Management of Candidemia in critically ill patients

Dr Ram Gopalakrishnan

Main pathogens

• Yeasts - look creamy, surface dissemination – Candida (70%) – Cryptococcus

• Moulds - look fuzzy, airborne dissemination – Aspergillus (20%) – Mucor

• Dimorphic fungi – Histoplasma capsulatum – Penicillium marneffii

Average mortality in IFI

• Candida 30%

• Aspergillus 50-60%

• Moulds 50-80%

• Unusuals (eg Scedosporium) 90%

Case

• 64 M with acute necrotizing pancreatitis, admitted 10 days ago.

• PMH: DM on insulin, CKD with creatinine of 1.8, seizure disorder on carbamazepine

• Right subclavian line placed on admission, through which TPN being given

• Foley catheter in situ

• On piperacillin-tazobactam for last 10 days

• Develops fever

Exam & labs

• Temp= 103

• HR= 130, BP=90/60, RR=24

• pH=7.3, bicarb=18, paO2=60

• WBC=28,000, platelets=68,000

• Creat=2.8

• Bili=3.3, ALT=40

Fever could be due to

• Central line infection

• Pancreatic abscess

• Urinary tract infection

• Disseminated candidiasis

• SIRS due to severe pancreatitis

What will you start immediately after drawing blood cultures?

• Vancomycin

• Imipenem

• Antifungals

• Nothing, wait for culture reports

Which antifungal?

• Fluconazole

• Voriconazole

• Amphotericin B deoxycholate

• Lipid associated amphotericin

• Anidulafungin

Blood culture is reported as growing yeast at 24hrs. You will give?

• Continue fluconazole

• Voriconazole

• Amphotericin

• Lipid associated amphotericin

• Anidulafungin

Fluconazole was continued, patient deteriorated

• Continue fluconazole

• Voriconazole

• Amphotericin

• Lipid associated amphotericin

• Anidulafungin

Candida species identified as krusei

• Continue fluconazole

• Voriconazole

• Amphotericin

• Lipid associated amphotericin

• Anidulafungin

Course of patient

• Anidulafungin started, central line changed

• Recovered slowly over next one week

• Funduscopic exam normal

Epidemiology of Candida • Part of the normal bowel flora • Grows out when normal bowel flora wiped out by antibiotics • Increasing in incidence worldwide, fourth commonest

bloodstream isolate in USA • Incidence per 1000 admissions varies by country:

– Brazil: 24.9 cases – South Africa: 8-21 – USA: 8 – India: 6.51

• Attributable mortality as high as 49% • Typically considered a late onset nosocomial infection but now

37% detected within 5 days of ICU stay – Crit Care Med 2009;37;1612

• Can be hand transmitted and cause outbreaks, especially C.parapsilosis in the neonatal ICU

Emerging trends in Candidemia: USA • Reduced incidence in neonates, rising in >65 y olds • Second Candidemia episode in 7% within 30 days • Polymicrobial candidemia being seen • US data: 7% fluconazole resistance, 1% echinocandin resistance • Echinocandin Resistance Increasing in C.glabrata

– from zero in 2001-2004 to 8-9% in 2006-2010 – increased from 4.9% to 12.3% and to FLC from 18% to 30%

between 2001 and 2010 at one center • Prior exposure was risk factor

• Mutations in the FKS1 and FKS2 genes are associated with echinocandin resistance.

• identified in 18% of 72 patients with C. glabrata candidemia. • Common risk factors for FKS mutant isolates included previous

echinocandin exposure [OR], 19.9; which also influenced response rates.

(J Clin Microbiol 2012 Jan 25; [e-pub ahead of print]. (http://dx.doi.org/10.1128/JCM.06112-11)

Clin Infect Dis. (2013) 56 (12):1724-1732.doi: 10.1093/cid/cit136

Clin Infect Dis. (2012) 55 (10):1352-1361. Clin Infect Dis. (2014) 59 (6):819-825.

