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Peter G. Pappas, John H. Rex, Jack D. Sobel, Scott G. Filler, William E. Dismukes, Thomas J. Walsh, John E. Candida species are the most common cause of fungal infections. Candida species produce infections that range from non—life-threatening mucocutaneous illnesses to invasive processes that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. Throughout this document, treatment recommendations are rated according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the supporting evidence and quality of the underlying data table 1.
This document covers the following 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. However, susceptibility testing of fungi is not considered a routine testing procedure in many laboratories, is not always promptly available, and is not universally considered as the standard of care.
Knowledge of the infecting species, however, is highly predictive of likely susceptibility and can be used as a guide to therapy. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with deep infection due to non— albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered.
Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis table 2.
Extensive data from randomized trials are available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports.
In general, amphotericin B—based preparations, the azole antifungal agents, and the echinocandin antifungal agents play a role in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B—based preparations and the echinocandin antifungal agents for some non— albicans species e.
Flucytosine has activity against many isolates of Candida but is infrequently used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and are safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to have repeated relapses. In some situations, the explanation for such a relapse is obvious e.
Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance with prolonged or repeated exposure. Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified patient group. Selected patient groups undergoing therapy that produces prolonged neutropenia e. Relationship between epidemiology of candidal infections and therapy.
Although Candida albicans remains the most common pathogen in oropharyngeal and cutaneous candidiasis, non- albicans species of Candida are increasingly associated with invasive candidiasis [ 1—5 ]. This shift is particularly problematic in patients with acute life-threatening invasive candidal infections.
Although the susceptibility of Candida to the currently available antifungal agents can be predicted if the species of the infecting isolate is known table 3 [ 1 , 4 , 6 , 11—17 , 20—24 ], individual isolates do not necessarily follow the general pattern. For example, C. However, azole resistance for this species is now well described among HIV-infected individuals with recurrent oropharyngeal candidiasis and is also reported sporadically in critically ill adults with invasive candidiasis [ 25 ] or in healthy adults [ 26 ].
For this reason, susceptibility testing for azole resistance is increasingly used to guide the management of candidiasis in patients, especially in situations where there is failure to respond to the initial empirical therapy. On the other hand, most Candida isolates appear to remain susceptible to amphotericin B, although recent data suggest that isolates of Candida glabrata and C.
Susceptibility testing and drug dosing. Intensive efforts to develop standardized, reproducible, and clinically relevant susceptibility testing methods for fungi have resulted in the development of the NCCLS MA methodology now updated with the essentially identical MA2 methodology for susceptibility testing of yeasts [ 27 , 28 ].
Data-driven interpretive breakpoints using this method are available for testing the susceptibility of Candida species to fluconazole, itraconazole, and flucytosine [ 28—31 ].
Several features of these breakpoints are important. First, these interpretive breakpoints should not be applied to other methods without extensive testing. Although the MA2 methodology is not the only possible way to determine an MIC, use of the MA2 interpretive breakpoints with other methods should be approached with caution—even small methodological variations may produce results that are not correctly interpreted by means of these breakpoints.
Second, these interpretive breakpoints place a strong emphasis on interpretation in the context of the delivered dose of the azole antifungal agent. Although trials to date have not used this method, administration of twice the usual daily dose of fluconazole as a loading dose is a pharmacologically rational way to more rapidly achieve higher steady-state blood concentrations. Finally, these breakpoints were developed on the basis of data from 2 groups of infected adult patients: patients with oropharyngeal and esophageal candidiasis for fluconazole and itraconazole and patients with invasive candidiasis mostly nonneutropenic patients with candidemia; for fluconazole only [ 30 ] and are supported by subsequent reports [ 27 , 31 , 33 , 34 ].
Although these limitations are similar to those of interpretive breakpoints for antibacterial agents [ 27 ], and extrapolation of these results to other diagnostic settings appears to be rational on the basis of data from in vivo therapy models, it is still prudent to consider the limitations of the data when making use of the breakpoints. Pharmacology, safety, published reports, drug interactions, and isolate susceptibility [ 27 ] must be considered when selecting a therapy.
For example, most isolates of Candida are susceptible to itraconazole, but this agent only recently became available as a parenteral preparation and has not been studied intensively for candidiasis, except for treatment of mucosal disease. Reliable and convincing interpretive breakpoints are not yet available for amphotericin B. Variations of the MA2 methodology using different media [ 6 ], agar-based MIC methods [ 12 , 35 , 36 ], and measurements of minimum fungicidal concentrations [ 11 ] appear to enhance detection of resistant isolates.
