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Antifungal Drugs

Antifungal agents are much more limited in number than are antibacterial drugs (22-24). Unfortunately, many of the available agents have significant cost and toxicity. Currently available drugs for the treatment of fungal infections are amphotericin B and the newer liposomal forms of amphotericin, flucytosine, and the azole drugs (25,26).

The polyene amphotericin B is the mainstay of therapy for serious fungal infections and remains the most broad-spectrum antifungal agent available. Its broad spectrum of activity and clinician experience with its use make it the drug of choice for Aspergillus infections and most other deep mycoses, despite its associated nephrotoxicity and other side effects. New liposomal amphotericin products are available that have less nephrotoxicity than the deoxycholate form (27,28). While effective in treating many serious fungal infections, their high cost has prompted many organizations to limit their use. Indeed, the cost-benefit comparison of amphotericin B vs. the new liposomal preparations has been the subject of much debate. Many institutions have restricted the use of liposomal preparations to patients who have developed nephrotoxicity in response to amphotericin B.

The new azole drugs represent an exciting advance for the treatment of serious fungal diseases (29,30). For the first time, oral agents with reliable efficacy are now available for the treatment of several of the fungal diseases. Fluconazole is a relatively nontoxic drug that has good efficacy in the treatment of Candida and some other fungal infections. It is available in both an oral and an intravenous form. Itraconazole has a broader spectrum of activity, including activity against some Aspergillus organisms, as well as Candida, Blastomyces, and Histoplasma. New azole drugs such as voriconazole appear promising. Azoles have effects on the P450 system, and other medications should always be reviewed to prevent adverse drug interactions.

Flucytosine is less widely used than amphotericin B or the azoles, owing to its more limited spectrum of activity and potential toxicity. However, flucytosine can play an important role in treatment of cryptococcal meningitis when used in combination with amphotericin B. To prevent toxicity, especially bone marrow suppression, serum drug levels must be monitored. Suggested therapeutic choices for the major fungal infections are outlined in Table 4, based on recent practice guidelines suggested by the Infectious Disease Society of America (IOSA) (31).

Treatment of Specific Fungal Infections

Candidiasis

Guidelines for the treatment of mucocutaneous candidiasis have been published by the American Academy of Dermatology (21). Thrush due to Candida spp. can be treated with many different agents, including clotrimazole troches, nystatin swish and swallow, amphotericin suspension, or the oral azoles. The widespread use of flucona-zole for treatment and prevention of thrush in patients with HIV has led to the emergence of azole-resistant strains (32). For this reason, many experts now urge use of nonazole drugs as a first choice, with fluconazole reserved for cases in which other drugs such as nystatin have failed. However, the efficacy and ease of use of fluconazole have interfered with widespread acceptance of this approach.

Many agents are available for the treatment of Candida vaginitis. A single dose of fluconazole is often effective. Because concerns about resistance are much lower in the situation in which short-term therapy is needed, this practice has been widely adopted. However, in some patient populations in which fluconazole prophylaxis has been used, especially HIV patients, vaginitis resistant to azoles has been recognized.

The management of serious Candida infections has given rise to much debate. A consensus publication on an approach to management and prevention of severe Candida infections has been published (33). Practice guidelines for treatment of candidia-sis have recently been issued by the IOSA (34). The need for a more aggressive approach to management of Candida infections was advocated, including emphasis of the need to treat all patients with candidemia. In most cases, fluconazole was considered appropriate first-line therapy for stable patients, while amphotericin B should still be used for those with life-threatening disease.

Table 4

Approach to Treatment of Fungal Infections

Disease Treatment Options

Classic Infections Aspergillosis

Allergic bronchopulmonary aspergillosis Aspergilloma Invasive Candidiasis w Mucocutaneous

Invasive Cryptococcosis Nonmeningeal Meningitis Sporotrichosis

Endemic infections Histoplasmosis Blastomycosis Coccidioidomycosis Nonmeningeal Meningitis Paracoccidioidomycosis Penicilliosis

