Antifungal Susceptibility Testing, Therapy, and Prevention

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Antifungal Susceptibility Testing, Therapy, and Prevention

Antifungal Susceptibility Testing

Antifungal susceptibility tests are designed to provide information that helps the physician select the appropriate antifungal agent to treat a specific infection. Although antifungal susceptibility testing perhaps has not advanced as far as methods for determining the susceptibility of bacteria to antimicrobial agents, significant progress has been made. Substantial efforts have attempted to develop a standardized method that is reproducible among different laboratories. All of the technical variables in the testing process have been standardized, and efforts are underway to develop interpretative guidelines for different antifungal agents.

The Clinical Laboratory Standards Institute (CLSI) sets the standards for antifungal susceptibility testing. The current guidelines for these tests are provided in the following three documents, which are available on the CLSI website (www.clsi.org):

• Document M27-A3, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Approved Standard, 3rd edition. This document covers requirements for use of the broth microdilution method. The standards for susceptibility testing are very specific about the inoculum size, test medium, incubation time and temperature, and end point of yeasts that cause invasive fungal infections.

• Document M38-A2, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi, Approved Standard, 2nd edition. This standard is a microdilution method for molds that cause invasive and cutaneous infections.

• Document M44-A2, Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts, 2nd edition, Approved Guideline. This standard provides methodology for disk diffusion testing for Candida spp., including quality control and interpretation guidelines. Also see the International Supplement M44S3.

It must be emphasized that the methodology and interpretation of antifungal susceptibility tests continue to evolve, and the laboratory should check for updated standards or a regular basis. Antifungal susceptibility tests are costly and time-consuming, but they may have value in the following circumstances:

The interpretative breakpoints for fluconazole, itraconazole, and flucytosine are based on experience in treating patients with mucosal infections, but they also appear to be consistent with information assembled for invasive infections. Problems that complicate the interpretative guidelines include:

Isolates of the same species may exhibit differences in minimum inhibitory concentrations (MICs) because of previous exposure to antifungal agents and/or acquisition of a genetic mechanism of resistance. For example, some isolates of Candida glabrata show susceptibility to fluconazole, but others do not. CLSI’s interpretative guidelines should be followed whenever possible, but anecdotal experience also is useful.

Despite the problems associated with antifungal susceptibility testing, many physicians believe that these tests are important for selecting an appropriate antifungal agent and as a method to detect the development of resistance of certain organisms during chemotherapy. A laboratory that is not equipped to perform CLSI methods, or validated equivalent methods, for susceptibility of clinically important fungal isolates should be prepared to send the isolate to a reference laboratory for testing. Amphotericin B, 5-fluorocytosine, ketoconazole, itraconazole, voriconazole, and fluconazole are common antifungal agents that traditionally have been tested; the newer antifungal agents may now be added to this list. For those interested in further information on this topic, the susceptibilities of many of the newer antifungal agents to some of the more challenging fungal pathogens have been published in a minireview by Lass-Florl et al.

Antifungal Therapy and Prevention

Numerous antifungal agents have been developed, and newer agents are on the horizon. The increasing number of immunosuppressed patients and the expansion of drug resistance of microorganisms make the development and appropriate use of antimicrobial agents two of the most important areas in microbiology and infectious diseases. This section is meant only to introduce the reader to the more commonly used antifungal agents; it is by no means comprehensive. Also, this section is not to be used as a guide for therapy. Therapeutic guidelines may be found in the texts listed in the bibliography.