Although these methods are as yet insufficiently standardized to permit routine use, several generalizations are becoming apparent. First, amphotericin B resistance appears uncommon among isolates of Candida albicans, Candida tropicalis , and C.
Second, isolates of Candida lusitaniae most often demonstrate readily detectable and clinically apparent amphotericin B resistance. Not all isolates are resistant [ 11 , 23 , 37 ], but therapeutic failure of amphotericin B is well documented [ 38 ]. Third, a growing body of data suggests that a nontrivial proportion of the isolates of C.
Of importance, delivery of additional amphotericin B by use of a lipid-based preparation of amphotericin B may be inadequate to overcome this resistance [ 22 ]. Also, because of in vitro effects of the lipid, tests for susceptibility to amphotericin B should always use the deoxycholate rather than the lipid formulation [ 39 ].
Unfortunately, the clinical relevance of these observations is uncertain. Most rational current therapy of infections due to these species C. When amphotericin B deoxycholate is used to treat infections due to C. Meaningful data do not yet exist for other compounds. This includes specifically the newer expanded-spectrum triazoles voriconazole, posaconazole, and ravuconazole and the echinocandins caspofungin, micafungin, and anidulafungin.
Although MIC data for these compounds are available for all major Candida species table 3 , the interpretation of those MICs in relation to achievable blood levels is uncertain [ 29 ]. This is particularly true for the echinocandin antifungal agents.
Practical clinical use of antifungal susceptibility testing. Antifungal susceptibility testing has not achieved the status of a standard of care and is not widely available, and results of testing may not be available for days. The strongest data to date are for fluconazole, an agent for which the issues of resistance are most compelling. The greatest concern for fluconazole resistance relates to C.
Testing is most often used in 1 of 2 ways [ 27 ]. First, susceptibility is useful in the evaluation of the possible causes of lack of clinical response.
Second, the data may be used to support a change in therapy from a parenteral agent of any class to oral fluconazole. This consideration is most relevant when considering outpatient therapy and for treating infections that require protracted therapy e. The rapid pace of antifungal drug development has resulted in the recent licensure of 2 new antifungal drugs voriconazole and caspofungin , along with the active development of 4 others ravuconazole, posaconazole, micafungin, and anidulafungin.
In addition, new data continue to accumulate for itraconazole and the lipid-associated preparations of amphotericin B. Although all these compounds appear to have significant activity against Candida species, the size of the published clinical database for these compounds for treatment of candidiasis is limited.
In an effort to integrate these agents into the guidelines, the available data on the newly licensed agents will be summarized here. This formulation is administered at a dosage of mg q12h for a total of 4 doses i. Itraconazole is well known to be active against mucosal forms of candidiasis see Nongenital Mucocutaneous Candidiasis, below , but the availability of an intravenous form of itraconazole allows for treatment of invasive disease.
Although itraconazole would be expected to have activity broadly similar to that of fluconazole, the 2 compounds have quite different pharmacological properties and clinical activities for other mycoses [ 45 ]. Moreover, formal studies of intravenous itraconazole for invasive candidiasis are not available. Therefore, the discussion of therapy for invasive candidiasis will generally not address intravenous itraconazole.
Voriconazole and the newer azole antifungal agents. Voriconazole is available in both oral and parenteral preparations. It is as active as fluconazole against esophageal candidiasis, although it was associated with more adverse events in a recent study [ 46 ].
Among 4 pediatric patients who received voriconazole as salvage therapy, candidemia cleared in 2 of 2 patients and disseminated candidiasis resolved in 1 of 2 patients [ 47 ]. It is notable that voriconazole appears to have the potential to be active against some fluconazole-resistant isolates. Of 12 HIV-infected subjects with fluconazole-refractory esophageal candidiasis due to C. Consistent with its activity against C. The in vitro anti- Candida activity of the other azoles under active development posaconazole and ravuconazole also appears to be good [ 50 ].
The available clinical data for posaconazole include reports of successful salvage therapy for invasive candidiasis [ 51 ], successful salvage therapy of azole-refractory oropharyngeal candidiasis in HIV-infected individuals [ 52 ], and 2 randomized comparisons showing efficacy comparable with that of fluconazole for non—azole-refractory esophageal candidiasis [ 53 , 54 ].
The available data for ravuconazole include a randomized phase II dose-ranging study showing efficacy comparable with that of fluconazole for non—azole-refractory esophageal candidiasis [ 55 ].
Caspofungin and the echinocandin antifungal agents.