josé manuel pereira - noticias e destaques manuel pereira... · josé manuel pereira ......

José Manuel Pereira

Serviço de Medicina Intensiva do Hospital S. João

Faculdade de Medicina do Porto

Grupo de Infecção e Sepsis

� Candida species are the most common cause of

invasive fungal infections

Wisplinghoff H et al. Clin Infect Dis 2004;39:309-317

25 hospitals , 9613 blood isolates

Fluit AC et al. Clin Infect Dis 2000; 30: 454-460

Other5%

PICU2%

Other8%

PICU3%

SICU17%

1996-2000

(n=309)

2004-2006

(n=566)

Medical32%

Surgical31%

SICU22%

MICU8%

Medical31%

Surgical26%

17%

MICU15%

Marchetti O et al. Clin Infect Dis 2004;38:311-20 Ongoing prospective study

� Candida species are the most common cause of

invasive fungal infections

� Candidemia is the 4th – 8th most common cause of

nosocomial BSI

� 1/3 of the episodes of candidemia occurs in the ICU

� Risk factors are well known bur rather non-specific

� New diagnostic tools and soring systems may help to

improve the management of patients with IC

� Overall mortality of candidemia is in the range of 25-

40%

Zaoutis TE et al. Clin Infect Dis 2005; 41:1232-9

The impact of Candidemia on excess mortality, increased length of

stay and the burden of cost of hospitalization underscores the need

for improved means of prevention and treatment candidemia

Pappas PG et al. Clin Infect Dis 2009; 48: 503-535

The The English planEnglish plan The Brasilian planThe Brasilian plan

The The French planFrench planThe Portuguese planThe Portuguese plan

Initial therapy

� Fluconazole: 12 mg/Kg (LD) → 6 mg/Kg/d

� Echinocandin:

- Caspofungin: 70 mg (LD) → 50 mg/d

- Anidulafungin: 200 mg (LD) → 100 mg/d- Anidulafungin: 200 mg (LD) → 100 mg/d

- Micafungin: 100 mg/d

Alternatives

� AmB deoxycholate: 0,5-1 mg/Kg/d

� Lipid formulation of AmB: 3-5 mg/Kg/d

A I

Empirical treatment for suspected Invasive Candidiasis

� Fluconazole: 12 mg/Kg (LD) → 6 mg/Kg/d

� Echinocandin:

- Caspofungin: 70 mg (LD) → 50 mg/d

- Anidulafungin: 200 mg (LD) → 100 mg/d- Anidulafungin: 200 mg (LD) → 100 mg/d

- Micafungin: 100 mg/d

Alternatives

� AmB deoxycholate: 0,5-1 mg/Kg/d

� Lipid formulation of AmB: 3-5 mg/Kg/d

BIII

Su

cce

ssfu

l ou

tco

me

s (%

)

40

60

80

100

73,4%

61,7%

80,7%

64,9%

Mora-Duarte J, et al. N Engl J Med. 2002;347:2020-2029.

Su

cce

ssfu

l ou

tco

me

s (%

)

Successful outcome = symptom resolution and microbiological clearance

0

20

4064,9%

Modified ITT(n= 224)

Evaluable patients(n= 185)

CaspoAmB AmBCaspo

p= 0,09 p= 0,03

Favorable overall response at end of i.v. therapy (MITT)Patients (%)

Mora-Duarte et al, N Engl J Med 2002; 347: 2020

Pathogen

C. albicans C. glabrata C. parapsilosis C. tropicalis

� Randomized, double-blind, multicenter, non-inferiority study

� Micafungin (100 mg/d) vs. Liposomal Amphothericin B (3 mg/Kg/d)

� n= 531 pts (ICU patients > 45%)

� Candida albicans: 44%

80

100 89,6

74,1

89,5

69,6

rate

(%

)

Kuse ER et al. Lancet 2007; 369: 1519-1527

0

20

40

60

80

Overall success MITT

Micafungin (n= 202) L-AmB (n= 190)

