Empiric Antifungal Therapy 09

8/19/2019 Empiric Antifungal Therapy 09

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Empiric Antifungal Therapy inthe ICU

Ramzi Moufarrej, M.D

Chief of Critical Care

Zaye Military !o"pital # A$u Dha$i


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Introuction

% In&a"i&e fungal infection" ha&e increa"e"ignificantly o&er the la"t ' ecae".

( aging population )ith life "u"taining therapie" li*erenal ialy"i"

( $roa "pectrum antimicro$ial therapy an in&a"i&emeical e&ice"

( $one marro) tran"plantation +MT- "oli organtran"plantation +/0T-

( inten"i&e chemotherapy for malignancie" ( !I1#AID/ epiemic.


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National Epidemiology of Mycosis Survey (NEMIS) was a prospective, multicenter study conducted at 6 US sites from 1!"1# to e$amine rates

of ris% factors for t&e development of candidal 'loodstream infections (SIs) among patients in surgical and neonatal intensive care units *+

&ours- .mong +/06 patients, +/ SIs occurred-

.dapted from lum'erg M et al, and t&e NEMIS Study 2roup Clin Infect Dis /3314!!5100"164 2ar'er 2 Drugs /3314

61(suppl 1)51"1/-

Ri"* for In&a"i&e Myco"i"%2on32eutropenic relate to $arrier $rea*o)n, change in colonizatio

( Acute renal failure +RR 4.'- ( 5arenteral nutrition )ith intralipi +RR 6.7- ( 5rior "urgery "pecially 8I +RR 9.6- ( In)elling central line : Triple lumen +RR ;.4- ( roa "pectrum anti$iotic" ( Dia$ete" ( urn" ( Mechanical 1entilation ( /teroi"

%2eutropenic relate to a$o&e plu" immune cell "uppre""ion anunerlying malignancy.

%/e&ere immuno"uppre""i&e< MT or /0T


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In&a"i&e Myco"i"

Caniia"i" A"pergillo"i"

Decrea"ing immunity

/0T or

MT

MICU or

/ICU

Barrier

immunity

Barrier plus

cellular immunit

0ncology


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% 5olyene"

( Amphotericin +Am- or =ipo"omal Am +*iney to>icity-% Azole" ( ?luconazole 4@@3@@ mg#ay +li&er to>icity, CB54;@- ( 1oriconazole +li&er to>icity, &i"ual i"tur$ance", CB54;@- ( 5o"aconazole +li&er to>icity, CB54;@-

% Echinocanin" ( Ca"pofungin i& +li&er to>icity-% Com$ination e>. Am# ?luconazole +li&er, *iney to>icity-

Choice of agents depends on whether the patient on previousazole prophylaxis, culture results, local fungal sensitivity,colonization, renal or liver disease, presence of drug-druginteractions, presence of hardware, immuno -suppresion, site ofdisease ex. urine.

Treatment of In&a"i&e Myco"i"


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/ite of Action of /electe Anti3fungal Agent"

Aapte from Anriole 1T J Antimicrob Chemother 44


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?ocu" on Caniia"i"% In&a"i&e Candida infection"<

( 4th mo"t common no"ocomial $loo"treaminfection in the U/A )ith mortality approaching4@H in line relate caniemia

In a !7year (1#"1) surveillance study of + &ospitals in t&e United States-

.dapted from Edmond M et al Clin Infect Dis 14/5/!"/++4 .ndriole 89 J Antimicrob Chemother 14++51#1"16/4U:un ;, .naissie E


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C. glabrata

16=

C. albicans#+=

C. parapsilosis1#=

C. tropicalis=

C. krusei/=

ot&er Candida spp#=

.dapted from >faller M. et al and 9&e SEN9?@ >artic2roup Antimicrob Agents Chemother /3334++50+0"0#1

/pecie" of Candida Mo"t CommonlyI"olate in loo"tream Infection"

In an international surveillance study 10715

Since t&en increase in Candida spp- wit& &ig&er incidence of flucona:ole resistanceSnydman DR. 2!. Chest "2!#Suppl $%&$S'$!S%. (arbino J. et al. 22. )edicine*+"&,2$',!!.


