Failure Of Amphotericin Research Articles

P173 PK PD rationale and efficacy of isavuconazole treatment after failure of amphotericin B and posaconazole for COVID-19 associated cranial Mucormycosis

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM ObjectiveThis case series describes our experience of using isavuconazole (ISVCZ), along with TDM, after the failure of treatment with Amphotericin B (AmB) and Posaconazole (PCZ) due to the better PK PD properties of ISVCZ.Patients and methodsThere were 6 patients with ROCM who had disease progression despite surgical debridement and adequate treatment with AmB and PCZ. Anti-fungal treatment was switched to ISVCZ which achieves levels in brain (1.86x)R and in bone-marrow (3x)R as compared to serum levelsR.ResultsPK PD considerations for ISVCZ treatment considering the likely levels in brain and bone-marrow and the MIC of majority of Mucoralean molds as ≤4RTable 1Table 2Results of treatmentConclusionTreatment with ISVCZ may mitigate some of the challenges in ROCM due to its PK PD properties. TDM for ISVCZ is not routinely recommended, but could be used to ensure high plasma exposures and enhanced penetration to the site of infection. Our results are encouraging although there are several limitations of a case series, confounding variables involved, and the use of ISVCZ as salvage after failure of previous treatment.Clinical success in this series suggests that extrapolative PK PD considerations in using ISVCZ for such ‘difficult to treat’ patients may be justified.

Use of voriconazole to successfully treat disseminated Trichosporon asahii infection in a patient with acute myeloid leukaemia.

Trichosporon spp. is an emerging fungal pathogen in immunocompromised hosts, and disseminated infection is often fatal in neutropenic patients. Reported here is a case of disseminated infection in a neutropenic patient with acute leukaemia. After failure of amphotericin B and fluconazole therapy, the course of infection dramatically improved with voriconazole treatment. A literature search revealed 69 additional cases of disseminated Trichosporon spp. infections in neutropenic patients, and these are also reviewed. Clinical symptoms that suggest infection include fever, disseminated papulopustular cutaneous lesions and pulmonary involvement. Despite treatment with antifungal agents (amphotericin B, fluconazole), 78% of patients died. Voriconazole may represent a promising therapy for this life-threatening infection.

Candida lusitaniae: a cause of breakthrough fungemia in cancer patients.

Candida lusitaniae is an infrequent cause of fungemia. We identified 12 cases of C. lusitaniae fungemia that occurred at the University of Texas M. D. Anderson Cancer Center from 1988 to 1999. The mean age of patients was 48 years (range 20--70 years). Eight patients had hematologic malignancy or had received a bone marrow transplant, and 4 had a solid tumor. Most patients (75%) were neutropenic (<10(3)/mm(3)). Treatment with amphotericin B alone failed for 3 of 6 patients, irrespective of neutropenic status. Fluconazole was effective as a single agent in 3 patients with solid tumors. The combination of amphotericin B plus fluconazole was effective treatment for two-thirds of patients with hematologic malignancy, despite persistence of neutropenia. The mortality rate associated with C. lusitaniae infection was 25%. C. lusitaniae presents as breakthrough fungemia in immunocompromised patients and is associated with failure of amphotericin B therapy. Fluconazole may be a useful agent in the treatment of this infection.

Itraconazole as Salvage Therapy in Invasive Pulmonary Aspergillosis Occurring during Amphotericin B Therapy in Neutropenic Patients

Amphotericin B is commonly used as prophylactic therapy in addition to broad-spectrum antibiotics in febrile neutropenic patients with leukaemia. Despite amphotericin B therapy, invasive pulmonary aspergillosis commonly occurs in such patients. This abstract reports 15 cases of invasive pulmonary aspergillosis occurring in neutropenic patients previously treated with intravenous amphotericin B, 0.89 mg/kg/day (range, 0.5-1.5 mg/kg/day) for a mean of 16.1 days (range, 5-70 days). The results are summarized in table 1. Seven patients achieved a complete haematological response with chemotherapy, and 8 patients did not achieve a complete haematological response and were considered to have progressive haematological disease. Deaths from invasive pulmonary aspergillosis occurred in 2/7 patients with a complete haematological response and in 3/8 patients with progressive haematological disease. Of 13 patients treated with itraconazole, 300-600 mg/day for a mean duration of 138 days (range, 74-225 days), 10 (77%) were improved. Among these 13 patients, the mean duration of neutropenia had a prognostic value for the outcome of itraconazole treatment failure (* p = 0.05, Mann-Whitney non-parametric test; see table 1). Itraconazole thus seems to be an effective treatment for invasive pulmonary aspergillosis in neutropenic patients, even after failure of amphotericin B.

The epidemiology and control of primary amoebic meningoencephalitis with particular reference to South Australia

This paper reviews the history, epidemiology and control of primary amoebic meningoencephalitis (PAM), caused by Naegleria fowleri, with particular reference to South Australia. The intention has been to outline misconceptions and uncertainties pervading the earlier literature. Although PAM infections elsewhere have been attributed to cysts in air-borne dust, we believe that contact with water in the domestic environment was not adequately considered as a potential source of these infections. Several reports have cast doubt on the effectiveness of chlorine in controlling N. fowleri, although there is laboratory and South Australian field experience to the contrary. These reports can be traced to a misunderstanding of the circumstances surrounding cases of PAM reported by other workers. Provided that a continuous free chlorine residual of 0·5 mg/l can be maintained in water accessible to N. fowleri, the risk of disease should be negligible. The failure of amphotericin B therapy to save recent victims of the disease, despite relatively prompt intervention, is disappointing. Possible reasons for this, and the reports that rifampin or tetracycline combined with amphotericin might be more successful, are discussed.

Therapy of deep-seated fungal infections with 5-fluorocytosine.

Summary: Administration of 5-fluorocytosine in fourteen cases of invasive or systemic fungal infection was accompanied in ten by elimination of the infection. Results which particularly indicated the usefulness of the drug consisted of instances where fungal infections were eliminated following the failure of amphotericin B treatment, and in some patients whose antimicrobial defences had been compromised by immunosuppressive therapy. Success was frequently obtained in infections with Candida and Aspergillus species, as well as in penetrating ocular infections where laboratory identification of the fungus had not been made. The outcome in two cases of Cryptococcus neoformans meningitis was unsatisfactory, and this was shown in one to be due to the emergence of a resistant strain. Toxicity of a minor and reversible nature was encountered in four patients, and consisted of diarrhoea, anaemia or hepatocellular damage.