Predisposing factors for invasive disease

• Central line

• Broad spectrum antibiotics

• TPN

• Diabetes

• Steroids

• Colonization at more than one site

• Foley catheter

• Chemotherapy induced neutropenia

• Burns

• Abdominal surgery

• Neonates

• Hemodialysis

Clinical prediction rule

• Mandatory: – systemic antibiotics

– presence of a CVC

• Two additional risk factors: – TPN, dialysis, steroid use, major surgery,

pancreatitis, other immunosuppressants

• Sensitivity 34%, specificity 90%

• Negative predictive value 97% – Eur J Clin Microbiol & Infect Dis 2007;26:271

A bedside scoring system for early antifungal treatment in non-neutropenic critically ill patients

Candida Score

• 1 for TPN • 1 for surgery • 1 for multifocal colonization • 2 for clinical severe sepsis

• CS score >3 and 1-3 beta d glucan level>75

independent predictors of invasive candidiasis

Crit Care Med 2006;34(3):730, Crit Care Med 2009;37:1624

Candida species ID is essential • C.albicans

-2% fluconazole resistant

• C. tropicalis – 9% fluconazole resistant

• C.parapsilosis – 5% fluconazole resistant – High echinocandin MIC

• C.guillermondii

• C.glabrata – fluconazole dose dependent in 20%,

resistant in 20% • C.krusei

– Inherently resistant to fluconazole • C.haemolunii

– Resistant to fluconazole • C.lusitaniae

– resistant to amphotericin

Candida Species Causing Bloodstream Infection Worldwide & India

Species USA 1997

Latin America 1997

Europe 1997

India 1991-2000

C. albicans 56 41 53 14

C. parapsilosis 9 38 21 2

C. glabrata 19 2 12 3

C. tropicalis 7 12 6 38

C. guilliermondii 1 2 4 12

C. krusei 2 - 1 5

Other Candida

species

6 5 3 26

Chakrabarti A. J Postgrad Med 2005;51:S16-S20

Ther Clin Risk Manag. 2014; 10: 95–105.

Ther Clin Risk Manag. 2014; 10: 95–105.

Latest multi-center Indian data • 1400 patients in 27 Indian ICUs studied • 6.51 cases per 1000 ICU admissions • Even patients with lower APACHE II score at admission

(median 17.0) • Median time to candidemia is 8 days • 30-day crude and attributable mortality rates of

candidemia patients were 44.7 and 19.6 %, respectively

• C.tropicalis commonest (41.6 %) • Followed by C.albicans (21%), C. parapsilosis 9.9% • C. hemulonii (5%), C.glabrata (5.2%) • Azole resistance in 11.8% • >98% echinocandin sensitive

Intensive Care Med 2015;41(2): 285

Summary of Malaysian data

• Typical risk factors

• C.albicans

• C.tropicalis

• C.parapsilosis

Who gets albicans, who gets non-albicans?

• Albicans :

– Receipt of TPN reduces risk (RR=0.16) (Clin Infect Dis 2008;46:1206)

• Non-albicans: – Receipt of prior

fluconazole (RR=11)

– Previous fluconazole exposure predisposes to fluconazole resistant C. glabrata

– (Arch Intern Med 2009;169;379)

Susceptibility testing

• Species ID is most important

• Do susceptibility testing routinely for all blood culture isolates

• Do for other sites if

– Not responding to therapy

– Azole resistance suspected

Clinical features of invasive candidiasis

• Types

– Candidemia without tissue organ involvement

– Invasive candidiasis without candidemia

• Invasive disease can present as

– Asymptomatic patient with positive blood culture

– ICU fever

– Severe sepsis/ septic shock

Candidemia- skin lesions

Candida endophthalmitis

Blood cultures for diagnosis of invasive candidiasis

• Culture at least 40 ml of blood in aerobic & anaerobic bottles, 5-30 minutes apart

• Sensitivity of Automated Blood Culture Systems : 55% to 70% Ann Intern Med 2005;143:857-869

• 83% in more recent studies

• Slow turn-around-time: • Blood culture collection to positive signal (median time

~35 hours)

• Positive signal to species identification & susceptibility results (at least 24-48 hours)

Pan fungal (1,3- Beta-D mannan) antigen

– Think of as “fungal endotoxin”, very non-specific – Gaps: Mucor sp, cryptococcus, blastomyces – Cut-off is 80 pg/ml – Sensitivity of 76% and specificity of 85% in meta-analysis (Clin infect Dis

2011;52:750)

-β-D-glucan levels ≥80 pg/mL predicted intra-abdominal candidiasis and did so a median of 5 days before culture positivity (Am J Respir Crit Care Med 2013 Nov 1; 188:1048).

