2012 glockner

Practical considerations on current guidelines for the management ofnon-neutropenic adult patients with candidaemia

A. Glockner1 and O. A. Cornely2

1BDH-Klinik Greifswald, Germany and 2Department I of Internal Medicine, Clinical Trials Centre Cologne, ZKS Koln, BMBF, Center for Integrated Oncology CIO

KolnBonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), German Centre for Infection Research, University of

Cologne, Cologne, Germany

Summary Recent guideline recommendations on the management of candidaemia providevaluable treatment guidance for routine clinical practice, but need to be interpreted in

the light of the actual situation of the patient and the local epidemiology of fungal

infections. Echinocandins emerge as the generally preferred primary treatment.

Treatment should be initiated immediately after notification of a Candida-positive blood

culture in all patients. Ambiguous issues include the definition of optimum duration of

treatment, the indication and time point to step down to oral azoles, catheter

management, and the appropriate approach in critically ill patients at high risk for

candidaemia in the absence of definitive proof of infection. Patients with clinical

suspicion of antifungal treatment failure need prompt workup for adequacy of

treatment, focal sources of sustained infection and potential superinfection.

Key words: candidaemia, treatment, guideline, echinocandin, azole.

Introduction

Candidaemia is a potentially devastating bloodstream

infection with Candida spp. predominantly affecting

hospitalised, severely ill patients. Candida spp. has been

implicated in up to 9% of cases in a large survey of over

24000 blood stream infections.1 Major risk factors for

candidaemia in non-neutropenic patients include gas-

trointestinal perforation, recent abdominal surgery,

prolonged stay on intensive care units, compromised

immune system, treatment with broad spectrum anti-

bacterial agents, malignant diseases, organ dysfunction,

the extremes of age, central venous catheters and

Candida colonisation. Despite substantial advances in

antifungal agents and treatment strategies, candida-

emia remains associated with high mortality. The

overall mortality is reported at 3060% and attributable

mortality rates of 2540% have been estimated.16

Candidaemia may cause severe sepsis and septic shock

leading to multiorgan failure and death.7 Other com-

plications include deep organ invasion, endocarditis and

septic thrombosis. Optimising the outcomes of candida-

emia, particularly in critically ill patients, requires the

timely initiation of adequate antifungal therapy.8

Four international expert panels of medical societies

have recently issued guidelines that include recommen-

dations on the management of candidaemia in non-

neutropenic non-haematological adult patients. TheInfectious Diseases Society of America (IDSA) practical

management guidelines of 20099; the guidelines of the

4th European Conference on Infections in Leukemia

(ECIL-4) of 2011,10 the recent candidiasis guidelines

presented in 2011 by the European Fungal Infections

Study Group (EFISG)11 of the European Society of

Microbiology and Infectious Diseases (ESCMID), and the

joint candidiasis guidelines of the German-speaking

Mycological Society and the Paul Ehrlich Society

(DMYKG PEG)12 (Table 1). Note that the EFISG guide-lines and the latest version of the ECIL guidelines are not

yet published as full papers and may be subject to

changes. These four guidelines are useful because of

their evidence-based approach that involves compre-

hensive appraisal of the available data supporting the

recommendations.

Correspondence: A. Glockner, BDH-Klinik Greifswald, Karl-Liebknecht-Ring

26a, 17491 Greifswald, Germany.

Tel.: +4 938 348 71231. Fax: +4 938 348 71226.

E-mail: [email protected]

Submitted for publication 16 December 2011

Revised 28 March 2012

Accepted for publication 4 April 2012

Review article

2012 Blackwell Verlag GmbH doi:10.1111/j.1439-0507.2012.02208.x

mycosesDiagnosis,Therapy and Prophylaxis of Fungal Diseases

This article reviews important aspects of these current

guidelines for the management of candidaemia in

non-neutropenic adult patients from the cliniciansperspective, trying to (i) bridge gaps between the

evidence-based recommendations and their implemen-

tation in routine clinical practice, and (ii) discuss

feasible approaches and their limitations in areas where

guidance is currently inconclusive due to lack of

evidence.

