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Addressing the Challenges of Fungal Infections in the ICU

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Critical Care Canada Forum

Toronto, Ontario / October 25-28, 2009

Invasive fungal infections, notably those caused by Candida and Aspergillus, are common in critically ill patients. Immediate empiric therapy has long been recognized as an important step toward reducing morbidity and mortality, but “the burden of disease seems to be progressing,” observed Dr. Yoanna Skrobik, Associate Professor of Medicine, Division of Critical Care, CHUM - Hôpital Maisonneuve-Rosemont, Montreal, Quebec, here at the CCCF.

Fungal micro-organisms are now the source of about 80% of infections in hospitalized patients and 15% of infections in patients in intensive care units (ICUs). Although C. albicans remains the most prevalent specific cause of nosocomial fungal infections, aspergillosis is often more difficult to control and more likely to be concentrated in seriously ill patients. In particular, the incidence of aspergillosis in the ICU has been reported to be 5.8% but recent data show that this organism represents a growing proportion of invasive mycoses (Mersseman et al. Clin Infect Dis 2007;45(2):205-16, Vandewoude et al. Medical Mycology 2006;44:S71-6).

Although any patient who requires care in an ICU is at increased risk for fungal infection, the risk is particularly great in those with neutropenia (<500 neutrophils/mm3), hematological malignancy, allogeneic bone marrow transplantation, extensive exposure to steroids, long-term therapy with broad-spectrum antibiotics, and a long ICU stay. Other risk factors include solid organ transplantation, the need for a central venous catheter and the need for mechanical ventilation.

Once acquired, a fungal infection greatly increases the risk of in-hospital death, particularly among patients who develop sepsis, according to Dr. Anand Kumar, Associate Professor of Medicine, Medical Microbiology and Pharmacology and Therapeutics, University of Manitoba, Winnipeg and attending physician, Health Sciences Centre. The risk of septic shock appears to be particularly high in ICU patients with leukemia or myeloma.

The Rationale for Empiric Therapy

Due to these risks, empiric therapy based on the probable organism is considered essential even as efforts are made to accelerate the diagnosis of the causative pathogen. One reason to initiate therapy empirically is that confirming the clinical importance of specific pathogens is often challenging. “The typical signs and symptoms of infection are absent or not helpful in patients who are prone to fungal infections… they may only report pain. Further, few clinical features are unique to systemic fungal infections,” Dr. Kumar told delegates. Exceptions include endophthalmitis, macronodular skin lesions and candiduria in a patient without an indwelling catheter. Another hindrance to diagnosis of fungal infections is “blood cultures pick up the minority of cases of fungal sepsis [about 30%],” Dr. Kumar observed.

“To save lives, we have to have better diagnostic means,” agreed Dr. Coleman Rotstein, Professor of Medicine, Division of Infectious Disease, University of Toronto and Director, Oncologic Infectious Disease, Toronto General and Princess Margaret Hospitals, Ontario. Computerized tomography scanning has been an important advance as it allows visualization of signs of invasive infections (e.g. macronodule, halo sign, consolidation, ground glass opacification) about five days before they are observable on X-ray. Serologic markers such as galactomannan (for Aspergillus) and beta glucan (for Aspergillus and Candida) are emerging; however, as yet, few Canadian centres have access to these tests and to date, low sensitivity and specificity have limited their clinical utility.

Selecting an Antifungal Agent

Although a diagnosis of fungal infection is ideal, clinicians must often consider prophylactic or presumptive/empiric therapy in patients with risk factors or suspected infection, respectively. “Empiric therapy in neutropenic or immunocompromised patients or critically ill patients with multiple risk factors may be the only way to provide early therapy; that is to say, we just may not have the definitive information before we start antifungal therapy,” emphasized Dr. Kumar.

The key treatment principle for severe fungal infections, and particularly those causing shock, Dr. Kumar contended, is to “hit the organism appropriately, hit it early, and hit it hard.” This approach includes first ensuring the antifungal therapy selected for first-line use covers the culprit pathogen.

