Opportunistic Fungal Infections in the Critically III

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Hematology and Oncology in Critical Care

Opportunistic Fungal Infections in the Critically Ill Brenda K. Shelton, MS, RN, CCRN, AOCN

Over the past decade, fungal infections have become an increasingly common source of morbidity for patients in intensive care units. Significant opportunistic fungal infections were rare before the 1960s, and were not believed to increase mortality. 14In the 1960s and 1970s, fungi were isolated in body fluids and identified histologically in organ infiltration, but it was not until the 1980s that they were recognized as important pathogens that could affect outcome in critically ill patients. 14·57 Candida! infections are currently the fourth most common source of septicemia among intensive care patients, with the highest actual mortality rate of all bloodstream infections. 22 Despite the clinical importance of fungal infections in care of the critically ill, little nursing literature has focused on this topic.3 This article outlines current trends regarding fungal illness in the critically ill, describes the infectious manifestations of candidiasis and aspergillosis, and reviews the available antifungal therapies. Fungal infection in the critically ill reflects the success of current lifesaving efforts in critical care. 57 As more patients survive their initial life-threatening illness, they develop complications of disrupted immune competence and maladaptive physical coping. 31· 76 The spe-

From the Johns Hopkins Oncology Center, Baltimore, Maryland

cific infecting organisms and clinical significance of the infection vary with host and environmental factors. In mildly immunecompromised patients, infection may be localized or limited to mucocutaneous tissues. Although not life threatening, infection in these patients can cause persistent, severe symptoms that diminish quality of life.6 Unfortunately, many others manifest as severe invasive infections, which can be fatal if diagnosis and treatment are delayed.

Risk Factors for Fungal Infection Defense against superficial and invasive fungal infection involves both cellular and phagocytic immune function. T-cell activity prevents colonization and superficial invasion, but once these barriers are breached, phagocytic immunity (neutrophils) prevents deeper invasion and hematogenous dissemination.14 Consequently, individuals with diminished T-cell function (e.g., people with HIV disease; organ transplant recipients) are more likely to develop frequent or persistent non-life-threatening cutaneous fungal infections, although invasive disease occurs less often. Patients from these groups report incidence rates of 35% to 80% when antifungal prophylaxis is not implemented. 19• 29 More recent reports about high-risk patients receiving oral systemic antifungal prophylaxis describe

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incidence rates under 30%. 55· 89• 91 Granulocyte defects occur in patients receiving chemotherapy for acute leukemia and in patients with diabetes; they are more likely to present with invasive fungal disease. 14 These patients have a lower reported incidence (20% to 45%) but a greater likelihood of mortality due to fungal infection. 49· 52· 75 The two main categories of risk factors for fungal infection are (1) immune defects leading to failure to recognize and destroy pathogenic fungal organisms and (2) mechanical disorders favoring fungal overgrowth. Multiple risk factors for fungal infection have been identified; some are unique for particular patient groups and others for specific fungal species. General risk factors and their typical infection profiles are listed in Table 1. Where available through literature review, approximate percentages of patients with fungal infection are given. Evidence of newly identified fungal pathogens and the prevalence of previously uncommon fungal diseases are related to increased numbers of vulnerable persons. Individuals most susceptible include those with HIV disease, recipients of bone marrow or organ transplant, cancer patients treated with high-dose chemotherapy and radiation, critically ill persons, and low-birthweight infants. 20 When all critically ill patients are considered together, the most common risks for fungal infection are mechanical ventilation for more than 48 hours, central venous catheters, burns, immune suppression, hematologic malignancy, and administration of multiple antibiotics.6· 14 In some critically ill populations, an acute physiology and chronic health evaluation (APACHE) score above 10 was also a significant risk factor for fungal infection. 14

Clinical Presentation The two categories of medically significant fungi are as follows: pathogenic fungi that cause infection in endemic areas (e.g., Histoplasma sp, Blastomycessp, Coccidioidessp) and less virulent opportunistic fungi (e.g., Candida sp, Torulopsis sp, Aspergillus sp, Cryptococcus sp) that cause infection only in hosts with decreased immune function or disruption of normal epithelial barriers. 14Opportunistic infections are the most prevalent in

