Antifungal Update

25 Pages·2011·0.28 MB·English

by  Scott Reeves

2/24/11
Antifungal Update
B. Joseph Guglielmo, Pharm.D.
Professor and Chair
Department of Clinical Pharmacy
School of Pharmacy
University of California San Francisco
The patient spikes a new fever and 3/3
blood cultures are positive for an
unidentified yeast………
Which is the most appropriate initial
empirical therapy in a candidemic
patient?
1.  An echinocandin
2.  Liposomal amphotericin
3.  Fluconazole
4.  Voriconazole
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Outcomes Attributable to Candidemia in
the United States, 2000
(Clin Infect Dis 2005; 41: 1232)
Not Attributable
Candidemic candidemic increase
Mortality 30.6 16.1 14.5
(%) (12.1-16.9)
Length of 18.6 8.5 10.1
Stay (days) (8.9-11.3)
Total 66,154 26,823 39,331
Charges ($) (33,600-45,
602)
Prospective Antifungal Therapy
(PATH) Alliance
•  Candidemia in 2019 patients
•  July 2004-March 2008
•  Crude 12-week mortality: 35.2%
•  Incidence of candidemia due to non-
albicans Candida species (54.4%)
compared with that due to Candida albicans
(Clin Infect Dis 2009; 48: 1695)
Prospective Antifungal Therapy
(PATH) Alliance
Agent All C albicans C glabrata C parapsilosis
N=2019 N=921 N=525 N-316
Fluconazole 1366 (67.7%) 714 (77.5%) 273 (52%) 233 (73.7%)
Voriconazole 136 (6.7%) 45 (4.9%) 44 (8.4%) 21 (6.6%)
LF-AMB 202 (10%) 74 (8.0%) 38 (7.2%) 52 (16.4%)
Echinocandin 988 (48.1%) 346 (37.5%) 348 (66.3%) 138 (43.6%)
(Clin Infect Dis 2009; 48: 1695)
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Disseminated Candidiasis: the Value
of the Germ Tube
•  Germ tube (known 1 ½ - 3 hrs of plating)
– If germ tube positive, yeast is almost
exclusively C. albicans (exception is C.
dubliniensis) and fluconazole can be used to
treat pending final cultures
– If germ tube negative, likely nonalbicans
Candida (including particularly C. glabrata, but
also C. tropicalis, C. kruseii)
Candida: In Vitro Antifungal
Susceptibility Testing
•  Candida and azoles: predictive for both mucosal and
invasive disease
•  Candida susceptibility to azoles is classified as
“susceptible”, “dose-dependent”, “resistant”,
however, the utility of the “dose-dependent”
categorization is questionable.
•  Recent data confirm a decrease in the rate of
fluconazole-susceptible with a concomitant increase
in fluconazole dose-dependent C. glabrata
(Antimicrob Agents Chemother 2008; 52: 2919)
Amphotericin B: “Gold
Standard”?
•  Licensed 1959 on the basis of open-label,
noncomparative data
•  Broad spectrum of activity
•  Low rates of resistance
•  “the toxicities with amphotericin are such
that one might speculate whether it….would
meet requirements for licensing”
(Clin Infect Dis 2003; 37: 416)
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Azoles
•  Fluconazole (Diflucan®)
•  Voriconazole (Vfend®)
•  Posaconazole (Noxafil®)
In vitro fluconazole and voriconazole susceptibility
Fluconazole Voriconazole
C. albicans 97.9% 98.4%
C. glabrata 68.9% 82.2%
C. tropicalis 90.4% 88.5%
C. parapsilosis 93.3% 96.8%
C. krusei 9.2% 82.9%
(J Clin Microbiol. 2007; 45: 1735-45)
Fluconazole vs AMB in the
Treatement of Candidemia
•  237 patients enrolled with candidemia
•  Successfully treated (14 days after last positive
blood culture):
– AMB: 81/103 (79 %)
– FLU: 72/103 (70%)
•  Predominantly C. albicans
•  Intravascular catheters most frequent source of
candidemia
•  Less toxicity with fluconazole (and PO
administration) than with amphotericin B.
(N Engl J Med 1994; 331: 1330)
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Voriconazole vs Amphotericin
followed by Fluconazole for
Candidemia
•  Non-neutropenic patients with candidemia
randomized 2:1 ratio to voriconazole
(n=283) or amphotericin followed by
fluconazole (n=139)
•  Primary efficacy analysis: clinical and
mycological response 12 weeks after end of
treatment (VOR: 41%; AMB/FLU: 41%)
(Kullberg et al. Lancet 2005; 366: 1435)
Caspofungin vs Amphotericin for
Invasive Candidiasis
•  Patients with clinical evidence of fungal
infection and positive culture for Candida
species from blood or other site.
•  Patient stratification by APACHE II score
and presence of neutropenia
•  Randomly assigned to receive placebo-
controlled caspofungin or amphotericin
(N Engl J Med 2002; 347: 2020)
Caspofungin vs Amphotericin for
Invasive Candidiasis
•  Caspofungin 70 mg loading dose IV, then 50 mg
IV daily
•  Amphotericin: if not neutropenic, patients were
given 0.6-0.7 mg/Kg/D IV; if neutropenic, patients
were given 0.7-1.0 mg/Kg/D IV
•  Minimum of 10 days of intravenous therapy and
14 days total therapy after most recent positive
culture
•  Fluconazole 400 mg PO QD after IV therapy (no
neutropenia, improved clinical condition, negative
cultures for 48hrs, NOT C. glabrata or C. krusei)
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Caspofungin vs Amphotericin for
