available, have many attractive att

available, have many attractive attributes for use
among critically ill ICU patients: limited toxicity,
safety in the presence of renal or hepatic impairment
(although caspofungin requires dose
reduction with moderate-to-severe hepatic impairment),
minimal drug interactions, broadspectrum
activity against most Candida spp.
and the theoretical advantage of a fungicidal
mechanism of action.[90,91] As such, despite considerably
greater cost, echinocandins are increasingly
replacing fluconazole as the antifungal of
choice in the ICU setting in many countries.
Clinical efficacy data for the echinocandins in the
treatment of IC has been derived from four published
randomized trials involving predominantly
non-neutropenic patients with candidaemia.[81-84]
Two trials compared an echinocandin with an
amphotericin B preparation: caspofungin versus
amphotericin B deoxycholate[81] and micafungin
versus liposomal amphotericin B.[82] In both, the
echinocandin proved to be noninferior but was
significantly better tolerated. The third trial
compared anidulafungin with intravenous fluconazole
and demonstrated a significantly greater
response rate, although caution in interpreting
superiority was advocated, as there was a suggestion
– but no definitive proof – of an effect
related to the study centre enrolling the most
patients.[83] Finally, a head-to-head comparison
of two micafungin dosing regimens (150 and
100 mg/day) and caspofungin (70 mg loading
dose then 50 mg/day) demonstrated noninferiority
and similar tolerability for the three
study arms.[84]
Taken together, these trials suggest that the
three echinocandin agents have similar efficacy
and safety. Clinical resistance to echinocandins
among Candida spp. is relatively rare, although
reports are emerging with their increasing use.
Echinocandins appear to have less activity
against C. parapsilosis in vitro than against other
Candida spp.,[92] a phenomenon related to amino
acid polymorphisms in the major subunit of glucan
synthase (Fks1), the echinocandin target.[93]
However, at present, interpretative MIC breakpoints
for the echinocandins against Candida spp.
include a ‘susceptible only’ breakpoint of
Table I.
£2 mg/L; those rare isolates manifesting MICs
Contd
Study Patient characteristics Intervention Comparator Duration Primary/other important
outcomea
Caspofungin vs micafungin
Pappas
et al.[84]
Predominantly non-neutropenic adults with
candidaemia or non-candidaemic IC (n = 593)
Micafungin (100 mg/d IV)
Micafungin (150 mg/d IV)
Caspofungin (70 mg load
then 50 mg/d IV)
‡10 d then
fluconazole po if
required
Response by MITT: 76
% vs 71
%
vs 72
% at EOIVT
Fluconazole and AmB-D vs fluconazole
Rex
et al.[85]
Non-neutropenic adults with candidaemia
(n = 219)
Fluconazole (800 mg/d IV for
‡5 d) and AmB-D
(0.6–0.7 mg/kg/d IV for 5–8 d)
Fluconazole (800 mg/d IV
for ‡5 d)
14 d following
response
Response in infected patients
receiving ‡1 dose: 69
% vs
56
%a up to 12 wk
AmB-LC vs AmB-D
Anaissie
et al.[86]
(abstract
data only)
Patients with candidaemia or noncandidaemic
IC; not stated if neutropenic or
not (n = 194)
AmB-LC (5 mg/kg/d IV) AmB-D
(0.6–1.0 mg/kg/d IV)
Duration not
stated
‘‘Overall success’’: 80
% vs 71
%
a Response usually defined as resolution of clinical signs of infection and of sterile site specimen cultures.
AmB-D = amphotericin B deoxycholate; AmB-LC = amphotericin B lipid complex; EOIVT = end of intravenous therapy; EOT = end of therapy; ITT = intention-to-treat; IV = intravenous;
L-AmB = liposomal amphotericin B; MITT = modified intention-to-treat; po = oral; * p < 0.05.