None or—itraconazole Observation; surgery; itraconazole

Amphotericin B or liposomal amphotericin, then consider itraconazole

Thrush-clotrimazole troches, nystatin swish and swallow, fluconazole, amphotericin solution, itraconazole if refractory; esophagitis—fluconazole, amphotericin if severe; vaginitis—fluconazole; topical preparations such as nystatin, miconazole Amphotericin B; fluconazole effective for most C. albicans

Fluconazole

Amphotericin B + flucytosine followed by fluconazole Potassium iodide if limited; itraconazole; amphotericin B

Observation if not severe; itraconazole; amphotericin B if severe Itraconazole; amphotericin B if severe

Observation if acute, not severe; fluconazole or itraconazole; amphotericin B if severe Amphotericin B or fluconazole Itraconazole; amphotericin B if severe Amphotericin B; itraconazole

Other invasive infections Zygomycosis

Hyalohyphomycosis

Phaeohyphomycosis Keratitis Skin Other

Miscellaneous Invasive

Pneumocystis carinii Pseudallescheria boydii i Malassezia furfur

5 Trichosporon beigelii

Saccharomyces cerevisiae Chromomycosis Mycetoma

Dermatophytes Onychomycosis Tinea skin infection

Correct predisposing disease process plus amphotericin B or liposomal amphotericin plus surgical debridement if possible (azoles not effective) Correct predisposing disease process including growth factors for neutropenia, plus amphotericin B or liposomal amphotericin, itraconazole (for some species)

Topical antifungal drugs

Surgical debridement plus itraconazole ± flucytosine

Amphotericin B plus itraconazole ± flucytosine; plus surgical debridement if possible

Trimethoprim-sulfamethoxyzole; intravenous pentamidine; others

Surgical drainage if possible; Optimal treatment unknown—? azole drugs (often resistant to amphotericin B) Fluconazole; remove catheter

Correct predisposing disease process including growth factors for neutropenia plus fluconazole. Amphotericin B ± flucytosine (azoles usually not effective)

Surgical excision if possible; optimal treatment unknown—trial of itraconazole often warranted Itraconazole effective in some cases. Surgical debulking if possible (R/O disease due to actinomycetes)

Terbinafine or itraconazole (intermittent therapy)

Topical azole drugs or terbinafine if localized; oral terbinafine or itraconazole

Uncomplicated candidemia can usually be treated successfully with fluconazole for 21 d (33). Complicated cases, such as those in immunocompromised patients or involving resistant organisms, require use of amphotericin B or longer courses of fluconazole. Given the difficulty with treating established fungal infections, prevention should be emphasized. The benefit of fluconazole prophylaxis in patients undergoing bone marrow/stem cell transplantation is widely accepted (36). Studies are underway to determine the benefit of azole or amphotericin prophylaxis in other high-risk populations, such as solid organ recipients, patients with hemotologic malignancies receiving cytotoxic therapy, and patients in surgical ICUs. However, the emergence of resistant fungal infections in patients prescribed fluconazole prophylaxis makes this an area of ongoing controversy (37).

The timing of initiation of empiric therapy for candidiasis in high-risk patients is also a subject of debate. Neutropenic patients with fever who fail to respond after 5-7 d of empiric antibacterial therapy may benefit from empiric treatment with antifungal agents. Furthermore, the high risk of candidemia in surgical ICU patients, and the high rate of failure to isolate the organisms from blood cultures in that setting, has led many clinicians to use empiric antifungal therapy in this population as well; further study is needed to define the optimal approach.

Aspergillosis

The IOSA has issued practice guidelines for the treatment of aspergillosis (38). Invasive infections due to Aspergillus spp. should usually be treated with amphotericin B. Recovery from disseminated disease is most often dependent on correcting the underlying immune defect, especially neutropenia. The use of liposomal amphotericin B should be considered in patients unable to tolerate amphotericin B deoxycholate, especially those with nephrotoxicity. Treatment of aspergillosis most often requires use of high daily doses (0.8-1 mg/kg) and significant total doses (1.5-2 g). Itraconazole has efficacy against Aspergillus and consideration can be given to switching to the azole drug once the infection has been controlled. Decisions on when to switch from amphotericin B to itraconazole and duration of therapy must be tailored to the individual, keeping in mind the status of the underlying disease. Combination therapy with amphotericin B and flucytosine has been advocated by some experts, especially if infection occurs at sites not well penetrated by amphotericin B, such as the CNS. Rifampin may provide some synergistic benefit as well. Surgical therapy can be considered as an adjunct for patients with isolated foci of disease.