general clinical practice and are the primary focus of this article. 31· 39· 40 Fungal diseases are particularly difficult to interpret because colonization is histologically similar to infection. 14 The similarity requires that clinicians thoroughly gather both clinical and laboratory evidence of infection and compare this evidence to risk factors for fungal disease and the typical presenting symptoms of the suspected pathogen. Terms involving fungal infection are similar to those used with bacterial infection but include parameters defining the number of colonyforming units. General definitions for infectious fungal diseases are listed in Table 2. As with infection caused by other organisms, the nurse must monitor for universal signs and symptoms, including fever, malaise, and leukocytosis. Because most patients at high risk for fungal infection are also immunocompromised, the most common signs and symptoms of infection may be blunted or absent. Readers are referred to the literature on general critical care, immunocompromised patients, and oncology for common signs and symptoms of infection and sepsis.65· 72 • 76 Myalgias and headache are seen more often with fungal than with bacterial infection. 6 Organism-specific signs and symptoms are described in the sections on local and invasive disease. Cultures for mycology are performed routinely when fungal infection is suspected, but often they do not reflect the true status of the disease. Colonization cannot be differentiated histologically from infection on mucosa! surfaces or wound cultures. 2· 14· 24· 37· 78·89 Additionally, the time to positive culture averages 3 days to 2 weeks, considerably longer than with bacterial infection.12 The need to treat empirically for probable infection usually becomes a prominent issue before culture results are available. With current culture media and techniques, less than 60% of patients with fungemia actually have positive blood cultures.14· 52 It is thought that blood culture yield is poor with invasive disease because organisms are difficult to grow in culture, and the bacteria present may deter fungal growth. 14 Some have postulated that diagnostic yield of blood cultures can be improved by using lysis centrifugation technique and by obtaining arterial rather than venous blood for culture. It is believed that the liver filters yeast, and

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Table 1 RISK FACTORS FOR FUNGAL DISEASE Risk Factors Immune Defects Burns Leukemia, acute Leukemia, chronic Lymphoma Diabetes mellitus

Bone marrow transplant

Corticosteroid therapy

HIV disease

Intravenous drug use Neutropenia ( < 1000 cells/mm 3) for more than 7 d Heart transplant Kidney transplant Liver transplant

Lung transplant

Special Features

Loss of normal skin flora increases risk of disseminated candidal superinfection

20%-25% incidence of invasive disease Disease associated with agammaglobulinemia and fungal disease is mucotaneous when alkylating agents used for treatment, but when antimetabolites (e .g. , fludarabine) are used, invasive disease is more likely More common in non-Hodgkins subtype Candidiasis is most common , although infections with Aspergillus and Cryptococcus also occur Most prevalent when hyperglycemia is uncontrolled 2%- 30% incidence of invasive disease Occurs later than with neutropenia, <20% occurred during neutropenic period; most were > 100 d after transplant Extensive graft versus host disease is most common risk factor 5%-15% incidence of invasive disease Candida most common pathogen, but Aspergillus common with long-term use Relatively unusual to have disseminated fungal disease when receiving corticosteroids for autoimmune disease 60%-80% incidence without prophylaxis, but currently only 20%-40% incidence Mucotaneous candidiasis most common Invasive Aspergillus sinusitis occurs more often than pulmonary Aspergillus infections; disorder almost always fatal May present as fungal endocarditis 10%-40% incidence of invasive disease Highest risk factors were central venous catheter, longer-term neutropenia, gram-positive bacteremia, corticosteroid use , younger age 40%-60% develop fungemia 10%-35% incidence of invasive disease 10%-20% incidence of invasive disease 30%-40% incidence of invasive disease 40% mortality rate due to fungal infection Peak incidence first 1-2 mo Candida most common , although Cryptococcus and Aspergil/us also reported Highest risk factors were high transfusion requirements and posttransplant bacterial infections 10%-34% incidence of invasive disease Aspergil/us most common pathogen High mortality rate Chest radiograph normal in 40% of patients

Mechanical Risks

Central venous catheter Disruption of GI or GU mucosa Mechanical ventilation

May manifest as fungal endocarditis Loss of barrier defenses and normal flora increase risk of disseminated candidal superinfection Oral esophageal candidiasis common, rarely pneumonia

> 48 h Multiple antibiotics Surgery

Total parenteral nutrition

Destruction of normal flora increases risk of superinfection (especially candidias) Cardiac surgery associated with fungal endocarditis Contaminated air systems associated with cataract introduced ocular Aspergillus infection Abdominal surgery introduces Candida from GI tract into peritoneum; candidal peritonitis common Candida glabrata and Torulopsis most common pathogens May manifest as fungal endocarditis

GI = gastrointestinal; GU = genitourinary Data from references 1, 5, 6, 9, 14, 21 , 25 , 29 , 35, 37, 38, 40, 41 , 49 , 51 , 52, 55 , 57 , 58, 62, 66 , 70, 76 , 77 , and 82.