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In&a"i&e Caniia"i" in the ICU

% Common in the ICU +.#@@@ ami""ion"- )ith highmor$iity +increa"e =0/ J'' ay"- mortality +J 6@34@H- re"ulting in increa"e co"t +J K44,@@@# epi"oe-.

% Difficult to iagno"e +culture" po"iti&e in only J ;@H-.% Ge can efine ICU ri"* factor" for caniia"i" an

target the population at highe"t ri"* )ith empiric R>.% Recent increa"e in Cania spp. re"i"tant to Diflucan.% A&ance" in antifungal therapy ha&e re"ulte in agent",

li*e echinocanin" an triazole", )ith high acti&ity, a$roa "pectrum, an lo) to>icity ieal for empirictherapy an com$ination therapy option".

5rophyla>i" an treatment of in&a"i&e caniia"i" in the inten"i&e care "etting.ur J Clin $icrobiol "nfect #is. '@@4


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Major Ri"* ?actor"

% 5rior anti$iotic u"e, central &enou" catheter",total parenteral nutrition, major "urgery )ithinthe preceing )ee*, "teroi", ialy"i" an

immuno"uppre""ion.% Inten"i&e care unit length of "tay i" an important

ri"* factor, )ith the rate of infection" ri"ingrapily after 93@ ay".

Dimopoulo" 8, et al. Caniemia in immunocompromi"e an immunocompetent critically ill patient"< a

pro"pecti&e comparati&e "tuy. Eur F Clin Micro$iol Infect Di". '@@9


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Ri"* ?actor /election

Unerlying

i"ea"e

Anti$iotic"

Colonization

?e&er

/election

/*in omuco

ama

$n!ection

MalignancyDia$ete"Renal i"ea"eCTD on "teroi"

Malnutrition on T52Mechanical 1entilation L 4hurn"

In"trumenC1 Cathenife


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In&a"i&e Caniia"i" After Colonizationan acteremia

acteremia

Colonization

Acute

In&a"i&eCaniia"i"

patient"

BE/ 6;20 47

3 N NNN4 '4

3 N NNN 9 6 ;

@ @ @

;6H8uiot et al. C"#.4


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=a$oratory Diagno"i"

% Micro$iology metho". ,6 $eta D glucan a""ay.

% !i"topatholgic metho".


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Clinical Diagno"i"

The clinical manife"tation" of IC are non"pecific, $ut may inclue<

% ?e&er an progre""i&e "ep"i" )ith multi3organ failure e"piteanti$iotic".

% In&a"i&e caniia"i" +IC- relate cutaneou" le"ion".

( Macronoular ra"h freOuently confu"e )ith rug allergie". A$iop"y of the eeper layer" of "*in particularly the &a"cularizearea" an the ermi" i" important.

% 0phthalmic le"ion" +Cania enophthalmiti"-.

( A funo"copic e&aluation for the pre"ence of Candida enophthalmiti" "houl $e performe in patient" )ithcaniemia.


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Therapy of IC in the ICU

% A efiniti&e iagno"i" of IC may $e elaye )hen theclinical an la$oratory tool" reaily a&aila$le toclinician" are u"e to a""e"" patient" for Candida infection.

% A elay in iagno"i" )ill unfortunately re"ult in a elay

in initiation of antifungal therapy, )hich i" a""ociate)ith increa"e mortality.

% Therefore, in the patient )ith "u"pecte Candida infection, treatment may nee to $e initiate on the

$a"i" of ini&iual patient factor" $efore a efiniti&eiagno"i" i" mae.