Much controversy has been raised about the use of combined amphotericin B and itraconazole. Potential antagonism has been postulated, possibly mediated by azole-induced alterations in ergosterol content of the fungi, making them less susceptible to amphotericin. However, there is little documentation of clinically significant detrimental interactions and many clinicians use amphotericin B and itraconazole together for life-threatening infections. Further study is needed.

Cryptococcosis

The IOSA has issued practice guidelines for the treatment of cryptococcosis (39). Amphotericin B with or without flucytosine remains the drug of choice for serious cryptococcal disease. Renal function and blood counts must be monitored closely with these potentially toxic drugs. Prolonged therapy may be necessary to prevent relapse.

Fluconazole also has efficacy, and may be considered in less severely ill patients. In AIDS and probably other immunosuppressed patients, cryptococcal meningitis is never cured, just controlled. Therefore, in HIV-infected individuals, lifelong maintenance therapy with fluconazole is indicated. All patients should be followed closely for signs of relapse, which can occur in the CNS or in sequestered foci such as the prostate.

Endemic Mycoses

The IOSA has issued practice guidelines for the treatment of blastomycosis (40), histoplasmosis (41), coccidoidomycosis (42), and sporotrichosis (43).

The introduction of itraconazole has significantly simplified the management of blastomycosis. While amphotericin B remains the drug of choice for treatment of severe disease, itraconazole is effective in treating less serious illness. Monitoring after completion of therapy for evidence of skin or bone involvement is necessary. Prolonged treatment courses may be needed for treatment of chronic pulmonary disease or disseminated disease.

Histoplasmosis also responds to either amphotericin B or itraconazole, with the former required for severe disease, especially if it occurs in immunocompromised patients. Itraconazole can be used for most disease in immunocompetent hosts and in nonsevere disease in immunocompromised patients. Because of the frequency of reactivation, especially in AIDS patients, HIV-infected individuals should receive lifelong maintenance therapy with itraconazole.

Disseminated coccidioidomycosis should be treated with amphotericin B in cases of severe disease in immunocompromised or other high-risk individuals. Both fluconazole and itraconazole have activity against Coccidioides immitis and can be used for treatment of mild disease in immunocompetent individuals and for prolonged therapy after response to amphotericin B.

Localized sporotrichosis may respond to potassium iodide but the azole drugs, particularly itraconazole, are more reliable. Amphotericin B should be used for treatment of disseminated disease. Amphotericin B is the drug of choice for treatment of disseminated penicilliosis in AIDS patients, although itraconazole may also be effective.

Zygomycosis

Azoles are not effective and amphotericin B is the drug of choice for treatment of zygomycete infections. However, antifungal therapy will be effective only if correction of the predisposing disease process can be accomplished. The need for high doses of ampho-tericin B has led to interest in the use of liposomal preparations, but studies are limited, and concerns have been raised about CNS penetration. Surgical debridement should be undertaken if possible. Mucormycosis with rhinocerebral involvement in diabetics should be treated by correction of the diabetic ketoacidosis, amphotericin B, and surgery.

Hyalohyphomycosis

Successful treatment of these infections is usually dependent on correction of the predisposing immune deficits. The use of growth factors to urgently reverse neutropenia has been advocated. For fusariosis, amphotericin B or liposomal amphotericin with or without flucytosine have been used most often, and a role for itraconazole is being investigated. Although some Paecilomyces species are susceptible to amphotericin B, other species are not. Use of experimental drugs such as voriconazole should be considered.

Phaeohyphomycosis

When agents of phaeohyphomycosis cause isolated ocular involvement, topical antifungal agents may be effective. Optimal treatment regimens for disseminated disease have not been established and response to amphotericin B or azole drugs is variable. Surgical debridement should be considered whenever possible.

