Outcomes by MIC Values for Patients Treated with Isavuconazole or Voriconazole for Invasive Aspergillosis in the Phase 3 SECURE and VITAL Trials.

This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of Aspergillus pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with drug MICs of ≥16 µg/ml, but there was no relationship with clinical outcomes in cases where the MIC was <16 µg/ml for either drug.

Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus.

BACKGROUND/AIMS: Invasive fungal infections of the head and neck are rare life-threatening infections where prompt diagnosis and intervention is critical for survival. The aim of this study is to determine the clinical characteristics and outcomes of invasive fungal disease of the sinus and orbit, and to compare mucormycosis and Aspergillus infection. METHODS: A retrospective review was conducted from a single tertiary care eye and ear hospital over 20 years (1994-2014). Twenty-four patients with a confirmed pathological diagnosis of invasive fungal disease of the sinus and/or orbit were identified and their medical records were reviewed. The main outcome measures were type of fungus, location of disease, mortality and visual outcome. RESULTS: Patients with orbital involvement had a higher mortality and higher likelihood of mucormycosis infection compared with those with sinus-only disease (78.6% vs 20%, p=0.01; 86% vs 30%, p=0.01, respectively). Patients with mucormycosis had a higher mortality (71%) than patients with Aspergillus (29%); however, this was not statistically significant (p=0.16). All patients with orbital involvement and/or mucormycosis infections were immunosuppressed or had inadequately controlled diabetes, and had a cranial neuropathy or ocular motility dysfunction. All five post-transplant patients with orbital infections died, while the two transplant patients with sinus infections survived. CONCLUSIONS: Patients with orbital fungal infections are more likely to be infected with mucormycosis compared with Aspergillus and have a higher mortality compared with infections sparing the orbit. History of transplant portends a dismal prognosis in orbital infections. Invasive fungal disease should be considered in any immunocompromised patient presenting with a new cranial neuropathy or ocular motility abnormality.

[Azole resistance with environmental origin: What alternatives for the future?]. / Résistance aux antifongiques azolés d'origine environnementale : quelles alternatives pour l'avenir ?

Azole resistant Aspergillus fumigatus strains are increasingly reported in many countries. One resistance mechanism is attributed to the use of azole fungicides in environment. Two mutations, TR34/L98H and TR46/Y121F/T289A, on the cyp51A gene, have been described. Results of 40 publications about azole resistant strain detections, with TR34/L98H and TR46/Y121F/T289A mutations, in clinical and/or environmental samples, are presented in this review. These cases, observed in many countries, suggest spreading phenomenon. Measures to moderate fungicides treatments and/or alternative treatments in environment should be established to preserve the effectiveness of azole antifungal therapy for at-risk patients.

MIC values of voriconazole are predictive of treatment results in murine infections by Aspergillus terreus species complex.

We evaluated the efficacy of voriconazole against nine strains of Aspergillus terreus with different MICs (0.12 to 4 µg/ml) by using a murine model. Markers of efficacy included survival, tissue burden, galactomannan antigenemia, and drug serum levels. Voriconazole was especially effective in prolonging survival and reducing the fungal load in infections by strains that showed MICs that were less than or equal to the epidemiological cutoff value (1 µg/ml). In vitro data might be useful for predicting the outcome of A. terreus infections.

Efficacy of anidulafungin against Aspergillus niger in vitro and in vivo.

In this study, anidulafungin (AFG) showed high in vitro activity against 10 isolates of Aspergillus niger by broth microdilution and disk diffusion methods. The efficacy of AFG at 1, 5 and 10 mg/kg was tested against six of the isolates in a murine model of disseminated infection. AFG was able to reduce mortality, showing survival rates of 70-100%, 60-100% and 30-60% in mice treated with AFG at 10, 5 and 1 mg/kg, respectively. AFG also showed a dose-response efficacy in reducing tissue burden in kidneys and spleen. A parallel experiment demonstrated that administration of AFG did not reduce serum concentrations of galactomannan in mice. Histopathological studies confirmed the efficacy of AFG.

