Mycotic Infections Part 3

Clinical presentations

Lymphocutaneous Sporotrichosis

Days to weeks after cutaneous inoculation of the fungus, a papule develops at the site of inoculation. The primary lesion can become nodular, but most often, it ulcerates. The drainage is not grossly purulent and has no odor, and the lesion is not terribly painful. Similar lesions subsequently occur along the lymphatic channels proximal to the original lesion. A fixed cutaneous lesion that is verrucous or ulcerative and that is not associated with lymphatic extension can also occur.

Visceral Sporotrichosis

Pulmonary sporotrichosis occurs most often in middle-aged men who have COPD and abuse alcohol.57 In contrast to most forms of sporotrichosis, systemic symptoms, including fever, night sweats, weight loss, and fatigue, are common. Dyspnea, cough, purulent sputum, and hemoptysis are common respiratory symptoms. A chest radiograph shows unilateral or bilateral upper lobe cavities with variable amounts of fibrosis and nodular lesions.

Osteoarticular sporotrichosis is found most often in middle-aged men and occurs more frequently in patients with alco-holism.58 Although some patients experience osteoarticular involvement after local inoculation, this form of infection most often develops through hematogenous spread. Infection may involve one joint or multiple joints. The joints most commonly affected are the knee, elbow, wrist, and ankle. Isolated cases of bursitis and tenosynovitis, sometimes presenting as nerve entrapment syndromes, have been reported.

S. schenckii has rarely been reported to cause localized infection of the meninges, pericardium, eye, perirectal tissues, larynx, breast, epididymis, spleen, liver, bone marrow, or lymph nodes.54 Disseminated sporotrichosis is very uncommon, with cases occurring primarily in patients with advanced HIV infec-tion.55 Most patients have widespread ulcerative cutaneous lesions and may or may not have visceral dissemination.

Diagnosis

Culture

Growth of S. schenckii from material aspirated from a lesion, a tissue biopsy specimen, sputum, or body fluid is the most sensitive method for establishing a diagnosis of sporotrichosis. Growth of the mold phase of S. schenckii is usually evident a few days after inoculation onto Sabouraud agar. Synovial tissue provides a better yield than synovial fluid.

Biopsy

Histopathologic examination of biopsy material shows a mixed granulomatous and pyogenic process. The organisms often are not visualized, even with special stains for fungi, because they are rarely present in large numbers. When visualized, S. schenckii yeasts are 3 to 5 |im in diameter; they are oval to cigar-shaped and may show multiple buds.

Serologic Studies

Serology is less useful in the diagnosis of sporotrichosis than in histoplasmosis and coccidioidomycosis. A tube agglutination test is available at the Centers for Disease Control and Prevention; however, the sensitivity and specificity of this assay has not been established.

Differential diagnosis

The differential diagnosis of lymphocutaneous sporotrichosis includes atypical mycobacterial infections, especially M. mar-inum infections; Nocardia infections, particularly N. brasiliensis infections; Leishmania brasiliensis infections; and tularemia.59 Both clinically and radiographically, pulmonary sporotrichosis mimics tuberculosis; nontuberculous mycobacterial infections; other fungal infections, especially histoplasmosis; and sarcoidosis. Os-teoarticular sporotrichosis is often thought to have a bacterial etiology and is often treated with antibiotics, to no avail. Growth of the organism in culture is the most important method of differentiating between these conditions.

Treatment

Guidelines for the management of the various forms of sporotrichosis have recently been published by the Mycoses Study Group and the Infectious Diseases Society of America.60 No comparative randomized, blinded treatment trials have been performed comparing various antifungal agents for the treatment of sporotrichosis. The guidelines are based entirely on open treatment trials and anecdotal experience.58,61-64 Because most S. schenckii infections are subacute to chronic and are localized, oral antifungal agents are preferred; amphotericin B is reserved for the uncommon visceral infections.

Lymphocutaneous Sporotrichosis

Itraconazole is the drug of choice for lymphocutaneous sporotrichosis.60 The usual dose is 200 mg/day. Treatment should continue for several weeks after all lesions have disappeared, usually for a total of 3 to 6 months.58,62,63 Fluconazole is less active against S. schenckii but may be effective when a daily dose of 400 mg is used.64 Saturated solution of potassium iodide (SSKI) is also effective and is much less costly than therapy with an azole. The initial dose is 5 to 10 drops three times daily in water or juice; the dose is increased each week to a maximum of 40 to 50 drops three times daily. SSKI is difficult for many patients to administer and tolerate; side effects include a metallic taste, salivary gland swelling, rash, and fever.

