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Therapy for Fungal Infections
Concise Review for Primary-Care Physicians Therapy for Fungal Infections GEORGE A. SAROSI, M.D.,
AND SCOTT F. D A VIES, M.D.
In the past, few pharmacologie agents were available for management of fungal disease. After the early introduction of amphotericin B and miconazole, the more recent advent of several new antifungal agents, including ketoconazole, fluconazole, and itraconazole has expanded the options for treatment of fungal infections. The dramatic increase in number of immunocompromised patients—both those with acquired immunodeficiency syndrome (AIDS) and those with immunosuppression for other reasons, such as organ transplantation—emphasizes the importance of therapeutic strategies for combating systemic myFungal infections continue to increase in importance because the number of immunocompromised patients is growing. In addition to posing special danger to patients with depressed immunity, the endemic mycoses of North America continue to infect hundreds of thousands of immunocompetent persons each year. Although most immunologically normal patients recover uneventfully, occasional patients do require specific antifungal therapy. The recent availability of several new antifungal drags makes it imperative that clinicians keep abreast of the indications for, recommended dosages of, and common side effects associated with the antifungal agents. In this review, the discussion will focus on individual mycoses because it is now possible to make a series of recommendations for the treatment of many fungal infections (Table 1). HISTOPLASMOSIS Most cases of acute histoplasmosis, even when symptomatic, resolve quickly without treatment. Usually, patients with acute infections are asymptomatic and do not seek medical attention. When the infecting aerosol is large, however—especially when the infection is acquired in a closed space—a serious From the Department of Medicine (G.A.S.), Santa Clara Valley Medical Center, San Jose, California, and Division of Pulmonary and Critical Care Medicine (S.F.D.), Hennepin County Medical Center, Minneapolis, Minnesota. Address reprint requests to Dr. S. F. Davies, Division of Pulmonary and Critical Care Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415-1829. MayoClinProc
1994;69:1111-1117
coses. In this article, we review our personal recommendations for treating histoplasmosis, blastomycosis, coccidioidomycosis, and cryptococcosis, along with other less common fungal infections, and discuss the efficacy and toxic effects of the various antifungal drugs. (Mayo Clin Proc 1994; 69:1111-1117) AIDS = acquired immunodeficiency syndrome; ΑΜΒ = amphotericin B; 5-FC = 5-fluorocytosine (flucytosine); HIV = human immunodeficiency virus; PDH = progressive disseminated histoplasmosis
and potentially lethal infection may develop. The infiltrates are diffuse and are often micronodular. The clinical picture may resemble the adult respiratory distress syndrome. Often, an invasive procedure is necessary for establishing the diagnosis. In nonimmunocompromised patients, the treatment of choice is amphotericin B (AMB), 500 to 1,000 mg (cumulative dose). The drug is highly effective, and patients usually respond within 1 or 2 weeks. No further therapy is needed. In contrast in immunocompromised patients, the same initial intensive therapy with AMB (usually, a total dose of 500 to 1,000 mg—to clinical stabilization) is followed by oral therapy with itraconazole (400 mg daily). In patients with reversible immunosuppression, oral therapy is continued until the immunosuppressed state is no longer present. In patients with moderate degrees of immunosuppression (for example, renal transplant recipients), oral treatment is continued for 6 to 12 months. In patients with severe immunosuppression, including all patients coinfected with human immunodeficiency virus (HIV), lifelong suppression with itraconazole is necessary.1 In patients with abnormal lungs, such as smokers with centrilobular emphysema, histoplasmosis often involves die upper lung zones and even appears cavitary as the infiltrate partly fills the abnormal airspaces. In approximately 20% of these patients, a progressive and destructive upper lobe infection ensues; when untreated, such an infection can result in further lung destruction and even death. The term "chronic cavitary histoplasmosis" has been applied to this clinical picture, which resembles tuberculosis clinically and roentgenographically. In many affected patients, ketoconazole therapy (400 to 800 mg daily for 6 to 12 months)
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© 1994 Mayo Foundation for Medical Education and Research
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Table 1.—Summary of Usual Therapy* for Systemic Mycosest Immunosuppressed host Type of infection Histoplasmosis Acute
Immunocompetent host Observe
Acute, with ventilatory failure
AMB (500-1,000 mg until improvement noted)
Cavitary
ITRA (400 mg/day for 6 mo) or KETO (400-800 mg/day for 6 mo) or AMB (35 mg/kg, total dose) AMB (500-1,000 mg until stable) then ITRA (400 mg/day for 6 mo) or AMB (40 mg/kg, total dose)
Progressive disseminated Blastomycosis Acute
Acute, with ventilatory failure Chronic pulmonary or extrapulmonary nonmeningeal Coccidioidomycosis Acute
Thin-walled cavity
Ruptured cavity with empyema and pneumothorax Rapidly progressive miliary Meningeal Patient awake Patient confused
Cryptococcosis Pulmonary
Extrapulmonary nonmeningeal Meningeal
Observe only if clinically improving at diagnosis, otherwise— ITRA (400 mg/day for 6 mo) or KETO (400-800 mg/day) AMB (500-1,000 mg until stable) then ITRA (400 mg/day) or KETO (400-800 mg/day) ITRA (400 mg/day for 6 mo) or KETO (400-800 mg/day for 6 mo) or AMB (2,000 mg, total dose) Observe, except "high-risk" patients!: rapid disease— AMB (1,500-2,000 mg, total dose); slow disease—FLU (400-800 mg for 12 mo) Observe if stable; symptomatic, enlarging—FLU (400 mg/day for 6 mo) or resect; high risk, even without symptoms—same as above AMB (1,500-2,500 mg, total dose)
Without AIDS AMB (500-1,000 mg) then ITRA (400 mg/day for 6 mo) AMB (1,000 mg) then ITRA (400 mg/day for 6 mo) or AMB (40 mg/kg, total dose) No specific information available; probably same as in immunocompetent host AMB (1,000 mg) then ITRA (400 mg/kg/day for 6 mo) or AMB (40 mg/kg, total dose)
With AIDS AMB (500-1,000 mg) then ITRA (400 mg/day for life) Same as above No information; probably same as above AMB (1,000 mg) then ITRA (400 mg/day for life)
AMB (1,000 mg) then ITRA (400 mg/day for 6 mo) or AMB (2,000-3,000 mg, total dose)
AMB (500-1,000 mg) then ITRA (400 mg/day for life)
Same as above
Same as above
AMB (500-1,000 mg until improvement noted) then ITRA (400 mg/day for 6-12 mo) or AMB (2,000-3,000 mg)
Same as above
Rapid disease—AMB (1,500-2,000 mg, total dose); slow disease— FLU (400 mg/day for 6-12 mo)
High-risk patients: rapid diseaseAMB (1,500-2,000 mg) then FLU (400-800 mg for life); slow disease—FLU (400-800 mg for life) FLU (400-800 mg for life)
FLU (400-800 mg/day for 6-12 mo)
AMB (1,500-2,500 mg, total dose) then FLU (400-800 mg/day for 12 mo) AMB (2,000-3,000 mg, total dose)
AMB (2,000-3,000 mg) then FLU (for life)
FLU (400-800 mg/day for 12 mo or longer, depending on symptoms) AMB (2,000-3,000 mg systemically + intracisternally 3x/wk until cultures neg, then decrease frequency); with improvement, FLU (400-800 mg/day for at least 12 mo)
FLU (400-800 mg/day, probably for life) Same as in immunocompetent host, but continue FLU (400-800 mg/day) for life (?)
FLU (400-800 mg for life) or AMB (2,000-3,000 mg systemically + intracisternally 3x/wk); once awake and cultures neg—FLU (400-800 mg for life)
Observe if LP neg; alternatively, FLU§ (200-400 mg/day)
AMB (0.7 mg/kg/day) with or without 5-FC (150 mg/kg/day) for 6 wk or until stable then FLU (200-400 mg/day for 12 mo) Same as above
AMB (0.7 mg/kg/day) + 5-FC (100 mg/kg/day) until stable then FLU (200-400 mg for life) Same as above
AMB (0.7 mg/kg/day) + 5-FC (150 mg/kg/day) for 6 wk; if awake and stable—FLU§ (400 mg/day for 6-12 mo)
Same as above
AMB (2,000-3,000 mg, total dose)
If stable—FLU (400 mg/day for 6 mo); if sick—AMB (0.4 mg/kg/day) + 5-FC (150 mg/kg/day) for 4 wk AMB (0.4 mg/kg/day) + 5-FC (150 mg/kg/day) for 4 wk; if awake and stable—FLU§ (400 mg/ day for 6-12 mo)
AMB (2,000-3,000 mg) then FLU (for life)
*Personal preferences of the authors; some recommendations remain controversial. tAIDS = acquired immunodeficiency syndrome; AMB = amphotericin B; 5-FC = 5-fluorocytosine (flucytosine); FLU = fluconazole; ITRA = itraconazole; KETO = ketoconazole; LP = lumbar puncture; neg = negative. ^Blacks and those with immunosuppression but without AIDS. §Role of this drug untested.