%$orrel $ et al. &''(. Antimicrob Agents Chemother. )*+* /)'-(

%0arey 1 et al. &''/. Clin "nfect #is. ) &(-2.


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Can )e )ait for the $loo culturere"ult" in caniemia:

% Retro"pecti&e cohort analy"i" #'@@3'#'@@4<2P;9 patient" )ith caniemia.

% Delay in empiric R> of caniemia till after $loo

culture" turn po"iti&e re"ulte in higher mortality.% /tart of anti3fungal R> L' hr" of ra)ing a

$loo culture that turn" po"iti&e ha A0RP '.@for mortality, pP@.@.

$orrel $ et al. &''(. Antimicrob Agents Chemother. )*+*/)'-(


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Treatment of /u"pecte In&a"i&eCaniia"i" +Definition"-

% Prohylactic theray%

protecti&e or pre&enti&e therapy gi&en toe&eryone in a gi&en cla"" +e>. MT patient" )ho are at &ery highri"* for IC-.

% Preemti&e theray% therapy gi&en to eter or pre&entanticipate infection patient" at ri"* are monitore clo"ely an

therapy i" initiate )ith early e&ience "ugge"ting infection +e>.po"iti&e Cania culture" at non3"terile "ite", clinical "u"picion-)ith the goal of pre&enting i"ea"e.

% Emirical theray< therapy guie $y practical e>perience ano$"er&ation, $ut )ith non"pecific e&ience in a gi&en patient +e>.therapy i" "tarte $ecau"e a cancer patient ha" remaine fe$rile

after "e&eral ay" of $roa3"pectrum anti$iotic"-.% 'irected theray% i" $a"e on a clinical or la$oratory fininginicating that an infection i" pre"ent +e>. po"iti&e $loo culture forCania "pecie"-.


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Timing of Inter&ention

basic disease

re!ractory !e&er

aseci!ic symtom early marers

seci!ic symtom

suressi&e *+

in!ection

Pro"ression

Empiric

5re3empti&e

5rophylactic

Directe

5rophylactic 5reempti&e or Empiric


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5rophylactic, 5reempti&e or EmpiricU"e of Anti3fungal"

% 5R0/ ( !igh Mortality

( Difficulty in Diagno"i"

( Unetecte Infection

( Reuce "y"temic myco"e"an impro&e mortality )ithprophyla>i"

% C02/ ( To>icity

( E>pen"e

( Diagno"i" not certain% Too much treatment )ithou

infection

% Too little treatment )ith

infection


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?luconazole 5rophyla>i" anColonization of 2eutropenic 5atient"

Gin"ton et al. Ann "ntern $ed. 6


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Cania prophyla>i" in the /urgical ICU+patient" )ith high ri"* for caniemia-

% Eggiman et al. . CCM '9< @773@9'. ( ?luconazole reuce cania peritoniti" an colonization in 46 patient" )ith

complicate 8I "urgerie". !igh ri"* patient" : Ga" it preempti&e therapy.

% 5elz et al. '@@. Ann /urg. '66< ;4'3;4. ( ?luconazole reuce cania infection in critically ill "urgical patient" in /ICU

L 6 ay". 2o mortality $enefit. ( 5reictor" inclue< A5AC!E II "core, fungal colonization, T52, ay" to fir"t

o"e of prophylactic rug.

% 5aphitou et al. '@@;. Me Mycol. 46+6-


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Cania 5rophyla>i" in MICU /ICU+M1 L 4h e>pecte =0/ L 9'h-

Garbino et al. Intensive are !ed.

"##"$"&'7#'7

Incience of ICP7H

Incience of ICP;.H


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/ummary +Cania 5rophyla>i"-

% 5rophyla>i" i" effecti&e in the highe"t ri"*patient".

% 5rophyla>i" reuce" the incience of IC.

% A po"iti&e impact on mortality ha" not $een"ho)n e>cept in "e&erely immunocompromi"eho"t" +neutropenia, MT, or "oli organtran"plantation-.

