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We have reported that a murine Histoplasma capsulatum-reactive CD4+ T-cell line and clones thereof did not adoptively transfer protection against H. capsulatum infection in normal or cyclophosphamide-treated C57BL/6 mice. One explanation for the results was that the T cells failed to traffic to lymphoid organs in these animals. In this study, we have sought to determine whether one of these clones, 2.3H3, could mediate protection in nude (C57BL/10) or irradiated (5 Gy) heterozygous nude (nu/+) C57BL/6 mice. Mice were inoculated intravenously with 10(7) resting 2.3H3 cells or with an equal number of cells of the ovalbumin-reactive clone 1S6; 2 h later, the mice were challenged intranasally with 5 x 10(6) yeast cells. By day 5 of infection, lungs, livers, and spleens of nude and irradiated nu/+ mice given 2.3H3 contained significantly fewer (P < 0.05) CFU than the same organs from mice inoculated with 1S6. This effect was specific for H. capsulatum, since 2.3H3 did not reduce the number of Coccidioides immitis CFU in lungs, livers, and spleens of irradiated nu/+ mice. By day 10, the amounts of H. capsulatum CFU in lungs, livers, or spleens of nude and irradiated nu/+ mice inoculated with 2.3H3 were smaller than those in 1S6-inoculated mice, but these differences did not reach statistical significance (P > 0.05). The mortality rate of mice inoculated with 2.3H3 and that of mice inoculated with 1S6 were similar. Histopathological examination of tissues from 2.3H3- and 1S6-inoculated mice demonstrated the presence of granulomatous inflammation in organs from both groups. Tissues from 2.3H3-treated mice contained fewer yeasts per high-power field than tissues from 1S6-treated mice. Thus, irradiated or nude mice are permissive for the expression of protective immunity by a CD4+ T-cell clone. Although the protective capacity of T cells in these animals is transient, these animals will be useful for differentiating protective from nonprotective T-cell clones.

Background. After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse. Methods. We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (≥15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture. Results. Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the rem...

Background: Voriconazole has an important role to play in the prophylaxis and management of fungal endophthalmitis and keratitis. New-generation triazoles, including voriconazole, posaconazole and ravuconazole, have been shown in laboratory studies and clinical experience to have very good safety profiles with few side effects. Fungal eye infections, while not common in temperate climates, have been notoriously difficult to diagnose and treat, and generally result in protracted therapy with poor final outcomes. Current treatment options are far from optimal. Aims: This paper will review studies and clinical case reports published in the ophthalmic literature that address the safety of these drugs in the eye, penetration and concentration in ocular tissues and media, and efficacy in treating common pathogens implicated in fungal keratitis and endophthalmitis. Conclusions: Over 40 clinical case reports of treatment with voriconazole suggest that it may be used safely and effectively against a broad range of fungal pathogens.

An emmetropic 42 year old immunocompetent woman with 6/6 vision developed left eye pain while wearing cosmetic soft contact lenses. She presented on 28 July 2000 to her ophthalmologist, who noted deep stromal infiltration accompanying a 2 × 3 mm pericentral corneal ulcer. Cultures yielded Staphylococcus aureus , Streptococcus viridans , and Fusarium solani . Initial therapy with tobramycin was followed by high dose topical hydroquinolones, whereafter the infection, continuing unabated, was construed to be fungal keratitis. High doses of amphotericin B both topical and intravenously, natamycin, and ketoconazole were administered, along with topical fortified cephazolin, neosporin, and atropine. Despite these, the lesion spread to involve much of the corneal periphery (Fig 1), and repeat corneal cultures confirmed the presence of amphotericin B resistant Fusarium spp (MIC 24:48 hours in μg/ml: amphotericin B 2:2; natamycin 32:32; posaconazole 1:8). On 1 September 2000, the anterior chamber was filled with fibrin with a central corneal descemetocele and near total corneal infiltration, affording …

A new session in this Congress was the development of a discussion panel regarding controversies and queries about the main topics of treatment and prophylaxis of severe systemic mycoses. Experts presenting each side of three controversial areas provided an interchange of ideas and clarified those areas where there remain substantial disagreements. Some common recommendations have been made, and some differences persist. The contents of this session are compiled in this paper. Due to the limitations of space, this paper presents the most relevant parts of each presentation. The large and up-to-date list of references should be useful to gain a better understanding of these subjects.