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yields improvement.2 When treatment is stopped, many patients experience a relapse and require re-treatment, either with ketoconazole again or with another orally administered agent such as itraconazole.3 Itraconazole (400 mg/day) is also effective as initial therapy.4 It is usually administered for 6 to 12 months, but the optimal duration of therapy and the exact risk of relapse after therapy are unknown. Occasionally, patients either fail to respond or else have repeated relapses after azole drug therapy is discontinued. For such patients, AMB is the best treatment. A minimal total cumulative dose of 35 mg/kg is administered during a 16- to 20week period. Even after this aggressive therapy, relapses can occur.5 Relapses in histoplasmosis are almost always due to defects in the host (either structural abnormalities in the lungs or depressed immunity) rather than to the development of drug resistance. Although progressive disseminated histoplasmosis (PDH) occasionally develops in immunocompetent patients, most cases occur in patients with depressed T-cell function. Patients with defective T-cell function include those infected with HIV and those receiving long-term corticosteroid therapy or long-term low-dose cytotoxic therapy. AMB is the preferred therapy for PDH. AMB is highly effective and usually curative if (1) the patient survives the first 1 or 2 weeks without succumbing to ventilatory failure, (2) an adequate total cumulative dose of AMB is given (usually, 40 mg/kg6), and (3) the patient has some degree of immunocompetence. With AMB, cure can be achieved even in the setting of solid organ transplantation and other moderate degrees of immunosuppression. Relapse is rare in patients who do not have the acquired immunodeficiency syndrome (AIDS), although it sometimes occurs in patients with Hodgkin's disease. In patients with AIDS, immunosuppression is severe and relentlessly progressive. Initial therapy with high-dose AMB is highly effective. After therapy with AMB is discontinued, relapse is almost universal. Ketoconazole is not an adequate maintenance drug.7 A maintenance regimen of weekly or biweekly infusions of AMB has been successful in preventing relapses.8 Studies by the Mycoses Study Group and the AIDS Clinical Trials Group have established that, after induction therapy with 500 to 1,000 mg of AMB, itraconazole (400 mg daily for life) is highly effective in preventing relapse of PDH in patients with AIDS.' BLASTOMYCOSIS Blastomycosis is far less common than histoplasmosis. The infection is coendemic with histoplasmosis throughout most of the central United States. As with histoplasmosis, many immunocompetent patients with acute blastomycosis recover without therapy. Recovery is likely if the disease is already subsiding when the diagnosis is made—a common
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situation because diagnostic delays often occur, including implementation of one or more courses of empiric antibacterial therapy.9 The difficulty in deciding which patients with acute blastomycosis should be treated cannot be overemphasized. Although we believe that many patients with acute blastomycosis can safely have weekly or biweekly follow-up surveillance of the disease, other investigators think that any patient with symptomatic blastomycosis should be treated as soon as it is diagnosed, even if the condition is improving. The drug of choice for acute non-life-threatening infection is itraconazole, 400 mg orally daily for at least 6 months.4 Despite its greater cost, it is usually recommended over ketoconazole because of higher perceived efficacy and lower toxicity. Ketoconazole (400 to 800 mg daily for 6 months) is also effective therapy for acute symptomatic blastomycosis,2 but it is associated with greater toxicity. Occasionally, patients with pulmonary blastomycosis have diffuse infiltrates and severe hypoxemia. The drug of choice is AMB, which should be administered until the patient's condition is stable (usually, a total cumulative dose of 500 to 1,000 mg). Itraconazole or ketoconazole can then be used in standard doses for a minimum of 6 additional months to complete therapy. In nonimmunocompromised patients with a stable condition, the treatment of nonmeningeal extrapulmonary disease is the same as the treatment of acute pulmonary blastomycosis. Ketoconazole and itraconazole are highly effective,2 and AMB can be reserved for rapidly progressive or refractory cases. When acute pulmonary blastomycosis with or without extrapulmonary involvement occurs in an immunocompromised patient, most authorities recommend 1,000 mg of AMB as primary therapy, followed by an azole for 6 months.10 AMB is effective for all types of blastomycosis, and a complete course (1,500 to 2,000 mg) of AMB should yield excellent results, especially in nonimmunocompromised patients. If blastomycosis involves the méninges, the treatment of choice is AMB. Although no controlled studies have been reported, most authorities recommend a total cumulative dose of 2,000 to 3,000 mg.9 When meningeal disease occurs in an immunocompromised patient, a prolonged course of AMB should be followed by either weekly administration of AMB (50 mg) or perhaps an extended course of therapy with itraconazole (400 mg daily).10 This latter therapy has been proposed, but inadequate data are available to support it as a firm recommendation. COCCIDIOIDOMYCOSIS In the United States, acute coccidioidomycosis is common in the endemic areas of the desert Southwest. Although most patients with acute pulmonary coccidioidomycosis recover without treatment, clinicians in the endemic area treat many
1114 THERAPY FOR FUNGAL INFECTIONS
patients with fluconazole (200 to 400 mg daily) for variable periods. No published studies have substantiated the effectiveness of this therapy. Most patients with disseminated coccidioidomycosis are in certain "high-risk" groups, including blacks, Filipinos, and immunocompromised patients. Because these high-risk patients have an increased likelihood of development of progressive disease—and because treatment of advanced disease is difficult—clinicians in the endemic area often treat acute coccidioidomycosis aggressively in these groups of patients. Sometimes, a total dose of 1,000 to 2,000 mg of AMB is used in an attempt to prevent progression," even though this therapeutic regimen has never been evaluated critically. Both ketoconazole and fluconazole have also been used extensively for this purpose, again without proven basis. Most experienced clinicians in the endemic area currently use fluconazole for 6 months in all high-risk patients with acute coccidioidomycosis. This therapy is logical as an attempt to prevent dissemination, but its efficacy has not been proved. Chronic residual cases of pulmonary coccidioidomycosis have also been treated with various regimens, even though the effectiveness of such treatment has not been carefully evaluated. The most common residual of acute pulmonary coccidioidomycosis is a persistent thin-walled cavity. Most authorities agree that such cavities can be observed and no treatment is necessary. When such cavities enlarge, however, or when symptoms develop (usually, a productive cough, hemoptysis, or both), treatment with fluconazole in a dosage of 400 mg for at least 6 months (or with AMB in a total dose of 1,000 to 1,500 mg) has been recommended." Alternatively, resection can be performed. Other findings associated with chronic pulmonary coccidioidomycosis (such as nodules or fibronodular infiltrates) can be treated with a course of AMB (1,000 to 2,500 mg) or with fluconazole (400 mg daily for at least 6 months). In occasional patients, a ruptured cavity complicates chronic pulmonary coccidioidomycosis. For such patients, who usually are very ill, we recommend AMB to a total dose of 1,500 to 2,500 mg in addition to chest tube drainage of the pleural space. Other investigators have used oral drug regimens, but we do not recommend orally administered agents because of the often rapid tempo of the disease. Although extrapulmonary dissemination of coccidioidomycosis can be slow moving, in a substantial minority of patients the tempo of the disease is rapid and death may occur. When the disease is indolent and the patient is immunocompetent, a course of fluconazole (400 mg daily for 6 to 12 months) can be tried, and AMB can be reserved for treatment failures. When the tempo of the disease is rapid or when the patient is in one of the high-risk groups, AMB should be given immediately. For such patients, we recom-