Pneumocystis carinii

The treatment of P. carinii pneumonia is quite distinct from that of most fungal infections. Trimethroprim-sulfamethoxyzole is the drug of choice for both prophylaxis and treatment. Unfortunately, a significant proportion of AIDS patients have allergies to sulfa agents and require the use of alternative agents. Dapsone, atovaquone, and aerosolized pentamidine are effective prophylactic drugs and intravenous pentamidine and atovaquone can be used for treatment. In AIDS patients, prophylaxis should be instituted for all patients with CD4 counts < 200 cells/mm3 and patients with previous PCP episodes. It is possible that prophylaxis can be discontinued in AIDS patients whose CD4 counts increase significantly to > 200 cells/mm3 after institution of highly active antiretroviral therapy, but further study of such immune reconstitution is needed before definite recommendations can be made.

Other Invasive Mycoses

Disseminated infection with M. furfur should be treated with fluconazole. Removal of the catheter used to administer the fatty acid containing hyperalimentation solution is critical. T. beigelii infections can be very difficult to treat and reversal of neutropenia with growth factors should be considered. Aggressive therapy with fluconazole and possibly amphotericin B is necessary. Invasive Saccharomyces infection should be treated with amphotericin B, with or without flucytosine. Symptomatic vulvovaginitis may also require therapy with amphotericin, as azoles are usually ineffective.

Chromomycosis

These infections are usually not life threatening, and the goal of therapy is often cosmetic improvement. Surgical excision for debulking or cryotherapy for small lesions may be helpful. Optimal treatment is incompletely defined, but consideration can be given to a trial of itraconazole.

Mycetoma

Because these infections can progress to bony destruction, improved therapy is desirable. Surgical excision may be helpful for debulking but amputation should be avoided. It is critical to ensure that disease is truly of fungal origin and is not due to actinomycetes which should be more amenable to antimicrobial therapy. A trial of itra-conazole is reasonable.

Dermatophytes

The American Academy of Dermatology has published guidelines to assist the clinician in management of superficial mycotic infections of the skin. The guidelines cover six areas related to superficial mycoses: (1) mucocutaneous candidiasis; (2) tinea capitis and tinea barbae; (3) onychomycosis; (4) pityriasis versicolor; (5) piedra; and (6) tinea corporis, tinea cruris, tinea faciei, tinea manuum, and tinea pedis (21). Pityriasis (tinea) versicolor often responds to therapy with topical imidazoles or other antifungals, but severe disease may require therapy with oral azole drugs. In contrast, tinea capitis and tinea barbae usually require management with oral azoles, with topical agents relegated to an adjunctive role only. The addition of corticosteroids or antibacterial drugs may be necessary. Family members should be evaluated. Tinea corporis, cruris, faciei, manuum, and pedis will respond to topical antifungal agents if the condition is noninflammatory and mild. Oral azole drugs should be used if lesions are inflammatory.

Onychomycosis can be a challenging clinical problem, but new drugs offer improved options. Itraconazole has good efficacy in treatment of onychomycosis but traditional prolonged treatment courses can be quite expensive. Terbinafine is a more cost-effective agent and is now recommended as the first-line agent by many experts. The recent recognition of the efficacy of intermittent therapy with either drug can further reduce cost. Aggressive management is particularly important in immunocompro-mised patients, including those with HIV infection or diabetes.

Special Considerations for Treatment of Resistant Fungi

Because C. krusei is inherently resistant to fluconazole, treatment with amphotericin B is mandatory. C. glabrata also demonstrates reduced susceptibility to azoles and amphotericin B may be necessary. Isolates resistant to azoles, especially fluconazole, are rising for C. albicans, and case reports of resistance in non-albicans Candida spp. are increasing in frequency. When patients fail to respond to azole therapy, the possibility of resistant organisms should be considered, and switching to amphotericin B may be appropriate. Although not widely routinely available, Candida susceptibility testing is an option and standards have been established by the NCCLS (13,15,26). Testing may be indicated for patients who fail to respond to appropriate empiric therapy. Finally, C. lusitaniae is remarkably resistant to amphotericin B and flucytosine, but usually remains susceptible to fluconazole.

