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Fungal Infections in the ICU

PCCSU Volume 25, Lesson 9

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Anil Ghimire, MD; and Charles S. Dela Cruz, MD, PhD

Dr. Ghimire is a Senior Fellow in Critical Care Medicine, and Dr. Dela Cruz is an Assistant Professor of Medicine, Section of Pulmonary and Critical Care Medicine, Yale School of Medicine, New Haven, CT

Drs. Ghimire and Dela Cruz have disclosed no significant relationships with the companies and organizations whose products or services may be discussed within this chapter.

Objectives

  1. Recognize the significance and epidemiology of fungal infections in the ICU.
  2. Describe the risk factors for fungal infections in the ICU.
  3. Identify the common fungal infections occurring in the ICU.
  4. Understand the use and limitations of the diagnostics tests for fungal infection.
  5. Describe an approach to treatment of the common fungal infections in the ICU.

Key words: aspergillosis; candidiasis; fungal infections; ICU

Abbreviations: BDG = (1→3)β-D-glucan; FDA = Food and Drug Administration; HSCT = hematopoietic stem cell transplantation; IDSA = Infectious Diseases Society of America; PCR = polymerase chain reaction; TPN = total parenteral nutrition

Invasive fungal diseases are known to cause significant morbidity and mortality in immunosuppressed patients, but the incidence of invasive fungal disease in immunocompetent critically ill patients is difficult to ascertain because of the lack of clear definitions and inaccurate diagnostic procedures. However, recent surveys indicate that the incidence is rising in such patients.1 Management of fungal infections in the ICU is complicated by their often nonspecific clinical presentation and their high mortality rates. This review addresses the epidemiology, risk factors, diagnosis, and treatment of the more common fungal infections encountered in the ICU, with specific focus on candidiasis and aspergillosis.

Epidemiology

The National Nosocomial Infection Surveillance Program has shown that although the total number of hospital beds in the United States has decreased, the number of ICU beds has significantly increased.2,3 In addition, advances in supportive medical care in the ICU have improved survival and prolonged ICU stay, rendering critically ill patients more susceptible to invasive fungal infections. A large European study found that almost half the patients in the ICU were treated for infection and that 17.1% of these infections were fungal.4 Moreover, there has been a steady increase in the rate of nosocomial fungal infections over the years, from 2.0 to 3.8 per 1,000 discharges.2

The most common cause of invasive fungal disease is infection with Candida species. Candidiasis is the fourth leading cause of nosocomial bloodstream infections, accounting for 9% of all such infections in the United States.5 Although Candida albicans is the most commonly identified species, the incidence of infection with non-albicans Candida species is increasing.6 In a multicenter surveillance study conducted in the United States from 2004 to 2008, 46% of 2,019 bloodstream isolates were C albicans, whereas 54% were non-albicans Candida species, including Candida glabrata (26% of all cases), Candida parapsilosis (16%), Candida tropicalis (8%), and Candida krusei (3%). Risk factors for developing non-albicans Candida infection included systemic antifungal therapy, central venous catheter placement, and prior GI surgery.7 Most cases of invasive candidiasis are caused by endogenous floral strains. However, nosocomial Candida infection can occur through transmission from health-care workers’ hands or contaminated fluids. The mortality rate from invasive candidiasis ranges from 40% to 60%.

Invasive aspergillosis is a serious complication in critically ill patients. Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger account for nearly all cases of aspergillosis. The incidence of invasive aspergillosis is difficult to estimate because of the lack of definitive diagnostic criteria. In a retrospective study of 100 medical ICU patients comparing premortem diagnosis and autopsy findings, 15% had invasive aspergillosis, and 5% of these cases had been missed before death.8 Patients with documented microbiologic or histopathologic evidence of aspergillosis in the ICU had a mortality rate of approximately 80%.9 In one study, 19% of patients with hospital-acquired pneumonia requiring ICU admission had microbiologic and/or pathologic evidence of aspergillosis.10 There is growing evidence that patients with COPD are at increased risk for invasive aspergillosis.11 In a review of 50 studies, COPD was the underlying condition in 26 of 1,941 patients (1.3%) with aspergillosis.12 Patients with COPD who receive high-dose or long-term corticosteroid therapy are at higher risk. A fumigatus is the most common species causing invasive disease, but Aspergillus terreus has been equally prevalent in some institutions. Patients are usually colonized with Aspergillus before they enter the hospital, and the infection becomes invasive because the patient’s immune system is suppressed as the result of disease severity or immunosuppressive therapy. However, Aspergillus can potentially be acquired in the ICU through improperly cleaned ventilation systems and contaminated water.

