1. Empiric Antifungal Therapy in the ICU
Ramzi Moufarrej, M.D
Chief of Critical Care
Zayed Military Hospital / Abu Dhabi

2. 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.
MICU/SICU: invasive candidiasis fourth leading cause of bloodstream infections with increased cost, morbidity and mortality.
Transplantation units: invasive aspergillosis one of the leading causes of infectious complications with an 80% mortality.

3. 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
Slide 3
The high incidence of invasive fungal infections has arisen primarily as a consequence of advanced medical treatment technologies, especially in gravely ill patients.1,2
Fungal invasion is prevalent1,2
When patients are immunosuppressed (e.g., neutropenic patients or solid-organ transplant recipients)
When there is disruption of the gastrointestinal tract (e.g., surgery, trauma, or chemotherapy)
If there is disruption of anatomical barriers (e.g., catheterization or mechanical ventilation)
In circumstances in which normal microflora are disturbed (e.g., through use of broad-spectrum antibiotics)
Awareness of risk factors for invasive fungal infection is key to identifying potential patient candidates for antifungal therapy.1,2
The multicenter National Epidemiology of Mycosis Survey (NEMIS) was the largest prospective study designed to determine risk factors for developing candidal bloodstream infections (CBSIs) among patients in surgical and neonatal intensive care units.1
Previous studies evaluating risk factors had several limitations, including the utilization of data from a single institution over a long time period, and not being prospective in design. In addition, few were focused on surgical intensive care unit populations.1
In NEMIS, independently associated risk factors for CBSIs included acute renal failure, parenteral nutrition, and prior surgery. Neutropenia was not an independent risk factor.1
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.
References
1. Blumberg HM, Jarvis WR, Soucie JM et al and the NEMIS Study Group. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: The NEMIS prospective multicenter study. Clin Infect Dis 2001;33:177–186.
2. Garber G. An overview of fungal infections. Drugs 2001;61(suppl 1):1–12.

4. Invasive Mycosis Aspergillosis Candidiasis SOT or BMT MICU or SICU
MICU/SICU: invasive candidiasis fourth leading cause of bloodstream infections with increased cost, morbidity and mortality.
Transplantation units: invasive aspergillosis one of the leading causes of infectious complications with an 80% mortality.
MICU/SICU: invasive candidiasis fourth leading cause of bloodstream infections with increased cost, morbidity and mortality..
SOT or BMT
MICU or SICU
Oncology
Barrier immunity
Barrier plus cellular immunity
Decreasing immunity

5. Treatment of Invasive Mycosis
Polyenes
Amphotericin B (AmB) or Liposomal AmB (kidney toxicity)
Azoles
Fluconazole 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.

6. Site of Action of Selected Anti-fungal Agents
Cell membrane
Polyenes AmB (sterols)
Azoles Fluconazole (CYP450)
Slide 6
Cell wall
Echinocandins Caspofungin (Glucan synthesis inhibitors)
Currently available antifungal agents can be classified by their site of action in fungal cells,1 which can have important implications for both efficacy and tolerability. Available agents include the polyenes, nucleoside analogs, and the azoles.1 These agents are not ideal because amphotericin B treatment is associated with severe side effects, and nucleoside analogs and azole possess a fungistatic rather than fungicial action.2 These classes are limited by lack of selective toxicity for fungal cells, that is, their therapeutic target is not exclusive to the fungal cell.2 For this reason, new antifungals—glucan synthesis inhibitors, also called echinocandins—that target the cell wall (not found in mammalian cells) are an important focus of current research which have the potential to provide a superior efficacy and safety profile versus current agents.2-5
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.
References
1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162.
2. Debono M, Gordee RS. Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol 1994;48: 471–497.
3. Graybill JR, Najvar LK, Luther MF et al. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41(8):1775–1777.
4. Marco F, Pfaller MA, Messer SA et al. Activity of MK-0991 (L-743,872), a new echinocandin, compared with those of LY and four other antifungal agents tested against blood stream isolates of Candida spp. Diagn Microbiol Infect Dis 1998;31:33–37.
5. Groll AH, Walsh TJ. Caspofungin: Pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Invest Drugs 2001;10(8):1545–1558.

