MEDLINE Abstracts: Management of Serious Fungal Infections
Application of Nucleic Acid Sequence-Based Amplification for Diagnosis of and Monitoring the Clinical Course of Invasive Aspergillosis in Patients with Hematologic Diseases

Yoo JH, Choi JH, Choi SM, et al

Clin Infect Dis . 2005;40:392-398

BACKGROUND AND METHODS: We evaluated nucleic acid sequence-based amplification (NASBA) and a galactomannan enzyme immunosorbent assay (GM-EIA) for the diagnosis of invasive aspergillosis (IA) in neutropenic febrile patients and for monitoring of its clinical course and outcome. Blood samples were collected twice per week from 128 patients with hematologic diseases during periods of neutropenic fever after undergoing chemotherapy or hematopoietic stem cell transplantation. A total of 448 blood samples were tested. RESULTS: There were 14 patients with IA (2 patients with proven IA and 12 with probable IA). The median index of the initial NASBA in the IA group was more than 10-fold higher than that in the non-IA group. Galactomannan antigenemia (index, >0.5) was detected with a sensitivity of 86%. In receiver-operator characteristic analysis, the cutoff index of NASBA for the presumptive diagnosis of IA was determined to be 5.0. Combination of these 2 parameters (either a GM-EIA index of >or=0.5 or a NASBA index of >or=5.0) improved the sensitivity of diagnosis to 100%. There was a close relationship between patient outcome and the kinetics of NASBA values: failure of negative conversion during treatment resulted in death in almost all cases. CONCLUSION: If either GM-EIA or NASBA results suggest IA, the diagnostic yield for IA could be improved, and NASBA could be a useful marker for predicting the clinical course and outcome of treatment.

Caspofungin as Second-line Therapy for Fever of Unknown Origin or Invasive Fungal Infection Following Allogeneic Stem Cell Transplantation

Trenschel R, Ditschkowski M, Elmaagacli AH, et al

Bone Marrow Transplant . 2005;35:583-586

Summary:Caspofungin (CAS) is the first of a new class of antifungal agents, the echinocandins, that interfere with fungal cell wall synthesis by inhibition of glucan synthesis. Here, we report the results of 31 patients treated with CAS following allogeneic SCT. CAS was administered as a second-line agent to patients with invasive fungal infection (IFI) (n=15) or fever of unknown origin (n=16) who were recalcitrant to or intolerant of prior antifungal therapy. Unsuccessful first-line regimes included amphotericin B (n=17), liposomal amphotericin B (n=5), fluconazole (n=3), itraconazole (n=1), and voriconazole (n=2). All patients received concomitant immunosuppressive therapy for graft-versus-host disease. In 23 patients, cyclosporin A (CSA) and CAS were administered concurrently without any major side effects detected. Observed increases in GPT were not clinically significant. Normalization of serum creatinine and significant reductions in C-reactive protein were observed in response to CAS. Favorable outcome to CAS were documented in eight of 15 patients with IFI and in 15 of 16 patients with fever of unknown origin. CAS is a promising alternative in patients with IFI and fever of unknown origin in the setting of allogeneic SCT.

Antifungal Activity of Posaconazole Compared With Fluconazole and Amphotericin B Against Yeasts From Oropharyngeal Candidiasis and Other Infections

Carrillo-Munoz AJ, Quindos G, Ruesga M, et al

J Antimicrob Chemother . 2005;55:317-319

OBJECTIVES: The in vitro antifungal activity of posaconazole was compared with that of fluconazole and amphotericin B. Materials and methods: A microdilution method (M27-A2) was used with 331 clinical yeast isolates. RESULTS: The geometric mean MICs of posaconazole, fluconazole and amphotericin B were 0.16, 0.91 and 0.15 mg/L, respectively. Posaconazole was markedly more active than fluconazole and was active against 9/11 fluconazole-resistant Candida albicans, and five Candida glabrata had an MIC of posaconazole of 16 mg/L. CONCLUSIONS: These data indicate that posaconazole is a potentially effective antifungal agent for the treatment of mycoses caused by yeasts.

Oral Bioavailability of Posaconazole in Fasted Healthy Subjects: Comparison Between Three Regimens and Basis for Clinical Dosage Recommendations.