Zygomycosis is an uncommon, potentially lethal, invasive disease involving the sinuses, lungs, GI tract, brain, and skin. There are no studies of zygomycosis in critically ill patients, but common risk factors include immunosuppression and hematopoietic stem cell transplantation (HSCT), diabetes mellitus with ketoacidosis, and treatment with desferoxamine. The disorder can also present as breakthrough fungal infection in patients taking voriconazole for prophylaxis or treatment of other fungal diseases.13

Risk Factors

Risk factors for infection with Candida and Aspergillus are shown in Table 1 and Table 2, respectively. These risk factors are very common in most hospitalized patients1,14; therefore, it is often difficult to determine which patients are at greatest risk for developing invasive fungal infections. Common risk factors include immunosuppressive therapy (for example, corticosteroids, cytotoxic chemotherapy), malnutrition, malignancy, and neutropenia. Other risk factors, such as extensive burns and the presence of an indwelling catheter, facilitate the entry of fungal organisms. Therapy with broad-spectrum antimicrobial agents and/or the prolonged use of these drugs in the ICU enable fungal organisms to proliferate in the GI tract, colonize the skin, and enter the bloodstream through central venous catheters. Direct translocation of fungal pathogens from the colonized GI tract into the bloodstream may also occur. The isolation of fungus from sites elsewhere in the body is an independent risk factor for nosocomial fungemia. Fungal opportunistic infections in patients with AIDS are less prevalent in developed countries since the advent of highly active antiretroviral therapy, but these infections still cause major morbidity and mortality in developing countries where AIDS is epidemic. The topic of opportunistic fungal infections in HIV-infected patients is covered in other reviews15 and is beyond the scope of this article.


Table 1Risk Factors Associated With Invasive Candidiasis

High Risk Nonspecific Risk
Colonization of multiple body sites Age (young and old)
Broad-spectrum antibiotic therapy Diabetes mellitus
Immunosuppression Renal failure
Neutropenia Recent surgery
Burns on >50% body surface area Urinary catheter
Perforation of digestive tract Vascular access
Major abdominal surgery Prolonged ICU stay
Urinary tract surgery in presence of candiduria Multiple transfusions
Major trauma  
Total parenteral nutrition  
Hemodialysis/hemofiltration  
APACHE II score >20  
Central venous catheter  
Candiduria (>105 cfu/mL)  

APACHE = acute physiology and chronic health evaluation. Adapted from De Gasperi et al14 with permission.


Table 2Risk Factors Associated With Invasive Aspergillosis

High Risk Intermediate Risk Low Risk
Prolonged neutropenia Prolonged corticosteroid therapy Severe burn
Hematologic malignancy COPD Other solid-organ transplantation
Allogeneic HSCT Autologous HSCT Corticosteroid therapy <7 days
  Cirrhosis with duration of stay >7 days Prolonged stay in ICU
  Solid-organ cancer Malnutrition
  HIV infection Cardiac surgery
  Lung transplantation  
  Systemic disease requiring prolonged immunosuppression  

Adapted from Meersseman et al1 with permission.