%Di"tinction $et)een prophylactic preempti&etherapy neee "pecially in ICU. Ri"* : Do"e:.


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A""e""ment of 5reempti&e Treatment topre&ent "e&ere caniia"i" in /ICU

% efore#after inter&ention "tuy +' year" pro"pecti&e hi"torical- % /y"tematic mycological "creening on all patient" amitte to the

/ICU Q ; ay", immeiately at amittance an then )ee*ly untili"charge. 5atient" )ith colonization ine> Q @.4 +u"e to a""e""inten"ity of muco"al colonization- recei&e early preempti&eantifungal R> +fluconazole I1 @@mg, then 4@@ mg#ay for ' )*"-.

% Cania infection" occurre more freOuently in the control cohort

+9H &". 6.H p P .@6-. Incience of /ICU3acOuire pro&en

caniia"i" "ignificantly ecrea"e from '.'H to @H +p .@@-.2o emergence of azole3re"i"tant Cania "pecie" )a" noteuring the pro"pecti&e perio.

5iarrou>, et al..Crit Care Me. '@@4 Dec6'+'-


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Arch /urgery. '@@67< 4@34@


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Temporal A""e""ment of Cania Ri"*?actor" in the /ICU


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5earl" of the "tuy

% Change in Cania ri"* factor" o&er time i" clinicallyrele&ant. ( Early ri"* factor" at ay , time of /ICU ami""ion. ( More than ri"* factor" at any time ( Rapi increa"e in ri"* factor" +clinical eterioration-

( A5AC!E II "core L ay 6 or 4% Early ri"* factor may$e e&ient from ay may$e

u"e )ith progre""ion of ri"* factor" a" fe&er, urationof anti$iotic" mechanical &entilation to a""e"" ri"*.

% : more aggre""i&e "ur&eillance culture" &". preempti&eor empiric therapy.

/ l i l M h : l i i i i


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/erological Metho" : early ai in empirictherapy eci"ion ma*ing

% 5la"ma $eta3D3glucan, a cell )all con"tituent of fungi, )a"mea"ure $efore "tarting antifungal therapy empirically onpo"toperati&e patient", colonize )ith cania ha&ing ri"*factor" for cania infection.

% 49H of tho"e )ith po"iti&e te"t re"pone to R> $ut H of tho"e

negati&e re"pone +p.@- +0RP 6-.% 2um$er of "ite" colonize )ith cania al"o preicte re"pon"e.

Colonization at Q 6 "ite" &". "ite +pP@.@6- +0RP9.;9-.

% In po"toperati&e patient" colonize )ith cania, )ith fe&er

e"pite anti$iotic" a $eta3D3glucan a""ay )a" u"eful foreciing )hether to "tart empiric therapy.

Ta*e"ue B et al. Gorl F /urg. '@@4 '+7-< 7';36@.


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Re"earch 0ngoing

% Ranomize /tuy of Ca"pofungin 5rophyla>i"

?ollo)e $y 5re3Empti&e Therapy for In&a"i&eCaniia"i" in the ICU.

% The "tuy )ill te"t the po""i$ility that ca"pofungin can"ucce""fully reuce the rate of cania infection" in "u$ject" at

ri"*. It )ill al"o te"t if ca"pofungin i" u"eful in treating "u$ject"for thi" i"ea"e )hen iagno"e u"ing a ne) $loo te"t that i"performe t)ice )ee*ly, permitting earlier iagno"i" than currentpractice "tanar".

% Thi" "tuy i" currently recruiting participant".

Myco"e" /tuy 8roup, Augu"t '@@9

C i ti i / l ti f E i i


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Con"ieration" in /election of Empiric Antifungal Therapy

!igh3ri"* ho"t )ith hematologic cancer, or "tem cell tran"plantation,"e&ere immuno"uppre""ion, hemoynamic in"ta$ility, guty"function or meication noncompliance u"e I1 agent".

