Clinical Mycology and Antifungal Therapy CME

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Clinical Mycology and Antifungal Therapy CME

Disclosures

Elias J. Anaissie, MD

Introduction

Invasive fungal infections continue to pose a diagnostic and

therapeutic challenge, particularly for clinicians caring for

immunocompromised patients. The availability of new, more potent

antifungal agents has resulted in a reduction in the incidence of

several mycoses, particularly candidiasis, but has had a limited

effect on the opportunistic molds. Fortunately, recent advances in

the epidemiology, prevention, early diagnosis, and therapy of

infections by opportunistic molds have been achieved, some of which

were presented at this year's ICAAC meeting.

Epidemiology and Infection Control

Patients with invasive mycoses may acquire their infection in the

hospital or in the community from different sources, including air

and water. Three studies presented at this year's ICAAC identified

additional sources of pathogenic fungi: the use of probiotics[1] for

the treatment and prevention of Clostridium difficile-associated

diarrhea, and bottled mineral water.[2] Treatment with the probiotic

Ultralevura was identified as the only risk factor for an outbreak

of fatal Saccharomyces cerevisiae infections in 3 patients cared for

in a heart surgery intensive care unit. Fungi recovered from the

Ultralevura capsules and clinical isolates were identified as S

cerevisiae, and DNA fingerprinting studies showed that the clinical

and the Ultralevura isolates were identical. Discontinuation of

Ultralevura use in the unit stopped the outbreak. Another study

evaluated the presence of fungal contamination in 68 commercially

available mineral waters, 1 tap water sample, and 1 water sample

from a natural well from 16 countries. All water samples were

submitted for fungal cultures, panfungal polymerase chain reaction

(PCR), and Aspergillus antigen testing (galactomannan platelia

assay). Overall, 4% of all samples yielded fungal growth. Molds were

detected in 3 samples. Aspergillus antigen was not detected.

Another study evaluated the fungal contamination of 39 healthcare

workers' overalls in 2 departments of one institution.[3] The

synthetic fiber overalls were worn by medical staff, nurses, and

technicians of the infectious diseases department and the mycology

laboratory. On each overall, 8 samples were collected. Contamination

was found in 9 of 20 in the mycology laboratory and 7 of 19 in the

infectious diseases department. Most frequently isolated fungi

included Aspergillus species, followed by Penicillium species,

Rhizopus species, and Candida species. The study authors suggest

that vigilance is required regarding cleaning and daily change of

overalls to avoid possible spread of pathogenic fungi.

Immunocompromised patients at risk for invasive fungal infection are

usually protected in special rooms equipped with HEPA filtration.

These patients, however, need to undergo testing, particularly

computed tomography (CT) scans of the chest, which may lead to their

exposure to fungal sources during their travel in various hospital

areas. One study found that protective clothing, in this case a

diving suit, can help to maintain the protective isolation of

immunocompromised patients during CT scan examination.[4] The diving

suit is a sterile, ambulatory, and transparent garment which allows

for continuous monitoring as well as visual and conversational

contact. The suit was supplied with air using a self-contained

station of ventilation (4-hour supply). Air contamination was

controlled with 2 HEPA filters. The unit was tested in 6 patients

and was well tolerated during the CT scan procedure. Whether this

new tool will prove practical and economical remains to be

determined.

Yet another example of the importance of patient exposure to fungi

in the development of invasive infection was presented at this

meeting. An outbreak of surgical-site infections (4 patients) by

Aspergillus fumigatus was observed in February 2001 among cardiac

surgery patients.[5] Environmental samples of the air-supply ducts

to the cardiac theaters and the heating coil yielded A fumigatus.

Isolates obtained from 3 case patients, and the environmental

samples were indistinguishable. The outbreak was terminated with

decontamination of the ventilation system and installation of point-

of-use HEPA filters.

Invasive fungal infections usually develop in the presence of risk

factors in susceptible patients. Thus, the identification of these

risk factors in specific patient populations is an important step in

preventing these infections. A prospective observational study (2002-

2003) was conducted in a surgical intensive care unit (ICU) to

identify the risk factors for colonization or infection with Candida

glabrata as compared with colonization or infection with non-C

glabrata yeasts.[6] Previous exposure to fluconazole was identified

as an independent risk factor for the development of C glabrata

infection.

Colonization by Aspergillus species in patients with hematologic

malignancies has been shown as a risk factor for developing invasive

aspergillosis. However, the clinical relevance of recovering

Aspergillus species in ICU patients is unknown. At this year's

meeting, a retrospective study was conducted to assess the

significance of recovering aspergilli from 172 ICU patients.

Clinicopathologic correlation concluded that almost half of these

patients (48%) had invasive pulmonary aspergillosis, while

colonization was considered present in the remaining patients.[7]

Recovering Aspergillus species from ICU patients should therefore be

considered a marker for the presence of invasive aspergillosis.

Confirmatory studies in this patient population are warranted.

The duration of colonization by strains of Aspergillus species is

not well defined. The results of one study suggest that persistence

of the fungus in the same patient could last as long as 5 years.[8]

The genetic variability of 7 A niger strains obtained from 2

patients with recurrent otomycosis was studied using RAPD-PCR

(random amplification of polymorphic DNA-polymerase chain reaction).

These strains were recovered from 1 ear over a period of 5 years in

1 patient and 2 months in the other. In each patient the recurrent

episodes of otitis were caused by a single genotype, indicating

persistence of infection with the same fungus rather than

reinfection with different strains.

Alemtuzumab (Campath) is a monoclonal antibody directed against the

CD52 antigen present on all lymphocytes. This agent produces

profound T-cell depletion and is increasingly used in the

conditioning regimen for hematopoietic and solid organ

transplantation. The risk of infection in solid organ transplant

recipients receiving alemtuzumab was studied among 445 organ

transplant recipients (kidney, liver, pancreas, lung, and

intestinal/multivisceral). Absolute CD4+ cell counts were low (< 50

cells/mcL in 61% of patients). Thirty-seven opportunistic infections

developed in 34 (8%) patients, 9 of which were fungal, including

invasive mold infections (4), cryptococcosis (3), and Candida

esophagitis (2).[9]

Surveillance of Species Distribution

Surveys of invasive fungal infections are important for identifying

changing epidemiologic trends, including resistance to antifungal

agents. At this year's meeting, investigators presented data

reported from 19 centers to the TransNet (CDC cooperative group)

during a 2-year-period prospective observational study. The patient

population included 6999 stem-cell transplant and 6474 solid organ

transplant recipients. Results of the survey showed that yeasts are

still the most frequent cause of invasive fungal infection,

particularly those caused by Candida species, while Aspergillus

species were the predominant molds, followed by the causative agents

of zygomycosis and fusariosis. Fungal infections were diagnosed

early after transplantation, with 73% of yeast and 45% of mold

infections occurring 60 days or less after the procedure. Solid

organ transplant recipients were more likely to develop yeast

infection, while stem-cell transplant recipients were at higher risk

for infection by the opportunistic molds. As expected, the lowest

rates of yeast and mold infections occurred among recipients of

autologous stem cell or kidney transplants.[10]

Another survey described the incidence of bloodstream infections

among 382 solid organ transplant recipients treated between 1991 and

2000. The results showed that 3% of 466 episodes of positive blood

cultures yielded fungi and that 4 of 15 (27%) patients with fungemia

died as result of infection.[11]

The epidemiology of candidemia may vary between countries. A

Brazilian multicenter surveillance study for candidemia was

conducted during a 6-month period in 12 hospitals. In this survey,

305 cases of candidemia were observed (incidence: 2.08 cases/1000

admissions and 3.17/10,000 patient-days) with an incidence 3- to 5-

fold higher than that reported in the United States or Europe.