There have been a number of changes in strategies in antifungal therapy in the past few years. AIDS related mycoses have decreased, and the increase of fluconazole resistant Candida albicans may be slowing because fewer severely immune depressed patients require constant fluconazole suppression. Candida species continue to be relatively common blood culture isolates. About half of these are C. albicans and half non-albicans species. In recent years, we have moved from the use of amphotericin B to fluconazole for initial treatment of candidemia. We have seen fluconazole resistant isolates emerge, primarily C. glabrata and a few C. krusei, but also C. albicans. It is unclear whether the increasing use of fluconazole in intensive care units will worsen this problem. There appears to be no advantage for the lipid formulations of amphotericin B, though they are useful to reduce or prevent renal toxicity. In the United States and Europe, prevention and treatment of aspergillosis have become increasingly important. There are increasing data suggesting that lipid formulations are more effective for both treatment and prevention of invasive disease in the most vulnerable patients with this infection. Renal toxicity is reduced but not avoided by use of the lipid formulations of amphotericin B. For those patients with less acutely progressing disease, the triazoles may be effective options. It is unclear at present whether itraconazole, voriconazole, or posaconazole will be the most favored drug. One promising new class, now in clinical trials, is the echinocandin group. Other agents, such as the sordarins, the chitin synthase inhibitors, and topoisomerase inhibitors, have promise but are much earlier in development. Unfortunately, we still have50% treatment failure with acute invasive aspergillosis, and 20%-30% failures with candidemia. Now that we have multiple classes of antifungal drugs available, and others in preclinical trials, it would be advantageous to begin more active exploration of combination therapy with antifungals and with combined immune modulators and antifungals.

A review of representative cases of invasive aspergillosis was conducted to describe current treatment practices and outcomes. Eighty-nine physicians experienced with aspergillosis completed case forms on 595 patients with proven or probable invasive aspergillosis diagnosed using modifications of the Mycoses Study Group criteria. Pulmonary disease was present in 56%, with disseminated infection in 19%. The major risk factors for aspergillosis were bone marrow transplantation (32%) and hematologic malignancy (29%), but patients had a variety of underlying conditions including solid organ transplants (9%), AIDS (8%), and pulmonary diseases (9%). Overall, high antifungal failure rates occurred (36%), and complete antifungal responses were noted in only 27%. Treatment practices revealed that amphotericin B alone (187 patients) was used in most severely immunosuppressed patients while itraconazole alone (58 patients) or sequential amphotericin B followed by itraconazole (93 patients) was used in patients who were less immunosuppressed than patients receiving amphotericin B alone. Response rate for patients receiving amphotericin B alone was poor, with complete responses noted in only 25% and death due to or with aspergillosis in 65%. In contrast, patients receiving itraconazole alone or following amphotericin B had death due to or with Aspergillus in 26% and 36%, respectively. These results confirm that mortality from invasive aspergillosis in severely immunosuppressed patients remains high even with standard amphotericin B. Improved responses were seen in the less immunosuppressed patients receiving sequential amphotericin B followed by itraconazole and those receiving itraconazole alone. New approaches and new therapies are needed to improve the outcome of invasive aspergillosis in high-risk patients.

