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Is combination antifungal therapy a viable option for the future?. Brian L Jones Glasgow Royal Infirmary UK. New Approaches in the Changing World of Antifungals 14th ECCMID, Prague 2004. Precedents - good & bad. Neutropenic Gram negative sepsis

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slide1

Is combination antifungal therapy

a viable option for the future?

Brian L Jones

Glasgow Royal Infirmary

UK

New Approaches in the Changing World of Antifungals

14th ECCMID, Prague 2004

slide2

Precedents - good & bad

  • Neutropenic Gram negative sepsis
  • - extended spectrum  lactam + aminoglycoside
  • Enterococcal endocarditis
  • - penicillin + aminoglycoside
  • Tuberculosis
  • - rifampicin + isoniazid + ethambutol
  • Pneumococcal meningitis
  • - penicillin + chloramphenicol
  • - decreased survival from 79 to 21%
  • Cryptococcal meningitis
  • - amphotericin B + flucytosine
  • - Saag et al Clin Infect Dis 2000;30:710-8
slide3

Is there a need for combination antifungal therapy?

Rate per 100,000 population

Mortality in US 1980-1997

McNeil et al Clin Infect Dis 2001;33:641-7

slide4

Probability of developing proven/probable IA

among patients alive at d.40

0.1-

HSCT 1993-98

HSCT 1987-92

0.05-

0

6

12

Months after transplantation

Marr et al Blood 2002;100:4358-66

slide5

Available antifungal agents

  • Cell membrane integrity
  • - polyenes
  • amphotericin, lipid preparations
  • nystatin
  • Ergosterol biosynthesis
  • - azoles
  • fluconazole, itraconazole, voriconazole,
  • posaconazole, ravuconazole
  • - allylamines
  • terbinafine
  • DNA synthesis
  • - pyrimidine analogues
  • flucytosine
  • Cell wall integrity
  • - echinocandins
  • caspofungin, anidulafungin, micafungin
slide6

Pharmacologic activity of antifungal combinations

  • Pharmacokinetic interactions
    • Direct or indirect interactions
  • - affect amount, rate and ratio of [drug] at site of infection
  • Pharmacodynamic interactions
    • Spectrum
    • Selection for resistance
    • Toxicity
    • Rate and extent of killing
    • - synergy or antagonism
  • Interactions
  • Cost
slide7

Definitions

  • Synergy
  • “improvement in fungicidal activity by a magnitude greater than
  • the expected sum of the individual activities of individual agents”
  • Antagonism
  • “antifungal activity of a combination is less than that of the
  • least active antifungal in the combination when given alone”
  • Additive- imprecise term
    • improvement in antifungal activity is no greater
    • than sum activity of individual drugs
    • it does not imply effects greater than expected

Indifferent

“combinations are no more effective than single most effective

agent used alone”

Greco Pharmacol Rev 1995;47:331

Lewis Pharmacotherapy 2001;21:149s

Johnson AAC 2004;48:693

slide8

Mechanisms of synergy or antagonism

  • Synergy
  • Sequential inhibition of different steps of a common biochemical pathway
  • eg terbinafine + azole
  • Simultaneous inhibition of cell wall and cell membrane targets
  • eg echinocandin + amphotericin B or azole
  • Cell wall/membrane active agents allow penetration of 2nd agent
  • eg amphoB, fluconazole, echinocandin
  • + flucytosine, quinolone, rifampicin
  • Antagonism
  • depletion or blocking of binding sites for another agent
  • eg azole + amphotericin

Lewis Pharmacotherapy 2001;21:149s

slide9

How can we predict what is going

to happen in the patient?

very difficult!

  • In vitro studies
  • - Perform with multiple isolates
  • - Wide range of drug concentrations
  • - Subject to statistical analysis
  • - Vary technical factors
  • But
      • - Methodological problems - lack of consensus
      • - Host factors ignored
      • - Lack of correlation with animal models/patients
slide10

In vitro studies

Chequerboard dilutions

FICI = (MIC drug A in combination/MIC drug A alone)

+ (MIC drug B in combination/MIC drug B alone)

FICI  0.5 synergy

> 4.0 antagonism

> 0.5 - 4.0 no interaction

Surface response modeling

E-test

Time-kill studies

slide11

In vivo studies - animal models

? more predictive of clinical efficacy

  • Strengths
  • Pharmacokinetic/toxicological
  • effects addressed
  • Homogeneous hosts
  • Host factors integrated
  • Quantitative endpoints analysed
  • Range of doses/combinations
  • can be tested
  • Weaknesses
  • Variability in methodology
  • Expensive & time consuming
  • Don’t mimic pathogenesis of
  • human disease
  • Inconsistencies in pharmacokinetics
  • Not statistically powered
  • Definition of synergy/antagonism
slide12

