Candida Fungemia Risks and Therapy

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Candida FungemiaRisks and Therapy

• Hail M. Al-Abdely, M.D.
• Associate Consultant
• King Faisal Specialist Hospital

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Questions need Answers

• How significant is Candidemia?
• Who gets Candidemia?
• Are there better ways to diagnose invasive
  Candidiasis than Candidemia?
• What are the best therapeutic strategies for
  Candidemia?

Continue . . .
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Questions need Answers

• What are the chemotherapeutic agents that can be
  used to treat candidemia? Is one better than the
  other?
• When to give prophylaxis against Candida? And
  with what?
• What is in the horizon?

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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
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Candida glabrata
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How significant is Candidemia?

• How prevalent?
• How serious?

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How prevalent is Candidemia?

• Hospital pathogen
• Primarily opportunist.

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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 556, 1988
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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
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
Blood stream infections 5.4 9.9
Beck-Sague CM, et al. J Infect Dis 1671247, 1993
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Candida species that cause Candidemia
Candida sp. C. albicans Non-albica
ns 1972-19771 54.3 45.7 1980-19902
66.9 33.1 1990-19923 60.0
40.0 1993-19943 47.0 53.0
1. Klein JI, et al. Am J Med 6751, 19792.
Beck-Sague CM, et al. J Infect Dis 1671247,
19933. Nguyen MH, et al. Am J Med 100617, 1996
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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
• P0.01. 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 (gt8 mcg/ml) 72 vs. 12

Nguyen MH, et al. Am J Med 100617, 1996
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Location of Patients with Candidemia at
KFSHRC 1994-1998
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C. albicans vs. Non-albicans Isolates at KFSHRC
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Mortality and Excess Hospital Stay due to
Candidemia
Variable Point Estimate Crude
mortality Cases (n88) 57
Controls (n88) 19 Attributable
mortality 38 Median length of hospitalStay (
34 surviving pairs) Cases 70
days Controls 40 days Attributable excess
stay 30 days
Wey SB, et al. Arch Intern Med 1482642, 1988
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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
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Outcome of Patients with Candidemia
Wenzel RP. Clin Infect Dis 201531, 1995
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Who gets Candidemia?
Risk Factors for Candidemia Neutropenia Multi
ple Blood transfusions Prolonged Central venous
catheters Candida colonization Diabetes Broad
spectrum antibiotics Length of ICU
stay Corticosteroids Immunosuppressives
Hemodialysis Parenteral alimentation Mechanica
l ventilation Prematurity
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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 306225, 1993
2. Martino P. Cancer 642030, 1989
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Candida colonization
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Therapy for Candidemia

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

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Targets for Antifungal Agents
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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
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Antifungal Agents
In the Pipeline
Polyenes Sordarins Liposomal Nystatin
GM 193663 Amphotericin B Cochleate GM
222712 KY62 GM 237354 Partricins
(IB643) Azoles Chintinases Voriconazol
e Pradimicins SCH56592 Nikkomycins BMS-207
147 Nikkomycin z UR-9825
Echinocandins Peptides M-0991
Defensin LY303366 Pretregrin
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Cell wall Envelope of C. albicans
Fimbrial Layer Mannoprotein B-Glucan B-Glucan,
Chitin
Pradimicin Echanocandins
Nikkomycin,Chinases
Mannoprotein Plasma membrane
Amphotericin
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Pharmacokinetics of AMB Lipid Formulations
Drug Lipid Mean Mean Mean Cmax Vd AUC AM
B NA 2.9 4 8.6 L-AMB Liposome ? ?
? ABCD Disklike ? ? ? ABLC Ribbon-like ?
Similar ?
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Amphotericin B versus ABLC for Invasive
Candidiasis (Prospective randomized multi-center
Study)
Response Parameter ABLC(5mg) Ampho
B(0.6mg) P value Overall response 81/124
(65) 43/70 (61) 0.64 Infection
type Candidemia 67/105 (64) 32/58 (55)
0.32 Single organ 13/18 (72) 11/12 (92)
0.36 Pathogen 0.53 C. albicans 45/66
(68) 21/33 (64) Non-albicans 32/50 (64) 22/30
(57)
Anaissie EJ, et al. 35th ICAAC, 1995
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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) 0.007 Median 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
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Therapeutic Strategies for Invasive Candidiasis?
Insensitive diagnostic tools for invasive
Candidiasis. Sensitivity 50.
Mortality of invasive Candidiasis 70
Available less toxic Antifungals

1. Targeted prophylaxis
2. Early presumptive therapy

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Prophylaxis against Candida

• Indicated
• Bone marrow transplant patients.
• Goodman, NEJM 326845, 1992

Invasive candidiasis by 50.

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

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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.
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A Randomized Double-Blind Safety Study
of AmBisome and ABLC in Febrile Neutropenic
Patients
ABLC L-AmB (5mg) L-AmB (5mg) P value n78
n81 n85 Chills 79.5 23.5
18.8 lt 0.001 Fever 57.7 19.8
23.5 lt 0.001 Hypoxia 11.5 1.2
0.00 lt 0.01 Others 41.0 25.9
18.8 lt 0.05
Doubling 42.3 14.8 14.1 lt 0.001
S Cr.
No difference in efficacy between all the 3 arms
Wingard JR, 9th FFI , March 1999
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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 2543, 1997
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Should all Candidemic patients be treated with
antifungals?
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WHAT ANTIFUNGAL AGENTS SHOULD BE USED FOR
CANDIDEMIA IN NON-NEUTROPENIC STABLE PATIENT?
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WHAT ANTIFUNGAL AGENTS SHOULD BE USED FOR
CANDIDEMIA IN NON-NEUTROPENIC UNSTABLE PATIENT?
Patients condition No prior Fluconazole
Rx Fluconazole 5/20 FlucAMB 5/20 AMB
8/20 Lipid AMB 2/20 Itraconazole 0/20
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Predictors of Poor Outcome in Candidemia