It has been well documented that serious fungal infections may cause death in 5% to 10% of patients in certain high risk groups, such as those undergoing lung, pancreas, or liver transplantation. Patients in intensive care units, such as those with underlying severe disease, multi-organ fungal infection, those with catheters, those on broad spectrum antibacterial agents, and those in renal failure are also at risk and may be candidates for antifungal prophylaxis. However, recommendations regarding the use of antifungal drugs for prophylaxis in non-neutropenic patients are unclear. Several clinical trials in transplant recipients have supported the use of fluconazole for prophylaxis, particularly in liver transplantation, though the data are too few to permit generalized conclusions for all organ transplant recipients. There is also a trial in which antifungal prophylaxis has been successful after gut perforation. However, there are also reports in which high doses of fluconazole have not reduced fungal infection. The appropriate circumstances for prophylaxis are still undergoing definition. It is the author's opinion that effective prophylaxis will become more problematic in the future. In a year or two, once the drug becomes generic, the price of fluconazole will fall dramatically. A sharp increase in use is likely to occur, and is likely to be followed by increasing fluconazole resistance in both Candida albicans and non-albicans colonization and infections. The situation is similar to the consequences of widespread fluconazole use in AIDS patients. The best methods to delay resistance include strict handwashing, careful control of antibacterials, restricting fluconazole use to those situations where it has been most clearly shown to be beneficial, and carefully monitoring patients in intensive care units.

This study was undertaken to characterize the laboratory and clinical course of patients with AIDS and cryptococcal meningitis who had normal or elevated cerebrospinal fluid (CSF) pressure. Data were obtained retrospectively from a randomized multicenter quasifactorial phase III study comparing amphotericin B with or without flucytosine in primary treatment of cryptococcal meningitis. CSF pressure was measured before treatment and at 2 weeks. Repeated lumbar punctures were done to drain CSF and to reduce pressure. Patients with the highest baseline opening pressures (or = 250 mm H2O) were distinguished by higher titers of cryptococcal capsular polysaccharide antigen in CSF; more frequently positive India ink smears of CSF; and more frequent headache, meningismus, papilledema, hearing loss, and pathological reflexes. After receiving antifungal therapy, those patients whose CSF pressure was reduced by10 mm or did not change had more frequent clinical response at 2 weeks than did those whose pressure increased10 mm (P.001). Patients with pretreatment opening pressure250 mm H2O had increased short-term survival compared with those with higher pressure. We recommend that opening pressures/=250 mm H2O be treated with large-volume CSF drainage.

Rhodococcus equi is a well-recognized pathogen in veterinary medicine and a rare but well-documented cause of cavitary pneumonia in immunocompromised patients. Most cases of Rhodococcus equi infections in these patients involve the lungs. Otomastoiditis due to Rhodococcus equi is rare, and disseminated Rhodococcus equi with otomastoiditis has never been reported. We report a case of otomastoiditis with systemic dissemination due to Rhodococcus equi in a patient with AIDS.

This study was designed to compare the effectiveness of fluconazole vs. itraconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. HIV-infected patients who had been successfully treated (achieved negative culture of CSF) for a first episode of cryptococcal meningitis were randomized to receive fluconazole or itraconazole, both at 200 mg/d, for 12 months. The study was stopped prematurely on the recommendation of an independent Data Safety and Monitoring Board. At the time, 13 (23%) of 57 itraconazole recipients had experienced culture-positive relapse, compared with 2 relapses (4%) noted among 51 fluconazole recipients (P = .006). The factor best associated with relapse was the patient having not received flucytosine during the initial 2 weeks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; P = .04). Fluconazole remains the treatment of choice for maintenance therapy for AIDS-associated cryptococcal disease. Flucytosine may contribute to the prevention of relapse if used during the first 2 weeks of primary therapy.

The antifungal agents currently available to treat invasive fungal infections are limited in both number and usefulness. Treatment with the polyene amphotericin B (AmB), and with several azoles, in particular fluconazole and itraconazole, is the mainstay of antifungal chemotherapy. However, the clinical usefulness of these drugs is hampered by drawbacks associated with their safety and/or efficacy. There are two approaches to overcome this situation. One is to discover and develop new antifungal agents or formulations with advantages over and/or complementary to existing drugs. For this purpose, the following three categories of new drugs have been the major targets of study and development: (i) lipid formulations of polyenes, (ii) azoles (including cyclodextrin-complexes), and (iii) nonazole compounds, particularly those of microbial origin (antibiotics).

