Empiric Antifungal Therapy in the ICU

Ramzi Moufarrej, M.D

Chief of Critical Care

Zayed Military Hospital / Abu Dhabi

Introduction• Invasive fungal infections have increased

significantly over the last 2 decades.– aging population with life sustaining therapies like

renal dialysis – broad spectrum antimicrobial therapy and invasive

medical devices – bone marrow transplantation (BMT) & solid organ

transplantation (SOT)– intensive chemotherapy for malignancies– HIV/AIDS epidemic.

National Epidemiology of Mycosis Survey (NEMIS) was a prospective, multicenter study conducted at 6 US sites from 1993–1995 to examine rates of risk factors for the development of candidal bloodstream infections (CBSIs) among patients in surgical and neonatal intensive care units >48 hours. Among 4276 patients, 42 CBSIs occurred.

Adapted from Blumberg HM et al, and the NEMIS Study Group Clin Infect Dis 2001;33:177–186; Garber G Drugs 2001;61(suppl 1):1–12.

Risk for Invasive Mycosis•Non-Neutropenic related to barrier breakdown, change in colonization.

– Acute renal failure (RR 4.2)– Parenteral nutrition with intralipid (RR 3.6)– Prior surgery specially GI (RR 7.3)– Indwelling central line ? Triple lumen (RR 5.4)– Broad spectrum antibiotics– Diabetes – Burns– Mechanical Ventilation– Steroids

•Neutropenic related to above plus immune cell suppression and underlying malignancy.

•Severe immunosuppressive: BMT or SOT

Invasive Mycosis

Candidiasis Aspergillosis

Decreasing immunity

SOT or BMT

MICU or SICU

Barrier immunity

Barrier plus cellular immunity

Oncology

• Polyenes– Amphotericin B (AmB) or Liposomal AmB (kidney toxicity)

• Azoles– Fluconazole 400-800 mg/day (liver toxicity, CYP450)– Voriconazole (liver toxicity, visual disturbances, CYP450)– Posaconazole (liver toxicity, CYP450)

• Echinocandins – Caspofungin iv (liver toxicity)

• Combination ex. AmB/ Fluconazole (liver, kidney toxicity)

Choice of agents depends on whether the patient on previous azole prophylaxis, culture results, local fungal sensitivity, colonization, renal or liver disease, presence of drug-drug interactions, presence of hardware, immuno -suppresion, site of disease ex. urine.

Treatment of Invasive Mycosis

Site of Action of Selected Anti-fungal Agents

Adapted from Andriole VT J Antimicrob Chemother 1999;44:151–162; Graybill JR et al Antimicrob Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Expert Opin Invest Drugs 2001;10(8):1545–1558.

Cell membranePolyenes AmB (sterols)

Azoles Fluconazole (CYP450)

Cell wall Echinocandins Caspofungin (Glucan

synthesis inhibitors)

Focus on Candidiasis• Invasive Candida infections:

– 4th most common nosocomial bloodstream infection in the USA with mortality approaching 40% in line related candidemia*

*In a 3-year (1995–1998) surveillance study of 49 hospitals in the United States.

Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244; Andriole VT J Antimicrob Chemother 1999;44:151–162; Uzun O, Anaissie EJ Ann Oncol 2000;11:1517–1521.

Coagulase-negative staphylococci 3908 31.9Staphylococcus aureus 1928 15.7Enterococci 1354 11.1Candida species 934 7.6

Pathogen No. of Isolates Incidence (%)

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:

Since then increase in Candida spp. with higher incidence of fluconazole resistance.Snydman DR. 2003. Chest 123(Suppl 5):500S-503S). Garbino J. et al. 2002. Medicine;81:425-433.

Invasive Candidiasis in the ICU

• Common in the ICU (9.8/1000 admissions) with high morbidity (increased LOS ~22 days) & mortality (~ 30-40%) resulting in increased cost (~ $44,000/ episode).

• Difficult to diagnose (cultures positive in only ~ 50%). • We can define ICU risk factors for candidiasis and

target the population at highest risk with empiric Rx.• Recent increase in Candida spp. resistant to Diflucan. • Advances in antifungal therapy have resulted in agents,

like echinocandins and triazoles, with high activity, a broad spectrum, and low toxicity ideal for empiric therapy and combination therapy options.

Prophylaxis and treatment of invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis. 2004:23; 739-744.

Major Risk Factors

• Prior antibiotic use, central venous catheters, total parenteral nutrition, major surgery within the preceding week, steroids, dialysis and immunosuppression.

• Intensive care unit length of stay is an important risk factor, with the rate of infections rising rapidly after 7-10 days.