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mend a minimum of 3,000 mg of AMB. If the patient is immunocompromised, even higher total doses of AMB may be needed. Whether lifelong suppressive therapy (perhaps with fluconazole after an initial course of AMB) should be given to patients with permanent immunosuppression is unclear, but such therapy is probably prudent. Meningeal dissemination of coccidioidomycosis was uniformly fatal in pre-AMB days. Since the availability of AMB, the prognosis has improved somewhat, although the disease remains surprisingly stubborn.12 For treatment of concomitant occult extrapulmonary disease, most authorities recommend administration of 1,500 to 2,500 mg of AMB systemically. Successful treatment of coccidioidal meningitis with AMB always necessitates intrathecal administration of AMB as well, which can be accomplished either by repeated cisternal puncture or by the placement of a subcutaneous reservoir. Usually, lifelong intrathecal treatment with AMB is recommended. Initially, therapy should be given two or three times weekly. As stabilization is achieved, the interval between treatments can be extended to weeks or occasionally 1 month. Some investigators believe that after a period of 1 to 2 years, treatment can be discontinued if the coccidioidomycosis is stable. Eventually, some of these patients will have a relapse. Because treating coccidioidal meningitis with AMB intravenously and intrathecally is extremely difficult, the availability of nontoxic oral therapy with fluconazole is a major advance. A recently published study13 showed that coccidioidal meningitis can be treated successfully with 400 to 800 mg of fluconazole daily. Preliminary studies have reported the potential usefulness of itraconazole, 300 to 400 mg daily, in coccidioidal meningitis.14 In patients with HIV infection, coccidioidomycosis is exceedingly aggressive. In endemic areas, it is common and often highly lethal.15 In occasional HIV-infected patients with early disease and relatively preserved T-cell function, coccidioidomycosis resembles that seen in nonimmunocompromised patients. In such patients, stabilization can be accomplished with either AMB or fluconazole.15 For suppression, fluconazole therapy is continued for life. In most patients with HIV and coccidioidomycosis, however, diffuse nodular pulmonary infiltrates are common, and the tempo of the disease is rapid; high-dose AMB (probably 1,000 to 1,500 mg) should be used as primary therapy, followed by fluconazole for continued suppressive therapy. Many such patients die early during AMB therapy. CRYPTOCOCCOSIS Symptomatic pulmonary cryptococcosis is rarely diagnosed. In comparison, chronic meningitis due to Cryptococcus is considerably more common and has been better studied. When cryptococcal pneumonia has been detected in
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nonimmunocompromised patients without meningeal involvement, a period of observation is indicated; most such patients will recover spontaneously without treatment.16 Nevertheless, a minor risk of meningitis does exist. Because fluconazole is relatively nontoxic, some physicians treat all recognized cases of pulmonary cryptococcosis with fluconazole for variable periods. This approach has not been thoroughly studied. When pulmonary cryptococcosis occurs in immunosuppressed patients, progression to meningitis is expected. All such patients should be treated promptly.16 A lumbar puncture is also highly recommended, even though the presence or absence of cryptococcal meningitis will not change the therapeutic approach. Pulmonary cryptococcosis in immunocompromised patients without AIDS should be treated with AMB, 0.7 mg/kg daily, with or without flucytosine (5-fluorocytosine [5-FC]), in a dosage of 100 to 150 mg/kg daily.17 Such treatment has proved effective for cryptococcal meningitis in similar patients. In patients with normal findings on a lumbar puncture, use of only AMB may be effective for pulmonary cryptococcosis. The standard therapy for cryptococcal meningitis in immunocompetent patients is AMB, 0.4 mg/kg daily, in combination with 5-FC, 100 to 150 mg/kg daily, for 4 weeks. During 5-FC therapy, blood levels must be monitored carefully to prevent bone marrow toxicity. Treatment of meningeal cryptococcosis in immunocompromised hosts without HIV can be accomplished by the daily administration of AMB, 0.7 mg/kg, and 5-FC, 150 mg/ kg, for 4 weeks. If the patient has received a solid organ transplant, the treatment should be extended to 6 weeks.18 Although cryptococcal meningitis in HIV-infected patients has been studied extensively, the optimal treatment has not been determined. Our current recommendation is that all such patients should receive primary therapy with AMB, 0.7 mg/kg daily, and 5-FC (if tolerated), 100 mg/kg daily (the dose of 5-FC is reduced as needed to maintain serum levels at less than 100 μg/mL).17 Fluconazole is well absorbed and has excellent tissue penetration. Cerebrospinal fluid levels are at least 70% of serum levels. Because of these features, fluconazole may yet prove to be the ideal drug for stable cryptococcal meningitis. In a large comparative study of AMB and fluconazole, these two drugs had similar efficacy.19 That study, however, has been questioned because the daily dose of AMB used was low (0.4 mg/kg). Until an ongoing trial by the Mycoses Study Group has been completed, we continue to recommend that initial therapy be high-dose AMB (0.7 mg/kg daily), as previously mentioned, in combination with 5-FC.17 After successful induction treatment of cryptococcal meningitis, HIV-infected patients require lifetime maintenance treatment, ideally with fluconazole suppressive
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therapy. In a large comparative trial, fluconazole outperformed weekly administration of AMB.20 It should be used in a dosage of 200 mg/day for the life of the patient to prevent clinical relapse of cryptococcal meningitis. SPOROTRICHOSIS The common lymphocutaneous type of sporotrichosis responds well to a saturated solution of potassium iodide administered in a dosage of 10 to 15 drops orally three times daily. Although this is a time-honored therapy, it is cumbersome, and serious reactions to iodides are common. Itraconazole, 200 to 400 mg daily for 6 months, is effective and less toxic, although more expensive.21 Pulmonary sporotrichosis is uncommon; thus, the best treatment for such involvement has not been established.22 Whenever possible, cavitary disease should be resected. If resection is impossible and the tempo of the disease is rapid, AMB to a total cumulative dose of 2,000 mg can be tried. Many authorities believe that itraconazole, 400 mg/day, might be preferable to AMB.23 Similarly, nonmeningeal extrapulmonary spread of sporotrichosis can be treated by either AMB or itraconazole. ASPERGILLOSIS An intracavitary fungus ball caused by Aspergillus does not respond well to systemic antifungal therapy. It should be resected if the patient is symptomatic (usually with hemoptysis) and pulmonary function allows surgical intervention. For allergic bronchopulmonary aspergillosis, the standard treatment is adequate doses of glucocorticoids to reduce specific IgE levels to normal.24 Itraconazole may be adjunctive therapy for this type of aspergillosis, but its specific role has not yet been established. Frequently, disseminated aspergillosis complicates the immunocompromised state, especially when both neutrophils and macrophages are suppressed. The tempo of the disease often is rapid, and AMB has been recommended as standard therapy. Occasionally, even AMB is ineffective.25·26 Higher daily doses (up to 1.5 mg/kg) are used than for the endemic mycoses, but these doses have considerable toxicity. Liposomal AMB therapy, in dosages of 5 mg/kg daily or higher, is associated with less renal toxicity. The relative efficacy in comparison with the standard AMB formulation, however, has not been established. Of the orally administered agents, itraconazole has the best activity against aspergillosis.27 Several studies have reported variable success with use of itraconazole in carefully selected patients who had a moderate tempo of disease. Our current recommendation is that all critically ill patients should receive initial treatment with AMB. Once the disease has been stabilized, itraconazole can be administered in a dosage of 400 to 800 mg/day.
