1. Clinical Practice Guideline for the
Management of Candidiasis
IDSA 2016 updated
Presenter: Yu Tian Hsieh
Preceptor : Pinzy Chen
15th, April
2. Outline
Part I
• Brief review of antifungal agent (spectrum, PK-PD)
• Candidemia in non-neutropenic & neutropenic
– Medication choice in C. parapsilosis
– CVC removal
• Empirical /prophylaxis in ICU
• Intra-abdominal candidiasis
• In disseminated(hepatosplenic) candidiasis
Part II
• Management of Candidiasis in other places
2
3. ±
Elizabeth S. Dodds Ashley et al. Clin Infect Dis. 2006;43:S28-S39
mold
yeast
±
3
Common
pathogen
C. glabrata : SDD- R (SDD: susceptible dose dependent )
C. parasilosis: S –R , but R uncommon
C. krusei : R to fluconazole, SDD –R to itraconazole, I-R to flucytosine
AmB: S─I to C. glabrata, C. krusei
4. Comparative pharmacokinetics of the antifungal agents.
Elizabeth S. Dodds Ashley et al. Clin Infect Dis. 2006;43:S28-
S39
CYP 3A4 , 2C19, 2C9
substrate/inhibitors
Renal dose adjustment only in
fluconazole, flucytosine
Only few data of dose in hepatic disease
• Voriconazole(mild-moderate cirrhosis)
• Caspofungin(svere liver disease
child-pugh score)
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6. Therapy
Candidmia Primary alternative Comment
Non-
neutropenic
Echinocandin
• Caspofungin LD 70 mg; 50 mg
• Micafungin 100 mg QD
• Anidulafungin LD: 200 mg,
then 100 mg QD
Fluconzaole
800 mg (12 mg/kg), then 400 mg
(6 mg/kg) in stable, seem S to flu-
AmB d
LF AmB (3-5 mg/kg daily)
• Transition to fluconazole after
5-7 days if Susceptible, clinical
stable, culture (-)
• Ophthalmological examination
1 week after dx
• Duration of therapy 14 days
after clearance of blood stream
and symptom resolved
• f/u blood culture qd/qod*
• Suggest azole susceptibility test
for all bloodstream Candida
isolate
• Test for Echinocandin if
previously echinocandin use, C.
glabrtata , C. parapsilosis
• early catheter, CVC removal
(individualized)
esp.C.parasilosis
Species
C. glabrata
• Echinocandin
Transition to
1. Higher dose of
fluconazole (800 mg)
2. Voriconazle
if susceptible
(3-4 mg/kg)
C. krusei
as above
• Voriconazole (6
mg/kg 2 dose, then
3 mg/kg BID) as
step-down therapy
C. Parapsilosis • No difference btw
candin and flu-[176]
7. Therapy
candidemia Initial alternatives Comment
Neutropenic Echinocandin • LF AmB (less attractive)
• Fluconazole [207]
• Voriconazole if mold
coverage is desired,
susceptible to
voriconazole
[weak, low]
• Step down to flu-/ voriconazole in clinical
stable
• catheter, CVC removal (individualized)
• Ophthalmological examination(after
neutropenic resolved)
• Duration of therapy 14 days after clearance
of blood stream+ neutropenia+ symptom
resolved
• Granulocyte transfusions in persistent
candidemia with anticipated protracted
neutropenia [weak, low]
Species Treatment
C. parapsilosis • Fluconazole . LF AmB is
prefered
• No clinical study
superior to fluconazole
• Systemic review includes 17 trials, randomized 342
neutropenic patient with invasive candidiasis show:
• Favors non-polyenes > polyenes [205]
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• New observative data from Spain (n=200)
show no difference of outcome [176]
8. 9
Study design prospective, multicenter(29 Spanish hospitals), population-based
surveillance program on Candida BSI
Inclusion criteria Incident episode ─first positive blood culture C. parapsilosis complex.