828 Playford et al.
ª 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (7)
of >2 mg/L should be designated ‘non-susceptible’
pending better understanding of their clinical
significance.[94]
Given poor outcomes associated with IC,
combination antifungal therapy is a theoretically
attractive approach. Indeed, in vitro and animal
model studies have demonstrated various antifungal
combinations to display synergy against
Candida spp.[95] The combination of amphotericin
B and flucytosine, although supported by very
limited clinical data,[96] is recommended for difficult
sites of infection, in particular those involving
the CNS.[97,98] The combination of amphotericin
B and fluconazole did not demonstrate improved
outcomes compared with high-dose fluconazole
in a randomized trial.[85]
5.2 Selecting the Initial Antifungal Regimen
for Proven IC
Based on efficacy data and pharmacological
attributes, the choice of initial therapy for IC in
the ICU setting usually lies between fluconazole
and an echinocandin. Drug selection, pending
species identification and susceptibility results,
should be based on host factors and knowledge of
local epidemiological patterns. Indeed, recent
guidelines advocate an echinocandin for patients
who have an increased risk for infection with
C. glabrata or other Candida spp. with azole resistance
or for those with haemodynamic instability.[97,98]
Unfortunately, estimation of an
individual’s risk of infection with an azoleresistant
Candida spp. on the basis of clinical
features or prior antifungal exposure is not
straightforward, and recent epidemiological studies
have yielded somewhat discrepant results,
probably related to methodological issues and
case mix variability. Some have failed to identify
any clinical variables associated with nonalbicans
Candida spp.,[99,100] whereas in one, prior
exposure to certain antibacterial – but not antifungal
– agents was independently associated
with an increased risk of candidaemia due to
C. glabrata/C. krusei.
[101] However, the seemingly
intuitive association between prior azole exposure
and subsequent azole-resistant or nonalbicans
candidaemia has been demonstrated in
other analyses.[102-104] Hence, it appears reasonable
that prior azole exposure be considered in
the selection of initial antifungal therapy for
candidaemic ICU patients. Where fluconazole is
initiated, it should be loaded at 12 mg/kg, which
may provide coverage against less susceptible
isolates of C. glabrata.
[97,98]
Although not based on firm data, the imperative
for broad-spectrum coverage of all potential Candida
spp. to minimize the chance of inadequate
empirical therapy underlies the recommendation
for an echinocandin over fluconazole among
patients with haemodynamic instability given their
poor outcome.[97,98]
5.3 Pharmacokinetic/Pharmacodynamic
Considerations
Failure to achieve pharmacodynamic targets
for fluconazole has been associated with worse
outcomes,[57-60] highlighting the importance of
dosing and the potential role of therapeutic drug
monitoring.
For fluconazole, the pharmacodynamic parameter
best correlating exposure with effect is the
area under the concentration-time curve (AUC)/
MIC ratio. Given relatively linear pharmacokinetics
and a relatively predictable daily doseexposure
relationship,[105] therapeutic drug
monitoring for intravenous administration is
unnecessary in most settings. However, dosing
should aim to achieve target AUC/MIC ratios of
at least 25 (using Clinical and Laboratory Standards
Institute MIC methodology)[106] or 100
(using European Committee on Antimicrobial
Susceptibility Testing MIC methodology)[60] to
maximize the probability of clinical success; these
should be achieved using 6 mg/kg/day (following
12 mg/kg loading) for susceptible isolates or
12 mg/kg/day for C. glabrata or other isolates
with MICs of 16–32 mg/L, as recommended in
recent guidelines.[97] Given that fluconazole is
predominantly (80%) cleared unchanged in the
urine, alternate dosing regimens may be required
for critically ill patients with hyperdynamic sepsis
and potentially augmented renal clearance.[107]
Unfortunately, little data are available to inform
such adjustments. Similarly, optimal doses for
Management of Invasive Candidiasis in the ICU 829
ª 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (7)
critically ill patients with renal impairment or
those managed with renal replacement therapies
(such as continuous haemofiltration or diafiltration)
are not clearly defined, although limited data
suggest at least 800 mg/day is required.[108,109]
Voriconazole has nonlinear pharmacokinetics
and significant inter-individual variability, making
dose-exposure assumptions difficult. Although
oral bioavailability is high, the extent
and predictability of absorption in critically ill
patients is uncertain and serious infections should
therefore be treated using intravenous administration,
at least initially. Dosing should be
weight-based (6 mg/kg every 12 hours intravenously
for 24 hours, then 3 mg/kg every
12 hours intravenously thereafter) and not rounded
down to the nearest ampoule size. Further
complicating the predictability of exposure assumptions
is the large number of potential drug
interactions. Given these issues, together with the
potential for hepatic and neurological toxicity
from elevated levels and treatment failure from
subtherapeutic levels, therapeutic drug monitoring
should be performed if voriconazole is used
for the treatment of IC in critically ill patients.
