The newest treatment strategies for candidemia

Candidemia has proven it is an important emerging nosocomial infection. Its prevalence in hospital settings has become alarming and should be considered an important pathogen when treating patients who have defined risk factors.

Candida species are the most common cause of fungal infections in humans. These infections can range from non-life threatening mucocutaneous disorders to invasive diseases that can involve one or multiple organs. Candidemia is defined as the presence of a Candida species in the bloodstream and remains the fourth most common cause of nosocomial bloodstream infections. Diagnosis and treatment of candidemia has increased the average length of stay by 22 days and average cost by approximately $40,000.

The most recent clinical practice guidelines for the management of candidiasis were published in March 2009. These guidelines update the previous guidelines from 2004. This column will focus on the newest recommendations for the treatment of candidemia, including new drug therapy, choosing the empiric agent, step-down therapy, the utility of susceptibility testing and the duration of therapy.

Risk factors for each patient must be assessed to choose the most appropriate therapy. The use of broad spectrum antibacterial agents, central venous catheters, implantable prosthetic devices, parenteral nutrition, renal replacement therapy, ICU patients, immunosuppressive therapy and neutropenia all are associated risk factors for the development of candidemia. Also, the clinical status of the patient needs to be assessed. The 2009 guidelines recommend different empiric agents for critically ill vs. noncritically ill, neutropenic vs. nonneutropenic and recent azole exposure patients.

Common Candida species

Candida species identified at multiple nonsterile sites often suggest colonization but this also can give insight into the type of Candida species that may cause invasive disease. Some of the most common Candida species include C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei and C. lusitaniae. A broad ‘candidal’ spectrum agent — such as amphotericin B or an enchinocandin — should be considered for empiric treatment of candidemia. Once the species is identified and susceptibilities are in progress, the ongoing treatment choice can be reconsidered.

In the 2004 guidelines, the role of the echinocandins or broadened spectrum azoles was not clear, as only caspofungin and voriconazole were on the market. Micafungin, anidulafungin and posaconazole were still being studied. Susceptibility testing of Candida species was not fully understood but intensive efforts to develop standardized, reproducible and clinically relevant susceptibility testing were underway. The Clinical and Laboratory Standards Institute has now developed M27-A3 methodology for susceptibility testing of yeast to fluconazole, itraconazole, voriconazole, flucytosine and the echinocandins. Interpretive breakpoints for amphotericin B are not yet available.

The 2009 guidelines address the utility of antifungal susceptibility testing in situations where there is failure to respond to initial antifungal therapy, for routine antifungal susceptibility testing to fluconazole for C. glabrata or if azole resistance is highly suspected. The panel does not endorse susceptibility testing on C. albican isolates, as resistance is rare. Many clinicians have applied antifungal susceptibility testing on all blood isolates, excluding C. albicans.

Identification

The identification of the Candida species is integral in defining the treatment strategy. The differences between the 2004 and 2009 guidelines are the options of empiric antifungal treatments and recommendations of step-down therapy. These recommendations come from the newer antifungal agents available on to the market and the newest studies evaluating optimal empiric therapy, dosing, and step-down therapy based on sensitivities. The recommendation regarding the duration of antifungal therapy for candidemia remains the same at 14 days after clearance of the bloodstream.

The recommendation of treatment strategies for nonneutropenic patients differ for that of neutropenic patients. No adequately powered, randomized controlled trials for candidemia in neutropenic patients have been published. It is thought that candidemia in neutropenic patients is life-threatening and is likely associated with disseminated candidiasis, sepsis-like syndrome, multiorgan failure and even death. A large retrospective cohort study conducted by Anaissie et al found patients with cancer who also had candidemia and persistent neutropenia had a greater chance of treatment failure.

Treating patients who do not have functional immune systems lead clinicians to treat with broader spectrum, more fungicidal antifungal agents such as an echinocandin or amphotericin B. The guidelines do endorse step down therapy to fluconazole or voriconazole (if mold prophylaxis is warranted) in neutropenic patients.

Change from previous guidelines

A major change from the previous guidelines is the recommendations around amphotericin B and lipid formulation amphotericin B products. Amphotericin B products used to be the primary therapy for candidemia, and the echinocandins and fluconazole were alternative therapy recommendations. The newest recommendations are just the opposite and more focused on treating the specific Candida species.