5rolonge an recent e>po"ure to azole" prior to current epi"oe or"ignificant li&er y"function or rug3rug interaction a&oi azole".

5athogen in &itro "u"cepti$ility pattern i" *no)n for a cla"" ofagent", "elect an agent that i" li*ely to $e effecti&e again"t the"pecific pathogen.

/ite of Infection<

% 0cular or central ner&ou" "y"tem infection a&oi echinocanin".

Can u"e lipo"omal amphotericin , fluconazole or &oriconazole.% Urinary e>. cy"titi" "elect fluconazole or ;3flucyto"ine.

Empiric Ca"pofungin in 5atient" )ith


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alsh et al. N Engl J Med. "##4$ 3*'&'39''4#".

;verall adAusted

success rate

3

13

/3

!3

+3

33.9%

#3

33.7%

".6% ''.*% '#.3%

'4.*%

Nep&roto$ic effect

(pB3-331)

Ciscontinued t&e study

prematurely (p+#.#3)

(as pofungin

Diposomal .m)

Empiric Ca"pofungin in 5atient" )ith2eutropenia an 5er"i"tent fe&er

P e r c e n t o f P a t i e n t s

Caspofungin had significantly fewer #rug-related clinical or lab adverse events, and

discontinuations due to serious drug-related clinical or lab As .

Empiric Ca"pofungin &" lipo"omal Am


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Empiric Ca"pofungin &". lipo"omal Amin per"i"tent ?e&er an 2eutropenia

P e r c e n t s

, r v i v a l

aspofungin (n##6)

D7.m (n#!)

-t,d da

p3-3++

/1 / !# 6!0 1+ #6++/

3

3133

3

03

63

#3

13

/3

!3

+3

/uperior in pre&entino&erall mortality )ithle"" to>icity.

Gal"h et al. 3 ngl J $ed. '@@46;


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Caniemia in 2on3neutropenic ICU 5atient"Ri"* ?actor" for 2on3al$ican" Cania /pp.

% 2ation)ie Au"tralian pro"pecti&e cohort "tuy.% 5atient" )ith ICU3acOuire caniemia o&er 6 yr.

% Mea"ure clinical ri"* factor" occurring up to 6@ ay"preceing caniemia.

% C al$ican" 7'H, C gla$rata H, C para"ilop"i" H, Ctropicali" 7H, C *ru"ei 4H, 0ther Cania "pp. 'H

% Inepenent ri"* factor" for 2CA or potentiallyfluconazole3re"i"tant "pecie"< age +0R .6-, recent 8I"urgery +0R '.-, prior e>po"ure to "y"temic antifungalagent" +0R 4.7- e"pecially fluconazole +0R ;.9-.

E8 5layfor et al. Crit. Care Me. '@@ 67+9-< '@643'@6.

E i i A ti C i Th C t


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Empiric Anti3Cania Therapy< Co"t3Effecti&ene""

% Target< 5atient" in the ICU L 6 ay" an unre"pon"i&e toanti$acterial therapy for L 6 ay".+J4@H all caniemia-.

% /trategie" compare< ?luconazole, Ca"pofungin, Aman =ipo"omal Am.

% E"timate"< R to ?luconazole P;H, co"t of Ca"pofungin P6K#ay, DiflucanP6;K#, IC in target population P@H% Re"ult"< Ca"pofungin the mo"t effecti&e $ut ?luconazole

more co"t3effecti&e.% If R to ?luconazole L 'H or if IC pre&elance P 7@H or if

co"t of ca"pofungin 7@ K#ay then Ca"pofungin moreco"t effecti&e.

0olan et al. &''(. Ann "ntern $ed42)5(6-5/*.

