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Презентация на тему Combination Antifungal Therapy
Содержание
- 2. The Past as PrologueWhat can we learn from prior work on antibacterial combinations?
- 3. History lessons: Stay alert!Combinations can be GOODEnterococcus:
- 4. About those words… Less than Same as More than expected expected expectedLoewe Antag. Additive SynergyBliss Antag. Independent SynergyThe word
- 5. About those numeric scores…What about FICIs and
- 6. Bug-, drug-, and & model-dependenceA thought experiment:
- 7. Antifungal CombinationsWith all that in mind, what
- 8. Drugs & AbbreviationsAmphotericin B (AmB): Membrane effects5-Flucytosine
- 9. 5-Flucytosine plus various thingsGenerally favorable
- 10. 5FC + ThingsCryptococcal meningitis⇑ success, ⇑ rate
- 11. Useful lesson: Dose matters!Murine models of cryptococcal
- 12. Candins plus various thingsA hot topic at present!
- 13. Aspergillus: Not quite dead (1)Rabbit model, Ara-C,
- 14. Aspergillus: Not quite dead (2)Anidulafungin, murine model,
- 15. For Aspergillus,Echinocandins alone do not completely killPersistent
- 16. In vivo data are supportiveMost data show
- 17. Human Data?Really scant so far. An anecdoteA.
- 18. Other FungiCryptococcusCandins alone have minimal effectsCFG +
- 19. Candin Combinations: Bottom LineI’d rate this as
- 20. Polyenes plus azolesThe really confusing one
- 21. Azoles + AmB: In vitroIn theoryAzole depletes
- 22. Aspergillus: Any answer you want…KETO first, AmB
- 23. Continued variationCryptococcus: GOODMurine model: FLU + AmB
- 24. Candida: We have some dataAll possible results
- 25. Candida: A caveatLouie et al. AAC 43:2831,
- 26. Human Data: Non-CandidaMostly a lot of anecdotes,
- 27. FLU + AmB for CandidemiaStudy ArmsFLU+Placebo: FLU
- 28. Prior Therapy: % Success (N)Group FLU+Placebo FLU+AmBNo prior therapy 61%
- 29. AmB + Azoles: Bottom LineYow! Very confusingMany
- 30. Further Afield
- 31. Terbinafine + AzolesA sequential one-two attackTERB: squalene
- 32. Terbinafine + Azoles: CandidaClinical anecdoteOPC unresponsive to
- 33. Terbinafine + Azoles: PythiumPythium is an aquatic
- 34. Others: Too many to discuss!NikZ + candin
- 35. And, at this meetingAt least 25 presentations
- 36. SummaryYour head is round so that your thinking can change direction…
- 37. Clinical Implications for TodayCryptococcusAdding 5FC is generally
- 38. Скачать презентацию
- 39. Похожие презентации
The Past as PrologueWhat can we learn from prior work on antibacterial combinations?
Слайд 3
History lessons: Stay alert!
Combinations can be GOOD
Enterococcus: PCN
(or amp or vanc) + gent
Good in endocarditis. But,
not clearly so at other sitesCombinations can be BAD
PCN + chloro in pneumococcal meningitis
Adding chloro decreased survival from 79 to 21%
Assessing all this in vitro is TRICKY
Technical: Enterococcus, PCN, & gent
Checkerboard is not reliable—must use time-kill
Some interactions (e.g., metabolic) not seen
Слайд 4
About those words…
Less than Same as More than
expected expected expected
Loewe Antag. Additive Synergy
Bliss Antag. Independent Synergy
The word additive
can be confusing
It really means that a drug added
to itself produces the expected sum of effectsIt does not imply effects greater than expected
“Indifferent” has no clear definition
Greco WR et al. Pharmacol Rev 1995;47:331
Слайд 5
About those numeric scores…
What about FICIs and other
numbers?
FICI = 1 is the null point
Other values are
parsed infinitely< 0.5 = synergism
0.5 to 4 = additive or indifferent or other phrases
> 4 = antagonistic
All is arbitrary and highly technique driven
I am going to be looking at mostly in vivo data
I will lump into positive, neutral, & negative
Слайд 6
Bug-, drug-, and & model-dependence
A thought experiment: Add
a drug to itself
1 μg/ml + 1 μg/ml =
2 μg/ml, right?Dose-response curve: shape & location…
94% @ 1
50% @ 2
6% @ 4
1% @ 8
Hill Slope = 4
Hill Slope = 0.25
Слайд 7
Antifungal Combinations
With all that in mind, what about
the antifungal agents?