The practicalities of this important issue have
been well summarized elsewhere.[110]
Echinocandin agents display linear pharmacokinetics.
The pharmacodynamic parameters
best correlated with outcome in animal models
are either the AUC/MIC or maximum concentration/MIC
ratios.[111] Although the use of
intermittent high doses of echinocandins is of
theoretical benefit, this strategy has not been
subject to clinical trial. Different dosing regimens
were compared in two randomized trials: micafungin
dosed at 150 mg/day versus 100 mg/day[84]
and caspofungin dosed at 70 mg on day 1 then
50 mg/day versus 150 mg/day.[112] Although neither
study was adequately powered, efficacy was
similar and the different drug doses were equally
well tolerated. Finally, although fixed dosing
of echinocandins is recommended, population
pharmacokinetics have s

Kết quả (Việt) 1:

có, có nhiều hấp dẫn thuộc tính để sử dụngtrong số cực kỳ bệnh bệnh: hạn chế độc tính,an toàn sự hiện diện của suy gan hoặc thận(mặc dù yêu cầu caspofungin liềugiảm với trung bình đến nặng suy gan),tương tác thuốc tối thiểu, broadspectrumCác hoạt động chống lại hầu hết Candida spp.và lợi thế lý thuyết của một nấmcơ chế của hành động. [90,91] là như vậy, mặc dù đáng kểlớn hơn chi phí, echinocandins đang ngày càngthay thế fluconazole như kháng nấm củasự lựa chọn trong cài đặt ICU ở nhiều quốc gia.Hiệu quả lâm sàng dữ liệu cho các echinocandins trong cácđiều trị của IC đã được bắt nguồn từ bốn xuất bảnthử nghiệm ngẫu nhiên liên quan đến chủ yếuPhòng không giảm bạch cầu trung các bệnh nhân với candidaemia. [81-84]Hai cuộc thử nghiệm so sánh một echinocandin với mộtchuẩn bị amphotericin B: caspofungin so vớiamphotericin B deoxycholate [81] và micafunginso với liposomal amphotericin sinh [82] trong cả hai, cácechinocandin đã chứng tỏ là noninferior nhưng đãđáng kể tốt hơn khoan dung. Thử nghiệm thứ baso anidulafungin với tiêm tĩnh mạch fluconazolevà chứng minh một lớn hơn đáng kểphản ứng tỷ lệ, mặc dù thận trọng trong giải thíchưu thế chủ trương, như đã có một đề nghị-nhưng không có bằng chứng cuối cùng-một hiệu ứngliên quan đến Trung tâm nghiên cứu ghi danh nhiều nhấtbệnh nhân. [83] cuối cùng, là một so sánh thành tích đối đầucủa hai micafungin cu phác (150 và100 mg/ngày) và caspofungin (70 mg tảiliều sau đó 50 mg/ngày) đã chứng minh noninferiorityvà tương tự như dung nạp cho banghiên cứu vũ khí. [84]Lấy nhau, những cuộc thử nghiệm cho thấy rằng cácba echinocandin đại lý có hiệu quả tương tựvà an toàn. Các kháng chiến lâm sàng để echinocandinstrong số Candida spp. là tương đối hiếm, mặc dùbáo cáo đang nổi lên với việc sử dụng ngày càng tăng.Echinocandins dường như có ít hoạt độngchống lại C. parapsilosis trong ống nghiệm hơn chống lại khácCandida spp., [92] một hiện tượng liên quan đến aminaxit polymorphisms trong tiểu đơn vị chính của glucansynthase (Fks1), mục tiêu echinocandin. [93]Tuy nhiên, lúc hiện nay, interpretative MIC điểm ngắtcho echinocandins chống lại Candida spp.bao gồm một ' dễ bị chỉ ' điểm ngắt củaBàn tôi.£2 mg/L; Tất cả những người hiếm hoi cô lập biểu hiện MICsContdNghiên cứu bệnh nhân đặc điểm thời gian so sánh sự can thiệp của chính/khác quan trọngoutcomeaCaspofungin vs micafunginPappaset al. [84]Chủ yếu là người lớn không giảm bạch cầu trung vớicandidaemia hoặc candidaemic IC (n = 593)Micafungin (100 mg/d IV)Micafungin (150 mg/d IV)Caspofungin (70 mg tảisau đó 50 mg/d IV)‡10 sau đó dFluconazole po nếuyêu cầuPhản ứng của MITT: 76% vs 71%vs 72% tại EOIVTFluconazole và AmB-D vs fluconazoleRexet al. [85]Phòng không giảm bạch cầu trung người lớn với candidaemia(n = 219)Fluconazole (800 mg/d IV cho‡5 d) và AmB-D(0,6-0.7 mg/kg/d IV cho 5-8 d)Fluconazole (800 mg/d IVcho ‡5 d)14 d sauphản ứngPhản ứng ở những bệnh nhân bị nhiễm bệnhreceiving ‡1 dose: 69% vs56%a up to 12 wkAmB-LC vs AmB-DAnaissieet al.