Terbinafine appears to be effective for sporotrichosis, but few patients have been treated with this agent to date.65 Local hyper-thermia, induced by a variety of different warming devices or baths, also has been used with minimal side effects for localized cutaneous sporotrichosis.

Visceral Sporotrichosis

For a seriously ill patient with pulmonary sporotrichosis, am-photericin B, 0.7 to 1.0 mg/kg/day, should be used as initial therapy.60 After the patient has shown improvement, therapy can be changed to itraconazole, 200 mg twice daily. Azole therapy should be continued for at least 1 to 2 years. For patients who are not acutely ill, therapy can be initiated with itraconazole, 200 mg twice daily.58 Surgical resection has proved to be useful for patients who have focal lesions and whose pulmonary function is adequate to withstand a lobectomy.61

Almost all patients who have osteoarticular sporotrichosis can be treated with itraconazole, 200 mg twice daily.60 Therapy should continue for 1 to 2 years.58 Other azoles are less effective, and SSKI is ineffective. Intravenous amphotericin B is rarely required.

Amphotericin B, 0.7 to 1.0 mg/kg/day, is the drug of choice for disseminated sporotrichosis, including meningeal infection.60 Itraconazole, 200 mg twice daily, can be used in those patients with disseminated skin lesions and other nonmeningeal manifestations as soon as the patient’s condition has stabilized. AIDS patients with disseminated sporotrichosis should receive lifelong maintenance therapy with itraconazole, 200 mg daily.55

Prognosis

The success rate for treatment of lymphocutaneous sporotri-chosis is 90% to 100%, but it is much lower for all other forms of the disease. This is undoubtedly related partly to delays in diagnosis and partly to the underlying diseases of the hosts who have noncutaneous forms of sporotrichosis. Joint function after cure of sporotrichal arthritis is often poor, and pulmonary function after treatment of pulmonary sporotrichosis is often marginal. The outcome of disseminated sporotrichosis in patients with HIV infection has been poor,55 but almost all reports are from studies conducted before the era of highly active antiretroviral therapy. Presumably, combination antifungal therapy and highly active antiretroviral therapy would improve the prognosis.

Antifungal Therapy

For treatment of the endemic mycoses, the choice of azoles or amphotericin B is dependent on the severity of the infection and the underlying conditions and the immune status of the host. In general, most mild to moderately ill patients can be very effectively treated with an azole; most severely ill patients should receive amphotericin B as initial therapy.67 Induction amphotericin B therapy can almost always be followed by consolidation therapy with an azole. The length of therapy is measured in months to years and is obviously managed primarily in the outpatient settting. For some patients (e.g., those with AIDS), lifelong maintenance therapy is required to prevent relapse. Thus, issues of compliance, absorption, and drug-drug interactions assume great importance in current treatment regimens for the endemic mycoses.

Use of azoles to treat endemic mycoses

There are three azole antifungal agents currently available: ke-toconazole, itraconazole, and fluconazole. Ketoconazole, which is available only in tablet form, is used infrequently now because of its greater toxicity, poor absorption, and modest spectrum of antifungal activity when compared with the other azoles.68 However, it is still used for some patients who require long-term therapy with an azole because it is much less expensive than itra-conazole and fluconazole. For most patients, itraconazole has supplanted ketoconazole because it is both more effective and better tolerated. Fluconazole is less active than itraconazole against most of the endemic mycoses,21,22,35,36,64 and except for coccidioidomycosis,45,48 it is a second-line agent. The newer azoles, voriconazole, posaconazole, and ravuconazole, have not been studied for the treatment of the endemic mycoses, with the exception of a very small trial that used posaconazole for the treatment of coccidioidomycosis. These agents are not indicated for the treatment of the endemic mycoses at this time.