My focus will be on combinations where
we can currently shown some clinical utility
Слайд 8
Drugs & Abbreviations
Amphotericin B (AmB): Membrane effects
5-Flucytosine (5FC):
DNA/RNA synthesis
Ergosterol pathway: azoles & allylamines
FLU, ITR, KETO, VOR,
RAV, POSTerbinafine (TERB)
Glucan synthesis: The candin/fungins
CFG, MFG, AFG
Chitin synthesis: Nikkomycin Z (NikZ)
Слайд 10
5FC + Things
Cryptococcal meningitis
⇑ success, ⇑ rate CSF
sterilized
⇓ AmB dose & thus nephrotoxicity
⇓ relapse rates (HIV)
Other
fungi: Not obviously good or badCandida: ?in vitro antag, but OK in case series
Aspergillus et al.: OK in vitro & tiny case series
Te Dorsthorst ICAAC ’02, M-850: +AmB is good, +ITR is bad
Block Proc Soc Exp Biol Med 142;476, ’73; Te Dorsthorst AAC 46:2982, ’02; Bennett NEJM 301:126, 1979; van der Horst NEJM 337:15, ’97; Saag CID 28:291, ’99; Saag CID 30:710, ’00; Te Dorsthorst AAC 46:2982, ’02; Martin AAC 38:1331, ’94; Barbaro Chest 110:1507, ’96; Polak Chemotherapy 33:381, ’87; Verweij Infection 22:81, ’94; Sllling Mycoses 42 (S2):101, ’99; Denning RID 12:1147, ‘90
Слайд 11
Useful lesson: Dose matters!
Murine models of cryptococcal meningitis
FLU
+ 5FC is generally quite favorable
Ding AAC 41:1589, ’97;
Allendoerfer AAC 35:726, ’91; Barchiesi AAC 44:2435, ‘00The place to be!
There is a zone of optimal interaction
Слайд 13
Aspergillus: Not quite dead (1)
Rabbit model, Ara-C, persistent
neutropenia
Anidulafungin (AFG), intratracheal inoculation
Control lung section
6.5 d survival
AmB, 1
mg/kg/d~1.5 log ↓ CFU/g
AFG, 10 mg/kg/d
No ↓ CFU/g
Petraitis et al., AAC 42:2898, 1998
Dead
Not quite
Слайд 14
Aspergillus: Not quite dead (2)
Anidulafungin, murine model, cyclophos
Model
produced transient neutropenia
IV infection with Aspergillus conidia
Lung CFU/g # Survivors
Control 310 0/10
AmB
2 mg/kg/d 90 7/10AFG 10 mg/kg/d 60 8/10
Verweij et al., AAC 42:873, 1998
Now we see a CFU drop
Слайд 15
For Aspergillus,
Echinocandins alone do not completely kill
Persistent neutropenia:
tissue may not clear
Transient neutropenia: tissue is cleared
So, the
candin needs a helping handSecond agent could be a neutrophil
Or a drug!
Слайд 16
In vivo data are supportive
Most data show strong
positive interactions
Candin plus AmB
CFG: (Flattery, ICAAC #J-61, ’98)
Value seen
in DBA2/N mice, but not pancytopenic miceMFG: (Kohno, ICAAC #1686, ’00); (Nakajima, ICAAC #1685, ’00)
Candin plus azole
VOR + CFG: (Kirkpatrick, AAC 46:2564, ’02)
RAV + MFG: (Petraitiene, ICAAC M-857, ’02)
A few differences here and there
MFG + AmB: Neutral (Capilla-Luque, ICAAC J-1834, ’01)
Cilofungin + AmB: Negative (Denning, AAC 35:1329, ’91)
Слайд 17
Human Data?
Really scant so far.
An anecdote
A. flavus
pneumonia & osteo in boy with CGD
CAS + VOR
held in check, but VOR alone did not.Open-label or salvage: Hard to interpret
Kontoyiannis, ICAAC ‘02, M-1820
50 with invasive aspergillosis. CFG+L-AmB
Thiebaut, ICAAC ’02, M-859
10 with various IFI. CFG + AmB
Gentina, ICAAC ’02, M-860
6 with IA, use of CFG + L-AmB and CFG + VOR
Слайд 18
Other Fungi
Cryptococcus
Candins alone have minimal effects
CFG + AmB:
Favorable in vitro, but no obvious in vivo advantage
Candida
In
vitro: candins are very potent, combos additiveBachman ICAAC ’02, M-1813: FLU+CAS bad in biofilm?
