Practice guidelines for the management of patients with sporotrichosis. For the Mycoses Study Group. Infectious Diseases Society of America.

The recommendations for the treatment of sporotrichosis were derived primarily from multicenter, nonrandomized treatment trials, small retrospective series, and case reports; no randomized, comparative treatment trials have been reported. Most cases of sporotrichosis are non life-threatening localized infections of the skin and subcutaneous tissues that can be treated with oral antifungal agents. The treatment of choice for fixed cutaneous or lymphocutaneous sporotrichosis is itraconazole for 36 months. The preferred treatment for osteoarticular sporotrichosis also is itraconazole, but therapy must be continued for at least 12 months. Pulmonary sporotrichosis responds poorly to treatment. Severe infection requires treatment with amphotericin B; mild to moderate infection can be treated with itraconazole. Meningeal and disseminated forms of sporotrichosis are rare and usually require treatment with amphotericin B. AIDS patients most often have disseminated infection and require life-long suppressive therapy with itraconazole after initial use of amphotericin B. OVERVIEW: Sporotrichosis is caused by the dimorphic fungus Sporothrix schenckii, which is found throughout the world in decaying vegetation, sphagnum moss, and soil. The usual mode of infection is by cutaneous inoculation of the organism. Pulmonary and disseminated forms of infection, although uncommon, can occur when S. schenckii conidia are inhaled. Infections are most often sporadic and usually associated with trauma during the course of outdoor work. Infection can also be related to zoonotic spread from infected cats or scratches from digging animals, such as armadillos. Outbreaks have been well-described and often are traced back to activities that involved contaminated sphagnum moss, hay, or wood. Most cases of sporotrichosis are localized to the skin and subcutaneous tissues. Dissemination to osteoarticular structures and viscera is uncommon and appears to occur more often in patients who have a history of alcohol abuse or immunosuppression, especially AIDS. Spontaneous resolution of sporotrichosis is rare, and treatment is required for most patients. Although sporotrichosis localized to skin and subcutaneous tissues is readily treated, management of osteoarticular, other localized visceral, and disseminated forms of sporotrichosis is difficult. OBJECTIVE: The objective of these guidelines is to provide recommendations for the treatment of various forms of sporotrichosis. OUTCOMES: The desired outcomes of treatment include eradication of S. schenckii from tissues, resolution of symptoms and signs of active infection, and return of function of involved organs. In persons with AIDS, eradication of the organism may not be possible, but clinical resolution should be attained and subsequently maintained with suppressive antifungal therapy. EVIDENCE: The English-language literature on the treatment of sporotrichosis was reviewed. Although randomized, blinded, controlled treatment trials were sought, none were found to have been performed for the treatment of sporotrichosis. Therefore, most weight was placed on those reports that were derived from multicenter trials of specific treatment modalities for sporotrichosis. Small series from a single institution and individual case reports were accorded less importance. VALUES: The highest value was placed on clinical efficacy and the ability of the antifungal regimen to eradicate the organism, but safety, tolerability, and cost of therapy were also valued. BENEFITS AND COSTS: The benefits of successfully treating sporotrichosis accrue primarily for the patient. Because this infection is not spread from person-to-person, public health aspects of treatment are of minor importance. Most forms of sporotrichosis are not life-threatening; thus, therapy is aimed at decreasing morbidity, improving quality of life, and allowing the patient to return to occupational and familial pursuits. (ABSTRACT TRUNCATED)     

Multifocal systemic sporotrichosis with lobar pulmonary involvement

Multifocal systemic sporotrichosis (disseminated sporotrichosis) with lobar pulmonary involvement is uncommon. We describe successful treatment with amphotericin B in such a patient and review data from 1 other similar case previously reported and 7 with nonlobar pulmonary involvement.     

Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS)

STUDY OBJECTIVE: To assess the efficacy and toxicity of long-term maintenance amphotericin B therapy in preventing relapses after treatment in patients with the acquired immunodeficiency syndrome (AIDS) and disseminated histoplasmosis. DESIGN: Open, nonrandomized pilot study. SETTING: Three private, university-affiliated community hospitals. PATIENTS: We studied 22 consecutive patients with disseminated histoplasmosis and human immunodeficiency virus (HIV) infection. Sixteen patients completed the study, 5 patients died before completing the initial intensive phase of treatment, and 1 patient received a different treatment regimen. INTERVENTIONS: Seven patients were treated with an initial intensive course of 1000 mg of amphotericin B, followed by weekly infusions of 50 to 80 mg until a cumulative dose of 2000 mg was attained; biweekly infusions of 50 to 80 mg were then continued indefinitely. Nine patients received an initial amphotericin B course of 2000 mg followed by weekly infusions of 80 mg. MEASUREMENTS AND MAIN RESULTS: Of the 7 patients in the 1000-mg intensive regimen group, 6 patients have survived without clinical or laboratory evidence of a histoplasmosis relapse, and 1 died of unrelated causes. Of the 9 patients in the 2000-mg intensive regimen group, 7 patients have survived, 1 patient died of a histoplasmosis relapse, and 1 patient died of other causes. Thus, 13 of 14 patients (93%) who did not die of other causes remained relapse-free. The median follow-up period was 14 months (range, 2 to 23 months). No apparent differences in outcome were observed between patients treated with weekly maintenance regimens and those treated with biweekly maintenance regimens. Sixty-three percent of patients developed intravascular device-related complications. CONCLUSIONS: Long-term, intermittent maintenance amphotericin B therapy in HIV-infected patients with disseminated histoplasmosis is well tolerated and is highly effective in suppressing relapses after treatment.     

Intracavitary amphotericin B in the treatment of symptomatic pulmonary aspergillomas

The optimal treatment of pulmonary aspergillomas is not established. Surgical resection is often impossible because of severe, underlying pulmonary impairment, and medical treatment has given negative or inconclusive results. Six patients with symptomatic pulmonary aspergillomas were treated with percutaneous instillation of intracavitary amphotericin B. Four patients who received the full course of therapy showed improvement and stabilization or reversal of progressive roentgenographic changes. Also, follow-up serologic studies of Aspergillus spp. precipitins were obtained in three and were negative. One patient did not tolerate this treatment because of repeated systemic reactions. Another patient did not respond clinically or roentgenographically. Intracavitary amphotericin B therapy should be considered in patients with symptomatic pulmonary aspergilloma, particularly when surgical resection is not feasible.     

Sporotrichosis: recurrent cutaneous, articular, and central nervous system infection in a renal transplant recipient

A case of recurrent, disseminated sporotrichosis in a renal transplant recipient is reported in which two joints, the skin, and the central nervous system were involved. The disease recurred both eight months and three years after the initial treatment with amphotericin B. The second course of therapy with amphotericin B required systemic and intraarticular administration of the drug. The third course of therapy included systemic and intrathecal administration. The function of the cadaveric transplanted kidney was maintained throughout the first recurrence of disease by careful reduction of immunosuppressive therapy and attention to the level of antifungal therapy. The kidney could not be salvaged after the second recurrence because of continued amphotericin B nephrotoxicity; however, the patient was cured of his infection. Sporothrix (Sporotrichum) schenckii may be a difficult organism to eradicate in chronically immunosuppressed patients, but the disease it causes may be successfully treated with aggressive systemic therapy.     

Sporotrichosis in renal transplant patients

The current report describes two renal transplant recipients who presented with sporotrichosis. In addition, the authors review the general aspects of sporotrichosis in renal transplant recipients reported in the literature. Sporotrichosis is a rare fungal infection in transplant patients and has been reported primarily in renal transplant recipients not treated with antifungal prophylaxis. Extracutaneous forms of sporotrichosis without skin manifestations and no previous history of traumatic injuries have been described in such patients and are difficult to diagnose. Renal transplant recipients with sporotrichosis described in the present report were successfully treated with antifungal therapy including amphotericin B deoxycholate, lipid amphotericin B formulations, fluconazole and itraconazole.     

