Originalvortrag von

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• Originalvortrag von
• Dr. Georg Maschmeyer, Berlin
• anläßlich des
• CANCIDAS Freestanding Symposiums
• 04.04.2003
• Hotel Bayerischer Hof, München
• Der Vortrag wurde uns mit freundlicher
  Genehmigung von Herrn Dr. Maschmeyer zur
  Weitergabe zur Verfügung gestellt.
• Bitte berücksichtigen Sie bei der Anwendung der
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Caspofungin in Invasive Candidiasis
Georg Maschmeyer, MD Charité University
Hospital Hematology and Oncology Humboldt
University of Berlin Germany georg.maschmeyer_at_char
ite.de
3
Antifungal ProphylaxisFluconazole vs Placebo

• Significant reduction of superficial and systemic
  fungal infections and of fungal infection-related
  mortality in patients post-BMT (n 358)
  (Goodman JL et al, N Engl J Med 326
  845-851, 1992)
• Significant reduction of colonization and
  superficial infections in patients with acute
  leukemia (n 257) (Winston DJ et al, Ann Intern
  Med 118 495-503, 1993)
• Significant reduction of systemic and superficial
  Candida infections, and colonization, and
  systemic amphotericin B and of mortality in BMT
  patients (n 300) (Slavin M et al, J Infect
  Dis 171 1545-1552, 1995)

4
Fluconazole Prophylaxis in Allogeneic BMT/SCT
Recipients Fluconazole-Resistant Candida spp.

• 136 (53) had at least 1 sample yielding
  non-albicans Candida spp.

Isolate n Fluconazole- Resistant C.
albicans 885 5.3 C. glabrata 398 99 C.
krusei 80 100 C. lusitaniae 20 30 C.
tropicalis 10 30 C. guillermondii 9 100 C.
lipolytica 2 100
Marr KA et al (FHCRC), J Infect Dis 181 309-316
(2000)
5
Fluconazole Prophylaxis in Allogeneic BMT/SCT
Recipients Candida spp. Isolated in Candidemia
(4.6)
Isolate n C. albicans 1 C. glabrata 14 C.
krusei 6 C. parapsilosis 7 C. guillermondii 1 C.
albicans C. glabrata 1
Marr KA et al (FHCRC), J Infect Dis 181 309-316
(2000)
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Candidemia Non-albicans Candida spp.
1992
1993
1999
7
Candidemia in Cancer Patients Overall Survival
According to Pathogen
Viscoli C et al (EORTC-IFIG), Clin Infect Dis
28 1071-1079 (1999)
8
Nosocomial Bloodstream Isolates (SCOPE Study)
Rank Pathogen No. of Isolates of
Isolates Associated Mortality 1 Coagulase-nega
tive staphylococci 3908 31.9 21 2 Staphylococcus
aureus 1928 15.7 25 3 Enterococci 1354 11.1 32 4
Candida spp. 934 7.6 40 5 Escherichia
coli 700 5.7 24 6 Klebsiella spp. 662 5.4 27 7 E
nterobacter spp. 557 4.5 28 8 Pseudomonas
spp. 542 4.4 33 9 Serratia spp. 177 1.4 26 10 Vi
ridans streptococci 173 1.4 23
Edmonds MB et al, Clin Infect Dis 29 239-244
(1999)
9
Nosocomial Candidemia in Non-Neutropenic
Patients, 1992-97 (Italy)

• n 189 episodes
• Underlying diseases
• Solid tumor (21)
• Trauma (17)
• Abdominal surgery (13)
• Cardiovascular disease (13)
• Venous catheter-associated 51/189 (27)
• 30-day mortality 45

Luzzati R et al (Verona), Eur J Clin Microbiol
Infect Dis 19 602-607 (2000)
10
Candidal Infections in Critically Ill Surgical
Patients
Pelz RK et al (Baltimore), Ann Surg 233 542-548
(2001)
11
Clinical Causes of Death vs Autopsy Diagnoses

• n 100 pts., died in medical ICU
• Autopsy rate 93
• Discordance of clinical vs postmortem diagnosis
  19
• Most frequent fungal infection, cardiac
  tamponade, abdominal hemorrhage, myocardial
  infarction

Roosen J et al (Leuven), Mayo Clin Proc 75
562-567 (2000)
12
D-AmB vs Fluconazole in Non-Neutropenic Patients
with Candidemia