Su

cce

ssfu

l ra

te (

%)

� Phase III, randomized, double-blind, multicenter, non-inferiority study

� Anidulafungin 200/100 mg/d vs. Fluconazole 800/400 mg/d

� n= 261 pts (25 pts enrolled in one center)

� Candida albicans: 62%

9089,5

0

10

20

30

40

50

60

70

80

90

End IV Tx 2-week FU 6-week FU

75,6

64,6

55,9

49,244,1

Anidulafungin

Fluconazole

Su

cce

ssfu

l ra

te (

%)

p= 0,01 p< 0,02

Reboli AC et al. NEJM 2007; 356: 242-282

� Frequency and type of side effects were similar in both groups:

�24,4% anidulafungin vs. 26,4% fluconazole

� Candidemia only (n= 219 patients)

� Anidulafungin 75,9% vs. Fluconazole 61,2% p= 0,02

� Other forms of Invasive Candidiasis (n= 26 patients)

� Anidulafungin 72,7% vs. Fluconazole 53,3%

Reboli AC et al. NEJM 2007; 356: 242-282

Moderately severe to severe ill Echinocandin A III

Recent azole exposure Echinocandin A IIIRecent azole exposure Echinocandin A III

Less critically ill patient and no recent

azole exposureFluconazole A III

Candida glabrata or Candida krusei Echinocandin B III

Candida parapsilosis Fluconazole B III

GUIDELINESGUIDELINES

Is that what is most needed to

improve outcome ?

New

antifungals

Better and

earlier

TO IMPROVE OUTCOMETO IMPROVE OUTCOME

EARLIER AND BETTER EARLIER AND BETTER

TREATMENTTREATMENT

earlier

diagnosticsBetter

therapeutic

strategy

� Earlier therapy Clinical suspicion

� Mycological diagnosis Directed therapy

� De-escalation / Transition

� Use PK/PD knowledge

� Indication for combination

Each hour of delay in antimicrobial administration over the ensuing 6 hours

associated with an average decrease in survival of 7,6%

By multivariate analysis, time to initiation of effective antimicrobial therapy

the single strongest predictor of outcome

Kumar A et al. Crit Care Med 2006; 34: 1589-1596

all

documented

suspected

culture +

culture -

bacteremia +

bacteremia -

community

nosocomial

1385

769

608

1546

459

1695

2154N

912

1242

Adjusted Odds Ratio of Death

1.0 1.1 1.2 1.3

nosocomial

gram +

gram -

fungal

respiratory

urinary tract

intra-abdominal

skin/soft tissue

912

768

584

838

131

230

156

641

Survival =

0.79/1.119x

x = delay (hrs)

Kumar A et al. Crit Care Med 2006; 34: 1589-1596

EtiologyEtiology All casesAll cases 00--2 h delay2 h delay 22--12 h12 h delaydelay > 12 h delay> 12 h delay

Bacteria Number (#) 2866 701 1279 706

% of total # 26,1 47,6 26,3

% survival 47,7 77,3 48,2 16

Candida Number (#) 308 16 62 230

% of total # 5,2 20,1 74,7

% survival 17,5 81,3 41,9 6,5

Median time to initiation of effective antimicrobial therapy in septic shock:

5,5 h for bacteria vs. 35,1 h for Candida

Kumar A et al. 47th ICAAC, Chicago, September 2007 K-2174

Independent determinants of

hospital mortality

� APACHE II score (p <0.001)� APACHE II score (p <0.001)

� Prior antibiotics (p = 0.028)

� Antifungal therapy 12 hours

after the first positive blood

culture (p = 0.018)

