Candida FungemiaRisks 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. albicansC. tropicalisC. parapsilosisC. glabrataC. kruseiC. LusitaniaeC. stellatoideaC. kyferC. rugosaC. dubliensisC. guilliermondiiC. lipolyticaC. zeylanoides

Candida glabrata

How significant is Candidemia?

• How prevalent?

• How serious?

How prevalent is Candidemia?

• Hospital pathogen

• Primarily opportunist.

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

1985-1988

Rank 1988 Pathogen Percent Rank 1984

1 Coag-neg Staph 25.5 1

2 S. aureus 15.0 2

3 Enterococci 7.9 6

4 Candida sp. 7.7 8

5 E. coli 6.8 3

6 Enterobacter 5.2 7

7 P. aeruginosa 5.0 5

8 Klebsiella spp. 4.4 4

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

National Nosocomial Infection Surveilance System (NNIS)1980-1990

Fungal Infection Rate 1980 1990

Small non-teaching Hospitals 0.9 2.4

Large non-teaching Hospitals 1.2 2.5

Small teaching Hospitals 2.1 3.5

Large teaching Hospitals 2.4 6.6

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

Total Number of Nosocomial Fungal Infections 30,477

Blood stream infections 5.4 9.9

Candida species that cause Candidemia

Candida sp. % C. albicans Non-albicans

1972-19771 54.3 45.71980-19902 66.9 33.1 1990-19923 60.0 40.0 1993-19943 47.0 53.0

1. Klein JI, et al. Am J Med 67:51, 19792. Beck-Sague CM, et al. J Infect Dis 167:1247, 19933. 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

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Candidemia at KFSH&RC

Location of Patients with Candidemia at KFSH&RC1994-1998

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C. albicans vs. Non-albicans Isolates at KFSH&RC

Mortality and Excess Hospital Stay due to Candidemia

Variable Point Estimate %

Crude mortality

Cases (n=88) 57 Controls (n=88) 19

Attributable mortality 38

Median length of hospitalStay ( 34 surviving pairs)

Cases 70 daysControls 40 days

Attributable excess stay 30 days

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

Pathogens in 2064 ICU-acquired Infection in EPIC Study

Pathogen Incidence %

Enterobacteriaceae 34.4

S. aureus 30.1

P. aeruginosa 28.7

Coag neg staph 19.1

Fungi 17.1

Die of Candidemia

35%Survive35%

Die of underlying

disease30%

Outcome of Patients with Candidemia

Wenzel RP. Clin Infect Dis 20:1531, 1995

Who gets Candidemia?

Risk Factors for Candidemia

NeutropeniaMultiple Blood transfusionsProlonged Central venous cathetersCandida colonizationDiabetesBroad spectrum antibioticsLength of ICU stayCorticosteroidsImmunosuppressives HemodialysisParenteral alimentationMechanical ventilationPrematurity

Candida colonization

Development of Candidemia in cancer Patients

Candidemia %

Ref 1 Ref 2

Multiple site colonization 22 32

Single site colonization 5 1

No colonization 0 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

PolyenesAmphotericin B (deoxycholate) - 1958Liposomal amphotericin B (AmBisome) - 1997Amphotericin Lipid Complex (ABLC) - 1996Amphotericin Colloidal Dispersion (ABCD) - 1996

AzolesMiconazole (intravenous) - 1979Ketoconazole (P.O) - 1981Fluconazole (P.O, intravenous) - 1990Itraconazole (capsule, solution, intravenous) - 1992

OthersGriseofulvin - 19595-Flucytosine - 1972Terbinafine - 1996

Currently available

Polyenes SordarinsLiposomal Nystatin GM 193663Amphotericin B Cochleate GM 222712KY62 GM 237354Partricins (IB643)

Azoles ChintinasesVoriconazole PradimicinsSCH56592 NikkomycinsBMS-207147 Nikkomycin zUR-9825

Echinocandins PeptidesM-0991 DefensinLY303366 Pretregrin

Antifungal Agents

In the Pipeline

Cell wall Envelope of C. albicans

Fimbrial Layer

Mannoprotein

B-Glucan

B-Glucan, Chitin

MannoproteinPlasma membrane

Pradimicin

Echanocandins

Nikkomycin,Chinases

Amphotericin

Pharmacokinetics of AMB Lipid Formulations

Drug Lipid Mean Mean MeanCmax Vd AUC

AMB NA 2.9 4 8.6

L-AMB Liposome

ABCD Disklike

ABLC Ribbon-like Similar

Amphotericin B versus ABLC for Invasive Candidiasis(Prospective randomized multi-center Study)

Response %Parameter ABLC(5mg) Ampho B(0.6mg) P valueOverall response 81/124 (65) 43/70 (61) 0.64Infection type

Candidemia 67/105 (64) 32/58 (55) 0.32Single organ 13/18 (72) 11/12 (92) 0.36

Pathogen 0.53C. albicans 45/66 (68) 21/33 (64)

Non-albicans 32/50 (64) 22/30 (57)

Anaissie EJ, et al. 35th ICAAC, 1995

Amphotericin B versus ABLC for Invasive Candidiasis(Prospective randomized multi-center Study)

Response %Parameter ABLC(5mg) Ampho B(0.6mg) P value

Doubling Cr 41/145 (28) 36/76 (47) 0.007Median time 82 days 19 days

0.028

Infusion-related toxicity 67/153 (44) 34/78 (44) 1.00

Anaissie EJ, et al. 35th ICAAC, 1995

Therapeutic Strategies for Invasive Candidiasis?

Insensitive diagnostic tools for invasive Candidiasis. Sensitivity ~ 50%.

Mortality of invasiveCandidiasis ~ 70%

1. Targeted prophylaxis2. Early presumptive therapy

Available less toxic Antifungals

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 ofAmBisome and ABLC in Febrile Neutropenic Patients

ABLC L-AmB (5mg) L-AmB (5mg) P value n=78 n=81 n=85

Chills 79.5 23.5 18.8 < 0.001Fever 57.7 19.8 23.5 < 0.001Hypoxia 11.5 1.2 0.00 < 0.01Others 41.0 25.9 18.8 < 0.05

Doubling 42.3 14.8 14.1 < 0.001 S Cr.

No difference in efficacy between all the 3 arms

Wingard JR, 9th 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?

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WHAT ANTIFUNGAL AGENTS SHOULD BE USEDFOR CANDIDEMIA IN NON-NEUTROPENIC STABLE

PATIENT?

02468

101214161820

Prior Fluc No fluc

Fluconazole

Itraconazole

AMB

Lipid AMB

WHAT ANTIFUNGAL AGENTS SHOULD BE USEDFOR CANDIDEMIA IN NON-NEUTROPENIC UNSTABLE

PATIENT?

Patient’s conditionNo prior Fluconazole Rx

Fluconazole 5/20

Fluc+AMB 5/20

AMB 8/20

Lipid AMB 2/20

Itraconazole 0/20

Predictors of Poor Outcome in Candidemia