Ezzet F, Wexler D, Courtney R, Krishna G, Lim J, Laughlin M

Clin Pharmacokinet . 2005;44:211-220

BACKGROUND AND OBJECTIVE: Posaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800 mg following administration of three different dose regimens to fasting adults. STUDY DESIGN: This was a randomised, open-label, three-way crossover study. METHODS: Subjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800 mg) given as a single dose (regimen A), 400 mg every 12 hours (regimen B) or 200 mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens. STUDY PARTICIPANTS: A total of 18 healthy men were enrolled in and completed the study. MAIN OUTCOME MEASURES AND RESULTS: Posaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 ± 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 ± 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 microg.h/L, with average plasma concentrations of 162, 320 and 517 microg/L for regimens A, B and C, respectively. CONCLUSION: These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

Liposomal Amphotericin B Activates Antifungal Resistance With Reduced Toxicity by Diverting Toll-like Receptor Signalling From TLR-2 to TLR-4

Bellocchio S, Gaziano R, Bozza S, et al

J Antimicrob Chemother . 2005;55:214-222

OBJECTIVES: Neutrophils play a crucial role in the control of the Aspergillus fumigatus infection and act in concert with antifungal drugs. This study was undertaken to obtain insights into the possible involvement of Toll-like receptors (TLRs) in the interaction of liposomal amphotericin B (L-AmB; AmBisome) with neutrophils in response to A. fumigatus. METHODS: For generation of bone marrow-transplanted mice, irradiated C57BL6 mice were infused with T cell-depleted allogeneic donor cells. For infection, mice were injected intranasally with Aspergillus fumigatus conidia and treated with L-Amb and deoxycholate amphotericin B prophylactically or therapeutically. For TLR-dependent antifungal functions, murine neutrophils were preincubated with antifungals or TLR ligands before the addition of Aspergillus conidia. RESULTS: The results show that: (a) neutrophil activation by Aspergillus occurs through TLR signalling pathways differently affecting the oxidative and non-oxidative mechanisms of the killing machinery; (b) by diverting signalling from TLR-2 to TLR-4, liposomes of AmBisome activate neutrophils to an antifungal state while attenuating the pro-inflammatory effects of deoxycholate amphotericin B; (c) this translates in vivo to the optimization of the AmBisome therapeutic efficacy in mice with aspergillosis. CONCLUSIONS: These results provide a putative molecular basis for the reduced infusion-related toxicity of AmBisome and suggest that TLR manipulation in vivo is amenable to the induction of optimal microbicidal activity in the absence of inflammatory cytotoxicity to host cells.

Painful Peripheral Neuropathy Associated With Voriconazole Use

Tsiodras S, Zafiropoulou R, Kanta E, Demponeras C, Karandreas N, Manesis EK

Arch Neurol . 2005;62:144-146

BACKGROUND: Voriconazole is a new antifungal agent that has been recently introduced into clinical practice. We found no published reports of painful peripheral neuropathy associated with its use. OBJECTIVE: To describe a unique case of painful peripheral neuropathy associated with voriconazole use. SETTING: University hospital. PATIENT: A 43-year-old patient who had undergone liver transplantation received voriconazole for invasive deep sinus aspergillosis and developed intolerable pain in all extremities. RESULTS: A laboratory workup and electromyographic and nerve conduction studies were performed to exclude other causes of neuropathy in this complicated patient. Results of electromyographic and nerve conduction studies were suggestive of a demyelinating neuropathy. Symptoms and signs of neuropathy disappeared shortly after voriconazole discontinuation, suggesting a possible role in the development of neuropathy. The patient continues to do well 10 months after this event. CONCLUSIONS: To our knowledge, this is the first reported case of voriconazole-associated peripheral neuropathy. Awareness of this association and careful monitoring for neurological signs are necessary for patients receiving voriconazole.

Invasive Fungal Infections in Pediatric Oncology Patients: 11-Year Experience at a Single Institution

Rosen GP, Nielsen K, Glenn S, Abelson J, Deville J, Moore TB

J Pediatr Hematol Oncol . 2005;27:135-140

The purpose of this study was to determine the incidence of fungal infections in pediatric hematology and oncology (PHO) patients and to describe variations regarding site of infection, organisms, and mortality. The records of 1,052 patients presenting to the UCLA PHO service with various malignancies from 1991 to 2001 were retrospectively reviewed. No patient received invasive antifungal prophylaxis. Transplant patients were excluded. The 11-year incidence of fungal infections in this pediatric oncology cohort was 4.9%. There was a linear increase in the incidence of fungal infections from 2.9% to 7.8% between 1996 and 2001 (P = 0.001). Patients with acute leukemia represented 36% of the population but had a disproportionate incidence (67%) of fungal infections. Adolescents had twice the expected incidence of infection (P < 0.0001). Overall, Candida sp. was the major pathogen. Over time, a trend of fewer infections caused by Candida and more due to Aspergillus was noted. Blood-borne infections decreased over time, while those in the urinary and respiratory tracts increased (P = 0.04). Sixty-two percent of infections occurred in neutropenic patients. PHO patients had an overall mortality of 21%, but those with fungal infections experienced a 2.6-fold higher mortality that was not attributable to infections alone. Empiric antifungal therapy had no effect on mortality rates. Concurrent nonfungal infections did not increase mortality rates. The incidence of fungal infections increased over time, possibly as a result of advances in antibacterial and chemotherapeutic regimens. Adolescents and patients with leukemia were especially at risk. Fungal infections are a poor prognostic factor, independent of fungal-related mortality. New diagnostic methods allowing for early detection and treatment as well as more effective therapies are needed.

