ,ther in)esti"ators +ere /na&le to reco)er "enital '!co las'as fro' the &lood or C*F of neonates +ith s/s ected se sis 04>4- 4>25. An association &et+een ersistent /l'onar! h! ertension and E. /real!tic/' se sis and ne/'onia has &een o&ser)ed 04>15. F/n"al Infections F/n"al se sis occ/rs in as 'an! as 42? of -B: infants 015. Most cases are as a res/lt of Candida s , artic/larl! C. al&icans 04>J,4><,4>%5. C. tro icalis, C. ara silosis, C. l/sitaniae, and C. "la&rata also ca/se s!ste'ic candidiasis 04>%5. Con"enital candidiasis is /nco''on and res/lts fro' ascendin" infection thro/"h intact 'e'&ranes. It /s/all! 'anifests +ith earl! sHin lesions 0e."., 'ac/lo a /lar rash, /st/les, )esicles, des7/a'ation, sHin a&scesses5, &/t disse'inated and life-threatenin" infections can occ/r 04>2,4>85. The incidence of candide'ia in NICEs is increasin" steadil!. In one s/ch /nit in NorfolH, 9ir"inia, the rate of candide'ia increased o)er 44-fold in the 4<-!ear eriod &et+een 4>84 and 4>><. Additionall!, C. ara silosis +as res onsi&le for %$? of all candide'ias d/rin" the last < !ears of the st/d! eriod 04>>5.

RisH factors for late-onset s!ste'ic candidiasis incl/de re'at/rit!, lo+ &irth +ei"ht, /se of &road-s ectr/' anti'icro&ial a"ents, C2 &locHer thera !, steroid thera !, central )asc/lar catheters, arenteral h! erali'entation, intrali id inf/sions, rolon"ed endotracheal int/&ation, necroti8in" enterocolitis, and i''/nolo"ic i''at/rit! 02$$,2$4,2$25. The 'ost i' ortant of these factors a ears to &e the n/'&er of rior anti&iotics and the d/ration of thera ! 02$1,2$J5. -B: infants in +ho' '/coc/taneo/s candidiasis de)elo s are at considera&le risH of s/&se7/ent in)asi)e disease 02$1,2$J,2$<5. Infants +ith in)asi)e candidiasis ca/sed &! C. al&icans are 'ore liHel! to ha)e antecedent candidal thr/sh or erineal der'atitis and to die of their infection than neonates +ith se)ere C. ara silosis infections 04>>,2$%5. Clinical 'anifestations )ar! and are indistin"/isha&le fro' those ca/sed &! other atho"ens. A f/n"al ca/se for se sis sho/ld &e considered stron"l! in an infant +ei"hin" less than 4,<$$ " +ho has &een hos itali8ed for a rolon"ed eriod, is recei)in" arenteral h! erali'entation thro/"h a central )asc/lar catheter, and re)io/sl! has &een treated +ith '/lti le anti&iotics6 a histor! of GI disease or s/r"er! adds to the clinical s/s icion. .iseases ca/sed &! Candida s incl/de, &/t are not li'ited to, ne/'onia, endocarditis, endo hthal'itis, 'enin"itis, cere&ral a&scesses, !elone hritis, renal '!ceto'a 0f/n"al &alls5, eritonitis, he atos lenic a&scesses, arthritis, and osteo'!elitis 04>J,2$2,2$8,2$>,24$,244,242,241,24J,24<5. Malasse8ia f/rf/r ca/ses in)asi)e neonatal f/n"al disease. Most infections in)ol)e chronicall! ill re'at/re infants +ho are recei)in" li id e'/lsions thro/"h a central )eno/s catheter 024%5. The 'ost co''onl! re orted resentin" si"ns incl/de fe)er 0<$?5 and res irator! distress 0<$?5. Patholo"ic anal!sis re)eals '!cotic thro'&i aro/nd catheter ti s, endocardial )e"etations, and l/n" lesions that incl/de '!cotic e'&oli +ith occl/sion of /l'onar! arteries, se tic thro'&i, /l'onar! )asc/litis, and al)eolitis 024%5. In)ol)e'ent of other or"ans is /nco''on. Malasse8ia ach!der'atis is a recentl! reco"ni8ed h/'an atho"en that has &een incri'inated in NICE o/t&reaHs of &loodstrea', /rinar! tract, and central ner)o/s s!ste' infections. In one re orted o/t&reaH, the so/rce of M. ach!der'atis +as the conta'inated hands of health care +orHers +ho +ere coloni8ed fro' their et do"s at ho'e 02425. *!ste'ic infections as a res/lt of other f/n"i s/ch as Tor/lo sis "la&rata, Cansen /la