Efficacy and safety of nebulised amphotericin B (NAB) in severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA)

Background and rationale: Antifungal therapy for severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) remains poorly studied. We assessed the efficacy and safety of NAB as second and third line therapy in SAFS and ABPA. Methods: 21 adult asthmatics with SAFS (n?=?11) and ABPA (n?=?10) who had either failed itraconazole (n?=?8), voriconazole proceeded by itraconazole (n?=?5) or developed adverse events (AEs) to either agent (n?=?7) were treated with 10mg of NAB (Fungizone) twice daily. We audited clinical and immunological response, using the Asthma Quality of Life Questionnaire (AQLQ-J) scores, asthma control, FEV1, healthcare utilisation and IgE. Patients were followed up for 12 months. Results: Twenty-one patients were treated (SAFS, n?=?11) and (ABPA, n?=?10), M: F?=?8:12, median age 65 years (range, 24–78). The median duration of therapy was 30 days (0–1825). Clinical benefit was observed in three (14.3 %) in which overall mean AQLQ-J score improved by?+?2.9, mean FEV1 improved by 0.5 L and there was improvement in overall asthma control. Seven (33%) failed initial dose (bronchospasm). Eleven (52.4%) discontinued within 12 months of therapy due to delayed bronchospasm (n?=?3, within 4 weeks), equipment problems (n?=?2, within 4 weeks) and lack of clinical benefit (n?=?4, within 16 weeks). Conclusion: Our data suggest that the overall efficacy of NAB in this group of patients is poor and associated with bronchospasm. However, the excellent response in 3 patients, suggest it may be considered when other alternatives have been exhausted. Overcoming the initial bronchospasm may improve tolerability.     

Efficacy of liposomal amphotericin B (AmBisome) in the treatment of persistent post-kala-azar dermal leishmaniasis (PKDL)

A dermatosis commonly known as post-kala-azar dermal leishmaniasis (PKDL) may develop following the treatment of human visceral leishmaniasis (VL). In about 15% of PKDL cases the disfiguring lesions persist, sometimes for many years. Such persistent lesions currently require daily injections of sodium stibogluconate (SSG) for 2-4 months and even then treatment may not be successful. Alternative, quicker and cheaper treatment options that cause less toxicity are being explored. Immuno-chemotherapeutic regimens (based on leishmaniasis candidate vaccines/BCG with SSG) are still experimental but treatment with liposomal amphotericin B (AmBisome) has already been found effective, albeit in a small number of patients. AmBisome is considered less nephrotoxic than non-liposomal amphotericin B because it specifically targets the macrophages in which the Leishmania parasites develop. The aim of the present study was to evaluate further the usefulness of AmBisome in the treatment of persistent PKDL, in Sudan. The 12 subjects, all of whom gave their informed consent, had each had PKDL lesions for >6 months and shown no improvement after repeated injections of SSG. During the study period, they were hospitalized and regularly screened, haematologically and biochemically, for adverse effects. The AmBisome, given intravenously at 2.5 mg/kg.day for 20 days, completely cleared the skin rash of 10 (83%) of the patients and caused no detectable adverse effects. In the 10 patients who responded well to the treatment, the papular lesions regressed and became flat while the hypopigmented lesions darkened (continuing to do so even after the last AmBisome injections). Treatment outcome appeared to be unaffected by the age or gender of the patient (P = 0.7 for each) but the time taken for the PKDL lesions to heal was correlated with the age of the lesions (P = 0.009). The macular lesions healed more slowly than the papular (P = 0.02). In conclusion, Ambisome appears suitable for the treatment of persistent PKDL lesions in Sudan. Once certain favourable clinical signs (the regression and/or darkening of the PKDL lesions) have been noted, the lesions will probably continue to clear without the need for more injections.     

Successful treatment of disseminated candidiasis resistant to amphotericin B by liposomal amphotericin B: a case report

The case of a female patient with acute lymphoblastic leukaemia and chronic disseminated candidiasis, who was refractory to 1.8 g conventional amphotericin B therapy, is reported. She experienced severe amphotericin-B-related side-effects in spite of pretreatment, but was subsequently successfully treated with 3 g of a small unilamellar liposome formulation of amphotericin B prepared from soya phosphatidylcholine and cholesterol in a 73 molar ratio at our institute. The patient experienced minimal side-effects with this preparation, although no pretreatment was given. Liposomal amphotericin B prepared in our institute appears to be a safe and effective therapy for systemic fungal infections. However, large controlled studies are required to determine more precisely the potential of liposomal amphotericin B in the treatment of severe systemic fungal infection.     