7. Focus on Candidiasis Invasive Candida infections:
4th most common nosocomial bloodstream infection in the USA with mortality approaching 40% in line related candidemia*
Slide 7
Pathogen No. of Isolates Incidence (%)
Serious fungal infections are on the rise as shown by the increase of life-threatening infections due to invasive Candida.1,2
Per a 1983 nationwide survey of medical and surgical patients in the United States, the 9th most common cause of nosocomial bloodstream infections was the Candida species.3
In a 3-year (1995–1998) surveillance study of 49 hospitals across the United States, the high incidence of Candida infections places it as the 4th leading cause of nosocomial bloodstream infections.4
In this study, only coagulase-negative staphylococci, Staphylococcus aureus, and enterococci have higher rates of incidence.4
Coagulase-negative staphylococci
Staphylococcus aureus
Enterococci
Candida species
*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.
References
1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162.
2. Uzun O, Anaissie EJ. Predictors of outcome in cancer patients with candidemia. Ann Oncol 2000;11:1517–1521.
3. Centers for Disease Control and Prevention. Nosocomial infection surveillance, Morb Mortal Wkly Rep 1984;33(2SS):9SS–21SS.
4. Edmond MB, Wallace SE, McClish DK et al. Nosocomial bloodstream infections in United States hospitals: A three-year analysis. Clin Infect Dis 1999;29:239–244.

8. Species of Candida Most Commonly Isolated in Bloodstream Infections
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 :
Since then increase in Candida spp. with higher incidence of fluconazole resistance.
Snydman DR Chest 123(Suppl 5):500S-503S). Garbino J. et al Medicine;81:
Slide 8
Data above are taken from 634 bloodstream isolates of Candida species reported in 34 medical centers over a two-year period (1997–1998)1
22 centers in the United States and 12 from Latin America/Canada1
This report was part of the SENTRY Antimicrobial Surveillance Program1
It shows that by far the most common species is C. albicans, accounting for 54% of reported incidence of Candida infections. C. glabrata accounts for 16%, C. parapsilosis for 15%, C. tropicalis for 8%, C. krusei for 2%, and other Candida species are noted as 5%.1
Reference
1. Pfaller MA, Jones RN, Doern GV et al and The SENTRY Participant Group. Bloodstream infections due to Candida species: SENTRY antimicrobial surveillance Program in North America and Latin America, 1997– Antimicrob Agents Chemother 2000;44:747–751.

9. 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;

10. 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

11. Risk Factor Selection Infection Fever Underlying disease Selection
Antibiotics
Skin or
mucosa
damage
Malignancy
Diabetes
Renal disease
CTD on steroids
Malnutrition on TPN
Mechanical Ventilation > 48h
Burns
Colonization
Instruments
CV Catheter
Knife

12. Invasive Candidiasis After Colonization and Bacteremia
81 patients
Bacteremia
NO 46
YES 35
Colonization
Acute
Invasive
Candidiasis
1 0 0
0 1 8
53%
Guiot et al. CID.1994;18:525-32

13. Laboratory Diagnosis Microbiology methods: Molecular 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.

14. Clinical Diagnosis
The 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.
IC-related cutaneous lesions: These lesions have been described in cancer patients and heroin addicts
About 15% of neutropenic patients with IC will have a characteristic macronodular rash; the rash may be isolated to the extremities or abdomen or may cover the entire body, and is frequently confused with drug allergies, which is why a biopsy of the deeper layers of skin (particularly the vascularized areas and the dermis) is important.[101] A significant percentage of patients with candidemia have 1 or more retinal lesions that may represent Candida endophthalmitis.[A fundoscopic evaluation for the presence of Candida endophthalmitis (typically with C albicans) should be performed. Endophthalmitis is a common complication of hematogenous candidiasis in the nonneutropenic patient and can be the initial manifestation of IC (Figure 5). Reports of the frequency of ocular involvement by Candida species vary widely (3%[105] to 78%),[ ] depending on the patient population (very rare in neutropenic patients), the diagnostic criteria used, the study design (prospective vs retrospective), and the physician performing the examination (best performed by an ophthalmologist). Fundoscopic examination should be repeated in critically ill patients with candidemia because ocular involvement can develop within 2 weeks after diagnosis

