Epidemiology, management and outcomes of Cryptococcus gattii infections: A 22-year cohort.

BACKGROUND: Cryptococcus gattii is a globally endemic pathogen causing disease in apparently immune-competent hosts. We describe a 22-year cohort study from Australia's Northern Territory to evaluate trends in epidemiology and management, and outcome predictors. METHODS: A retrospective cohort study of all C. gattii infections at the northern Australian referral hospital 1996-2018 was conducted. Cases were defined as confirmed (culture-positive) or probable. Demographic, clinical and outcome data were extracted from medical records. RESULTS: 45 individuals with C. gattii infection were included: 44 Aboriginal Australians; 35 with confirmed infection; none HIV positive out of 38 tested. Multifocal disease (pulmonary and central nervous system) occurred in 20/45 (44%). Nine people (20%) died within 12 months of diagnosis, five attributed directly to C. gattii. Significant residual disability was evident in 4/36 (11%) survivors. Predictors of mortality included: treatment before the year 2002 (4/11 versus 1/34); interruption to induction therapy (2/8 versus 3/37) and end-stage kidney disease (2/5 versus 3/40). Prolonged antifungal therapy was the standard approach in this cohort, with median treatment duration being 425 days (IQR 166-715). Ten individuals had adjunctive lung resection surgery for large pulmonary cryptococcomas (median diameter 6cm [range 2.2-10cm], versus 2.8cm [1.2-9cm] in those managed non-operatively). One died post-operatively, and 7 had thoracic surgical complications, but ultimately 9/10 (90%) treated surgically were cured compared with 10/15 (67%) who did not have lung surgery. Four patients were diagnosed with immune reconstitution inflammatory syndrome which was associated with age <40 years, brain cryptococcomas, high cerebrospinal fluid pressure, and serum cryptococcal antigen titre >1:512. CONCLUSION: C. gattii infection remains a challenging condition but treatment outcomes have significantly improved over 2 decades, with eradication of infection the norm. Adjunctive surgery for the management of bulky pulmonary C. gattii infection appears to increase the likelihood of durable cure and likely reduces the required duration of antifungal therapy.

Drug development for cryptococcosis treatment: what can patents tell us?

BACKGROUND: Cryptococcosis is one of the most devastating fungal infections in humans. Despite the disease's clinical importance, current therapy is based on limited antifungals that are either toxic, inefficient, unavailable worldwide, or that quickly lead to resistance. OBJECTIVES: The goal of this study was to provide insight into the future of cryptococcosis treatment by describing the patent scenario in this field. METHODS: We identified and analysed patent documents revealing compounds with anti-cryptococcal activity supported by experimental evidence. FINDINGS: Patenting in this field has been historically low, with an overall tendency of increase since 2012. Most applications are single filings, suggesting that they do not encompass strategic inventions requiring broad protection. Research and development essentially took place in China and the United States, which also represent the main countries of protection. Both academic and corporate institutions contributed to patenting in this field. Universities are the leading actors, with the highest patent family counts. CONCLUSION: The low number of patents in this field indicates that efforts to mitigate the unmet needs for cryptococcosis treatment remain insufficient. Without investment to drive research and innovation, patients will likely continue to face inadequate assistance. Given the current scenario characterised by poor funding and low interest for technological development, drug repurposing may be the best alternative for cryptococcosis treatment.

In Vitro and In Vivo Assessment of FK506 Analogs as Novel Antifungal Drug Candidates.

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with that of FK506. The four FK506 analogs generally possessed lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of its in vivo antifungal efficacy in a murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, when it was used in combination with fluconazole, it significantly extended the survival of C. neoformans-infected mice, confirming the synergistic in vivo antifungal efficacy between these two agents.

Population Pharmacokinetic Modeling to Describe the Total Plasma and Free Brain Levels of Fluconazole in Healthy and Cryptococcus neoformans Infected Rats: How Does the Infection Impact the Drug's Levels on Biophase?

PURPOSE: The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats. METHOD: The infection was induced by the administration of 100 µL of inoculum (1.105 CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (µD). Blood and µD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration-time profiles were analyzed by non-compartmental and population pharmacokinetics approaches. RESULTS: A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and µD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04 ± 0.31 vs 0.69 ± 0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400-2000 mg for humans. CONCLUSIONS: FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 µg/mL.

