Candida Fungemia Risks

and

Therapy

Hail M. Al-Abdely, M.D.

Associate Consultant King Faisal Specialist Hospital

Questions need Answers

1. How significant is Candidemia?

2. Who gets Candidemia?

3. Are there better ways to diagnose invasive Candidiasis than Candidemia?

4. What are the best therapeutic strategies for Candidemia?

Continue . . .

Questions need Answers

5. What are the chemotherapeutic agents that can be used to treat candidemia? Is one better than the other?

6. When to give prophylaxis against Candida? And with what?

7. What is in the horizon?

Pathogenic Candida Species C. albicans C. tropicalis C. parapsilosis C. glabrata C. krusei C. Lusitaniae C. stellatoidea C. kyfer C. rugosa C. dubliensis C. guilliermondii C. lipolytica C. zeylanoides

Candida glabrata

How significant is Candidemia?

• How prevalent?

• How serious?

How prevalent is Candidemia?

• Hospital pathogen • Primarily opportunist.

4 5 6 7 8 Rank 1988 1 2 3

Nosocomial Blood Stream Infections, National Nosocomial Infection Surveilance System (NNIS) 1985-1988

Pathogen Coag-neg Staph S. aureus Enterococci Candida sp.

E. coli Enterobacter P. aeruginosa Klebsiella spp.

Percent 25.5

15.0

7.9

7.7

6.8

5.2

5.0

4.4

8 3 7 5 4 Rank 1984 1 2 6

Horan T, et al. Antimicrob Newsletter 5:56, 1988

National Nosocomial Infection Surveilance System (NNIS) 1980-1990 Total Number of Nosocomial Fungal Infections 30,477 Fungal Infection Rate 1980 1990

Small non-teaching Hospitals Large non-teaching Hospitals Small teaching Hospitals Large teaching Hospitals Blood stream infections 0.9

1.2

2.1

2.4

5.4

2.4

2.5

3.5

6.6

9.9

Beck-Sague CM, et al. J Infect Dis 167:1247, 1993

Candida species that cause Candidemia

1972-1977 1 1980-1990 2 1990-1992 3 1993-1994 3 Candida sp. %

C. albicans

54.3

66.9

60.0

47.0

Non-albicans

45.7

33.1

40.0

53.0

1.

Klein JI, et al.

Am J Med 67:51, 1979 2. Beck-Sague CM, et al. J Infect Dis 167:1247, 1993 3. Nguyen MH, et al. Am J Med 100:617, 1996

Candidemia in Tertiary Care Centers in the US 1990-1994 • Prospective observational Study of pts with positive blood cultures for Candida sp. In 4 tertiary care centers.

• Non-albicans Candidemia increased significantly in each center P=0.01. And during 1993-94 it surpassed C. albicans Candidemia 40% to 53%.

• 13% of Candidemias occurred in patients already on antifungals • C. parapsilosis and C. krusei- prior fluconazole • C. glabrata – prior Ampho B.

• Isolates causing break through Candidemia exhibited higher MIC to fluconazole (>8 mcg/ml) – 72% vs. 12%

Nguyen MH, et al. Am J Med 100:617, 1996

Candidemia at KFSH&RC

50 40 30 20 10 0 1994 1995 1996 1997 1998

Location of Patients with Candidemia at KFSH&RC 1994-1998

35 30 25 20 15 10 5 0 NICU Hem.

MSICU PICU CSICU Surgical Pediatric Medicine

C. albicans vs.

Non-albicans Isolates at KFSH&RC

25 20 5 0 15 10 1994 1995 1996 1997 1998

Mortality and Excess Hospital Stay due to Candidemia Variable

Crude mortality Cases (n=88) Controls (n=88) Attributable mortality Median length of hospital Stay ( 34 surviving pairs) Cases Controls Attributable excess stay

Wey SB, et al. Arch Intern Med 148:2642, 1988

Point Estimate %

57 19 38 70 days 40 days 30 days

Pathogens in 2064 ICU-acquired Infection in EPIC Study Pathogen Enterobacteriaceae S. aureus P. aeruginosa Coag neg staph Fungi Incidence % 34.4

30.1

28.7

19.1

17.1

Outcome of Patients with Candidemia Survive 35% Die of Candidemia 35%

Wenzel RP. Clin Infect Dis 20:1531, 1995

Die of underlying disease 30%

Who gets Candidemia?