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Table 2 TERMS DEFINING FUNGAL INFECTION Term General Colonization

Mucocutaneous infection Fungemia Catheter infection Invasive fungal infection Organ Specific Moniliosis Tinea Thrush

Defining Characteristics

Tissue or fluid culture containing > 5 CFU by roll plate technique or > 50 CFU by sonication method Fungal dermatophytes detectable below keratin layers Isolation of pathogenic species of Candida from at least one blood culture Catheter tip producing >15 CFU by roll plate technique or >100 CFU by sonication method At least 105 organisms/g tissue Dissemination evident by noncontiguous invasion of organs Vaginal candidal infection Ringworm infection Candida! infection of the mouth

CFU = colony-forming units Data from references 12 and 14.

therefore arterial blood may have higher concentrations of yeast to grow in culture. 78 Other laboratory tests, such as antigen or immunoassay tests for fungal infections, lack sensitivity and specificity; therefore, most diagnoses of invasion or dissemination depend on careful data collection and correct interpretation of clinical evidence. 2• 14• 26• 57• 63 Localized Fungal Infection

By definition, a superficial infection invades and survives in the dead keratin of the epidermis. 28 Fungi that infiltrate keratin then produce an enzyme enabling them to digest keratin. Deeper cutaneous infection occurs when the fungus excretes exotoxins that injure and inflame the living skin beneath the keratin layer. At this level of local invasion, pain and bleeding may be present. The most common local or superficial fungal infections seen in high-risk patients are candidiasis and tinea. Candida! colonization of normal mucosa! surfaces has a greater potential for overgrowth and localized infection. Tinea is a commonly occurring dormant infection that can be reactivated in times of stress or immune compromise. 28 Although not likely to be life threatening, these infections can produce considerable pain, itching, and skin or mucous membrane disruption.27 Prompt diagnosis can lead to effective local treatment and reduced incidence of secondary bacterial infections or skin breakdown. 74 Localized candidal infection occurs in warm, moist, dark locations, particularly

when normal bacterial flora are absent. Infection occurring in the mouth is termed thrush, and vaginal infections may be called moniliosis. Other common sites of infection in critically ill patients are the perineum, underarms, and abdominal skinfolds. Infection is characterized by creamy or curdled, white or yellow exudates. The lacelike appearance of some exudates on microscopy demonstrates the dermatophyte structure. Lesions usually look removable, but the ulcerated mucosa! surface is apparent with cleansing or scraping. Immunocompromised patients have little exudate, and infection may appear only as a raised, tender, macular, red rash. 3· 76 Oral candidal infection has four identified clinical presentations: typical white plaque (pseudomembranous) lesions; spotty red patches (erythematous or atrophic lesions); hyperplastic "candidal leukoplakia" (nonremovable white lesions); and angular cheilitis (erythema and fissures in the corners of the mouth). 5 Diagnosis is based primarily on symptoms, although ultraviolet examination of scrapings also reveals evidence of disease. Candida organisms are generally vulnerable to topical nystatin liquid, powder, or cream and any of the azole agents. Treatment should be continued at least 7 to 14 days.13 Tinea is a mycosis better known by its common names of athlete's foot, jock itch, or ringworm. It is transmitted by direct contact or contact with an environment conducive to fungus growth. Although it may occur in the same circumstances as candidiasis, tinea is

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much more difficult to treat because it may remain dormant and become reactivated with every new episode of stress or immune compromise. It usually presents with an inflammatory red and scaly border or ring surrounding a red scaly interior. In severe disease, vesicles may appear around the border. Itching and burning are common complaints. The immunocompromised patient may present with an atypical, slightly red, dry area, with a less defined border. 28 Certain infection sites have unique defining features that vary from this general description. The presenting sites and clinical signs and symptoms are summarized in Table 3. Tinea is usually easily detectable with wet-mount examination of lesion scrapings. Cultures may be needed for more deep-seated infection, such as those involving the nails. Location and clinical characteristics

Table 3

Treatment

Tinea barbae (beard) or capitus (head)

Griseofulvin, 3-4 wk, and then continue 2 wk after negative cultures Terbinafine, 6 wk ltraconazole, 3-10 wk Topical antifungal creams: Lamisil , Loprox, Lotrimin , Monistat, Nizoral, bid, 2-4 wk

Tinea cruris (groin, jock itch)

Topical antifungal creams: Lamisil, Loprox, Lotrimin, Monistat, Nizoral, bid, 2-4 wk

Tinea of nails

Fluconazole or itraconazole, 4-6 wk

Tinea mannus (hands) or pedis (foot)

Terbinafine, 1% cream or 125-250 mg, po, bid, 2-6 wk Griseofulvin, 250-500 mg, po, bid, 6 wk Naftine cream, 4 wk

Fluconazole, 150 mg, po, q wk for 3 wk Data from references 27 and 28.

provide insight into refractoriness of disease. Local treatment with antifungal creams may be adequate for some patients, but not for others. Unique treatment implications are also included in Table 3. Invasive or Disseminated Fungal Infection

The most common fungus to disseminate or become invasive is Candida albicans1 4• 18 ; Aspergillus sp, although second most common, carries a more ominous prognosis. 47• 70 Invasive means that the fungus is involved in the lower healthy epithelial tissues, is refractory to topical medications, and often requires systemic antifungal therapy. 40 • 70 Invasion is less severe than dissemination, or infiltration of visceral tissues such as the peritoneum, lung,

