By Stephen W. Crawford, MD
In a recent issue of Critical Care Alert (2002;10:30-32) I discussed the epidemiology and pathophysiology of invasive fungal infections that afflict patients in the ICU.1 In this issue, I review the current treatment options.
First among the treatment approaches is correction of the factors that place the patient at risk. Most importantly, immune function (especially neutrophil-related immune function) should be restored. This may require decreasing corticosteroid dose or use, treating underlying hematological malignancy, or administering white cell transfusions or hematologic growth factors. Limitations in improving immune function present a major barrier to curing invasive fungal infection. Surgical options are discussed later in the article.
Most of the treatment options include antifungal agents. As an overview, the presently available agents include amphotericin B, the imidazoles, the triazoles, and the echinocandins (see Table 1, below).
Current Antifungal Agents for Systemic Infection
Azole agents, which include the imidazoles
Table 2 summarizes some of the agents undergoing clinical investigations.
Investigational Antifungal Agents
Adapted from: Klepser ME, et al. Ann
Amphotericin B. For the most of the last 40 years, the primary agent available for treating deep-seated or systemic fungal in infections (and the only agent for treating aspergillus infections) was amphotericin B deoxycholate. Amphotericin B has the advantage of having a very broad spectrum for many fungal species, but its use is limited by its toxicity, especially renal dysfunction.
Recent advances in amphotericin B include the development of lipid formulations. The clinical responses to these formulations are as good (or as bad, depending upon your perspective) as those seen with conventional amphotericin B.2-4 All of these formulations demonstrate reduced nephrotoxicity compared to the parent compound. The reduced toxicity profiles allow administration of significantly higher doses of amphotericin B. However, it is unclear that these higher doses lead to improved efficacy.5 It is clear, however, that these newer formulations are more expensive.
The lipid-complexed amphotericin B preparations are highly lipophilic, and have decreased toxicity to human cells due to affinity to fungal ergosterols. Although commonly referred to as "liposomal" agents, only one of these (AmBisome) is a true liposome (see Table 3). All of these preparations display decreased toxicity, especially nephrotoxicity, as compared to conventional amphotericin B. In general, AmBisome has the least toxic reactions reported, followed by Albecet and then Amphocil. Given their lipophilic natures, these preparations are preferentially taken-up by reticuloendothelial system. This makes the pharmacokinetics difficult to follow in serum.
Lipid Formulations of Amphotericin B
Amphocil®—Amphotericin B Colloidal Dispersion ("ABCD")
Albecet®—Amphotericin B Lipid Complex ("ABLC")
AmBisome®—Liposomal Amphotericin B
Imidazoles. In general, the imidazoles have played a very small role in the treatment of deep-seated or invasive fungal infections and will not be discussed here. Ketoconazole may have a role in chronic suppression of Candida species.
Triazoles. Fluconazole is the major triazole anti-fungal agent in common use for deep-seated or invasive fungal infections. Fluconazole is water-soluble and its absorption is not dependent on gastric pH. The drug is almost completely absorbed after oral administration and can be given either intravenously or orally. Excretion is primarily renal. It is indicated primarily for treatment of candida and Cryptococcus neoformans infections. In addition, it is useful for the prevention of candida infections in high-risk patients. Fluconazole has marginal activity against Candida krusei and C glabrata. These organisms are inherently resistant and infections with these yeasts commonly increase when fluconazole is used prophylactically. Fluconazole is not active against Aspergillus species.
The most frequently used second-generation triazole antifungal agent is itraconazole. Similar to fluconazole, it inhibits cytochrome P450-dependent synthesis of ergosterol. However, it has a broader spectrum. It demonstrates in vitro activity against Candida albicans and other Candida species, Aspergillus fumigatus, Blastomyces dermatitidis, and Histoplasma capsulatum. Itraconazole is available in capsule, oral solution, and IV formulations.
Boogaerts and associates recently compared the efficacy and safety of intravenous itraconazole with amphotericin B as empiric antifungal therapy in patients with hematological malignancies.6 This international, multicenter, open-labeled, prospective randomized study included 384 adults with hematological malignancies who had neutropenia expected to last for 7 days, had persistent fever of unknown origin, and were unresponsive to broad-spectrum antibiotics.
Response rates were better (but not statistically different) for itraconazole (47%) as compared to amphotericin B (38%). There were no differences in rates of breakthrough fungal infection or deaths. However, the amphotericin B patients experienced significantly more drug-related adverse effects (54% vs 5%) and premature discontinuations secondary to adverse events (38% vs 19%). In addition, responding patients receiving itraconazole could be switched to oral therapy. Such studies suggest that itraconazole may be a reasonable alternative to conventional amphotericin B for empiric therapy.
Voriconazole is a newer triazole antifungal with broad-spectrum of activity against most human fungal pathogens, including Candida, Aspergillus, and Cryptococcus species, filamentous fungi, and dimorphic fungi. Cross-resistance with fluconazole for some Candida species has been reported. Twice daily dosing (both IV and oral) is available.