94,3% of the patients

hours

Morrell M et al. Antimicrob Agents Chemother 2005; 49: 3640-3645

• Retrospective cohort study of 230 pts

• 70% with non-surgical hospital admission

• C. albicans: 56% pts

• 192 pts with no previous fluconazole tx

� A delay in the initiation of fluconazole therapy in hospitalized patients with

candidemia significantly impacted mortality

� New methods to avoid delays in appropriate antifungal therapy, such as rapid

diagnostic tests or identification of unique risk factors, are needed

Garey KW et al. Clin Infect Dis 2006; 43:25 - 31

• 192 pts with no previous fluconazole tx

� Prior abdominal surgery

� Central venous catheter

� Acute renal failure

� Parenteral nutrition

Multiple antibiotics

� Corticosteroids

� Neutropenia

� Chemotherapy

� Malignancy

Haemodialysis� Multiple antibiotics

� Length of ICU stay > 7 days

� Candida isolated from

other sites

� Haemodialysis

� Burns

� Pancreatitis

� Severity of illness

Fungal colonization index1

� Colonization at multiple sites associated with increased risk of invasive

Candida infection

“Candida Score”2

� Score ≥ 2.5 predictive

Independent Risk Factors Points

Clinical sepsis 2

Surgery on ICU admission 1 Score ≥ 2.5 predictive

of invasive fungal infection

- 81% sensitivity

- 74% specificity

BAMSG predictive rule for identifying high risk patients3

�≥4 ICU days, CVC, diabetes mellitus, new hemodialysis, parenteral nutrition,

broad spectrum antibiotics

- Invasive candidiasis rate: 16.6%

- Captured 78% of patients who developed invasive candidasis

Surgery on ICU admission 1

Total parenteral nutrition 1

Multifocal Candida colonization 1

Note: BAMSG=Bacteriology and Mycology Study Group1Pittet D et al. Ann Surg 1994;220:751-758; 2Leon C et al. Crit Care Med 2006;34:730-737;

3Paphitou NI et al. Med Mycol 2005;43:235-43

One major

Any systemic antibiotic (D1 – D3)

Presence of CVC (D1 – D3)

AND

Sensitivity 34 %

Specificity 90 %AND

At least two minor

Total parenteral nutrition (D1 – D3)

Any dialysis (D1 – D3)

Any major surgery (D -7 – D0)

Pancreatitis (D -7 – D0)

Use of steroids (D -7 – D3)

Use of other immunosupressive agents (D -7 – D0)

Specificity 90 %

PPV 10 %

NPV 97 %

Relative risk 4,36

Ostrosky-Zeichner O et al. Eur J Clin Microbiol Infect Dis 2007; 26: 271-276

Pfaller MA et al. J Clin Microbiol 2008; 46:150-156

Breakthrough (n=49)Non-Breakthrough (n=430)

Uzun O et al. Clin Infect Dis 2001;32:1713-17

Mortality: 50% vs. 76%

24% of all episodes of

Candida glabrata fungemia

were associated with receipt

Malani A et al. CID 2005; 41:975-981

were associated with receipt

of an antifungal agent

within 30 days before onset;

In 85% of these the

antifungal was fluconazole

SpeciesSpecies Frequency Frequency %%

FluFlu ItraItra AmBAmB VoriVori PosaPosa CandinsCandins

C. albicansC. albicans 4646 SS SS SS SS SS SS

C. glabrataC. glabrata 2020 SS--DDDD//RR SS--DDDD//RR SS//II SS//II SS//II SS

C. parapsilosisC. parapsilosis 1414 SS SS SS SS SS SS//II

NOTE: Mixed species/others ~5%

S=Susceptible S-DD=Susceptible-Dose Dependent I=Intermediate R=Resistant

C. tropicalisC. tropicalis 1212 SS SS SS SS SS SS

C. kruseiC. krusei 22 RR SS--DDDD//RR SS SS SS SS

C. dubliniensisC. dubliniensis <1<1 SS//SS--DDDD SS SS//II SS//II SS//II SS

C. lusitaniaeC. lusitaniae <1<1 SS SS SS//RR SS SS SS

Pappas PG et al, Pappas PG et al, ClinClin Infect Infect DisDis 2004;38:1612004;38:161--89; 89; BartizalBartizal K et al, K et al, AntimicrobAntimicrob Agents Agents ChemotherChemother 1997;41:23261997;41:2326--32; 32; Patterson TF. Patterson TF. J J ChemotherChemother 1999;11:5041999;11:504--12; 12; PfallerPfaller MA et al, MA et al, AntimicrobAntimicrob Agents Agents ChemotherChemother 2002;46:17232002;46:1723--7; 7;

