Invasive Candidiasis

1
Invasive Candidiasis
John H. Rex, M.D. Associate Professor of
Medicine Division of Infectious
Diseases University of Texas Medical
School-Houston Medical Director for Epidemiology,
Hermann Hospital
2
Invasive CandidiasisDiseases Definitions

• Candidemia is what we most often clearly
  diagnose. How do the various forms of candidiasis
  relate?

3
Candidemia is a broad topic
Some trial data
Mostly anecdotal
4
So, is candidemia a bad marker?

• How should we interpret candidemia?
• It is not an all-inclusive marker (low
  sensitivity)
• Yield increases w/ Isolator, BacT/Alert, large
  volume Bactec
• Said to not always imply invasion (low
  specificity)
• Benign, transient, line-related candidemia
• But, when present...
• 25 with candidemia die within 14 days
• Overall mortality 30-80 70-80 with cancer or
  BP
• Attributable mortality of 38
• Not a bad markerjust an incomplete marker

5
How else to diagnose?

• Non-sterile site cultures
• Urine, sputum common, but non-specific
• Strong hints, however powerful risk factors
• Non-culture tests
• Antibodies, antigens, metabolites, PCR
• Some are intriguing (e.g., glucan detection)
• None are ready for prime time
• Candidemia remains our primary tool

6
Treatment of candidemia and its consequences

• So, lets talk about what we can at least identify

7
Big Picture of Current Data

• IDSA MSG recently wrote a set for fungi
• Get from IDSA web site www.idsociety.org
• Candidemia some data
• Stable patient fluconazole usually used
• Unstable or prior fluconazole amphotericin B
• Remove existing central venous catheters
• All else follow ideas of candidemia
• Lots of anecdotes, most with amphotericin B
• Fluconazole works for cleanup, suppression

8
Candidemia
9
Therapeutic Trials

• Mostly C. albicans fungemia in non-neutropenics
• Flu (400/d) vs. AmB (0.5-0.6 mg/kg/d). Success
• Randomized, N206, Flu 70, AmB 79, P 0.22
• Randomized, N103, Flu 56, AmB 60, P 0.80
• Observational, N294, Flu 73, AmB 69, P 0.58
• Observational, N479, Flu 71, AmB 73, P gt 0.38
• ABLC (5 mg/kg/d) vs. AmB (0.6-1 mg/kg/d)
• Randomized, N194, ABLC 65, AmB 61, P 0.64
• Rex, 1994 Phillips 1997 Nguyen, 1995 Anaissie,
  1998

10
Candidemia neutropenia

• Anaissie Am J Med 104238, 1998
• Retrospective study 476 episodes candidemia
• Neutropenia 44 cure, non-neutropenia 74
• Species C. parapsilosis had better outcome
• Logistic regression only APACHE III, visceral
  dissemination, and remaining neutropenic were
  significant drug choice did not alter outcome
• But
• Limited data in very ill pts. Ampho preferred.

11
Catheter Management

• Yankem out vs. sitting tight

12
Catheters Candidemia

• Non-neutropenic
• 1 source!
• Cancer patients
• Tunneled lines are less often sources
• The gut is probably a frequent source in
  neutropenic patients with mucositis
• Consider changing lines. May help some pts.

Start Rx
13
OK, I took it out. What else?

• You still have to treat!
• High-density fungemia! Seeding may occur! DO AN
  EYE EXAM! Please!
• No need for TEE or other studies
• A story
• 50-year-old, ruptured divertic, somewhat messy
  course, central line, fever and BC C. albicans
• Line removed, fever abates, patient released
• 10 days later cant see from right eye!
• This is a legal issue as well. Get that exam!

14
Dose and Duration of Therapy
15
Not too much, not too little

• Data from trials on duration
• Generally for 14 days after symptoms gone
• Relapse/complication rate 1
• Doses
• Fluco at least 6 mg/kg. 12 mg/kg being studied
  and may be better for C. glabrata
• Ampho at least 0.5 mg/kg. More for glabrata?
• Lipid ampho 3 mg/kg seems comparable to 0.6-1
  mg/kg for Candida (Walsh et al. AAC 411944,
  1997 Linden et al. Pharmacotherapy 191261, 1999)

16
Persistent Fungemia
17
Persistent Fungemia

• Median time to negative BC after start drug
• 2.6 d with catheter exchange, 5.6 d without
• Fungemia that persists longer
• Dirty line, endocarditis, septic phlebitis
• Dirty lines breakthru infections of susceptible
  bugs!
• Persistent neutropenia
• Therapy
• Fix what you can, wait out what you cant, MIC?
• Add 5-FC? Other combinations? A candin?

18
Candiduria

• So, tell me, just exactly why did you order this
  urine culture?