There are 2 international, randomized trials comparing voriconazole to amphotericin B. Herbrecht and associates compared voriconazole to conventional amphotericin B for treatment of documented invasive aspergillus infection.7 The voriconazole cohort had a higher success rate (53% vs 31%; P < 0.0001) and a lower death rate (29% vs 42%; P = NS). Walsh et al compared voriconazole to liposomal amphotericin as empirical therapy in neutropenic fever.8 Success rates were similar for the 2 cohorts (26% vs 31%; P < 0.0001), and the voriconazole cohort had fewer breakthrough fungal infections (2% vs 5%; P = 0.02).
Review of these studies illustrates several confounders in the study of aspergillus treatment. Treatments were based either on empirical evidence of aspergillus infection or on proven (documented) infection. Also, newer pharmacological interventions can be compared to either conventional amphotericin B or to a lipid preparation. Thus, interpretation and application of these studies can be confusing. At this time, one can justify using any of the available agents.
Other triazoles undergoing investigation include ravuconazole and posaconazole. Both are active against Candida albicans and nonalbicans Candida species, Cryptococcus species, Aspergillus species and fluconazole-resistant strains of Candida species.
Echinocandins. In an apparent advance in the treatment of fungal infections, caspofungin acetate (Cancidas) represents the first of a new class of antifungal drugs (echinocandins or glucan synthesis inhibitors) that inhibit the synthesis of ß-(1,3)-D-glucan, an integral component of the fungal cell wall.9 Of note, ß-(1,3)-D-glucan is not present in mammalian cells. Caspofungin is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system, unlike the triazoles. The agent has in vitro and in vivo activity against Candida species, Aspergillus species, and Histoplasma capsulatum. Also, it is effective against fluconazole-susceptible and fluconazole-resistant Candida strains. However, it is not effective against Cryptococcus neoformans. Caspofungin is available in intravenous formulation only and has a very low toxicity profile. Because it has a different site and mechanism of action there is reason to believe that it may be useful in combination with currently available antifungals, such as amphotericin or the triazoles. This possibility of multi-drug therapeutic approach is very exciting and may present a significant breakthrough in treatment. Empirical successes have been reported, however controlled trials are lacking.10
Managing Invasive Pulmonary Aspergillosis
Invasive pulmonary aspergillosis (IPA) in the immunosuppressed bears many epidemiological similarities to bronchogenic carcinoma: the presentation is most often localized; the patients have identified risk factors; and "chemo" (drug therapy) alone is of limited value. Also, the causes of death for both are similar: spread to brain or heart, or erosion into thoracic vessels causing massive hemoptysis. For these reasons, I consider IPA to be the "Bronchogenic Carcinoma Equivalent."
For the same reasons we believe that surgical resection is the best treatment option for localized non-small cell bronchogenic carcinoma, I think we should consider surgical resection of IPA. Such resection is potentially curative, and may serve to "debulk" devascularized tissue that does not permit distribution of antifungal agents to the organisms. Although numerous reports suggest that surgical resection can be carried out safely, it is difficult to prove that outcomes are improved. Regardless, I think resection should be considered in any case of localized IPA (proven or suspected) in which continued immunosuppression is anticipated.
Alternative (or adjunctive) strategies to the treatment of invasive pulmonary aspergillosis are advisable since the prognosis with the usual approaches is so dismal. There are anecdotal reports of success with granulocyte transfusions, however no controlled studies to support the practice. Alternatively, I believe that the use of hematopoietic growth factors to augment phagocytic numbers and function has a potential sound rationale in neutropenic patient. Again, this is difficult to support with controlled trials. There are mixed reports of success when used prophylactically for lung cancer treatments.
In summary, there are new drugs approved for the treatment of serious invasive fungal infections. These have primarily been studied in the neutropenic patient population. Compared to those of conventional amphotericin B, the safety and toxicity profiles of these new agents are favorable. Response rates are at least equivalent to conventional treatment. The most novel of the new agents is the first of the echinocandin class, caspofungin. Its novel mechanism of action raises the possibility (so far, supported only by anecdotes) that combination therapy with amphotericin or triazole compounds may have increased efficacy. Despite these advances, the major limitation to recovery from serious invasive fungal infection for most patients remains the underlying disease that produced their immune suppressed state.
Note—The views and opinions expressed are not necessarily those of the US Navy or US Government. Dr. Crawford is a member of the Ortho-Biotech, Inc speaker’s bureau.
1. Crawford SW. Systemic fungal infections: Epidemiology and pathogenesis. Critical Care Alert. 2002;10:30-32.
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6. Boogaerts M, et al. Ann Intern Med. 2001;135:412-422.
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8. Walsh TJ, et al. N Engl J Med. 2002;346:225-234.
9. Denning DW. J Antimicrobial Chemotherapy. 2002; 49:889-891.
10. Rubin MA, et al. Clin Infect Dis. 2002;34:1160.