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Aspergillosis as a complication of HIV infection can be treated similarly. Although data are scarce, itraconazole may be effective in this setting. For other immunosuppressed patients, we continue to recommend AMB when the tempo of the disease is rapid and reserve itraconazole for patients who are less critically ill. ZYGOMYCOSIS For the treatment of zygomycosis (also known as mucormycosis), no controlled studies have been conducted for any type of involvement—sino-orbital disease, pulmonary disease, or disseminated disease. Most authorities agree that complete excision, whenever practical, followed by highdose AMB is the preferred strategy.28 The results are often poor, and most successfully treated patients have had extensive débridement of all necrotic tissue, followed by a variable course of AMB (usually 1,000 to 2,000 mg, total dose). PSEUDALLESCHERIASIS Pseudallescheriasis, an uncommon fungal infection, clinically resembles aspergillosis. It is the one fungal infection in which miconazole may be more active than AMB.29 Information about this infection is sparse, and treatment results are purely anecdotal. CANDIDIASIS The treatment of candidiasis is difficult to discuss intelligently. We will restrict our comments to candidemia, Candida endophthalmitis, renal candidiasis, and hepatosplenic candidiasis. The concept of benign or transient candidemia is flawed and should be abandoned. In most reported cases, candidemia occurs in the setting of indwelling catheters, multiple antibiotics, and glucocorticoid therapy. In a few affected patients, removal of the catheter apparently was adequate therapy because Candida subsequently cleared from the blood without other intervention. Recent information shows, however, that candidemia is a serious infection associated with high morbidity and mortality.30 In our opinion, every patient with candidemia should be treated because the risks are increased with no treatment. The treatment of choice for candidemia has been AMB and removal of the indwelling catheter. The cumulative total dose of AMB, although highly variable, is usually from 1,000 to 2,000 mg.30 In patients with proven catheter-associated candidemia, many clinicians recommend 500 mg of AMB. Because of the known synergy between AMB and 5FC, many authorities recommend the addition of 5-FC at the maximal tolerated dose. In a recent study,31 AMB was compared prospectively with fluconazole. Because patients with neutropenia were excluded, the results cannot yet be applied to such patients. In that carefully conducted study, fluconazole was as effec-
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tive as AMB for candidemia and was less toxic. When fluconazole is used to treat candidai infections, the organism should be identified to the species level, inasmuch as certain species such as C. krusei and C (Torulopsis) glabrata are likely to be resistant. The most common isolate recovered from clinical specimens is C. albicans, which is usually susceptible to fluconazole. Candida endophthalmitis, which invariably occurs as a result of candidemia, should always be treated with AMB, even if the patient does not have neutropenia. Experimental data do not support the use of fluconazole.32 Because of the high renal clearance of fluconazole, renal candidiasis can be treated effectively with this drug. The exact dose and duration of therapy have not been determined. For hepatosplenic candidiasis, a disease that frequently complicates the treatment of acute leukemia, fluconazole therapy has been successful. Two studies33-34 have shown good results equivalent to therapy with AMB; however, almost all patients had received AMB before randomization. Nevertheless, the best evidence suggests that fluconazole may be used as primary therapy in this group of patients. REFERENCES 1. Wheat J, Hafner R, Wulfsohn M, Spencer P, Squires K, Powderly W, et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1993; 118:610-616 2. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Treatment of blastomycosis and histoplasmosis with ketoconazole: results of a prospective randomized clinical trial. Ann Intern Med 1985;103:861-872 3. Quinones CA, Reuben AG, Hamill RJ, Musher DM, Gorin AB, Sarosi GA. Chronic cavitary histoplasmosis: failure of oral treatment with ketoconazole. Chest 1989;95:914-916 4. Dismukes WE, Bradsher RW Jr, Cloud GC, Kauffman CA, Chapman SW, George RB, et al. Itraconazole therapy for blastomycosis and histoplasmosis: NIAID Mycoses Study Group. Am J Med 1992; 93:489-497 5. Parker JD, Sarosi GA, Doto IL, Bailey RE, Tosh FE. Treatment of chronic pulmonary histoplasmosis. N Engl J Med 1970; 283:225229 6. Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histoplasmosis: results of long-term follow-up. Ann Intern Med 1971;75:511-516 7. Sarosi GA, Johnson PC. Disseminated histoplasmosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1992; 14(Suppl 1):S60-S67 8. McKinsey DS, Gupta MR, Riddler SA, Driks MR, Smith DL, Kurtin PJ. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;111:655-659 9. Sarosi GA, Davies SF, Phillips JR. Self-limited blastomycosis: a report of 39 cases. Semin Respir Infect 1986; 1:40-44 10. Pappas PG, Threlkeld MG, Bedsole GD, Cleveland KO, Gelfand MS, Dismukes WE. Blastomycosis in immunocompromised patients. Medicine 1993;72:311-325 11. American Thoracic Society. Treatment of fungal diseases. Am Rev Respir Dis 1979;120:1393-1397 12. Labadie EL, Hamilton RH. Survival improvement in coccidioidal meningitis by high-dose intrathecal amphotericin B. Arch Intern Med 1986; 146:2013-2018
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Galgiani JN, Catanzaro A, Cloud GA, Higgs J, Friedman BA, Larsen RA, et al. Fluconazole therapy for coccidioidal meningitis: the NIAID-Mycoses Study Group. Ann Intern Med 1993;119:28-35 Tucker RM, Denning DW, Dupont B, Stevens DA. Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med 1990; 112:108-112 Fish DG, Ampel NM, Galgiani JN, Dois CL, Kelly PC, Johnson CH, et al. Coccidioidomycosis during human immunodeficiency virus infection: a review of 77 patients. Medicine 1990;69:384-391 Kerkering TM, Duma RJ, Shadomy S. The evolution of pulmonary cryptococcosis: clinical implications from a study of 41 patients with and without compromising host factors. Ann Intern Med 1981; 94:611-616 Sugar AM, Saunders C. Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med 1988;85:481-489 Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. NEnglJMed 1987;317:334-341 Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. NEnglJMed 1992;326:83-89 Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jacobson JM, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992; 326:793-798 Restrepo A, Robledo J, Gomen I, Tabares AM, Gutierrez R. Itraconazole therapy in lymphangitic and cutaneous sporotrichosis. Arch Dermatol 1986; 122:413-417 Gerding DN. Sporotrichosis. In: Sarosi GA, Davies SF, editors. Fungal Diseases of the Lung. 2nd ed. New York: Raven Press, 1993: 113-123 Sharkey-Mathis PK, Kauffman CA, Graybill JR, Stevens DA, Hostetler JS, Cloud G, et al. Treatment of sporotrichosis with itraconazole. Am J Med 1993;95:279-285
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28. 29.
30. 31.
32. 33. 34.
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Wang JL, Patterson R, Roberts M, Ghory AC. The management of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1979; 120:87-92 Fisher BD, Armstrong D, Yu B, Gold JW. Invasive aspergillosis: progress in early diagnosis and treatment. Am J Med 1981; 71:571577 Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis 1990; 12:1147-1201 Denning DW, Lee JY, Hostetler JS, Pappas P, Kauffman CA, Dewsnup DH, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med 1994;97:135-144 Walsh TJ, Rinaldi MR, Pizzo PA. Zygomycosis of the respiratory tract. In: Sarosi GA, Davies SF, editors. Fungal Diseases of the Lung. 2nd ed. New York: Raven Press, 1993: 149-170 Patterson TF, Andriole VT, Zervos MJ, Therasse D, Kauffman CA. The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection. Mycoses 1990; 33:297-302 Edwards JE Jr, Filler SG. Current strategies for treating invasive candidiasis: emphasis on infections in nonneutropenic patients. Clin Infect Dis 1992; 14(Suppl 1):S106-S113 Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM, Edwards JE, et al. Fluconazole (FLU) vs. amphotericin B (AMB) for treatment of candidemia: results of a randomized, multicenter trial [abstract]. Intersci Conf Antimicrob Agents Chemother Program Abstr 1993; 33:267 Savani DV, Perfect JR, Cobo LM, Durack DT. Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother 1987;31:6-10 Kauffman CA, Bradley SF, Ross SC, Weber DR. Hepatosplenic candidiasis: successful treatment with fluconazole. Am J Med 1991;91:137-141 Anaissie E, Bodey GP, Kantarjian H, David C, Barnett K, Bow E, et al. Fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior amphotericin B therapy. Am J Med 1991;91:142-150
Questions About Therapy for Fungal Infections (See article, pages mi to ill?) Note: Select the single best answer. 1.
The best initial therapy for a patient with lifethreatening pulmonary blastomycosis (diffuse pulmonary infiltrates and severe hypoxemia) is: a. b. c. d.
2.
Orally administered ketoconazole Orally administered itraconazole Intravenously administered miconazole Intravenously administered amphotericin B
Treatment of progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome should include: a. Induction therapy with amphotericin B (500 to 1,000 mg), followed by lifetime maintenance therapy with ketoconazole b. A total cumulative dose of 3,000 mg of amphotericin B, to effect a lasting cure and prevent relapse c. Induction therapy with amphotericin B (500 to 1,000 mg), followed by lifetime maintenance therapy with itraconazole d. Oral therapy with ketoconazole for 6 to 12 months
3.
Mild to moderate cases of pulmonary or disseminated blastomycosis in immunocompetent patients can be effectively treated with: a. b. c. d.
4.
Itraconazole, 400 mg daily for 6 months Amphotericin B, total cumulative dose of 2,000 mg Ketoconazole, 400 to 800 mg daily for 6 months All of the above
The type and duration of therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection are: a. Amphotericin B (0.7 mg/kg daily) plus flucytosine for 4 weeks b. Amphotericin B (0.7 mg/kg daily) plus flucytosine for 6 weeks c. Induction therapy with amphotericin B (0.7 mg/kg daily) plus flucytosine (if tolerated) until improvement, followed by oral lifetime maintenance therapy with fluconazole (200 mg/day) d. Amphotericin B only, total cumulative dose of 2,000 mg
Correct answers: o-p ' ? χ 'o-Z
'p\
AND SCOTT F. D A VIES, M.D.