 

Invasive Candidiasis
Distinguishing between colonization with Candida and invasive candidiasis in critically ill patients can be difficult because the clinical presentation of invasive disease is nonspecific and blood cultures are positive in only half of affected patients. The Candida colonization index has been developed to help identify colonized patients who are likely to develop invasive disease.16 The index is the ratio of body sites colonized with genotypically identical strains of Candida over the total number of body sites investigated; a value of >0.5 indicates invasive candidiasis. The density of colonization is included to calculate a corrected colonization index to improve the accuracy of the index. Although this has not been investigated in a prospective study, a corrected index >0.4 is considered to be 100% specific for invasive candidiasis, with a very high negative predictive value.17

A major risk factor for candidemia is the presence of a central venous catheter, particularly in patients receiving total parenteral nutrition (TPN). Catheter-related candidemia accounts for 30% to 80% of proven or suspected cases of invasive fungal disease in the ICU.17 Prior antibiotic therapy is also a major risk factor for invasive candidiasis. Longer duration of antibiotic therapy, exposure to more than four different antibiotics over the course of ICU stay, and the use of broad-spectrum antibiotics (especially cephalosporin and antianaerobic agents) are associated with increased risk of candidiasis. Other risk factors, such as a length of ICU stay of >7 days, therapy with H2-blockers, and the presence of renal failure, do not independently predict candidemia.

Invasive Aspergillosis
Prolonged (>10 days) and severe (absolute neutrophil count <100/μL) neutropenia is a major risk factor for invasive aspergillosis, especially after cytotoxic chemotherapy for hematologic malignancies and myeloablative HSCT.18 In allogeneic transplantation, the risk is highest before engraftment, whereas in autologous transplantation, the risk increases after episodes of graft-vs-host disease and increased exposure to immunosuppressive agents. However, invasive aspergillosis increasingly occurs in patients who are less immunosuppressed in the ICU.1 In immunocompetent patients, the immunosuppressive effects of critical illness alone affect microbial phagocytosis and other mechanisms of immunity, leading to increased risk of invasive disease. Patients with COPD who receive long-term systemic or inhaled corticosteroid therapy are at significant risk for invasive disease. The risk for invasive aspergillosis in patients receiving corticosteroid therapy for <7 days for sepsis is less clear; however, even short courses of corticosteroids have been shown to affect phagocytosis and accelerate the growth of Aspergillus in vitro. Fatal invasive aspergillosis has been reported in patients with cirrhosis.

Diagnosis

Candidiasis
The European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus statement revised in 2008 categorized invasive fungal disease into “definitive” and “probable” disease.19 Isolation of Candida from the blood is usually accepted as definitive for infection; however, blood cultures are often not positive until late in the course of the disease and can be falsely negative in up to 50% of patients. Histologic confirmation of Candida also definitively establishes infection, but tissue diagnosis is not always possible in critically ill ICU patients. The disease is not well characterized in immunocompetent patients.

Invasive candidiasis can be diagnosed by either the use of risk factor-based prediction rules or microbiologic and molecular methods. The risk factor-based approach uses risk factors for invasive disease to classify patients as either low risk or high risk to guide the initiation of therapy. In a prospective study, León and colleagues20,21 used four risk factors to which numeric values were assigned as follows: TPN (1 point), multifocal colonization sites (1 point), severe sepsis (2 points), and surgery (1 point). A cut-off value of 3.0 predicted invasive fungal disease with a sensitivity of 81% and specificity of 74%.20,21 This prediction rule was later validated in a prospective study of nonneutropenic critically ill patients.21 In a multicenter retrospective study, critically ill patients who were receiving systemic antibiotics by central venous catheter and who had at least two specific risk factors (the risk factors are TPN, major surgery, immunosuppression, pancreatitis, dialysis, and corticosteroid therapy) were at increased risk for candidemia (sensitivity, 34%; specificity, 90%).22 These prediction rules, however, need to be validated in larger, multicenter, prospective studies before they can be advocated for general use.