Time of antifungal treatment initiation

Several analyses performed in the past years have

shown a dramatic effect of delays in the initiation of

adequate antifungal treatment on the mortality of

candidaemia patients, with extreme effects of even short

delays in those with Candida septic shock.1316

As a performance criterion of candidaemia manage-

ment, the IDSA expert panel requests the initiation of

antifungal therapy in all candidemic patients within

24 h after a blood culture positive for yeast.9 This

suggestion appears clearly inadequate if it refers to the

time of the actual detection of Candida in the incubating

blood sample.

Rather, an immediate start of therapy after notifica-

tion of Candida-positivity in a blood culture appears

necessary, since early treatment initiation increases

the probability of survival. Actually, this approach is

Table 1 Therapeutic recommendations for candidaemia in non-neutropenic adult patients without upfront information on Candida species

and or susceptibility.

IDSA [9]

ECIL-4 (for overall

population) [10] EFISG (ESCMID) [11] DMYKG PEG [12]

Indication for

antifungal therapy

All pts with Candida-positive blood culture



All pts with Candida-positiveblood culture

Preferred first line

therapy

EC or FLC EC or L-AMB or FLC orVORI

EC EC or FLC L-AMB alternative in

critically ill pts

Criteria for choice

of drug

EC: moderately to severelyill, recent azole exposure

FLC: less severely ill

FLC and VORI: avoidafter azole prophylaxis

FLC: avoid if severely ill

Only EC asrecommended first

line therapy

FLC: avoid after azoleprophylaxis and in critically

ill pts

Duration of

therapy

2 weeks afterdocumented clearance

of Candida from

bloodstream

AND

resolution of symptomsattributable to

candidaemia

14 d after last positiveblood culture

AND

resolution of signs andsymptoms

14 d after end ofcandidaemia

14 d after first negativeblood culture

AND

complete resolution of allsigns and symptoms

attributable to

candidaemia

Blood culture

monitoring on

therapy

Recommended, withdaily or every other

day sampling

No statement Recommended, withdaily sampling

Recommended No statement on

frequency

Step down therapy

to oral fluconazole

May step down to oralFLC (or VORI) after

35 days of EC in

stable pts

No statement After 10 d of IV therapy if FLC-susceptible species oral therapy tolerated patient stable

Optional after 10 d of IV

therapy if

negative blood cultures proven susceptibility of

isolate

clinical stabilisation ability to take oral

medication

unrestricted GI absorptionCatheter

removal

Stronglyrecommended

Recommended (alwaysif C. parapsilosis

detected)

Recommended in ptsreceiving azoles or

AMB-D

Not recommended forpts treated with EC

or L-AMB

Recommended for all pts

Fundoscopy Recommended; withinthe first week of therapy

No statement Recommended Recommended; Prior to endof therapy

pts, patients; EC, echinocandin; FLC, fluconazole; VORI, voriconazole; L-AMB, liposomal amphotericin B; IV, intravenous.

A. Glockner and O. A. Cornely

2 2012 Blackwell Verlag GmbH

recommended by the EFISG and the DMYKG PEGguidelines.11,12

However, the median time to Candida positivity in

blood cultures is 32 h according to a recent analysis.17

This raises the issue of pre-emptive antifungal therapy

i.e. treatment initiation in the absence of culture positive

samples in non-neutropenic critically ill patients with

signs of severe sepsis and presence of risk factors for

invasive fungal infection.

Although the EFISG guideline panel voted against the

use of fluconazole in non-neutropenic adult patients

with APACHE II score >16 and fever despite broad-

spectrum antibiotics, it still argues that antifungal

therapy of high-risk patients with persistent fever of

unknown origin may be an option in patients at high

risk.11 This approach appears particularly appropriate if

such a patient develops severe sepsis or septic shock.

Risk scores based on clinical characteristics and

fungal colonisation insufficiently identified patients

who may benefit from early antifungal therapy based

on clinical features or surrogate fungal markers,

respectively, in the absence of positive fungal blood

culture.

The use of molecular markers of infection, i.e.

detection of fungal cell wall components (1,3-beta-D-

glucan) or Candida nucleic acids (via PCR), is an

attractive approach to identify patients who might

benefit from early antifungal therapy. As far as beta-D-

glucan is concerned this approach is only marginally

supported by the EFISG guidelines because of issues in

test performance, mostly false positivity due to difficult-

to-control confounding factors.11 Although generally

highly sensitive, PCR still lacks the degree of standardi-

sation and validation required for its use in treatment

decisions for early antifungal therapy.