Medical mycology is of increasing interest to the basic scientist, pathologist, microbiologist and clinician. This interest has been prompted by the rising number of immunosuppressed patients with opportunistic fungal infections, the expanding boundaries of the so-called endemic mycoses, the recognition of several major new endemic mycoses and a variety of other emerging fungal infections, and the development of potent, non-toxic antifungal drugs to treat these infections. The world of mycology is changing dramatically, especially in developing countries which have only limited resources to cope with the impact of the compromised host and the introduction of costly new antifungal drugs. Consequently, there is an urgent need to increase our effectiveness as teachers of medical mycology at all levels and in all regions of the world.

BMS 181184 (BMS), an analogue of pradimicin, was administered intravenously to neutropenic mice infected with either a fluconazole-susceptible or a fluconazole-resistant clinical isolate of Candida tropicalis. BMS prolonged survival at doses3 mg kg -1 day-1, and at higher doses reduced tissue counts in mice. BMS was less potent mg for mg than amphotericin B. Combined BMS and amphotericin B were no more effective than either of the individual drugs.

Patients with immune depression are at increased vulnerability to a variety of mycotic infections. These range from mucosal and disseminated candidiasis to invasive aspergillosis to regional mycoses, such as histoplasmosis and Penicillium morneffei, and the emerging mycoses including zygomycetes, phaeohyphomycetes, Fusarium sp, Trichosporon sp, and others. An increasing variety of antifungal drugs, among which are fluconazole and itraconazole, are used for the treatment of these opportunistic infections. Fluconazole has excellent absorption, linear renal excretion of largely active drug, and limited spectrum, primarily against yeast pathogens such as Candida sp. In its capsule formulation, itraconazole has broader activity, including mycelial pathogens, but suffers from irregular absorption, lack of intravenous formulation, and complex hepatic excretion. Itraconazole has recently undergone reformulation as a solution, which gives significant added advantages in bioavailability and increases the practical applications. It is at present unclear whether voriconazole, SCH56592, or itraconazole solution will be equally potent and have a similar range of applications.

Treatment with low-dose amphotericin B (0.4 mg per kilogram of body weight per day) or oral azole therapy in patients with the acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis has been associated with high mortality and low rates of cerebrospinal fluid sterilization.In a double-blind multicenter trial we randomly assigned patients with a first episode of AIDS-associated cryptococcal meningitis to treatment with higher-dose amphotericin B (0.7 mg per kilogram per day) with or without flucytosine (100 mg per kilogram per day) for two weeks (step one), followed by eight weeks of treatment with itraconazole (400 mg per day) or fluconazole (400 mg per day) (step two). Treatment was considered successful if cerebrospinal fluid cultures were negative at 2 and 10 weeks or if the patient was clinically stable at 2 weeks and asymptomatic at 10 weeks.At two weeks, the cerebrospinal fluid cultures were negative in 60 percent of the 202 patients receiving amphotericin B plus flucytosine and in 51 percent of the 179 receiving amphotericin B alone (P=0.06). Elevated intracranial pressure was associated with death in 13 of 14 patients during step one. The clinical outcome did not differ significantly between the two groups. Seventy-two percent of the 151 fluconazole recipients and 60 percent of the 155 itraconazole recipients had negative cultures at 10 weeks (95 percent confidence interval for the difference in percentages, -100 to 21). The proportion of patients who had clinical responses was similar with fluconazole (68 percent) and itraconazole (70 percent). Overall mortality was 5.5 percent in the first two weeks and 3.9 percent in the next eight weeks, with no significant difference between the groups. In a multivariate analysis, the addition of flucytosine during the initial two weeks and treatment with fluconazole for the next eight weeks were independently associated with cerebrospinal fluid sterilization.For the initial treatment of AIDS-associated cryptococcal meningitis, the use of higher-dose amphotericin B plus flucytosine is associated with an increased rate of cerebrospinal fluid sterilization and decreased mortality at two weeks, as compared with regimens used in previous studies. Although consolidation therapy with fluconazole is associated with a higher rate of cerebrospinal fluid sterilization, itraconazole may be a suitable alternative for patients unable to take fluconazole.