Invasive Candidiasis
•  Modified intention to treat analysis
demonstrated similar efficacy between
groups
– Caspofungin: 73.4%
– Amphotericin: 61.7%
•  Prespecified criteria for evaluation:
– Caspofungin: 80.7%
– Amphotericin: 64.9% (p=0.03)
Caspofungin vs Amphotericin for
Invasive Candidiasis
•  Fever, chills, infusion-related events
– Caspofungin: 0.9%
– Amphotericin: 32%
•  Nephrotoxicity
– Caspofungin: 8.4%
– Amphotericin: 24.8%
•  Hypokalemia
– Caspofungin: 9.9%
– Amphotericin: 23.4%
Micafungin vs Liposomal
Amphotericin
•  RCT comparing micafungin 100 mg/D versus
liposomal amphotericin 3 mg/Kg/D
•  Candidemia and invasive candidiasis
•  Treatment success in 89.6% of micafungin-treated
patients and 89.5% liposomal amphotericin-
treated patients
•  Significantly more increases in serum creatinine,
back pain, infusion reactions with liposomal
amphotericin
(Lancet 2007; 369: 1519-1527)
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Anidulafungin versus Fluconazole
for Invasive Candidiasis
•  RCT of patients with invasive candiasis
•  Anidulafungin 200 mg on day 1 and 100 mg
daily versus fluconazole 800 mg on day 1
and 400 mg daily
•  Patients in both groups could be switched to
PO fluconazole after 10 days of intravenous
therapy
(N Engl J Med 2007; 356: 2472-2482)
Fluconazole Anidulafungin
(N=118) (N=127)
End of IV 60.2% 75.6%*
therapy
End of all 56.8% 74.0%*
therapy
2 week follow- 49.2% 64.6%*
up
6 week follow- 44.1% 55.9%
up
(N Engl J Med 2007; 356: 2472-2482)
2009 IDSA Candidiasis Practice
Guidelines
•  Fluconazole 800 mg loading dose, then 400
mg daily or an echinocandin is
recommended for most adult patients
•  An echinocandin is recommended for
patients with moderately severe to severe
illness or for patients who have had recent
azole exposure
[Clin Infect Dis 2009; 48 (1 March): 503-35]
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2009 IDSA Candidiasis Practice
Guidelines
•  Transition from an echinocandin to
fluconazole is recommended for patients
with isolates likely to be susceptible to
fluconazole (i.e. C. albicans)
•  Voriconazole offers little advantage over
fluconazole (and is better used for other
fungal infections)
[Clin Infect Dis 2009; 48 (1 March): 503-35]
Which is the most appropriate initial
empirical therapy in a candidemic
patient?
1.  An echinocandin
2.  Liposomal amphotericin
3.  Fluconazole
4.  Voriconazole
Of the following echinocandins,
which is the best choice in the
treatment of deep-seated fungal
infection?
1.  Anidulofungin
2.  Caspofungin
3.  Micafungin
4.  Any echinocandin
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Anidulafungin, Caspofungin or
Micafungin?
•  Spectrum of activity: identical for all three agents
(anidulafungin, caspofungin, micafungin)
– Highly active (and cidal) : C. albicans, C. glabrata, C.
tropicalis
– Very active: C. parapsilosis, Aspergillus
– Some activity: Coccidiodes, Blastomyces,
Scedosporium, Histoplasma
– Inactive: Zygomycetes, Cryptococcus, Fusarium
(Denning et al. Lancet 2003; 362: 1142)
Multiresistant C. parapsilosis
51 yo male 7 months S/P AVR with positive blood
cultures for C. parapsilosis initially treated with
conventional amphotericin and 5FC for 7 days.
After episode of acute renal insufficiency
associated with AMB, he was switched to
caspofungin 50 mg/D + fluconazole 400 mg/D for
6 weeks. Subsequently, he was given fluconazole
400 mg/D as suppressive therapy
(Moudgal et al. Antimicrob Agents Chemother 2005; 49: 767)
Multiresistant C. parapsilosis
3 months later readmitted with fever, chills and
positive blood cultures for C. parapsilosis. The
suppressive fluconazole was discontinued and
caspofungin was restarted. Despite 10 days of
therapy, his blood cultures remained positive. He
was switched to ABLC 5 mg/Kg/D and his blood
cultures became negative
(Moudgal et al. Antimicrob Agents Chemother 2005; 49: 767)
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In vitro Susceptibilities of Serial
C. parapsilosis Isolates
FLU VOR CAS MIC ANI AMB
IS #1 1.0 0.03 2.0 8.0 1.0 0.25
IS #2 >64 >16 >16 >16 2.0 0.5
(Moudgal et al. Antimicrob Agents Chemother 2005; 49: 767)
2009 IDSA Candidiasis Practice
Guidelines
•  For infection due to C. parapsilosis,
treatment with fluconazole is recommended
•  For patients who have initially received an
echinocandin, are clinically improved, and
whose follow-up culture results are
negative, continuing use of an echinocandin
is reasonable
[Clin Infect Dis 2009; 48 (1 March): 503-35]
Echinocandins vs Nonechinocandins
in the Treatment of C parapsilosis
•  Meta-analysis of 1169 patients with
invasive candidiasis or candidemia treated
with echinocandin or other antifungal
agents
•  202 patients with C. parapsilosis
(Echinocandin: 102; Other: 100
•  Success rate: Echinocandin (76.5%) vs
Other (73%)
(Pharmacother 2010; 30: 1207)
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