Approach
Candida species in a blood culture should never be considered as a contaminant and in all cases requires treatment with an antifungal agent.[22] It should not be assumed that removal of a catheter alone is adequate therapy for candidaemia. Given the high mortality associated with systemic candidiasis, treatment should not be delayed. Delay of appropriate antifungal therapy contributes to higher mortality.[37][38][39]
Antifungal agents
Antifungal therapy has progressed dramatically from the period when the only drug available was the frequently toxic intravenous amphotericin. Clinicians have a wide choice of antifungals, none of which has been shown to be superior to amphotericin-B. There are now two additional classes of antifungal agents. Neither are vastly superior to amphotericin-B, but they are easier to use and possess superior safety profiles.
Amphotericin-B deoxycholate was previously the standard drug for systemic candidiasis. It is rapidly cidal in vitro and possesses broad-spectrum activity against most Candida species except C lusitaniae, but it is significantly nephrotoxic and associated with frequent infusion toxicity. Lipid formulations of amphotericin-B have largely replaced the deoxycholate formulation, with reduced, but not absent, nephrotoxicity. However, these agents are expensive, and although less toxic, not therapeutically superior.
Echinocandins are non-competitive inhibitors of synthesis of beta 1,3-beta-D-glucan, a major component of the fungal cell wall, and include caspofungin, anidulafungin, and micafungin.[40] They have excellent activity against all Candida species and a good safety profile.[41] No dose adjustments are required for advanced renal disease. The echinocandins are preferred over azole agents for the initial treatment of candidaemia, particularly if C krusei, C glabrata, or C auris are suspected or documented and in critically ill, haemodynamically unstable patients.[16][22][42][43] The highest minimum inhibitory concentrations are found with C parapsilosis (1-2 microgram/mL), although clinical efficacy is comparable to other agents and failures with this organism are extremely rare.[44] Similarly, acquired resistance to all or any of the 3 agents in this class remains relatively rare, although it is increasing, particularly among C glabrata isolates.[45][46] The 3 echinocandin drugs are widely considered as therapeutically equivalent.[22][47]
Azoles inhibit the formation of ergosterol in the fungal cell membrane. Fluconazole has been widely used for candidiasis for more than 15 years, and has a good safety record and a favourable toxicity profile. Several large studies have shown equivalent activity and success when compared with polyenes, such as amphotericin-B, and the newer echinocandins in non-neutropenic hosts.[48][49][50] However, growing resistance now limits its use to empirical therapy in settings where fluconazole resistance is low and/or echinocandins are not available. Fluconazole is also preferred over echinocandins if infection is suspected in body compartments where echinocandins have poor penetration (e.g., central nervous system, eye, and urinary tract). Voriconazole can retain activity against fluconazole against most Candida species and is active against fluconazole-resistant C krusei and some strains of fluconazole-resistant C glabrata. Its efficiency in treatment of invasive candidiasis has been demonstrated in a large prospective, randomised study.[51] However, its lack of superiority, additional cost and less favourable toxicity profile, particularly numerous drug interactions, have resulted in voriconazole being reserved for selected patients with fluconazole-resistant but voriconazole-sensitive strains.
Treatment for suspected cases
Antifungal therapy should be started in patients who are critically ill and have risk factors for systemic candidiasis, and for whom other causes of fever have been excluded. This decision should be based on clinical assessment and results of cultures from non-sterile sites. Local pathogen knowledge is also important when deciding on empirical therapy.
Non-neutropenic patients
First-line choice is an echinocandin (e.g., caspofungin, anidulafungin, or micafungin). An echinocandin is preferred over azole agents for the initial treatment of candidaemia if C krusei, C glabrata, or C auris are suspected or documented, particularly in critically ill, haemodynamically unstable patients; those who have had recent exposure to an azole; and those colonised with azole-resistant Candida species.[16][22][42][43] Fluconazole is an acceptable first-line alternative for patients who have had no recent azole exposure and are not colonised with azole-resistant Candida species.[22] If initial antifungals are not tolerated or are not available, recommended alternatives include the lipid formulation of amphotericin-B.