In the past, few pharmacologie agents were available for management of fungal disease. After the early introduction of amphotericin B and miconazole, the more recent advent of several new antifungal agents, including ketoconazole, fluconazole, and itraconazole has expanded the options for treatment of fungal infections. The dramatic increase in number of immunocompromised patients—both those with acquired immunodeficiency syndrome (AIDS) and those with immunosuppression for other reasons, such as organ transplantation—emphasizes the importance of therapeutic strategies for combating systemic myFungal infections continue to increase in importance because the number of immunocompromised patients is growing. In addition to posing special danger to patients with depressed immunity, the endemic mycoses of North America continue to infect hundreds of thousands of immunocompetent persons each year. Although most immunologically normal patients recover uneventfully, occasional patients do require specific antifungal therapy. The recent availability of several new antifungal drags makes it imperative that clinicians keep abreast of the indications for, recommended dosages of, and common side effects associated with the antifungal agents. In this review, the discussion will focus on individual mycoses because it is now possible to make a series of recommendations for the treatment of many fungal infections (Table 1). HISTOPLASMOSIS Most cases of acute histoplasmosis, even when symptomatic, resolve quickly without treatment. Usually, patients with acute infections are asymptomatic and do not seek medical attention. When the infecting aerosol is large, however—especially when the infection is acquired in a closed space—a serious From the Department of Medicine (G.A.S.), Santa Clara Valley Medical Center, San Jose, California, and Division of Pulmonary and Critical Care Medicine (S.F.D.), Hennepin County Medical Center, Minneapolis, Minnesota. Address reprint requests to Dr. S. F. Davies, Division of Pulmonary and Critical Care Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415-1829. MayoClinProc
1994;69:1111-1117
coses. In this article, we review our personal recommendations for treating histoplasmosis, blastomycosis, coccidioidomycosis, and cryptococcosis, along with other less common fungal infections, and discuss the efficacy and toxic effects of the various antifungal drugs. (Mayo Clin Proc 1994; 69:1111-1117) AIDS = acquired immunodeficiency syndrome; ΑΜΒ = amphotericin B; 5-FC = 5-fluorocytosine (flucytosine); HIV = human immunodeficiency virus; PDH = progressive disseminated histoplasmosis
and potentially lethal infection may develop. The infiltrates are diffuse and are often micronodular. The clinical picture may resemble the adult respiratory distress syndrome. Often, an invasive procedure is necessary for establishing the diagnosis. In nonimmunocompromised patients, the treatment of choice is amphotericin B (AMB), 500 to 1,000 mg (cumulative dose). The drug is highly effective, and patients usually respond within 1 or 2 weeks. No further therapy is needed. In contrast in immunocompromised patients, the same initial intensive therapy with AMB (usually, a total dose of 500 to 1,000 mg—to clinical stabilization) is followed by oral therapy with itraconazole (400 mg daily). In patients with reversible immunosuppression, oral therapy is continued until the immunosuppressed state is no longer present. In patients with moderate degrees of immunosuppression (for example, renal transplant recipients), oral treatment is continued for 6 to 12 months. In patients with severe immunosuppression, including all patients coinfected with human immunodeficiency virus (HIV), lifelong suppression with itraconazole is necessary.1 In patients with abnormal lungs, such as smokers with centrilobular emphysema, histoplasmosis often involves die upper lung zones and even appears cavitary as the infiltrate partly fills the abnormal airspaces. In approximately 20% of these patients, a progressive and destructive upper lobe infection ensues; when untreated, such an infection can result in further lung destruction and even death. The term "chronic cavitary histoplasmosis" has been applied to this clinical picture, which resembles tuberculosis clinically and roentgenographically. In many affected patients, ketoconazole therapy (400 to 800 mg daily for 6 to 12 months)
1111
© 1994 Mayo Foundation for Medical Education and Research
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1112 THERAPY FOR FUNGAL INFECTIONS
Table 1.—Summary of Usual Therapy* for Systemic Mycosest Immunosuppressed host Type of infection Histoplasmosis Acute
Immunocompetent host Observe
Acute, with ventilatory failure
AMB (500-1,000 mg until improvement noted)
Cavitary
ITRA (400 mg/day for 6 mo) or KETO (400-800 mg/day for 6 mo) or AMB (35 mg/kg, total dose) AMB (500-1,000 mg until stable) then ITRA (400 mg/day for 6 mo) or AMB (40 mg/kg, total dose)
Progressive disseminated Blastomycosis Acute
Acute, with ventilatory failure Chronic pulmonary or extrapulmonary nonmeningeal Coccidioidomycosis Acute
Thin-walled cavity
Ruptured cavity with empyema and pneumothorax Rapidly progressive miliary Meningeal Patient awake Patient confused
Cryptococcosis Pulmonary
Extrapulmonary nonmeningeal Meningeal
Observe only if clinically improving at diagnosis, otherwise— ITRA (400 mg/day for 6 mo) or KETO (400-800 mg/day) AMB (500-1,000 mg until stable) then ITRA (400 mg/day) or KETO (400-800 mg/day) ITRA (400 mg/day for 6 mo) or KETO (400-800 mg/day for 6 mo) or AMB (2,000 mg, total dose) Observe, except "high-risk" patients!: rapid disease— AMB (1,500-2,000 mg, total dose); slow disease—FLU (400-800 mg for 12 mo) Observe if stable; symptomatic, enlarging—FLU (400 mg/day for 6 mo) or resect; high risk, even without symptoms—same as above AMB (1,500-2,500 mg, total dose)
Without AIDS AMB (500-1,000 mg) then ITRA (400 mg/day for 6 mo) AMB (1,000 mg) then ITRA (400 mg/day for 6 mo) or AMB (40 mg/kg, total dose) No specific information available; probably same as in immunocompetent host AMB (1,000 mg) then ITRA (400 mg/kg/day for 6 mo) or AMB (40 mg/kg, total dose)
With AIDS AMB (500-1,000 mg) then ITRA (400 mg/day for life) Same as above No information; probably same as above AMB (1,000 mg) then ITRA (400 mg/day for life)
AMB (1,000 mg) then ITRA (400 mg/day for 6 mo) or AMB (2,000-3,000 mg, total dose)
AMB (500-1,000 mg) then ITRA (400 mg/day for life)
Same as above
Same as above
AMB (500-1,000 mg until improvement noted) then ITRA (400 mg/day for 6-12 mo) or AMB (2,000-3,000 mg)
Same as above
Rapid disease—AMB (1,500-2,000 mg, total dose); slow disease— FLU (400 mg/day for 6-12 mo)
High-risk patients: rapid diseaseAMB (1,500-2,000 mg) then FLU (400-800 mg for life); slow disease—FLU (400-800 mg for life) FLU (400-800 mg for life)
FLU (400-800 mg/day for 6-12 mo)
AMB (1,500-2,500 mg, total dose) then FLU (400-800 mg/day for 12 mo) AMB (2,000-3,000 mg, total dose)
AMB (2,000-3,000 mg) then FLU (for life)
FLU (400-800 mg/day for 12 mo or longer, depending on symptoms) AMB (2,000-3,000 mg systemically + intracisternally 3x/wk until cultures neg, then decrease frequency); with improvement, FLU (400-800 mg/day for at least 12 mo)
FLU (400-800 mg/day, probably for life) Same as in immunocompetent host, but continue FLU (400-800 mg/day) for life (?)
FLU (400-800 mg for life) or AMB (2,000-3,000 mg systemically + intracisternally 3x/wk); once awake and cultures neg—FLU (400-800 mg for life)
Observe if LP neg; alternatively, FLU§ (200-400 mg/day)
AMB (0.7 mg/kg/day) with or without 5-FC (150 mg/kg/day) for 6 wk or until stable then FLU (200-400 mg/day for 12 mo) Same as above
AMB (0.7 mg/kg/day) + 5-FC (100 mg/kg/day) until stable then FLU (200-400 mg for life) Same as above
AMB (0.7 mg/kg/day) + 5-FC (150 mg/kg/day) for 6 wk; if awake and stable—FLU§ (400 mg/day for 6-12 mo)
Same as above
AMB (2,000-3,000 mg, total dose)
If stable—FLU (400 mg/day for 6 mo); if sick—AMB (0.4 mg/kg/day) + 5-FC (150 mg/kg/day) for 4 wk AMB (0.4 mg/kg/day) + 5-FC (150 mg/kg/day) for 4 wk; if awake and stable—FLU§ (400 mg/ day for 6-12 mo)
AMB (2,000-3,000 mg) then FLU (for life)
*Personal preferences of the authors; some recommendations remain controversial. tAIDS = acquired immunodeficiency syndrome; AMB = amphotericin B; 5-FC = 5-fluorocytosine (flucytosine); FLU = fluconazole; ITRA = itraconazole; KETO = ketoconazole; LP = lumbar puncture; neg = negative. ^Blacks and those with immunosuppression but without AIDS. §Role of this drug untested.