Patients with hematologic malignancy were more likely to have early

candidemia (median time, 10 days or less after admission) than the

rest of population studied (median time, 18 days). Candida albicans

was the most frequently isolated species (45%), followed by C

tropicalis (24%) and C parapsilosis (19%); C glabrata comprised only

3% of cases. All isolates were susceptible to fluconazole,

amphotericin B, and voriconazole.[12]

In Norway (population 4.5 million), a prospective nationwide

candidemia study that has been ongoing since 1991 showed that the

candidemia rate significantly increased during 2000-2003 (n = 841)

compared with the 1991-1999 period (n = 559). C albicans accounted

for 71% of the episodes. The species distribution varied with

patient age, with infants infected by either C albicans (91.5%) or C

parapsilosis (8.5%). By contrast, older patients (> 79 years) were

more likely to be infected by either C albicans (55%) or C glabrata

(30%).[13]

In Spain, the incidence of candidemia among the newborn population

was reported to be 16.3/100,000. Very-low-birth-weight infants (<

1500 g) represented 82% of cases (291/356). Compared with the study

from Norway, a wider variety of species accounted for infections in

newborns, including C albicans (58%), followed by C parapsilosis

(33%), C glabrata (5%), and C tropicalis (3%). All isolates were

susceptible to fluconazole. Crude mortality rate was 23%.[14]

A retrospective study from Italy evaluated candidemia in adult

medical and surgical ICU patients during 1999-2003 and showed that

Candida species ranked sixth among pathogens causing nosocomial

bloodstream infections (10% of 1616 episodes). C albicans accounted

for 40% of 162 episodes, followed by C parapsilosis (26%), C

tropicalis (11%), C glabrata (11%), and others species (14%). The

overall incidence rate of C albicans decreased slowly over the 5-

year period, while isolation of non-albicans (especially C

parapsilosis and C glabrata) increased from 31% in 1999 to 64% in

2003 (P < .05). This observation could be explained by the

increasing share of fluconazole among all prescriptions for

antifungal agents: from 35% in 1998 to 74% in 2003 (P < .001).[15]

These 4 studies showed that C albicans remains the most frequent

cause of nosocomial candidiasis.

Recurrent vulvovaginal candidiasis affects millions of women

worldwide and its pathogenesis remains unclear. In a study

addressing this issue, investigators performed genotyping (using

contour-clamped homogeneous electric-field [CHEF] technology) on

isolated strains from 387 women with recurrent vulvovaginal

candidiasis who were treated with placebo or fluconazole after

clinical remission had been induced with fluconazole (3 doses 150 mg

at 72-hour intervals). The results indicated that recurrence was due

to reinfection with the same strain (58%-64%), relapse with the same

strain, or infection with a different strain.[16]

In addition to Aspergillus species, other molds are emerging as

opportunistic pathogens. These include Fusarium, Zygomycetes,

Scedosporium, and Alternaria species.

A 1-year study of Alternaria species was conducted in a hospital

ward harboring hematopoietic stem cell transplant recipients.

Although none of the 55 transplanted patients developed infection

with Alternaria species, the organism was recovered from various

environmental sources (air, toilet, bed, and floor) and was the most

commonly isolated mold (52% of 186 isolates obtained from 876

environmental cultures). Despite positive pressure and HEPA

filtration, air sampling yielded Alternaria species.[17] Given the

significant environmental colonization in this unit, opportunistic

alternariosis is likely to develop in severely immunocompromised

patients.

Scedosporium species now account for a significant proportion of non-

Aspergillus mold infections among solid organ transplant recipients.

A review of 58 patients with scedosporiosis reported that 82% of

patients were infected with S apiospermum (S prolificans accounted

for the remaining infections) and that almost half of these

infections were disseminated at diagnosis. Central nervous system

involvement was present in about a quarter of the patients. Overall

mortality was high (90% for S prolificans and 55% for S

apiospermum). Renal failure, central nervous system infection, and

dissemination were associated with higher mortality, but the use of

voriconazole was protective.[18]

A few case reports suggested a causal relationship between a rise in

rates of zygomycosis and voriconazole use. At this year's ICAAC

meeting, a matched case-control observational study of 27 recently

treated cancer patients with zygomycosis indicated that Rhizopus was

the most common species involved, and that the clinical strains were

not genetically related and were resistant to voriconazole.

Prophylaxis with voriconazole and sinus involvement were suggestive

of zygomycosis. As expected, the risk factors for zygomycosis

included corticosteroids and diabetes mellitus. A trend, though

nonstatistically significant (odds ratio [OR], 1.21; 95% confidence

interval [CI], 0.97-1.5; P = .08), suggested that receipt of

voriconazole at diagnosis of zygomycosis may also be a risk factor

for this infection.[19] These and previous reports on the same

subject are intriguing. It is important to remember, however, that

an earlier report[20] from the same center had described an

increasing rate of zygomycosis even prior to the introduction of

voriconazole, and that the observed association between voriconazole

and risk for zygomycosis was not statistically significant.

A nested case-control study among transplant recipients reporting to

the TransNet group determined the predictive factors associated with

zygomycosis and fusariosis. Cases were defined as patients with

infections due to Zygomycetes (28 patients) or Fusarium species (13

patients); control patients were those with invasive aspergillosis

(229 patients). In this study, both zygomycosis and fusariosis were

independently associated with previous voriconazole use and invasive

sinus and cutaneous infection.[21]

Three cases of infection caused by Phaeoacremonium parasiticum, a

rarely pathogenic mold, were presented at this meeting with

supporting identification by molecular methods and in vitro

susceptibility testing. Two of these patients were

immunocompromised, developed disseminated disease with skin lesions,

and died despite surgical and antifungal therapy. The third patient

developed septic arthritis and osteomyelitis of the knee after

trauma, and responded to surgical debridement and prolonged

voriconazole therapy.[22]