Dimopoulos G, et al. Candidemia in immunocompromised and immunocompetent critically ill patients: a

prospective comparative study. Eur J Clin Microbiol Infect Dis. 2007

Risk Factor Selection

Underlying disease

Antibiotics

Colonization

Fever

Selection

Skin ormucosadamage

Infection

MalignancyDiabetesRenal diseaseCTD on steroidsMalnutrition on TPNMechanical Ventilation > 48hBurns

InstrumentsCV Catheter Knife

Invasive Candidiasis After Colonization and Bacteremia

Bacteremia

Colonization

AcuteInvasiveCandidiasis

81 patients

YES 35NO 46

- + +++14 24 8

- + +++ 7 13 15

1 0 0 0 1 8

53%Guiot et al. CID.1994;18:525-32

Laboratory Diagnosis

• Microbiology methods: – Recovery of Candida species from sterile sites (ex. blood,

peritoneal fluid) is diagnostic of IC and recovery from multiple non-sterile sites is highly suggestive of IC in the at-risk patient.

– Blood culture is positive in less than 50% of patients with autopsy proven IC.

• Molecular methods:

– early identification ex PNA FISH

• Serological methods: – early diagnosis ex. 1,3 beta D glucan assay.

• Histopatholgic methods.

Clinical DiagnosisThe clinical manifestations of IC are nonspecific, but may include:

• Fever and progressive sepsis with multi-organ failure despite antibiotics.

• Invasive candidiasis (IC) related cutaneous lesions.– Macronodular rash frequently confused with drug allergies. A

biopsy of the deeper layers of skin particularly the vascularized areas and the dermis is important.

• Ophthalmic lesions (Candida endophthalmitis).– A fundoscopic evaluation for the presence of Candida

endophthalmitis should be performed in patients with candidemia.

Therapy of IC in the ICU

• A definitive diagnosis of IC may be delayed when the clinical and laboratory tools readily available to clinicians are used to assess patients for Candida infection.

• A delay in diagnosis will unfortunately result in a delay in initiation of antifungal therapy, which is associated with increased mortality*.

• Therefore, in the patient with suspected Candida infection, treatment may need to be initiated on the basis of individual patient factors before a definitive diagnosis is made.

*Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9): 3640-5.*Garey K et al. 2006. Clin Infect Dis. 43: 25-31.

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 

Treatment of Suspected Invasive Candidiasis (Definitions)

• Prophylactic therapy: protective or preventive therapy given to everyone in a given class (ex. BMT patients who are at very high risk for IC).

• Preemptive therapy: therapy given to deter or prevent anticipated infection; patients at risk are monitored closely and therapy is initiated with early evidence suggesting infection (ex. positive Candida cultures at non-sterile sites, clinical suspicion) with the goal of preventing disease.

• Empirical therapy: therapy guided by practical experience and observation, but with nonspecific evidence in a given patient (ex. therapy is started because a cancer patient has remained febrile after several days of broad-spectrum antibiotics).

• Directed therapy: is based on a clinical or laboratory finding indicating that an infection is present (ex. positive blood culture for Candida species).

Timing of Intervention

basic disease

refractory fever

aspecific symptom ± early markers

specific symptom

suppressive Rx

infection

Progression

Empiric

Pre-emptive

Prophylactic

Directed

Prophylactic, Preemptive or Empiric Use of Anti-fungals

• PROS– High Mortality

– Difficulty in Diagnosis

– Undetected Infection

– Reduced systemic mycoses and improved mortality with prophylaxis

• CONS– Toxicity

– Expense

– Diagnosis not certain• Too much treatment without

infection• Too little treatment with

infection

Fluconazole Prophylaxis and Colonization of Neutropenic Patients

Winston et al. Ann Intern Med. 1993;118:495-503

Candida prophylaxis in the Surgical ICU(patients with high risk for candidemia)

• Eggiman et al. 1999. CCM 27: 1066-1072.– Fluconazole reduced candida peritonitis and colonization in 43 patients with

complicated GI surgeries. High risk patients ? Was it preemptive therapy.

• Pelz et al. 2001. Ann Surg. 233: 542-548.– Fluconazole reduced candida infection in critically ill surgical patients in SICU

> 3 days. No mortality benefit.– Predictors included: APACHE II score, fungal colonization, TPN, days to first

dose of prophylactic drug.

• Paphitou et al. 2005. Med Mycol. 43(3):235-43. – 327 patients in SICU > 3 days were reviewed to identify predictive factors.– Combination of DM, HD, TPN, broad-spectrum antibiotics had an invasive

candidiasis rate of 16.6% versus a 5.1% rate for patients lacking these characteristics (P = 0.001). The rule captured 78% of patients with IC.