Algorithm for Empiric Therapy


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Algorithm for Empiric Therapy

% Emiric treatment !or in&asi&ecandidiasis based on the

hemodynamic status o! the atient,% -nstable atients% broad.sectrum

anti!un"al a"ents/ which can benarrowed once the atient hasstabilized the identity o! thein!ectin" secies is established,

% $n stable atients% !luconazole/ro&ided that the atient is notcolonized with !luconazole resistantstrains or there has been recentast e+osure to an azole(120 days),

% $n contrast/ re.emti&e theray isbased on the resence o! surro"atemarers e+ colonization inde+,

/pell$erg et al. +'@@7-. Clin Infect Di" 4'


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/ummary +Empiric Therapy-

% In the patient )ith "eptic "hoc* ri"* factor" for caniemia

"houl $e e&aluate.% If Candida infection i" "u"pecte, treatment )ill nee to $e

initiate empirically )ithout elay on the $a"i" of ini&iuapatient factor" $efore a efiniti&e iagno"i" i" mae.

% Choice of agent )ill rely on local re"i"tance pattern",micro$iology ata, prior azole therapy, recent 8I "urgery,neutropenia, hemoynamic "ta$ility, other ho"t factor".

% Azole" are effecti&e unle"" high rate" of re"i"tance, orneutropenia in )hich ca"e echinocanin" or triazole"

"houl $e u"e.

/ur&i&ing /ep"i" Campaign< International 8uieline" for Management of /e&ere /ep"i" an /eptic /hoc*< CCM

Directe Therapy


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Directe Therapy

% Azole"< ?luconazole i" the mo"t common agent u"e to treatclinical Candida infection". !o)e&er, fluconazole ha" limiteacti&ity again"t C glabrata and C 7rusei . The e&olution ofre"i"tance an tren" to)ar more non3albicans "pecie", maylimit it" role in the future.

% Triazole" ha&e a role in 2CA an immune "uppre""e patient".% Amphotericin < acti&e $ut i" not "uperior to other therapie" antherefore oe" not ju"tify the ri"* for to>icity. =ipo"omal Am i"the lea"t to>ic.

% Echinocanin"< "ho)n to $e a", if not more, effecti&e than Am

an =3Am are not a""ociate )ith "ignificant re"i"tance.=imite C2/ an genitourinary penetration may limit it" u"e.

Remo&al of all foreign o$ject"


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Remo&al of all foreign o$ject"correlate" )ith $etter outcome"

% C. albicans $iofilm" forme onan implante meical e&ice e>.C1C, urinary catheter, ETT,pro"thetic heart &al&e, orpacema*er play a role in theper"i"tence an profileration ofCaniia"i". Cell" in $iofilm" aremuch more re"i"tant toantifungal agent".

% The echinocanin" ha&epenetration an action inCania $iofilm" an thu" may

ha&e an a&antage in thi""etting. C. albicans ahe"ion a" a &irulence factor

% 3ucci $ et al. &''&. C"#4 ) (*2-(**.%% 1uhn et al. &''&. Antimicrob Agents Chemother4 )/266-265'.

/ummary


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/ummary

% Caniemia i" a""ociate )ith high mor$iity mortality in ICU.

% Early appropriate therapy i" e""ential for the pre&ention of "e&erecomplication", incluing eath.

% A com$ination of clinical la$ fining" i" u"e to ma*e aiagno"i" +no relia$le iagno"tic mar*er" for early etection ofpatient" at ri"* for in&a"i&e caniia"i"-

% Early empiric therapy )ill nee to $e initiate on the $a"i" ofini&iual patient ri"* factor" $efore a efiniti&e iagno"i" i" mae

% 5rophylactic 5reempti&e therapy may$e inicate in high ri"*population" at ri"* for cania infection gi&en the high mortality.

% Ghen caniemia i" ocumente, ID of the infecting Candida

"pecie" i" e""ential for the in"titution of appropriate therapy$ecau"e of the &aria$le "u"cepti$ility of Candida "pecie" toifferent antifungal agent". DonSt forget to are"" the $iofilm.


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Empiric Antifungal Therapy 09