Laboratory diagnostic tests can improve the accuracy for diagnosing invasive candidiasis in the appropriate clinical settings. Current tests detect candidal antigens, antigen components, nucleic acids, or antibodies in the blood; however, the fungal antigen tests are nonspecific and their diagnostic accuracy is still debated (Table 3). (1→3)-β-D-glucan (BDG) is a component of the cell wall of certain fungi. The BDG assay, which detects the cell wall component of pathogenic fungus, was first validated in patients with hematologic malignancy for the early diagnosis of invasive fungal infection.23 Serial serum samples were obtained from patients with acute myeloid leukemia or myelodysplastic syndrome who were receiving antifungal prophylaxis, and at least one serum sample was positive for BDG at a median of 10 days before the clinical diagnosis in 100% of subjects with definitive or probable invasive fungal infection. The specificity was 90% for a single positive result and 96% for sequential positive results. In a multicenter study of mixed medical and hematologic patients who had definitive or suspected invasive fungal disease, the test had a specificity of 62.4% and sensitivity of 92.4%.24 The BDG assay, however, does not differentiate among Aspergillus, Candida, and Fusarium and is negative in Cryptococcus and Zygomycetes infections. Therefore, in a patient with a positive BDG test, other diagnostic tests are necessary to identify and confirm the fungal species. A positive test can, however, be useful in starting empiric antifungal treatment in the ICU in acutely ill, often immunosuppressed patients. The performance characteristics of the BDG assay in immunocompetent patients is unknown, especially in critically ill patients in the ICU who often receive albumin, immunoglobulin, hemodialysis using cellulose membranes, and certain types of gauzes, all of which have been reported to cause false-positive results. Therefore, a single positive test is likely to be a false positive, and serial testing might be more predictive of true infection; however, the role of serial testing in immunocompetent ICU patients has not been studied. In a prospective study of critically ill nonneutropenic patients, a polymerase chain reaction (PCR) assay had a sensitivity of 90.9% and specificity of 100% for the diagnosis of candidemia.25 Although these results are promising, the extent to which they affect clinical outcomes, prescribing practice, and cost-effectiveness of care remains to be determined.


Table 3Serologic and Molecular Tools in the Diagnosis of Invasive Fungal Diseases

Test Detects Test Performance Comments
BDG Present in cell wall of most fungi except Cryptococcus and Zygomycetes Sensitivity 92% and specificity 62% (cut-off value >80 pg/mL) in hematologic patients False-positive results with patients receiving albumin, immunoglobulins, hemodialysis with cellulose membrane and certain types of gauze
Cannot differentiate between Candida and Aspergillus Test performance not known for immunocompetent ICU patients and those receiving prophylactic antifungal therapy  
Screening test for invasive fungal disease    
Galactomannan Relatively specific for Aspergillus Serum: Sensitivity 71% and specificity 89% in high-risk HSCT patients, but sensitivity is only 53% in nonneutropenic ICU patients False-positive with piperacillin- tazobactam use
  BAL: Sensitivity 88% and specificity 87% in non-high-risk group  
PCR Nucleic acids Promising, but no standardized test Difficulty in distinguishing colonization from disease; potential for contamination with fungal DNA

Adapted from Meersseman et al1 with permission.


 

Aspergillosis
Invasive aspergillosis can be diagnosed by CT imaging, histopathology, culture, direct microscopy, molecular detection of cell wall components, and nucleic acid detection by PCR. Although histopathologic identification and fungal cultures are the gold standard, they are often of limited utility in the ICU because of the long turnaround time and difficulty obtaining tissue samples in critically ill patients. CT scans showing the “halo sign” or “crescent sign” are highly suggestive of invasive aspergillosis in neutropenic patients26; however, these findings are present in only 5% of nonneutropenic patients in the ICU. CT imaging is further confounded by other radiologic abnormalities, such as atelectasis, ARDS, and ventilator-associated pneumonia, which are common in patients in the ICU.

Galactomannan is a component of the cell wall of Aspergillus. Detection of galactomannan in serum and BAL fluid has been studied in patients with neutropenia and/or hematologic malignancy. A recent meta-analysis of serum galactomannan in these high-risk patients showed a sensitivity of 71% and a specificity of 89% for definitive cases of invasive aspergillosis.27 In a study of ICU patients without high-risk factors, serum galactomannan was detected in only 53% of patients with definitive or probable invasive aspergillosis.9 The BAL-fluid assay is more sensitive than the serum assay.28 Nguyen and colleagues29 studied 73 immunocompetent patients who underwent BAL for the evaluation of pulmonary infiltrates and found that BAL-fluid galactomannan had a sensitivity of 100% and specificity of 88% for invasive aspergillosis. A well-designed prospective study showed that the BAL-fluid galactomannan assay had better sensitivity than the serum assay in neutropenic (90%) and nonneutropenic (88%) patients.30 The specificity remained high (87%) in patients receiving the combination antibiotic piperacillin/tazobactam, previously reported to affect the assay.