Candida Prophylaxis in MICU & SICU (MV > 48h & expected LOS > 72h)

Garbino et al. Intensive Care Med. 2002;28:1708-17

Incidence of IC=16%

Incidence of IC=5.8%

Summary (Candida Prophylaxis)

• Prophylaxis is effective in the highest risk patients.

• Prophylaxis reduces the incidence of IC. • A positive impact on mortality has not been

shown except in severely immunocompromised hosts (neutropenia, BMT, or solid organ transplantation).

• Distinction between prophylactic & preemptive therapy needed specially in ICU. Risk ? Dose?.

Assessment of Preemptive Treatment to prevent severe candidiasis in SICU

• Before/after intervention study (2 years prospective & historical) • Systematic mycological screening on all patients admitted to the

SICU ≥ 5 days, immediately at admittance and then weekly until discharge. Patients with colonization index ≥ 0.4 (used to assess intensity of mucosal colonization) received early preemptive antifungal Rx (fluconazole IV 800mg, then 400 mg/day for 2 wks).

• Candida infections occurred more frequently in the control cohort

(7% vs. 3.8%; p = .03). Incidence of SICU-acquired proven candidiasis significantly decreased from 2.2% to 0% (p < .001). No emergence of azole-resistant Candida species was noted during the prospective period.

Piarroux, et al..Crit Care Med. 2004 Dec;32(12):2443-9.

Arch Surgery. 2001;136: 1401-1409

Temporal Assessment of Candida Risk Factors in the SICU

Pearls of the study

• Change in Candida risk factors over time is clinically relevant.– Early risk factors at day 1, time of SICU admission.– More than 8 risk factors at any time– Rapid increase in risk factors (clinical deterioration)– APACHE II score > 18 day 3 or 4

• Early risk factor maybe evident from day 1 & maybe used with progression of risk factors as fever, duration of antibiotics & mechanical ventilation to assess risk.

• ? more aggressive surveillance cultures vs. preemptive or empiric therapy.

Serological Methods ? early aid in empiric therapy decision making

• Plasma beta-D-glucan, a cell wall constituent of fungi, was measured before starting antifungal therapy empirically on postoperative patients, colonized with candida & having risk factors for candida infection.

• 47% of those with positive test responded to Rx but 9% of those negative responded (p<.01) (OR= 13).

• Number of sites colonized with candida also predicted response. Colonization at ≥ 3 sites vs. 1 site (p=0.03) (OR=7.57).

• In postoperative patients colonized with candida, & with fever despite antibiotics a beta-D-glucan assay was useful for deciding whether to start empiric therapy.

Takesue Y et al. World J Surg. 2004; 28(6): 625-30.

Research Ongoing• Randomized Study of Caspofungin Prophylaxis

Followed by Pre-Emptive Therapy for Invasive Candidiasis in the ICU.

• The study will test the possibility that caspofungin can successfully reduce the rate of candida infections in subjects at risk. It will also test if caspofungin is useful in treating subjects for this disease when diagnosed using a new blood test that is performed twice weekly, permitting earlier diagnosis than current practice standards.

• This study is currently recruiting participants. Mycoses Study Group, August 2007

Considerations in Selection of Empiric Antifungal Therapy

High-risk host with hematologic cancer, or stem cell transplantation, severe immunosuppression, hemodynamic instability, gut dysfunction or medication noncompliance use IV agents.   

Prolonged and recent exposure to azoles prior to current episode or significant liver dysfunction or drug-drug interaction avoid azoles.

Pathogen in vitro susceptibility pattern is known for a class of agents, select an agent that is likely to be effective against the specific pathogen.

Site of Infection: • Ocular or central nervous system infection avoid echinocandins.

Can use liposomal amphotericin B, fluconazole or voriconazole.• Urinary ex. cystitis select fluconazole or 5-flucytosine.

Walsh et al. N Engl J Med. 2004; 351:1391-1402.

Overall adjusted success rate

0

10

20

30

40

33.9%

50

33.7%

2.6% 11.5% 10.3%

14.5%

Nephrotoxic effect(p<0.001)

Discontinued the study prematurely (p=0.03)

Caspofungin Liposomal AmB

Empiric Caspofungin in Patients with Neutropenia and Persistent fever

Per

cent

of

Pat

ient

s

Caspofungin had significantly fewer : Drug-related clinical or lab adverse events, and

discontinuations due to serious drug-related clinical or lab AEs .

**

Empiric Caspofungin vs. liposomal AmB in persistent Fever and Neutropenia

Per

cent

su

rviv

al

Caspofungin (n=556)L-AmB (n=539)

Study day

p=0.044

21 28 35 637 14 564942

0

90

100

80

70

60

50

10

20

30

40

Superior in preventing overall mortality with less toxicity.