Mayo Clin Proc, November 1994, Vol 69
yields improvement.2 When treatment is stopped, many patients experience a relapse and require re-treatment, either with ketoconazole again or with another orally administered agent such as itraconazole.3 Itraconazole (400 mg/day) is also effective as initial therapy.4 It is usually administered for 6 to 12 months, but the optimal duration of therapy and the exact risk of relapse after therapy are unknown. Occasionally, patients either fail to respond or else have repeated relapses after azole drug therapy is discontinued. For such patients, AMB is the best treatment. A minimal total cumulative dose of 35 mg/kg is administered during a 16- to 20week period. Even after this aggressive therapy, relapses can occur.5 Relapses in histoplasmosis are almost always due to defects in the host (either structural abnormalities in the lungs or depressed immunity) rather than to the development of drug resistance. Although progressive disseminated histoplasmosis (PDH) occasionally develops in immunocompetent patients, most cases occur in patients with depressed T-cell function. Patients with defective T-cell function include those infected with HIV and those receiving long-term corticosteroid therapy or long-term low-dose cytotoxic therapy. AMB is the preferred therapy for PDH. AMB is highly effective and usually curative if (1) the patient survives the first 1 or 2 weeks without succumbing to ventilatory failure, (2) an adequate total cumulative dose of AMB is given (usually, 40 mg/kg6), and (3) the patient has some degree of immunocompetence. With AMB, cure can be achieved even in the setting of solid organ transplantation and other moderate degrees of immunosuppression. Relapse is rare in patients who do not have the acquired immunodeficiency syndrome (AIDS), although it sometimes occurs in patients with Hodgkin's disease. In patients with AIDS, immunosuppression is severe and relentlessly progressive. Initial therapy with high-dose AMB is highly effective. After therapy with AMB is discontinued, relapse is almost universal. Ketoconazole is not an adequate maintenance drug.7 A maintenance regimen of weekly or biweekly infusions of AMB has been successful in preventing relapses.8 Studies by the Mycoses Study Group and the AIDS Clinical Trials Group have established that, after induction therapy with 500 to 1,000 mg of AMB, itraconazole (400 mg daily for life) is highly effective in preventing relapse of PDH in patients with AIDS.' BLASTOMYCOSIS Blastomycosis is far less common than histoplasmosis. The infection is coendemic with histoplasmosis throughout most of the central United States. As with histoplasmosis, many immunocompetent patients with acute blastomycosis recover without therapy. Recovery is likely if the disease is already subsiding when the diagnosis is made—a common
THERAPY FOR FUNGAL INFECTIONS
1113
situation because diagnostic delays often occur, including implementation of one or more courses of empiric antibacterial therapy.9 The difficulty in deciding which patients with acute blastomycosis should be treated cannot be overemphasized. Although we believe that many patients with acute blastomycosis can safely have weekly or biweekly follow-up surveillance of the disease, other investigators think that any patient with symptomatic blastomycosis should be treated as soon as it is diagnosed, even if the condition is improving. The drug of choice for acute non-life-threatening infection is itraconazole, 400 mg orally daily for at least 6 months.4 Despite its greater cost, it is usually recommended over ketoconazole because of higher perceived efficacy and lower toxicity. Ketoconazole (400 to 800 mg daily for 6 months) is also effective therapy for acute symptomatic blastomycosis,2 but it is associated with greater toxicity. Occasionally, patients with pulmonary blastomycosis have diffuse infiltrates and severe hypoxemia. The drug of choice is AMB, which should be administered until the patient's condition is stable (usually, a total cumulative dose of 500 to 1,000 mg). Itraconazole or ketoconazole can then be used in standard doses for a minimum of 6 additional months to complete therapy. In nonimmunocompromised patients with a stable condition, the treatment of nonmeningeal extrapulmonary disease is the same as the treatment of acute pulmonary blastomycosis. Ketoconazole and itraconazole are highly effective,2 and AMB can be reserved for rapidly progressive or refractory cases. When acute pulmonary blastomycosis with or without extrapulmonary involvement occurs in an immunocompromised patient, most authorities recommend 1,000 mg of AMB as primary therapy, followed by an azole for 6 months.10 AMB is effective for all types of blastomycosis, and a complete course (1,500 to 2,000 mg) of AMB should yield excellent results, especially in nonimmunocompromised patients. If blastomycosis involves the méninges, the treatment of choice is AMB. Although no controlled studies have been reported, most authorities recommend a total cumulative dose of 2,000 to 3,000 mg.9 When meningeal disease occurs in an immunocompromised patient, a prolonged course of AMB should be followed by either weekly administration of AMB (50 mg) or perhaps an extended course of therapy with itraconazole (400 mg daily).10 This latter therapy has been proposed, but inadequate data are available to support it as a firm recommendation. COCCIDIOIDOMYCOSIS In the United States, acute coccidioidomycosis is common in the endemic areas of the desert Southwest. Although most patients with acute pulmonary coccidioidomycosis recover without treatment, clinicians in the endemic area treat many
1114 THERAPY FOR FUNGAL INFECTIONS
patients with fluconazole (200 to 400 mg daily) for variable periods. No published studies have substantiated the effectiveness of this therapy. Most patients with disseminated coccidioidomycosis are in certain "high-risk" groups, including blacks, Filipinos, and immunocompromised patients. Because these high-risk patients have an increased likelihood of development of progressive disease—and because treatment of advanced disease is difficult—clinicians in the endemic area often treat acute coccidioidomycosis aggressively in these groups of patients. Sometimes, a total dose of 1,000 to 2,000 mg of AMB is used in an attempt to prevent progression," even though this therapeutic regimen has never been evaluated critically. Both ketoconazole and fluconazole have also been used extensively for this purpose, again without proven basis. Most experienced clinicians in the endemic area currently use fluconazole for 6 months in all high-risk patients with acute coccidioidomycosis. This therapy is logical as an attempt to prevent dissemination, but its efficacy has not been proved. Chronic residual cases of pulmonary coccidioidomycosis have also been treated with various regimens, even though the effectiveness of such treatment has not been carefully evaluated. The most common residual of acute pulmonary coccidioidomycosis is a persistent thin-walled cavity. Most authorities agree that such cavities can be observed and no treatment is necessary. When such cavities enlarge, however, or when symptoms develop (usually, a productive cough, hemoptysis, or both), treatment with fluconazole in a dosage of 400 mg for at least 6 months (or with AMB in a total dose of 1,000 to 1,500 mg) has been recommended." Alternatively, resection can be performed. Other findings associated with chronic pulmonary coccidioidomycosis (such as nodules or fibronodular infiltrates) can be treated with a course of AMB (1,000 to 2,500 mg) or with fluconazole (400 mg daily for at least 6 months). In occasional patients, a ruptured cavity complicates chronic pulmonary coccidioidomycosis. For such patients, who usually are very ill, we recommend AMB to a total dose of 1,500 to 2,500 mg in addition to chest tube drainage of the pleural space. Other investigators have used oral drug regimens, but we do not recommend orally administered agents because of the often rapid tempo of the disease. Although extrapulmonary dissemination of coccidioidomycosis can be slow moving, in a substantial minority of patients the tempo of the disease is rapid and death may occur. When the disease is indolent and the patient is immunocompetent, a course of fluconazole (400 mg daily for 6 to 12 months) can be tried, and AMB can be reserved for treatment failures. When the tempo of the disease is rapid or when the patient is in one of the high-risk groups, AMB should be given immediately. For such patients, we recom-