Hyperbaric oxygen in the treatment of invasive fungal infections: a single-center experience.

BACKGROUND: Invasive fungal infections by Mucorales or Aspergillus spp. are lethal infections in immune compromised patients. For these infections a multimodal approach is required. One potential tool for treating these infections is hyperbaric oxygen. OBJECTIVES: To evaluate the clinical course and utility of hyperbaric oxygen in patients with invasive fungal infections by Mucorales or Aspergillus spp. METHODS: We conducted a retrospective chart review of 14 patients treated with HBO as part of their multimodal therapy over a 12 year period. RESULTS: Most patients had significant immune suppression due to either drug treatment or their underlying disorder. Thirteen of the 14 underwent surgery as part of the treatment and all were receiving antifungal therapy while treated with the hyperbaric oxygen. The number of HBO sessions ranged between 1 and 44. Seven of the patients survived the infection. No patient developed complications due to HBO therapy. CONCLUSIONS: HBO is a potentially significant adjunct in the treatment of invasive fungal infections. Evidence on its usefulness as a standard of care in these infections is still lacking. Since it will be difficult to generate conclusive data regarding the importance of HBO in these infections, the value of HBO in these patients should be considered on an individual basis.

Efficacy of ambruticin analogs in a murine model of invasive pulmonary aspergillosis.

Ambruticins are a family of polyketides. The antifungal activity of an ambruticin, KOSN-2079, was tested in the mouse model of invasive aspergillosis. KOSN-2079 significantly reduced pulmonary fungal burdens and improved survival over that with the vehicle control. These results support the continued development of ambruticins as antifungal agents.

Caspofungin: antifungal activity in vitro, pharmacokinetics, and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis.

OBJECTIVES: Evaluation of the potential of caspofungin, in relation to pharmacokinetics, in order to optimize its use in the treatment of filamentous fungal infections. METHODS: The in vitro antifungal activity, pharmacokinetics and therapeutic efficacy of caspofungin versus amphotericin B was investigated in vitro as well as in a model of aerogenic Aspergillus fumigatus infection in neutropenic rats, using rat survival and decrease in fungal burden as parameters for therapeutic efficacy. RESULTS: In contrast to amphotericin B, caspofungin shows a concentration-dependent gradual decrease in fungal growth in vitro, which makes it difficult to perform visual readings of antifungal activity (CLSI guidelines). The quantitative XTT [2,3-bis(2-methoxy-4-nitro-5-[(sulphenylamino) carbonyl]-2H-tetrazolium-hydroxide] assay measuring a decrease in fungal metabolic activity seems more appropriate for caspofungin susceptibility testing. Using this assay, in vitro caspofungin was 4-fold less active than amphotericin B. In the infection model, therapy was started 16 h after fungal inoculation, and continued once daily for 10 days. Caspofungin was administered intraperitoneally at 1, 2, 3 or 4 mg/kg/day (CAS 1, 2, 3 or 4), amphotericin B at 1 mg/kg/day (AMB 1). Treatment with CAS 1 or AMB 1 provided modest prolongation of animal survival. The combination of caspofungin and amphotericin B did not show additive effects. Increasing the dosage of caspofungin to 2, 3 or 4 mg/kg/day resulted in a dose-dependent significant increase in efficacy. There was 100% survival among rats in the CAS 4 group, which was correlated with a significant decrease in fungal burden, based on the concentration of A. fumigatus galactomannan in serum and lung tissue and quantification of A. fumigatus DNA in lung tissue. Pharmacokinetic analysis suggested that the CAS 4 dose in rats produced drug exposure comparable to the human situation, visualized by similar 24 h AUC and trough concentrations. CONCLUSIONS: The therapeutic efficacy of caspofungin is superior to amphotericin B, which seemed to be discrepant with their in vitro antifungal activity.

Pharmacodynamic activity of amphotericin B deoxycholate is associated with peak plasma concentrations in a neutropenic murine model of invasive pulmonary aspergillosis.