For the time being, initiation of a risk-based antifun-

gal therapy while awaiting a blood culture result should

be considered for non-haematological patient groups

who have been shown to benefit from antifungal

prophylaxis, i.e. predominantly those with gastrointes-

tinal anastomotic leakage or relapsed gastrointestinal

perforation.18

As Kumar et al. [15] impressively demonstrated in a

retrospective analysis of patients with septic shock, the

dismal survival rates of the subpopulation with fungal

sepsis were predominantly due to delays in treatment for

more than 26 h after onset of hypotension. Initiating

pre-emptive antifungal therapy within this window of

opportunity may thus be life saving for some patients

and may be used to buy time while additional

exploration of the causes of exacerbating sepsis is

undertaken.

Factors determining the initial choice oftherapy

Severity of illness

The current IDSA guidelines9 favour the use of echino-

candins in moderately to severely ill patients without

giving a closer definition of these terms besides hemo-

dynamic instability. Similarly, the ECIL-3 guidelines

discourage the use of fluconazole in severely ill

patients.11 The rationale behind these recommenda-

tions is recent data showing improved outcomes of

candidaemia in patients with early adequate therapy,

particularly in those with severe sepsis. As echinocan-

dins have a broader spectrum of antifungal activity and

are considered fungicidal against many Candida isolates,

this class of antifungals should be preferred in critically

ill patients.

Traditionally, patients with hemodynamic instability,

i.e. those requiring vasopressors were considered as

being at highest risk for unfavourable outcomes of

candidaemia invasive candidiasis. However, this ap-proach may be too narrow as it focuses on one single

systemic hallmark of severe infection. Rather the full

clinical picture and organ dysfunction pattern should be

considered.

Candidaemia patients with acute failure of one or

more organs should generally be considered as being

severely ill. Consequently, all patients treated on

intensive care units should be included into this

category and thus receive an echinocandin as the

primary treatment.

A randomised study comparing anidulafungin vs.

fluconazole for candidaemia showed a significantly

higher global success rate in the total population for

the echinocandin.19 In subgroup analyses, patients with

organ dysfunction (lung, kidney, liver or cardiovascu-

lar) had consistently higher global success rates in the

anidulafungin group.20 The difference was significant

for patients with APACHE II scores >15 and those with

severe sepsis and multiorgan dysfunction.20

On the basis of the results of this study 19 and the

cumulative experience with this class of antifungals

the EFISG panel chose to recommend echinocandins as

the class of choice (recommendation grade A; evidence

grade I) for primary targeted therapy of candidaemia in

all patients.11 We agree with the recommendation of

the EFISG, where fluconazole is no longer considered a

preferred option for the targeted initial treatment

of candidaemia. Its use is only marginally recom-

mended (grade CI) due to its therapeutic inferiority to

anidulafungin.11

Practical considerations on current guidelines

2012 Blackwell Verlag GmbH 3

Pre-exposure to azole antifungals

Azole antifungals are commonly used as prophylactic

agents in patients at risk for invasive fungal infection or

as antifungal therapy for suspected mycosis. As the

widespread use of azoles may select for Candida strains

or species with reduced susceptibility to azoles,21

current guidelines recommend echinocandins for pri-

mary treatment in patients with recent history of

exposure (IDSA) or previous prophylaxis (ECIL-3)10

with azole antifungals, without giving a precise defini-

tion of these terms. The EFISG circumvents this issue as

it does not support primary use of azoles at all.11

Evidently, candidaemia after immediately preceding

prophylaxis, i.e. a breakthrough infection, requires the

use of a non-azole antifungal. But what about patients

who received azoles some time ago? As there are no data

available on the evolution of the species distribution of

colonising Candida after previous exposure to azoles in

individual patients, no inferences can be made regard-

ing a safe interval between the previous azole use and

the current candidaemia episode.

It thus appears that all candidaemia patients ever

having received prophylactic azoles may be excluded

from primary therapy with an azole antifungal. The

term recent exposure to an azole used by the IDSA

panel is poorly defined and requires interpretation.9 A

recently published multicentre analysis of 2441 yeast

bloodstream infections in France revealed a significant

association of infection with isolates of reduced fluco-

nazole-susceptibility and pre-exposure to fluconazole

within 30 days before the current episode.22 Thus, it is

reasonable to exclude at least those patients from

primary treatment with fluconazole who received any

amount of azoles in the preceding month.