Clinical trials

  • This is what matters!
  • But…
  • Expensive
  • Slow
  • Subjects and isolates are heterogeneous
  • Cannot control underlying disease
  • Subjective assessment of efficacy based on clinical outcome
  • Dose ranges limited
amb plus 5fc in the treatment of cryptococcal meningitis
AmB plus 5FC in the treatment of cryptococcal meningitis
  • Prospective, randomised, comparative trial (HIV-negative)
  • Low-dose AmB (0.3 mg/kg/d) plus flucytosine 150 mg/kg/d for 6 w. vs. AmB alone (0.4 mg/kg/d) for 10 w.
  • Combination - cured or improved 68% (23/34) vs 47% (15/32) - produced fewer failures or relapses (3 vs. 11)

- fewer deaths 24% vs 47% (p<0.05)

- more rapid CSF sterilization (p < 0.001)

- less nephrotoxicity (p<0.05)

  • Adverse reactions to flucytosine occurred in 11/34 pts but were not life-threathening

Bennett et al NEJM 1979;301:126-131

amb plus 5fc in the treatment of cryptococcal meningitis16
AmB plus 5FC in the treatment of cryptococcal meningitis
  • Double blind multicenter comparative trial (HIV-positive)
  • AmB (0.7 mg/kg/d) +/- 5FC(100 mg/kg/d) for 2 w.

Followed by 8 w. with ITC or FLC (400 mg/d)

  • CSF sterility at 2w in 60% of the 202 pts receiving combo vs 50% of the 179 receiving AmB alone (P=0.06)
  • No differences in clinical/microbiological response beyond 2w.
  • No difference in mortality rates at 2 weeks
  • 5FC associated with fewer relapses

Van der Horst et al NEJM 1997;337:15-21

slide17

5FC - azole combinations

  • 5FC + FLC
  • Reduced failure rateWitt CID 1996;22:322-8
  • 6m survival 22% vs 12% p=0.022
  • no serious toxicityMayanja-Kizza CID 1998;26:1362-6
  • 10w 5FC (150mg/kg) + FLC (400mg) 63% clinical success
  • 5FC discontinued in 28%
  • Larsen CID 1994;19:741-5
  • 5FC + ITC
  • comparable or better than ITC alone
  • Viviani J Infect 1989;18:151-65
  • Viviani J Amer Acad Dermatol 1990;23:587-93
slide18

Triple combinations: AmB + 5FC + triazoles

  • Randomized study
  • 100 patients AIDS-associated cryptococcal meningitis
  • AmB (0.3mg/kg/d) + 5FC (150mg/kg) for 6w. vs
  • same + ITC (400mg) until neg cultures (mean 2.4w),
  • then ITC for 6w. total
  • Triple therapy group
  • - better overall success 50/50 vs 45/50 (p=0.03)
  • - early reolution of fever 5.9 vs 8.8 (p=0.02)
  • - better CSF sterilisation rates at 2w
  • - but higher relapse rates after switching to ITC
idsa guidelines for the management of cryptococcal disease
IDSA Guidelines for the Management of Cryptococcal Disease

Cryptococcal meningitis, HIV-negative:

  • AmB 0.7- 1 mg/kg/d + 5FC 100 mg/Kg/d for 2w. then FLC 400 mg/d for 8w.
  • AmB 0.7- 1 mg/kg/d + 5FC 100 mg/kg/d for 6-10w.

Cryptococcal meningitis, HIV-positive

  • As above, 1 & 2
  • FLC 400-800 mg/d + 5FC 100-150 mg/kg/d for 6w.

Pulmonary cryptococcosis, HIV-positive:

  • FLC 400 mg/d + 5FC 100-150 mg/kg/d for 10w.

Saag CID 2000;30:710-18

slide21

Candida - in vitro studies 1

Johnson, AAC 2004;48:693-715

Te Dorsthorst AAC 2002;46:2982

Hirasawa JAC 2004;53:225

slide23

Candida - animal models 1

Johnson, AAC 2004;48:693-715

slide24

Candida - animal models 2

Johnson, AAC 2004;48:693-715

slide25

Candida - clinical studies 1

5FC - AmB non-neutropenics in ICU

success rates similar to FLC

better at sterilizing tissue and treating peritonitis

Abele-Horn Infection 1996;24:426

cleared cultures faster in peritonitis cf FLC

Kujath Infection 1993;21:376

good efficacy in meningitis - HIV/non HIV associated

Casado CID 1997;25:673

Smego Rev Infect Dis 1984;6:791

slide26

Candida - clinical studies 2

High dose FLC plus placebo vs FLC plus AmB as

therapy for candidemia in non-neutropenic subjects

  • Randomised, blind, multicentre
  • Non-C. krusei candidemia
  • FLC 800 mg/d for 14 d after resolution symptoms
  • plus either placebo or AmB 0.7mg/kg/d for first 3 - 8d
  • ≥ 1 BC positive ≤ 4d prior to entry + clinical signs
  • Success if
    • BC negative at end therapy and follow up
    • resolution signs and symptoms
    • sterile site cultures negative
    • local inflammation resolved

Rex CID 2003;36:1221

slide28

IDSA Guidelines for treatment of candidiasis

Key recommendations

  • Candidemia caspo, FLC
  • AmB prep - consider 5FC
  • FLC + AmB
  • L-AmB in neutropenia
  • Hepatosplenic FLC, AmB, L-AmB
  • candidiasis consider 5FC
  • Endocarditis AmB ± 5FC
  • Meningitis AmB + 5FC
  • Endophthalmitis AmB ± 5FC