Establishing a cost-per-result of laboratory-based, reflex Cryptococcal antigenaemia screening (CrAg) in HIV+ patients with CD4 counts less than 100 cells/µl using a Lateral Flow Assay (LFA) at a typical busy CD4 laboratory in South Africa.

INTRODUCTION: Cryptococcal meningitis is a major cause of mortality and morbidity in countries with high HIV prevalence, primarily affecting patients whose CD4 are < = 100 cells/µl. Routine Cryptococcal Antigen (CrAg) screening is thus recommended in the South African HIV treatment guidelines for all patients with CD4 counts < = 100 cells/µl, followed by pre-emptive anti-fungal therapy where CrAg results are positive. A laboratory-based reflexed CrAg screening approach, using a Lateral Flow Assay (LFA) on remnant EDTA CD4 blood samples, was piloted at three CD4 laboratories. OBJECTIVES: This study aimed to assess the cost-per-result of laboratory-based reflexed CrAg screening at one pilot CD4 referral laboratory. METHODS: CD4 test volumes from 2014 were extracted to estimate percentage of CD4 < = 100 cells/µl. Daily average volumes were derived, assuming 12 months per/year and 21.73 working days per/month. Costing analyses were undertaken using Microsoft Excel and Stata with a provider prospective. The cost-per-result was estimated using a bottom-up method, inclusive of test kits and consumables (reagents), laboratory equipment and technical effort costs. The ZAR/$ exchange of 14.696/$1 was used, where applicable. One-way sensitivity analyses on the cost-per-result were conducted for possible error rates (3%- 8%, reductions or increases in reagent costs as well as test volumes (ranging from -60% to +60%). RESULTS: The pilot CD4 laboratory performed 267000 CD4 tests in 2014; ~ 9.3% (27500) reported CD4< = 100 cells/µl, equivalent to 106 CrAg tests performed daily. A batch of 30-tests could be performed in 1.6 hours, including preparation and analysis time. A cost-per-result of $4.28 was reported, with reagents contributing $3.11 (72.8%), while technical effort and laboratory equipment overheads contributed $1.17 (27.2%) and $0.03 (<1%) respectively. One-way sensitivity analyses including increasing or decreasing test volumes by 60% revealed a cost-per-result range of $3.84 to $6.03. CONCLUSION: A cost-per-result of $4.28 was established in a typical CD4 service laboratory to enable local budgetary cost projections and programmatic cost-effectiveness modelling. Varying reagent costs linked to currency exchange and varying test volumes in different levels of service can lead to varying cost-per-test and technical effort to manage workload, with an inverse relationship of higher costs expected at lower volumes of tests.

Cryptococcus gattii infections: contemporary aspects of epidemiology, clinical manifestations and management of infection.

Cryptococcus gattii is an important primary and opportunistic pathogen, predominantly causing meningoencephalitis and pulmonary disease with substantial mortality. Initially considered geographically restricted to immune-competent, highly exposed individuals in the tropics, an apparent epidemic in North America has led to new perspectives on its ecology, epidemiology and clinical associations, which are distinct from its sibling species Cryptococcus neoformans. The role of C. gattii molecular genotypes/subtypes in different settings is under investigation. Diagnostic and treatment strategies are similar to those for C. neoformans in immunocompetent hosts, although data indicate that more prolonged induction, as well as total duration of therapy, is required. Exclusion of CNS involvement is mandatory. Brain cryptococcomas are characteristic of C. gattii infection, and raised intracranial pressure is common, for which surgery is often required. Immune reconstitution syndrome may occur. Ongoing C. gattii research and greater awareness and availability of specific diagnostic tests are required to improve patient outcomes.

Cost of invasive fungal infections in the era of new diagnostics and expanded treatment options.

STUDY OBJECTIVE: To determine the true institutional cost of treating invasive fungal infections in light of recent advances in diagnostic techniques and antifungal therapies for both treatment and prophylaxis of these infections. DESIGN: Economic analysis. SETTING: Academic medical center. PATIENTS: A total of 200 patients discharged from the hospital during 2004-2005 with a diagnosis of proven, probable, or possible aspergillosis, cryptococcosis, invasive candidiasis, or zygomycosis (cases). Patients were matched in a 1:1 fashion with patients having similar underlying disease states but no invasive fungal infections (controls). MEASUREMENTS AND MAIN RESULTS: Data on demographic and clinical characteristics were collected from patients' medical records. In addition, information concerning each patient's hospitalization was recorded. Resource utilization data for a patient's entire hospitalization were collected from the hospital's charge databases and converted to costs. These data were compared between the cases and the controls. After adjusting for race-ethnicity, sex, age, and comorbid illnesses, mean total hospital cost for cases was $32,196 more than for controls (p<0.0001). Nonpharmacy costs accounted for the majority (63%) of this difference, and an additional $3996 was attributed to systemic antifungal drugs. The mean length of hospital stay was longer for cases than controls (25.8 vs 18.4 days). CONCLUSION: Treatment of patients with invasive fungal infections was associated with a significantly higher inpatient hospital cost compared with controls. However, due to new diagnostic techniques and effective antifungal therapy, the relative cost of these infections appears to be at least stable compared with the previous decade. These findings can help assess the utility of cost-avoidance strategies such as antifungal prophylaxis and application of appropriate treatment.