One step is to recognize institution-specific patterns of disease so that the empiric therapy is the best fit for the probable organism. Commenting on candidiasis, Dr. Skrobik noted, “Only about 60% [of Candida species] at my hospital are C. albicans and the remaining Candida infections, which are potentially resistant to drugs like fluconazole, constitute a good 15%,” she remarked. The same point is relevant to other fungal organisms. In centres with recent episodes of invasive aspergillosis, a high suspicion of this organism should be entertained. The “Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America” recommends voriconazole for cases of confirmed or probable invasive aspergillosis (Clin Infect Dis 2008;46(3):327-60). Regarding specific drug selection, the risk of drug interactions and strategies to minimize promoting drug resistance are also important considerations, according to Dr. Skrobik.

Dr. Kumar explained, “If you have a fungal infection, you have to cover it at the first opportunity because failure to do so will increase the mortality risk.” In patients with shock—whether caused by fungal or bacterial infection—the impact of inappropriate initial therapy on mortality is greatly accentuated.

Delaying therapy until culture results are available can lead to a poor outcome. In a recent retrospective study of hospitalized patients with candidemia (Morrell et al. Antimicrob Agents Chemother 2005;49:3640-5), appropriate therapy started within 12 hours of drawing blood for culture was associated with a mortality rate of 12%. With delays of 24 to 48 hours, mortality increased to about 30%. In patients with shock, added Dr. Kumar, the adjusted odds ratio for death is about 12% per hour.

Dr. Kumar has found there is typically a significant delay in the initiation of antifungal therapy to patients with septic shock in Canadian ICUs. In his study, median time to administration was 35 hours for antifungal therapy vs. 5.5 hours for antibiotics. “If both groups get their drug therapy within two hours they have very similar survival, [approximately 80%]… Overall, it turns out that the difference in time to antimicrobial therapy accounts for about 90% of the difference in survival. Almost all the difference in survival in fungal septic shock is related to how much longer it takes to get therapy on board,” he emphasized.

The third component of the treatment principle—hitting the organism hard—involves ensuring the pathogen is killed rapidly. While voriconazole is an appropriate first-line therapy in cases of suspected aspergillosis, hitting invasive aspergillosis hard may entail the use of additional agents in highly compromised patients, particularly when recent cases of aspergillosis have been difficult to control. Although proof of clinical benefit remains to be established, the use of two or more medications targeting different components of fungal cells may allow an enhanced therapeutic effect with lower toxicity and less potential for resistance, observed Dr. Rotstein. An ongoing phase III trial is comparing voriconazole alone with voriconazole plus anidulafungin (http://ClinicalTrials.gov:NCT00531479). The primary end point is all-cause mortality, measured six weeks after invasive aspergillosis in patients with proven or probable infection.

New, more potent immunosuppressive agents are driving the increasing rates of nosocomial fungal infections. Combined with advances in intensive care that are also permitting survival in compromised patients, the increasing use of bone marrow transplants, advanced chemotherapies, and supportive care in advanced renal impairment predicts a continuation of the ongoing rise in the rates of invasive fungal diseases. Failure to initiate timely empiric therapy and to streamline diagnostic procedures is likely to emerge as a growing obstacle to survival in patients who might otherwise respond to treatments for their underlying condition.

Summary

While new and improved methods for diagnosing invasive fungal infections are emerging, empiric administration of antifungals in advance of diagnosis remains a mainstay strategy for improving survival. Understanding the likelihood of specific pathogens within the institution is important for initiating effective agents rapidly. In suspected fungal infections, it is helpful to differentiate the risks and signs of probable candidiasis and aspergillosis to initiate an appropriate first-line agent. While there is particular urgency for quickly initiating the best agent with adequate potency in patients in septic shock, effective antifungal therapy is emerging as one of the most important components of extending life in patients hospitalized for serious diseases.

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