Risk Factors for Invasive Aspergillosis in Neutropenic Patients With Hematologic Malignancies

Muhlemann K, Wenger C, Zenhausern R, Tauber MG

Leukemia . 2005 Feb 24; [Epub ahead of print]

Risk factors for invasive aspergillosis (IA) are incompletely identified and may undergo changes due to differences in medical practice. A cohort of 189 consecutive, adult patients with neutropenia hospitalized in the hemato-oncology ward of the University hospital Berne between 1995 and 1999 were included in a retrospective study to assess risk factors for IA. In total, 45 IA cases (nine proven, three probable, 33 possible), 11 patients with refractory fever and 133 controls were analyzed. IA cases had more often acute leukemia or myelodysplastic syndrome (MDS) (88 vs 38%, P<0.001) and a longer duration of neutropenia (mean 20.6 vs 9.9 days, P<0.001). They also had fewer neutropenic episodes during the preceding 6 months (mean 0.42 vs 1.03, P<0.001), that is, confirmed (82%) and probable (73%) IA occurred most often during the induction cycle. A short time interval (≤14 days) between neutropenic episodes increased the risk of IA four-fold (P=0.06). Bacteremia, however, was not related to the number of preceding neutropenic episodes. Therefore, neutropenic patients with leukemia or MDS have the highest risk of IA. The risk is highest during the first induction cycle of treatment and increases with short-time intervals between treatment cycles.

Candidemia in Patients With Diabetes Mellitus: Epidemiology and Predictors of Mortality

Bader MS, Lai SM, Kumar V, Hinthorn D

Scand J Infect Dis . 2004;36:860-864

Candidemia is the fourth most frequent nosocomial bloodstream infection in the US. The clinical characteristics and outcome of candidemia in adult patients with diabetes mellitus (DM) have not been reported in the literature. The objective of the study was to determine the epidemiology and determinants of mortality in diabetic patients with candidemia. A retrospective cohort study among diabetic patients with candidemia was carried out at 2 medical centers. The primary outcome was death from any cause after the onset of candidemia until discharge from the hospital. A stepwise logistic regression analysis was performed to determine the predictors of mortality. From June 1995 to June 2003, 87 patients with both DM and candidemia were studied. Candida albicans was the most common (48/87, 55%) and Candida glabrata the second most common isolate of candidemia (18/87, 21%). Overall hospital mortality was 39% (34/87). Logistic regression analysis identified 3 independent determinants of death; Apache II score > or =23 (OR 8.3, 95% CI{2.7, 25.4}, p =0.0002), nosocomial candidemia (OR 10.2, 95% CI{1.1, 97.9}, p = 0.04), and mechanical ventilation (OR 3.6, 95% CI{1.1, 11.2}, p = 0.03). The study demonstrates the emergence of non-albicans species of Candida as major causes of candidemia among diabetic patients. The severity of illness reflected by Apache II was the most significant predictor of mortality among diabetic patients with candidemia.

Coccidioidomycosis in Patients With Hematologic Malignancies

Blair JE, Smilack JD, Caples SM

Arch Intern Med . 2005;165:113-117

BACKGROUND: An endemic fungal infection of the desert southwestern United States, coccidioidomycosis is generally a self-limited illness in healthy persons. Immunosuppressed persons who contract coccidioidomycosis, however, are at increased risk for disseminated infection. METHODS: We conducted a retrospective review of patients with coccidioidomycosis and hematologic malignancy or bone marrow disease. RESULTS: Fifty-five patients were identified. The most common underlying malignancies were non-Hodgkin lymphoma and chronic lymphocytic leukemia. Extrathoracic (or disseminated) infection was observed in 12 patients (22%). Fifteen patients (27%) died with active coccidioidomycosis. Treatment of the hematologic disease with corticosteroids or antineoplastic chemotherapy increased the risk of death. CONCLUSION: To date, this is the largest case series of patients with hematologic malignancy and coccidioidomycosis. In persons with hematologic malignancy, coccidioidomycosis can be a severe illness with a high risk for disseminated infection and death.