• Yield in Candidemia (CID 2012)

• Blood culture + PCR: 98% • Blood culture + Beta d glucan: 79%

Useful both in neutropenic patients and ICU setting- sensitivity 71% and specificity 81% (Clin Infect Dis 2009;49:1650)

Earlier diagnosis of Candida BSI

Direct detection in blood culture – Mannan/anti-mannan recommended by ESCMID – PCR – SeptiFast (Roche), SeptiTest, Viracor-IBT – MT-PCR Once blood culture flags – MALDI-TOF – PNA-FISH:

• differentiates albicans/parapsilosis, tropicalis, glabrata/krusei within 2.5 hrs

– Oligonucleotide arrays – MT-PCR

T2 Magnetic Resonance Assay for the Rapid Diagnosis of Candidemia in Whole Blood

• T2Dx lyses the red blood cells, concentrates the pathogen cells and cellular debris, lyses the Candida cells by mechanical bead beating, amplifies Candida DNA using a thermostable polymerase

• finally detects amplified product by amplicon-induced agglomeration of supermagnetic particles and T2MR measurement

• overall sensitivity was found to be 91.1%

• overall specificity per assay of 99.4%

• mean time to negative result of 4.2 ± 0.9 hours

• 3 results are reported: – C. albicans/C. tropicalis

– C. krusei/C. glabrata

– C. parapsilosis

• FDA approved

Clin Infect Dis 2015 60: 892-899

Mortality Related to Delays in Therapy for Candidemia

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Administration of Antifungal Treatment

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Retrospective cohort study of 230 patients from 4 medical centers2

2Garey KW et al. Clin Infect Dis 2006;43:25-31

When you think of Candida, cover it!

Mortality falls from 97% to 52 % in Candida septic shock if antifungals started within 24 hrs and source controlled.

Study in neonates: empirical antifungal

treatment had lower neuro-developmental impairment and mortality (50% vs 64%; P=0.03)

(Clin Infect Dis 2012 published 15 March 2012, 10.1093/cid/cis305 (J Pediatr 2012 Aug; 161:264)

Available antifungal drugs

Amphotericin B deoxycholate Lipid associated amphotericin 5-flucytosine • Azoles

– Fluconazole – Itraconazole – Voriconazole – Posaconazole – Isavuconazole

• Echinocandins – Caspofungin – Micafungin – Anidulafungin

Amphotericin B deoxycholate

• Broadest spectrum drug, gold standard • Only parenteral agent against Mucormyces • Nephrotoxic • Dose varies:

– 0.7 mg/kg/day for Candida albicans – 1.0 mg/kg if glabrata/krusei – 1.5-2 mg/kg for molds

• Continuous infusion over 24 hrs & saline loading will reduce nephrotoxicity

• Gaps in spectrum: – C. lusitaniae – Scedosporium – A. niger, A. terreus

Lipid associated amphotericin

• Many preparations available – Liposomal has maximum efficacy data – Colloidal dispersion

• Dose is – 3mg/kg for Candida – 3-5 mg/kg against Aspergillus – 5-10 mg/kg against other moulds

• Reduces but does not eliminate – Infusion related toxicity – nephrotoxicity $$$$ !!