• n 237 (12/89 - 4/93, 24 centers)
• Renal failure, solid tumor, GIT disease, GC
  0.5/nl
• C. albicans 65, C. tropicalis 15, C
  parapsilosis 12, C. glabrata 12, C. krusei
  1.5, C. lusitaniae 1, C.lipolytica 0.5,
  multiple Candida spp. 6
• AmB 0.5-0.6 mg/kg/d vs FLU 400 mg/d, both d 1 -
  14
• Success 79 vs 70 (p 0.22)
• Death 40 vs 33 (p 0.20)
• Nephrotoxicity 37 vs 2 (p lt 0.001)

Rex JH et al., N Engl J Med 331 1325-1330 (1994)
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Fluconazole vs Fluconazole D-AmB in
Non-Neutropenic Patients with Candidemia

• n 211 evaluable, GC 0.5/nl
• Flu 800 mg/d Placebo vs Flu D-AmB 0.7 mg/kg/d
• Overall success 56 vs 68 (p lt 0.05)
• BC not sterilized 17 vs 7 (p lt 0.05)
• Death rate 39 vs 40 (n. s.)
• Nephrotoxicity 4 vs 24 (p lt 0.001)
• Significant impact of catheter removal in both
  groups

Rex JH et al., 41st ICAAC, J681a (2001)
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Candidemia Impact of Catheter Removal

• 58 of pts. require catheter removal
• Luzzati R et al, Eur J Clin Microbiol Infect Dis
  19 602-607 (2000)
• Significant impact of catheter removal on
  clinical outcome
• Nguyen MH et al, Arch Intern Med 155 2429-2435
  (1995)
• Rex JH et al, Clin Infect Dis 21 994-996 (1995)
• Nucci M et al, Infect Control Hosp Epidemiol 19
  846-850 (1998)

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Caspofungin Other AF against Candida albicans
in Biofilms

• C. albicans strain 3153A, adherent
• Caspo SMIC50 consistently low ( 0.125 µg/ml)
• Not completely eradicated, but gt 97 reduction in
  metabolic activity
• Fluconazole SMIC50 64 µg/ml
• Caspo AmB fastest killing

Bachmann SP et al (San Antonio), 42nd ICAAC 2002,
1512 and 1813
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Disseminated Candidiasis in Chronically
Neutropenic Mice Survival
Caspofungin (1 mg/kg)
Amphotericin B (1 mg/kg)
Amphotericin B (0.25 mg/kg)
Caspofungin (0.25 mg/kg)
Survival ()
Fluconazole (80 mg/kg)
Treatment
Placebo
Fluconazole (20 mg/kg)
Days Post-Infection
Day -3
Day 28
Immunosuppression with Cyclophosphamide
Abruzzo GK et al, AAC 44 2310-2318 (2000)
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Caspofungin-Treated Candida Esophagitis
Before After
Patient 1 Patient 2
Arathoon EG et al, AAC 2002 46 451-457
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Caspofungin vs AmB in Esophageal Candidiasis
(Protocol 003)

• Randomized phase II study

Caspofungin (78 HIV) AmB (82 HIV) 50 mg 70
mg Total 0.5 mg/kg n/N () n/N () n/N () n/N
() 38/46 (82.6) 25/28 (89.3) 63/74 (85.1) 36/54
(66.7)
Villanueva A et al, CID 2001 33 1529-1535
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Caspofungin vs Fluconazole in Candida Esophagitis
(Protocol 020)
Caspofungin 50 mg Flu 200 mg (n 83 84
HIV) (n 94 84 HIV) Clinical
response 90 89 Endoscopical response 85 86 Med
ian time to response 5d 5d Drug-related adverse
events 3.6 1.1 Serious AE (n) 0 1 Discontinuat
ion 0 1 Death 0 0
Villanueva A et al, Am J Med 2002 113 294-299
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Invasive Candidiasis Study (Protocol 014)

• Multicenter, randomized, double-blind study
• Caspofungin 70 mg day 1, followed by 50 mg/d, vs.
• Amphotericin B 0.6-0.7 mg/kg/d in non-neutropenic
  patients and 0.7-1.0 mg/kg/day in neutropenic
  patients
• Designed to test for equivalent efficacy and
  superior safety
• Study monitored by DSMB
• gt Mora-Duarte J et al, 12th ECCMID, Milan, April
  2002

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Protocol 014 Inclusion Criteria

• Age of 18 years or greater
• Clinical AND microbiological evidence of invasive
  Candida infection
• Microbiological Culture positive for Candida
  spp. from blood or another sterile, invasive site
  of infection within 96 hours of study entry.
• Patients with evidence of infection limited to a
  positive culture of the urine, sputum, BAL, or
  indwelling drains were excluded.

