Clinical Practice Guideline for the Management of Candidiasis

IDSA 2016 updated Presenter: Yu Tian Hsieh

Preceptor : Pinzy Chen 15th, April

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

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Elizabeth S. Dodds Ashley et al. Clin Infect Dis. 2006;43:S28-S39

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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

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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CANDIDEMIA, PROPHYLAXIS, EMPIRIC IN ICU DISSEMINATED CANDIDIASIS INTRA-ABDOMINAL

Part I.

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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 • Fluconazole

• No difference btw candin and flu-[176]

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• Isavuconazole ≈ vori/posa[ref. ]??

• Espcially , C. parasilo

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]

問 Extensively prophylaxis in hematology patients cause lack meaningful prospective data, and diminished therapeutic role, except maintenance or step-down 去確認

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• New observative data from Spain (n=200) show no difference of outcome [176]

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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%)

Results

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Initially echinocandin in C. parapsilosis candidemia doesn’t affect outcome

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Primary

Secondary

No difference of C. parapsilosis BSI btw Azole & echinocandin

CVC REMOVAL DURING ANTIFUNGAL THERAPY IN CANDIDEMIA

A recently study

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Clin Infect Dis.-2012-Andes-1110-22

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)

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CVC removal & APACH II score

15 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

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]

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 )

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

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] 20

Part II. outline Candida isolated • respiratory tract not recommended (not change) Candidiasis • Intravascular infections

(endocarditis & implantable cardiac devices & pericarditis/myocarditis)

• Osteomyelitis & septic arthritis • UTI • Endophthalmitis • CNS • Oropharyngeal & Esophageal (not change) • Vulvovaginal (not change) • Neonate

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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

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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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

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 25

TDM : 2- 5 μ g/ml

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

26 S& S : sign and symptom

Oropharyngeal & esophageal candidiasis

• Who: commonly occur in immunocompromised patients, like HIV infection, malignancies, steroid use, leukemia…

• Presentation: Dysphagia, odynophagia

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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

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

Summary –1 Treatment

• 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 30

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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THANK YOU FOR YOUR ATTENTION !!!

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