Surveillance of Antifungal Susceptibility

Surveillance studies of antifungal susceptibility are important to

evaluate the impact of antifungal agents on the development of

resistance. One large multinational surveillance study (the fungal

surveillance component of the SENTRY Program for 2003) reported

results comparable to those reported by the same group during the

1997 survey. A total of 1397 Candida species, 73 Aspergillus

species, 53 C neoformans species, and 25 other isolates from

patients from North America, Europe, and Latin America were tested

for susceptibility to 5-fluorocytosine, fluconazole, itraconazole,

ketoconazole, voriconazole, ravuconazole, and amphotericin-B. C

albicans, C parapsilosis, and C tropicalis were highly susceptible

to voriconazole, ravuconazole, and fluconazole (</= 1.3%

resistance). Resistance of C glabrata to voriconazole, ravuconazole,

and fluconazole was noted among 19.5%, 19% and 12%, respectively. Of

note, Latin American strains of C glabrata were more commonly

resistant to ravuconazole and amphotericin B (33% and 27%,

respectively) than the North American strains (17% and 13%,

respectively). Resistance of Aspergillus fumigatus was observed to

be occasionally present (11%), with voriconazole, ravuconazole, and

itraconazole being most active (percentage resistant, respectively:

11%; 38%, and 52%).[23]

In a 5-year study, prophylactic administration of fluconazole during

the first 6 weeks of life in high-risk preterm infants was not found

to be associated with increasing antifungal resistance.[24]

Animal reservoirs of antimicrobial resistance are of concern

worldwide. A study conducted among undomesticated animals (birds,

mammals, and reptiles) and humans showed that although C albicans is

part of normal flora of both humans and undomesticated animals, C

albicans from animal sources does not serve as a reservoir of

resistance to antifungal agents.[25]

Diagnosis

The evaluation of the severity of the candidemia could help

determining the best therapeutic strategies. Time to positive

culture (TTP) (time required for a blood culture to become positive

for yeast) is affected in vitro by the quantity (colony forming

units [CFU]) of Candida. The objective of this study was to

determine whether a correlation exists between TTP and the patient's

acute physiology and chronic health evaluation score (APACHE II) or

death. TTP was measured from venipuncture until positive by the

BACTEC 9240 machine. The study concluded that TTP was dependent on

the number of candidal organisms present in the blood specimen.

Preliminary data also suggested a correlation between TTP and the

patient's APACHE II score. However, data were considered

insufficient to assess a relationship between TTP and death.[26]

Antifungal Agents and Therapy

Salvage Therapy: A Word of Caution

Several interesting reports (discussed below) describe the results

of salvage antifungal therapy studies in immunocompromised patients,

a setting in which appropriate determination of the activity and

safety of an investigational agent is very difficult. These trials

are typically nonrandomized, and enroll patients with different

underlying diseases and conditions and with different infections

(species, sites). Further, patients are enrolled on the basis of

lack of response or intolerance to first-line antifungal therapy, 2

criteria that vary greatly between studies and between investigators

even on the same study, given that accepted definitions for failure

and intolerance do not exist. These studies frequently focus on

pulmonary aspergillosis, whose radiologic findings may temporarily

worsen (during recovery from neutropenia) before they resolve.

Enrolling such patients (a common scenario in these trials) can lead

to an overestimation of the effect of the salvage study drug or

regimen when these patients may have actually been responding to

initial antifungal therapy and to recovery from neutropenia. To

further confuse the matter, detailed reporting of changes in the

patient's immune status after the introduction of the salvage agent

is usually lacking.

Thus, evaluation of the efficacy of antifungal agents should be made

primarily on the basis of randomized trials with adequate

definitions and endpoints and reporting of changes in the immune

status of the host.

Triazoles

Posaconazole. The long-term safety of posaconazole, an oral,

extended-spectrum triazole antifungal agent, was evaluated in the

setting of salvage therapy. The drug was well tolerated at the 800-

mg/day dose given in divided doses. Of 330 patients, 102 were

treated for more than 6 months (including 27 treated for more than 1

year). The most common treatment-related adverse events included

headache (10%), nausea and vomiting (8% and 4%, respectively),

abdominal pain (5%), increased liver function tests (5%), and

diarrhea (4%); these were more commonly reported during the first 6

months of therapy.[27]

Recent experience suggests that the combination of liposomal

amphotericin B and caspofungin may improve the outcome of patients

with refractory invasive aspergillosis. A retrospective study (1999-

2003) was conducted to compare the efficacy of this intravenous

combination (43 patients) to that of oral posaconazole (48 patients)

in refractory invasive aspergillosis in patients with hematologic

malignancies. The study authors reported that the response rate was

twice as high with oral posaconazole than with the combination of

intravenous liposomal amphotericin B plus caspofungin (29% vs 19%,

respectively [P = .08]). However, posaconazole-treated patients were

less frequently in the ICU (23% vs 51%; P < .01) or on mechanical

ventilation (13% vs 40%; P < .01), indicating that the more

critically ill patients may have received the intravenous

combination, while those who were stable enough to receive oral

medications were given posaconazole (posaconazole is only available

orally). Adjusting for severity of illness and persistently severe

neutropenia and immunosuppression will be needed to explain this

unexpected outcome.[28]

The efficacy of posaconazole was also evaluated in an open-label,

multicenter, international phase 3 trial for azole-refractory

oropharyngeal and esophageal candidiasis in HIV/AIDS patients. Oral

posaconazole (400 mg twice daily for 3 days, followed by 400 mg

daily or 400 mg twice daily for 25 days) was effective in 75% of 199

enrolled patients.[29] Two randomized comparative trials of

posaconazole in antifungal prophylaxis (one in allogeneic stem cell

transplant recipients and the other in patients with acute leukemia

undergoing remission induction chemotherapy) should further support

the uncontrolled data suggesting that posaconazole is indeed a

uniquely effective agent and are awaited. The results of these 2

controlled trials are particularly important given that an

intravenous formulation of posaconazole is not available.

An open-label multicenter salvage trial of posaconazole in 330

patients with proven or probable invasive fungal infection, and who

were intolerant of or refractory to antifungal therapy, was

presented. A posaconazole daily dose of 800 mg in divided doses was

given for up to 12 months. A contemporaneous external control set of

279 patients was developed, and data from 238 of the 330

posaconazole patients (72%) and from 218 of the 279 control patients

(78%) were examined. Most infections (86%) were considered

refractory to previous therapy, primarily amphotericin B. Successful

outcomes at the end of therapy for the posaconazole and the control

group, respectively, were as follows:

aspergillosis: 107 (42%) vs 86 (26%) (P = .006);

fusariosis: 18 (39%) vs 4 (50%);

zygomycosis: 11 (56%) vs 8 (50%);

coccidioidomycosis: 16 (69%) vs 7 (43%);

candidiasis: 23 (52%) vs 30 (53%);

cryptococcosis: 31 (48%) vs 64 (58%);

chromoblastomycosis/mycetoma: 11 (81%) vs 2 (0); and

infection with other fungi: 30 (64%) vs 20 (60%).[30]

In this study, 8 of 330 patients had refractory invasive fungal

infection (7 proven and 1 probable) that did not respond to

voriconazole from 19-249 days. Four of these patients responded to

posaconazole therapy.[31]

Therapy for coccidioidomycosis remains a clinical challenge.