[86](abstractdata only)Patients with candidaemia or noncandidaemicIC; not stated if neutropenic ornot (n = 194)AmB-LC (5 mg/kg/d IV) AmB-D(0.6–1.0 mg/kg/d IV)Duration notstated‘‘Overall success’’: 80% vs 71%a Response usually defined as resolution of clinical signs of infection and of sterile site specimen cultures.AmB-D = amphotericin B deoxycholate; AmB-LC = amphotericin B lipid complex; EOIVT = end of intravenous therapy; EOT = end of therapy; ITT = intention-to-treat; IV = intravenous;L-AmB = liposomal amphotericin B; MITT = modified intention-to-treat; po = oral; * p < 0.05.828 Playford et al.ª 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (7)of >2 mg/L should be designated ‘non-susceptible’pending better understanding of their clinicalsignificance.[94]Given poor outcomes associated with IC,combination antifungal therapy is a theoreticallyattractive approach. Indeed, in vitro and animalmodel studies have demonstrated various antifungalcombinations to display synergy againstCandida spp.[95] The combination of amphotericinB and flucytosine, although supported by verylimited clinical data,[96] is recommended for difficultsites of infection, in particular those involvingthe CNS.[97,98] The combination of amphotericinB and fluconazole did not demonstrate improvedoutcomes compared with high-dose fluconazolein a randomized trial.[85]5.2 Selecting the Initial Antifungal Regimenfor Proven ICBased on efficacy data and pharmacologicalattributes, the choice of initial therapy for IC inthe ICU setting usually lies between fluconazoleand an echinocandin. Drug selection, pendingspecies identification and susceptibility results,should be based on host factors and knowledge oflocal epidemiological patterns. Indeed, recentguidelines advocate an echinocandin for patientswho have an increased risk for infection withC. glabrata or other Candida spp. with azole resistanceor for those with haemodynamic instability.[97,98]Unfortunately, estimation of anindividual’s risk of infection with an azoleresistantCandida spp. on the basis of clinicalfeatures or prior antifungal exposure is notstraightforward, and recent epidemiological studieshave yielded somewhat discrepant results,probably related to methodological issues andcase mix variability. Some have failed to identifyany clinical variables associated with nonalbicansCandida spp.,[99,100] whereas in one, priorexposure to certain antibacterial – but not antifungal– agents was independently associatedwith an increased risk of candidaemia due toC. glabrata/C. krusei.[101] However, the seeminglyintuitive association between prior azole exposureand subsequent azole-resistant or nonalbicanscandidaemia has been demonstrated inother analyses.[102-104] Hence, it appears reasonablethat prior azole exposure be considered inthe selection of initial antifungal therapy forcandidaemic ICU patients. Where fluconazole isinitiated, it should be loaded at 12 mg/kg, whichmay provide coverage against less susceptibleisolates of C. glabrata.[97,98]Although not based on firm data, the imperativefor broad-spectrum coverage of all potential Candidaspp. to minimize the chance of inadequateempirical therapy underlies the recommendationfor an echinocandin over fluconazole amongpatients with haemodynamic instability given theirpoor outcome.