ano'ala, As er"ill/s s , Cr! tococc/s neofor'ans, Coccidioides i''itis, Blasto'!ces s , and Trichos oron &ei"elii are rare 0248,24>,22$,2245. -a&orator! Tests and Findin"s *ince the earl! 4>2$s, se)eral screenin" tests and scorin" s!ste's ha)e &een descri&ed that are /r orted to aid the h!sician in 'aHin" the dia"nosis of neonatal infection. Altho/"h a fe+ are hel f/l in identif!in" the infant at hi"h risH of de)elo in" infection, the dia"nosis of se tice'ia can &e 'ade onl! &! reco)er! of the or"anis' fro' &lood c/lt/res or other nor'all! sterile &od! fl/ids 0224,2225. It is i' erati)e that these c/lt/res &e o&tained &! strict ase tic techni7/e. Blood sho/ld &e o&tained fro' a eri heral )ein rather than fro' the /'&ilical )essels, the o/ter se)eral 'illi'eters of +hich are conta'inated

fre7/entl! +ith &acteria. Fe'oral )ein as iration 'a! res/lt in c/lt/res conta'inated +ith colifor' or"anis's fro' the erine/'. CeelsticH sa' les ha)e lo+ sensiti)ities. The sHin P.42JJ o)erl!in" the )ein to &e /nct/red sho/ld &e cleansed +ith an antise tic sol/tion, s/ch as an iodo hor, and allo+ed to dr! for 'aNi'al antise tic effect. The a'o/nt of &lood dra+n is critical6 4 to 2 '- of &lood is re7/ired for o ti'al res/lts 02215. The sensiti)it! of a sin"le &lood c/lt/re in identif!in" se tice'ia is onl! 8$? 02225. ,&tainin" &lood c/lt/res fro' '/lti le sites 'a! enhance the !ield and aid in identif!in" false- ositi)e res/lts 022J5. e/antitati)e &lood c/lt/res, if a)aila&le, are hel f/l in differentiatin" tr/e atho"ens fro' c/lt/re conta'inants 022<,22%5. Ro/tine &lood c/lt/re 'ethods are s/fficient for the detection of Candida se tice'ia 022256 ho+e)er, if M. f/rf/r is a s/s ected atho"en, the 'icro&iolo"! la&orator! sho/ld &e alerted so that &lood can &e inoc/lated onto s ecial 'edia that ro)ide for the or"anis''s a&sol/te n/tritional re7/ire'ent for 'edi/'-chain fatt! acids 04>%5. It fre7/entl! is hel f/l to o&tain c/lt/res of other sites &efore initiatin" anti'icro&ial thera !. For eNa' le, erc/taneo/s &ladder as iration of /rine for c/lt/re can &e hel f/l in identif!in" the /rinar! tract as the foc/s of infection. This is artic/larl! tr/e for illness occ/rrin" after the third ostnatal da!. Naso har!n"eal, sHin, /'&ilical cord, "astric, and rectal c/lt/res fre7/entl! are ositi)e in the earl! se tice'ic for' of listeriosis and GB* disease. Co+e)er, these coloni8ation sites are not redicti)e of the ca/se of &loodstrea' infection and sho/ld not &e /sed to "/ide anti'icro&ial thera ! 02285. All clinicall! sta&le infants +ith s/s ected se tice'ia sho/ld ha)e C*F o&tained for eNa'ination and c/lt/re &efore thera !. This ractice has &een challen"ed for infants !o/n"er than 2 da!s of a"e &eca/se of its lo+ !ield6 the !ield fro' a l/'&ar /nct/re is '/ch hi"her +hen erfor'ed on infants older than 4 +eeH of a"e 022>,21$,214,212,211,21J,21<5. Practitioners o tin" to fore"o erfor'in" a l/'&ar /nct/re for infants +ith s/s ected earl! onset se sis sho/ld antici ate that, on occasion, the dia"nosis of 'enin"itis +ill &e dela!ed or 'issed &eca/se not all ne+&orns +ith &acterial 'enin"itis ha)e ositi)e &lood c/lt/re res/lts 021J,21%5. The eri heral le/Hoc!te co/nt is the 'ost fre7/entl! /sed indirect indicator of &acterial infection. After correction for the n/cleated er!throc!te co/nt, the total a&sol/te ne/tro hil co/nt and the ratio of i''at/re to total ne/tro hilic for's are co' ared +ith nor'al standard )al/es for a"e. In the a&sence of 'aternal h! ertension, se)ere as h!Nia, eri)entric/lar he'orrha"e, 'aternal fe)er, or he'ol!tic disease, a&sol/te total ne/tro enia and an ele)ated ratio of i''at/re to total ne/tro hilic for's s/""est &acterial infection 0212,2185. Infants &orn in hi"h-altit/de areas ha)e hi"her total and i''at/re ne/tro hil co/nts 021>5. :ide interreader differences in &and ne/tro hil identification ha)e &een o&ser)ed, there&! li'itin" the /tilit! of the i''at/re to total ne/tro hil ratio in