Side Effects

Idiosyncratic, non-dose-related hepatitis, which can sometimes be severe, occurs rarely with all azoles.68,69 Before therapy is started, liver enzyme and bilirubin levels should be measured; they should be measured again after several weeks of therapy and then every 1 to 2 months in patients receiving long-term therapy. Mild elevations in the levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (i.e., a twofold to threefold increase over normal levels) do not require discontinuance of the drug, but such increases do require very careful follow-up. If the ALT and AST levels continue to rise, the drug should be discontinued. If therapy with an azole is required, another azole can be cautiously given after the ALT and AST levels return to normal, but liver enzyme levels should be assessed weekly, and the drug must be stopped if the ALT and AST levels rise threefold or more while the patient is receiving the second azole.

It is uncommon for hypertension, edema, and hypokalemia to occur with itraconazole therapy; such side effects usually occur in older adults and require discontinuance of the drug.70 Whether these effects are related to the recently described myocardial dysfunction noted with itraconazole has not yet been elucidated.

Rash and nausea can occur with all azoles. Long-term therapy with fluconazole has been associated with alopecia, which is reversible when the drug is discontinued.72 All azoles are con-traindicated during pregnancy; teratogenicity in animals has been noted, and several cases of fetal malformations have been reported in women taking fluconazole during pregnancy.

Absorption Issues

Both ketoconazole and itraconazole require gastric acid for absorption, and the capsule formulation of itraconazole also requires food for absorption. Therefore, histamine receptor antagonists (H2 receptor blockers), antacids, and proton pump inhibitorscannot be administered to patients receiving these agents.68 Older adults, who are often achlorhydric, may not absorb these agents well. For the treatment of endemic mycoses, itraconazole is commonly used at a daily dose of 400 mg; regardless of whether solution or capsules are prescribed, the drug should be administered in twice-daily doses of 200 mg, rather than a once-daily dose of 400 mg, to achieve appropriate serum drug levels. At doses higher than 200 mg, decreased absorption of the drug occurs.

The oral-suspension formulation of itraconazole was developed specifically to overcome the poor absorption characteristics of the capsules. The suspension requires neither acid nor food for absorption. When taken on an empty stomach, absorption is approximately 30% better than when the capsule formulation is given with both food and acid.74 Although compliance with long-term use of the oral suspension may be difficult, the suspension is preferred to ensure adequate serum levels. In patients with serious infection and those who do not respond to therapy, serum itraconazole levels should be obtained at a reference mycology laboratory to ensure that absorption is adequate.

Use of the intravenous formulation of itraconazole, solubi-lized in cyclodextrins, avoids absorption problems.75 The intravenous formulation has been approved for use for periods of only 2 weeks because of concerns about the nephrotoxicity of the cyclodextrin vehicle, which is used to solubilize the drug. The intravenous formulation cannot be given if the rate of creatinine clearance is less than 30 ml/min. The dosage of the intravenous formulation is 200 mg twice daily for 2 days, followed by 200 mg daily for the next 12 days; intravenous therapy is usually followed by treatment with the oral supension.

Fluconazole, which is nearly 100% bioavailable, has none of the absorption problems that have been so troublesome with itraconazole. It distributes into most body compartments, including the eye and the CSF; is excreted as active drug in the urine; and can be given in a once-daily dose.

Drug-Drug Interactions

The azoles interact with many other drugs primarily through their interactions with cytochrome P-450 3A4 but also to a lesser extent through their interactions with several of the other cy-tochrome enzymes and with P-glycoprotein.69 These interactions can be serious and even life-threatening. It is absolutely essential that the patient’s concomitant medications be reviewed and the package insert read before use of any azole for the treatment of any fungal infection. Major interactions for the azoles are detailed [see Tables 1 and 2].

Table 1 Effects of Concomitantly Administered Drugs on Serum Levels of Azoles

Drug Affecting Azole Serum Level	Effects That Other Drugs Have on Azole Serum Levels
	Ketoconazole	Itraconazole	Fluconazole
Antituberculous drugs
Rifampin	Decreased	Decreased	Decreased
Rifabutin	None known	Decreased	No effect
Isoniazid	Decreased	None known	None known
Anticonvulsants
Phenytoin	Decreased	Decreased	None known
Carbamazepine	None known	Decreased	None known
Gastric acid lowering agents*
Antacids	Decreased	Decreased	No effect
H2 receptor blockers	Decreased	Decreased	No effect
Proton pump inhibitors	Decreased	Decreased	No effect
Sucralfate	Decreased	None known	No effect

* Gastric acid-lowering agents should not be used with ketoconazole or itraconazole capsules; if necessary, they can be used with itraconazole suspension.

