Management of Candidiasis in ICU

DR AZMIN HUDA ABDUL RAHIM

Content

• Introduction

• Diagnostic tools

• Prophylaxis,preemptive, empirical therapy in ICU,

• Targeted therapy in ICU

Invasive Candidiasis in ICU

15% of nosocomial infection

High morbidity: increase LOS

High mortality :30%-40%

Bassetti et al, Critical care 2010

Crit Care Med. 1999 May;27(5):853-4.

Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections

Surveillance System

Crit Care Med. 1999 May;27(5):853-4.

Candida species was the most common organisms in BSI

C. glabrata 16%

C. albicans 54%

C. parapsilosis 15%

C. tropicalis 8%

C. krusei 2%

other Candida spp 5%

Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747–751.

Species of Candida Most Commonly Isolated in Bloodstream Infections

In an international surveillance study 1997-1998:

Risk factors

• Critical illness with prolonged ICU stay

• Abdominal surgery

• Acute necrotising pancreatitis

• Haematologic malignant disease

• Use broad spectrum antibiotics

• Presence of central vascular catheter,TPN

• Haemodialysis

• Glucocorticoids

• Candida colonisation, multifocal

Pathophysiology

Colonisation of mucous membrane

with candida

Alteration of barrier

function Candidaemia

Prolonged ICU stay Use of antibiotics Critically ill status:APACHEII score

Wounds Surgery Intravascular devices Urinary catheters

Diagnostic Tools

Colonization Index

Candida Score

Prediction Rule

The Colonization Index

Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8 Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8 Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8

• Corrected colonisation Index Score(CCIS)-

CCIS score <0.5 means unlikely to have infection

Has high negative predictive value(91%)

The Candida Score

Coefficient (β) Rounded

Multifocal Candida species colonization

1.112 1

Surgery on ICU admission

0.997 1

Severe sepsis 2.038 2

Total parenteral nutrition

0.908 1

Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7

Calculation of the Candida score:

Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7

The Candida Score

Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7

With a cut-off value of 2.5: sensitivity of 81% and a specificity of 74%, we shall only need the presence of sepsis and any one of the three other remaining risk factors or the presence of all of them together except sepsis in order to consider starting antifungal treatment for one particular patient.

Clinical Prediction Rule

One of the following factors:

Systemic Antibiotic Presence of CVC

+ at least two other risk factors

Total parenteral nutrition

Major surgery

Pancreatitis

Any use of steroids

Use of immunosuppressive agents

Ostrosky-Zeichner L et al. Eur J Clin Michrobiol Infect Dis 2007, 26:271-276

Sensitivity of 34% and specificity of 90%, a positive predictive value of 10% an a negative predictive value of 97%. Helps in ruling out invasive candidiasis

Ostrosky-Zeichner L et al. Eur J Clin Michrobiol Infect Dis 2007, 26:271-276

Diagnosis- culture method

• Blood culture is the mainstay of diagnosis

• Sensitivity of blood culture is 20-71%

• Time to positivity 2- 3days(> 7days)

• Negative if low level/intermittent candidaemia or deep seated candidiasis

NEJM 2015: 373,1445-1454

Can we wait for the blood culture results in candidemia?

• Retrospective cohort analysis 1/2001-12/2004: N=157 patients with candidemia.

• Delay in empiric Rx of candidemia till after blood cultures turn positive resulted in higher mortality.

• Start of anti-fungal Rx >12 hrs of drawing a blood culture that turns positive had AOR= 2.09 for mortality,

• p=0.018. Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9):3640-5

Non-culture method-antigen/antibody

• In a meta-analysis of 14 studies, the sensitivity/specificity for the diagnosis of invasive candidiasis of mannan 58%/93%

• IgG antimannan was reported 59%/83%, respectively

IDSA 2016

Non culture: β-D-glucan

• β-D-glucan is a cell wall constituent of Candida species, Aspergillus, pneumocystis jirovecci.

Advantages:

• Detection can identify cases of invasive candidiasis days to weeks prior to positive blood cultures.

• Shorten initiation of anti-fungal

Non culture: β-D-glucan

• The major concern about β-D-glucan detection is the potential for poor specificity and false positivity

• Preemptive therapy using β-D-glucan suggest high negative predictive value—useful to exclude invasive candidiasis in ICU.

Non culture-PCR

• Candida PCR shares many of the potential benefits and shortcomings of β-D-glucan detection.

• The pooled sensitivity and specificity were 95% and 92% respectively.

PCR

Advantages

• Higher specificity 95%

• Higher sensitivity 92%

• Shorten time to diagnosis of invasive candidiasis

• Capacity to detect species identification

Disadvantages

• Limited role in detection of candidiasis in samples other than blood

Concept of antifungal treatment in critically ill patients

Prophylaxis

• Meta-analysis comparing azole-prophylaxis with placebo, antifungal prophylaxis decrease rate of fungal infections but no significant improved in survival.

[Shorr et al. 2005; Vardakas)

Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: Mortality

E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638 E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638

Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: Invasive Infections

Slide 28

E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638 E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638

Clinical infectious disease 2016; 62:409-17

Prophylaxis

• Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6mg/kg)daily, could be used in high risk patients in adult ICU with a high rate >5% of invasive candidiasis

• (weak recommendation; moderate-quality evidence).

IDSA 2016

Prophylaxis

• Alternative: echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily,micafungin 100 mg daily,anidulafungin 200mg, 100 mg OD)

• (weak recommendation; low-quality evidence)

IDSA 2016

• Daily bathing of ICU patients with chlrohexidine,shown to decrease incidence of bloodstream infections, including candidaemia.