act/al clinical ractice 02J$5. Re eatin" co' lete &lood co/nts +ithin 2J ho/rs of &irth 'a! enhance the )al/e of the test as a screen for se sis hi"h-risH infants 021>5. In the a&sence of clinical si"ns of se sis, le/Hoc!te )al/es are /nliHel! to r/le o/t infection. In a ros ecti)e, o&ser)ational st/d! of 8<% near-ter' or ter' neonates +itho/t clinical si"ns of se sis +ho +ere eN osed to 'aternal chorioa'nionitis, >>? had at least 4 a&nor'al ne/tro hil )al/e &ased on /&lished reference )al/es 0212,218,21>,2J$,2J4,2J25. *in"le or serial ne/tro hil )al/es did not assist in the dia"nosis of earl! onset infection or deter'ination of d/ration of anti&iotic thera ! in the at risH &/t c/lt/re-ne"ati)e infants 02J15. Gastric as irate stains and c/lt/re, er!throc!te sedi'entation rate, C-reacti)e rotein 0CRP5, and the nitro&l/e tetra8oli/' test ha)e not ro)ed /sef/l as indicators of &acterial infection, altho/"h in co'&ination these tests 'a! offer so'e "/idance 02JJ5. CRP )al/es a ear not to &e infl/enced &! erinatal as h!Nia, h! er&ilir/&ine'ia, eri)entric/lar he'orrha"e, or res irator! distress s!ndro'e 02J<5. *erial CRP 'eas/re'ents 'a! &e hel f/l in identif!in" infants not liHel! to &e infected and in +ho' anti&iotics can &e safel! sto ed 02J%5. The detection of interle/Hin-% 0I--%5 in ser/', es eciall! in conP/nction +ith an ele)ated CRP or rocalcitonin 'eas/re'ent, 'a! &e /sef/l in the earl! dia"nosis of neonatal infection 02J1,2JJ,2J<,2J%,2J2,2J8,2J>,2<$,2<4,2<25. The le)els of "ran/loc!te colon!-sti'/latin" factor, ne/tro hil C.44& eN ression, circ/latin" intracell/lar adhesion 'olec/le-4, interle/Hin-4 rece tor anta"onist 0I--4ra5, ser/' rocalcitonin, and interle/Hin-8 are all ele)ated in ne+&orns +ith se sis, &/t ho+ these la&orator! findin"s can &est &e /tili8ed for the dia"nosis of neonatal se sis is !et to &e defined 02J2,2J>,2<$,2<1,2<J5. In one st/d!, I--4ra and I--% le)els +ere fo/nd to &e ele)ated 0a 4<-fold 'edian 'aNi'al increase5 2 da!s &efore a dia"nosis of se sis +as 'ade 02<$5. .etection of the sol/&le anti"ens of (. coli Ll, GB*, C. infl/en8ae t! e &, N. 'enin"itidis, and *. ne/'oniae &! lateN article a""l/tination 0-PA5 is /sef/l for identif!in" the infant infected +ith these atho"ens. The a&sence of anti"en does not r/le o/t infection &! these or"anis's. */&stantial sensiti)it! differences ha)e &een fo/nd a'on" the co''erciall! a)aila&le -PA assa!s for GB* anti"en 02<<5. False- ositi)e -PA test res/lts for GB* in /rine s eci'ens can res/lt fro' conta'ination of &a" s eci'ens +ith these &acteria fro' erineal and rectal coloni8ation, cross-reactin" anti"ens, or a&sor tion of anti"en fro' the GI tract 02<%,2<25. *i'ilar false- ositi)e test res/lts 'a! &e o&tained for the other &acteria. Ra id dia"nosis of in)asi)e Candida infection &! detection of its circ/latin" cell +all 0e."., 'annan5, c!to las'ic 0e."., enolase5, or heat-la&ile anti"ens is ossi&le, altho/"h the relia&ilit! of these tests is !et to &e ro)ed 02<85. Thera ! After se tice'ia is s/s ected, s/ita&le c/lt/res sho/ld &e o&tained and thera ! +ith a' icillin and an a'ino"l!coside started i''ediatel!. If 'enin"itis has &een eNcl/ded, a' icillin is ad'inistered intra)eno/sl! or intra'/sc/larl! in