Posaconazole at 800 mg/day in divided doses was given to 15 patients

with proven and refractory coccidioidomycosis. Sites of infection

were pulmonary (7 patients) and disseminated (8 patients), of which

1 involved the central nervous system. Patients had been refractory

to previous therapy (including amphotericin B with or without an

azole) for a median of 306 days. A success rate of 73% (4 complete

and 7 partial responses) was achieved at the end of treatment (34-

365 days), suggesting that oral posaconazole could be an important

agent for the treatment of refractory coccidioidomycosis.[32]

Voriconazole. Scedosporium species now account for 25% of mold

infections other than aspergillosis in organ transplant recipients.

A review of 13 cases and 45 others reported in the literature

suggested that the use of voriconazole portends a better outcome and

warrants consideration as a therapeutic modality in these patients.

[33]

These clinical data were partially supported by in vitro

susceptibility data on 117 clinical isolates of Scedosporium species

(84 S prolificans and 33 S apiospermum) recovered at a single

institution during a 16-year period. As expected, amphotericin B,

itraconazole, caspofungin, micafungin, voriconazole, and

posaconazole exhibited poor activity against S prolificans. By

contrast, S apiospermum isolates were more susceptible, with the

highest activity exhibited by voriconazole, followed by posaconazole.

[34] The same authors also tested the in vitro activity of new and

conventional antifungal agents against 97 clinical isolates of

Fusarium isolates covering the same 16-year period. Caspofungin and

micafungin had no activity against Fusarium isolates. The most

active agent was voriconazole, followed by itraconazole and

posaconazole, while the susceptibility to amphotericin B was

variable.[35]

Echinocandins in Candidiasis

Caspofungin. A retrospective study evaluated the activity of

caspofungin in the treatment of 73 consecutive episodes of invasive

candidiasis at a single tertiary hospital (2001-2004). The majority

of the infections were caused by non-albicans species (71%, mainly C

glabrata), and had received previous antifungal treatment. Clinical

and microbiological cure rates were 79% and 75%, respectively.

Overall mortality was 39%, with 18% attributable to candidiasis. The

study authors suggested that caspofungin could be used as first-line

therapy for non-albicans invasive candidiasis.[36]

Caspofungin is occasionally used in pediatric patients. A

multicenter retrospective review of 53 immunocompromised pediatric

patients (the majority with hematologic malignancies) treated with

caspofungin showed that the drug displayed an acceptable safety

profile and may be effective. Patients were given caspofungin for

refractory infection (35), intolerance of standard antifungal agents

(7), or as primary therapy (11). Mean duration of therapy was 41

days (range, 2-159 days). Therapy was not discontinued in any of

these patients because of toxicity. Adverse events (mild to

moderate) were observed in 43% patients and included an increase in

liver function tests. Overall survival at end of therapy and at 3-

month follow-up was 72% and 64%, respectively.[37]

Despite the excellent in vitro susceptibility of C glabrata to the

echinocandins, emergence of resistance during therapy was reported

at this meeting. A 64-fold increase in caspofungin mean inhibitory

concentrations (MICs) was documented during therapy in 1 patient who

failed to clear the organism from blood. A 41-year-old man with

orthotopic liver transplantation developed C glabrata candidemia and

received IV caspofungin 70 mg loading, followed by a daily 50-mg

dose for 60 days. During therapy, cultures from various sites

(blood, bronchoalveolar lavage, peritoneal fluid, and abdominal wall

abscess) continued to yield C glabrata until the patient's death.

Pulsed-field gel electrophoresis of chromosomal DNA demonstrated

that the original strain of C glabrata was genetically identical to

the C glabrata strain recovered during therapy. The baseline

caspofungin MIC for the C glabrata blood isolate was 0.125, compared

with 8 for the organism recovered during therapy. This patient's

death was likely secondary to the persistence of an abdominal

abscess. Nonetheless, this case raises concerns about the potential

for increasing resistance following therapy with caspofungin.[38]

The effectiveness of caspofungin in salvage therapy for invasive

aspergillosis has been suggested by 2 open-label noncomparative

studies with a 40% to 45% response rate (N = 138). Conflicting data

exist regarding a drug-drug interaction (elevation of liver

transaminases) when caspofungin and cyclosporine A are used in

combination. A report from Australia described the efficacy of

caspofungin as salvage therapy for invasive aspergillosis and

evaluated potential interactions between caspofungin and cyclosporin

A. The medical records of 65 patients enrolled in the Australian

caspofungin trial (April 2001-August 2002) were retrospectively

reviewed with outcomes assessed at end of therapy. Most patients had

an underlying hematologic malignancy, were neutropenic at

enrollment, and had refractory pulmonary aspergillosis. Caspofungin

was given at standard doses (IV 70 mg × 1, then 50 mg/day) and liver

function tests were monitored weekly in 8 patients who received the

drug in combination with cyclosporin A. A favorable outcome was

observed in 40% of subjects (complete response 17%, partial response

23%) and the drug was well tolerated. One of the 8 patients

receiving the combination of caspofungin and cyclosporin A had

elevation of liver transaminases to more than 3 times baseline

values, but therapy was continued without deleterious consequences.

[39]

Anidulafungin.Anidulafungin is a novel echinocandin with potent in

vitro and in vivo activity against Candida species, including azole

and polyene-resistant organisms A phase 3 randomized, multicenter,

double-blind study compared anidulafungin and fluconazole in the

treatment of moderate-to-severe esophageal candidiasis in 37 HIV-

seronegative patients. Anidulafungin was given as a 100 mg IV

loading dose on day 1 followed by a daily dose of 50 mg, while

therapy with fluconazole consisted of a 100-mg oral daily dose after

an initial dose of 200 mg. Both agents were continued for 14-21

days. All patients achieved a complete response at end of therapy,

as measured by endoscopic evaluation.[40]

Azole-refractory mucosal candidiasis (ARMC) is associated with

prolonged azole therapy, especially in patients with AIDS.