Mucormycosis in hematologic malignancies: an emerging fungal infection

BACKGROUND AND OBJECTIVES. In recent years pulmonary mucormycosis has been reported in patients with leukemia and lymphoma and bone marrow transplant recipients. It carries an extremely poor prognosis. We report our experience of clinical findings, diagnostic procedures, treatment and outcome of mucormycosis diagnosed in neutropenic patients affected by hematologic neoplasms admitted to our Department. DESIGN AND METHODS. From November 1987 to July 1999 we observed 13 cases of Mucor. Their median age was 61 years (range 20-75), and they were predominantly in the aplastic post-chemotherapy period (12/13), affected by acute myeloid leukemia (11 cases ) or non-Hodgkin's lymphoma (2 cases). Six patients (all with leukemia) were receiving inductionEth consolidation therapy, 7 had progressive hematologic disease. At the onset of infection all patients were neutropenic (N < 0.5x10(9)/L). No patients had diabetes mellitus. Two patients had been receiving steroid therapy for 5 and 7 days. RESULTS. The lung was involved in all cases (13/13); disseminated disease was present in 8/13 patients. All cultures (blood, sputum, nasal swabs and bronchoalveolar lavage) were negative. In 3 patients a histologic diagnosis was made in vivo: in 1 patient by percutaneous pulmonary biopsy, in 1 patient by pulmonary lobectomy, and in the last patient by percutaneous pulmonary biopsy confirmed by excision of a cerebellar abscess. In the remaining 10 cases diagnosis was made post-mortem. Five patients were not treated, 2 because of poor clinical condition and 3 because fungal infection was not suspected. Amphotericin B (1 mg/kg/day) was given empirically to 6 patients and 2 responded to treatment. The remaining 2 patients with neurologic symptoms at the onset of infection were treated with liposomal amphotericin, Ambisome, one with 3 and one with 5 mg/kg/day; of these two patients the first died in 4 days; the second, with both pulmonary and cerebellar localizations, was treated successfully with 5 mg/kg/day for 4 weeks and then with 3 mg/kg/day, and excision of a brain abscess at neutrophil recovery (total dose of Ambisome: 12,000 mg). The 3 surviving leukemic patients were able to complete subsequent consolidation therapy using amphotericin B or liposomal amphotericin as secondary prophylaxis during aplasia. INTERPRETATION AND CONCLUSIONS. In neutropenic hematologic patients Mucor is rarely suspected. In our patients infection was often characterized by disseminated disease and a rapidly fatal course; only early aggressive amphotericin B (or Ambisome) treatment together with neutrophil recovery appeared to improve the outcome. Diagnosis is very important for programming antifungal therapy and secondary prophylaxis with amphotericin B, because Mucor is usually resistant to itraconazole.     

Failure of ketoconazole in two patients with blastomycosis

Two patients with severe pulmonary blastomycosis were treated with ketoconazole. One patient developed disseminated disease while receiving this drug. After responding to incomplete treatment with amphotericin B, this patient relapsed while continuing ketoconazole therapy. The second patient failed to respond to ketoconazole and died shortly after treatment with amphotericin B was instituted. We conclude that it is dangerous to use ketoconazole as initial treatment in patients with severe forms of blastomycosis. Death, relapse, and prolonged morbidity may be the result. In such cases, amphotericin B is still the drug of first choice despite its toxicity, inconvenience, and expense of administration.     

肺毛霉病三例临床分析

目的探讨肺毛霉病的临床表现、诊断和治疗方法。方法报道2006年我院收治的、经纤维支气管镜检查和组织病理确诊且具有完整资料的3例肺毛霉感染病例并结合国内外文献进行复习。结果3例均为农民，女2例，男1例，年龄42～48岁。例1和例2为糖尿病酮症酸中毒患者，例1在确诊次日因大咯血死亡；例2应用大剂量两性霉素B（总剂量2g）治愈；例3为肺鳞癌右上叶切除术后伴支气管狭窄，通过应用大剂量两性霉素B（总剂量1．5g）和支气管镜介入治疗成功治愈；例2和例3随诊0．5～1年均无复发。结论肺毛霉病患者痰培养阳性率极低，病死率很高。对临床可疑病例应及时行纤维支气管镜检查，并经组织病理学确诊；治疗的关键在于早期诊断、控制基础病、应用大剂量的两性霉素B和及时的外科手术。     