indi)id/al doses of <$ '"TH" "i)en e)er! 42 ho/rs, or 8 ho/rs for infants +ei"hin" A2,$$$ " or g2,$$$ ", res ecti)el!. The fre7/enc! is increased 1 or J ti'es dail! for infants 4 to J +eeHs of a"e, de endin" on their &irth +ei"ht. The selection of the a'ino"l!coside P.42J< anti&iotic sho/ld &e &ased on anti'icro&ial s/sce ti&ilities of enteric or"anis's isolated fro' infants in each n/rser!. Genta'icin is the dr/" of choice for treat'ent of infections ca/sed &! s/sce ti&le "ra'-ne"ati)e or"anis's and is ad'inistered intra)eno/sl! or intra'/sc/larl! in a dosa"e of J to < '"TH" at 2J to J8 ho/r inter)als de endin" on the infant's ost'enstr/al and ostnatal a"e 02<>5. A'ino"l!coside-resistant (. coli ha)e &een enco/ntered in so'e n/rseries in North A'erica. In these n/rseries or in an infant fro' +ho' an isolate is sho+n to &e resistant to Hana'!cin or "enta'icin, a'iHacin or cefotaNi'e sho/ld &e /sed. *t/dies ha)e de'onstrated no si"nificant ototoNicit! in infants and children +ho +ere treated in the neonatal eriod +ith Hana'!cin or "enta'icin 0J85. Co+e)er, in re'at/re infants and in those recei)in" these dr/"s for rolon"ed eriods, &rainste' e)oHed res onse a/dio'etr! sho/ld &e erfor'ed +hene)er ossi&le. *er/' concentrations of the a'ino"l!cosides sho/ld &e 'onitored in -B: re'at/re infants &eca/se of erratic a&sor tion and eli'ination of the dr/"s in these infants. Altho/"h cefotaNi'e sho/ld not &e /sed ro/tinel! for initial e' iric thera ! of neonatal se sis, it is an effecti)e a"ent +hen /sed alone or co'&ined +ith an a'ino"l!coside for infections ca/sed &! colifor' &acilli. :hen the t! e of sHin lesions or historic eN erience s/""ests the ossi&ilit! of Pse/do'onas infection, cefta8idi'e, i eracillin or ticarcillin +ith or +itho/t an a'ino"l!coside is the thera ! of choice. Altho/"h not a ro)ed for /se in neonates &! the Food and .r/" Ad'inistration, +e ha)e s/ccessf/ll! /sed ticarcillin-cla)/lanate and i eracillin-ta8o&acta' for treat'ent of se sis ca/sed &! '/ltiresistant "ra'-ne"ati)e enteric &acilli, Pse/do'onas, and anaero&ic &acteria. If *. a/re/s se sis is s/s ected &/t not ro)ed, arenteral 'ethicillin or nafcillin sho/ld &e s/&stit/ted for enicillin or a' icillin, &eca/se a roNi'atel! 8$? of these sta h!lococci +ill &e enicillin-resistant. Altho/"h "enta'icin and Hana'!cin ossess acti)it! a"ainst 'ost sta h!lococci, these a"ents cannot &e reco''ended &eca/se there are no st/dies of their efficac! in neonatal sta h!lococcal disease. For disease ca/sed &! coa"/lase ne"ati)e sta h!lococci or '/ltiresistant *. a/re/s strains, )anco'!cin is the referred thera !. PeaH and tro/"h ser/' )anco'!cin concentrations sho/ld &e 'onitored &eca/se of the dr/"'s narro+ thera e/tic indeN. After the atho"en is identified and its anti'icro&ial s/sce ti&ilities are Hno+n, the 'ost a ro riate dr/" or dr/"s sho/ld &e selected. As a "eneral r/le,

"enta'icin alone or in co'&ination +ith a' icillin, or cefotaNi'e alone or in co'&ination +ith an a'ino"l!coside, sho/ld &e /sed for s/sce ti&le (. coli, Lle&siella s , and (ntero&acter s 6 a'iHacin alone or in co'&ination +ith cefotaNi'e for "enta'icin-resistant colifor' &acteria6 cefta8idi'e, i eracillin, ticarcillin, i ercillin-ta8o&acta', or ticarcillin-cla)/lanate, +ith or +itho/t an a'ino"l!coside, for Pse/do'onas6 a' icillin alone or in co'&ination +ith an a'ino"l!coside for P. 'ira&ilis, enterococci, and -. 'onoc!to"enes6 and enicillin for other "ra'- ositi)e or"anis's, eNce t for enicillin-resistant *. a/re/s, for +hich 'ethicillin or nafcillin is the dr/" of choice. 