CFG + AmB: Favorable in vivo effect
Also reported with cilofungin + AmB
Franzot AAC 41:331, ’97; Flattery ICAAC #J-61, ’98; Smith EJCMID 10:588, ’91; unpublished data (Rex); Sugar AAC 35:2128, ’91; Roling DMID 43:13, ‘02
Слайд 19
Candin Combinations: Bottom Line
I’d rate this as very
interesting
Aspergillus data are especially powerful
These data really make sense
based on our understanding of the relative drug effectsA serious clinical study is in order!
The other fungi?
Not so obvious why you should do it
But, you can do it without ill-effect, should you need a combination to get a broader spectrum
Слайд 21
Azoles + AmB: In vitro
In theory
Azole depletes ergosterol,
AmB needs ergosterol
Thought experiment
If azole works, who cares?
Always at
least azole effect?In practice…
AmB first? No negative effect
Together? Negative at [sub-MIC]
Azole first? Often negative, especially w/ ITR, KETO
Scheven AAC 39:1779, ’95, Scheven Mycoses 38 (S1):14, ‘95
Valley of antagonism
Слайд 22
Aspergillus: Any answer you want…
KETO first, AmB second:
Bad in rat model
ITR and AmB together
Series of murine
disseminated disease modelsMostly no interaction, occasionally slightly negative
POS+AmB: neutral (Najvar, ICAAC ’02, M-1818)
Murine CNS aspergillosis model
Combination trended towards better survival then either alone. Not negative, for sure!
Key: Result is model-, drug-, site-specific
Schaffner JID 151:902, ’85; Polak Chemotherapy 33:381, ’97; Chiller ICAAC #J-1615, ’01.
Слайд 23
Continued variation
Cryptococcus: GOOD
Murine model: FLU + AmB gave
best results!
But, FLU first was bad
Histoplasma: BAD
Higher lung &
spleen CFU with FLU + AmBTrichosporon: GOOD
FLU + AmB was better than AmB alone
And, FLU + AmB + levofloxacin was best of all!
Barchiesi AAC 44:2435, ’00; LeMonte JID 182;545, ’00; Louie ICAAC J-1619, ‘01
Note color coding: blue for FLU, yellow for AMB
Слайд 24
Candida: We have some data
All possible results seen.
The azole matters
AmB + Pos: Combo best (Cacciapuoti ICAAC
’02 M-1814)AmB + ITR: Combo < AmB (? 2° toxicity)
FLU, two murine models, C. albicans
Sugar JID 177:1660, ’98; Sugar AAC 38:371, ’94; Sugar AAC 39:598, ’95; Louie AAC 43:2841, ‘99
FLU + Amb was best
FLU + Amb was < AmB
Слайд 25
Candida: A caveat
Louie et al. AAC 43:2831, ’99
Clearance
of heart valves (rabbits, C. albicans)
Log CFU
Day
FLU + Amb
was intermediate between FLU and AmB alone
Слайд 26
Human Data: Non-Candida
Mostly a lot of anecdotes, mostly
OK
Anecdotal use of AmB+5FC+FLU for crypto
AIDS/Histo, crypto: alternate azole
& AmB useStray anecdotes
ITR + L-AmB cured skull base aspergillosis
ITR + L-AmB failed in in two cases of aspergillosis
ITR + L-Amb used without comment (!)
And, we’ve got a serious trial in Candida…
Streppel Ann Otol Rhinol Laryngol 108:205, ’99; Bajjoka Pharmacotherapy 19:118, ’99; Caillot JCO 15:139, ‘97
Слайд 27
FLU + AmB for Candidemia
Study Arms
FLU+Placebo: FLU 800
mg/day plus MVI
FLU+AmB: FLU 800 mg/day + 0.7 mg/kg
dAmBPlacebo/AmB x 3-8 days & was blinded!
Results: FLU + AmB…
Was favored overall (P = 0.04 to 0.08)
Was more nephrotoxic (no surprise)
Gave lowest rate persistent +BC ever seen!