Anidulafungin was studied in an open-label, multicenter study in 18

patients with ARMC (17 with AIDS) at a dose of 50 mg/day IV (loading

dose 100 mg day 1) for 14-21 days. Most patients had CD4+ cell

counts < 50 cells/mcL and had infections caused by C albicans; 6 had

concomitant infection with C glabrata. Seventeen of 18 patients had

a successful complete response at end of therapy, and the drug was

well tolerated.[41]

Liposomal Amphotericin B

The clinical efficacy of liposomal amphotericin B (L-AmB [AmBisome])

in invasive fungal infections has been reported. Data from 3

published trials and a prospective, compassionate-use study were

analyzed applying currently accepted European Organization for

Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG)

diagnostic criteria. Sixty-nine cases meeting these criteria were

included. Most patients had hematologic malignancies and had

undergone stem cell transplantation. Fungal pathogens included 61

Aspergillus species, 6 Zygomycetes species, 4 Fusarium species, and

1 unidentified mold. Lungs were the organ most commonly involved (48

patients). L-AmB dosing ranged from 1 to 15 mg/kg/day (median, 4

mg/kg/day). Favorable responses (complete and partial responses)

were observed in 35 patients (51%). The response rate was higher

when L-AmB was used as first-line therapy (27/44 patients; 61%) than

for salvage (8/25 patients; 32%). The study authors concluded that

the clinical efficacy of L-AmB exceeded that reported with

conventional amphotericin B deoxycholate and was comparable to that

associated with voriconazole.[42]

Combination Antifungal Therapy

Combinations of antifungal agents for primary treatment of invasive

aspergillosis appear to be widely employed despite the lack of

clinical data to support this practice. A retrospective cohort study

of patients with invasive aspergillosis and an underlying

hematologic condition treated between 1998 and 2003 was presented at

this year's meeting. Outcomes of patients treated with single-agent

vs combination antifungal therapy were compared. The primary outcome

was survival at 12 weeks; the secondary outcome was clinical and

radiologic response at 12 weeks, which was categorized as complete

or partial response, stable disease, or failure (progressive

infection and/or death). In total, 45 patients were included, 34

with proven or probable invasive aspergillosis. No survival

difference between single vs combination therapy could be

identified. In a subset analysis, patients with probable or proven

disease involving sinuses or lungs were reported to have survived

longer (median of 102 days vs 40 days) if they received combination

therapy. Notably, none of the 45 patients evaluated achieved a

complete response at the 12-week endpoint.[43]

A retrospective 19-center study attempted to determine the patient

population at greatest risk of death from invasive aspergillosis

after stem cell transplantation, and which patients would

potentially benefit from combination antifungal therapy as primary

treatment. The records of 51 patients with proven and probable

aspergillosis (41 allogeneic; 10 autologous stem cell transplant

recipients) were examined. The proportion of deaths attributed to

aspergillosis within 4 months after diagnosis was 0.62 [range, 0.47-

0.76] with a median time to death of 12 days. Prognostic factors for

death were age 12-35 years (10 of 13 died) (hazard ratio

---

= 2.49

[CI, 1.14-5.47]), disseminated infection (HR = 2.84 [CI, 1.25-

6.44]), presence of pleural effusion (HR = 3.44 [CI, 1.36-8.75]),

prolonged steroid treatment (HR = 3.05 [CI, 1.43-6.49]), and

uncontrolled graft-vs-host disease (allogeneic patients only) (HR =

4.02 [CI, 1.54-10.49]).[44]

The combined efficacy of micafungin and amphotericin B was studied

in 6 patients with pulmonary aspergillosis. The duration of

treatment varied from 14 to 90 days. Amphotericin B dose ranged from

0.8 to 1.5 mg/kg/day; micafungin was given at a dose of 150-300

mg/day. Five patients responded to this therapy.[45]

Empiric Antifungal Therapy

Empiric antifungal therapy is an established indication in

neutropenic patients with persistent fever refractory to broad-

spectrum antibiotic therapy. Clinical trials testing various

antifungal agents could not demonstrate the superiority of any drug

using the composite endpoint as commonly applied. A meta-analysis of

studies that compared itraconazole (IV 400 mg/d days 1-2, 200 mg/d

days 3-7/14; oral solution: 400 mg/d days 8/15+) with amphotericin B

deoxycholate (0.7-1.0 mg/kg/d) in neutropenic cancer patients showed

that itraconazole was superior to amphotericin B: Response rates

were 54% (138/257) and 38% (99/260), respectively (OR = 0.53; 95%

CI, 0.38-0.75; P = .0004). The number of breakthrough invasive

fungal infections was not different (10/260 vs 8/262). Treatment

withdrawal due to an adverse event was significantly less frequent

with itraconazole (15% vs 37%) (OR = 0.32; 95% CI, 0.22-0.47; P

< .0001), and the absolute risk of failure was reduced by 16% (OR -

0.16, 95% CI, -0.24 to -0.07; P = .0003). The study authors

concluded that IV followed by oral itraconazole solution was equally

effective but significantly better tolerated than amphotericin B for

empirical antifungal therapy.[46]

Antifungal Prophylaxis in Surgical Patients

The severe clinical burden of fungal infections in liver transplant

recipients suggests that the use of antifungal prophylaxis may be

warranted. A meta-analysis of randomized clinical trials comparing

systemic antifungal agents (fluconazole, itraconazole, or liposomal

amphotericin) vs controls (placebo, no treatment, or minimal

treatment with topical agents) showed a clear beneficial effect of

antifungal prophylaxis upon some parameters of infectious morbidity

and mortality. A total of 698 treated patients (6 studies) were

compared with placebo/oral nystatin patients (5 studies). Mortality

due to fungal infection (risk ratio [RR] = 029; 95% CI, 0.11-0.75),

but not overall mortality, was reduced in patients receiving

prophylaxis. Prophylaxis reduced colonization and total proven

fungal infections (RR = 0.31; 95% CI, 0.21-0.45), both superficial

(RR = 0.26; 95% CI, 0.16-0.44) and invasive (RR = 0.32; 95% CI, 0.18-

0.58).[47]

Another meta-analysis supported the use of antifungal prophylaxis in

trauma and surgical ICU patients. Ketoconazole or fluconazole were

compared with placebo or no treatment among 975 patients. Mortality

due to fungal infection (RR = 025; 95% CI, 0.08-0.80) and overall

mortality (RR = 0.65; 95% CI, 0.45-0.94) were reduced in patients

receiving prophylaxis. Moreover, prophylaxis reduced total fungal

infections (RR = 0.48; 95% CI, 0.31-0.75), deep tissue infections

(RR = 0.29; 95% CI, 0.15-0.55), and episodes of fungemia (RR = 0.29;

95% CI, 0.10-0.82).[48]

Strategies for the prevention of invasive aspergillosis include the

use of antifungal prophylaxis in patients at high risk for this

infection. Reported risk factors for invasive aspergillosis among

heart transplant recipients include reoperation, cytomegalovirus

disease, posttransplant hemodialysis, and a prior episode of

aspergillosis (2 months before or after the transplantation date).

Itraconazole prophylaxis (3-6 months) has been shown to be an

independent predictor for protection[49]; however, the optimal

duration of prophylaxis remains unknown. A study presented at this

year's ICAAC addressed this issue and concluded that prophylaxis

should be administered for 1-2 months after resolution of all risk

factors for aspergillosis.[50]

Antifungal Prophylaxis in Patients With Hematologic Malignancies

A randomized trial compared the efficacy of itraconazole vs

fluconazole, both given orally or intravenously, for prevention of

invasive fungal infection in 196 hematopoietic stem cell transplant

(HSCT) and acute leukemia patients (December 2001 to February 2003).