Other factors predisposing for infection with

fluconazole-resistant Candida

According to the IDSA guidelines, elderly patients, those

with malignant disease and patients with diabetes

mellitus should not receive fluconazole initially, as these

factors favour infection with C. glabrata.9 This recom-

mendation may be extended to include patients with

previous hospitalisation because they are at increased

risk of being colonised by C. glabrata.23

Candida species

As of the reasons for the downgrading of fluconazole as

an option for first-line therapy of candidaemia, the

EFISG cited the limited spectrum of antifungal activity

and a high likelihood of insufficient susceptibility of

C. glabrata and C. krusei, in particular.11 With respect to

the infecting Candida species, the IDSA as well recom-

mends to prefer an echinocandin in patients with

C. glabrata (or C. krusei) infection.9 Thus, using echino-

candins in blood stream infections with these species

appears to be a general consensus.

On the basis of low-level evidence the IDSA panel

states that C. parapsilosis infections should preferably be

treated with fluconazole. This notion is not supported by

the EFISG experts who generally prefer echinocandins

for initial therapy, and only marginally consider the use

of fluconazole as an option for documented C. parapsi-

losis candidaemia (grade of recommendation C; evidence

level I).11

According to the IDSA guidelines, candidaemia due to

C. albicans, C. tropicalis and C. parapsilosis may be

treated with fluconazole in less critically ill patients.9

However, it should be kept in mind that Candida

speciation is not absolutely predictive of fluconazole

susceptibility. Firstly, while isolates of C. albicans,

C. tropicalis and C. parapsilosis are susceptible to fluco-

nazole in the majority of cases, this is not always the

case. In a recent survey, Oxman et al. [24] found that

these species comprised 36% of the isolates with reduced

fluconazole susceptibility and 48% of the resistant

isolates. Eight per cent of C. albicans showed reduced

susceptibility to fluconazole. Therefore, the local fungal

epidemiology with respect to resistance must be mon-

itored and considered in treatment decisions. While in

microbiological surveys the great majority of C. albicans

isolates are susceptible to fluconazole it should be kept in

mind that also in candidaemia with fluconazole-suscep-

tible fungal species, data from the phase III trial of

anidulafungin vs. fluconazole19 indicate that an echi-

nocandin appears to be the superior choice even in less

critically ill patients, as in the subpopulation with

APACHE II scores

given the fact that C. parapsilosis causes 13% of all

candidaemias in Europe28 and echinocandins are rec-

ommended by the IDSA and EFISG as first-line therapy

in severely ill patients in the absence of species

information. As resistance of clinical Candida isolates of

different species is being described for echinocandins as

well,29 susceptibility testing appears prudent if thera-

peutic failure is suspected.

When interpreting susceptibility data, the recently

revised breakpoints for fluconazole and echinocandins of

the European Committee on Antimicrobial Susceptibility

Testing (EUCAST) and the US Clinical Laboratory

Standards Institute (CLSI) for antifungal susceptibility

testing should be considered.3032 The new values are

based on epidemiological data on susceptibility distri-

butions of wild-type isolates. Fluconazole breakpoints

issued by the EUCAST are now considerably lower than

the former values without changes in the underlying

testing methodology. This fact may lead to reduced rates

of isolates classified as susceptible to fluconazole and

may further restrict its usefulness in clinical practice.

Due to the generally low and inconsistent activity of

fluconazole against C. glabrata, the EUCAST generally

discourages the use of fluconazole for infection with this

species and therefore did not issue a breakpoint for

C. glabrata. The CLSI breakpoints for echinocandins now

reflect species- and drug-specific differences in wild-type

distributions that should be respected when interpreting

susceptibility data. The EUCAST has not completed the

process of breakpoint definition for echinocandins yet.

The available values for anidulafungin are species-

specific as well.

Catheter management

As stated in the IDSA guidelines and confirmed by

similar recommendations of ECIL and DMYKG PEG acentral venous catheter (CVC) should be removed in

patients with candidaemia whenever possible, given the

role of catheters as a reservoir for Candida spp. in

biofilms33,34 and a potential source for persistent

candidaemia.35

Analyses of data from recent studies and several older

investigations suggested more favourable outcomes;

lower mortality and shorter duration of candidaemia

in patients who have their CVC removed early, i.e.

