Intrinsic Resistance
Certain fungi exhibit intrinsic resistance to specific antifungal agents, meaning they are inherently resistant to those drugs regardless of prior exposure. Recognizing these patterns is crucial for selecting appropriate antifungal therapy from the outset. We’ll explore the concept of intrinsic resistance and highlight key examples, focusing on Candida krusei and other notable cases
Intrinsic Resistance
- Definition: Intrinsic resistance refers to the inherent resistance of a microorganism to a particular antimicrobial agent, regardless of prior exposure to the drug. This resistance is due to the organism’s genetic makeup and is not acquired through mutation or horizontal gene transfer
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Importance: Recognizing intrinsic resistance patterns is essential for:
- Selecting appropriate initial antifungal therapy
- Avoiding unnecessary use of ineffective agents
- Preventing treatment failure
- Guiding antifungal stewardship efforts
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Mechanisms: Intrinsic resistance can arise from various mechanisms, including:
- Target Modification: The fungal target of the antifungal agent may be structurally different in intrinsically resistant species, preventing the drug from binding effectively
- Reduced Permeability: The fungal cell wall or membrane may be less permeable to the antifungal agent, limiting its entry into the cell
- Efflux Pumps: The fungus may possess efflux pumps that actively transport the antifungal agent out of the cell, reducing its intracellular concentration
- Enzymatic Inactivation: The fungus may produce enzymes that inactivate the antifungal agent
Key Examples of Intrinsic Resistance
Candida krusei
- Intrinsic Resistance: Fluconazole
- Clinical Significance: Candida krusei is intrinsically resistant to fluconazole, a commonly used antifungal agent. This means that fluconazole should not be used to treat infections caused by C. krusei
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Alternative Agents: Alternative antifungal agents that are typically effective against C. krusei include:
- Echinocandins (e.g., caspofungin, micafungin, anidulafungin)
- Voriconazole
- Amphotericin B
Candida glabrata
- Intrinsic Resistance: Although not completely resistant, Candida glabrata often exhibits reduced susceptibility to azoles, particularly fluconazole. It also has a propensity to develop acquired resistance to azoles during treatment
- Clinical Significance: Infections caused by C. glabrata may require higher doses of azoles or alternative antifungal agents
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Alternative Agents:
- Echinocandins
- Amphotericin B
- Voriconazole (may be effective at higher doses)
Candida auris
- Intrinsic Resistance: Candida auris exhibits variable susceptibility to azoles, amphotericin B, and echinocandins, and multidrug-resistant strains are increasingly common
- Clinical Significance: Infections caused by C. auris can be difficult to treat due to its resistance to multiple antifungal agents
- Treatment: Treatment decisions should be guided by antifungal susceptibility testing results. Combination therapy may be necessary for multidrug-resistant strains
Scedosporium spp.
- Intrinsic Resistance: Scedosporium species are often resistant to amphotericin B and many azoles
- Clinical Significance: Infections caused by Scedosporium can be difficult to treat due to their resistance to commonly used antifungal agents
- Treatment: Voriconazole is often the preferred agent, but susceptibility testing is essential to guide therapy. Other options include posaconazole and isavuconazole
Fusarium spp.
- Intrinsic Resistance: Fusarium species exhibit variable susceptibility to antifungal agents, but they are often resistant to amphotericin B and many azoles
- Clinical Significance: Infections caused by Fusarium can be difficult to treat due to their resistance to commonly used antifungal agents
- Treatment: Voriconazole, posaconazole, and isavuconazole may be effective, but susceptibility testing is essential to guide therapy. Combination therapy may be necessary
Laboratory Considerations
- Antifungal Susceptibility Testing: It is essential to perform antifungal susceptibility testing on clinically significant fungal isolates to guide therapy and detect resistance
- Quality Control: Ensure that antifungal susceptibility testing methods are properly validated and that quality control procedures are followed
- Reporting: Report antifungal susceptibility testing results accurately and include interpretive comments to guide clinical decision-making
- Communication: Communicate with clinicians about intrinsic resistance patterns and the implications for antifungal therapy
Key Takeaways
- Intrinsic resistance is the inherent resistance of a microorganism to a particular antimicrobial agent
- Recognizing intrinsic resistance patterns is essential for selecting appropriate antifungal therapy
- Candida krusei is intrinsically resistant to fluconazole
- Candida glabrata often exhibits reduced susceptibility to azoles
- Scedosporium and Fusarium species are often resistant to amphotericin B and many azoles
- Mucorales are intrinsically resistant to voriconazole
- Antifungal susceptibility testing is essential to guide therapy and detect resistance
Key Terms
- Intrinsic Resistance: The inherent resistance of a microorganism to a particular antimicrobial agent
- Acquired Resistance: Resistance that develops in a microorganism as a result of exposure to an antimicrobial agent
- Target Modification: A mechanism of resistance in which the fungal target of the antifungal agent is altered, preventing the drug from binding effectively
- Reduced Permeability: A mechanism of resistance in which the fungal cell wall or membrane is less permeable to the antifungal agent
- Efflux Pump: A protein that actively transports antimicrobial agents out of the cell, reducing their intracellular concentration
- Enzymatic Inactivation: A mechanism of resistance in which the fungus produces enzymes that inactivate the antifungal agent
- Antifungal Stewardship: A program to promote the appropriate use of antifungal agents
- Minimum Inhibitory Concentration (MIC): The lowest concentration of an antimicrobial agent that inhibits the visible growth of a microorganism
- Broth Microdilution (BMD): A manual method for AFST that involves preparing two-fold dilutions of antifungal agents in a broth medium
- Etest: A manual method for AFST that uses a plastic strip containing a gradient of antifungal concentrations
- Automated System: A laboratory instrument that automates various steps of AFST
- CLSI (Clinical and Laboratory Standards Institute): A non-profit organization that develops standards for laboratory testing
- EUCAST (European Committee on Antimicrobial Susceptibility Testing): A European organization that develops standards for antimicrobial susceptibility testing
- RPMI 1640: A common broth medium used for AFST
- Mould-Specific Identification: Refers to laboratory techniques, including microscopic examination and molecular assays, used to accurately identify specific mold species in clinical samples, aiding in diagnosis and treatment of infections caused by these fungi
- Panfungal PCR: is a molecular diagnostic technique that utilizes polymerase chain reaction (PCR) to amplify and detect conserved DNA sequences present in a wide range of fungi, allowing for the identification of fungal infections, even when traditional culture methods are negative or impractical