9anco'!cin is /sed for coa"/lase-ne"ati)e sta h!lococci and MR*A. Rarel!, coa"/lase-ne"ati)e sta h!lococcal strains that are resistant to )anco'!cin can e'er"e d/rin" treat'ent +ith this a"ent 02%$5. *. a/re/s strains +ith red/ced s/sce ti&ilit! to )anco'!cin 0"l!co e tide-inter'ediate *. a/re/s ;GI*A=5 ha)e &een isolated fro' a fe+ atients +ith a )ariet! of infections. The first s/ch clinical isolate +as descri&ed in a J-'onth-old Ma anese infant +ith a nosoco'ial s/r"ical site infection 02%4,2%25. No GI*A strains ha)e &een identified in ne+&orns to date. Treat'ent of GI*A-related infections "enerall! re7/ires the /se of dr/"s s/ch as line8olid. The MIC and 'ini'al &actericidal concentration 0MBC5 of enicillin and a' icillin sho/ld &e deter'ined for GB* &eca/se a s'all ercenta"e of these or"anis's are tolerant 0i.e., ha)e an MBC to MIC ratio "reater than 125 to these anti&iotics 02%15. These strains are &est treated +ith a enicillin-a'ino"l!coside co'&ination. Penicillin resistant and )anco'!cin-tolerant ne/'ococci ha)e &een re orted in ne+&orn infants in France &/t not !et in North A'erica 02%J5. The thera e/tic o tions for )anco'!cin-resistant enterococcal infections in neonates are serio/sl! li'ited. *o'e strains 'a! &e s/sce ti&le to a co'&ination of enicillin or a' icillin and an a'ino"l!coside. Chlora'- henicol or tetrac!clines 'a! &e effecti)e a"ainst so'e strains, &/t these dr/"s ha)e serio/s toNicities for neonates. Nitrof/rantoin is acti)e a"ainst 'an! )anco'!cin-resistant enterococcal strains and has &een /sed to treat enterococcal /rinar! tract infections in ad/lts. .alfo ristin-7/in/ ristin is a ro)ed for /se in ad/lts, &/t there are no data on its /se in infants. *e)eral in)esti"ational Hetolides, oNa8olidinones, "l!c!lc!clines, and e)en ne+er se'is!nthetic "l!co e tides +ith in )itro acti)ities a"ainst )anco'!cin-resistant enterococci are &ein" e)al/ated 02%<5. E /real!tic/' infections are treated +ith er!thro'!cin 02%%5. Three classes of antif/n"als are co''onl! /sed in the treat'ent of s!ste'ic f/n"al infections in neonates: the ol!ene 'acrolides 0a' hotericin B ;deoN!cholate and li id re arations=56 the a8oles 0fl/cona8ole56 and the fl/orinated !ri'idines 0fl/c!tosine5. The dr/" of choice for s!ste'ic f/n"al infections is a' hotericin B, +ith or +itho/t fl/c!tosine 04>J,2%25. The half-life and ser/' concentrations of a' hotericin B are hi"hl! )aria&le d/rin" the neonatal eriod 02%85. The dr/" a ears to &e &etter tolerated &! infants than older children and ad/lts, &/t renal and he atic f/nctions sho/ld &e 'onitored caref/ll! 04>J,2%>5. The o ti'al dail! dosa"e of a' hotericin B is not /ni)ersall! a"reed on. The 'ost co''onl! /sed dosa"e re"i'en is to &e"in +ith $.< '"TH" of the dr/" on the first da! and, if tolerated, to increase the dail! dosa"e to 4.$

'"TH" &! the second or third da! of treat'ent. The c/'/lati)e dosa"e of a' hotericin B needed for the ade7/ate treat'ent of s!ste'ic Candida infection is not +ell defined, &/t it is esti'ated to &e 2$ to 1$ '"TH" 04>J5. Resistance to a' hotericin B a'on" Candida s ecies is not a 'aPor clinical ro&le' 022$5. A' hotericin B fre7/entl! is co'&ined +ith fl/c!tosine for the treat'ent of central ner)o/s s!ste' f/n"al infection &eca/se of fl/c!tosine's P.42J% eNcellent C*F enetration and the in )itro s!ner"! of this dr/" co'&ination a"ainst Candida. GI intolerance, '!elos/ ression, and he atotoNicit! are co''on side effects of fl/c!tosine 04>J5. (N erience +ith the /se of li oso'al a' hotericin B re arations in ne+&orns is "ro+in" 0224,222,221,22J,22<,22%5. -inder and collea"/es 022<5 co' ared the effecti)eness and tolera&ilit! of three antif/n"al re arations, a' hotericin B, li oso'al a' hotericin B 0-a'B5 and a' hotericin B colloidal dis ersion 0ABC.5, for the treat'ent of <2 neonates +ith Candida &loodstrea' infection. *terili8ation of the &lood +as achie)ed +ith a' hotericin B in %8? of atients, -a'B in 81? and ABC. in <2?, +hen /sed as 'onothera !6 +ith the addition of a second antif/n"al a"ent, s/ccess rates +ere 4$$?, 81.1?, and >2.8?, res ecti)el!. There +ere no differences &et+een the "ro/ s in the ti'e to resol/tion of f/n"e'ia. No atients had i''ediate local or s!ste'ic ad)erse e)ents and none sho+ed deterioration in renal f/nction. M/ster-Reicher and collea"/es 022%5 e)al/ated hi"h-dose 0<-2 '"TH"Tda!5 li oso'al a' hotericin B in 12 )er! lo+ &irth +ei"ht infants +ith s!ste'ic candidiasis. Candidiasis +as as a res/lt of C. ara silosis in 42 cases, and C. al&icans in 4< cases. F/n"al eradication +as achie)ed in 0><?5 e isodes6 'edian d/ration of thera ! /ntil f/n"al eradication +as 8.2% J.< da!s. The a/thors concl/ded that hi"h-dose li oso'al a' hotericin B +as effecti)e and safe in the treat'ent of neonatal candidiasis. Additionall!, f/n"al eradication +as 'ore ra id in atients treated earl! +ith hi"h doses and in atients +ho recei)ed hi"h-dose li oso'al a' hotericin B as first-line thera !. At resent, li id for'/lations of a' hotericin B do not a ear to &e 'ore efficacio/s than con)entional a' hotericin B deoN!cholate, and their /se sho/ld &e li'ited to atients +ho are either refractor! to, or intolerant of, the re"/lar a' hotericin B re aration 02225. The /se of fl/cona8ole for the treat'ent of neonatal candidiasis is increasin" slo+l!, &/t the c/'/lati)e /&lished eN erience is 'ea"er 0228,22>,28$5. :en8l and collea"/es 028$5 s/ccessf/ll! treated three re'at/re infants 0"estational a"es 2J to 2> +eeHs5 +ith C. al&icans se sis /sin" oral fl/cona8ole at doses of J.< to % '"TH" once dail! for J to % +eeHs. C/tto)a and associates 022>5 fro' the *lo)aH Re /&lic treated J$ ne+&orns +ith fl/cona8ole, 28 of +ho' +ei"hed less than 4,<$$ " at &irth. All infants had f/n"e'ia +ith C. al&icans. Fl/cona8ole +as ad'inistered as a sin"le dail! intra)eno/s dose of % '"TH" for a total of % to J8 da!s. A c/re rate of 8$? +as achie)ed6 4$? died as a direct conse7/ence of

their infection. Mild ele)ations of li)er en8!'e concentrations +ere noted in <? of neonates. The sa'e "ro/ has s/&se7/entl! re orted their eN erience in J$ neonates +ith &reaHthro/"h f/n"e'ias as a res/lt of C. al&icans and C. ara silosis a earin" altho/"h recei)in" fl/cona8ole thera ! e)en tho/"h initial antif/n"al s/sce ti&ilit! testin" de'onstrated that the isolates +ere s/sce ti&le to fl/cona8ole 02845. At resent, there is little e)idence to s/ ort the /se of fl/cona8ole as 'ono-thera ! in neonatal f/n"al se sis. G/idelines for deter'inin" d/ration of thera ! in the neonatal eriod often are lacHin", &eca/se o&Pecti)e e)idence of illness 'a! &e 'ini'al. C/lt/re of the &lood sho/ld &e re eated 2J to J8 ho/rs after initiation of thera !6 if ositi)e, alteration of thera ! 'a! &e necessar!. In the a&sence of dee tiss/e in)ol)e'ent or a&scess for'ation, treat'ent /s/all! is contin/ed < to 2 da!s after clinical i' ro)e'ent. If '/lti le or"ans are in)ol)ed or clinical res onse is slo+, treat'ent 'a! need to &e contin/ed for 2 to 1 +eeHs. */s ected central )eno/s catheter-related &acterial se sis can &e 'ana"ed initiall! +ith the intral/'inal inf/sion of )anco'!cin co'&ined +ith cefta8idi'e or an a'ino"l!coside. After infection is confir'ed and the atho"en identified, sin"le-dr/" thera ! /s/all! is s/fficient. Re orted c/re rates +ith anti&iotics alone +itho/t catheter re'o)al ha)e ran"ed fro' <$? to 'ore than >$? for ediatric atients. Persistentl! ositi)e &lood c/lt/res after 2 to J da!s of a ro riate anti'icro&ial