CLINICAL PRESENTATION OF TINEA INFECTION

Infection Name

Tinea corporis (trunk, face, limbs)

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Defining Characteristics Most common in crowded living conditions, when bedding or personal care items are shared Begins as one or more patches of scaly scalp or alopecia May develop into a tumorlike mass with scarring and hair loss Presents as round or oval lesions Begins as flat scaly spots, develops into red, raised borders that extend outward Borders may be slightly irregular with papules or vesicles Can be itchy or asymptomatic Occurs most often in warm weather Prevalent after sweating Men> women Lesions advance in half-moon shape out of crural fold , often red-brown , bordered with scaling or papules Nail changes preceded by pain, redness of nails Thick, hardened, yellow nail beds Separation of nail from cuticle occurs late Most common form of disease Men> women Risk factors: tight shoes, dark socks , foot sweating, unclean showers Dorsal aspect of foot: ringworm pattern lnterdigital tinea pedis: dry and scaly with fissure, or white and macerated; itching greatest after shoes removed Moccasin type: scaly, hyperkeratotic areas on plantar surface; involves sides of foot in moccasin pattern; skin may be red or tender

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liver, or ocular regions. 4°Fungus can disseminate to almost any area of the body; however, the most common sites are the brain, blood, liver, and lung. 40 Immunocompromised patients cannot afford to experience dissemination in a disease that is usually localized, because all normally predictive treatment plans are less effective against invasive or disseminated disease. 7° Fungi known to become invasive include Aspergillus, Candida, Cryptococcus, Blastomyces, and Histoplasma spp. 70 Because of their prevalence and clinical significance, invasive infections with Candida and Aspergillus spp are discussed more thoroughly in the following sections. Candida/ Infection

Candida is a ubiquitous organism that is a component of the normal gastrointestinal (GI) and genitourinary (GU) flora in more than 50% of all persons.6 The normal bacterial flora usually control candidal growth so that overproduction and disease do not occur. Candida spp present as disease in both yeast and mycelial subtypes. The yeast formation is the normal colonizing type of unicellular Candida, which multiplies by budding with nuclear division into segments called blastophores. When the new blastophores stick together, they form a structure called a pseudohyphae that becomes the mycelial form. Unlike other fungi, the mycelial form is more invasive and resistant than the yeast. 14 There are six different candidal species, each with key defining characteristics pertinent to nurses. Candida albicans is the most common, but others are emerging as clinically significant in specific circumstances. 32·62 These differences are reviewed in Table 4. Mucocutaneous candidiasis is a common superinfection with mildly immunecompromised individuals, including healthy persons who are under physical or emotional stress. For this reason, thrush or vaginitis may occur in more than half of high-risk patients, but it is often self-limiting or resolves as immune defenses return to normal. Disruption in GI integrity can lead to esophagitis and GI candidiasis that presents as diarrhea. 6 Approximately 60% to 80% of HIV-positive patients will develop a localized candidal infection, but its presence is predictive of disease progression. 6 More than half of these individuals

will present with the full clinical syndrome of AIDS within 2 years, and about 14% will have clinically significant esophageal candidiasis. 5· 6· 9 The liver is considered the most important filtering organ for fungal organism; therefore, the first month after liver transplant is a period of significant risk for development of disseminated candidal infection. 29· 55 Mucotaneous candidal infection presents with a characteristic white or creamy secretion, often with raised lesions that adhere to and ulcerate underlying mucosa! tissue.5 When the disease is beyond the visible mucosa! surfaces, thick white exudate or cloudy body fluid (e.g., urine) is notable. Patients complain of painful, itchy lesions, but bleeding rarely occurs. Clearly localized candidiasis is usually susceptible to topical or local treatment with agents such as nystatin or miconazole cream. 5 Severe mucotaneous disease requires systemic therapy with one of the azole antifungal agents. 5· 13 When oral therapy is poorly absorped or not tolerated, amphotericin is administered.13Candida spp are highly susceptible to killing by amphotericin, and a low to moderate dose of0.3 to 0.6 mg/kg is adequate treatment if the total dose is 30 to 40 mg/kg. 5 Because colonization and infection with Candida organisms are difficult to differentiate, clinicians use the evidence of infection in unusual organ sites, or colonization with other symptoms of infection, as the threshold for treating empirically as disseminated candidiasis.60 Systemic illness in patients is thought to be the result of hematogenous spread and is indicative of candidemia, even without positive blood cultures.14 Symptoms of meningitis, encephalitis, hepatitis, peritonitis, endocarditis, pneumonitis, and osteomyelitis are suspicious for candidal infection. 6· 14· 57· 60 The most common sites of disseminated candidal infection are the urinary tract, eye, liver, spleen, and lung.14· 29· 55 Pneumonia is unusual; when present, it indicates hematogenous seeding from a fungemia. 14· 42 Candida! pneumonia may be indistinguishable from bacterial pneumonia and demonstrates clinical variations of alveolar or interstitial findings. 42 Aspiration causes peribronchiolar nodular infiltrates, whereas a diffuse bilateral miliarynodular pattern is more typical of pulmonary candidiasis.42 Pulmonary hemorrhage has also been documented as a clinical presentation