Successful treatment of hepatosplenic candidiasis with a liposomal amphotericin B preparation.

The case of a granulocytopenic patient with acute undifferentiated leukaemia and hepatosplenic candidiasis who was refractory to conventional deoxycholate amphotericin B (AmpB) and 5-flucytosine therapy is reported. He experienced severe AmpB-related side-effects, and was subsequently successfully treated with a pharmaceutical preparation of AmpB (5.7 g) entrapped in sonicated liposomes, composed of lecithin, cholesterol and stearylamine in a molar ratio of 4:3:1. Three months later, during maintenance chemotherapy, liposomal AmpB (5.1 g) was reinstituted due to the finding of biopsies positive for Candida albicans at bronchoscopy. After healing of the patient's fungal infection a left upper lobe resection was performed, which showed advanced fibrosis with signs of inflammation, but no evidence of fungal disease. Since no acute side-effects and only moderate hypokalaemia were observed, it appears that liposomal AmpB is superior to conventional AmpB treatment in granulocytopenic patients with hepatosplenic candidiasis and unbearable therapy-related side-effects.     

Successful treatment of candidal osteomyelitis with fluconazole following failure with liposomal amphotericin B

A case of multiple relapses of Candida albicans infection of deep tissues is described. Treatment was complicated by renal impairment, but therapy with a liposomal amphotericin product failed to eradicate the third recurrence which subsequently resolved after protracted exposure to oral fluconazole.     

Efficacy of liposomal amphotericin B (AmBisome) in the eradication of Fusarium infection in a leukaemic patient.

We recently succeeded in eradicating a Fusarium infection by treatment with liposomal amphotericin B (L-AmB). The patient, a 22-year-old man with acute lymphoblastic leukaemia (ALL), developed fever and diffuse cutaneous maculopapular necrotising nodules during post-chemotherapy neutropenia. Fusarium verticilloides was isolated from the skin, and hyphae were observed on direct microscopy. Despite increased WBC and amphotericin B (AmB) treatment (0.7 mg/kg/day for 11 days), he remained febrile and a chest X-ray revealed pulmonary lesions. Fusarium infection was confirmed by bronchial aspirate. AmB was increased to 1 mg/kg/day, and continued for 16 days (total dose 1630 mg). A slight improvement was observed at tomography, but nephrotoxicity developed. Treatment was changed to L-AmB (3 mg/kg/day). The patient received this drug for 20 days (total dose of 3850 mg) with complete regression of the pulmonary lesions. No adverse event occurred, and nephrotoxicity resolved. The patient was discharged from hospital cured of the Fusarium infection and in clinical and haematological remission. No relapse of fusariosis occurred, despite additional courses of intensive chemotherapy. Ambisome could represent an important advance in antifungal treatment since it allows aggressive treatment and eradication of mycoses refractory to conventional therapy while avoiding renal toxicity.     

Treatment of systemic fungal infections with liposomal amphotericin B

Forty-six patients with systemic fungal infections were treated with liposomal amphotericin B. Twenty-one patients had disseminated candidiasis, 19 had aspergillosis, and the rest had a variety of other fungal infections. Forty patients failed to respond to conventional amphotericin B therapy, and 6 patients were given liposomal amphotericin B because conventional amphotericin B caused severe side effects. Twenty-four patients had a complete response, and 22 patients failed to respond. No short- or long-term toxic reactions were observed. The acute side effects such as fever, chills, and potassium loss were infrequent and milder than those commonly observed with conventional amphotericin B. No chronic renal, hematologic, or central nervous system side effects were observed. Liposomal amphotericin B therapy was effective and less toxic than conventional amphotericin B therapy.     

Visceral leishmaniasis in renal transplant recipients: successful treatment with liposomal amphotericin B (AmBisome).

Visceral leishmaniasis (VL) is a rare disease in renal transplant recipients. Liposomal amphotericin B (AmBisome) is known to be effective against VL. However, previously there has been no experience with administration of such treatment to renal transplant recipients. We report herein four patients with VL complicating renal transplantation who were treated successfully with liposomal amphotericin B (total dose, 23-40 mg/kg). Neither adverse reactions nor clinical relapses of VL were observed.