Pulmonary sporotrichosis: review of treatment and outcome

Four culture-documented cases of pulmonary sporotrichosis, three primary infections and one with multisystem involvement, are presented. Two of these patients are the first reported cases of primary lung disease treated with ketoconazole. This antifungal agent appears to be ineffective in eradicating this infection. The four cases, as well as a review of the literature, illustrate several important aspects of this rare disease. Pulmonary sporotrichosis is most commonly found in males with a history of alcohol abuse who are between the ages of 30 and 60. The infection is usually confined to the parenchyma of the lung but can involve hilar and mediastinal lymph nodes, pleura, skin, subcutaneous tissue, and joints. All but two cases have been reported in the United States, and the majority reside within states bordering the Missouri or Mississippi rivers. Direct occupational or environmental exposure appears to be an important predisposing risk factor. The onset of the disease is insidious, presenting in a manner similar to many other granulomatous or neoplastic diseases. Tuberculosis is the most common suspected diagnosis before confirmation of sporotrichosis. The chest radiograph most commonly demonstrates upperlobe cavitary disease with surrounding parenchymal infiltrates. The diagnosis can be suspected with high serologic titers or skin-test positivity, but needs to be confirmed by culture. The organism can usually be grown from sputum, as well as routine bronchoscopic procedures, open-lung biopsy specimens or pleural fluid. Histologic examination shows granulomas of both the caseating and noncaseating varieties. Frequently, organisms can be seen in necrotic areas of the lung tissue by diastase-modified GMS or PAS staining. Staining by direct fluorescent antibody technique can also be done and appears to be highly specific. Treatment is controversial, but total surgical resection of diseased lung as well as a perioperative regimen of SSKI or amphotericin B appears to be the most efficacious therapy. Medical therapy alone with SSKI or amphotericin B may be useful in selected cases but has been disappointing in the majority of reports. The imidazoles are usually ineffective, and the search for more effective medical therapy continues.     

A case of primary pulmonary sporotrichosis

We report the first case of primary pulmonary sporotrichosis in Japan. A 53-year-old man was admitted to our hospital for further examination of the abnormal shadows on chest X-ray film. Six months before admission, he was admitted to another hospital because of alcoholic liver disease and diabetes mellitus. Since the initial chest film showed cavities with infiltration in the left upper lung field, he was treated with antituberculous drugs despite negative sputum cultures for mycobacterium. In spite of the medication, his chest X-ray film revealed another cavitary lesion, so he was referred to our hospital. He had been asymptomatic during this period. Chest X-ray on admission disclosed multiple cavities in the left upper lobe and a cavity in the right lower lobe. Repeated sputum specimens, bronchial washings and brushings for cytology and cultures were all negative. In an attempt to clarify the pathogen, percutaneous lung aspiration (PLA) was performed. The PLA sample yielded a positive culture of Sporothrix shenckii. After the diagnosis, S. schenckii was also cultured from sputa. A sporothrix skin test and yeast agglutination test for S. schenckii were positive. In the absence of a history for skin lesion, the patient was diagnosed as a primary pulmonary sporotrichosis. As iodide therapy was ineffective, he was started on a regimen of intravenous amphotericin B. However his renal function progressively deteriorated, so amphotericin B was discontinued. Now he receives miconazole intravenously and is still under careful observation. As far as we know, this is the first report of primary pulmonary sporotrichosis in Japan. The possibility of sporotrichosis should be considered in any cases of undiagnosed cavitary lung diseases.     