The diagnosis of invasive aspergillosis should not be based on a single test. BAL-fluid galactomannan should be used as an adjunct to other tests. The sensitivity of the test depends on the cut-off optical density value of the assay used, the degree of the patient’s immunosuppression, and the use of prophylactic antifungal agents. Combining the BAL galactomannan assay with PCR can increase the detection rate of aspergillosis in neutropenic patients. PCR techniques have to be standardized and their performance validated in large studies of nonneutropenic ICU patients. A common diagnostic dilemma in the ICU occurs when Aspergillus is isolated from a respiratory sample from patients who lack the traditional risk factors for invasive disease. This finding could indicate true current infection or colonization or be a marker for the development of future invasive disease. The predictive value of Aspergillus isolation as a marker for development of invasive disease is high in patients with HSCT and neutropenia. Isolation of Aspergillus from a respiratory specimen in critically ill ICU patients should trigger further diagnostic work-up, even in the absence of significant risk factors.

Treatment

Candidiasis
Treatment of Definitive Infections: In patients with definitive candidemia, all catheters should be removed if possible. Septic phlebitis and endocarditis, abscesses, and tissue-invasive candidiasis (such as endophthalmitis) should be excluded. Early antifungal therapy should be considered. In unstable or septic patients, two sets of blood cultures should routinely be obtained. Patients who are less ill or who have no specific risk factors should be evaluated once every 1 to 2 weeks for colonization through testing of urine, sputum, postsurgical drainage, wound or skin breakdown, perineal-area specimens, and catheter insertion sites. If the Candida colonization index is >0.5, fungal blood cultures should be obtained.

Antifungal agents available for the treatment of invasive candidiasis include the mold-active azoles (fluconazole, voriconazole, itraconazole, posaconazole), polyenes such as amphotericin B formulations (deoxycholate, liposomal, lipid complex, colloidal dispersion), and echinocandins (caspofungin, micafungin, anidulafungin) (Table 4). The choice of the particular agent depends on the patient’s history of recent azole exposure, intolerance to antifungal agents, dominant Candida species and susceptibility pattern in the ICU, and whether the patient is clinically stable. The Infectious Diseases Society of America (IDSA) 2009 guidelines recommend fluconazole as the drug of choice in stable, nonneutropenic patients and echinocandin in unstable neutropenic patients.31 However, fluconazole should be avoided if infection with C glabrata and C krusei is common (accounting for >15% of Candida species) in the institution, if the patient has been exposed to azole therapy within the past 30 days, or if the patient has had persistent Candida infection for >5 days.31 In such cases, patients should be treated with an echinocandin or lipid formulation of amphotericin B. Voriconazole does not offer additional advantage over fluconazole in nonneutropenic patients except for suspected infection with C krusei and azole-sensitive C glabrata, in which case it can be used as step-down oral therapy.31 Liposomal amphotericin B has been shown to be as effective as fluconazole in immunocompetent patients. However, liposomal amphotericin B is not as well tolerated and is associated with renal and liver side effects; it is therefore used only as a second-line treatment after fluconazole and the echinocandins. The echinocandins are less active against C parapsilosis, and patients with candidemia caused by this species should be treated with fluconazole. However, for patients with C parapsilosis candidemia who have improved clinically with echinocandin therapy and whose follow-up blood cultures are negative, continuation of the echinocandin is reasonable. There are few differences among the echinocandins, and any of the three approved agents in this drug class can be used. Treatment is continued for 2 weeks after the last positive blood cultures provided that clinical signs of infection have resolved. The role of combination antifungal therapy in patients with invasive candidiasis is not well established. In one study that compared fluconazole with fluconazole plus amphotericin B, candidemia resolved more rapidly with the combination therapy, but the overall success rate was similar in the two groups.32


Table 4General Guidelines for Treatment of Invasive Candidiasis and Aspergillosis