An echinocandin or lipid formulation amphotericin B(LFAmBs) are the favored agents for critically ill patients, patients who have recent azole exposure and neutropenic patients. Fluconazole at high dose (12 mg/kg), then 6 mg/kg is still highly recommended for treatment of candidemia. Fluconazole has the most well-studied, documented success for treatment of candidemia. Fluconazole is still considered first-line therapy for patients with mild-moderate illness that remain hemodynamically stable, no previous azole exposure or those patients at higher risk for non-albicans Candida species (with the exception of C. glabrata).

Each of the treatment strategies and Candida species has some nuances. C. albicans maintains excellent susceptibility to all antifungal agents. The other Candida species that likely maintain susceptibility to fluconazole are C. parapsilosis and C. tropicalis. C. parapsilosis uniquely shows less in vitro susceptibility to echinocandins than do other Candida species. Fluconazole is the recommended first-line therapy for infections due to those species. Infections related to C. glabrata and C. krusei should be treated with an enchinocandin, and transition to fluconazole or voriconazole should be avoided until confirmation of susceptibilities. If an amphotericin B product is chosen to treat C. glabrata or C. krusei, higher doses should be considered, given these species have overall decreased susceptibility (amphotericin B- conventional 1 mg/kg daily or LFAmB 3-5 mg/kg daily).

If patients receive fluconazole and voriconazole empirically and clinically improve but subsequently isolate C. glabrata or C. krusei, completing the azole to duration of therapy is appropriate. For patients with candidemia and suspected endocardial or CNS involvement, a fungicidal agent such as echinocandin or amphotericin B is recommended. The echinocandins do not achieve therapeutic CSF levels. Once a patient has clinically improved and the species and susceptibilities are identified, step down to fluconazole therapy for endocardial or CNS infection is reasonable.

New approach

The approach in the new guidelines is to start “transition” or “step-down” therapy once the species is known and the patient has clinically improved. The idea is the same as treating bacteria: obtain cultures, isolate a pathogen, evaluate susceptibilities and de-escalate therapy. The same steps ring true for treating candidemia. The step-down method provides a narrower spectrum agents and more cost-effective alternatives to treat the fungemia. A clear recommendation regarding step-down therapy to an oral agent (ie, PO fluconazole or PO voriconazole) is not well defined in the guidelines. Fluconazole and voriconazole are ≥90% bioavailable. This makes both agents excellent oral options. From a pharmacokinetic standpoint, using oral options as step-down is a reasonable choice. Voriconzole offers minimal advantage over fluconazole and is significantly more expensive. Step-down therapy with voriconazole should be for selective cases of candidemia with C. krusei or voriconazole-susceptible C. glabrata.

As the world of medicine continues to advance, our patients will continue to live longer. Even so, a whole new burden will weigh on health care. The development of more invasive, life-threatening illnesses such as invasive candidiasis and candidemia will affect our patients. Clinicians will need to make critical, evidence-based decisions to treat their patients. The 2009 Infectious Diseases Society of America’s clinical practice guidelines for the management of candidiasis will assist clinicians in making the best decisions possible.

To ensure optimal care when treating candidemia, make sure to:

• select an empiric agent based on clinical status and risk factors,
• identify the Candida species and have the susceptibilities on non-albican isolates,
• optimize the drug therapy by dosing aggressively while still monitoring adverse effects of the drug,
• step down therapy once the patient is clinically stable, and treat the patient for 14 days from negative blood cultures.

Kimberly Boeser, PharmD, is the Infectious Disease Clinical Pharmacologist at the University of Minnesota Medical Center, Fairview in Minneapolis, where she coordinates the antimicrobial stewardship program.

For more information:

• Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of Candidiasis: 2009 update by the Infectious Diseases Society of America. CID. 2009;48:503-35.
• Pappas PG, Rex JH, Sobel JD, et al. Guidelines for Treatment of Candidiasis. CID. 2004;38:161-89.
• Anaissie EJ, Rex JH, Uzun O, et al. Predictors of adverse outcome in cancer patients with candidemia. AM J Med 1998; 104:238-45.