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Diagnosis and Treatment of Fungal Infections

Diagnosis and Treatment of Fungal Infections

John E. Bennett

MYCOLOGY FUNDAMENTALS

Fungi can appear microscopically as either rounded, budding forms (yeastlike organisms) or hyphae (molds). Yeastlike colonies are smooth, while mold colonies are fuzzy; fungi that grow as yeasts include species of Candida and Cryptococcus, while fungi that grow as molds include species of Aspergillus, Rhizopus, and dermatophytes (ringworm fungi). The fungi that cause histoplasmosis, blastomycosis, sporotrichosis, coccidioidomycosis, and paracoccidioidomycosis are called dimorphic (“having two forms”) because they are spherical in tissue but grow like molds when cultured at room temperature. Candida species other than Candida glabrata appear in tissue as both budding yeasts and tubular elements called pseudohyphae. Pseudohyphae, unlike true hyphae, have constrictions in the cell wall where septa are located and have septa at branching points. Pneumocystis is closer to fungi than to parasites by ribosomal sequences. Because the drugs used to treat Pneumocystis pneumonia are also used to treat parasitic or bacterial infections, those drugs will not be discussed in this chapter.

Many fungi can form two different types of spores and are given different names, depending on the spore-bearing structures. When the spores are produced by mitosis, the fungus is said to be an anamorph, or to be in the imperfect state. Many fungi can have different sporulating structures in which genetic recombination occurs, often as a result of coculture with a strain of the opposite mating type. A fungus producing those distinctive spores is said to be a teleomorph, or to be in the perfect state. Diagnostic laboratories usually use the name of the anamorph because they do not use culture conditions that would produce the teleomorph. One exception is Scedosporium apiospermum, which is often observed as a teleomorph in the diagnostic laboratory and identified as Pseudallescheria boydii.

Most fungi that are pathogenic for humans are saprophytes in nature; they cause infection when airborne spores reach the lung or paranasal sinus or when hyphae or spores are accidentally inoculated into the skin or cornea. Acquisition of infection from another person or an animal has been reported in the case of ringworm but is very rare in other mycoses. Thus, hospitalized patients with fungal infections do not require special isolation. Most fungi infect hosts preferentially by one route and only infrequently by other routes. For example, the agents of ringworm, pityriasis versicolor, and piedra infect the epidermis and its appendages. Sporotrichosis and mycetoma usually arise from subcutaneous inoculation. Inhalation is the route of inoculation for the agents of most deep mycoses. Ingestion of fungi rarely causes infection; Candida albicans, a normal commensal in the mouth and intestine, reaches deeper tissues only when mucosal or cutaneous barriers are breached by disease, surgery, trauma, or catheterization. Histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis have been called “endemic” mycoses to emphasize their restricted geographic distribution. Some fungi, such as Aspergillus and Fusarium, are said to be opportunists in that they usually infect hosts with compromised immunity. This distinction is relative, not absolute.

Immunity after exposure to fungi may confer partial protection against reinfection. Residents of areas in which mycoses are endemic are less subject to infection than are newcomers. Predisposing factors are helpful in defining host defense. Immunoglobulin deficiencies do not appear to predispose to any mycosis, whereas neutropenia is common among patients who develop invasive mold infections or deep candidiasis. Cell-mediated immunity appears to be of paramount importance in cryptococcosis, histoplasmosis, and coccidioidomycosis.

DIAGNOSIS

Many fungi can be identified to the genus or even the species level by microscopic examination of smears or biopsy specimens. Calcofluor white staining with fluorescence microscopy is a sensitive technique for smears of sputum, bronchoalveolar lavage fluid, or pus. India ink smear remains the method of choice for detecting cryptococci in cerebrospinal fluid (CSF). Candida yeast cells and pseudohyphae are the only fungi that are usually gram-positive on smears. For other fungi, Gram's staining is distinctly suboptimal. For histopathology slides, Gomori methenamine silver and a neutral counterstain are preferred.