• (weak recommendations,moderate quality evidence)

Empirical therapy

• Empiric antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever

• Should be based on clinical assessment of risk

factors, surrogate markers for invasive candidiasis and /or culture data from non sterile sites

• (strong recommendation;moderate quality evidence)

IDSA 2016

Empirical therapy-non neutropaenic

• Preferred: echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily,micafungin 100 mg daily,anidulafungin 200mg, 100 mg OD

• (strong recommendation; high-quality evidence).

IDSA 2016

• Fluconazole, intravenous or oral, 800-mg (12 mg/kg) loading,400 mg(6mg/kg) daily.

• Alternative to an echinocandin as initial therapy in selected patients ,not critically ill and unlikely to have fluconazole resistant.

• (strong recommendation; high-quality evidence). IDSA 2016

• Lipid formulation AmB, 3–5 mg/kg daily, is an alternative if there is intolerance to other antifungal agents.

• (strong recommendation;low quality of evidence)

IDSA 2016

• Recommended duration of empiric therapy for suspected invasive candidiasis in patients who improve is 2 weeks, same as treatment for candidaemia

• (weak recommendation; low-quality evidence).

IDSA 2016

• Patients who have no clinical response to empiric antifungal therapy at 4-5 days and

• who do not have subsequent evidence of invasive candidiasis after the start of empiric therapy.

• or have a negative non-culture-based diagnostic

IDSA 2016

• Consideration should be given to stopping antifungal therapy

• (strong recommendation;low quality evidence)

Preemptive

Bassetti et al, Critical care 2010

Preemptive therapy

• Small studies basing preemptive therapy on β D,glucan testing suggest high negative predictive value

• Useful to exclude invasive candidiasis

IDSA 2016

Treatment of Candidaemia -non neutropaenic

• An echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily,micafungin 100 mg daily, anidulafungin 200mg, 100 mg OD

• (strong recommendation; high-quality evidence).

IDSA 2016

• Fluconazole, intravenous or oral, 800-mg (12 mg/kg) loading,400 mg(6mg/kg) daily.

• Alternative to an echinocandin as initial therapy in selected patients ,not critically ill and unlikely to have fluconazole resistant.

• (strong recommendation; high-quality evidence). IDSA 2016

Double-blind non inferiority study Involving 245 patients with invasive candidiasis

• Overall response rates were significant

higher with anidulafungin than with fluconazole (76% vs 80% p= 0.01)

• Superiority of anidulafungin over fluconazole

was most distinct in patients infected with

C. albicans (global response, 81% vs. 62%; P = 0.02),

• Transition from an echinocandin to fluconazole (usually within 5-7 days is recommended for patients who are clinically stable

• Or have isolates that are susceptible to

fluconazole eg C.albicans • And have negative repeat blood cultures

following initiation of antifungal therapy • Strong recommendation,moderate-quality evidence). IDSA 2016

• Lipid formulation AmB (3–5 mg/kg daily) is a reasonable alternative if there is intolerance or resistance to other antifungal or limited availability

• (strong recommendation;high quality evidence)

IDSA 2016

• All non-neutropenic patients with candidaemia should have a dilated opthalmological examination by opthalmologist within the first week of diagnosis

• (strong recommendation; low-quality evidence).

IDSA 2016

• Recommended duration of therapy for candidaemia without obvious metastatic complications is for 2 weeks after documented clearance of Candida species from the blood stream

• (strong recommendation; moderate-quality evidence)

IDSA 2016

Should Central Line be removed in Non neutropaenic Patients with Candidaemia?

• CVCs should be removed as early as possible in the course of candidaemia when the source is presumed to be the CVC

• The catheter can be removed safely; this decision should be individualised for each patient

• (Strong recommendation,moderate-quality evidence). IDSA 2016

Does the Isolation of Candida Species From the Respiratory Tract

Require Antifungal Therapy?

• Growth of Candida from respiratory secretions usually indicates colonisation and rarely requires treatment with anti-fungal.

• (strong recommendation; moderate-quality evidence)

IDSA 2016

What is the treatment for intrabdominal candidiasis?

• Empiric antifungal therapy should be considered for patients with clinical evidence of intrabdominal infection and significant risk factors for candidiasis.

• Abdominal surgery, anastomotic leaks, or necrotizing pancreatitis

• (strong recommendation; moderate-quality evidence). IDSA 2016

What Is the Treatment for Urinary Tract Infections Due to Candida

Species?

• Asymptomatic Candiduria

• Elimination of predisposing factors, such as indwelling bladder catheters

• (Strong recommendation; low-quality evidence)

IDSA 2016

Symptomatic Candida Cystitis?

• For fluconazole-susceptible organisms, oral fluconazole, 200mg daily (3mg/kg)for 2 weeks is recommended

• Strong recommendation; moderate-quality evidence.

IDSA 2016

Symptomatic Candida Cystitis?

• Fluconazole resistant : C.glabrata, C.krusei, AmB deoxycholate 0.3-0.6mg/kg for 1 week

• (strong recommendation,low quality of evidence)

IDSA 2016

Conclusion

• Managing candidiasis in ICU remains an enormous challenge

• Diagnostic tools and surrogate markers may assist in diagnosing candidiasis in ICU but with several limitations .

• Prophylaxis(critically ill,ICU) fluconazole in most studies-may reduce infection rate but no improvement in survival

Conclusion

• Empirical therapy has similar recommendation as targeted therapy.

• IDSA guideline 2016-Invasive

candidiasis

Echinocandins is recommended as initial

therapy

Liposomal AmB and fluconazole:

alternatives