(peripheral vein) ; Of 752 episodes, 200 (26.6%) episodes
Exclusion criteria • simultaneously non–C. parapsilosis (mixed candidemia)
• Patients who died within the first 72 hours
Management initial antifungal in first 72 hrs,
Antifungal agent : azole, echinocadin, AmB, combination
1st endpoint (1) all-cause mortality between days 3 - 30 from the initial blood culture(+)
or
(2) persistent C. parapsilosis BSI for ≥72 hours after the initiation therapy
2nd endpoint 30-day all-cause mortality
The Prospective Population Study on Candidemia in Spain
(CANDIPOP) ─ C. Parapsilosis related candidemia
Clin Infect Dis 2014; 58:1413–21.
Therapy 152 Episodes Detail
Azoles –based 73 (42.0%) Fluconazole 70
Voriconazole 3
Echinocandin 43 (24.7) Caspofungin 23
Anidulafungin 12
Micafungin 8
Amphotericin B 33 (19.0%),
combination 25 (14.4%)
11. CVC REMOVAL DURING ANTIFUNGAL
THERAPY IN CANDIDEMIA
A recently study
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Clin Infect Dis.-2012-Andes-1110-22
12. Inclusion criteria :
1. Review 7 RCT, compare antifungal therapy for candidemia , IC
2. Available data on mortality & treatment success with each
Candida species (individual patient-level data)
Primary outcome: 30 day all cause mortality
Secondary outcome:
• clinical and microbiologic success (symptom resolution and
negative cultures at the end of therapy, typically 14 days)
14. CVC removal & APACH II score
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12 24 36 47
P= 0.05 P= 0.01 P= 0.002 P= 0.41
CVC removal during treatment can applied to
different severity of disease (Individualized)
Clin Infect Dis.-2012-Andes-1110-22
15. III. Empiric treatment for suspected invasive
candidiasis in non-neutropenic patients in ICU
• Who : critically ill patients, who has risk factors, unknown fever,
culture from non-sterile site
• When: as early as possible if risk factors and sign of septic shock
• Why：high prevalence and mortality in ICU
• What: as candidemia in non-neutropenic
• How long/ when to stop
– 2 weeks after improve ( same as treatment)
– if no clinical response x 4-5 day, no subsequent evidence of invasive
candidiasis / non-culture based diagnosis( high sensitivity ) consider
stop antifungal
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Risk factors: candida colonization, severity of illness, number/
duration of using broadspectrum abx, previous surgery , dialysis,
CVC, TPN, length of ICU stay…
if no timely source control, antifungal < 24 hr approches
100 % mortality in septic shock with candidemia [14]
16. Prophylaxis antifungal be use in ICU patients?
Solid organ transplant, neutropenia with chemotherapy,
stem cell transplant
Who ： high-risk patients in adult ICU with high rate (>5%)
of candidiasis [260-262]
What -dose same as previously
• Fluconazole [263]
• Echinocandin as alternatives [249]
Others
• Daily bathing with Chlorhexidine decrease bloodstream
infection, includes candidemia in a 2012 meta-analysis
[weak, moderate] [274]
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2014, multicenter placebo-controlled,
blinded trial of caspofungin prophylaxis
in ICU for high risk of invasive
candidiasis (NOT achieve significant
difference, n =102, 84 )
17. Intra-abdominal Candidiasis
1. Infection usually polymicrobial, yeast 20 % in all cases,
40 % in gastroduodenal perforation
2. 40% of patient with 2nd /3rd peritonitis, developed with
high mortality rate, except for appendicitis
3. Blood culture often (-), hard to distinguish with
contaminated, colonized
• Treatment
– Source control, appropriate drainage, and / or debridement
– Empiric antifungal for recently IAI, significant risk factors,
abdominal surgery, anastomotic leaks, necrotizing pancreatitis
• Choice of medication: same as treatment / empiric
therapy in non-neutropenic
IAI: intra-abdominal infection 19