We studied the effect of the severity of meningitis on the response to therapy with fluconazole and flucytosine in a murine model of cryptococcal meningitis. Meningitis was established by intracerebral injection of Cryptococcus neoformans. The severity of meningitis was varied by delaying the onset of treatment from 3 to 7 days. Animals were sacrificed after 14 days of treatment, and the numbers of C. neoformans per gram of brain tissue were quantified. The range of effective dose combinations of fluconazole and flucytosine became progressively reduced as the severity of meningitis increased. The magnitude of treatment effect, as measured by the numbers of CFU/gram of brain tissue, was also reduced with increasing severity of meningitis. In this model, as the severity of meningitis increases, higher doses of fluconazole are required to achieve equivalent levels of activity. The combination of fluconazole and flucytosine appears to have the most-potent antifungal effects. This is most readily observed in animals with more-severe meningitis.

This study elucidates the role of combined fluconazole and flucytosine as therapy for cryptococcosis in the murine model of meningitis. Three strains of Cryptococcus neoformans for which the range of fluconazole MICs was wide--2 microg/ml (susceptible strain), 8 microg/ml (moderately susceptible strain), and 32 microg/ml (resistant strain)--were used for infection. One day postinfection, the mice were randomized into eight treatment groups: placebo; flucytosine (40 mg/kg of body weight/day); fluconazole at 3 mg/kg/day (low dosage), 10 mg/kg/day (moderate dosage), or 20 mg/kg/day (high dosage); and combined flucytosine and fluconazole at low, moderate, or high doses of fluconazole. Three major findings were demonstrated: (i) correlation between the MICs for the isolates and the in vivo effectiveness of fluconazole as assessed by the reduction in cryptococcal brain burden, (ii) a dose-response curve (a higher dose of fluconazole was significantly more efficacious than a lower dose [P < 0.001]), and (iii) synergism between fluconazole and flucytosine (therapy with a combination of fluconazole and flucytosine was superior to therapy with either agent alone [P < 0.01]).

Albendazole has in vitro activity against Cryptococcus neoformans and reduced in vitro activity for albendazole when compared with Candida albicans. The major metabolite of albendazole, albendazole sulphoxide showed no in vitro activity against isolates of either fungus. Immunocompetent mice infected intravenously (i.v.) with C. albicans were treated with albendazole doses of 20-600 mg kg-1 per day in noble agar or sesame oil for per oral (PO) administration, or 80 mg kg-1 per day in DMSO for intraperitoneal (i.p.) and i.v. administration for 10 days, and were observed for survival. Mice infected with C. neoformans intracranially received albendazole in daily doses of 600 mg kg-1 prepared in DMSO (i.p.) or peanut butter/rat chow (PO) for 10 days and were observed for survival. Mortality was not different between the treated and control animals in any study. Plasma samples from uninfected mice dosed with similar formulations and doses of albendazole were analysed by HPLC for albendazole and albendazole sulphoxide. No albendazole could be detected in any sample, while concentrations of albendazole sulphoxide (286-8697 ng ml-1) were observed in all samples. These data suggest that the absence of in vivo activity for albendazole is due to rapid conversion to the inactive albendazole sulphoxide metabolite.

Because of the rapidly increasing incidence of serious candidal infections, a consensus conference of 22 investigators from the United States, Europe, and Japan was held to discuss strategies for the prevention and treatment of deep-organ infections caused by Candida species. Commonly asked questions concerning the management of candidal infections were selected for discussion by the participating investigators. Possible answers to the questions were developed by the investigators, who then voted anonymously for their preferences. In certain instances, unanimity or a strong consensus was the result. In all cases, the full spectrum of responses was recorded and is presented in this report. The forms of candidal infection addressed included candidemia, candiduria, hepatosplenic candidiasis (chronic systemic candidiasis), candidal endophthalmitis, and candidal peritonitis. Prevention and treatment strategies were considered for patients who have undergone surgery, for neutropenic and nonneutropenic patients, and for patients who have undergone bone marrow and solid organ transplantation. The therapeutic roles of amphotericin B (standard and lipid formulations) and the azoles were considered.