19
Thinking About Candiduria

• In the symptomatic or febrile patient
• Treat symptomatic UTI (of course!)
• View as a risk factor for dissemination in the
  febrile and critically-ill patient
• In the asymptomatic patient
• Approach as you would bacteruria
• Correct anatomic factors
• Treatment is probably irrelevant
• This is idea is now supported by data...

20
A very instructive study!

• Sobel et al., CID 3019-24, 2000
• Asymptomatic candiduria (Cx, no fever, no sx)
• Fluco (200/d, N 159) vs. placebo (N 157) x
  14d
• Fluco cleared urine in 50, placebo in 29
• Continuous cath reduced efficacy 63 vs. 39
• 50 C. albicans, mix of others. C. tropicalis was
  most difficult to clear.
• Funguria two weeks later Same cure rate in both
  groups! (60 with cath, 70 without cath)

21
Empirical Therapy

• Not debated in cancer, fever, neutropenia.
• BUT, what about ICU, fever, and leukocytosis?

22
Empirical Therapy in the ICU

• In the febrile non-neutropenic patient?
• Early treatment is theoretically attractive
• IDSA Guidelines
• Appropriate use has not been defined
• My rules
• Antibiotics, lines, no other source, and
• Colonized somewhere with Candida
• I dont distinguish sites anywhere works for me
• More sites/fungus, more risk (Pittet, Ann Surg
  220751, 1994)

23
Prophylaxis

• A stitch in times saves nine, but where to put
  that stitch?

24
Prophylaxis in Cancer, Transplant

• Has shown benefit in several higher-risk
  populations
• BMT
• Higher risk leukemia
• Higher risk liver transplant
• Key is degree of risk
• Once frequency exceeds 10, value of prophylaxis
  is relatively easy to show

25
Prophylaxis in the (S)ICU

• Pelz et al., Ann Surg 233542-548, 2001
• Fluco vs. placebo in extremely high risk ICU
• Placebo 16 rate of invasive candidiasis
• This rates equals that in BMT!!!
• Fluco 400/d 8 rate
• P lt 0.01
• BUT, BUT, BUT A very unusual population
• Median APACHE III 60, lots of liver transplant
• Applicability in most ICUs is unclear

26
(New) Azoles
27
Itraconazole Solution vs. Capsules

• Capsules
• Relatively unpredictable absorption
• Need to be taken with food
• Gastric acid is also relevant
• Solution in cyclodextrin
• Increased bioavailability (at least 30 more)
• Increased predictability
• EMPTY STOMACH! Gastric acid less important since
  itra is already in solution.

28
IV Itraconazole

• Licensed based on comparative PK studies
• Itraconazole in hydroxypropyl-b-cyclodextrin
• Dose 200 q12h x 2d then 200 qd
• Same drug interactions
• BUT, guaranteed blood levels!
• New twist Whereas itraconazole is cleared by the
  liver, HPbCD is cleared by the kidneys.
• Few data in patients with CrCl lt 30.
• PO cyclodextrin is not absorbed no renal issue

29
What are we currently seeing?

• For invasive disease... MIC50-90
• Flu Itra AmB 5-FC
• C. albicans gt 50 S S S S
• C. parapsilosis 10-20 S S S S
• C. tropicalis 10-20 S S S S
• C. glabrata 10-30 SDD-R SDD-R S-i S
• C. krusei lt 1 R SDD I-r S-I
• C. lusitaniae lt 1 S S-SDD S-r S
• Adapted from multiple sources Susceptibilities
  from recent MSG survey

1!
30
Focus on C. glabrata

• Azoles recent bloodstream isolates
• 10-15 R to both fluconazole itraconazole
• Itra really adds little to fluconazole for
  Candida
• 50 S-DD (big doses/high levels needed)
• Amphotericin B C. glabrata is different

31
The New Broad-Spectrum Azoles

• Voriconazole (Pfizer). Late phase III
• Example Efficacy AmBisome in febrile
  neutropenia (Walsh, ICAAC 2000, LB-1). Potent in
  vivo on C. glabrata, C. krusei (Ghannoum J.
  Chemother 1134, 1999 and in press).
• Posaconazole (Schering Plough). Phase II
• Example feature Cleared Fusarium in a murine
  model AAC 43589, 1999
• Ravuconazole (Bristol-Myers). Phase II
• Example feature Excreted in bile, limited P450
  metabolism or interactions in animals ICAAC 2000,
  839

32
Voriconazole

• The front runner among the new azoles
• PO and IV
• But, like itraconazole, the IV form uses a
  cyclodextrin carrier. So, at least for now, there
  will be a limitation on its use with CrCl lt 30.
• Safety More like itraconazole than fluconazole.
  Lots of drug interactions, unclear if well need
  to monitor serum levels. The only novel
  side-effect is a visual brightening that is
  transient and seems totally with consequence.