18. Treatment of disseminated ( hepatosplenic )
candidiasis
• Uncommon syndrome, except for hematologic malignancy
• Presentation: fever, upper quadrant discomfort, nausea,
elevation of LFTs, occur following return of neutrophils and
persist for month unless treatment
• Pathogen : C. albican most common, others also seen
• Antifungal : initially fluconazole, AmB-d, LF AmB OR
echinocandin for several weeks, then PO fluconazole if not
resistance (as neutropenic tx)
• Duration : months after return of neutrophils, f/u by CT
• Others: Short term steroid (tapering dose) or NSAID can
achieve afebrile, improve LFTs [WEAK, LOW]
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20. Management of osteomyelitis, septic arthritis
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Osteoarticular Primary Alternatives comment
Osteomyelitis • Fluconazole, (6 mg/kg) daily,
for 6–12 mons OR
• echinocandin for at least 2
wks followed by fluconazole,
for 6–12 mons
• AmB d
LF AmB(less attractive) ,3–5
mg/kg daily, for at least 2 wks
followed by fluconazole, 6
mg/kg daily, for 6–12 months
• Mech. Hematogenous
dissemination or
contiguous spread
• Surgical debridement is
recommended [strong,
low]
Septic Arthritis • Fluconazole, (6 mg/kg) daily,
for 6 wks OR
• echinocandin for at least 2
wks followed by fluconazole,
for 4 wks (at least)
• AmB d
LF AmB(less attractive) ,3–5
mg/kg daily, for at least 2 wks
followed by fluconazole, 6
mg/kg daily, for 4 wks (at
least)
[strong, moderate]
• Surgical drainage in all
cases
• Prosthetic device
removal
[strong, low]
• Chronic suppression
with fluconazole, if
susceptible
21. Treatment of Asymptomatic Candiduria
• Not recommend treatment
• Elimination of predisposing factors, such as indwelling
bladder catheter is recommended, whenever feasible
• Except for high risk of dissemination:
– Neutropenia, infant < 1500 g treat as candidemia
– Urologic procedure oral fluconazole 6 mg/kg_ , AmB
deoxycholate, 0.3-0.6 mg/kg daily for several days BEFORE,
AFTER procedures. [strong, low]
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22. Symptomatic candiduria ─ cystitis /pyelonephritis
• Susceptibility & urine penetration is the key
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UTI Primary Alternatives comment
Cystitis Fluconazole
3 mg/kg PO QD
for 2 weeks
Fluconazole resistance C. glabrata
• AmB deoxycholate 0.3–0.6 mg/kg for 1–7 days;
• OR flucytosine 25 mg/kg qid for 7–10 days
C. Krusei
• AmB deoxycholate 0.3–0.6 mg/kg for 1–7 days;
Both can consider AmB deoxycholate irrigation 50
mg/L sterile water daily for 5 days, but highly
recurrent rate in several weeks [weak, low]
Removal of indwelling
device, if feasible
Pyelonephritis Fluconazole
3- 6 mg/kg PO
QD for 2 weeks
Fluconazole resistance C. glabrata
• AmB deoxycholate 0.3–0.6 mg/kg for 1–7 days
± flucytosine 25 mg/kg qid for 1-7 days
• Monotherapy of flucytosine x 2 weeks [weak,low]
C. Krusei
• AmB deoxycholate 0.3–0.6 mg/kg for 1–7 days
Adjunct irrigation with AmB-d (conc. As above)
Removal of indwelling
device, if feasible
Elimination of urinary
tract obstruction
Fungus ball 1. Surgical intervention in adult 2. antifungal as above(both) 3. irrigation thru nephrostomy
23. Management of Candidia Chorioretinitis ±
vitritis
• Consult ophthalmologist (dilated retinal examination)
• Vitrectomy considered in macular/vitritis involvement [strong, low]
Fluconazole / voriconazole- susceptible isolates
– Fluconazole LD: 12 mg/kg, then 6-12 mg/kg daily
– Voriconazole 6 mg/kg BID, then 4 mg/kg BID (IV/PO)
Fluconazole / voriconazole- resistance- isolates
– Liposomal AmB 3-5 mg/kg IV ± flucytosine 25 mg/g QID
– Chandin, AmB d
With macular or vitritis involvement
– PLUS intravitreal injection of AmB deoxycholate 5-10 μ g or
Voriconazole 100 μg in 0.1 ml sterile water
• Duration：at least 4-6 weeks with resolution of lesion