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily).

The study objective was to obtain preliminary information regarding the safety and efficacy of amphotericin B (AmB) lipid complex (ABLC) in the treatment of AIDS-associated cryptococcal meningitis. Of 55 patients randomly assigned to 6 weeks of therapy with ABLC (1.2-5.0 mg/[kg.d], with ascending doses for three sequential cohorts) or AmB (0.7-1.2 mg/[kg.d]), 46 receivedor = 12 doses. Transfusion requirements, mean decreases in hemoglobin level, and mean increases in creatinine level were significantly greater with AmB than with ABLC. The total number of adverse events, infusion-related events, and occurrences of hypomagnesemia and hypokalemia associated with each form of therapy were similar. Among 21 recipients of ABLC at a dosage of 5 mg/kg (daily for 2 weeks and then thrice weekly for 4 weeks), symptoms and signs resolved for 18 (86%). Of those receivingor = 12 doses of ABLC, cultures converted to negative for 8 (42%), were undeterminable for 3 (16%), and remained positive for 8 (42%) despite resolution of symptoms. Although preliminary, these data suggest ABLC has significant activity in patients with AIDS-associated cryptococcal meningitis. Because this formulation has less hematologic and renal toxicity than does AmB, further evaluation of ABLC is warranted.

This article explores the growing importance of systemic mycoses, considering briefly their present and future roles as infecting agents, and considers the rapid changes occurring in antifungal therapy. This article also speculates on the major developments anticipated for the next decade.

To describe the clinical presentation and outcomes of treatment with itraconazole in patients with sporotrichosis.A culture for Sporothrix schenckii or compatible histopathology was required for inclusion in the study. Patients with both cutaneous and systemic sporotrichosis were treated. Patients received from 100 to 600 mg of itraconazole daily for 3 to 18 months. Patients were classified as responders or nonresponders. Responders were further classified as remaining on treatment, relapsed, or free of disease. Nonresponders included patients who failed to respond or progressed during treatment with itraconazole.Twenty-seven patients (mean age: 53 years) were treated with 30 courses of itraconazole. Diabetes mellitus and alcoholism were present in eight and seven patients, respectively. Sites of involvement included lymphocutaneous alone in 9 patients, articular/osseous in 15 (multifocal in 3), and lung in 3. Prior therapy was unsuccessful in 11 patients. Among the 30 courses, there were 25 responders and 5 nonresponders. All 5 nonresponders received at least 200 mg daily of itraconazole for durations that ranged from 6 to 18 months. Of the 25 responders, 7 relapsed 1 to 7 months after treatment durations of 6 to 18 months. Of the 7 who relapsed, 2 are responding to a second course. One responder was lost to follow-up after 10 months of treatment with itraconazole. Of the remaining 17 responders, 3 remain on treatment, and 14 are free of disease over follow-up durations of 6 to 42 months (mean: 17.6 months). Itraconazole was well tolerated with few side effects noted.These results document the efficacy of itraconazole in the treatment of cutaneous and systemic sporotrichosis.

The manifestations of histoplasmosis in 20 patients with the acquired immunodeficiency syndrome are presented. In this series, patients were treated with either itraconazole or fluconazole. Twelve patients received treatment with itraconazole at 400 mg/day, including two patients who had not responded to treatment with fluconazole at 100 mg/day. Of the responses, seven were classified as remissions (mean treatment duration of 24 months), two as improvements, and three as failures. Ten patients received fluconazole. Of the responses, three were classified as remissions (mean treatment duration of 12 months), one as improvement, and six as failures. Of the 10 patients treated with fluconazole, five received doses of 100 mg/day, and five were given doses of 400 or 800 mg/day. The differences in outcome among the five patients receiving the lower dose of fluconazole (one remission, one improvement, and three failures) and the five patients given the higher doses of fluconazole (two remissions and three failures) were negligible. One other patient showed signs of histoplasmosis while receiving fluconazole at 50 mg/day for treatment of thrush. Three failures (two treated with itraconazole and one with fluconazole) followed lapses in azole therapy because of associated conditions. Azole therapy was well tolerated. The treatment responses in this pilot series appear promising in comparison with those reported in the literature with amphotericin B or ketoconazole.