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Table 4 CLINICAL FEATURES OF CANDIDA SPECIES Species

Frequency

Candida albicans

Most common

Candida tropicalis

Second most common

Candida parapsilosis

Third most common

Candida krusei

Previously rare , now 1%- 3% of cases

Candida (Torulopsis) glabrata

No information available

Candida lusitaniae

No information available

Clinical Features Colonizes mucosa! tissue of GI and GU tracts in 50% of people with intact immune system Most likely isolated from body tissue or fluids Most common form of noninvasive infection Autopsy evaluation indicates it may be invasive in organs with little clinical evidence May demonstrate dose-dependent susceptibility to azoles Most likely with hematologic malignancy and diabetes Associated with embolic skin lesions (biopsy proves invasive disease) Associated with hyperalimentation and indwelling catheters Commonly found colonizing on hands Seen in nononcologic and solid organ transplant patients Less virulent and better prognosis Rare disseminated infection, but can cause endocarditis Important pathogen in hematologic malignancies and neutropenia Resistant to fluconazole Colonizes mucosal surfaces of GU and GI tracts Usually less virulent, but 50%-70% mortality when causing renal infection in diabetic patients Affects surgical and solid organ transplant Dissemination rare Associated with malignancy, neutropenia, prolonged antibiotics, or indwelling catheters Commonly presents as fungemia May be resistant to amphotericin B and azole agents Prognosis poor with disseminated disease

GI = gastrointestinal; GU = genitourinary Data from referenc es 38, 58, and 81 .

of candidiasis. 50 Clinical disorders associated with a 30% to 50% chance of association with candidemia are endophthalmitis 21 and candiduria .14 Approximately 13% of patients with candidemia also have a maculopapular or nodular rash that may be hemorrhagic, and 50% have positive cultures on biopsy. 14· 76 Antigen titers can be obtained but cannot differentiate between noninvasive and invasive candidal disease. Investigational serologic tests for fungal cell components have mixed sensitivity and specificity, but it is possible to test {3-l glucan (cell wall component), o-arabinitol (cell membrane metabolite), and enolase (cell cytoplasm). 14 Effective treatment of disseminated candidal infection requires systemic treatment. An oral azole agent, or intravenous amphotericin B (0 .6 to 1.0 mg/kg/ d) , is usually prescribed for 14 days. 5· 13 Emerging resistant species of Candida may necessitate changing to intravenous amphotericin B or longer therapy; however, response to fluconazole has

still been noted in the presence of in vitro resistance. 5 Aspergil/us Infection Aspergillus fumigatus is a mold that is present in the environment worldwide, yet is able to infect only debilitated or immunodepressed individuals. 71 It has been identified in soil, ceilings, building material, cereal dust, 42 and ventilation and water systems. 6• 18· 30 Nosocomial outbreaks of infection have been associated with hospital reconstruction,11 · 30, 59, 1 1• 79 aerosolization from wound infection, 89 water sources, 89 and multiuse equipment. 89 Spores are released into the environment; when inhaled by immunodepressed patients, they can produce clinical disease. The mold itself is commonly associated with hypersensitivity lung syndromes such as asthma, extrinsic allergic alveolitis, and allergic bronchopulmonary aspergillosis. 47· 71 • 92 These syndromes must be differentiated clinically from infection