Preventing deaths from cryptococcal meningitis: from bench to bedside.

Cryptococcal meningitis (CM), a fungal disease caused by Cryptococcus spp., is the most common form of meningitis and a leading cause of death among persons with HIV/AIDS in sub-Saharan Africa. Detection of cryptococcal antigen, which is present several weeks before overt signs of meningitis develop, provides an opportunity to detect infection early. Screening persons with HIV for cryptococcal infection when they access healthcare can identify asymptomatic infected patients allowing for prompt treatment and prevention of death. A newly developed point-of-care assay for cryptococcal antigen, as well as growing evidence supporting the utility and cost-effectiveness of screening, are further reasons to consider broad implementation of cryptococcal screening in countries with a high burden of cryptococcal disease.

Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence.

OBJECTIVES: To measure the burden of disease and describe the epidemiology of cryptococcosis in Gauteng Province, South Africa. DESIGN AND METHODS: The study was an active, prospective, laboratory-based, population-based surveillance. An incident case of cryptococcosis was defined as the first isolation by culture of any Cryptococcus species from any clinical specimen, a positive India ink cryptococcal latex agglutination test or a positive histopathology specimen from a Gauteng resident. Cases were identified prospectively at all laboratories in Gauteng. Case report forms were completed using medical record review and patient interview where possible. RESULTS: Between 1 March 2002 and 29 February 2004, 2753 incident cases were identified. The overall incidence rate was 15.6/100 000. Among HIV-infected persons, the rate was 95/100 000, and among persons living with AIDS 14/1000. Males and children under 15 years accounted for 49 and 0.9% of cases, respectively. The median age was 34 years (range, 1 month-74 years). Almost all cases (97%) presented with meningitis. Antifungal therapy was given to 2460 (89%) cases of which 72% received fluconazole only. In-hospital mortality was 27% (749 cases). Recurrences occurred in 263 (9.5%) incident cases. Factors associated with death included altered mental status, coma or wasting; factors associated with survival included employment in the mining industry, visual changes or headache on presentation. CONCLUSIONS: This study demonstrates the high disease burden due to cryptococcosis in an antiretroviral-naive South African population and emphasizes the need to improve early recognition, diagnosis and treatment of the condition.

Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America.