Far and away the most common fungal infection associated with HIV infection is candidiasis. This tends to produce mucosal topical infections and local treatment may be enough to control them. Generally we prefer courses of 1-2 weeks rather than chronic suppression, for fear of eliciting overgrowth of resistant isolates. Fluconazole resistant Candida species may be an increasing problem over the next decade. For cryptococcoses the problem is both simpler and more complicated. Fluconazole is highly effective for chronic suppression, but not very effective for initial therapy. Here a short course of amphotericin B, just 2 weeks in length, is followed by chronic azole suppression. Fluconazole appears excellent, but itraconazole may also be effective. For histoplasmosis itraconazole appears to be the most advantageous drug, with excellent clinical response within 2 weeks. A role for fluconazole is unclear. Coccidioidomycosis is uncommon, but difficult. I cannot offer any suggestions on "ideal" therapy here. Other diseases, such as aspergillosis, are extremely uncommon but still are AIDS associated mycoses. It is my personal fear that as we go along identifying the AIDS virus and its complications, aspergillosis and zygomycosis may establish themselves as the future "black hats" for which we will need to pull something out of the "box". What to pull is not very clear.

After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse.We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture.Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fisher's exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002).Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

The first oral agents for treatment of mycoses included potassium iodide, griseofulvin and flucytosine. While each is still used in specific indications, the advent of ketoconazole in the late 1980s radically expanded the spectrum and efficacy of oral antifungals. Ketoconazole was the first drug sufficiently potent and benign to permit use for both superficial and deep fungal infections. Ketoconazole quickly proved highly effective in many systemic and cutaneous infections, but it was soon appreciated that high doses caused impairment of testosterone and ultimately cortisol synthesis. Dose-dependent nausea and vomiting also became apparent, as did the necessity for very high doses for treatment of fungal meningitis. Hepatic cellular toxicity was also noticed, particularly after prolonged treatment at high doses. Just as these limitations became apparent, Janssen, Pfizer and, most recently, Schering brought forth the triazole antifungals. These differ markedly in pharmacokinetics and fungal spectrum, requiring careful consideration of the appropriate drug. In addition to the above, terbinafine has been recently developed for dermatophytes, particularly refractory onychomycoses.

The purpose of this study was to assess the tolerance and efficacy of itraconazole in the treatment of coccidioidomycosis.Fifty-one patients with nonmeningeal coccidioidomycosis were considered for treatment with intraconazole. Forty-nine patients who met study criteria were treated with itraconazole given orally in doses of 100 to 400 mg/day for periods up to 39 months. Of these patients, 12 had osteoarticular disease, 23 had chronic pulmonary disease, and 14 had skin or soft tissue disease. Clinical response was evaluated using a scoring system accounting for lesion number and size, symptoms, culture, and serologic titer. Remission was defined as reduction of the pretreatment score by 50% or more.Patients with osteoarticular, chronic pulmonary, and soft tissue disease improved at similar rates. Because two patients had no scoring assessment for efficacy, they were considered inassessable for efficacy. Forty-seven patients are evaluable. Of these patients, 44 have completed therapy, and three are still receiving itraconazole. Of the 44 patients no longer receiving therapy, 25 (57%) achieved remission. Of the 25 patients achieving remission, four later experienced a relapse. Therapy failed in 19 patients (43%). Of these cases, 16 (36%) were clinical failures and three (7%) developed drug intolerance that precluded continuation of treatment. Evaluation of culture conversions was of limited value in the osteoarticular patients, fewer than half of whom had follow-up biopsies. However, culture conversions were a useful index of response in patients with chronic pulmonary disease. During the course of treatment, serologic titers declined in the two groups with extrapulmonary disease, but not in patients with pulmonary coccidioidomycosis. Possible toxicities were generally mild.Itraconazole appears efficacious and very well tolerated in patients with coccidioidomycosis.