The method used has a marked effect on the rapidity and sensitivity of blood cultures for fungi except in the case of Candida species, which are relatively easy to grow. For most other fungi, concentration of the blood by lysis centrifugation and culture on solid medium constitute the optimal technique. Commercially available nucleic acid hybridization techniques can speed the identification of slow-growing molds, such as Histoplasma capsulatum and Coccidioides immitis. Serology has limited value, but testing of serum or CSF for cryptococcal antigen or antibody to C. immitis can be diagnostic. Detection of Histoplasma antigen in urine or serum is helpful in diagnosis and in following the results of treatment for disseminated histoplasmosis. Skin testing with fungal antigens is not useful in detecting active infection.

ANTIFUNGAL THERAPY

Topical Agents

Imidazoles and Triazoles

These synthetic compounds act by inhibiting ergosterol synthesis in the fungal cell wall and, when given topically, may cause direct damage to the fungal cytoplasmic membrane. The imidazoles available for cutaneous application include clotrimazole, econazole, ketoconazole, sulconazole, oxiconazole, and miconazole. Vaginal formulations include four imidazoles (miconazole, clotrimazole, tioconazole, and butoconazole) and one triazole (terconazole). As yet, no substantial differences in the efficacy of or local intolerance to the various topical azoles have become apparent. All are effective in the treatment of cutaneous candidiasis, tinea (pityriasis) versicolor, and mild to moderately severe ringworm of the glabrous skin. Vaginal formulations are effective for vulvovaginal candidiasis. Clotrimazole is poorly absorbed from the gastrointestinal tract, but the oral troche is useful as a topical treatment for oral and esophageal candidiasis.

Polyene Macrolide Antibiotics

These broad-spectrum antifungal agents combine with sterol in the fungal cytoplasmic membrane, increasing membrane permeability. Topically, they are not active against ringworm but are effective against candidiasis of the skin and mucous membranes. Nystatin and amphotericin B suspensions are effective in oral thrush, and vaginal troches are effective in vulvovaginal candidiasis. Both nystatin and amphotericin B are available in topical preparations for cutaneous candidiasis.

Other Topical Antifungals

Ciclopirox olamine, haloprogin, terbinafine, and naftifine have the same clinical spectrum among the cutaneous mycoses as the imidazoles. Tolnaftate and undecylenic acid are effective against ringworm but not candidiasis. Keratolytic agents, such as salicylic acid, are helpful as accessory drugs for some hyperkeratotic skin lesions.

SYSTEMIC ANTIFUNGALS

Griseofulvin

Griseofulvin is a useful drug in the treatment of certain kinds of ringworm; however, it is ineffective in the treatment of candidiasis. The microcrystalline and ultramicrocrystalline preparations differ in dose but not in efficacy. Absorption of both is enhanced when the drug is ingested with fat-containing foods. Griseofulvin interacts with phenobarbital and warfarin.

Terbinafine

Oral terbinafine (250 mg once daily) is at least as effective as itraconazole and more effective than griseofulvin in onychomycosis and ringworm. Treatment duration ranges from 3 months for fingernails to 6 months for toenails. Gastrointestinal distress is the most common side effect. Rash, hepatitis, and pancytopenia have occurred, but serious adverse effects have been uncommon. Terbinafine decreases cyclosporine levels. Cimetidine increases and rifampin decreases terbinafine levels in blood.

Imidazoles and Triazoles

GENERAL FEATURES

The azole antifungals include imidazoles and triazoles. Fluconazole, itraconazole, voriconazole, and the investigational azoles posaconazole and ravuconazole are all triazoles, so named because they have three nitrogens in the ring structure. This class has less impact on human hormonal synthesis and less hepatotoxicity than the only widely used systemic imidazole, ketoconazole. Itraconazole has many structural features in common with ketoconazole; however, it has a broader spectrum of activity and has largely replaced ketoconazole.

Interactions between azoles and other drugs can increase the plasma concentrations of the other drugs to toxic levels or decrease the azole plasma concentrations to subtherapeutic levels. A few drugs can increase the plasma concentrations of azoles, but the effect is modest. Drug-drug interactions are most numerous with itraconazole and ketoconazole; some drugs are contraindicated for concomitant use with these agents. Azole interactions with any one class of drugs, such as benzodiazepines, HMG-CoA reductase inhibitors, or drugs that decrease gastric acidity, should be considered to apply to all drugs of that class until proven otherwise. Fluconazole differs substantially from itraconazole: unlike that of itraconazole, the absorption of fluconazole is independent of food or gastric acid, and fluconazole has much less effect on the hepatic metabolism of other drugs than does itraconazole. High fluconazole blood levels engendered by azotemia or by dosages above those used in pharmacologic studies may lead to new and profound drug interactions.