Risk Factors for Candidemia Neutropenia Multiple Blood transfusions Prolonged Central venous catheters

Candida

colonization Diabetes Broad spectrum antibiotics Length of ICU stay Corticosteroids Immunosuppressives Hemodialysis Parenteral alimentation Mechanical ventilation Prematurity

Candida

colonization

Development of Candidemia in cancer Patients Candidemia % Multiple site colonization Single site colonization No colonization Ref 1 22 5 0 Ref 2 32 1 0.5

1. Martino P. Am J Med Sci 306:225, 1993 2. Martino P. Cancer 64:2030, 1989

Candida

colonization

Therapy for Candidemia 1. The pathogen • Drug selection • • Optimize dose Adjunctive therapy (e.g surgery) 2. The host • Modify risk factors • Immunomodulation. ?cytokine therapy

Targets for Antifungal Agents

Antifungal Agents Currently available Polyenes Amphotericin B (deoxycholate) 1958 Liposomal amphotericin B (AmBisome) 1997 Amphotericin Lipid Complex (ABLC) 1996 Amphotericin Colloidal Dispersion (ABCD) 1996 Azoles Miconazole (intravenous) 1979 Ketoconazole (P.O) 1981 Fluconazole (P.O, intravenous) 1990 Itraconazole (capsule, solution, intravenous) 1992 Others Griseofulvin 1959 5-Flucytosine 1972 Terbinafine 1996

Antifungal Agents In the Pipeline Polyenes Liposomal Nystatin Amphotericin B Cochleate KY62 Partricins (IB643) Azoles Voriconazole SCH56592 BMS-207147 UR-9825 Echinocandins M-0991 LY303366 Sordarins GM 193663 GM 222712 GM 237354 Chintinases Pradimicins Nikkomycins Nikkomycin z Peptides Defensin Pretregrin

Pradimicin Echanocandins Nikkomycin, Chinases Amphotericin

Cell wall Envelope of C. albicans

Fimbrial Layer Mannoprotein B-Glucan B-Glucan, Chitin Mannoprotein Plasma membrane

Drug AMB L-AMB ABCD ABLC Pharmacokinetics of AMB Lipid Formulations Lipid NA Liposome Disklike Ribbon-like   Mean Cmax 2.9

 Mean Vd 4   Similar Mean AUC 8.6

  

Amphotericin B versus ABLC for Invasive Candidiasis (Prospective randomized multi-center Study) Parameter Overall response Infection type Candidemia Single organ Pathogen C. albicans Non-albicans Response % ABLC(5mg) 81/124 (65) 67/105 (64) 13/18 (72) 45/66 (68) 32/50 (64) Ampho B(0.6mg) 43/70 (61) 32/58 (55) 11/12 (92) 21/33 (64) 22/30 (57) P value 0.64

0.32

0.36

0.53

Anaissie EJ, et al. 35 th ICAAC, 1995

Amphotericin B versus ABLC for Invasive Candidiasis (Prospective randomized multi-center Study) Parameter Response % ABLC(5mg) Doubling Cr Median time 41/145 (28) 82 days Infusion-related toxicity 67/153 (44) Ampho B(0.6mg) 36/76 (47) 19 days 34/78 (44) P value 0.007

0.028

1.00

Anaissie EJ, et al. 35 th ICAAC, 1995

Therapeutic Strategies for Invasive Candidiasis?

Mortality of invasive Candidiasis ~ 70% Insensitive diagnostic tools for invasive Candidiasis. Sensitivity ~ 50%. Available less toxic Antifungals 1. Targeted prophylaxis 2. Early presumptive therapy

Prophylaxis against Candida Indicated • Bone marrow transplant patients.

Goodman, NEJM 326:845, 1992

Invasive candidiasis by 50%.

? Indicated • Leukemia • Multiple risk factors for invasive Candidiasis > 14 days of Antibiotics CVL Hyperalimentation Complicated intra-abdominal surgery Colonization from multiple sites

Early Presumptive Therapy Definition Initiation of systemic antifungal therapy in patients with sepsis that are at high risk of invasive Candidiasis and no identifiable source or explanation for sepsis.

A Randomized Double-Blind Safety Study of AmBisome and ABLC in Febrile Neutropenic Patients ABLC n=78 L-AmB (5mg) n=81 L-AmB (5mg) n=85 P value Chills Fever 79.5

57.7

Hypoxia 11.5

Others 41.0

Doubling 42.3

S Cr.

23.5

19.8

1.2

25.9

14.8

18.8

23.5

0.00

18.8

14.1

< 0.001

< 0.001

< 0.01

< 0.05

< 0.001

No difference in efficacy between all the 3 arms

Wingard JR, 9 th FFI , March 1999

International Conference of a Consensus on the Management of Candidiasis • Careful selection of 22 experts on treatment of Candidiasis • Participants are from USA, Europe and Japan • Met in a conference room at UCLA • Voting was anonymous by an electronic device • Data was generated by a computer system • Question on different management issues relating to Candidiasis

Edwards JE, Clin infect Dis 25:43, 1997

Should all Candidemic patients be treated with antifungals?

19 20 15 10 5 0 YES NO 1

WHAT ANTIFUNGAL AGENTS SHOULD BE USED FOR CANDIDEMIA IN NON-NEUTROPENIC STABLE PATIENT?

20 18 16 14 12 10 8 6 4 2 0 Prior Fluc No fluc Fluconazole Itraconazole AMB Lipid AMB

WHAT ANTIFUNGAL AGENTS SHOULD BE USED FOR CANDIDEMIA IN NON-NEUTROPENIC UNSTABLE PATIENT?

Fluconazole Fluc+AMB AMB Lipid AMB Itraconazole Patient’s condition No prior Fluconazole Rx 5/20 5/20 8/20 2/20 0/20

Predictors of Poor Outcome in Candidemia