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Caspofungin vs D-AmB in Invasive
CandidiasisResponse at End of IV Therapy
Caspofungin AmB Difference 70/50 mg 0.6-1.0
mg/kg (adjusted for strata) MITT (n 224)
80/109 71/115 12.7 (73.4) (61.7) 0.7
26.0 Evaluable (n 185) 71/88
63/97 15.4 (80.7) (64.9) 1.1 29.7
p value 0.0861 p value 0.0346
Mora-Duarte J et al, N Engl J Med 347 2020-2029
(2002)
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Protocol 014 Overall Efficacy Results
Overall Response at End of IV Therapy (test of
cure)
Caspofungin
100
Amphotericin B
90
80
70
60
Success ()
50
40
30
20
10
0
MITT (Primary Analysis)
EP (Secondary Analysis)
Mora-Duarte J et al, N Engl J Med 347 2020-2029
(2002)
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Efficacy Results Response by Candida spp.
Favorable Overall Response at End of IV Therapy
(MITT)
Caspofungin 70/50 mg
Amphotericin B 0.6-1.0 mg/kg
n/m ()
n/m ()
Pathogen
34/59 (57.6) 8/10 (80.0) 1/1
(100.0) 0/1 (0.0) 13/20 (65.5) 10/14
(71.4) 2/4 (50.0)
23/36 (63.9) 10/13 (76.9) 3/3
(100.0) 4/4 (100.0) 14/20 (70.0) 17/20
(85.0) 3/3 (100.0)
C. albicans C. glabrata C. guilliermondii C.
krusei C. parapsilosis C. tropicalis Mixed
infection
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Efficacy Results Response by Site of Infection
Overall Response at End of IV Therapy (MITT)
Caspofungin 70/50 mg
Amphotericin B 0.6-1.0 mg/kg
n/m ()
n/m ()
59/94 (62.8) 16/25 (64.0)
66/92 (71.7) 18/22 (81.8)
Blood (Candidemia) other
Mora-Duarte J et al, N Engl J Med 347 2020-2029
(2002)
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Time to First Negative Blood Culture
100
Caspofungin (n 92)
90
Amphotericin B (n 94)
80
70
Caspofungin Amphotericin
B Day 4 19.6 19.1 Day 7
12.0 9.0 Day 9
6.5 6.4
60
50
PERCENT OF RESPONDERS
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
STUDY DAY
Mora-Duarte J et al, N Engl J Med 347 2020-2029
(2002)
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Protocol 014 Efficacy by Neutropenic Status
Favorable Overall Response at End of IV Therapy
(MITT)
Caspofungin
Amphotericin B
n/m ()
n/m ()
Neutropenic (ANC lt 500 mL at
study entry)
4/10 (40)
7/14 (50)
67/105 (64)
Non-neutropenic (ANC gt 500 mL at study
entry)
73/95 (77)
Mora-Duarte J et al, N Engl J Med 347 2020-2029
(2002)
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Mortality Assessment(Study Therapy and Follow-Up)
Caspofungin 70/50 mg
Amphotericin B 0.6-1.0 mg/kg
n ()
p value
n ()
0.528

38 (30.4) 9 (7.2)
39 (34.2) 5 (4.4)
Crude Mortality Attributable
Mortality
0.566
) Defined as meeting any one of the following
criteria (a) Positive Candida culture within
48 hours of death (b) Histopathological or
microbiological evidence of Candida on autopsy
(c) Candida infection identified as an
investigator-determined cause of death
Mora-Duarte J et al, N Engl J Med 347 2020-2029
(2002)
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Protocol 014 Adverse Events
Amphotericin B 0.6-1.0 mg/kg
Caspofungin 70/50 mg
n/m ()
n/m ()
94/125 (75.2) 29/125 (23.2) 61/125
(48.8) 33/125 (26.4) 26/105 (24.8)
All drug-related AEs Discontinuations due to
drug-related AEs Infusion-related
AEs Hypokalemia Nephrotoxicity
48/114 (42.1) 3/114 (2.6) 23/114
(20.2) 13/114 (11.4) 8/95 (8.4)
) All p values lt 0.03
Mora-Duarte J et al, N Engl J Med 347 2020-2029
(2002)
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Caspofungin Safety Profile
Sable CA et al, Transpl Infect Dis 2002 4
25-30
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Summary

• Invasive fungal infections are increasingly
  common and affect a broad spectrum of patients
• A considerable number of IFI might be overlooked
• Among invasive Candida infections, there is a
  shift towards non-albicans species
• Therefore, the recommendation of fluconazole use
  for first-line treatment of invasive candidiasis
  is questionable
• Caspofungin is at least as effective and
  significantly better tolerated when compared with
  D-AmB in patients with invasive candidiasis