amphotericin-b--deoxycholate-drug-combination and Coccidioidomycosis

This article summarizes the diagnosis and treatment of coccidioidal meningitis (CM) and its complications. An overview of current and prospective pharmacologic treatment options and monitoring parameters is provided. A consensus has not been reached regarding universally accepted therapeutic serum levels for azoles because of insufficient evidence. We describe the preferred therapeutic drug level ranges that our institution uses to monitor azole therapy.. Ho et al. described the preparation and administration of intrathecally delivered amphotericin B deoxycholate. Thompson et al. described possible benefits of controversial adjuvant corticosteroid therapy for secondary prevention of vasculitic infarction secondary to CM. CM was universally fatal until the advent of intrathecal amphotericin B deoxycholate therapy, the introduction of which changed the natural history of the disease in much the same way as penicillin changed the natural history of bacterial meningitis. Although there was still significant morbidity, survival rates drastically increased to approximately 70%. The introduction of azole therapy has decreased the side effects and burden of treatment but without a significant change in CM-related mortality and morbidity compared with the use of intrathecal amphotericin B deoxycholate therapy.

Topics: Amphotericin B; Antifungal Agents; Coccidioides; Coccidioidomycosis; Cognitive Dysfunction; Deoxycholic Acid; Disease Management; Drug Combinations; Humans; Hydrocephalus; Injections, Spinal; Meningitis; Prospective Studies; Treatment Outcome

Prior to the 1950s no effective therapy for coccidioidomycosis existed. The advent of amphotericin B ushered in the therapeutic era for coccidioidomycosis. Until this time amphotericin B and its lipid congeners have been regarded as the "gold standard" of therapy for severe pulmonary and disseminated coccidioidomycosis. The availability of azoles and later triazoles for the past three decades have relegated the amphotericins into a rescue mode, used mainly in widely disseminated cases, azole intolerance, or when there are contraindications to Azoles, such as pregnancy. In meningitis the intrathecal use of amphotericin B is still used frequently by some clinicians alone or with a triazole. The newer lipid preparations, while more expensive, have significantly reduced toxicity, particularly nephropathy.

Topics: Amphotericin B; Antifungal Agents; Coccidioides; Coccidioidomycosis; Deoxycholic Acid; Drug Combinations; Female; Humans; Kidney Diseases; Lipids; Meningitis; Pregnancy; Treatment Outcome; Triazoles

Coccidioidal meningitis remains difficult to treat. The newer triazole, isavuconazole, has demonstrated efficacy in invasive fungal disease with less side effects than other azoles. We describe a case of refractory pediatric coccidioidal meningitis with disease stabilization and improvement on isavuconazole after failing treatment with other antifungal agents.

Topics: Amphotericin B; Antifungal Agents; Child; Coccidioides; Coccidioidomycosis; Deoxycholic Acid; Drug Combinations; Humans; Meningitis, Fungal; Nitriles; Pyridines; Salvage Therapy; Triazoles; Voriconazole

Intrathecal amphotericin B deoxycholate (AmB-d) can be prescribed as an adjunct to systemic therapy for severe or recalcitrant cases coccidioidal meningitis. Recently intravenous (IV) Liposomal amphotericin B (L-AmB) has been recommended as monotherapy therapy for refractory coccidioidal meningitis based on its advantages over (AmB-d), however, its intrathecal use has not been reported. Moreover, there is nothing in the literature quantifying clinical improvement with objective laboratory data in human patients. Consequently, there are no guidelines on how to monitor regularly for improvement of coccidioidal meningitis with treatment of intrathecal L-AmB. The present case addresses both of these. We report intrathecal use of L-AmB for refractory coccidioidal meningitis. Our data demonstrate that there is a correlation between clinical improvement and a decrease in cerebrospinal fluid (CSF) white blood cells (WBC's), protein, and coccidioidal titers with treatment of intrathecal L-AmB with serial collection of CSF studies at the same site, in our case via collection through an external ventricular drain (EVD). As a result, one may postulate that serial CSF collection can be used to monitor the treatment of coccidioidal meningitis; however this case also addresses the risk of developing ventriculitis with sustained EVD placement.