Intra-articular amphotericin B treatment of Sporothrix schenckii arthritis

Arthritis caused by Sporothrix schenckii may not respond satisfactorily to a full course of intravenous amphotericin B therapy. Left untreated, the fungus continues to be recovered from cultures of joint fluid, and the patient typically has serious joint disability. We have shown in one patient with sporotrichosis of the knee that direct low-dose injections of amphotericin B can be performed safely, resulting in eradication of the fungus. The patient has had continued useful range of motion and weight bearing on the involved knee.     

Lipid-based amphotericin in pulmonary zygomycosis: safety and efficacy of high exposure in a renal allograft recipient

Zygomycosis is associated with a high mortality in immunosuppressed patients. Treatment typically includes surgical resection and administration of intravenous amphotericin B. Success of treatment may require withdrawal of immunosuppression, with risk of graft loss. We report the successful treatment of invasive pulmonary zygomycosis, following initial surgical resection, using very high doses of lipid-based amphotericin B without withdrawal of immunosuppression. The patient received daily doses up to 10 mg/kg/day (51 g cumulatively) of lipid-based amphotericin B along with a brief course of intrapleural amphotericin. Despite immunosuppression not being withdrawn, the patient's kidney allograft function remained stable. We conclude that high doses of lipid-based amphotericin B can be safe and effective as part of the treatment regimen for pulmonary zygomycosis.     

Sarcoidlike manifestations of histoplasmosis

We have evaluated 11 patients with sarcoidosis accompanied by laboratory evidence for histoplasmosis. Clinical findings were typical of those described in sarcoidosis. Eight patients were treated with corticosteroids and responded promptly without progression of histoplasmosis. One patient received a 35 mg/kg course of amphotericin B without clinical improvement, but responded appropriately to corticosteroid therapy. Another patient had positive sputum cultures for Histoplasma capsulatum 5 years after initial diagnosis of sarcoidosis, but showed no improvement in the pulmonary infiltrate after treatment with amphotericin B. Although histoplasmosis and sarcoidosis may be interrelated in several ways, we postulate that H capsulatum may have triggered a chronic inflammatory disease recognized as sarcoidosis in some of these patients, a hypothesis yet to be tested. Alternative explanations for the association of histoplasmosis and sarcoidosis include the coincidental occurrence of two separate illnesses in a "hyperendemic" area for histoplasmosis and false-positive serologic test results caused by the heightened humoral immune response observed in sarcoidosis.     

The use of ketoconazole in the treatment of blastomycosis

We retrospectively reviewed our experience using ketoconazole in the therapy of blastomycosis. Over the course of 30 months, blastomycosis was diagnosed in 11 patients. Their clinical presentations ranged from the asymptomatic pulmonary nodule to the adult respiratory distress syndrome. Six of 8 patients treated with ketoconazole completed a 6-month course of 400 mg daily. Seventeen to 40 months after completion of therapy, the patients who had completed 6 months of therapy were well. Ketoconazole should play a major role in the therapy of blastomycosis because of its efficacy and because its administrative costs are lower than those of amphotericin B. It can be recommended for patients who have been symptomatic for longer than 3 wk and are not improving and for those who undergo resection of an asymptomatic pulmonary nodule. Amphotericin B remains the drug of choice in patients with life-threatening illness who require ventilatory assistance, have developed renal failure, or have central nervous system involvement. Severely immunocompromised patients with disseminated disease should also be treated with amphotericin B. Patients treated with ketoconazole should have close medical follow-up.     

Central nervous system toxicity associated with liposomal amphotericin B therapy for cutaneous leishmaniasis

AmBisome (liposomal amphotericin B) is used for prophylaxis and treatment of fungal infections, treatment of visceral leishmaniasis, and more recently, treatment of cutaneous leishmaniasis. Although the package insert cites neurologic toxicities in up to 20% of cases, review of the literature did not reveal any specific cases describing this side effect, particularly in a patient without comorbidities. We describe a healthy 38-year-old male treated with liposomal amphotericin B for cutaneous leishmaniasis acquired during military duties in Iraq. Shortly after completion of his treatment course, he reported memory difficulties and confusion. Further evaluation revealed no other source, and his cognitive issues were attributed to liposomal amphotericin B toxicity. These issues resolved over a few weeks, which is consistent with data about the drug's tissue penetration and metabolism available in the literature. This is a potential side effect of liposomal amphotericin B that can be observed in otherwise healthy patients.     