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with invasive disease , because treatment of allergic reactions includes corticosteroids, which are contraindicated in invasive infection. 71 The risk of aspergillus infection from spore exposure in the hospital may vary with the patient's underlying condition and degree of exposure (number of colony forming units in ambient air). 30 Hepafiltration units have been proven to prevent infection in high-risk patients. 11 ·30·59·69 Specific protective guidelines for construction in or around patient care areas have also been established to prevent nosocomial infection. 20· 44 There are five species of Aspergillus, but Aspergillus fumigatus is the most common cause of clinical disease.80 The unique species Aspergillus niger is more likely to present as otomycosis, and Aspergillus terrus is resistant to amphotericin. 80 Allergic pulmonary aspergillosis is the only "localized" manifestation of the disease, so evidence of significant aspergillus infiltration is always considered evidence of disseminated disease. The largest risk groups are patients with acute leukemia and patients with prolonged granulocyte suppression such as occurs with diabetes or corticosteroid treatment. 40· 51· 86· 91 Aspergillus may present as an invasive, necrotizing infection (e.g., pulmonary aspergillosis or central nervous system abscess) , or it may infiltrate organs such as the sinuses, kidney, liver, heart, and thyroid. 6·35·40·41·80 Patients who experience severe invasive aspergillosis once have at least a 30% chance of recurrence during subsequent immunosuppressive episodes and a 50% to 80% chance of mortality if it recurs ; therefore, patients with a history of aspergillosis are poor candidates for organ transplant. 5, 42, 53 The most common pathologic presentation is angioinvasive pulmonary aspergillosis, which carries a 64% to 80% mortality rate. 16· 42 · 47 Patients with this disorder begin with fever, cough, dyspnea, and restrosternal or pleuritic pain that is often mistaken for bacterial pneumonia or pulmonary embolism. Pleural friction rub and weight loss are common. Hemoptysis occurs in 50% to 90% of patients with aspergillus pneumonia. 42 Hemoptysis may result from friction of the mycetoma on surrounding alveoli; fungal endotoxins possessing hemolytic properties; or local vascular invasion. 42 Radiographs may show almost any pneumonic pattern, but most common is a patchy

bronchopneumonia with multiple focal peripheral lesions located in the lung septation. 19· 42 The nodules usually measure 1 to 3 cm and are surrounded by wedge-shaped infarcts.19· 40 Less often, tracheobronchial thickening, pleural invasion, and hilar or medistinal masses are seen. 19· 40· 42 A less common form of invasive disease is airway invasion and hematogenous spread of the fungus characterized by multiple nodules (smaller than 1 cm) scattered throughout the lung. 40· 42 Despite what often appears to be extensive lung disease , less than 30% of sputum cultures are positive. 26 Unless a nodule can be biopsied, bronchoalveolar lavage is also less than 50% diagnostic. 26 · 54 · 63 The gold standard of diagnostic testing for aspergillus infection is CT because it often reveals lesions not detectable on chest radiogra ph.19· 42 · 43 Characteristic lesions on radiograph or CT scan include the halo sign in early disease and the air crescent sign, which occurs later in about half of patients. The presence of the air crescent sign is associated with improved survival rates. 42 Invasive aspergillus infection can also affect the sinuses,48 eye, 35 liver, heart, 41 joints, 77 and skin.36 Brain abscesses occur less frequently, unless invasive aspergillus sinusitis or ocular infection is present. 35• 70 Sinusitis presents as nasal stuffiness, sinus pressure, headache, periorbital edema, epistaxis, facial pain, and fever. 70 Unlike bacterial sinus infections, little or no purulent drainage occurs. Cultures can be positive, but more often are not. The CT scan is the diagnostic test of choice because it can detect and define the invasiveness of disease. 25 Aspergillus sinusitis can be lethal if not treated aggressively with multimodal therapy. Long-term systemic antifungal pharmacotherapy is combined with surgical debridement25· 82 and granulocyte support. 82 Other methods of diagnosing invasive aspergillus infection include antigen testing, detection of cell wall components through enzyme immunoassays (EIA),45 and polymerase chain reactions (PCR). 24 Antigen testing is not helpful in immunocompromised patients, because their inflammatory responses are so suppressed.83 An EIA test for galactomannan is commercially available in Europe. It shows a promising 92.6% sensitivity and 95.4% specificity in the highest risk populations of acute leukemia and bone marrow transplant patients , but has not been studied in lower risk groups. 45

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Because cultures are often not positive even in severe disease, it is vital that antifungal drug susceptibility testing be as accurate as possible. The National Committee for Clinical Laboratory Standards (NCCLS) is slated to release a proposal to standardize antifungal susceptibility testing procedures. Aspergillus spp are notable for resistance to single-agent antifungal therapy. In fact, only 30% to 35% of patients with aspergillus infection will respond to amphotericin alone. 16· 17 All azole agents are ineffective, and high doses of amphotericin (greater than 1.25 mg/kg/d) may be needed to kill the organism, or to penetrate the site of infection. 5 In many instances, amphotericin resistance becomes a problem, and amphotericin may need to be combined with 5-fluorocytosine or rifampin. 5 When an isolated aspergilloma is located peripherally, surgical excision is remarkably effective and should be performed whenever possible if further myelsosuppressive therapy is planned.4· 7 In angioinvasive pulmonary aspergillosis, surgery may be indicated emergently if the fungal organism erodes into one of the pulmonary arteries, precipitating severe pulmonary hemorrhage. Patients at risk for this complication are usually well into their treatment, because necrotization and vascular invasion occur as the healing lesion cavitates.42 Patients present with acute, severe hemoptysis , often followed rapidly by shock. Prompt intubation and ventilation of the good lung, or insertion of a dual-lumen endotracheal tube with one side occluded, is the emergency treatment of choice until the patient can be prepared for surgery.4. 7 These patients require rapid intervention by intensivists and thoracic surgeons as well as massive fluid and blood transfusion. Antifungal Therapy