An 8-person subcommittee of the National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group evaluated available data on the treatment of cryptococcal disease. Opinion regarding optimal treatment was based on personal experience and information in the literature. The relative strength of each recommendation was graded according to the type and degree of evidence available to support the recommendation, in keeping with previously published guidelines by the Infectious Diseases Society of America (IDSA). The panel conferred in person (on 2 occasions), by conference call, and through written reviews of each draft of the manuscript. The choice of treatment for disease caused by Cryptococcus neoformans depends on both the anatomic sites of involvement and the host's immune status. For immunocompetent hosts with isolated pulmonary disease, careful observation may be warranted; in the case of symptomatic infection, indicated treatment is fluconazole, 200-400 mg/day for 36 months. For those individuals with non-CNS-isolated cryptococcemia, a positive serum cryptococcal antigen titer >1:8, or urinary tract or cutaneous disease, recommended treatment is oral azole therapy (fluconazole) for 36 months. In each case, careful assessment of the CNS is required to rule out occult meningitis. For those individuals who are unable to tolerate fluconazole, itraconazole (200-400 mg/day for 6-12 months) is an acceptable alternative. For patients with more severe disease, treatment with amphotericin B (0.5-1 mg/kg/d) may be necessary for 6-10 weeks. For otherwise healthy hosts with CNS disease, standard therapy consists of amphotericin B, 0.7-1 mg/kg/d, plus flucytosine, 100 mg/kg/d, for 6-10 weeks. An alternative to this regimen is amphotericin B (0.7-1 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 2 weeks, followed by fluconazole (400 mg/day) for a minimum of 10 weeks. Fluconazole "consolidation" therapy may be continued for as along as 6-12 months, depending on the clinical status of the patient. HIV-negative, immunocompromised hosts should be treated in the same fashion as those with CNS disease, regardless of the site of involvement. Cryptococcal disease that develops in patients with HIV infection always warrants therapy. For those patients with HIV who present with isolated pulmonary or urinary tract disease, fluconazole at 200-400 mg/d is indicated. Although the ultimate impact from highly active antiretroviral therapy (HAART) is currently unclear, it is recommended that all HIV-infected individuals continue maintenance therapy for life. Among those individuals who are unable to tolerate fluconazole, itraconazole (200-400 mg/d) is an acceptable alternative. For patients with more severe disease, a combination of fluconazole (400 mg/d) plus flucytosine (100-150 mg/d) may be used for 10 weeks, followed by fluconazole maintenance therapy. Among patients with HIV infection and cryptococcal meningitis, induction therapy with amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d for 2 weeks) followed by fluconazole (400 mg/d) for a minimum of 10 weeks is the treatment of choice. After 10 weeks of therapy, the fluconazole dosage may be reduced to 200 mg/d, depending on the patient's clinical status. Fluconazole should be continued for life. An alternative regimen for AIDS-associated cryptococcal meningitis is amphotericin B (0.7-1 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 6-10 weeks, followed by fluconazole maintenance therapy. Induction therapy beginning with an azole alone is generally discouraged. Lipid formulations of amphotericin B can be substituted for amphotericin B for patients whose renal function is impaired. Fluconazole (400-800 mg/d) plus flucytosine (100-150 mg/kg/d) for 6 weeks is an alternative to the use of amphotericin B, although toxicity with this regimen is high. In all cases of cryptococcal meningitis, careful attention to the management of intracranial pressure is imperative to assure optimal c

Carrier effects on biological activity of amphotericin B.

Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.

Computed tomographic assessment of noninvasive intranasal infusions in dogs with fungal rhinitis.

The distribution of infusate administered to 12 dogs with fungal rhinitis, using a noninvasive, intranasal technique, was evaluated by computed tomography (CT). In every dog, contrast medium was identified on the postinfusion CT images, within the frontal sinuses, and throughout all areas of the nasal cavity. Adverse effects were transient and mild. The results of this study indicate that intranasal infusion may be a viable alternative to trephination of the frontal sinuses to administer antifungal medications in dogs with fungal rhinitis.

Liposomal amphotericin B, AmBisome.

The unilamellar liposomal formulation of amphotericin B, AmBisome, is composed of hydrogenated soy phosphatidylcholine, distearoyl phosphatidylglycerol and cholesterol. Early studies of its efficacy in an open design showed that remissions could be induced in candidosis and aspergillosis and that doses of up to 5 mg/kg could be used. Adverse events were infrequent, with the main abnormality seen being hypokalaemia in about 18% of patients. Subsequent developments have extended this work. AmBisome has been used in two open studies of patients with invasive aspergillosis; in one of these remission was achieved in 77% of 17 patients with confirmed infection who had failed to respond to conventional amphotericin B. In AIDS patients with cryptococcosis AmBisome given for 6 weeks at 3 mg/kg daily produced mycological remission of meningitis in 67%. Other infections treated with the drug include zygomycete (mucormycosis) and Fusarium infections. AmBisome has also been used as preventative therapy in bone marrow transplant recipients and was found to reduce fungal colonisation rates. There were fewer systemic fungal infections in the treated versus placebo groups although this did not achieve statistical significance. Lack of renal and liver toxicity or anaemia has been confirmed in subsequent studies. In addition febrile reactions to the AmBisome are rare. The drug has also been used effectively in children, including infants, with systemic fungal infections. In visceral leishmaniasis patients, including HIV positive individuals, remissions have been obtained using drug regimens of 1-2 mg/kg of 2.1 days and 3 mg/kg for 10 days.

Cryptococcosis in cats: clinical and mycological assessment of 29 cases and evaluation of treatment using orally administered fluconazole.