[97,98]5.3 Pharmacokinetic/PharmacodynamicConsiderationsFailure to achieve pharmacodynamic targetsfor fluconazole has been associated with worseoutcomes,[57-60] highlighting the importance ofdosing and the potential role of therapeutic drugmonitoring.For fluconazole, the pharmacodynamic parameterbest correlating exposure with effect is thearea under the concentration-time curve (AUC)/MIC ratio. Given relatively linear pharmacokineticsand a relatively predictable daily doseexposurerelationship,[105] therapeutic drugmonitoring for intravenous administration isunnecessary in most settings. However, dosingshould aim to achieve target AUC/MIC ratios ofat least 25 (using Clinical and Laboratory StandardsInstitute MIC methodology)[106] or 100(using European Committee on AntimicrobialSusceptibility Testing MIC methodology)[60] tomaximize the probability of clinical success; theseshould be achieved using 6 mg/kg/day (following12 mg/kg loading) for susceptible isolates or12 mg/kg/day for C. glabrata or other isolateswith MICs of 16–32 mg/L, as recommended inrecent guidelines.[97] Given that fluconazole ispredominantly (80%) cleared unchanged in theurine, alternate dosing regimens may be requiredfor critically ill patients with hyperdynamic sepsisand potentially augmented renal clearance.[107]Unfortunately, little data are available to informsuch adjustments. Similarly, optimal doses forManagement of Invasive Candidiasis in the ICU 829ª 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (7)critically ill patients with renal impairment orthose managed with renal replacement therapies(such as continuous haemofiltration or diafiltration)are not clearly defined, although limited datasuggest at least 800 mg/day is required.[108,109]Voriconazole has nonlinear pharmacokineticsand significant inter-individual variability, makingdose-exposure assumptions difficult. Althoughoral bioavailability is high, the extentand predictability of absorption in critically illpatients is uncertain and serious infections shouldtherefore be treated using intravenous administration,at least initially. Dosing should beweight-based (6 mg/kg every 12 hours intravenouslyfor 24 hours, then 3 mg/kg every12 hours intravenously thereafter) and not roundeddown to the nearest ampoule size. Furthercomplicating the predictability of exposure assumptionsis the large number of potential druginteractions. Given these issues, together with thepotential for hepatic and neurological toxicityfrom elevated levels and treatment failure fromsubtherapeutic levels, therapeutic drug monitoringshould be performed if voriconazole is usedfor the treatment of IC in critically ill patients.The practicalities of this important issue havebeen well summarized elsewhere.[110]Echinocandin agents display linear pharmacokinetics.The pharmacodynamic parametersbest correlated with outcome in animal modelsare either the AUC/MIC or maximum concentration/MICratios.[111] Although the use ofintermittent high doses of echinocandins is oftheoretical benefit, this strategy has not beensubject to clinical trial. Different dosing regimenswere compared in two randomized trials: micafungindosed at 150 mg/day versus 100 mg/day[84]and caspofungin dosed at 70 mg on day 1 then50 mg/day versus 150 mg/day.[112] Although neitherstudy was adequately powered, efficacy wassimilar and the different drug doses were equallywell tolerated. Finally, although fixed dosingof echinocandins is recommended, populationpharmacokinetics have s