The ideal management of fungal infection is prevention. We can clearly define patients at risk for the disease , and several preventive strategies have proven helpful in clinical practice.18 The Infectious Disease Society's published guidelines for preventing nosocomial pneumonia now include precautions against transmission of airborne pathogens (e.g., Aspergillus) through air-handling systems and in-hospital construction. 11 Specifically constructed barrier devices are required for all

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activities involving the removal of ceiling or air filters in patient care areas. 18· 20· 3o, 44 · 86· 89 In addition, patients at highest risk should be placed in single-patient rooms supported by hepafiltration devices. 59·86 These standards are also established guidelines for management of patients undergoing bone marrow transplantation.18· 59·86· 89 In this author's experience at a comprehensive cancer center, patients have also been provided with high-filtration masks when being transported outside the hepafiltered areas, particularly when hospital construction was underway nearby. Door opening, which disrupts the filtration and laminar air-flow filters , has also been eliminated by limiting use of an on-unit stairwell to emergencies only. The incidence of life-threatening fungal infection is so significant in some patient populations that antifungal drug prophylactic therapy has become routine to prevent severe candidal infections; however, its value in preventing aspergillus infection is unclear. 15· 18· 56 Patient groups who are most likely to receive antifungal prophylaxis include those with acute leukemia or HIV disease and patients receiving blood transfusions or liver transplant.15· 18· 56, 69, 84• 85 The question of whether this approach is rational and safe should be based on consideration of cost and benefit balanced with an understanding of prevalence rates and the risk of mortality associated with development of fungal infection. Generally, the incidence rate in the specific patient group should exceed 10% before any prophylactic regimen truly results in lower infection rates. 56 Prophylactic fluconazole has been associated with emergence of more resistant strains of Candida organisms, such as Candida krusei, and therefore should be limited in duration and given only to those potentially at highest risk for aspergillosis infection.84 Most medical antifungal therapy targets the cell membrane, which is essential to cell function and viability. Unlike bacteria, the cell membranes of fungi contain sterols. Mammalian cell walls contain sterols in the form of cholesterol, whereas fungi contain either ergosterol or zymosterol. Drug resistance is becoming more common as the incidence of fungal infection rises; resistance is thought to be related to reduced ergosterol production or modification of ergosterol, with less efficient binding.13

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With localized fungal infection, topical antifungal powders or creams adequately infiltrate the organism and exhibit effective cell kill with minimal adverse effects. Severe mucocutaneous or systemic disease requires oral therapy. Antifungal agents are either cell membrane inhibitors or antimetabolites. The cell membrane inhibitors are divided further into polymixins, polyenes, and azoles. The azole agents and amphotericin or its lipid formulations are most commonly used. A general overview of these agents is provided in Table 5. Since the introduction of azole antifungal agents in the 1980s, treatment options for patients with severe or disseminated fungal infection have become increasingly less toxic. These synthetic compounds target ergosterol within the fungal cell membrane. They inhibit ergosterol synthesis and cell replication. Because of their interference in the P-450 cytochrome enzymatic reactions, they also interfere with normal endocrine and metabolic processes such as hepatic metabolism and the action of adrenal hormones. 13 These adverse effects are partly resolved in the newer triazole drugs such as fluconazole and itraconazole.13These agents are available only in oral forms and have strict bioavailability profiles, limiting their benefit in patients with a poorly functioning gut. 13 Amphotericin B is a lipophilic fungicide produced by Streptomyces nodosus and is structurally similar to membrane sterols. When administered, it creates a one-to-one polyene-sterol interaction resulting in lethal pores in the cell membrane. Its specificity is thought to be related to the preferential binding with ergosterol in the fungal cell membrane; however, binding to cholesterol leads to toxicities such as potassium and magnesium wasting and renal dysfunction. 34 It can be given intravenously and intrathecally, but newer oral swishes and nose sprays are currently under investigation. 15· 39 Infusional toxicities peak about 90 minutes after starting the infusion and include fever, chills, nausea, headache, myalgias, and hypotension or hypertension.8· 33· 34 Premedication with acetaminophen, diphenhydramine, or hydrocortisone can abrogate these effects.a· 34 Rigors usually herald the onset of fever. 33 Many practitioners advocate intravenous demerol or morphine, but others suggest covering the