7% vs. 17%: this is better than ANY previous study
And, as for antagonism…
ICAAC 2001, #J681a
Слайд 28
Prior Therapy: % Success (N)
Group FLU+Placebo FLU+AmB
No prior therapy 61% (46) 69%
(39)
FLU only 56% (48) 67% (55)
AmB only 17% (6) 73% (11)
FLU & AmB 50%
(4) 50% (2)Any drug 52% (58) 68% (68)
A good number of cases.
Not even a hint of in vivo antagonism.
No antagonism in vitro, either.
Слайд 29
AmB + Azoles: Bottom Line
Yow! Very confusing
Many negative
trends, but many surprises
Cryptococcus: Combination often positive
Candida: A wild
range of resultsThe one human trial was NOT negative
Can do if needed. This strategy pursued to get better spectrum. Candins should render moot.
Aspergillus
Start w/AmB, switch to azole, may overlap
Слайд 31
Terbinafine + Azoles
A sequential one-two attack
TERB: squalene epoxidase,
upstream of
Azoles: 14-α-demethylase
In vitro is almost entirely favorable
Candida: FLU,
ITR, POS, VOR, AmBA. fumigatus: FLU, ITR
Unfavorable with AmB, 5FC
Zygomycetes: AmB, VOR
& more: Scopulariopsis, Pythium, Trichosporon
Brachiesi JAC 41:59, ’98 & AAC 41:1812, ’97; Perea JCM 40:1831, ’02; Mosquera 40:189, ’02; Dannaoui AAC 46:2708, ’02; Ryder Mycoses 42 (Suppl. 2): 115, ‘99
Слайд 32
Terbinafine + Azoles: Candida
Clinical anecdote
OPC unresponsive to FLU
at 200/d x 2 weeks
FLU MIC of 32 μg/ml
FLU 200/d + TERB 250/d: Clears completely
Clinical study Flu-refractory OPC in HIV
TERB 1000-1500/d alone: 15-17% response
TERB with 200/d FLU: 23% response
Right direction, just not very strong
Ghannoum Clin Diag Lab Immunol 6:921, ’99; Vazquez ICAAC 2000 (Toronto), #1418
Слайд 33
Terbinafine + Azoles: Pythium
Pythium is an aquatic near-fungus
Causes
“swamp cancer” in horses
Unremitting tissue destruction
Responds poorly drugs –
surgery is keyA 2-year-old had deeply invasive infection
Surgery not an option
In vitro, TERB + ITR favorable (esp. for MLC)
Responds completely to 1 year of ITR + TERB!
This is really quite striking
Shenep CID 27:1388, ‘98
Слайд 34
Others: Too many to discuss!
NikZ + candin or
azole
Azoles + quinolones (yes, quinolones)
FLU + trova = AmB
in murine Rhizopus modelQuin effect might include immune enhancement
Rifampin, azithromycin, tetracycline
Protein synth. Inhibitors: Often positive in vitro
Cyclosporine plus azoles or candins
Makes azoles cidal in endocarditis models!
Chiou AAC 45:3310, ’01; Li AAC 43: 1401, ’99; Capilla-Luque ICAAC #J-1834, ’01; Sugar AAC 44:2004, ’00; Sugar AAC 41:2518, ’97; Shalit 46:2442, ’02; Arroyo AAC 11:21, ’77; Clancy AAC 42:509, ‘98; Clancy JAC 41:127, ’98; Ernst RID 5:S626, ’83; Graybill RID 5:S620, ’83; Hughes AAC 25:560 & 26:837, ’84; Huppert AAC 5:473, 1974; Kitahara JID 133:633, 1976; Marchetti AAC 44:2373, ’00; Marchetti AAC 44:2932, ’00; Heitman EMBO J 21:546, ‘02
Слайд 35
And, at this meeting
At least 25 presentations on
combinations
Poster session at noon today (11-12:30)
Slide session with mini-lecture
Monday AMSome highlights
Sophisticated in vitro models
Cotrimoxazole as a co-agent
Lots of candin-based work
Interesting terbinafine-based data
Слайд 37
Clinical Implications for Today
Cryptococcus
Adding 5FC is generally good.
+FLU is better?
Candida
Can combine fluconazole with AmB
But, probably should
avoid in endocarditisCandins may render this idea moot
Aspergillus
Candin-based combos look like the way to go
Keep terbinafine-based combos in mind