We conducted a dose fractionation study of neutropenic, corticosteroid-immunosuppressed mice to characterize the pharmacodynamic/pharmacokinetic (PK/PD) parameter most closely associated with amphotericin B (AMB) efficacy in the treatment of invasive pulmonary aspergillosis. Pharmacokinetic parameter estimates were determined by a nonparametric population pharmacokinetic analysis of plasma drug concentrations following single intraperitoneal doses (0.25, 1.0, and 3.0 mg/kg of body weight) of amphotericin B deoxycholate. Three dosage groups (0.5, 0.75, and 1.0 mg/kg) fractionated into three dosing intervals (every 8 h [q8h], q24h, or q72h) were tested to discriminate between the PK/PD parameters (the ratio of maximum concentration of drug in serum [Cmax]/MIC, the ratio of area under the concentration-time curve/MIC, and percentage of time above MIC) most closely associated with AMB efficacy over a range of clinically achievable exposures in humans. The efficacy of each regimen was determined by quantitative PCR and survival. Reductions in pulmonary fungal burden and improvements in survival were maximized at the highest peak plasma concentrations in each of the dosage groups. Reductions in pulmonary fungal burden and increased survival were most closely associated with Cmax/MIC, with maximal activity occurring as the Cmax/MIC approached 2.4. In our model, Cmax/MIC is the PK/PD parameter most closely associated with efficacy in the treatment of invasive pulmonary aspergillosis. These data predict that less frequently administered, higher dosages of AMB would optimize efficacy.

Treatment failure in invasive aspergillosis: susceptibility of deep tissue isolates following treatment with amphotericin B.

OBJECTIVES: To determine whether treatment failure in invasive aspergillosis (IA) is the result of resistance of Aspergillus spp. isolates to amphotericin B. METHODS: Six Aspergillus fumigatus and six Aspergillus flavus isolates cultured from deep tissue biopsies in 11 patients with haematological malignancies during 1991-1998 were tested. A method based on the NCCLS M38-A broth microdilution method, with colorimetric determination of MICs, was used to determine the MICs of amphotericin B and itraconazole. RESULTS: All A. fumigatus isolates were susceptible to amphotericin B (MIC 0.25-0.5 mg/L), as were three A. flavus isolates (MIC 1 mg/L), but three were less susceptible (MIC 2 mg/L). All isolates were susceptible to itraconazole (MIC 0.125-0.25 mg/L). All patients had been treated with amphotericin B, having received a median of 12 days of treatment when the tissue was obtained. CONCLUSION: The difficulty in treating IA may not be because of the susceptibility of the isolates, but because of poor penetration of antifungal agents into infected tissue. Aspergillus spp. invade blood vessels causing thrombosis and tissue infarction, and therefore it may be difficult for antifungal drugs to exceed MICs in infected tissues. This highlights the need for different treatment strategies, such as surgery and the administration of cytokines.

Invasive aspergillosis treated with adjunctive hyperbaric oxygenation: a retrospective clinical series at a single institution.

BACKGROUND: Invasive aspergillosis is the leading cause of early death in many transplant centers and has a major impact on the management of hematologic malignancies. The mortality rate with current therapy (amphotericin B and surgery) has remained unacceptably high. In vitro data along with a few case reports have suggested a potential benefit of hyperbaric oxygen (HBO). METHODS: We retrospectively studied all patients referred to our service when histologic specimens suggested invasive aspergillosis. Our main assessment of outcome was survival 3 months after initiation of HBO. RESULTS: Ten patients were included. All received adjunctive HBO along with the standard of care. Rhinosinusinal infection was the primary presentation. The most common underlying conditions were hematologic malignancies. Six patients were free of signs of infection 3 months after the first HBO treatment. CONCLUSIONS: Adjunctive HBO appears to be a valuable tool in this devastating condition. Further studies are warranted to clarify its role.

Fluconazole to prevent yeast infections in bone marrow transplantation patients: a randomized trial of high versus reduced dose, and determination of the value of maintenance therapy.

