Re: Clinical Mycology and Antifungal Therapy CME: authors

Posted December 20, 2004 · December 20, 2004

http://www.medscape.com/viewprogram/3694_authors

44th Interscience Conference on Antimicrobial Agents & Chemotherapy

Selected Topics in Infectious Disease Medicine CME

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Authors and Disclosures

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content.

Author

Elias J. Anaissie, MD

Professor of Medicine; Director, Supportive Care, Myeloma Institute

for Research and Therapy, Arkansas Cancer Research Center,

University of Arkansas for Medical Sciences, Little Rock, Arkansas

Disclosure: Elias J. Anaissie, MD, has disclosed that he has

received grants for educational activities from Gilead.

G. Bartlett, MD

Professor of Medicine, s Hopkins University School of Medicine,

Baltimore, land; Chief, Infectious Disease Division, s

Hopkins Hospital, Baltimore, land

Disclosure: G. Bartlett, MD, has no significant financial

interests or relationships to disclose.

Editor

Craig Sterritt

Site Editor/Program Director, Medscape HIV/AIDS, Medscape Infectious

Diseases

Disclosure: Craig Sterritt has no significant financial interests or

relationships to disclose.

M.

Clinical Editor, Medscape Neurology

Disclosure: has no significant financial interests to

disclose.

--- In , " tigerpaw2c " <tigerpaw2C@n...>

wrote:

>

> http://www.medscape.com/viewarticle/495502

>

> 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.

>

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> 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.

Posted December 20, 2004 · December 20, 2004