72 h after onset of candidaemia.3640 On the basis ofthis evidence, the EFISG as well recommends the

removal of indwelling vascular access lines at least for

patients receiving azoles or amphotericin B deoxycho-

late (grade BII).11 For patients receiving echinocandins

this may not be as crucial as removal of indwelling

lines within 48 h after treatment initiation was not

associated with a higher survival rate.

However, some studies that attempted to adjust their

analyses for potential confounders4144 and particularly

a recent multivariate analysis of data from two phase III

trials performed by Nucci et al. [45] did not find any

benefit of early catheter removal. This somewhat

unexpected result may actually relate to the fact that

both trials underlying the analysis by Nucci and

colleagues involved drugs with known activity against

biofilm-associated sessile Candida cells (echinocandins

or liposomal amphotericin B),4649 potentially making

catheter removal a less critical factor. Nonetheless, as

prospective studies on the benefits of catheter removal

are lacking and probably may not be feasible at all it

appears prudent to remove CVCs in candidaemia

patients whenever possible.

It may be argued that patients with CVCs usually

have their catheters for a reason. Early replacement

rather than omission of the catheter will therefore be

required in many situations. Catheter replacement in

situ via a guide wire is inadequate due to the risk of

reseeding the new catheter with Candida. The following

approach appears reasonable: after removal of the

indwelling catheter, the new catheter should be inserted

via de-novo puncture at a different body site, avoiding

the groin if possible. To further reduce the risk of

recolonisation of the new catheter, it may be preferable

to do the replacement after administration of the first

dose(s) of the antifungal via the old catheter, allowing

for reduction of the overall fungal load. In patients who

can be managed by peripheral venous access for a short

interval, a hiatus of one day between CVC removal and

reinsertion may add to the protection of the new

catheter. It should be evident that patients who require

reinsertion of a new catheter and those in whom an

indwelling CVC or other implanted devices cannot be

removed at all should be treated with antifungals active

against biofilm-associated Candida, i.e. an echinocandin

or liposomal amphotericin B, a notion that is consistent

with the current EFISG guidelines.

In routine clinical practice, the fate of a central

venous catheter will often be determined before the

causative pathogen of a developing clinical sepsis can be

identified, making the considerations discussed above

less critical.

As a bottom line it may be concluded that catheters

and other indwelling devices should be removed or

replaced whenever possible and as early as feasible. An

echinocandin or liposomal amphotericin B should be

used if a catheter or other device in the blood stream

must absolutely be left in place. To avoid creating a safe



haven for fungi in biofilms, the antifungal should then

in theory be administered through all lumina which

appears challenging from a practical point of view.

Blood culture monitoring on antifungaltreatment

In the absence of sufficiently validated reliable molec-

ular or surrogate markers positive blood culture

remains the diagnostic tool in Candida blood stream

infection and blood culture monitoring is a major factor

guiding treatment decisions after initiating antifungal

therapy, particularly with respect to treatment response

and duration. The IDSA expert panel recommends

drawing blood samples for follow-up blood cultures

daily or every other day, whereas the EFISG prefers daily

sampling.11

In our view, the frequency of sampling may be

reduced after 5 days, as 80% of patients had negative

cultures after this treatment period in the randomised

trials. However, as blood culture negativity is a

requirement for treatment discontinuation and or stepdown to oral therapy, it may still be cost-effective to

have high-frequency sampling in the whole time period

up to the first negative blood culture.

Duration of therapy

On the basis of the treatment duration defined in the

protocols of clinical trials, the guidelines recommend

duration of therapy of two weeks (14 days) after (i) the

resolution of symptoms and (ii) the end of candidaemia

whereas the latter is not uniformly defined. The most

unequivocal definition is the first negative blood

culture as stated in the guidelines of IDSA and

DMykG PEG.12 The criterion of the last positive bloodculture is less robust as it depends in the frequency of

blood culture sampling. We therefore prefer using the

time of blood sampling for the first negative blood

culture as the starting point for the residual 2 weeks of

therapy.