Invasive Candidiasis
Hemodynamically stable patients Consider risk of azole resistance (local epidemiology, history of fluconazole-resistant strains or non-Albicans species, recent azole exposures)
     Low probability: Fluconazole (alternatives: voriconazole, echinocandins,
     amphotericin B)
     High probability: Echinocandins (alternative: liposomal form of
     amphotericin B)
If patient is neutropenic and not critically ill, can use fluconazole if patient is without risk for azole resistance
Hemodynamically unstable patients Echinocandins or liposomal form of amphotericin B
Duration of therapy without persistent fungemia or obvious metastatic complications: 2 wk after documented clearance of Candida and resolution of symptoms and neutropenia (if present)
Invasive Aspergillosis
Voriconazole (alternative: liposomal form of amphotericin B, echinocandins, other azoles, such as posaconazole and itraconazole). Combination therapy as salvage only.
Duration of therapy: minimum of 6 to 12 weeks. Therapy is generally continued until signs and symptoms have resolved for 2 weeks and chest imaging has stabilized.

Adapted from Pappas et al31 and Walsh et al35 with permission.


Preemptive Treatment: Because invasive candidiasis is associated with a high mortality rate, it is important to identify patients who would benefit from early antifungal treatment. Preemptive treatment consists of antifungal therapy in colonized patients who have risk factors for candidemia but lack a diagnosis of candidemia or other invasive fungal infections. Whether patients with multiple sites of colonizations but not a diagnosis of invasive infection benefit from early antifungal treatment is controversial because critically ill patients are often colonized with Candida but invasive disease develops in only a few of them. In a prospective study of surgical ICU patients, the frequency of definitive candidiasis in patients with a corrected colonization index >0.4 who received preemptive antifungal therapy with fluconazole is 3.8%, compared with 7.0% in the control group.33 The incidence of surgical ICU–acquired definitive candidiasis decreased significantly, from 2.2% to 0%. However, another randomized trial of patients from mixed medical and surgical ICUs did not show any difference in composite outcome in groups receiving preemptive fluconazole compared with placebo.34 The efficacy of preemptive antifungal therapy remains unsettled, and further study of its cost-effectiveness and survival benefit is needed.

Prophylactic Therapy: Azole prophylaxis is routinely given to patients receiving chemotherapy for hematologic malignancy with expected prolonged neutropenia and to patients undergoing HSCT. The 2009 IDSA guidelines also recommend prophylaxis in patients with solid organ transplants (for example, liver, pancreas, and small bowel). The guidelines also recommend prophylaxis for nonneutropenic ICU patients who are at high risk for candidemia.31 None of the studies of antifungal prophylaxis in the ICU have demonstrated increased resistance to fluconazole or major ecological shifts in Candida species, although this remains a real concern.

Other Issues: Catheter-Associated Candidemia—There are no randomized controlled trials documenting the benefits of removing central venous catheters in patients with candidemia. However, observational studies have shown that the removal of infected central venous catheters results in early resolution of fungemia and improved survival, especially in nonneutropenic patients.32 In neutropenic patients with cancer, however, removal of the catheter does not necessarily confer overall survival advantage.35 Some clinicians do not remove catheters in neutropenic patients in whom the GI tract is suspected to be the source of infection. However, current IDSA guidelines recommend the removal of a central venous catheter in definitive candidemia, if possible.31 In addition, antifungal drug therapy is required. All patients with candidemia should undergo dilated ophthalmic evaluation when their condition becomes stable. Surgical partial vitrectomy with intravitreal antifungal therapy is recommended for documented ophthalmic candidiasis.