PfallerPfaller MA et al, MA et al, J J ClinClin MicrobiolMicrobiol 2002;40:8522002;40:852--66

Candida Candida

albicans non-albicans Azole-

Susceptible

Azole-

Resistant

“For infections due to to Candida parapsilosis,

Fluconazole is preferred as initial therapy (BIII)”

Pappas PG et al. Clin Infect Dis 2009; 48: 503-535

Shorr et al. Crit Care Med 2007; 35: 1077-1083

� No variable, including both previous fluconazole and severity of illness, correlated

Chow JK et al. Clin Infect Dis 2008; 46: 1206-1213

� Receipt of fluconazole� Receipt of fluconazole

� Central venous exposure

Lin et al. Antimicrob Ag Chemother 2005; 49: 4555-4560

� Certain antibacterial were associated with Candida glabrata/ krusei BSI

Playford EG et al. Crit Care Med 2008; 36:2034-2039

� Prior antifungal exposure

� Gastrointestinal surgical procedures

Stage 1

� Administering broad-spectrum antibiotics therapy to improve

outcomes (decrease mortality, prevent organ dysfunction and

decrease length of stay)

Stage 2

� Focusing on de-escalating as a means to minimize resistance

and to improve cost-effectiveness*

Transition or stepdowtherapy in the IDSA guidelines for

invasive candidiasis

* In some cases to cover resistant pathogens not covered with the initiaal regimen, to

provide source control or to treat fungal pathogens

Echinocandin → FluconazoleClinically stable + isolate

susceptible to fluconazoleA II

Clinically stable + isolate AmB-D, L-AmB → Fluconazole

Clinically stable + isolate

susceptible to fluconazoleA I

Step-down therapyVoriconazole

(VRC-S C. glabrata or krusei)B III

Sensitivity > 55%;

False + in bacteremia

Specificity 96%; High NPV

If negative, stop

Senn L et al. CID 2008; 46: 878-885

BOTTOM LINE

HIGHER DOSING

=

BETTER OUTCOME

Manjunath PP et al. Antimicrob Agents Chemother 2007; 51(1): 35-39

� Dose dependent antifungal activity in rabbit aspergillosis

Petraitene R et al. Antimicrob Agents Chemother 2001; 45: 857-69

� Higher plasma concentrations associated with higher

response rates in humansresponse rates in humans

Walsh TJ et al. CID 2007; 44: 2-12

Keeping voriconazole trough levels inside the therapeutic range of 1-

5,5 mg/l during the first week of therapy may prevent treatment

failures and neurological toxicity.

Pascual A et al. CID 2008; 46: 201-211

AMB deoxAMB deox LL--AMBAMB FLUCOFLUCO VORICOVORICO ECHINOECHINO

CNS penetration

%< 10 < 10 80 90 NA

%< 10 < 10 80 90 NA

SNC:

- Linear relationship between the voriconazole dose and CSF concentration

- Median CSF : plasma concentration ratio of 0,5

Pearson MM et al. Ann Pharmacother 2003; 37: 420-32

� Candidemia causes chorioretinitis in 10% of patients

� Candins diffuse poorly into the eye and are notindicated, at least as the sole antifungal to treatendophthalmitis.