Step-down therapy

According to the IDSA guidelines it is reasonable to

switch (step down) patients from an echinocandin to

oral fluconazole if they have an initial fungal isolate

likely to be susceptible to fluconazole (e.g. C. albicans,

C. parapsilosis, C. tropicalis) and if they clinically im-

proved after initial intravenous echinocandin therapy.9

Similarly, the EFISG considers a step down to oral

fluconazole feasible after 10 days of intravenous anti-

fungal therapy adequate if (i) the species is susceptible to

fluconazole (ii) the patient is clinically stable and (iii)

tolerates oral medication.11

These recommendations aim at (i) a reduction of the

overall exposure to echinocandins, thus minimising the

selective pressure on fungal isolates with reduced

echinocandin susceptibility, (ii) the reduction of health

resource consumption (iii) simplification of therapy.11

Although the last two effects are undisputed, the effect

of shortening the echinocandin exposure on the risk of

emergence of resistant strains is less clearly established.

The step-down concept is based on several rando-

mised trials50 which allowed for a switch to oral

fluconazole after at least 10 days of intravenous treat-

ment with the respective study drugs if this was

clinically and microbiologically appropriate. The trial

protocols stated somewhat divergent requirements for

the switch that generally included the following:

ability to tolerate oral medication, afebrile body temperature for at least 24 h, most recent blood culture remaining negative forCandida species (for at least 48 h in one study 50),

clinical improvement, initial fungal isolate which is not C. glabrata orC. krusei and tested fully susceptible to fluconazole.

It should be noted as a caveat that the evidence base

supporting the step-down concept is limited, as only 15

35% of the patients were actually switched to oral

therapy in these trials.19,50,51

As discussed above, Candida species determination is

not sufficiently predictive of fluconazole susceptibility.

Thus, susceptibility testing of the initial isolate is

explicitly recommended by the ECIL-3 before stepping

down to fluconazole.10

Besides the requirements listed above, signs of

improvement should additionally include the following:

reduced or resolved need of vasopressors (if initially

present), improvement of organ function and regression

of infection markers in the lab. The patient must have

adequate enteral absorption capacity. This will usually

be the case in those who mainly receive oral or enteral

nutrition and have no clinically relevant diarrhoea,

recurrent vomiting or evidence of ileus. In addition,

patients should not receive renal replacement therapies

to avoid the need of complex dose adjustments associ-

ated with fluconazole use in this setting. In addition,

hepatic dysfunction, potentially interacting concomi-

tant medications and unremovable CVCs or devices may

limit the usability of azoles.

Although in the randomised trials, the step-down

option was limited to oral fluconazole, and the guide-

lines only mention this approach, a switch to an



intravenous azole may well be an option for patients

fulfilling the above-listed requirements with the excep-

tion of reliable enteral absorption. Both approaches

appear to be supported by the randomised trial con-

ducted by Kullberg et al. [52], who compared vorico-

nazole vs. amphotericin B followed by fluconazole for

candidaemia. In the comparator arm, patients switched

from amphotericin B to either intravenous or oral

fluconazole after a median of 4 days with evidence of

adequate treatment efficacy. Since the exposure of

intravenous fluconazole is at least equivalent to the

oral formulation, this approach appears adequate

regardless of the drug used for previous primary

therapy.

This finding relates to the unresolved issue of the

required minimal duration of initial echinocandin

therapy before the transition to oral fluconazole. The

above-mentioned echinocandin phase III trials required

10 days of randomised intravenous therapy. However

indicating the scarcity of data supporting this approach

the IDSA guideline panel discusses the possibility of

reducing the initial intravenous echinocandin treat-

ment to 35 days in stable patients, thus restricting

this approach to less critically ill patients.

Davis et al. [53] recently presented a two-period

single-centre study comparing a retrospective period

one with unrestricted use of echinocandins (caspofun-

gin or micafungin) for invasive candidiasis vs. an

interventional period two involving formal in-house

recommendations for a step down by day 5 from

intravenous anidulafungin to an oral azole (fluconazole;

or voriconazole for patients with C. glabrata or unknown

species) if certain criteria for oral treatment had been

met (negative blood cultures, functional gastrointestinal

tract, hemodynamic stability and improved clinical

profile including leucocyte counts and body tempera-

ture). The rate of patients receiving oral step-down

therapy was significantly increased in period two, the

duration of intravenous therapy and the total duration

of therapy were decreased, whereas the clinical success

rate remained unchanged, and hospital mortality

showed no significant difference. While the use of

historical controls and potential educative effects of the

intervention may have biased the results, these data

suggest that an early step down to an oral azole may be

feasible in certain patients without jeopardising out-

comes.

