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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1994 1995 1996 1997 1998
Candidemia at KFSH&RC
Location of Patients with Candidemia at KFSH&RC1994-1998
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35
Ca
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NICU Hem. MSICU PICU CSICU Surgical Pediatric Medicine
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1994 1995 1996 1997 1998
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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YES NO
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