Pappas CID 2004;38:161

slide30

Aspergillus - in vitro studies

Johnson AAC 2004;48:693-715 Steinbach CID 2003;37(Suppl 3) S188

slide32

Aspergillus - animal models 2

Echinocandin combinations

Caspo + VRC Guinea pig model

survival similar to VRC alone

improved sterilization of tissues (103 fold)

Kirkpatrick AAC 2002;46:2564

Caspo + ITCreduced fungal burden

Douglas ICAAC 2002 M-1819

Mica + RVCimproved survival

Petraitiene ICAAC 2002 M-857

Mica + ITC improved survival

Mica + Nikkomycin Zimproved survival

Luque AAC 2003;47:1452

slide33

Aspergillus - animal models 3

  • Neutropenic rabbit IPA model
  • Micafungin + ravuconazole
  • Pharmacokinetics verified to ensure drug exposure similar to humans
  • Improved survival
  • combo 9/12 vs Mica 0/8 vs RVC 2/8 vs controls 0/8 p ≤ 0.001
  • Reduced - residual fungal burden p ≤ 0.05
  • - GM antigenaemia p ≤ 0.01
  • - Infection mediated pulmonary injury p ≤ 0.05
  • - no. of pulmonary infiltrates on CT p ≤ 0.001
  • No toxicity
  • Synergy confirmed in vitro

Petraitis JID 2003;187:1834

slide35

Caspofungin + L-AmB as primary or salvage therapy of IA

  • %
  • Overall response 42
  • prov/prob 22
  • poss 60
  • Prior L-AmB response 35
  • prov/prob 18
  • Primary therapy 53
  • prov/prob 33
  • Overall mortality 35
  • 5 pts responded while neutropenic
  • Mild-mod renal impairment in 15%
  • 48 pts 23 prov/prob
  • 25 poss
  • 65% salvage Rx
  • 35% primary Rx
  • 50%BMT
  • 63% neutropenic
  • Prior L-AmB 9d (7-35)
  • Combination Rx 20d (7-180)

Kontoyiannis Cancer 2003;98:292

slide36

Caspofungin + L-AmB for salvage

therapy of IPA in acute leukaemia

  • 30 pts - 26 acute leuks
  • IPA 6 prov, 4 prob, 20 poss
  • 27/30 prior L-AmB
  • Median L-AmB Rx 12d (4-65)
  • Combination Rx 24d (3-74)
  • Favourable response in 18/30 (60%)
  • (proven 5/6)
  • 17/18 survived to discharge
  • Complete resolution in 6/18 (20%)

 Randomized clinical trial planned

Aliff Cancer 2003;97:1025

slide37

IDSA guidelines for aspergillosis

  • Early management
    • Prompt, aggressive diagnosis
    • Therapy initiated on suspicion of diagnosis
  • Antifungal therapy
    • Intravenous therapy initiated
    • AmB deoxycholate at max. doses (1-1.5 mg/kg/d)
    • Lipid AmB: impaired renal function or intolerance
    • or concomitant nephrotoxic drugs
    • Itraconazole: oral therapy, sequential use
  • Adjunctive therapy: surgery, immunotherapy
  • New therapies and diagnostic tools needed to improve prognosis
  • Combination therapy not recommended

Stevens CID 2000;30:696

slide38

The real world…

Combinations are used in haematology units

more in hope than based on any hard evidence!

We have preliminary evidence of efficacy

Now we need trials…but…

Recruitment

Proven/probable infection

Prohibitively expensive - who’s going to pay?

Three arm protocol: A vs. B vs. A+B

Voriconazole vs. Caspofungin vs. VRC + Caspo

Voriconazole vs. AmBisome vs. VRC + AmB

AmBisome vs. Caspofungin vs. AmB + Caspo

slide39

What of other approaches to improve efficacy?

  • New approaches to current agents
  • high dose AmBisome - Skinner abstr. SIOP 2003
  • - Kinsey abstr. BSH 2004
  • Immunomodulation
  • Better diagnosis
  • HRCT - Caillot JCO 1997;15:139
  • - Ellis Abstr. 2103, ASH 2001
  • GM - Maertens Blood 2001;97:1604
  • PCR - Hebart JID 2000;181:1713
  • Concept of preemptive therapy
  • not yet shown to improve outcome
  • How should combination therapy be used?
  • targeted?
  • preemptively?
slide40

CONCLUSIONS

  • Outcomes remain suboptimal
  • Combination therapy is attractive
  • Extrapolation of in vitro/animal data to clinic is difficult
  • In general most combinations exhibit neutral to positive effects
  • Caution with AmB - azole combinations
  • Crypto/Candida - combinations included in guidelines
  • Aspergillus - combinations not recommended
  • - echinocandins + AmB or azoles look promising
  • Timing of use unclear
  • Need data from controlled clinical trials
  • but don’t hold your breath!