The feasibility of an early intravenous-to-oral switch

strategy largely depends on the question if it requires a

negative blood culture, since it is a matter of debate after

which incubation time blood cultures should be

regarded as negative. Strictly speaking, this may require

a full week of no detectable growth. Negativity after

48 h of incubation as required in the randomised trial of

caspofungin vs. amphotericin B does not safely exclude

persistent candidaemia: in an analysis of fungal blood

culture dynamics, Taur et al. [17] reported incubation

times to Candida positivity >50 h in 14% of patients.

Based on these data, a switch to oral fluconazole after

less than 10 days (as required in the randomised trials)

would be feasible only in a minority of patients with

early clearance of the blood stream as the median time

to the first blood sample that remained culture negative

was 23 days in randomised trials.51,54

Therefore it may be questioned if documented blood

culture negativity is absolutely required for an early (i.e.

after

No adequate study data are available for the pre-

emptive use of echinocandins in non-neutropenic

patients at high-risk of candidaemia before positive

blood culture results are available. Therefore no dis-

tinctions between the individual agents can be made for

this treatment situation.

Clinical therapeutic failure persistentcandidaemia

The issue of therapeutic failure and persistent candida-

emia is only addressed by the current guideline of

DMykG PEG. Given the considerable time lag betweenblood sampling and culture positivity, assessing thera-

peutic failure should rely primarily on clinical rather

than microbiological criteria in critically ill patients. In

accordance with the DMYG PEG guidelines, we con-sider it appropriate to assess treatment response for

clinical failure after 72 h of treatment.

When pondering the decision to switch treatment

particularly if definite evidence of failure of the first line-

agent to clear Candida from the bloodstream has not

been obtained yet clinicians should consider the

following questions: Is the primary therapy adequate in

terms of antifungal coverage and dosage? Was a central

venous catheter or another potentially infected device

left in place? Is there evidence of endocarditis, septic

thrombosis or an abscess that may continue seeding

fungal cells into the bloodstream? Is there evidence of

superinfection with other pathogens that may explain

the lack of clinical improvement? Is there an urgent

need of action due to increasingly severe sepsis?

While ensuring effective therapy is vital to prevent

deep organ dissemination, a premature switch may

expose the patient to unnecessary drug toxicity, as in

patients receiving primary treatment with an echino-

candin, the most likely secondary option will be

liposomal amphotericin B.

Conclusions

Several recently published guidelines address the man-

agement of candidaemia in non-neutropenic adult

patients. While giving valuable guidance, the recom-

mendations need to be interpreted in the light of the

actual clinical situation of a given patient.

Factors influencing the choice of initial therapy include

severity of illness, previous exposure to antifungals,

patient age, species of the initial isolate (if available) and

catheter issues. Antifungal therapy should be started

immediately after notification of positive blood cultures.

Pre-emptive antifungal therapy while awaiting a positive

blood culture resultmaybeneeded in severely ill high-risk

patients. In general, echinocandins emerge as the

preferred primary treatment option and should definitely

be used in more severely ill patients. Close blood culture

monitoring is advisable to inform on microbiological

efficacy and guide treatment duration. Treatment should

be continued for 14 days after the first negative blood

culture and resolution of signs and symptoms of infection.

To limit a selection pressure and reduce cost of treatment,

step-down therapy from an intravenous echinocandin to

an oral azole is desirable. The optimum time point

although remains unknown. Clinical suspicion of thera-

peutic failure should prompt early reconsideration of

treatment adequacy, search for a potential fungal focus,

and frequently a switch in antifungal class to prevent

persistence of infection and deep organ dissemination.

Disclosure

The authors were involved in the preparation of the

following guidelines: OAC: EFISG, DMykG PEG; AG:DMykG PEG. AG is a consultant to Astellas, MSD, Pfizerand served at the speakers bureau of Astellas, MSD,

Pfizer.

OAC is supported by the German Federal Ministry of

Research and Education (BMBF grant 01KN1106), has

received research grants from Actelion, Astellas, Basi-

lea, Bayer, Biocryst, Celgene, F2G, Genzyme, Gilead,

Merck/Schering, Miltenyi, Optimer, Pfizer, Quintiles,

and Viropharma, is a consultant to Astellas, Basilea,

F2G, Gilead, Merck/Schering, Optimer, and Pfizer, and

received lecture honoraria from Astellas, Gilead, Merck/

Schering, and Pfizer.

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