Mayo Clin Proc, November 1994, Vol 69
mend a minimum of 3,000 mg of AMB. If the patient is immunocompromised, even higher total doses of AMB may be needed. Whether lifelong suppressive therapy (perhaps with fluconazole after an initial course of AMB) should be given to patients with permanent immunosuppression is unclear, but such therapy is probably prudent. Meningeal dissemination of coccidioidomycosis was uniformly fatal in pre-AMB days. Since the availability of AMB, the prognosis has improved somewhat, although the disease remains surprisingly stubborn.12 For treatment of concomitant occult extrapulmonary disease, most authorities recommend administration of 1,500 to 2,500 mg of AMB systemically. Successful treatment of coccidioidal meningitis with AMB always necessitates intrathecal administration of AMB as well, which can be accomplished either by repeated cisternal puncture or by the placement of a subcutaneous reservoir. Usually, lifelong intrathecal treatment with AMB is recommended. Initially, therapy should be given two or three times weekly. As stabilization is achieved, the interval between treatments can be extended to weeks or occasionally 1 month. Some investigators believe that after a period of 1 to 2 years, treatment can be discontinued if the coccidioidomycosis is stable. Eventually, some of these patients will have a relapse. Because treating coccidioidal meningitis with AMB intravenously and intrathecally is extremely difficult, the availability of nontoxic oral therapy with fluconazole is a major advance. A recently published study13 showed that coccidioidal meningitis can be treated successfully with 400 to 800 mg of fluconazole daily. Preliminary studies have reported the potential usefulness of itraconazole, 300 to 400 mg daily, in coccidioidal meningitis.14 In patients with HIV infection, coccidioidomycosis is exceedingly aggressive. In endemic areas, it is common and often highly lethal.15 In occasional HIV-infected patients with early disease and relatively preserved T-cell function, coccidioidomycosis resembles that seen in nonimmunocompromised patients. In such patients, stabilization can be accomplished with either AMB or fluconazole.15 For suppression, fluconazole therapy is continued for life. In most patients with HIV and coccidioidomycosis, however, diffuse nodular pulmonary infiltrates are common, and the tempo of the disease is rapid; high-dose AMB (probably 1,000 to 1,500 mg) should be used as primary therapy, followed by fluconazole for continued suppressive therapy. Many such patients die early during AMB therapy. CRYPTOCOCCOSIS Symptomatic pulmonary cryptococcosis is rarely diagnosed. In comparison, chronic meningitis due to Cryptococcus is considerably more common and has been better studied. When cryptococcal pneumonia has been detected in
Mayo Clin Proc, November 1994, Vol 69
nonimmunocompromised patients without meningeal involvement, a period of observation is indicated; most such patients will recover spontaneously without treatment.16 Nevertheless, a minor risk of meningitis does exist. Because fluconazole is relatively nontoxic, some physicians treat all recognized cases of pulmonary cryptococcosis with fluconazole for variable periods. This approach has not been thoroughly studied. When pulmonary cryptococcosis occurs in immunosuppressed patients, progression to meningitis is expected. All such patients should be treated promptly.16 A lumbar puncture is also highly recommended, even though the presence or absence of cryptococcal meningitis will not change the therapeutic approach. Pulmonary cryptococcosis in immunocompromised patients without AIDS should be treated with AMB, 0.7 mg/kg daily, with or without flucytosine (5-fluorocytosine [5-FC]), in a dosage of 100 to 150 mg/kg daily.17 Such treatment has proved effective for cryptococcal meningitis in similar patients. In patients with normal findings on a lumbar puncture, use of only AMB may be effective for pulmonary cryptococcosis. The standard therapy for cryptococcal meningitis in immunocompetent patients is AMB, 0.4 mg/kg daily, in combination with 5-FC, 100 to 150 mg/kg daily, for 4 weeks. During 5-FC therapy, blood levels must be monitored carefully to prevent bone marrow toxicity. Treatment of meningeal cryptococcosis in immunocompromised hosts without HIV can be accomplished by the daily administration of AMB, 0.7 mg/kg, and 5-FC, 150 mg/ kg, for 4 weeks. If the patient has received a solid organ transplant, the treatment should be extended to 6 weeks.18 Although cryptococcal meningitis in HIV-infected patients has been studied extensively, the optimal treatment has not been determined. Our current recommendation is that all such patients should receive primary therapy with AMB, 0.7 mg/kg daily, and 5-FC (if tolerated), 100 mg/kg daily (the dose of 5-FC is reduced as needed to maintain serum levels at less than 100 μg/mL).17 Fluconazole is well absorbed and has excellent tissue penetration. Cerebrospinal fluid levels are at least 70% of serum levels. Because of these features, fluconazole may yet prove to be the ideal drug for stable cryptococcal meningitis. In a large comparative study of AMB and fluconazole, these two drugs had similar efficacy.19 That study, however, has been questioned because the daily dose of AMB used was low (0.4 mg/kg). Until an ongoing trial by the Mycoses Study Group has been completed, we continue to recommend that initial therapy be high-dose AMB (0.7 mg/kg daily), as previously mentioned, in combination with 5-FC.17 After successful induction treatment of cryptococcal meningitis, HIV-infected patients require lifetime maintenance treatment, ideally with fluconazole suppressive
THERAPY FOR FUNGAL INFECTIONS
1115
therapy. In a large comparative trial, fluconazole outperformed weekly administration of AMB.20 It should be used in a dosage of 200 mg/day for the life of the patient to prevent clinical relapse of cryptococcal meningitis. SPOROTRICHOSIS The common lymphocutaneous type of sporotrichosis responds well to a saturated solution of potassium iodide administered in a dosage of 10 to 15 drops orally three times daily. Although this is a time-honored therapy, it is cumbersome, and serious reactions to iodides are common. Itraconazole, 200 to 400 mg daily for 6 months, is effective and less toxic, although more expensive.21 Pulmonary sporotrichosis is uncommon; thus, the best treatment for such involvement has not been established.22 Whenever possible, cavitary disease should be resected. If resection is impossible and the tempo of the disease is rapid, AMB to a total cumulative dose of 2,000 mg can be tried. Many authorities believe that itraconazole, 400 mg/day, might be preferable to AMB.23 Similarly, nonmeningeal extrapulmonary spread of sporotrichosis can be treated by either AMB or itraconazole. ASPERGILLOSIS An intracavitary fungus ball caused by Aspergillus does not respond well to systemic antifungal therapy. It should be resected if the patient is symptomatic (usually with hemoptysis) and pulmonary function allows surgical intervention. For allergic bronchopulmonary aspergillosis, the standard treatment is adequate doses of glucocorticoids to reduce specific IgE levels to normal.24 Itraconazole may be adjunctive therapy for this type of aspergillosis, but its specific role has not yet been established. Frequently, disseminated aspergillosis complicates the immunocompromised state, especially when both neutrophils and macrophages are suppressed. The tempo of the disease often is rapid, and AMB has been recommended as standard therapy. Occasionally, even AMB is ineffective.25·26 Higher daily doses (up to 1.5 mg/kg) are used than for the endemic mycoses, but these doses have considerable toxicity. Liposomal AMB therapy, in dosages of 5 mg/kg daily or higher, is associated with less renal toxicity. The relative efficacy in comparison with the standard AMB formulation, however, has not been established. Of the orally administered agents, itraconazole has the best activity against aspergillosis.27 Several studies have reported variable success with use of itraconazole in carefully selected patients who had a moderate tempo of disease. Our current recommendation is that all critically ill patients should receive initial treatment with AMB. Once the disease has been stabilized, itraconazole can be administered in a dosage of 400 to 800 mg/day.