Table 2 Effects of Azoles on Serum Levels of Other Drugs

Drug Affected by Azole	Effects That Azoles Have on Other Drugs’ Serum Levels
	Ketoconazole	Itraconazole	Fluconazole
Immunosuppressants
Cyclosporine	Increased*	Increased*	Increased*
Tacrolimus	Increased*	Increased*	Increased*
Anticonvulsants
Phenytoin	Increased*	Increased*	Increased*
Carbamazepine	Increased*	Increased*	Increased*
Antihistamines
Loratadine	Increased	None known	None known
Terfenadine	Increasedt	Increasedt	No effect
Astemizole	Increasedt	Increasedt	None known
Sedatives
Triazolam	Increased*	Increased*	Increased*
Midazolam	Increased*	Increased*	Increased*
Cholesterol-lowering agents
Lovastatin	None known	Increasedt	None known
Simvastatin	None known	Increasedt	None known
Antiretroviral agents
Indinavir	Increased	None known	None known
Saquinavir	Increased	None known	None known
Ritonavir	Increased	Increased	Increased
Nelfinavir	Increased	None known	None known
Antituberculous drugs
Rifampin	Decreased	None known	None known
Isoniazid	Decreased	None known	None known
Rifabutin	None known	Increased	Increased
Other drugs
Cisapride	Increasedt	Increasedt	Increasedt
Warfarin	Increased*	Increased*	Increased*
Digoxin	None known	Increased*	None known
Sulfonylureas	Increased*	Increased*	Increased*
Quinidine	Increasedt	Increasedt	None known

^Significant interaction; monitoring of drug serum levels, clinical status, or both is required. ^Life-threatening interaction; these agents should not be used together.

Itraconazole and ketoconazole have the most drug-drug interactions, but fluconazole shares several significant interactions. Increased serum levels of warfarin, phenytoin, and oral hypo-glycemic agents occur when azoles are given with these commonly used drugs. Itraconazole increases serum levels of digoxin in some but not all patients. Thus, serum levels of these agents must be closely monitored in those receiving an azole.

Itraconazole and ketoconazole should never be given to patients receiving cholesterol-lowering agents, such as simvastatin and lovastatin, because of the potential for life-threatening rhab-domyolysis, nor should these agents be given to those receiving midazolam or triazolam because of the possibility of markedly increased sedation. Coadministration of an azole with cisapride, astemizole, or terfenadine is contraindicated because azoles potentiate the prolongation of the QT interval that is induced by these drugs.

Several commonly used drugs have the effect of inducing the metabolism of the azoles and thus decreasing serum azole concentrations and diminishing effectiveness. This has been reported with rifampin, phenytoin, and carbamazepine.

Use of amphotericin b to treat endemic mycoses

Amphotericin B is fungicidal against a broad range of fungi. The major drawbacks are the need for intravenous administration and the inherent toxicity of the drug.76 Some, but not all, of the infusion-related reactions to amphotericin B can be minimized with the use of preinfusion medications77; however, nephrotoxicity will almost always develop during the course of therapy with this agent.78

In an attempt to decrease the toxicity of amphotericin B, the drug has been incorporated into liposomes and other lipid delivery vehicles. Three formulations are currently available: liposomal amphotericin B (AmBisome, L-AmB); amphotericin B lipid complex (Abelcet, ABLC); and amphotericin B colloidal dispersion (Amphotec or Amphocil, ABCD). Each differs from the others and from amphotericin B deoxycholate with regard to composition, pharmacologic parameters, toxicity, recommended dosages, and cost.79’80 All of these preparations are clearly less nephrotoxic than amphotericin B deoxycholate, and two of the three cause fewer infusion-related reactions than amphotericin B deoxycholate. However, they are all much more costly than standard amphotericin B. Because of cost considerations, many hospitals restrict the use of these preparations to patients who have preexisting renal disease or have developed some degree of renal failure related to amphotericin B deoxycholate administration (as evidenced, for example, by a serum creatinine level of more than 2 or 3 mg/dl).

