One hundred ninety-four patients with cryptococcal meningitis were enrolled in a multicenter, prospective, randomized clinical trial to compare the efficacy and toxicity of four as compared with six weeks of combination amphotericin B and flucytosine therapy. Among 91 patients who met preestablished criteria for randomization, cure or improvement was noted in 75 percent of those treated for four weeks and in 85 percent of those treated for six weeks. The estimated relapse rate for the four-week regimen was higher--27 as compared with 16 percent--whereas the incidence of toxic effects for the two regimens was similar--44 as compared with 43 percent. Among 23 transplant recipients, 4 of 5 treated for four weeks relapsed, leading to the decision to treat the rest of the group for six weeks. Only 3 of the 18 treated for six weeks relapsed. In a third group of 80 patients, the protocol was not followed during the initial four weeks, and these patients were not randomized. Thirty-eight died or relapsed. Multifactorial analysis of pretreatment factors for all 194 patients identified three significant predictors (P less than 0.05) of a favorable response: headache as a symptom, normal mental status, and a cerebrospinal fluid white-cell count above 20 per cubic millimeter. These and other findings in this study are consistent with the view that the four-week regimen should be reserved for patients who have meningitis without neurologic complications, underlying disease, or immunosuppressive therapy; a pretreatment cerebrospinal fluid white-cell count above 20 per cubic millimeter and a serum cryptococcal antigen titer below 1:32; and at four weeks of therapy, a negative cerebrospinal fluid India ink preparation and serum and cerebrospinal fluid cryptococcal-antigen titers below 1:8. Patients who do not meet these criteria should receive at least six weeks of therapy.
Fungal peritonitis is a rare complication in patients on continuous ambulatory peritoneal dialysis. We report five recent cases and their management. The fungi isolated were Candida albicans, C. parapsilosis, Exophiala jeanselmei, Drechslera spicifera, and a Fusarium species. Chemotherapy was attempted with various regimens including oral ketoconazole, intravenous or intraperitoneal amphotericin B, and oral flucytosine. Pharmacokinetic studies were done in two patients receiving treatment with one of these drugs. Three patients were cured of their fungal infection. Three patients whose Tenckhoff catheters were left in situ died, whereas two patients whose catheters were removed survived. Our experience suggests that removal of the peritoneal catheter should be considered once the diagnosis of fungal peritonitis is established.
Liposomes were prepared to incorporate large amounts of amphotericin B. BALB/c mice were challenged with Cryptococcus neoformans and given liposome-associated amphotericin B (AMBL) or amphotericin B-deoxycholate (AMBD) intravenously. Mice that were treated with AMBL survived longer and had lower tissue counts of cryptococci than mice treated with AMBD or untreated control mice. The reduced acute toxicity of AMBL permitted much larger doses of amphotericin B to be given than were possible with AMBD. AMBL is a novel vehicle of administration that reduces toxicity and concentrates the drug in the appropriate target organs.
The development of the polyene antibiotic, amphotericin B, provided for the first time a drug which was clinically effective in many serious mycotic diseases. Unfortunately, it requires parenteral administration and is often toxic, factors which limit the total cumulative dose which can be given. Efforts to utilise combinations of amphotericin B with other agents were best realised with amphotericin B/flucytosine in cryptococcal meningitis, and to a lesser degree in systemic candidiasis. More recently, the introduction of new imidazoles has extended the range of applications of these drugs to fungal diseases. Two members of this group, miconazole and ketoconazole, are promising agents. Miconazole is a parenterally administered agent for patients acutely ill with candidiasis and other mycotic infections. It may be the drug of choice for Petriellidium boydii infections and it is an attractive alternative to amphotericin B for intrathecal administration to patients with fungal meningitis. Ketoconazole offers much less toxicity, the advantage of oral administration, and the possibility of indefinitely prolonged therapy. However, it does not attain high concentrations in either the urine or cerebrospinal fluid. With the imidazoles, we have entered a new era of antifungal therapy which may produce even better antifungal agents than those currently available.
One hundred sixty patients were entered in two multicenter protocols to receive 400 to 2,000 mg of ketoconazole once daily for nonmeningeal or meningeal coccidioidomycosis. For 24 h after administration of all doses, mean concentrations in serum exceeded MICs for Coccidioides immitis (trough concentrations, >1 ,ug/ml). Mean peak concentrations occurred 4 to 6 h after administration, ranging from 7 to 17 ,ug/ml for doses of 400 to 2,000 mg. Incremental increases in peak concentrations in serum were greatest at doses of .1,200 mg. To investigate whether long-term therapy altered concentrations in serum, serial data were studied by several methods. The results suggested a trend to increased levels in serum with prolonged therapy, but were not statistically significant. All 168 cerebrospinal fluid (CSF) samples from meningitis patients contained c2.9,ig/ml, and only 6 contained >1 ,ug/ml.
The role of the biliary system in excretion of amphotericin B was explored in a dog model that allowed either external diversion of all bile or complete biliary obstruction. In dogs with biliary diversion, which were given a single dose of amphotericin B intravenously, excretion of amphotericin B in the bile lasted for seven to 10 days and accounted for only 3% +/- 2% (mean +/- SD) of the dose, whereas excretion in the urine was prolonged (23--35 days) and greater (21% +/- 5% of the dose); the stool contained no amphotericin B. However, bile salt depletion may have depressed biliary excretion of amphotericin B: in a dog with an intact biliary system, 19% of the dose was excreted in the stool over 11 days. In dogs given amphotericin B daily, serum levels were 19% +/- 3% higher during periods of biliary obstruction than during periods of free bile flow (P less than 0.05). Thus, excretion of amphotericin B in the bile (less than or equal to 19% of the dose) and in the urine (21% of the dose) accounted for a minority of total drug clearance. Nevertheless, prolonged excretion of amphotericin B by these routes after a single dose suggests that infrequent doses of amphotericin B may provide effective treatment for certain forms of fungal infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.