All azoles have the potential for embryotoxicity and teratogenicity. In fact, it seems likely that azoles should not be given during pregnancy without a discussion of the serious risks and possible benefits with the mother. Four infants born to mothers taking at least 400 mg of fluconazole daily for coccidioidal meningitis have had severe bone, craniofacial, or cardiac abnormalities. Similarity of these abnormalities to those in pregnant animals given fluconazole suggests that fluconazole caused the defects.

ITRACONAZOLE

Itraconazole is useful in the treatment of blastomycosis, histoplasmosis, cutaneous candidiasis, coccidioidomycosis, sporotrichosis, pseudallescheriasis, onychomycosis, ringworm, tinea versicolor, and indolent cases of aspergillosis. The drug is metabolized in the liver, with the hydroxy metabolite accounting for at least half of the antifungal activity in serum. The sum of the blood levels of the native drug and its hydroxylated metabolite is usually at least 2 µg/mL a few hours after oral administration. Almost no bioactive drug appears in urine or CSF.

Itraconazole is available as a 100-mg capsule, an oral solution, and an intravenous formulation. Although itraconazole capsules are less expensive and cause less gastrointestinal distress than the oral solution, their absorption is sometimes problematic. Cyclodextrin, which is used to formulate both the oral solution and the intravenous formulation, is renally excreted but is not absorbed from the gastrointestinal tract. Food increases the absorption of itraconazole capsules by about threefold but substantially reduces the absorption of the cyclodextrin suspension.

The oral solution is effective in oropharyngeal and esophageal candidiasis at a dose of 100 mg (10 mL) twice daily and has also been used at twice that dose for the treatment of deep mycoses in patients who absorb itraconazole capsules poorly. The efficacy of itraconazole in mycoses of the central nervous system has been modest at best, given the drug's inability to reach the CSF. For deep infections, itraconazole capsules are given at an initial dosage of 600 to 800 mg daily for 3 days and a subsequent dosage of 200 to 400 mg once daily continued for 6 to 12 months. Itraconazole blood levels (see above) are helpful in documenting absorption when the oral drug is used for the treatment of deep mycoses. The commercially available intravenous formulation should be considered for initial therapy in hospitalized patients whose itraconazole absorption from the gastrointestinal tract may be suboptimal and whose creatinine clearance rate exceeds 30 mL/min. The dose is 200 mg twice daily for four doses followed by 200 mg daily for up to 2 weeks. Intravenous itraconazole, followed by the oral solution, is approved for the treatment of fever of unknown origin in neutropenic patients not responding to at least 96 h of therapy with antibacterial antibiotics.

Except for gastrointestinal distress from the oral solution, the toxicity of itraconazole is generally low, although life-threatening hepatotoxicity, congestive heart failure, edema, cardiac dysrhythmias, and peripheral neuropathy have been reported.

FLUCONAZOLE

This triazole can be administered in tablet form, as a suspension, or as an intravenous infusion. With a half-life of about 31 h, fluconazole can be given once a day. Approximately 80% of the drug is excreted unchanged in the urine. Patients with creatinine clearance rates of 21 to 50 mL/min and 11 to 20 mL/min should have their fluconazole doses reduced by 50 and 75%, respectively. The drug penetrates the CSF and other body fluids very well.

Nausea and abdominal distress are the most common forms of dose-limiting fluconazole toxicity. An allergic rash may develop and is particularly common among patients infected with HIV. Fatal cases of Stevens-Johnson syndrome have been described in the HIV-infected population. Alopecia commonly follows prolonged administration of ≥400 mg daily but resolves when therapy is discontinued. Rare cases of anaphylaxis, hepatic necrosis, and neutropenia have been described.