� However, published studies have not reported greater� However, published studies have not reported greaterlevels of failure in patients with chorioretinitis treatedwith a candin

� Although urinary elimination of candins is < 3%, limitedexperience with caspo for candiduria has beenfavorable

Khan FA et al. Pharmacotherapy 2007; 27: 1711-21

Sobel JD et al. Clin Infect Dis 2007; 44: 46-49

1st choice Alternative Duration

Cystitis Fluconazole (3 mg/Kg) If F-R AmB-d 0,3-0,6 mg/Kg/dF – 2 w

AmB d – 7 d

Pyelonephritis Fluconazole (3-6 mg/Kg) If F-R AmB-d 0,5-0,7 mg/Kg/d 2 w

Osteomyelitis *Fluconazole (3-6 mg/Kg)

LFAmB 3-5 mg/Kg/d6-12 monthsOsteomyelitis *

LFAmB 3-5 mg/Kg/d6-12 months

CNS* LFAmB 3-5 mg/Kg/d Several weeks

EndophtalmitisAmB-d 0,7-1 mg/Kg/d

Fluconazole**

LFAmB

Echinocandins

Voriconazole

4-6 w

Endocarditis* LFAmB 3-5 mg/Kg/d *AmB-d 0,6-1 mg/Kg/d

Echinocandins (higher doses)

6 w after valve

replacement

* Fluconazole (6-12 mg/Kg/d) as stepdown therapy

** For less severe cases

AMB deox L-AMB FLUCO VORICO CASPOANIDULA

and MICA

Renal failureRenal failure NoNo NoNo YesYes No *No * NoNo NoNo

Moderate liverModerate liver

failurefailureNoNo NoNo NoNo YesYes YesYes NoNo

* IV vorico* IV vorico contraindicated if Cr Cl < 50 ml/mincontraindicated if Cr Cl < 50 ml/min

France 1 USA 2

Risk of PPDI 27% 70%

Rifampicin (45%)

Cyclosporin (40%)

Prednisone (25%)

Midazolam (18%)

Potential interactions

Cyclosporin (40%)

Glimepiride (10%)

Glibenclamide (5%)

Midazolam (18%)

Warfarin (15%)

Methylprednisolone (14%)

Cyclosporine (11%)

Nifedipine (10%)

1 Depont F et al. Pharmacoepidemiol Drug Saf 2007; 16: 1227-1233

2 Yu DT et al. Pharmacoepidemiol Drug Saf 2005; 14: 755-767

Caspofungin- Efavirenz, carbamazepine, phenytoin, phenobarbital or dexhametasonecan reduce efficacy of caspo and doses should be increased to 70 mg/day

- Rifampicin usually reduces levels of caspo by approximately 30%, thus a 70mg daily (q.d.) dose may be recommended for persons receiving both rifampin and caspofungin (?)

- Caspo decreases serum levels of tacrolimus by 20%

- Cyclosporin increases caspo plasma concentrations by 35% but no significant adverse events have been reported, so prior recommendations to avoid the use of adverse events have been reported, so prior recommendations to avoid the use of cyclosporine and caspofungin concomitantly are largely not applicable anymore.

MicafunginMay increase the blood levels of drugs metabolized by the cytochrome P450 (CYP)3A4 system

Is a mild inhibitor of cyclosporine metabolism, cyclosporine levels should be monitored

Serum concentrations of sirolimus and nifedipine increase by 21 and 18%, respectively and their levels should be monitored

Stone JA et al. Antimicrob Agents Chemother 2004; 48: 4306-14

Hebert MF et al. J Clin Pharmacol 2005; 45: 954-60

Trissel L et al. Am J Health Syst Pharm 2005; 62: 834-7

The echinocandins caspofungin and micafungin The echinocandins caspofungin and micafungin

undergo hepatic degradation undergo hepatic degradation

via hydrolysis and Nvia hydrolysis and N--acetylation, acetylation,

Metabolism:Metabolism:

> 90% chemical degradation in the blood> 90% chemical degradation in the blood

Bypasses hepatic metabolismBypasses hepatic metabolism

Control

Fluconazole

Itraconazole

KetoconazoleFlucytosine

Fungicidal activity against Fungicidal activity against C.C. albicansalbicans

1.0E+06

1.0E+07

1.0E+08

Log

CF

U/m

L

Zhanel G et al. Antimicrob Agents Chemother. 2001;45:2018-2022.