For patients who have no clinical response to empiric antifungal therapy at 4 to 5 days and who do not have subsequent evidence of invasive candidiasis after the start of empiric therapy or if cultures and surrogate markers are negative, consideration should be given to stopping antifungal therapy.[22]
Neutropenic patients
First-line choices are caspofungin, anidulafungin, or micafungin.[52] Lipid amphotericin B is also effective, although increased toxicity makes it less attractive as initial therapy. Fluconazole and voriconazole are alternative agents. An echinocandin is preferred over azole agents for the initial treatment of candidaemia if C krusei, C glabrata, or C auris are suspected or documented, particularly in critically ill, haemodynamically unstable patients; those who have had recent exposure to an azole, and those colonised with azole-resistant Candida species.[16][22][42][43] If patients have received an azole for prophylaxis, an azole should not be given as empirical therapy. Prophylactic antifungals are standard of care and routinely used in patients with neutropenia likely to persist longer than 7 days.
Treatment for confirmed cases
The recommended duration of therapy for systemic candidiasis with no complications is 2 weeks beyond clearance of Candida from the blood and when clinical symptoms have resolved. Intravascular catheter removal is recommended in all patients who have a confirmed diagnosis.
Non-neutropenic patients
Initial therapy is with an echinocandin (e.g., caspofungin, anidulafungin, or micafungin) or fluconazole as first-line choices.
An echinocandin is preferred for patients who are critically ill, who have had recent azole exposure, or in whom the infection is caused by C glabrata, C krusei, or C auris.[16][22][42][43] Some experts consider echinocandins to be agents of first choice for all patients as initial therapy.[53]
Fluconazole is an acceptable first-line option for patients who are not critically ill and who are considered unlikely to have fluconazole-resistant Candida species.
Lipid formulations of amphotericin-B are considered alternatives if initial antifungal agents are not tolerated or are not available.
Transition from an echinocandin to fluconazole is recommended for patients who are clinically stable, who have documented clearance of Candida from the bloodstream, and who are infected with an organism that is susceptible to fluconazole (e.g., C albicans, C parapsilosis, and C tropicalis).[22]
Voriconazole is effective for candidaemia but offers little advantage over fluconazole as initial therapy. It is recommended as step-down oral therapy for selected cases of candidaemia due to C krusei or for C glabrata that has been shown to be susceptible.[22]
Neutropenic patients
Initial therapy for most patients should be with an echinocandin, especially if infection is caused by C glabrata.
Echinocandins are recommended as initial therapy for C auris species, as most strains in the US are susceptible.[16]
Lipid formulations of amphotericin-B are considered an alternative therapy in this patient group.
Fluconazole is an alternative for patients who are not critically ill and who have had no prior azole exposure.
If mould coverage is required, voriconazole can be used. It can also be used as step-down therapy during neutropenia in clinically stable patients who have had documented bloodstream clearance and isolates that are susceptible to voriconazole.
Treatment of complications
If patients have complications (e.g., endocarditis, endophthalmitis, renal candidiasis), more prolonged therapy is required depending upon the site involved.[22]
For endocarditis, the combination of lipid amphotericin-B ± flucytosine is preferred, with high-dose echinocandins as an alternative. Fluconazole can be used as step-down therapy. Total duration of treatment is at least 6 weeks, although in patients not able to undergo valve replacement, long-term suppression with fluconazole may be considered.
Endophthalmitis should be treated with lipid amphotericin-B with flucytosine for infections due to azole-resistant isolates, although fluconazole or voriconazole should be used in azole-susceptible isolates. The echinocandins may not be useful in this context due to inadequate penetration into the vitreous.[54] Treatment should be continued for 4 to 6 weeks or longer, depending on clinical response as determined by serial ophthalmological examinations. Vitrectomy should be strongly considered as well, along with intravitreal injection of amphotericin-B or voriconazole in cases of vitritis or macular involvement.[22]
Therapy for renal candidiasis varies depending on the clinical syndrome; pyelonephritis should be treated with fluconazole for 2 weeks, with amphotericin-B as an alternative.
Supportive care
If the patient is critically ill with sepsis, he or she may need to be admitted to the intensive care unit and require additional care in the form of vigorous fluid resuscitation. If hypotension persists, vasopressors or inotropes may be required.
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