If patients with candidiasis fail to respond to therapy with fluconazole, alternative agents should be considered. Increasing the dose of fluconazole may be effective in treating some infections caused by C. albicans and non-albicans Candida spp. (e.g., C. glabrata) with relative resistance to fluconazole. Dosages as high as 800 mg/d have been used in recalcitrant cases. For fungi without cross-resistance to other azoles, itra-conazole may be effective. Oral amphotericin can be used for oropharyyngeal candidi-asis in HIV patients with disease unresponsive to azoles. Intravenous amphotericin B may be necessary in severe cases. New experimental drugs such as voriconazole offer hope for the future.

Aspergillus species will not respond to fluconazole, and amphotericin B should be used for treatment of serious disease. Itraconazole does have efficacy and can be used for less severe disease or for completion of therapy after initial response to ampho-tericin B.

Case reports of fluconazole resistance to C. neoformans have been reported, although the drug has good efficacy in most cases. Amphotericin B and flucytosine remain the mainstay of initial therapy, although fluconazole is occasionally used for the entire treatment course in some patients and is an important drug for maintenance therapy. If patients fail on fluconazole, a switch to amphotericin B is appropriate. Consideration can be given to susceptibility testing of Cryptococcus organisms in cases of nonresponse to the azole drugs.

Table 5

Potential New Antifungal Drugs

• Echinocandins (1, 3-ß-D-glucan synthase inhibitors)

Voriconazole

SCH56592 (derivative of itraconazole)

• Chitin synthase inhibitors

• Sodarins (protein synthesis inhibitors)

Nikkomycin

• Dicationic aromatic compounds

The zygomycetes and many of the agents of hyalohyphomycosis and phaeohy-phomycosis are generally resistant to the azole drugs. In addition, some fungi causing hyalohyphomycosis are resistant to amphotericin B. For example, Paecilomyces lilacinas is resistant to amphotericin B and flucytosine in vitro. Azole drugs should be used. Sedosporium prolificans, which causes disease in the category of phaeohy-phomycosis, demonstrates intrinsic resistance to all currently available antifungal drugs. P. boydii and T. beigelii also are resistant to amphotericin B. Azoles can be used but treatment is difficult and prognosis poor unless the underlying immune defects can be reversed. New, investigational drugs are under study and are urgently needed for management of these challenging diseases.

New Antifungal Drugs

The increase in fungal infections caused by well-recognized pathogens, the expanded recognition of resistant fungal strains, and the emergence of infections due to strains previously considered nonpathogenic highlight the need for development of innovative approaches to antifungal therapy. Several new drugs are under investigation and initial results portend an exciting future (1,22,23,29) (Table 5).

A number of new azole drugs are currently being studied. Voriconazole is a new tri-azole derivative of fluconazole currently in phase III trials that has a broad spectrum of activity against Candida spp., Aspergillus spp., dimorphic fungi, and other molds (29). Voriconazole seems to have activity against Candida spp. such as C. krusei which are resistant to fluconazole. Voriconazole also appears to have better activity against Aspergillus spp. than itraconazole. SCH 56592 is a derivative of itraconazole. This new drug appears to have better activity against Aspergillus spp. than itraconazole and broad-spectrum activity against a variety of yeasts, dimorphic fungi, and molds, including the zygomycetes and dematiaceous fungi. Other azole drugs are in earlier stages of development.

An exciting new class of antifungal function is the echinocandins. These drugs are fungicidal due to their inhibition of 1, 3P-d glucan synthase and consequent inhibition of P-glucan synthesis in the fungal cell wall. These compounds appear to have activity against Candida spp., Aspergillus spp., fungi causing endemic mycoses, and P. carinii, as well as other yeasts and molds. Nikkomycin is a fungicidal compound that inhibits chitin synthesis in the fungal cell wall. It may particularly prove useful in treatment of infections due to the endemic fungi, especially coccidioidomycosis. Studies are needed to determine if fungal cell membrane active agents (azoles and polyenes) and cell wall active agents (nikkomycin and echinocandins) might be synergistic if used in combination.

Other Approaches

Other approaches to optimizing antifungal therapy include use of growth factors to correct underlying neutropenia and cytokines and other immunomodulatory interventions. Further studies to determine which patient populations will benefit from antifungal prophylaxis are also needed (44-46).

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