Patients were randomly assigned to receive fluconazole (99) or

itraconazole (96) prophylaxis, after stratification by risk

category: high risk (50 patients with allogeneic HSCT and relapsed

or resistant acute leukemia) or low risk (146 patients with

autologous HSCT or newly diagnosed acute leukemia). Prophylaxis was

initiated at start of chemotherapy and continued until resolution of

neutropenia or until empiric amphotericin B was commenced. Twenty-

three patients (12%) developed invasive fungal infection (11 in the

fluconazole group, 12 in the itraconazole group), including 3

episodes of invasive candidiasis and 20 episodes of invasive

aspergillosis, equally distributed among the 2 study groups.

Although no difference could be detected in the incidence of fungal

infection, the mortality of patients with invasive aspergillosis was

lower among itraconazole recipients (4/10 [40%]) compared with those

who received fluconazole (7/10 [70%]).[51]

Secondary prophylaxis for invasive fungal infections is needed to

prevent infection relapse among cancer patients receiving additional

immunosuppressive therapies. Although secondary prophylaxis is

commonly practiced in this setting, few data exist to support its

use with the novel antifungal agents. A survey of secondary

prophylaxis in 54 tertiary care centers in 15 countries was

conducted. 166 patients with acute myelogenous leukemia and

proven/probable fungal pneumonia following chemotherapy-induced

neutropenia were evaluated. Infections included aspergillosis (78%),

zygomycosis (8%), and infections by other fungi. Patients received

secondary prophylaxis with amphotericin B deoxycholate (D-AmB),

lipid-based amphotericin B, itraconazole, voriconazole, caspofungin,

or no secondary prophylaxis. Recurrent proven invasive fungal

infection (mostly pneumonia) developed in 2 of 166 patients (1%),

while probable infection was diagnosed in 24 of 166 (15%). The

highest rates of recurrence were seen among patients who did not

receive prophylaxis (9 of 42; 21%) or who were given D-AmB (5 of 24,

21%). Recurrence was also observed with itraconazole (9 of 57, 16%),

compared with 8% with voriconazole (2 of 26, 8%) and lipid

amphotericin B (1 of 12, 8%). Eleven patients died (7%), with 1

death attributed to fungal infection. The study authors concluded

that secondary prophylaxis with agents other than D-AmB is

effective. Of note, allogeneic stem cell transplant recipients were

not included in this group of patients.[52]

New Antifungal Agents, Drug Delivery, and Pharmacodynamics

Icofungipen is a novel oral antifungal compound, primarily active

against Candida species, including azole-resistant strains. A

comparative, randomized, double-blind study was conducted to assess

the efficacy and safety of icofungipen in 48 male HIV-positive

patients with oropharyngeal candidiasis. Patients were randomized in

a 1:1:1 ratio to receive a 2-week treatment with icofungipen, 150 mg

every 12 hours (twice daily), icofungipen 150 mg every 8 hours (3

times daily), or fluconazole, 100 mg once daily. Response was

evaluated at the end of treatment and after a 4-week follow-up

period. Patients treated with icofungipen were more immunosuppressed

and had more severe oropharyngeal candidiasis than those receiving

fluconazole. Clinical success rates at the end of treatment were 67%

and 79% in the twice-daily and 3-times-daily icofungipen groups,

respectively, compared with a 100% response in the fluconazole

group. Mean sum-scores of oropharyngeal candidiasis-specific

symptoms and signs decreased during treatment by 52% and 65% in the

twice-daily and 3-times-daily icofungipen groups, and by 63% among

fluconazole-treated patients. This clinical response contrasted with

significantly lower mycologic eradication rates (13%, 0%, and 56% in

the twice-daily and 3-times-daily icofungipen groups and fluconazole

group, respectively). Both drugs were well tolerated. The most

common adverse events associated with icofungipen were mild

gastrointestinal disturbances and headache. The study authors

concluded that icofungipen was clinically effective in HIV-positive

patients with oropharyngeal candidiasis, but doses higher than 150

mg would be needed to achieve optimal responses.[53]

L-AmB is cleared slowly from the bloodstream. A nonlinear

relationship exists between L-AMB plasma pharmacokinetics parameters

and dosage, suggesting that elimination of the drug is altered with

higher daily dosing. The pharmacokinetics and tissue penetration of

L-AmB following a single 15-mg/kg dose was compared with a 1-mg/kg

dose administered daily. Eleven adults who underwent allogeneic or

autologous peripheral stem cell transplantation were block-

randomized into this open-label pharmacokinetics study and received

either 1 mg/kg L-AmB daily for 15 days or a single 15-mg/kg dose.

Repeated blood sampling was performed on days 1 and 7, and trough

samples were collected every 48 hours. Single buccal mucosal tissue

samples were obtained on days 7 and 15. A single 15-mg/kg L-AmB dose

was well tolerated and achieved high and sustained tissue

concentrations on day 7 (mean, 8.1 mcg/g) similar to those achieved

with 1-mg/kg daily dosing (mean, 9.7 mcg/g).[54]

The pharmacokinetics, safety, and efficacy of nebulized L-AmB in

lung allograft recipients were assessed in an open-label clinical

trial (April 2003-February 2004). A dose of 24 mg, 3 times a week,

was given between days 0 and 60 after transplantation. The dosing

interval was subsequently increased to once a week (months 2-6) and

later to once monthly (more than 6 months after transplantation).

Amphotericin B concentrations were measured by high-performance

liquid chromatography in bronchoalveolar lavage (BAL) samples from

25 bronchoscopies (23 patients) with simultaneous measurement of

amphotericin B serum concentrations. Results were given as mean ± SD

of mcg/mL of amphotericin B concentrations in BAL and were as

follows:

at 4 hours (n = 4) 10.9 ± 11.6;

at 7 days (n = 13) 10.2 ± 9.8; and

at 14 days (n = 8) 6.6 ± 5.1.

No drug levels were detected in blood samples. There were no

significant changes in spirometry values observed before and after

nebulized L-AmB. No episodes of invasive fungal infection were

diagnosed. Fungal colonization was documented in 6 patients (5.8%),

but resolved after increasing the dose interval of nebulized L-AmB.

One patient suffered from tracheobronchitis that responded to

voriconazole. Nebulized L-AmB was stopped in only 1 of 102 patients

(1%) because of cough and dyspnea. The study authors concluded that

nebulized L-AmB is well tolerated, achieves significant

concentrations in BAL 2 weeks after beginning of nebulization, and

may be effective in preventing invasive aspergillosis in lung

transplant recipients.[55]

Supported by an independent educational grant from Pfizer.