thera ! +arrants catheter re'o)al. A contin/o/s inf/sion of a lo+ dose of /roHinase for 2J ho/rs 'a! hel in clearin" catheterrelated infections in so'e infants +ho fail con)entional anti&iotic thera ! &/t this rod/ct is no lon"er a)aila&le 02825. Patients res ondin" to anti&iotic thera ! sho/ld &e treated for 2 to 1 +eeHs or at least for 4$ da!s fro' the ti'e of the first ne"ati)e &lood c/lt/re. Catheter-related f/n"al infections are rarel! c/red +itho/t catheter re'o)al 02815. I''/nothera ! of neonatal se sis is disc/ssed in Cha ter J%. (Ntracor oreal 'e'&rane oN!"enation for ne+&orns +ith ersistent /l'onar! h! ertension as a res/lt of o)er+hel'in" earl! onset GB* se sis 'a! i' ro)e their s/r)i)al 028J5. Pre)ention The identification of hi"h-risH GB*-carrier 'others and the s/&se7/ent interr/ tion of )ertical trans'ission &! intra art/' 'aternal che'othera ! can re)ent 'an! cases of earl!-onset neonatal GB* disease 0J1,J>,>>,44$5. Man! a roaches ha)e &een s/""ested and so'e ha)e &een tested. The! ran"e fro' "i)in" enicillin ro h!laNis to all ne+&orns or ceftriaNone ro h!laNis to all +o'en in la&or, to screenin" all re"nant +o'en for GB* carria"e at one or 'ore oints in re"nanc! and treatin" ante art/' or intra art/' +ith enicillin or a' icillin, to onl! offerin" intra art/' anti&iotics to +o'en +ho 'eet certain criteria that lace the' at hi"h risH of deli)erin" an infant +ith earl! onset GB* disease. C/rrentl!, the C.C and the A'erican Colle"e of ,&stetricians and G!necolo"ists reco''end /ni)ersal screenin" to detect 'aternal GB*

coloni8ation and treat'ent of those "ra)idas +ho are ositi)e +ith intra art/' anti&iotics 0Ta&le J2-15. Intra art/' anti&iotic ro h!laNis-related ad)erse effects incl/de the s'all &/t real risH of death fro' ana h!laNis for +o'en 0esti'ated risH of $.$$4?5 and an increase in the ro ortion of infants +ith se sis ca/sed &! a' icillin-resistant &acteria 0J5. A recent st/d! eNa'ined the s/sce ti&ilit! rofile of 44> coloni8in" and 8 in)asi)e GB* strains P.42J2 collected fro' t+o hos itals in Bir'in"ha', Ala&a'a, &et+een Man/ar! 4>>% and *e te'&er 4>>2 fro' redo'inantl! )a"inall! deli)ered ter' ne+&orns and fo/nd that the GB* isolates al'ost /ni)ersall! +ere enicillin s/sce ti&le, +ith onl! a s'all 'inorit! of the strains sho+in" 'oderate enicillin or a' icillin s/sce ti&ilit! 028<5. Co+e)er, &et+een 4%? to 24? of GB* isolates are er!thro'!cin resistant and J? to 4<? are clinda'!cin resistant, +hich raises concerns a&o/t the ossi&le inade7/ac! of c/rrentl! reco''ended alternati)es for enicillin- aller"ic +o'en 028<,28%5. TAB-( J2-1 *EMMAR@ ,F C(NT(R* F,R .I*(A*( C,NTR,- AN. PR(9(NTI,N R(C,MM(N.ATI,N* F,R TC( PR(9(NTI,N ,F N(,NATA- (AR-@-,N*(T GR,EP B *TR(PT,C,CCA- *(P*I* All re"nant +o'en sho/ld &e screened at 1<ahR12 +eeHs "estation for )a"inal and rectal GB* coloni8ation. At the ti'e of la&or or r/ t/re of 'e'&ranes, intra art/' che'o ro h!laNis sho/ld &e "i)en to all re"nant +o'en identified as GB* carriers. :o'en +ith GB* isolated fro' the /rine in an! concentration d/rin" their c/rrent re"nanc! sho/ld recei)e intra art/' che'o ro h!laNis. :o'en +ho ha)e re)io/sl! "i)en &irth to an infant +ith in)asi)e GB* disease sho/ld recei)e intra art/' che'o ro h!laNis. If the res/lt of GB* c/lt/re is not Hno+n at the onset of la&or, intra art/' che'o ro h!laNis sho/ld &e ad'inistered to +o'en +ith an! of the follo+in" risH factors: "estation A12 +eeHs, d/ration of 'e'&rane r/ t/re abc48 ho/rs, or a te' erat/re of abc4$$.J]QF 0abc 18.$]QC5. :o'en +ith threatened reter' 0A12 +eeHs' "estation5 deli)er! sho/ld &e assessed for need for intra art/' ro h!laNis to re)ent erinatal GB* disease. GB*-coloni8ed +o'en +ho ha)e a lanned cesarean deli)er! erfor'ed &efore r/ t/re of 'e'&ranes sho/ld not ro/tinel! recei)e intra art/' che'o ro h!laNis for erinatal GB* disease re)ention. For intra art/' che'o ro h!laNis, the follo+in" re"i'en is reco''ended for +o'en +itho/t enicillin aller"!: enicillin G, < 'illion /nits intra)eno/sl! initial dose, then 2.< 'illion /nits intra)eno/sl! e)er! J ho/rs /ntil deli)er!. An