Flucytosine

Ampho B

Concentrations used were the MIC of each compound

0 5 10 15 20 25

1.0E+02

1.0E+03

1.0E+04

1.0E+05

Time (hours)

Log

CF

U/m

L

Anidulafungin

� Candida spp. adhere to inert and biological surfaces – associated with virulence

� Catheter-related infections

� Biomaterial surfaces (implants, dentures, prostheses)

Candida albicans biofilm

dentures, prostheses)

� Biofilm-associated infections (endocarditis, oropharyngealcandidiasis)

� High level of antifungal resistance

� Fluconazole & polyene resistance

� Echinocandin susceptibility

Bachmann SP, et al. Antimicrob Agents Chemother 2002;46:3591-6; Ramage G, et al. Antimicrob Agents Chemother 2002;46:3634-6

Non-neutropenic patients

� Catheter frequently implicated—change indicated

� Unless other obvious source (urine, abscess)

Neutropenic patients

� Mucositis: gut source

� Tunneled line removal may be difficult & benefit less clear

Candida parapsilosis

� Strongly catheter-associated

� Very difficult to eradicate without line removal

Rex JH et al. CID 1995; 21: 994-996

Echinocandin → FluconazoleClinically stable + isolate

susceptible to fluconazoleA II

AmB-D, L-AmB → FluconazoleClinically stable + isolate

susceptible to fluconazoleA I

Step-down therapyVoriconazole

(VRC-S C. glabrata or krusei)B III

Duration of therapy

2 w after clearance of

Candida BSI and resolution of

symptoms

A III

IV catheter removal All A II

� Randomized, blinded, multicenter trial

� Fluconazole (800mg/d) + Placebo vs. Fluconazole (800 mg/d) + Ampho B

(0,6-0,7 mg/Kg) for 5-7 days

� n= 219 patients with candidemia (except C. krusei)

Successful outcome

Monotherapy 56%

vs.

Combination therapy 69%

p= 0,043

Rex JH et al. CID 2003; 36: 1221-1228

Combination Monotherapy p=

Time to failure 69% 57% 0,08

Persistent candidemia 6 % 17% 0,02

Duration of therapy 15 16,7 0,123

Nephrotoxicity 23% 3% < 0,001

Mortality within 90 days 40% 39% NS

CONCLUSION

In non neutropenic patients, the combination of fluconazole plus AmBwas not antagonistic compared with fluconazole alone, and thecombination trended toward improved sucess and more rapid clearancefrom the bloodstream

Rex JH et al. CID 2003; 36: 1221-1228

Pachl et al. CID 2006; 42: 1404-1413

Mycograb plus lipid–associated amphotericin B produced

significant clinical and culture confirmed improvement in

outcome for patients with invasive candidiasis

Host Host & fungus adapted antifungal & fungus adapted antifungal therapytherapy

Patient-based decisions

Host Host & fungus adapted antifungal & fungus adapted antifungal therapytherapy

� High level of clinical suspicion

� Early antifungal therapy

� Remove CVC

� Mycological diagnosis

� PK / PD

� Direct / Stepdown / Transition

� Monitor response: fundoscopic exam &

negative blood cultures

20

30

40

5049

4740

38

45

42

48

38

39

35

0

10

20

4

17

8 69

dist

ribut

ionn

(%

)

20

30

40Bacterial septic shock (n=3590); median 5.5 hrCandida septic shock (n=443); median 35.1 hr

time to effective antimicrobial (hrs)0-2 hrs2-6 hrs6-12 hrs12-24 hrs24-72 hrs72+ hrs

dist

ribut

ionn

(%

)

0

10

20

Sur

viva

l (%

)

60

80

100Bacterial septic shock (n=3590)Candida septic shock (n=443)

Time to effective antimicrobial (hrs)0-2 hrs2-6 hrs6-12 hrs12-24 hrs24-72 hrs72+ hrsAll

Sur

viva

l (%

)

0

20

40

Sur

viva

l (%

to

tal)