Twenty-nine cats with naturally occurring cryptococcosis were evaluated prior to commencing oral fluconazole therapy (25-100 mg every 12 h). Affected cats ranged from 2 to 15 years-of-age. Male cats (19; 66%) and Siamese cats (5; 21%) appeared to be over-represented in comparison to the hospital's cat population. Mycotic rhinitis was observed in 24 (83%) of the cases, although nasal cavity involvement was subtle in four animals. Disease of the skin and subcutaneous tissues was present in 15 cases (52%) and amongst these the nasal plane (seven cats) and bridge of the nose (seven cats) were most commonly involved. Primary infection of the central nervous system was not encountered, although one cat developed meningoencephalitis and optic neuritis as a sequel to longstanding nasal cavity disease. Antibodies against the feline immunodeficiency virus (FIV) were detected in eight cats (28%), and these cats tended to have advanced and/or disseminated disease. There was a tendency for cats to develop cryptococcosis during the Australian summer. Organisms were cultured from 27 cases. Cryptococcus neoformans var. neoformans was isolated from 21 cats, while C. neoformans var. gattii was identified in the remaining six. The response to oral fluconazole was excellent in this series, which included many cats with advanced, longstanding or disseminated disease. The fungal infection resolved in all but one advanced case which died after only 4 days of therapy. A dose of 50 mg per cat, given every 12 h, produced a consistently good response without side effects. Lower doses were effective in some cases, while 100 mg every 12 h was required to control the infection in one cat. Serum fluconazole levels obtained during chronic dosing (50 +/- 18 mg l-1, mean +/- SD; 50 mg per cat every 12 h) were highly variable (range 15-80 mg l-1). Concurrent FIV infection did not impart an unfavourable prognosis, although affected cats often required prolonged courses of therapy.

Fluconazole: a new triazole antifungal agent.

Fluconazole is a recently approved agent for the treatment of certain fungal infections. Based on available studies, the drug is clearly effective in oropharyngeal candidiasis in immunosuppressed hosts. Current evidence suggests it may be more efficacious than other azole drugs for oropharyngeal disease. It is probably also effective in other infections due to Candida species, but controlled studies are lacking. Fluconazole is also efficacious in the treatment of cryptococcal meningitis, but recent reports question its use as initial therapy in HIV-infected patients with this illness. The drug, however, is clearly more effective than amphotericin B in the suppression of cryptococcal meningitis in AIDS patients and is the treatment of choice in this situation.

Cost implications of alternative treatments for AIDS patients with cryptococcal meningitis. Comparison of fluconazole and amphotericin B-based therapies.

The extra demands placed upon health care resources by management of AIDS patients have increased the focus on cost implications of therapeutic alternatives. Cryptococcal meningitis is a common life-threatening infection in AIDS patients, usually treated with amphotericin B, often in combination with flucytosine. Administered intravenously, this therapy is associated with frequent and often severe side effects. Fluconazole is a new alternative which can be given orally once daily and has fewer such side effects. The purpose of this study was to examine the cost implications of these different therapies for both primary and maintenance treatment of cryptococcal meningitis. Comparison of these two therapies in recent clinical trials has indicated that fluconazole is at least as effective as amphotericin B, and therefore cost-minimisation analysis is an appropriate method to study the economic consequences of the alternative treatments. Patient management and resource-use information for both treatments was obtained using a modified Delphi technique with a panel of European physicians experienced in the treatment of this disease, and three models were developed to reflect the variability of practice evident among the panel members. U.K. health care costs were used to value these resources. The results indicated that, despite the higher cost of the drug itself, the costs associated with fluconazole were likely to be markedly less than those for amphotericin B for primary treatment, and similar or slightly cheaper for maintenance treatment. Over 1 year of treatment, the saving from the use of fluconazole would be in the range of 4000-14,000 pounds.

[Pulmonary cryptococcosis]. / Criptococosis pulmonar.

The authors present the clinical history of a 61 year old woman who was treated in the Metropolitan Hospital Complex Arnulfo Arias Madrid of the Social Security. The patient had experienced weight loss, chills and pain in the left chest for a period of one month. The chest X-ray showed an irregular oval shaped pulmonary infiltrate, 5 x 5 cm, in the upper one third of the left lung field. Fiberoptic bronchoscopy revealed an endobronchial lesion in the superior division of the left upper lobe bronchus. Transbronchial biopsy and bronchial brushings showed Crytpcoccus neoformans. Clinical evaluations did not reveal involvement of the central nervous system, the immunological system or evidence of neoplastic disease. The patient was treated with Amphotericin B and Ketoconazole resulting in a complete cure. Amphotericin B was used on an ambulatory basis for the first time in their institution and in Panama.