15. 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 Antimicrob Agents Chemother. 49(9):
*Garey K et al Clin Infect Dis. 43:

16. Can we wait for the blood culture results in candidemia?
Retrospective cohort analysis 1/ /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.
134/157 had therapy after cultures turn positive.
Morrel M et al Antimicrob Agents Chemother. 49(9):3640-5 

17. 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).

18. Timing of Intervention
Directed
Empiric
infection
specific symptom
Pre-emptive
refractory fever
Prophylactic
aspecific symptom ± early markers
suppressive Rx
basic disease
Progression

19. 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

20. Fluconazole Prophylaxis and Colonization of Neutropenic Patients
Winston et al. Ann Intern Med. 1993;118:

21. Candida prophylaxis in the Surgical ICU (patients with high risk for candidemia)
Eggiman et al CCM 27:
Fluconazole reduced candida peritonitis and colonization in 43 patients with complicated GI surgeries. High risk patients ? Was it preemptive therapy.
Pelz et al Ann Surg. 233:
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 Med Mycol. 43(3):
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.

22. Candida Prophylaxis in MICU & SICU (MV > 48h & expected LOS > 72h)
Incidence of IC=5.8%
Fluconazole reduced candida infection and colonization in SICU and MICU patients. No mortality benefit.
Incidence of IC=16%
Garbino et al. Intensive Care Med. 2002;28:

23. 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?.

24. 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.
with 2-yr prospective and 2-yr historical control cohorts in SICU ≥ 5 days
Piarroux, et al..Crit Care Med Dec;32(12):

25. Arch Surgery. 2001;136:

26. Temporal Assessment of Candida Risk Factors in the SICU

27. 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.

28. 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):

29. 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
For patients at lower initial risk, pre-emptive therapy should be based on a management strategy that takes into account the presence of definite risk factors and the dynamics of candida colonisation

30. 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.

31. Empiric Caspofungin in Patients with Neutropenia and Persistent fever50
Caspofungin
Liposomal AmB 40 30
33.9%
33.7%
Percent of Patients
Slide 31 * 20 *
14.5% 10
11.5%
2.6%
10.3%
Overall adjusted success rate
Nephrotoxic effect
(p<0.001)
Discontinued the study prematurely (p=0.03)
Caspofungin had significantly fewer : Drug-related clinical or lab adverse events, and
discontinuations due to serious drug-related clinical or lab AEs .
Walsh et al. N Engl J Med ; 351:
Reference
1. Mora-Duarte J, Betts R, Rotstein C et al for the Caspofungin Invasive Candidiasis Group. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347:2020–2029.

32. Empiric Caspofungin vs
Empiric Caspofungin vs. liposomal AmB in persistent Fever and Neutropenia
Percent survival
Caspofungin (n=556)
L-AmB (n=539)
Study day
p=0.044 21 28 35 63 7 14 56 49 42 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 ;351:

33. Candidemia in Non-neutropenic ICU Patients
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):

34. 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 Ann Intern Med;143:

35. 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

36. 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.
Clinicians should also consider whether candidemia is a likely pathogen when choosing initial therapy. When deemed warranted, the selection of empirical antifungal therapy (e.g., fluconazole, amphotericin B, or echinocandin) will be tailored to the local pattern of the most prevalent Candida species and any prior administration of azoles drugs.[44] Risk factors for candidemia should also be considered when choosing initial therapy.
* Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: CCM 2008

37. 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.

38. 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 CID; 34:
** Kuhn et al Antimicrob Agents Chemother; 46:

39. 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.

40. Interactive Case Questions Thank you
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