Fluconazole is useful in the treatment of oropharyngeal and esophageal candidiasis in adults. A single 150-mg tablet is effective in vulvovaginal candidiasis. Catheter-acquired candidemia in the immunocompetent host responds to 400 mg of fluconazole daily in conjunction with the removal of the infected catheter. Treatment should be continued for 10 to 14 days after the patient has become afebrile. Fluconazole is also effective in initial and maintenance therapy for cryptococcal meningitis in patients with AIDS, although most of these patients should initially receive a 2-week course of intravenous amphotericin B. Fluconazole is the drug of choice for coccidioidal meningitis.

The incidence of deep candidiasis among recipients of allogeneic bone marrow transplants can be reduced by the administration of fluconazole (400 mg daily) for 75 days after initiation of the transplantation-preparative regimen. Prophylaxis in other neutropenic patients has not appeared useful. Fluconazole (200 mg daily) reduced the incidence of cryptococcosis and mucosal candidiasis among AIDS patients whose CD4+ cell counts were <200/µL and was particularly effective among those with counts of <50/µL. However, this regimen is not recommended because it does not reduce mortality, is expensive, and can lead to drug resistance.

Fluconazole is less effective than itraconazole in blastomycosis, histoplasmosis, and sporotrichosis. The drug is not active in aspergillosis, pseudallescheriasis, or mucormycosis.

VORICONAZOLE

This recently marketed triazole is available as 50- and 200-mg tablets and as vials of 200 mg for intravenous administration. The average-sized adult is given 6 mg/kg intravenously every 12 h for two doses followed by maintenance doses of 4 mg/kg intravenously every 12 h. In patients whose condition is improving, the regimen can be changed to 200 mg twice daily by mouth. Up to 300 mg twice daily by mouth can be given to patients who do not respond adequately to the lower dose.

Voriconazole is well absorbed from the gastrointestinal tract and is metabolized completely by the liver by way of CYP2C9, CYP2C19, and CYP3A4. Genetic polymorphisms in CYP2C19 activity cause substantial variation in voriconazole metabolism. Dose adjustment for azotemia is not necessary, but the dose should be reduced by half in patients with moderate liver disease. Because the cyclodextrin used in the intravenous formulation is renally excreted, oral—not intravenous—voriconazole should be used in patients with creatinine clearance rates below 50 mL/min. Penetration into the CSF is good. Concurrent use of sirolimus is contraindicated because its serum levels are markedly increased in the presence of voriconazole. Until more complete data are available, the drug interactions for voriconazole should be considered to be similar to those for itraconazole. The toxic effects of voriconazole include transient visual disturbances (color changes, blurring) in 30% of patients, hepatotoxicity in 10%, and rash in 5%.

The spectrum of voriconazole includes all the fungi against which itraconazole and fluconazole are active. Voriconazole is indicated for initial treatment of invasive aspergillosis, pseudallescheriasis, and fusariosis. The drug is also useful as empirical therapy in febrile neutropenic patients who do not respond to at least 96 h of treatment with antibacterial antibiotics and who are at high risk of invasive mold infections.

INVESTIGATIONAL TRIAZOLES

Posaconazole and ravuconazole, which are undergoing early clinical trials, have antifungal spectra similar to that of voriconazole. Ravuconazole is notable for a half-life of ~1 week.

Echinocandins

One echinocandin (caspofungin) is on the market, and two others (micafungin and anidulafungin) are being assessed in clinical trials. All are administered intravenously and act by inhibiting synthesis of (1,3)β-D-glucan in the cell wall. The in vitro activity of these drugs against nearly all Candida species is similar and is independent of azole resistance. The possible exception is Candida parapsilosis, a species whose susceptibility varies with the isolate and the particular echinocandin. Activity against Aspergillus species is more obvious in experimentally infected animals than in vitro, where changes in hyphal shape are more obvious than decreased growth. The recommended regimen is a 70-mg loading dose followed by 50 mg daily. Toxicity is low and includes histamine-like acute infusion reactions and hepatotoxicity. Cyclosporine elevates caspofungin blood levels, but other drug-drug interactions have been minor so far. No dosage adjustment is needed in patients with azotemia or hemodialysis, but the dose should be reduced for moderate hepatic insufficiency. Penetration into CSF is negligible. On the basis of an open trial in 63 patients, caspofungin has been approved for salvage therapy in aspergillosis. Data on candidemia in nonneutropenic patients indicate an efficacy equivalent to that of fluconazole or amphotericin B.