References

Muñoz P, -Somolinos M, Pérez M, et al. Outbreak of

Saccharomyces cerevisiae infection in a heart surgery intensive care

unit (HSICU). Program and abstracts of the 44th Interscience

Conference of Antimicrobial Agents and Chemotherapy; October 30-

November 2, 2004; Washington, DC. Abstract K-877.

Klont R, Rijs A, Warris A, Sturm D, Verweij P. Bacterial and fungal

contamination of commercial bottled mineral water from 16 countries.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract K-1603 .

Pavie J, Bouakline A, Feuilhade M, Molina J, Derouin F. Fungal

contamination of hospital healthcare workers' overalls. Program and

abstracts of the 44th Interscience Conference of Antimicrobial

Agents and Chemotherapy; October 30-November 2, 2004; Washington,

DC. Abstract M-1031.

Thiebaut A, Perraud M, Ozil S. Diving suit: sterile, ambulatory,

personal device for protective and preventive isolation of

nosocomial invasive fungal infections (ifi) in neutropenic patients

hospitalised in laminar air flow room who need a disruption of

isolation. Program and abstracts of the 44th Interscience Conference

of Antimicrobial Agents and Chemotherapy; October 30-November 2,

2004; Washington, DC. Abstract K-1449 .

Loo V, Hébert G, Jarand J, et al. Outbreak of Aspergillus infections

among surgical cardiac patients. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract K-878.

Gentry C, Callen E, Flournoy D, Winner J, Slater L. A prospective

evaluation determining risk factors for colonization or infection

with Candida glabrata in an SICU. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract K-1434.

Vandewoude K, Colardyn F, Verschraegen G, et al. Clinical relevance

of positive aspergillus cultures in respiratory tract secretions in

ICU patients. Program and abstracts of the 44th Interscience

Conference of Antimicrobial Agents and Chemotherapy; October 30-

November 2, 2004; Washington, DC. Abstract K-1440.

Klont R, Strijbosch S, Melchers W, Verweij P. Relapsing Aspergillus

niger (An) otomycosis is caused by a single persistent genotype.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1049.

Paterson D, Ndirangu M, Kwak E, et al. Opportunistic infections in

solid-organ transplant recipients pre-treated with almetuzumab.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract K-1427.

J, B, Wannemuehler K, et al. Quantification of risk

for invasive fungal infections (IFI) among transplant (TX)

recipients reporting to TRANSNET. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1058.

Moreno A, Soto G, Almela M, et al. Bacteremia and fungemia in solid

organ transplantation (SOT). Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract K-1424.

Colombo A, Nucci M, Park B, et al. Epidemiology of candidemia in

Brazil: results from prospective multicenter surveillance. Program

and abstracts of the 44th Interscience Conference of Antimicrobial

Agents and Chemotherapy; October 30-November 2, 2004; Washington,

DC. Abstract M-1030.

Sandven P, Bevanger L, Digranes A, Gaustad P, Haukland H, Mannsaker

T. Candidemia in Norway 1997 - 2003: results from a nationwide

study. Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1061.

Rodríguez D, Almirante B, Cuenca-Estrella M, et al. Candidemia in

neonatal intensive care unit (NICU) patients. Program and abstracts

of the 44th Interscience Conference of Antimicrobial Agents and

Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract

M-1045.

Bassetti M, Righi E, Rebesco B, et al. Epidemiological trends in

nosocomial candidemia in ICU: a five-year Italian perspective.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1048.

Chen A, Sobel J, Boikov D, Vazquez J. Molecular characterization of

recurrent vulvovaginal candidasis following a placebo-controlled

trial of maintanace fluconazole therapy. Program and abstracts of

the 44th Interscience Conference of Antimicrobial Agents and

Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract

M-1021.

Sotiropoulos D, Zahari H, Kokinidis D, et al. Alternaria spp. in a

bone marrow transplantation (BMT) unit: a surveillance study.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract K-1447.

Singh N, Muñoz P, Forrest G, et al. Scedosporium Infections in organ

transplant recipients: impact of antifungal agent therapy on

outcome. Program and abstracts of the 44th Interscience Conference

of Antimicrobial Agents and Chemotherapy; October 30-November 2,

2004; Washington, DC. Abstract M-1018.

Kontoyiannis D, Lionakis M, R, Walsh T, Raad I. Zygomycosis

(Z) in the era of voriconazole (VRC) in a cancer center: a matched

case-control observational study of 27 recent patients (pts).

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-665.

Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KV. Zygomycosis in the

1990s in a tertiary-care cancer center. Clin Infect Dis. 2000;30:851-

856.

Park B, Kontoyiannis D, Pappas P, et al. Comparison of zygomycosis

and fusariosis to invasive aspergillosis (IA) among transplant

recipients reporting to TRANSNET. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-666.

Baddley J, Mostert R, Summerbell R, Moser S. Phaeoacremonium

parasiticum: an uncommon cause of opportunistic mould infection.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1059.

Messer S, R, Fritsche T. International surveillance of Candida

spp. and Aspergillus spp.: Report from the SENTRY Antimicrobial

Surveillance Program (2003). Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1797.

Kaufman D, Boyle R, Hazen K, Patrie J, M, Grossman L.

Sensitivities of fungal isolates in high-risk preterm infants

exposed to fluconazole prophylaxis in a neonatal intensive care unit

over a 5-year period. Program and abstracts of the 44th Interscience

Conference of Antimicrobial Agents and Chemotherapy; October 30-

November 2, 2004; Washington, DC. Abstract M-1808.

Pfaller M, Pujol C, Diekema D, Mecer S, Hollis R, Soll D. Animal

isolates of Candida albicans are not a source of resistance ® to

common antifungal agents. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1768.

Dean J, Chapman S, Ceary J. Time to positive effect on outcome of

patients with Candidemia. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-254.

Graybill J, Raad I, Negroni R, Corcoran G, Pedicone L. Posaconazole

(POS) Long-term safety in patients with invasive fungal infections

(IFIs). Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1025.

Raad I, Boktour M, Hanna H, Kontoyiannis D, Hachem R. Posaconazole

(POS) compared to amphotericin B lipid formulations (AmB/LPD) in

combination with caspofungin (CASP) as salvage therapy for invasive

aspergillosis (IA) in patients (pts) with hematologic malignancy

(HM). Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1035.

Skiest D, Vazquez J, Graybill J, et al. Open-label trial of

posaconazole (POS) for azole-refractory oropharyngeal (OP) and

esophageal (ES) candidiasis in HIV/AIDS Patients: Final Analysis.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1027.

Raad I, Chapman S, Bradsher R, et al. Posaconazole (POS) salvage

therapy for invasive fungal infections (IFI). Program and abstracts

of the 44th Interscience Conference of Antimicrobial Agents and

Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract

M-669.

Herbrecht R, Marr K, Catanzaro A, et al. Posaconazole (POS) as

salvage therapy for invasive fungal infections (IFIs) unresponsive

to voriconazole: a case series. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1044.

s D, Rendon A, Gaona V, et al. Posaconazole (POS) therapy for

chronic refractory coccidioidomycosis. Program and abstracts of the

44th Interscience Conference of Antimicrobial Agents and

Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract

M-663.