PURPOSE: To determine the optimal dose and duration of fluconazole antifungal prophylaxis therapy in bone marrow transplantation patients. SUBJECTS AND METHODS: Two hundred and fifty-three pediatric and adult bone marrow transplantation patients were randomly assigned to receive fluconazole 400 mg daily (high dose) or 200 mg daily (low dose) while they were neutropenic. After neutrophil recovery, patients were randomly assigned to receive maintenance therapy with either fluconazole (100 mg daily) or clotrimazole troches (10 mg 4 times daily) until 100 days after transplantation. Patients were monitored until 2 weeks after completion of early prophylaxis and to 100 days after transplantation. RESULTS: During the early prophylaxis phase, rates of yeast colonization and infections were similar in both treatment groups. By day 50, the incidence of Candida infections in the high-dose group was 4% (95% confidence interval [CI]: 1% to 7%; n = 5), compared with 1% in the low-dose fluconazole group (95% CI: 0% to 3%; n = 1; P = 0.08). During the same period, the incidence of Aspergillus infections was 4% (95% CI: 1% to 7%; n = 5) in the high-dose group and 2% (95% CI: 0% to 4%; n = 2; P = 0.33) in the low-dose group. During the maintenance prophylaxis phase, rates of yeast colonization and superficial infections were similar in the fluconazole and clotrimazole groups. Four patients developed systemic fungal infection in the maintenance phase (1 who received clotrimazole and 3 who received fluconazole). CONCLUSION: High-dose (400 mg daily) and low-dose (200 mg daily) fluconazole have similar efficacy in reducing the incidence of yeast colonization, superficial infection, and systemic infection in neutropenic pediatric and adult patients undergoing bone marrow transplantation. Rates of yeast colonization after neutrophil recovery were similar in patients treated with fluconazole or clotrimazole.

Efficacy of ravuconazole (BMS-207147) in a guinea pig model of disseminated aspergillosis.

Ravuconazole (BMS-207147, ER-30346), an oral triazole, was evaluated in an immunosuppressed temporarily neutropenic guinea pig model of invasive aspergillosis. In this model, guinea pigs were immunosuppressed with triamcinolone 20 mg/kg sc od beginning 4 days before challenge and made neutropenic with cyclophosphamide 300 mg/kg ip 1 day before challenge. Treatments of ravuconazole 5, 10 and 25 mg/kg po od were compared with itraconazole 2.5 and 5.0 mg/kg po bd and amphotericin B 1.25 mg/kg ip od. Treatment began 24 h after lethal intravenous challenge with Aspergillus fumigatus and continued for 5 days. Mortality occurred in eight of eight untreated control animals versus none of eight treated with ravuconazole 5 or 10 mg/kg/day or itraconazole 10 mg/kg/day. Mortality occurred in one of eight animals treated with ravuconazole 25 mg/kg/day, one of eight with amphotericin B and two of eight treated with itraconazole 5 mg/kg/day. Compared with controls, each of the antifungals examined significantly reduced the tissue burden in liver and brain, although only the highest doses of the azole drugs and amphotericin B significantly reduced tissue burden in the kidney. All three doses of ravuconazole improved survival and also reduced the tissue burden of ASPERGILLUS: In this model of invasive aspergillosis, ravuconazole showed significant activity and may be a useful compound in human disease.

FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. II. In vitro and in vivo activities.

FR901469 is a water-soluble macrocyclic lipopeptidolactone (C71H116N14O23) that has inhibitory activity against 1,3-beta-glucan synthase and exhibits in vitro and in vivo antifungal activity against both Candida albicans and Aspergillus fumigatus. The MICs of FR901469 against Candida albicans FP633 and Aspergillus fumigatus FP1305 in a micro-broth dilution test were 0.63 and 0.16 microg/ml, respectively. FR901469 showed excellent efficacy by subcutaneous injection against both Candida albicans and Aspergillus fumigatus in a murine systemic infection mode, with ED50s of 0.32 and 0.2 mg/kg, respectively. This compound also showed potent anti-Pneumocystis activity in the nude mice model with experimental Pneumocystis pneumonia. The hemolytic activity of FR901469 towards mouse red blood cells, is about 30-fold weaker than that of amphotericin B.