Amphotericin B

A colloidal deoxycholate complex of the polyene drug amphotericin B is available for intravenous or intrathecal administration. The catabolism of amphotericin B is extremely slow and is not influenced by renal failure, hepatic failure, or hemodialysis. The drug's penetration into CSF and vitreous humor is poor; however, the concentrations in pleural, peritoneal, and articular exudates are adequate for many mycoses. Histoplasmosis, blastomycosis, paracoccidioidomycosis, candidiasis, and cryptococcosis are the most responsive mycoses; coccidioidomycosis, extraarticular sporotrichosis, aspergillosis, and mucormycosis are less responsive; and chromoblastomycosis, mycetoma, and pseudallescheriasis respond little, if at all. The usual course is 0.5 to 0.7 mg/kg daily for 8 to 10 weeks. Infusions are generally given in 5% dextrose over 2 to 4 h.

Initial doses of amphotericin B occasionally cause marked febrile reactions that may be poorly tolerated by adult patients with limited cardiac or pulmonary function. It may be prudent to give such patients an initial 1-mg test dose followed by rapidly escalating doses, depending on tolerance. Premedication with aspirin or acetaminophen or the addition of hydrocortisone (25 mg) to the infusion decreases chills and fever. Azotemia during treatment is usual, the extent depending on the daily dose, underlying renal disease, and concomitant nephrotoxic agents. Saline infusions have been advocated to reduce azotemia. Continuous amphotericin B infusions may reduce nephrotoxicity, but the impact on efficacy is unknown. Other side effects include anemia, hypokalemia, renal tubular acidosis, nausea, anorexia, weight loss, phlebitis, and occasionally hypomagnesemia. Intrathecal amphotericin B has been used in coccidioidal meningitis and refractory cryptococcal meningitis, although this therapy is associated with transient fever, headache, nausea, and vomiting.

Three lipid formulations of intravenous amphotericin B are commercially available in the United States. These formulations and their usual once-daily doses are amphotericin B lipid complex (ABLC), 5 mg/kg; amphotericin B colloidal dispersion (ABCD), 6 mg/kg; and liposomal amphotericin B (L-AB), 4–5 mg/kg. The most nephrotoxic lipid formulation is ABLC; ABCD causes less azotemia; and L-AB is the least nephrotoxic. Acute, febrile, infusion-related reactions occur with all amphotericin B formulations; their degree of severity is greatest with ABCD and lesser with ABLC and L-AB. The recommended duration for initial infusions of ABCD is 6 h for 6 mg/kg, slower than the 2-h duration of ABLC or L-AB infusions. Infusions of ABCD given more rapidly than 1 mg/kg per hour have caused severe reactions with fever and hypoxia. Use of these remarkably expensive formulations should be restricted to patients who cannot tolerate the nephrotoxicity of the deoxycholate formulation (ABD). Although the lipid formulations are also approved for patients with mycoses failing to respond to ABD, there is no indication that these formulations are more effective than ABD for any mycosis. ABLC and L-AB are probably equivalent in efficacy to ABD for most mycoses. Data on the efficacy of ABCD are largely confined to aspergillosis, in which the efficacy of this lipid formulation was equivalent to that of conventional amphotericin B.

Flucytosine

Flucytosine (5-fluorocytosine) is a synthetic oral drug useful in cryptococcosis, candidiasis, and chromoblastomycosis. Within the fungal cell, flucytosine is converted to the antimetabolite 5-fluorouracil. Drug resistance appears rather rapidly when flucytosine is used alone. For this reason, the drug is generally used in combination with amphotericin B. The usual dose of flucytosine is 25 to 37.5 mg/kg every 6 h. Flucytosine is well absorbed from the gastrointestinal tract. The drug penetrates well into the CSF and is excreted unchanged in the urine. Even modest reductions in renal function may elevate flucytosine blood levels into the toxic range (≥100 to 125 µg/mL). Elevated levels are associated with a significant incidence of neutropenia and thrombocytopenia and also seem to predispose to colitis, the other major toxic effect of this drug. Hepatotoxicity is idiosyncratic and uncommon. An allergic rash may develop.

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