Fluconazole

Narrow spectrum yeast drug

Dose is 12 mg/kg for systemic mycoses inadequate doses is a risk factor for mortality

Dose is 600-800 mg in adults

C. glabrata /krusei /haemulonii resistant

Combination of levofloxacin/fluconazole associated with a significant increase in QTc (mean, +9.5 milliseconds) (Antimicrob

Agents Chemother 2013 Mar; 57:1121)

Completely dialysed dose is 600 mg q12h in CRRT (better to avoid)

Voriconazole

• Broad spectrum azole with coverage against most fungi except mucor

• Best agent vs Aspergillus • Equivalent to amphotericin for Candidemia • Good CNS penetration • Trough plasma levels between 1.5 and 4.5

mg/L were associated with –a probability of clinical response >85% –a probability of neurotoxicity <15%

Dosing of voriconazole

• Loading dose

– 6mg/kg IV bd

• Maintenance dose

– 3-4mg/kg bd IV

– 200 mg bd orally • IV preparation has a cyclodextrin vehicle

– accumulates if creat cl<50 and is potentially nephrotoxic

– median serum creatinine decreased on iv voriconazole for 7d

– Voriconazole route of administration was not predictor of worsening renal dysfunction

(Antimicrob Agents Chemother 2012; 56:3133–7) EOT (Clin Infect Dis 2012 published 19 January 2012, 10.1093/cid/cir969

Echinocandins

• Narrow spectrum drugs active vs Candida & Aspergillus

• Only parenteral preparation available

• Gaps in spectrum: – No activity against cryptococcus and mucor

– C. parapsilosis has higher MIC

• Poor CNS & eye penetration, no urine levels

• Minimal toxicity

Caspofungin

• May be synergistic with amphotericin vs Mucor • Dose is 70 mg load, then 50 mg daily • No dosage adjustment for renal dysfunction • Reduce dose for severe hepatic dysfunction • drug interactions with tacrolimus, cyclosporine,

rifampicin • Approved for

– disseminated candidiasis – salvage therapy of aspergillosis – persistent febrile neutropenia

Micafungin

• Equivalent to caspofungin for systemic candidiasis

• Approved in children

• Exact dose unclear

• Interaction with sirolimus, nifedipine

• Theoretical concern re hepatic tumors in animals

Anidulafungin

• No drug interactions

• Loading dose 200 mg first day, then 100 mg daily

• No dosage adjustment for liver or renal dysfunction

Trials in candidemia

• Pre-1994: Amphotericin was the gold standard

• 1994: fluconazole = amphotericin (NEJM)

• 2003: caspofungin same as amphotericin, fewer side effects (NEJM)

• 2003: amphotericin + 12 mg/kg fluconazole better than amphotericin alone (CID)

• 2005: voriconazole = amphotericin (Lancet)

• 2007: anidulafungin better than fluconazole (NEJM)

• 2007: micafungin = liposomal amphotericin (Lancet)

• 2007: micafungin = caspofungin (CID)

Treatment guidelines for candidemia

• Drugs of choice: – IDSA: Echinocandin or fluconazole – ESCMID: Echinocandin –Amphotericin or lipid associated

amphotericin acceptable if intolerance or limited availability of above

–Voriconazole effective but offers little benefit over fluconazole and recommended as step down therapy only

(Clin Infect Dis 2009; 48;503) (Clin Microbiol Infect 2012;18(suppl 7:19-37)

Empiric therapy of suspected disseminated candidiasis in non-neutropenic host

• Severe or moderately severe illness : echinocandin

• Less severely ill, no previous azole exposure: fluconazole (IDSA)

• Recent azole exposure: echinocandin

• Renal dysfunction:

– Echinocandin or fluconazole

– avoid amphotericin and parenteral voriconazole

Review of 1915 patients from 7 candidemia trials

• Overall mortality was 31.4%

• Rate of treatment success was 67.4%.

• Increased mortality with

– Increased age/APACHE score/ immunosuppression

– C. tropicalis • Reduced mortality

– removal of a CVC (OR, 0.50)

– treatment with an echinocandin (OR, 0.65) • 30 day mortality was 27%, compared with 36% for

other regimens

Clin Infect Dis 2012 published 12 March 2012, 10.1093/cid/cis021

Adjunctive measures

• Emphasize species ID and susceptibility • Repeat blood cultures q24-48h till cleared • Treat for two weeks after resolution of

symptoms and last positive blood culture • Step down treatment to azole acceptable after

10 days • Look for endocarditis with TEE (ESCMID) • One dilated eye exam later in course of therapy essential

– Ocular involvement seen in 16% – Albicans has greatest propensity – However endophthalmitis seen only in 1.6%