Topics: Adult; Amphotericin B; Antifungal Agents; Coccidioidomycosis; Deoxycholic Acid; Drug Combinations; Humans; Injections, Spinal; Male; Meningitis

The therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate was evaluated in treatment of murine coccidioidomycosis.. Survival and tissue burdens of the spleens and livers were used as antifungal response markers. In a monotherapy study, caspofungin was injected intraperitoneally at 0.1, 0.2, 0.5, 1 and 5 mg/kg per day on days 2 through 15. Amphotericin B deoxycholate was given at 0.1, 0.2 and 0.5 mg/kg intravenously and 1 and 5 mg/kg intraperitoneally three times per week for 2 weeks. In a combination therapy study, amphotericin B deoxycholate at 0.1 mg/kg was administered intravenously three times per week for 2 weeks, respectively, with and without caspofungin intraperitoneally given at 0.1, 0.5 and 5 mg/kg daily on days 2 through 15 post-infection.. The study shows that caspofungin and amphotericin B deoxycholate at > or =0.5 and > or =0.1 mg/kg, respectively, were significant in both prolongation of survival and reduction of the tissue fungal burdens of mice compared with controls. No sterilization of either organ was observed with caspofungin doses. In combination therapy, any combination of caspofungin (0.1, 0.5 and 5 mg/kg) with amphotericin B deoxycholate (0.1 mg/kg) improved the period of survival and significantly reduced spleen and liver counts compared with controls.. This study indicates that caspofungin has efficacy against systemic coccidioidomycosis in a murine model given in combination with amphotericin B deoxycholate.

Topics: Amphotericin B; Animals; Antifungal Agents; Caspofungin; Coccidioides; Coccidioidomycosis; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echinocandins; Humans; Lipopeptides; Male; Mice; Mice, Inbred ICR; Treatment Outcome

The comparative activities of two preparations of amphotericin B against Coccidioides immitis were investigated. These preparations were a deoxycholate suspension (conventional amphotericin B) and a lipid-based formulation, amphotericin B lipid complex (ABLC). In-vitro susceptibility testing demonstrated that the MICs of ABLC were < or = 0.25 mg/L and of conventional amphotericin B were 0.5 mg/L for C. immitis. However, conventional amphotericin B was at least four-fold more fungicidal, with a minimum fungicidal concentration of 4.0 vs > 16 mg/L for ABLC. The therapeutic efficacies were tested in murine models of acute systemic coccidioidomycosis. Female CD-1 mice were infected iv with C. immitis arthroconidia to establish high (> 50%) or low (< 50%) mortality models. Therapy with conventional amphotericin B or ABLC was given three times per week for two weeks starting three days post-infection. Controls received no therapy or drug-free diluent only. Survival was tallied up to 49 days post-infection and the fungal cfu counts in spleen, liver, and lungs of all survivors were determined. In the low mortality study all treated mice survived and all therapy regimens reduced infection in all organs. All mice given ABLC 6.6 or 13.2 mg/kg/dose and 80% given ABLC 16.5 mg/kg/dose, as well as 90% given conventional amphotericin B 0.66 mg/kg/dose were free of infection; all controls remained infected. In two high mortality studies, all mice given ABLC 0.66-20 mg/kg/dose or conventional amphotericin B 0.22 or 0.66 mg/kg/dose survived compared with 0-20% of controls. Thirty per cent of uninfected mice given ABLC 20 mg/kg/dose and 40% given conventional amphotericin B 2.0 mg/kg/dose died due to drug toxicity. Mice given ABLC or conventional amphotericin B had lower residual cfu counts of C. immitis in all organs than did controls. Sixty to one hundred per cent of mice given ABLC regimens > or = 6.6 mg/kg/dose were cured, whereas all controls and 50-60% of mice receiving the highest non-toxic conventional amphotericin B regimen (0.66 mg/kg/dose) remained infected. At equal non-toxic amphotericin B doses, conventional amphotericin B was more effective than ABLC in reducing cfu in infected organs.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Amphotericin B; Animals; Antifungal Agents; Coccidioidomycosis; Deoxycholic Acid; Drug Combinations; Female; Mice; Microbial Sensitivity Tests