33
Cell Wall Synthesis Inhibitors

• Great promise for treatment of candidiasis

34
Are Candins Really Cidal?
This AIDS patient failed everything fluco,
(lipid) ampho. The only thing that helped even a
little was chewing itraconazole capsules.
Before Candin
After Candin
Images courtesy Laboratory for Medical Mycology,
University of Texas Medical School-Houston,
Houston, TX
35
Micafungin Dose-Ranging Study of Therapy for
Esophagitis
n 18
n 20
n 22
n 15
n 20
Nice Dose Response!
Daily Dose
36
Caspofungin Candidal Esophagitis
Treatment Groups
Caspofungin 35 mg 50 mg 70 mg
Amphotericin B 0.5 mg/kg
Treatment Duration
X X X X X
X X
14 days 7 to 10 days
Study A Study B
Response rates 74 88 89
69
Note Dose Response!
Diagnostic Criteria Symptoms plus micro
documentation Favorable Response Resolution of
symptoms and significant
reduction in endoscopic or oropharyngeal lesions
Arathoon IDSA 99, 1998. Sable ICAAC LB-33, 1997.
37
Candins for Candidiasis Summary

• Micafungin Caspofungin show activity
• Caspofungin at gt 50 mg/d
• Micafungin at gt 50 mg/d
• Data so far limited to esophageal disease
• C. albicans is the principal fungus studied
• No data yet on anidulafungin
• Invasive studies are underway
• Are MICs are meaningful for these drugs?
• What about the higher MICs of C. parapsilosis?

38
Candida MICs for Candins

• MIC90 (n) Anid Casp Mica
• C. albicans (733) 0.06 1 0.03
• C. dubliniensis (18) 0.13 0.5 0.06
• C. tropicalis (307) 0.13 1 0.06
• C. glabrata (458) 0.13 1 0.13
• C. krusei (50) 0.25 2 0.25
• C. lusitaniae (20) 0.25 2 0.25
• C. parapsilosis (391) 2 2 4
• Recent bloodstream isolates in the United States,
  NIAID MSG
• NCCLS M27A 24h MIC at 100 growth reduction

Artifact or Relevant?
39
Dosing Issues Non-albicans Candida

• Micafungin, murine model, cyclophos
• Survival ED50 (mg/kg/d) Mica Fluco
• C. albicans 0.14 2.15
• C. tropicalis 0.28 3.71
• C. glabrata 0.30 6.27
• C. krusei 0.77 9.52
• C. parapsilosis 1.00 10.9
• 2 log ? tissue CFU/g at ED50 for all drugs
  Ikeda et al., AAC 44 614, 2000
• ? In vitro difference of 20-100x does not hold

40
Candins in Practical Use

• Caspofungin (Cancidas, Merck)
• Indicated ONLY for invasive aspergillosis when
  refractory of/intolerant to other therapy
• Has shown activity vs. esophageal candidiasis
  deep candidiasis studies are underway
• Promising, but use ONLY as indicated. Other
  things should be tried first. I am very excited
  about this class, but remember that this is a
  brand new class. Safety data are LIMITED!
• Also, the parapsilosis issue is not sorted out

41
Summary
42
Key Ideas for Candidiasis

• Both amphotericin B and fluconazole work
• Be sure to use enough
• Treat for several weeks
• Glucan synthesis inhibitors in future
• Catheters are a major nidus
• But you still have to treat with drugs
• MICs have value
• But knowledge of species is almost as good

43
FAQ Summary for Candidiasis (1)

• Positive catheter tip with fever -BC
• I would treat this as if had BC
• Solid data on empirical therapy in ICU?
• No
• Solid data on prophylaxis? (CID 321181, 2001)
• Sound theory, hard in practice. Risk is key
• C. glabrata fungemia
• Check MIC. Fluco HAS worked, but most data in
  non-neutropenic. Glabrata is weak pathogen.

44
FAQ Summary for Candidiasis (2)

• Will the new azoles really work on krusei?
• I dont know. They might, but R still possible.
• Are Isolator BC really the best?
• Bac-T-Alert works just as well for Candida. But,
  for Histo, youd prefer Isolator.
• Rx complete failure of licensed therapies?
• Consider a candin or a new azole
• Most common mistake?
• Failure to get an eye exam in a candidemic pt

45
FAQ Summary for Candidiasis (3)

• Are azoles MICs useful?
• Predictive power that of bacterial MICs.
  Knowledge of species is almost as good.
• Are amphotericin B MICs useful?
• Hugely debated. Complete R is rare, but some
  species (glabrata, krusei) do consistently have
  higher MICs
• Are candin MICs useful?
• Completely unknown. Currently not needed as
  species consistently accurately predicts MIC.

46
Stay Alert!

• To believe is very dull.
• To doubt is intensely engrossing.
• Oscar Wilde