alternati)e re"i'en is a' icillin, 2 " intra)eno/sl! initial dose, then 4 " intra)eno/sl! e)er! J ho/rs /ntil deli)er! Intra art/' che'o ro h!laNis for enicillin-aller"ic +o'en &/t not at hi"h risH for ana h!laNis sho/ld &e "i)en cefa8olin, 2 " intra)eno/sl! initial dose, then 4 " intra)eno/sl! e)er! 8 ho/rs /ntil deli)er!. :o'en at hi"h risH for ana h!laNis sho/ld &e "i)en either clinda'!cin, >$$ '" intra)eno/sl! e)er! 8 ho/rs /ntil deli)er!, ,R er!thro'!cin, <$$ '" intra)eno/sl! e)er! % ho/rs /ntil deli)er!. Ro/tine /se of anti'icro&ial ro h!laNis for ne+&orns +hose 'others recei)ed intra art/' che'o ro h!laNis for GB* infection is not reco''ended. Ada ted fro' *chra" *, Gor+it8 R, F/lt8-B/tts L, et al. Pre)ention of erinatal "ro/ B stre tococcal disease. Re)ised "/idelines fro' C.C. MM:R Reco'' Re 2$$26<4:4, +ith er'ission. The recto)a"inal s+a&s for GB* c/lt/res sho/ld &e laced in a trans ort 'edi/' that +ill 'aintain GB* )ia&ilit!, /nless direct inoc/lation into a selecti)e &roth 'edi/' is ossi&le. ,ne st/d! s/""ests that recto)a"inal s+a&s laced in standard trans ort 'edia can &e /sed as lon" as the s eci'ens s/&se7/entl! are transferred to selecti)e "ro+th 'edia +ithin 2 ho/rs of collection 02825. The 'ana"e'ent of infants &orn to +o'en "i)en intra art/' anti'icro&ial ro h!laNis de ends on their clinical stat/s. If si"ns or s!' to's s/""esti)e of se sis are resent, then a f/ll dia"nostic e)al/ation is erfor'ed and e' iric anti&iotic thera ! is started. If the neonate has no clinical si"ns of se sis at &irth &/t is less than 1< +eeHs of "estation, or if the infant is 'ore than or e7/al to 1< +eeHs of "estation &/t intra art/' anti&iotic ro h!laNis +as "i)en J ho/rs or less &efore deli)er!, then a co' lete &lood co/nt and differential and a &lood c/lt/re sho/ld &e o&tained and the infant sho/ld &e o&ser)ed for at least J8 ho/rs. If se sis s/&se7/entl! is s/s ected &ased on clinical si"ns, then a f/ll dia"nostic +orH/ and e' iric thera ! are initiated. No e)al/ation or thera ! is needed for neonates +itho/t si"ns of se sis &orn at 'ore than or e7/al 1< +eeHs of "estation and +hose 'others had recei)ed intra art/' anti&iotic ro h!laNis 'ore than J ho/rs &efore deli)er!. These infants sho/ld &e o&ser)ed for at least J8 ho/rs for si"ns s/""esti)e of se sis 0>>5. The ti'in" of intra art/' enicillin or a' icillin ad'inistration is i' ortant. In one st/d! fro' * ain, the rate of GB* coloni8ation of neonates &orn to carrier 'others +as J%?, 2>?, 2.>?, and 4.2? +hen a' icillin +as "i)en less than 4 ho/r, 4 to 2 ho/rs, 2 to J ho/rs, and 'ore than J ho/rs &efore deli)er!, res ecti)el! 02885. I''/nolo"ic a roaches to re)ention incl/de assi)e or acti)e i''/ni8ation of 'others, +ith trans lacental assa"e of rotecti)e anti&odies to the fet/s. A n/'&er of )accines are c/rrentl! &ein" de)elo 'ent a"ainst Gro/ B stre tococcal ca s/lar ol!saccharide anti"ens of serot! es Ia, I&, II, III and 9 028>,2>$,2>4,2>25. Altho/"h these tetan/s toNoid conP/"ate )accines a ear to &e safe and i''/no"enic, the! ha)e not &een e)al/ated eNtensi)el! d/rin" re"nanc!, and are not c/rrentl! a)aila&le o/tside of clinical trials.

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