Walsh et al. N Engl J Med. 2004;351:1391-1402

Candidemia in Non-neutropenic ICU Patients. Risk Factors for Non-albicans Candida Spp.

• Nationwide Australian prospective cohort study.• Patients with ICU-acquired candidemia over 3 yr.• Measured clinical risk factors occurring up to 30 days

preceding candidemia.• C albicans 62%, C glabrata 18%, C parasilopsis 8%, C

tropicalis 6%, C krusei 4%, Other Candida spp. 2%• Independent risk factors for NCA or potentially

fluconazole-resistant species: age (OR 1.3), recent GI surgery (OR 2.9), prior exposure to systemic antifungal agents (OR 4.6) especially fluconazole (OR 5.7).

EG Playford et al. Crit. Care Med. 2008; 36(7): 2034-2039.

Empiric Anti-Candida Therapy: Cost-Effectiveness

• Target: Patients in the ICU > 3 days and unresponsive to antibacterial therapy for > 3 days.(~40% all candidemia).

• Strategies compared: Fluconazole, Caspofungin, AmB and Liposomal AmB.

• Estimates: R to Fluconazole =5%, cost of Caspofungin = 381$/day, Diflucan=135$/d, IC in target population =10%.

• Results: Caspofungin the most effective but Fluconazole more cost-effective.

• If R to Fluconazole > 28% or if IC prevelance = 60% or if cost of caspofungin <160 $/day then Caspofungin more cost effective.

Golan et al. 2005. Ann Intern Med;143:857-869.

Algorithm for Empiric Therapy

• Empiric treatment for invasive candidiasis based on the hemodynamic status of the patient.

• Unstable patients: broad-spectrum antifungal agents, which can be narrowed once the patient has stabilized & the identity of the infecting species is established.

• In stable patients: fluconazole, provided that the patient is not colonized with fluconazole resistant strains or there has been recent past exposure to an azole (<30 days).

• In contrast, pre-emptive therapy is based on the presence of surrogate markers ex colonization index.

Spellberg et al. (2006). Clin Infect Dis 42:244–251

Summary (Empiric Therapy)

• In the patient with septic shock risk factors for candidemia should be evaluated.

• If Candida infection is suspected, treatment will need to be initiated empirically without delay on the basis of individual patient factors before a definitive diagnosis is made*.

• Choice of agent will rely on local resistance patterns, microbiology data, prior azole therapy, recent GI surgery, neutropenia, hemodynamic stability, & other host factors.

• Azoles are effective unless high rates of resistance, or neutropenia in which case echinocandins or triazoles should be used.

* Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: CCM 2008

Directed Therapy

• Azoles: Fluconazole is the most common agent used to treat clinical Candida infections. However, fluconazole has limited activity against C glabrata and C krusei. The evolution of resistance and trends toward more non-albicans species, may limit its role in the future.

• Triazoles have a role in NCA and immune suppressed patients.• Amphotericin B: active but is not superior to other therapies and

therefore does not justify the risk for toxicity. Liposomal AmB is the least toxic.

• Echinocandins: shown to be as, if not more, effective than AmB and L-AmB & are not associated with significant resistance. Limited CNS and genitourinary penetration may limit its use.

Removal of all foreign objects correlates with better outcomes*

• C. albicans biofilms formed on an implanted medical device ex. CVC, urinary catheter, ETT, prosthetic heart valve, or pacemaker play a role in the persistence and profileration of Candidiasis. Cells in biofilms are much more resistant to antifungal agents*.

• The echinocandins have penetration and action in Candida biofilms and thus may have an advantage in this setting**. C. albicans adhesion as a virulence factor

* Nucci M et al. 2002. CID; 34: 591-599.** Kuhn et al. 2002. Antimicrob Agents Chemother; 46:1773-1780.

Summary

• Candidemia is associated with high morbidity & mortality in ICU.• Early appropriate therapy is essential for the prevention of severe

complications, including death. • A combination of clinical & lab findings is used to make a

diagnosis (no reliable diagnostic markers for early detection of patients at risk for invasive candidiasis)

• Early empiric therapy will need to be initiated on the basis of individual patient risk factors before a definitive diagnosis is made.

• Prophylactic & Preemptive therapy maybe indicated in high risk populations at risk for candida infection given the high mortality.

• When candidemia is documented, ID of the infecting Candida species is essential for the institution of appropriate therapy because of the variable susceptibility of Candida species to different antifungal agents. Don’t forget to address the biofilm.

Interactive Case Questions

Thank you

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