Transition therapy in Candidemia after species ID and clinical stability

• C.albicans: fluconazole

• C.tropicalis: fluconazole or voriconazole

– amphotericin or caspofungin for poor responders

• C.glabrata: echinocandin or amphotericin 1 mg/kg, transition to azole only if susceptibility available

• C. parapsilosis: fluconazole

• C.krusei: voriconazole

• C.lusitaniae: echinocandin

• Emerging strategy: de-escalation as early as day 3

Scenarios when empiric therapy started

• Candidemia confirmed: Treat as per guidelines • Patient clinically better, no confirmation, no other

cause of sepsis identified: Finish 10-14 day course of anti-fungals

• Patient continues to remain septic, no confirmation: – Look for alternative etiologies – ? Stop anti-fungals – Randomized trial of ICU patients who had fever on broad

spectrum antibiotics of fluconazole 800mg daily for 14 days or placebo (Ann Intern Med 2008;149:83)

• Success rates 36% vs 38% • So no role for routine empiric therapy

Emerging strategy: Stop empiric therapy at day 3 if blood culture/PCR/Beta d glucan all negative

Role of fluconazole

• Inferior to anidulafungin in RCT

• Only in hemodynamically stable patients without fluconazole exposure

• Less expensive

• Consider as first line if source is urinary tract

• If used, give a loading dose of 12 mg/kg and then 6-12 mg/kg

Role of amphotericin B deoxycholate

• Equivalent to caspofungin but more side effects

• Nephrotoxic, especially in severe sepsis

• Requires 24h infusion

• C.krusei may be resistant

• Only advantage is cost

When patient fails, consider

• Retained foreign bodies

• Clots

• Undrained abscesses

• Resistance to antifungal used

• Other causes of fever

Candiduria

• Common in ICUs

• Risk factors: broad spectrum antibiotics, urinary tract instrumentation, old age

• Foley catheter is main route of entry

• Can result from ascending infection or via hematogenous seeding

• Cannot reliably distinguish colonization from true infection- need to clinically decide

Treatment of candiduria

• Change of Foley resolves 20%

• Removal of Foley resolves 40%

• Fluconazole 200 mg for 14 days vs placebo: initial clearance but 4 week rates same

• Treat – Symptomatic or septic patients

– renal allograft, urologic instrumentation, neutropenic patients

– ELBW neonates – always at high risk for disseminated disease

CID 2012:54 (1 February) 331

Treatment options for candiduria

• Fluconazole

• Amphotericin deoxycholate

• ?Flucytosine

• ?Amphotericin bladder wash

• Voriconazole & echinocandins achieve levels in renal parenchyma but not in urine

Candida in the respiratory tract

• Candida part of normal respiratory flora, grows out in patients on antibiotics

• Rarely a cause of pneumonia-either via aspiration or via hematogenous route

• No cases of Candida pneumonia at autopsy of 135 patients with pneumonia (77 patients with positive airway cultures and 62 patients without)

• Intensive Care Med 2009;35:1526

• Treatment not indicated on grounds of a positive ET culture alone- invasive pneumonia found only in ~6%

• However can be a risk factor for disseminated Candida

Candida prophylaxis in the medical ICU

• Caspofungin vs placebo trial for prophylaxis

– difference was not statistically significant

– costly and may preclude use of echinocandins for therapy

• IDSA guideline

– recommends prophylaxis for selected patients in ICUs with high rates of Candidemia

– strategy does not reduce mortality

(Clin Infect Dis. (2014) 58 (9): 1219-1226. )

Prophylaxis against Candida in the surgical ICU

• Abdominal surgery patient or patient with GI perforations or anastomotic leakages

• Indicated in the high risk patient only with

– Broad spectrum antibiotic exposure

– Central line

– TPN

– Hyperglycemia

• Fluconazole 400 mg daily effective Crit Care Med 2004;32:2443

In conclusion

• Suspect Candidemia/ disseminated candidiasis in any critically ill patient with a central line and broad spectrum antibiotic exposure

• Blood cultures and newer diagnostics should be used

• Start therapy as soon as cultures drawn

• Echinocandins are the drugs of choice for empiric and definitive treatment