Philip C. Craven

Treatment of Cryptococcal Meningitis with Combination Amphotericin B and Flucytosine for Four as Compared with Six Weeks

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 in Patients on Continuous Ambulatory Peritoneal Dialysis

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.

Treatment of Systemic Mycoses with Ketoconazole: Emphasis on Toxicity and Clinical Response in 52 Patients: National Institute of Allergy and Infectious Diseases Collaborative Antifungal Study

The pharmacology, in vitro mycologic activity, toxicity, and efficacy of ketoconazole were studied in a Phase-II evaluation by the National Institutes of Health and National Institute of Allergy and Infectious Disease Mycoses Study Group. This report emphasizes the toxicity and clinical response data in 52 patients with the following systemic mycoses: blastomycosis in 16 patients; nonmeningeal coccidioidomycosis in 13; histoplasmosis in 8; nonmeningeal cryptococcosis in 7; sporotrichosis in 7; and both blastomycosis and nonmeningeal coccidioidomycosis in 1. Maximum daily doses of ketoconazole were 100 mg in 1 patient; 200 mg in 23; 400 mg in 12; and 600 mg in 16. In 52% of the patients, duration of therapy ranged from less than 1 to 6 months, whereas in 35%, duration ranged from 7 to 12 months, and in 13%, from 12 to 22 months. In 35 patients (67%), evidence of toxicity was not seen. Nausea, anorexia, or vomiting occurred in 21%. Cure or marked improvement was shown in 27 patients (52%), whereas failure of the primary course was seen in 14 (27%) and relapse after ketoconazole was discontinued in 11 (21%). Although this evaluation did not provide clear-cut clinical response data, our results indicate that ketoconazole, in the dosage regimens used, was more effective in patients with histoplasmosis and nonmeningeal cryptococcosis than in patients with blastomycosis and nonmeningeal coccidioidomycosis, and least effective in patients with sporotrichosis.

Antifungal Agents Used in Systemic Mycoses

SummaryThe 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.

High-Dose Ketoconazole for Treatment of Fungal Infections of the Central Nervous System

Mortality and complication rates remain unacceptably high with conventional intravenous and intrathecal therapy for patients with coccidioidal meningitis and intracerebral fungal lesions. We studied the ventricular and lumbar cerebrospinal fluid penetration of ketoconazole and the responses to therapy in two patients receiving ketoconazole orally, 800 mg daily, and amphotericin B intraventricularly for meningeal and extrameningeal coccidioidomycosis. Five patients received only 1200 mg of ketoconazole: one had uncomplicated coccidioidal meningitis, three had obstructive hydrocephalus due to coccidioidal meningitis, and one had a histoplasmal brain abscess. Ketoconazole concentrations in ventricular and lumbar fluid ranged from 0.05 to 1.65 micrograms/mL 4 and 8 hours after the dose. The mean penetration of ketoconazole (+/- SD) was 1.9% +/- 0.8% for ventricular fluid and 5.4% +/- 2.6% for lumbar fluid. Ketoconazole concentrations in cerebrospinal fluid varied directly with those in serum and with cerebrospinal fluid protein content. The encouraging clinical responses, convenience, safety, and the consistent penetration of ketoconazole into obstructed and nonobstructed cerebrospinal fluid support the use of these regimens as alternatives to conventional therapy.

Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome

A 57-year-old man with a prior episode of lymphatic toxoplasmosis presented with signs of anterior panhypopituitarism, which was confirmed by standard endocrinologic evaluation. The diagnosis of central nervous system toxoplasmosis was established by brain biopsy after nondiagnostic serologic and radiographic studies. At autopsy, the anterior pituitary was necrotic, with Toxoplasma abscesses in neighboring brain structures. Clinical and laboratory data met the criteria for the acquired immune deficiency syndrome. Although this is the first reported case of toxoplasmosis presenting as panhypopituitarism, future cases may be identified since central nervous system toxoplasmosis is being recognized more frequently in patients with immunodeficiency.

Amikacin therapy of patients with multiply antibiotic-resistant serratia marcescens infections: Development of increasing resistance during therapy

Over a recent 22 month period, 222 patients in two adjacent hospitals became infected with a multiply antibiotic-resistant strain of Serratia marcescens; 13 were bacteremic. Nineteen patients with clinically significant infections received amikacin. Nine of 11 patients with urinary tract infections were cured. In contrast, only one of eight patients with pneumonia or other deep tissue infections was cured and four died. These eight patients were severely ill; many had infections with multiple microorganisms. In four of five patients in whom the infection failed to clear promptly. Serratia strains became increasingly resistant to amikacin during therapy and these strains contributed to the death of two of these patients. Amikacin proved useful in treating patients with infections due to gentamicin-resistant S. marcescens organisms, especially urinary tract infections. However, the capacity of some strains of S. marcescens to develop resistance to amikacin may limit the usefulness of this antibiotic in the treatment of deep tissue infections which involve this microorganism.

Treatment of experimental murine candidiasis with liposome-associated amphotericin B

Mice were challenged intravenously with Candida albicans, and then treated either with nothing (controls), amphotericin B-desoxycholate (AMB), or amphotericin B associated with liposomes (AMB-lipo). AMB-lipo permitted larger doses of amphotericin B to be given, and also appeared to have no severe toxicity in the animal model. High doses of AMB-lipo were protective, but at equal doses, AMB-lipo was not as effective as commercial AMB.

Interaction of Chemotherapy and Immune Defenses in Experimental Murine Cryptococcosis

Congenitally athymic nude (nu/nu) and thymus-containing heterozygous (nu/X) mice were infected intraperitoneally with Cryptococcus neoformans over a wide range of challenge doses. Cryptococcal disease progressed more rapidly in nude mice than in their nu/X littermates. When nu/X mice were treated with amphotericin B, all survived an otherwise lethal dose of C. neoformans. At larger challenge doses, survival was prolonged in nu/nu mice treated with amphotericin B, but they later succumbed to cryptococcosis. At lower challenge doses, amphotericin B was curative in some nude mice. Therapy of nude mice with both amphotericin B and flucytosine further prolonged survival at high-dose challenge and increased the number of cures at low-dose challenge. These studies support an interaction of antifungal chemotherapy with thymus-dependent immune defense mechanisms. This interaction is most evident at high challenge doses, where antifungal chemotherapy cures nu/X mice but only modestly prolongs survival in nude mice.

PERIPHERALLY INSERTED CENTRAL VENOUS CATHETERS FOR OUTPATIENT INTRAVENOUS ANTIBIOTIC THERAPY

Because of its advantages in maintaining venous access, the peripherally inserted central venous catheter was studied in an outpatient setting. One hundred forty-three patients were selected for the placement of 2.8 and 3.8 French silastic catheters by an intravenous therapy nurse in an infectious diseases practice. Placements were successful in 137 patients. Lines were used for 5–120 days (average of 29.9 days). The phlebitis that occurred in 10% of cases correlated with the experience of the person inserting the catheter and correlated inversely with the size of catheter. Only three catheters had to be removed because of phlebitis, and none of those were infected. In conclusion, peripherally inserted central venous catheters offer a useful, convenient, and safe alternative to peripheral lines in outpatient intravenous antibiotic therapy.