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TDM : 2- 5 μ g/ml
24. CNS candidiasis
• Presentation: as meningitis (fever, neck stiff, headache, others)
• Initial : liposomal AmB, 5 mg/kg daily ± oral flucytosine, 25 mg/kg
QID
• Step down :
– fluconazole (6-12 mg/kg) daily , Voriconazole in rare case of C. glabrtata,
or C. krusei meningitis (but no report of voriconazole use in CNS candidisis)
• Duration: until all S&S, CSF, radiological resolved (longer for abscess)
• Remove implantable devices, include drain, shunt, wafers…, If can’t
remove devices intraventricular AmB-d into (0.01-0.5 / 2 ml D5W) ;
toxicity : headache, N&V
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S& S : sign and symptom
25. Oropharyngeal & esophageal candidiasis
• Who: commonly occur in immunocompromised
patients, like HIV infection, malignancies, steroid use,
leukemia…
• Presentation: Dysphagia, odynophagia
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26. Oropharyngeal candidiasis
• Mild : Clotrimazole troche or miconazole mucoadhesive buccal,
alternative nystatin suspension 4-6 ml 4 times daily OR nystatin
pastilles
• Moderate to severe*： PO fluconazole 100-200 mg(≤ 3mg/kg)daily,
• Fluconazole refractory：
– Itraconazole solution 200 mg QD / Posaconazole suspension 400 mg(10 c.c)
BID for 3 days, then 400 mg QD, up to 28 days (effectious in 75 %)
– alternative: voriconazole IV/PO 200 mg BID or AmB-d oral suspension, 100
mg/cc QID [strong. weak] IV echinocandin or IV AmB-d (0.3 mg/kg) [weak,
moderate]
• Duration: 7-14 days
• Suppressive therapy is not recommended (resistance ↑)
• Denture-related disinfection of the denture + antifungal 28
27. Esophageal candidiasis
• Diagnostic trial of antifungal before endoscopic examination
Systemic antifungal
1. PO Fluconazole (3-6 mg/kg) daily for 14-21 days
2. IV fluconazole (6 mg/kg), echinocandin# if can’t tolerte oral
therapy( mica-150 mg , anidula-200 mg daily, caspo- usual daily)
[strong, high]
• Alternative : AmB deoxycholate* 0.3-0.7 mg/kg daily [strong,
MODERATE]
• De-escalating to oral fluconazole if stable to tolerate oral intake
Fluconazole refractory
• itraconazole solution(80%), voriconazole IV/PO(~fluconazole效果),
Echinocandin # 14-21 days, AmB deoxycholate * for 21 days [strong, high]
• Posaconazole suspension 400 mg BID, ER-table 300 mg QD [weak, low]
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Recurrent infections：
• Long term prophylaxis of fluconazole: 100-200 mg 3 times
/week in AIDS with CD4 cell count(< 50 cell/𝜇g)
• Anti-retroviral therapy in HIV-infected
• GM-CSF / InF- 𝛾 can be used as adjunctive
28. Summary –1Treatment
• Non-neutropenic : higher dose of fluconzole, voriconazle for C. glabrata;
suggest susceptibility of azole, echinocandin( prior exposure)
• Neutropenic：LF AmB (less attractive); granulocyte in prolong neutropenic
• Down-grade to fluconazole/ voriconazole if susceptible, stable
• CVC removal may be individualized
• Initial echinocandin doesn’t affect outcome in treating with C. parapsilosis
candidemia
Empiric
• non-neutropenic : As early as possible , stop if no responses after 4-5 days
• intra-abdominal : high risk patient should considered
Prophylaxis in ICU
• Echinocandin consider as alternatives
• Bath chlorhexidine can be considered
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29. Summary –2
• AmB-d become less attractive, except for eye, CNS(LF
AmB 5 mg/kg) , UTI (pyelonephritis: 0.3–0.6 mg/kg ) ,
oropharyngeal & esophageal
• Echinocandin move ahead, except eye involved
• High risk with asymptomatic candiduria, treat as
candidemia (neutropenic) ; higher dose of fluconazole
(urologic procedure)
• Medication choice : susceptibility, penetration to tissue,
dosage, route , toxicity should be considerate to make
appropriate treatment
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