50

60

70

80

fungal (n=131)

bacterial (n=1925)

69

Antimicrobial Initiation Delay

Sur

viva

l (%

0

10

20

30

40

Overall 0-2hr 2-6 hr 6-12 hr >12 hr

2004 2009

Neutropenia Severity of illness

Azole exposure

C. glabrata and krusei local

prevalence

Antifungal spectra differ between the three major antifungal classes, and even between agents within the classes, and impact on the choice of antifungal drug

Invasive candidiasis if severe or in centres with fluco Invasive candidiasis if severe or in centres with fluco resistance > 24% :resistance > 24% : Caspo or AnidulafunginCaspo or Anidulafungin

Candida glabrataCandida glabrata or or kruseikrusei:: Caspo or AnidulafunginCaspo or Anidulafungin

Candida parapsilosisCandida parapsilosis:: FluconazolFluconazol

� High level of clinical suspicion

� Early antifungal therapy

� Remove CVC

CONCLUSIONS:CONCLUSIONS:BETTER BETTER STRATEGYSTRATEGY

� Remove CVC

� PK / PD

� Mycological diagnosis

� Direct / Stepdown / Transition

� Monitor response: fundoscopic exam &

negative blood cultures

�� Invasive candidiasis if severe or in centres with fluco resistance > Invasive candidiasis if severe or in centres with fluco resistance > 24% :24% : EchinocandinEchinocandin

�� Candida Candida glabrataglabrata or or kruseikrusei:: EchinocandinEchinocandinCandida Candida glabrataglabrata or or kruseikrusei:: EchinocandinEchinocandin

�� Candida Candida parapsilosisparapsilosis:: FluconazoleFluconazole

PK/PD attributes and toxicity profiles of the antifungal agents are of paramount importance, as they allow antifungal choice to adapt to the host characteristics

� Concomitant use of CYP metabolised drugs: Anidulafungin

� Renal failure: No IV voriconazole and no Ampho B

� Meningitis or endophtalmitis or urinary: Voriconazole or fluconazole

� Biofilm (CVC, biomaterial, endocarditis): Echinocandin

squalenessqualenes

allylaminesallylamineseg terbinafineeg terbinafineallylaminesallylamineseg terbinafineeg terbinafine

acetylacetyl--CoCo--AAnucleosidesnucleosideseg 5eg 5--flucytosineflucytosinenucleosidesnucleosideseg 5eg 5--flucytosineflucytosine

nucleic acid synthesisnucleic acid synthesis

echinoocandinsechinoocandinseg caspofungineg caspofunginechinoocandinsechinoocandinseg caspofungineg caspofungin

glucan synthesisglucan synthesis

ergosterolergosterol

polyenespolyeneseg amphotericin Beg amphotericin Bpolyenespolyeneseg amphotericin Beg amphotericin B

azolesazoleseg fluconazoleeg fluconazoleazolesazoleseg fluconazoleeg fluconazole

squalenessqualenes

lanosterollanosterolKK++

Mg Mg 2+2+

eg caspofungineg caspofungineg caspofungineg caspofungin

nikkomycinsnikkomycinsnikkomycinsnikkomycinschitin synthesischitin synthesis

azasordarinsazasordarinsazasordarinsazasordarinsprotein synthesisprotein synthesis

40

50

60

70

Mo

rta

lity

(%

)

Crude & Attributable Mortality in

Nosocomial Candidemia

57%

38%

49%

61%

0

10

20

30

40

1983-1986 1997-2001

Mo

rta

lity

(%

)

Crude mortality

Attributable

mortality

Wey et al Arch Intern Med 1988;148:2642-5; Gudlaugsson et al Clin Infect Dis 2003;37:1172-7

Wisplinghoff H et al. CID 2004; 39:309-317

Benefits

� Reduce toxicity

� Increase tissue penetration

� Reduce risk of resistance� Reduce risk of resistance

� Improve efficacy (fungistatic drugs)

Disadvantages

� Risk of antagonism

� Price

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