Candidiasis: New agents for invasive infections
Candida albicans ©Dennis Kunkel Microscopy, Inc./Visuals Unlimited
Infection with the ubiquitous fungus Candida cuts across a broad spectrum of severity that ranges from common and superficial mucocutaneous variants to invasive disease that can be life-threatening.
The addition of important new antifungal agents to the candidiasis armamentarium has led the Infectious Diseases Society of America to issue updated Clinical Practice Guidelines for the Management of Candidiasis to replace the 2004 version.
These agents—the echinocandins caspofungin, anidulafungin, and micafungin—are essentially reserved for candidemia and other invasive forms of candidiasis. The Guidelines also incorporate new data on the treatment of mucocutaneous disease and on the prevention of invasive disease in high-risk patients.
Office-based primary-care providers “probably see [relatively benign] aspects of candidiasis most often: oropharyngeal infection (thrush) and vaginitis. They will see Candida in urine, where the question is whether it is causing infection or just hanging out,” says Carol A. Kauffman, MD, professor of internal medicine at the University of Michigan in Ann Arbor, chief of infectious diseases in the VA Ann Arbor Healthcare System, and an author of the Guidelines.
Candidemia and other forms of invasive candidiasis are generally encountered in the hospital setting (candidemia is the fourth most common nosocomial bloodstream infection in the United States) but may develop in community-dwelling patients as well (e.g., those who are leukemic, have an indwelling catheter, are on dialysis, or are receiving cancer chemotherapy via a port or central line), according to Dr. Kauffman.
For vulvovaginal infection, the Guidelines endorse both topical and systemic approaches. The authors list a number of topical antifungal formulations in cream, tablet, and suppository form and note that none has been shown superior to the others. Patient and clinician preferences most often make the systemic route—a single dose of fluconazole—the treatment of choice, says Dr. Kauffman.
For recurring vulvovaginal infection (four or more episodes in a year), the Guidelines recommend control of contributing factors (such as diabetes) and 10-14 days of either topical or systemic azole therapy, followed by a maintenance regimen of once-weekly fluconazole for six months.
The diagnosis can usually be made clinically, but because the symptoms of vulvovaginal infection are nonspecific, clinicians should confirm the presence of yeast before initiating empirical antifungal therapy, the Guidelines say.
Oropharyngeal infection, when mild, is best treated topically, with azole troches, pastilles, or suspension. A seven-day course of fluconazole is an alternative for those who prefer it. When infection is moderate to severe, the Guidelines recommend a 7- to 14-day course of fluconazole. Disease that fails to respond adequately to fluconazole should be treated with one of the other azoles or an echinocandin. For esophageal infection, oral fluconazole for 7-14 days is appropriate as initial therapy.
Oropharyngeal candidiasis may be related to the use of steroid inhalers, or it may follow a course of antibiotics. Patients who have had radiation for head or neck cancer or who have developed xerostomia for other reasons, are also at risk, as are older patients with irritation (usually in the area of the palate) caused by dentures, observes Dr. Kauffman. The possibility of HIV infection should not be overlooked, however, particularly in the absence of other obvious risk factors. The index of HIV suspicion should be higher in the context of esophageal candidiasis, she notes.
Candida in the urinary tract
Yeast in the urine (visible on microscopic examination or grown in culture) is common, while UTI caused by yeast is not. Most asymptomatic patients with candiduria do not require treatment, the Guidelines say. Any predisposing conditions, such as an indwelling catheter, should be corrected.
There are exceptions. In neonates or severely immunocompromised patients, candiduria may indicate disseminated candidiasis, which demands aggressive treatment. A patient who will shortly undergo a urologic procedure should be covered by antifungal treatment (e.g., fluconazole 200-400 mg) for several days before and after the event.
Symptomatic cystitis or pyelonephritis due to Candida should be treated with 7-14 days of oral fluconazole—one of the few antifungal agents that get into the urine (the echinocandins and other azoles do not). If the organism is resistant to fluconazole (e.g., most Candida glabrata), the Guidelines recommend amphotericin B deoxycholate or flucytosine.
Fungus ball, abscess, or anatomic obstruction may be a factor in candiduria or candidal UTI. The authors advocate ultrasonography in high-risk patients to rule out this possibility.
Invasive candidiasis, which in many patients represents a life-threatening condition, is “largely a disease of medical progress,” according to the Guidelines. Risk factors include the use of broad-spectrum antibiotics and immunosuppressive agents, central venous catheters, dialysis, parenteral nutrition, and implantable prosthetic devices.
The availability of echinocandins has altered the treatment of candidemia, particularly in neutropenic patients. The mechanism of action of these agents is different from that of older drugs: “Echinocandins attack the cell wall, while azoles and amphotericin B attack the membrane,” Dr. Kauffman states. Since human cells have no cell wall, the echinocandins have far fewer adverse effects than other antifungals.
The echinocandins are also more powerful, killing the target organism outright rather than inhibiting its growth, and active against several Candida species, i.e., C. glabrata and Candida kruzei, that have become increasingly resistant to fluconazole, the most widely used azole. “The chink in the echinocandin armor is Candida parapsilosis; the newer agents are least active against this species,” Dr. Kauffman observes.
The Guidelines recommend an echinocandin as initial therapy for candidemia in neutropenic patients and in non-neutropenic individuals who have moderately severe to severe illness or had recent azole exposure. If the organism is later found likely to be fluconazole-susceptible (e.g., Candida albicans), the Guidelines recommend a switch to fluconazole once the patient is clinically stable. The recommendations for empirical treatment of suspected invasive candidiasis are similar.
Although antifungal prophylaxis remains an area of controversy, new data have strengthened recommendations for its use under specified circumstances in patients who are judged to be at high risk of invasive candidiasis.
Fluconazole or another antifungal is recommended for organ transplant recipients with additional risk factors and for patients in ICUs, where the incidence of invasive candidiasis is high. As long as neutropenia persists, the Guidelines recommend fluconazole, posaconazole, or caspofungin for patients on chemotherapy and fluconazole, posaconazole, or micafungin for stem-cell transplant recipients.
Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America was published in Clinical Infectious Diseases (2009;48:503-535).