Singh N, Muñoz P, Forrest G, et al. Scedosporium infections in organ

transplant recipients: impact of antifungal agent therapy on

outcome. Program and abstracts of the 44th Interscience Conference

of Antimicrobial Agents and Chemotherapy; October 30-November 2,

2004; Washington, DC. Abstract M-1018.

Pelaez T, Guinea J, ez-Alarcon J, et al. Epidemiology and in

vitro activities of new and conventional antifungal agents against

clinical scedosporium isolates: an overview of a 16-year period in a

general hospital. Program and abstracts of the 44th Interscience

Conference of Antimicrobial Agents and Chemotherapy; October 30-

November 2, 2004; Washington, DC. Abstract M-1806.

Pelaez T, Guinea J, -Escribano N, et al. Fusarium:

epidemiology and antifungal susceptibility over 16 years. Program

and abstracts of the 44th Interscience Conference of Antimicrobial

Agents and Chemotherapy; October 30-November 2, 2004; Washington,

DC. Abstract M-1026.

Zaas A, Dodds E, B, M, Perfect J.

Caspofungin for invasive candidiasis: Experience at DUMC 2001-2004.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1015.

Lehrnbecher T, Attarbaschi A, Schuster F, et al. Caspofungin in

immunocompromised pediatric patients without therapeutic

alternative: a multicenter survey. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1019.

Villarreal N, Fothergill A, C, J, Rinaldi M,

T. Candida glabrata resistance to caspofungin during

therapy. Program and abstracts of the 44th Interscience Conference

of Antimicrobial Agents and Chemotherapy; October 30-November 2,

2004; Washington, DC. Abstract M-1034.

sey C, Slavin M, O'reilly M, Daffy J, Coyle L. Caspofungin

(CAS) as salvage therapy (Rx) for invasive aspergillosis (IA):

results of the Australian Compassionate Access Program (CAP).

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-670.

Viljoen J, Schranz J, Krause D, Simjee A, Van Rensburg C, Walsh T.

Clinical efficacy results from a phase 3 study of anidulafungin

(ANID) versus fluconazole (FLU) in HIV negative patients with

esophageal candidiasis (EC). Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1023.

Vazquez J, Schranz J, Krause D, et al. Efficacy of anidulafungin

(ANID) in patients (Pts) with azole-refractory mucosal candidiasis

(ARMC). Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-1038.

Cordonnier C, Bresnik M, Ebrahimi R. Liposomal amphotericin B (L-

AMB) efficacy in invasive filamentous fungal infections (IFFI):

pooled analysis. Program and abstracts of the 44th Interscience

Conference of Antimicrobial Agents and Chemotherapy; October 30-

November 2, 2004; Washington, DC. Abstract M-1022.

Munoz L, Ruthazer R, Boucher H, Loudon S, Skarf L, Hadley S.

Combination antifungals for primary treatment of invasive

aspergillosis (IA): do they work? Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1024.

Cordonnier C, Ribaud P, Herbrecht R, Milpied N, Valteau-Couanet D,

Wade A. Prognostic factors for death from invasive aspergillosis

(IA) after hematopoietic stem cell transplantation (SCT): a one-year

retrospective, consecutive survey in french transplant centers.

Program and abstracts of the 44th Interscience Conference of

Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004;

Washington, DC. Abstract M-668.

Miyazaki Y, Mori M, Tashiro T, Kohno S. Clinical efficacy for the

combination of micafungin with amphotericin B against pulmonary

aspergillosis. Program and abstracts of the 44th Interscience

Conference of Antimicrobial Agents and Chemotherapy; October 30-

November 2, 2004; Washington, DC. Abstract M-1052.

Glasmacher A, Boogaerts M, Schuler U, et al. Combined analysis of

two randomized, controlled trials comparing empirical antimycotic

therapy with intravenous itraconazole or amphotericin B in

neutropenic patients with persistent fever. Program and abstracts of

the 44th Interscience Conference of Antimicrobial Agents and

Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract

M-1016.

Cruciani M, Malena M, Bosco O, Mengoli C. Antifungal prophylaxis in

liver transplant patients: a meta-analysis. Program and abstracts of

the 44th Interscience Conference of Antimicrobial Agents and

Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract

K-1432.

Cruciani M, Mengoli C, Lalla F. Meta-analysis of antifungal

prophylaxis in trauma and surgical intensive care patients. Program

and abstracts of the 44th Interscience Conference of Antimicrobial

Agents and Chemotherapy; October 30-November 2, 2004; Washington,

DC. Abstract K-1433.

Munoz P, C, Bouza E, Palomo J, Yanez JF, Dominguez MJ,

Desco M. Risk factors of invasive aspergillosis after heart

transplantation: protective role of oral itraconazole prophylaxis.

Am J Transplant 2004;4:636-643.

Muñoz P, Rodríguez C, Palomo J, Yánez J, Desco M, Bouza E. Tailoring

antifungal prophylaxis in heart transplant (HT) patients. Program

and abstracts of the 44th Interscience Conference of Antimicrobial

Agents and Chemotherapy; October 30-November 2, 2004; Washington,

DC. Abstract K-1431.

Brockmeyer N, Ruhnke M, Oreskovic K, J. Phase II study of

icofungipen (PLD-118) in the treatment of oropharyngeal candidiasis

(OPC) in HIV-positive patients. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1036.

Cornely O, Böhme A, Reuter S, et al. Efficacy of secondary

antifungal prophylaxis (SP) and risk factors for breakthrough

infection (IFI) after pulmonary IFI in AML patients: a Multinational

Case Registry. Program and abstracts of the 44th Interscience

Conference of Antimicrobial Agents and Chemotherapy; October 30-

November 2, 2004; Washington, DC. Abstract M-664.

Brockmeyer N, Ruhnke M, Oreskovic K, et al. Phase II study of

icofungipen (PLD-118) in the treatment of oropharyngeal candidiasis

(OPC) in HIV-positive patients. Program and abstracts of the 44th

Interscience Conference of Antimicrobial Agents and Chemotherapy;

October 30-November 2, 2004; Washington, DC. Abstract M-1036.

Gubbins P, McConnell SA, Amsden JR, et al. Comparison of liposomal

amphotericin B plasma and tissue concentrations following a single

large (15mg/kg) dose or daily 1mg/kg dosing. Program and abstracts

of the 44th Interscience Conference of Antimicrobial Agents and

Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract

A-33.

Monforte V, Gavalda J, Roman A, et al. Pharmacokinetics and efficacy

of nebulized ambisome (n-Amb) in lung transplantation (Lt). Program

and abstracts of the 44th Interscience Conference of Antimicrobial

Agents and Chemotherapy; October 30-November 2, 2004; Washington,

DC. Abstract M-1042.