1116 THERAPY FOR FUNGAL INFECTIONS
Aspergillosis as a complication of HIV infection can be treated similarly. Although data are scarce, itraconazole may be effective in this setting. For other immunosuppressed patients, we continue to recommend AMB when the tempo of the disease is rapid and reserve itraconazole for patients who are less critically ill. ZYGOMYCOSIS For the treatment of zygomycosis (also known as mucormycosis), no controlled studies have been conducted for any type of involvement—sino-orbital disease, pulmonary disease, or disseminated disease. Most authorities agree that complete excision, whenever practical, followed by highdose AMB is the preferred strategy.28 The results are often poor, and most successfully treated patients have had extensive débridement of all necrotic tissue, followed by a variable course of AMB (usually 1,000 to 2,000 mg, total dose). PSEUDALLESCHERIASIS Pseudallescheriasis, an uncommon fungal infection, clinically resembles aspergillosis. It is the one fungal infection in which miconazole may be more active than AMB.29 Information about this infection is sparse, and treatment results are purely anecdotal. CANDIDIASIS The treatment of candidiasis is difficult to discuss intelligently. We will restrict our comments to candidemia, Candida endophthalmitis, renal candidiasis, and hepatosplenic candidiasis. The concept of benign or transient candidemia is flawed and should be abandoned. In most reported cases, candidemia occurs in the setting of indwelling catheters, multiple antibiotics, and glucocorticoid therapy. In a few affected patients, removal of the catheter apparently was adequate therapy because Candida subsequently cleared from the blood without other intervention. Recent information shows, however, that candidemia is a serious infection associated with high morbidity and mortality.30 In our opinion, every patient with candidemia should be treated because the risks are increased with no treatment. The treatment of choice for candidemia has been AMB and removal of the indwelling catheter. The cumulative total dose of AMB, although highly variable, is usually from 1,000 to 2,000 mg.30 In patients with proven catheter-associated candidemia, many clinicians recommend 500 mg of AMB. Because of the known synergy between AMB and 5FC, many authorities recommend the addition of 5-FC at the maximal tolerated dose. In a recent study,31 AMB was compared prospectively with fluconazole. Because patients with neutropenia were excluded, the results cannot yet be applied to such patients. In that carefully conducted study, fluconazole was as effec-
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tive as AMB for candidemia and was less toxic. When fluconazole is used to treat candidai infections, the organism should be identified to the species level, inasmuch as certain species such as C. krusei and C (Torulopsis) glabrata are likely to be resistant. The most common isolate recovered from clinical specimens is C. albicans, which is usually susceptible to fluconazole. Candida endophthalmitis, which invariably occurs as a result of candidemia, should always be treated with AMB, even if the patient does not have neutropenia. Experimental data do not support the use of fluconazole.32 Because of the high renal clearance of fluconazole, renal candidiasis can be treated effectively with this drug. The exact dose and duration of therapy have not been determined. For hepatosplenic candidiasis, a disease that frequently complicates the treatment of acute leukemia, fluconazole therapy has been successful. Two studies33-34 have shown good results equivalent to therapy with AMB; however, almost all patients had received AMB before randomization. Nevertheless, the best evidence suggests that fluconazole may be used as primary therapy in this group of patients. REFERENCES 1. Wheat J, Hafner R, Wulfsohn M, Spencer P, Squires K, Powderly W, et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1993; 118:610-616 2. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Treatment of blastomycosis and histoplasmosis with ketoconazole: results of a prospective randomized clinical trial. Ann Intern Med 1985;103:861-872 3. Quinones CA, Reuben AG, Hamill RJ, Musher DM, Gorin AB, Sarosi GA. Chronic cavitary histoplasmosis: failure of oral treatment with ketoconazole. Chest 1989;95:914-916 4. Dismukes WE, Bradsher RW Jr, Cloud GC, Kauffman CA, Chapman SW, George RB, et al. Itraconazole therapy for blastomycosis and histoplasmosis: NIAID Mycoses Study Group. Am J Med 1992; 93:489-497 5. Parker JD, Sarosi GA, Doto IL, Bailey RE, Tosh FE. Treatment of chronic pulmonary histoplasmosis. N Engl J Med 1970; 283:225229 6. Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histoplasmosis: results of long-term follow-up. Ann Intern Med 1971;75:511-516 7. Sarosi GA, Johnson PC. Disseminated histoplasmosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1992; 14(Suppl 1):S60-S67 8. McKinsey DS, Gupta MR, Riddler SA, Driks MR, Smith DL, Kurtin PJ. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;111:655-659 9. Sarosi GA, Davies SF, Phillips JR. Self-limited blastomycosis: a report of 39 cases. Semin Respir Infect 1986; 1:40-44 10. Pappas PG, Threlkeld MG, Bedsole GD, Cleveland KO, Gelfand MS, Dismukes WE. Blastomycosis in immunocompromised patients. Medicine 1993;72:311-325 11. American Thoracic Society. Treatment of fungal diseases. Am Rev Respir Dis 1979;120:1393-1397 12. Labadie EL, Hamilton RH. Survival improvement in coccidioidal meningitis by high-dose intrathecal amphotericin B. Arch Intern Med 1986; 146:2013-2018
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13. 14. 15. 16.
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THERAPY FOR FUNGAL INFECTIONS
Galgiani JN, Catanzaro A, Cloud GA, Higgs J, Friedman BA, Larsen RA, et al. Fluconazole therapy for coccidioidal meningitis: the NIAID-Mycoses Study Group. Ann Intern Med 1993;119:28-35 Tucker RM, Denning DW, Dupont B, Stevens DA. Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med 1990; 112:108-112 Fish DG, Ampel NM, Galgiani JN, Dois CL, Kelly PC, Johnson CH, et al. Coccidioidomycosis during human immunodeficiency virus infection: a review of 77 patients. Medicine 1990;69:384-391 Kerkering TM, Duma RJ, Shadomy S. The evolution of pulmonary cryptococcosis: clinical implications from a study of 41 patients with and without compromising host factors. Ann Intern Med 1981; 94:611-616 Sugar AM, Saunders C. Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med 1988;85:481-489 Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. NEnglJMed 1987;317:334-341 Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. NEnglJMed 1992;326:83-89 Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jacobson JM, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992; 326:793-798 Restrepo A, Robledo J, Gomen I, Tabares AM, Gutierrez R. Itraconazole therapy in lymphangitic and cutaneous sporotrichosis. Arch Dermatol 1986; 122:413-417 Gerding DN. Sporotrichosis. In: Sarosi GA, Davies SF, editors. Fungal Diseases of the Lung. 2nd ed. New York: Raven Press, 1993: 113-123 Sharkey-Mathis PK, Kauffman CA, Graybill JR, Stevens DA, Hostetler JS, Cloud G, et al. Treatment of sporotrichosis with itraconazole. Am J Med 1993;95:279-285
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Wang JL, Patterson R, Roberts M, Ghory AC. The management of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1979; 120:87-92 Fisher BD, Armstrong D, Yu B, Gold JW. Invasive aspergillosis: progress in early diagnosis and treatment. Am J Med 1981; 71:571577 Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis 1990; 12:1147-1201 Denning DW, Lee JY, Hostetler JS, Pappas P, Kauffman CA, Dewsnup DH, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med 1994;97:135-144 Walsh TJ, Rinaldi MR, Pizzo PA. Zygomycosis of the respiratory tract. In: Sarosi GA, Davies SF, editors. Fungal Diseases of the Lung. 2nd ed. New York: Raven Press, 1993: 149-170 Patterson TF, Andriole VT, Zervos MJ, Therasse D, Kauffman CA. The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection. Mycoses 1990; 33:297-302 Edwards JE Jr, Filler SG. Current strategies for treating invasive candidiasis: emphasis on infections in nonneutropenic patients. Clin Infect Dis 1992; 14(Suppl 1):S106-S113 Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM, Edwards JE, et al. Fluconazole (FLU) vs. amphotericin B (AMB) for treatment of candidemia: results of a randomized, multicenter trial [abstract]. Intersci Conf Antimicrob Agents Chemother Program Abstr 1993; 33:267 Savani DV, Perfect JR, Cobo LM, Durack DT. Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother 1987;31:6-10 Kauffman CA, Bradley SF, Ross SC, Weber DR. Hepatosplenic candidiasis: successful treatment with fluconazole. Am J Med 1991;91:137-141 Anaissie E, Bodey GP, Kantarjian H, David C, Barnett K, Bow E, et al. Fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior amphotericin B therapy. Am J Med 1991;91:142-150
Questions About Therapy for Fungal Infections (See article, pages mi to ill?) Note: Select the single best answer. 1.
The best initial therapy for a patient with lifethreatening pulmonary blastomycosis (diffuse pulmonary infiltrates and severe hypoxemia) is: a. b. c. d.
2.
Orally administered ketoconazole Orally administered itraconazole Intravenously administered miconazole Intravenously administered amphotericin B
Treatment of progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome should include: a. Induction therapy with amphotericin B (500 to 1,000 mg), followed by lifetime maintenance therapy with ketoconazole b. A total cumulative dose of 3,000 mg of amphotericin B, to effect a lasting cure and prevent relapse c. Induction therapy with amphotericin B (500 to 1,000 mg), followed by lifetime maintenance therapy with itraconazole d. Oral therapy with ketoconazole for 6 to 12 months
3.
Mild to moderate cases of pulmonary or disseminated blastomycosis in immunocompetent patients can be effectively treated with: a. b. c. d.
4.
Itraconazole, 400 mg daily for 6 months Amphotericin B, total cumulative dose of 2,000 mg Ketoconazole, 400 to 800 mg daily for 6 months All of the above
The type and duration of therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection are: a. Amphotericin B (0.7 mg/kg daily) plus flucytosine for 4 weeks b. Amphotericin B (0.7 mg/kg daily) plus flucytosine for 6 weeks c. Induction therapy with amphotericin B (0.7 mg/kg daily) plus flucytosine (if tolerated) until improvement, followed by oral lifetime maintenance therapy with fluconazole (200 mg/day) d. Amphotericin B only, total cumulative dose of 2,000 mg
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