Cluster of pulmonary infections caused by Cunninghamella bertholletiae in immunocompromised patients.

Cunninghamella bertholletiae is a rare cause of pulmonary mucormycosis. We describe a cluster of invasive pulmonary infections caused by C. bertholletiae in 4 immunocompromised patients that occurred during a 2-year period at 1 center. Three of the patients were receiving antifungal prophylaxis with itraconazole. Presenting symptoms were fever unresponsive to antibacterial chemotherapy, hemoptysis, and infiltrates on chest radiograms. Three patients were treated with liposomal amphotericin B. Only 1 patient survived.     

Intradialytic administration of amphotericin B: clinical observations on efficacy and safety

BACKGROUND: Amphotericin B is used commonly to treat fungal infections. Unfortunately, little information exists regarding the use of intravenous amphotericin B in patients with end-stage renal disease (ESRD). METHODS: We retrospectively reviewed the clinical course of patients receiving amphotericin B during hemodialysis (HD). Twenty-five episodes of systemic fungal infection occurring in 24 patients with ESRD treated with parenteral amphotericin B administered during HD were noted. Patients received a maintenance dose of 0.5 to 1.0 mg/kg amphotericin B intravenously thrice weekly during HD sessions. Twenty-three patients received either 500 or 1000 mg of amphotericin B, whereas 1 patient with AIDS received a total of 6,500 mg. RESULTS: Intradialytic hypotension developed in 27.7% of HD sessions during treatment with amphotericin B compared with 28.8% of 20 HD sessions evaluated before initiation of amphotericin B therapy. Four patients exhibited a temperature rise greater than 38.8 degrees C during drug infusion (1 episode per patient). Increases in heart rate and ventricular ectopy were rare. Serum potassium concentrations as well as Kt/V and urea reduction ratio did not change significantly. All patients (except the patient with AIDS) resolved their respective fungal infections. CONCLUSIONS: Intradialytic administration of amphotericin B was generally well tolerated. Our observations suggest that amphotericin B is effective and safe for outpatient intradialytic therapy when administered according to protocol.     

Chronic pulmonary histoplasmosis with declining complement fixation titers and persistence of positive sputum culture. A case report.

A patient with culturally proved chronic pulmonary histoplasmosis was treated with amphotericin B. Complement fixation titers decreased but sputum cultures remained positive for Histoplasma capsulatum 5 months after original therapy. Lobectomy and a subsequent course of amphotericin B were necessary. Exceeding the minimal inhibitory concentrations of amphotericin B did not eradicate the organism and declining complement fixation titers failed to have prognostic significance.     

Deep fungal infection in systemic lupus erythematosus - three cases reported, literature reviewed.

Three patients with systemic lupus erythematosus (SLE) and deep fungal infection are described. Two patients had disseminated cryptococcal infection and the third disseminated histoplasmosis. Allwere receiving corticosteroids at the time fungal infection developed. One patient with disseminated cryptococcosis improved after treatment with amphotericin B and 5-fluorocytosine. The other patient with disseminated cryptococcosis died before adequate therapy could be given. The patient with histoplasmosis responded satisfactorily to amphotericin B. A survey of the literature revealed 30 additional cases of deep fungal infection in patients with SLE, most of whom were on corticosteroid therapy. The majority of the patients had candidiasis (14 patients); 11 patients had severe cryptococcal infection. Other fungal infections reported were histoplasmosis, aspergillois, coccidioidomycosis, and maduromycosis caused by Allerscheria boydii. Twenty-seven patients died; in 22 death was related to the fungal infection. The fungal infection was not diagnosed until necropsy in at least 11 persons. Deep fungal infections should be considered whenever patients with SLE have fever of unknown origin, diffuse pulmonary infiltrates, or unexplained CNS symptoms.