Aspergillosis
Antifungal drugs used in the treatment of invasive aspergillosis include azoles, echinocandins, and amphotericin B. Amphotericin B had been the mainstay of therapy, but because this drug is associated with such serious adverse effects as nephrotoxicity, hypokalemia, and fever, voriconazole has become the new standard of care for invasive aspergillosis. For primary treatment, the IDSA guidelines recommend IV or oral voriconazole for most patients.36 In a study comparing voriconazole with amphotericin B deoxycholate for invasive aspergillosis in patients with neutropenia and hematologic malignancy, voriconazole therapy resulted in better responses, improved survival (70.8% vs 57.9%), and fewer adverse effects than amphotericin B.37 However, this study excluded critically ill patients who were receiving mechanical ventilation. Voriconazole has poor activity against Zygomycetes, and if fungal sinusitis from Zygomycetes is suspected, liposomal amphotericin B should be considered. Therapeutic drug monitoring of voriconazole levels should be considered in patients in whom aspergillosis is refractory to therapy or drug toxicity is suspected. The recommended trough level of voriconazole is >1 and <5.5 mg/L.

Second-line therapy for invasive aspergillosis consists of amphotericin B, the echinocandins, and combination therapy. The nephrotoxicity of amphotericin B limits its use in critically ill patients who are at high risk for development of acute kidney injury. Lipid formulations of amphotericin are often better tolerated than the conventional formulation. Higher doses of liposomal formulation do not confer additional efficacy. Itraconazole is not recommended by the IDSA for refractory invasive aspergillosis. Voriconazole has greater intrinsic activity against Aspergillus than itraconazole. In an uncontrolled study of posaconazole as salvage therapy in patients intolerant of or refractory to voriconazole, 42% of patients achieved complete or partial response compared with 26% of patients in an external control group.36 However, posaconazole is not approved by the Food and Drug Administration (FDA) for invasive aspergillosis, and the drug is available only in oral form, which makes it less useful in the ICU, where patients often have impaired drug absorption from the GI tract. Caspofungin has been used as salvage therapy, either alone or in combination with other antifungal medications. As a salvage monotherapy for definitive or probable invasive disease, the overall success rate was 45%. In this salvage study, patients who are initially intolerant of the primary conventional therapy did better than patients whose infections were refractory to the primary conventional treatment (75% vs 40%).38

Data on combination therapy are limited and mainly come from animal studies and observational studies. The combination of an echinocandin with an azole or a polyene inhibits fungal growth at two different sites of action, whereas the combination of a polyene and an azole acts on only the fungal cell wall. An open-label randomized pilot study of liposomal amphotericin B plus caspofungin compared with high-dose liposomal amphotericin B showed a 20% reduction in mortality for the combination regimen as primary therapy for probable invasive aspergillosis.39 It should be noted that most of these combination therapy studies were performed before voriconazole became available. Another study reported a survival advantage for voriconazole plus caspofungin compared with voriconazole alone when used as salvage therapy.40 There is an ongoing randomized trial of voriconazole plus anidulafungin compared with voriconazole alone. However, the value of combination therapy for invasive aspergillosis remains unproven.

The IDSA guidelines recommend administering antifungal therapy for at least 6 to 12 weeks. Therapy is generally continued until signs and symptoms have been resolved for 2 weeks and chest imaging shows no further progression of the lung lesion after initial improvement. Persistent neutropenia and chronic graft-vs-host disease are two of the most important variables for poor outcome in invasive aspergillosis. In most neutropenic patients, it is appropriate to initiate empiric antifungal therapy after 4 days of persistent fever despite antibiotics. In immunosuppressed patients, antifungal therapy is continued until neutropenia resolves or immune function recovers. If possible in such patients, immunosuppressive therapy should be reduced or discontinued. Although colony-stimulating factors are widely used to attempt to reduce the duration of neutropenia, there are limited data from randomized, controlled trials demonstrating that granulocyte-macrophage colony-stimulating factor prevents the development of invasive aspergillosis in patients with prolonged neutropenia. Patients with previous episodes of neutropenia-related invasive aspergillosis should receive antifungal prophylaxis if neutropenia is expected to occur after chemotherapy or at the beginning of conditioning until engraftment of HSCT. Galactomannan levels, which have been shown to predict survival in patients with hematologic malignancy with or without neutropenia, can be used to monitor the response to antifungal therapy. The best therapy for breakthrough invasive aspergillosis has not been established. Surgical removal of necrotic lesions should be considered but is often not possible in critically ill ICU patients who have profound thrombocytopenia.