Other than two studies that show liposomal amphotericin B to be superior to amphotericin B deoxycholate for the treatment of severe histoplasmosis in AIDS patients and for the empirical treatment of febrile neutropenic patients,23,81 there is little evidence to suggest that lipid formulations of amphotericin B are more efficacious than the standard formulation. Thus, for most patients, a lipid formulation of amphotericin B will not be used as a first-line antifungal agent but will be reserved for patients who cannot tolerate amphotericin B deoxycholate.

Nephrotoxicity Nephrotoxicity is seen in most patients receiving amphotericin B. Diminished creatinine clearance is the major manifestation, but profound hypokalemia, hypomagne- semia, or both are also common. Patients with underlying renal disease show a more rapid rise in creatinine levels than patients with normal renal function. Use of other nephrotoxic drugs, such as aminoglycosides, cisplatinum, cyclosporine, or tacrolimus, should be avoided when amphotericin B is being used.

Table 3 Administration of Amphotericin B for Treatment of the Endemic Mycoses

General Guidelines

Do not use in-line filters; no need to cover drug while infusing

Use central I.V. catheter if at all possible. With peripheral I.V. catheter, 1,000 units of heparin can be added to the drug in an attempt to decrease phlebitis

Dilute drug to a concentration of 0.1 mg/ml

For the initial dose, infuse very slowly for the first 20 minutes and assess for the rare occurrence of anaphylaxis or arrhythmias

Infuse drug over 2 to 4 hours; for patients with infusion-related reactions, slower infusion times are often better tolerated; for others, 2-hr infusion times are appropriate

For subacute or chronic infections, start with 0.2 mg/kg and increase daily by the same increment until the desired daily dose is reached; use pretreatment medications only if required

For life-threatening infections, give the desired daily dose within the first 24 hr; preinfusion medications should be given before the first dose because reactions are frequent

Measures to Decrease Infusion-Related Reactions (chills, fever, nausea and vomiting, headache, myalgia)

Medications before beginning infusion of amphotericin B: acetaminophen (650 mg p.o.), diphenhydramine (50 mg p.o.), prochlorperazine (25 mg p.o. for nausea and vomiting), and meperidine (50-75 mg I.V. or I.M. for rigors); administer hydrocortisone (25-50 mg I.V) if reactions do not improve with the above drugs

Measures to Reduce Nephrotoxicity

Assess volume status before treatment; stop diuretics, if possible; do not restrict sodium

Before each dose, infuse 500 ml 0.9% saline over 1 hr

Required Laboratory Studies to Assess Toxicity

Baseline creatinine, blood urea nitrogen, potassium, magnesium levels; blood count, liver function tests

Monitor creatinine, blood urea nitrogen, potassium, magnesium levels every other day

Monitor blood count weekly; repeat liver function tests if clinically indicated

Sodium loading is now routinely employed in an attempt to decrease nephrotoxicity82 [see Table 3]. Potassium and magnesium losses can be large and can contribute to other organ dysfunction; for this reason, electrolytes should be monitored carefully, and electrolytes should be replaced as soon as the serum levels show even a slight decrease. In many patients, intravenous repletion is ultimately required to keep pace with the renal loss. Early oral repletion will obviate the need for intravenous repletion in many patients.

Infusion-related reactions Infusion-related reactions are the most common adverse events experienced by patients receiving amphotericin B. Chills or rigors, fever, nausea, headache, and myalgias occur in the majority of patients treated with ampho-tericin B. Most of these side effects can be diminished by prescribing a variety of medications before infusion of amphotericin B77 [see Table 3].

Patients with life-threatening infections that require immediate treatment with large doses of amphotericin B are more likely to have infusion-related reactions. Pretreatment medications should be given before the first dose of amphotericin B in these patients. For others who have subacute to chronic infections, the dosage of amphotericin B can be increased gradually over a few days, decreasing the risk of immediate reactions.

Other side effects Most patients receiving amphotericin B develop a normocytic, normochromic anemia, but transfusion is rarely required.83 Other side effects, including leukopenia, thrombocytopenia, hepatotoxicity, neuropathy, and acute pulmonary edema, are rare.