A patient with chronic lymphocytic leukemia developed extensive pneumonia due to Cryptococcus neoformans. A presumptive diagnosis based on results of a Wright's stain of the sputum was made and appropriate antifungal therapy was started. C neoformans was cultured in COUNTS AS HIGH AS 8 X 10(5)/ml of sputum and was present morphologically for three weeks after sputum cultures had become negative. During the patient's first week of hospitalization, C neoformans was cultured from sputum and on cough plates but from no other source in his room. This suggests the possibility of transmitting the fungus to susceptible persons by droplets from patients having extensive pulmonary cryptococcosis.

Congenitally athymic nude (nu/nu) mice, when injected intraperitoneally with Histoplasma capsulatum, developed a rapidly fatal disseminated infection characterized by heavy parasitization of reticuloendothelial tissues. In contrast, their heterozygous (nu/X) littermates, which possessed a functioning thymus, developed only a low-grade infection which was apparently self-limited and rarely fatal. Transplantation of thymic tissue into nu/nu mice diminished greatly the severity of infection and reduced mortality by about 50%. These studies emphasize the importance of cell-mediated immunity in host defense against histoplasmosis and suggest that the nude mouse may be a valuable model for the study of this chronic intracellular infection.

Results are reported on the fertilization (to 18%) of steelhead trout (Salmo gairdneri) eggs with cryo-preserved sperm. Fresh semen was progressively diluted to 1: 4 with an extender containing 5 or 12.5% dimethyl sulfoxide, sealed in 1.0-ml ampoules, frozen in the vapor of liquid nitrogen, and subsequently thawed in a 4 C water bath. The fertilized eggs and alevins produced appeared normal when compared with those from fresh spermatozoa.

In a model of experimental murine aspergillosis, efficacy of amphotericin B (AMB) desoxycholate was compared with SCH 28191, the D-ornithyl methyl ester derivative of amphotericin B (SCH). In vitro studies showed that the Aspergillus isolate was equally susceptible to AMB and SCH. Both drugs were equally effective in prolonging survival after intravenous challenge with conidia of A. fumigatus. This was apparent when treatment was begun 24 h after challenge or delayed until mice were moribund; SCH appears to be as equally effective as AMB in treatment of murine aspergillosis.

Seven patients infected with Pseudallescheria boydii were treated with oral ketoconazole, 200 to 600 mg/day for one to 13 months. Five patients had pulmonary infections; two had skeletal infections. Improvement of pretreatment abnormalities occurred in five patients, one of whom had concurrent arthrodesis of his infected knee. The other two patients were subsequently healed by surgical resection of their pulmonary lesions. Ketoconazole appeared less active than miconazole against 22 clinical isolates of P boydii when tested by two in vitro methods. We conclude that ketoconazole is effective treatment for some patients infected with P boydii, although this may not be predicted by current in vitro susceptibility tests. Further experience is needed to establish the optimal use of ketoconazole with respect to its dosage, duration of administration and concurrent surgical resection.

Currently, even optimal therapy of cryptococcal meningitis is associated with appreciable mortality, drug toxicity, and prolonged hospitalization. Ketoconazole, a new oral imidazole, has therefore been evaluated in a murine model of cryptococcosis. Cryptococcal meningitis was induced in BALB/c mice by intracranial injection of Cryptococcus neoformans. The mice developed infection characterized by diffuse meningitis and extracerebral dissemination. Oral ketoconazole therapy prolonged survival of infected mice, but most mice ultimately succumbed to infection. Ketoconazole dramatically reduced the cryptococcal counts in the liver, but had minimal effect on counts in the brain. Paralleling these results were high concentrations of ketoconazole found in lung, spleen, and heart muscle and lower concentrations (2 to 5 micrograms/ml) found in the brain. The detection of biologically active drug in the brain, and the prolongation of survival afforded by ketoconazole, suggest a potential role for this agent in the theory of cryptococcal meningitis.

BALB/c mice were given cyclophosphamide and challenged with Cryptococcus neoformans. Delayed-type hypersensitivity was transiently depressed, and survival was either unaffected or shortened by cyclophosphamide.