Interactive mortality factors in common loons from Maritime Canada.

Between August 1992 and November 1995, 31 moribund or dead common loons (Gavia immer) found in the three Maritime provinces of Canada (New Brunswick, Nova Scotia, Prince Edward Island) were necropsied. Eight of these birds were in good body condition and died acutely from drowning or trauma. The remaining 23 birds were in poor body condition and had either chronic lead poisoning, respiratory mycosis, or oil contamination of their plumage. Loons in poor body condition had significantly higher numbers of intestinal trematodes and significantly higher levels of total renal mercury than loons in good body condition. Therefore, poor body condition in many loons was associated with two or more concurrent potential disease processes, although we could not establish a cause-effect relationship among these processes in individual birds. These results suggest that mortality in chronically ill wild animals can result from synergism among several potentially debilitating agents present in their environment.

Evaluation of SCH51048 in an experimental model of pulmonary aspergillosis.

The efficacy of a novel triazole, SCH51048, was assessed with a murine model of pulmonary aspergillosis and was compared with those of SCH39304 and itraconazole. A wide range of doses of SCH51048 (5 to 50 mg/kg of body weight) was evaluated. Mortality was significantly delayed in mice treated with doses of 5 mg of SCH51048 per kg or greater in comparison with mortality in controls (P < 0.05). Both SCH51048 and SCH39304 at higher doses (30 and 50 mg/kg) reduced the number of viable Aspergillus fumigatus organisms in lung tissue (P < 0.05). In the present model, itraconazole neither delayed mortality nor significantly reduced the counts in tissue at the doses used. We conclude that SCH51048 is an effective therapy for murine pulmonary aspergillosis.

Virulence studies of Aspergillus nidulans mutants requiring lysine or p-aminobenzoic acid in invasive pulmonary aspergillosis.

To identify steps in fungal intermediary metabolism required by Aspergillus spp. during invasive pulmonary aspergillosis, we have developed murine models involving Aspergillus nidulans as the inoculum. The advantages of using A. nidulans over Aspergillus fumigatus or Aspergillus flavus, which are the most common agents of clinical disease, are the well-understood genetics of A. nidulans and a large range of mutants of this species which are affected in a variety of metabolic pathways. Comparison of the virulence of A. nidulans strains carrying mutations which block the biosynthesis of lysine (lysA2) and p-aminobenzoic acid (pabaA1) shows that lysA2 strains have reduced virulence while pabaA1 strains are entirely nonpathogenic. The pathogenicity of pabaA1 strains can be restored by supplementing the drinking water of animals with p-aminobenzoic acid. The results indicate that the availability of lysine in the lung is limited, and p-aminobenzoic acid is probably not available at all. Thus, models of invasive pulmonary aspergillosis involving A. nidulans can be used to identify metabolic pathways that may be essential for the pathogenicity of A. fumigatus, the predominant pathogenic species, suggesting potential new targets for antifungal therapy.

Saperconazole therapy in a rabbit model of invasive aspergillosis.

The efficacy of orally and intravenously administered saperconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis and compared with that of amphotericin B. Oral saperconazole at dosages of 5, 10, and 15 mg/kg of body weight per day improved survival compared with that of controls. In addition, saperconazole at 10 and 15 mg/kg/day reduced the tissue burden and reduced levels of circulating antigen, which correlated with increasing dosages of saperconazole. Intravenous saperconazole produced levels in serum more than 10-fold that of oral therapy. Intravenous saperconazole not only improved survival and reduced antigen levels but also significantly eradicated A. fumigatus from tissues compared with those of controls and was as effective as amphotericin B in these studies. Saperconazole was effective in the treatment of experimental invasive aspergillosis and demonstrates the potential of the newer azoles in therapy for invasive aspergillosis.