The adverse effects of antifungal drug therapy and drug-drug interactions are important to consider in the treatment of invasive fungal infections. Azoles are potent inhibitors of cytochrome P450 enzymes that can metabolize some chemotherapeutic agents (eg, cyclophosphamide) and immunosuppressive agents (eg, cyclosporine, sirolimus). Azoles are hepatotoxic and fatal hepatotoxicity has been reported in patients who are receiving concurrent highly active antiretroviral therapy. In addition, azoles reduce the clearance of IV midazolam, which is commonly used for sedation in the ICU. Amphotericin B is often not well tolerated owing to nephrotoxicity and infusion-related reactions, although this is less of an issue with the lipid formulations. Echinocandins can cause hepatic impairment and therefore levels of immunosuppressive drugs, such as cyclosporine or tacrolimus, must be closely monitored. Tables 4 and 5 offer a summary of the general treatment guidelines and specific antifungal medications used for candidiasis and aspergillosis.


Table 5Medications Used in Treatment of Invasive Fungal Infections

Antifungal Agents Dose Comments
Azoles    
   Fluconazole IV or oral: Loading dose 12 mg/kg, then 6 mg/kg/d Drug of choice for nonneutropenic, stable patients with invasive candidiasis (except for C glabrata) with no prior azole exposure. No activity against aspergillosis.
   Voriconazole IV: 6 mg/kg q12h for two doses, then 4 mg/kg q12h
Oral: 200 mg bid or 4mg/kg q12h
Drug of choice for invasive aspergillosis; recommended as step-down therapy for selected cases of candidiasis; poor activity against Zygomycetes.
   Itraconazole IV: 200 mg bid for four doses, then 200 mg/d
Oral: 400 mg/d in one dose or two divided doses
Not recommended by the IDSA for invasive aspergillosis because Aspergillus is less susceptible to itraconazole than voriconazole and because of the erratic bioavailability and toxicity.
   Posaconazole Salvage treatment (unlabeled use): 200 mg qid, then change to 400 mg bid at hospital discharge or after disease stabilization
Prophylaxis: 200 mg tid
Not FDA approved for invasive aspergillosis.
Echinocandins    
   Caspofungin IV: 70 mg/d for the first dose, then 50 mg/d Drug of choice for invasive candidiasis in neutropenic or unstable patients with prior azole exposure. Approved as salvage therapy, often in combination with voriconazole for invasive aspergillosis.
   Micafungin IV: 100 mg/d In vitro activity against Aspergillus similar to activity against Candida, but not FDA approved for invasive aspergillosis. Relative efficacies of the different echinocandins are similar for invasive candidiasis.
   Anidulafungin Invasive candidiasis: Only oral therapy, 200 mg for first dose, then 100 mg/d Optimal dose for invasive aspergillosis has not been defined Effective against invasive aspergillosis in vitro and in animal models (no clinical trials). Relative efficacies of different echinocandins are similar for invasive candidiasis.
Amphotericin B    
   Amphotericin B
   deoxycholate
IV: 1.0 to 1.5 mg/kg/d Alternative drug of choice for invasive fungal diseases if there is intolerance to or limited availability of other antifungals.
   Liposomal
   amphotericin B
IV: 3 to 5 mg/kg/d Less nephrotoxic and fewer infusion- related reactions compared with deoxycholate formulation.

Adapted from Pappas et al31 and Walsh et al35 with permission.


 

Conclusions

The increased use of invasive monitoring and aggressive therapeutic and surgical technologies in the ICU, along with the widespread use of broad-spectrum antibiotics, has not only improved survival of critically ill patients with life-threatening illnesses but has also increased the risk for fungal infections in these patients. Fungal infections can become severe and rapidly progressive and are often difficult to diagnose and treat. Although diagnostic and therapeutic modalities for some of the fungal infections are improving (such as for C albicans), more studies are needed for non-albicans Candida species, such as C glabrata. Invasive mold infections such as Aspergillus are increasing in incidence. Further studies are needed to determine the populations at particularly high risk for opportunistic fungal infections who might benefit from targeted antifungal prophylaxis and preemptive therapies.


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