patient with warm blankets before the onset of chills. 33 Although less common, allergic bronchospasm also can occur, which limits use of amphotericin B. Unfortunately, invasive fungal disease often necessitates higher doses of amphotericin B, resulting in ototoxicity or dose-limiting nephrotoxicity. Several interventions have been employed to reduce nephrotoxicity, but no randomized trials have supported their use. Renal-dose dopamine (dosed 1-4 ,ug/kg/ min) has been used because it was believed to enhance renal perfusion and reduce toxic effects, but recent research does not support this hypothesis.10 Saline loading and hydration before and after infusion of amphotericin is proposed to reduce renal tubular damage.33 Infusion times vary from 1 to 6 hours, but the only patients who appear truly to require longer times are those with altered creatinine clearance or severe documented infusion reactions.a· 34 • 68 Although amphotericin B is the treatment of choice for most systemic or refractory fungal infections, escalating dose requirements for certain fungi and severe adverse reactions limit its administration. 90 Several lipid-based formulations of amphotericin have been developed to overcome these limitations, but most have been studied only in refractory disease or in patients unable to tolerate the adverse effects of amphotericin B. 32 Three significantly different molecular structures have been devised and are available as amphotericin B colloidal dispersion (ABCD [Amphotec, Amphocil]), amphotericin B lipid complex (ABLC [Abelcet]), and liposomal amphotericin (Ambisome). 90 These agents have been developed to improve tissue penetration of amphotericin while reducing renal toxicity. 46· 67 Depending on the specific formulation, other adverse effects can be unaffected or more pronounced with these agents. The molecular structure, proposed benefits, and other clinical variations of these three lipid formulations of amphotericin are summarized in Table 6. Despite some clinical differences in action, dose, and adverse effects, no compelling evidence exists that these agents are more effective than amphotericin B. 90 All are three to five times more expensive than regular amphotericin B, necessitating careful consideration of therapeutic choices. The (Text continued on page 338)

Table 5 Agent

ANTIFUNGAL THERAPY

Indications

Dosage

Special Clinical Impl ications

Mucotaneous (noninvasive) candidal infections

Parenteral : 25,000 U/kg/d in divided doses every 12 h lntrathecal: 50,000 U/d for 3 - 4 d, then qod until 2 wk after cultures are negative Ophthalmic: 1-2 gtt 2-6 times/d

Reconstitute with large volume of dextrose fluid and administer over 60- 90 min Lowers seizure threshold Enhances effects of neuromuscular blocking (NMB), anesthetic and skeletal muscle relaxing agents Primarily renal clearance (50%-60%), administer cautiously in patients with renal insufficiency Observe for rash and urticaria indicative of hypersensitivity reaction Discontinue if severe diarrhea occurs with drug administration

Oral or skin surface candidal infection

Oral infection : 400,000- 600,000 qid oral swish and swallow GI infections: 500,000-1,000,000 tid Vaginal infection: 1-2 tablets (100,000 U each) inserted bid Topical: cover entire area and several mm more bid to tid for 14 d Varies with specific organism: Candida: 0.5- 0.7 mg/kg/d Aspergil lus: 1.0- 1.25 mg/ kg/d Cryptococcus: 7 mg/kg/d with flucytosine

Sweet smell and taste induces nausea and vomiting for some patients. Taste can be masked if given over ice or in strong flavoured liquid such as grape juice Observe for rash and urticaria indicative of hypersensitivity reactions Store oral solution in light resistant containers

All patients get loading dose twice the daily dose. Daily doses are: Systemic candida: 400 mg

Administer no faster than 200 mg/h (new research studies permitting 400 mg/h) Use in-line filter for IV administration May prolong myelosuppression Table continued on following page

Polymixins Polymixin B sulfate

Polyenes Nystatin

u

u

Amphotericin B

Candidiasis Aspergillosis Cryptococcosis

Only compatible with dextrose Hypersensitivity in about 20% of patients Give 1 mg test dose over 30 min to assess for hypersensitivity reactions lnfusional reactions- fever , rigors, headache, myalgias , hypotension , hypertension- peak about 90 min into infusion Adverse effects: hypokalemia, hypomagnesemia, nephrotoxicity

lmidazoles Fluconazole

c.> c.> c.>

Candidiasis Cryptococcal Meningitis BMT

(.,)

(.,)

.i:.

Table 5 Agent

Dosage

Indications Prophylaxis against invasive fungal infection

ANTIFUNGAL THERAPY (Continued).

Oropharyngeal candida: 100 mg Esophageal candida: 100 mg Vaginal candidiasis: 150 mg po single dose BMT prophylaxis: 400 mg

Ketoconazole (enhances anticoagulant effects of warfarin)*

Candidiasis Histoplasmosis Coccidiomycosis Blastomycosis Refractory dermatophyte infections Tin ea

Miconazole (Monistat, Micatin)

Aspergillus Coccidioides Cryptococcus Candida Dermatophytes Histoplasma

IV infusion: 200-3600 mg/d in three divided doses lntrathecal: 20 mg with IV doses Topical: apply to affected area bid for 2-4 wk

Blastomycosis Histoplasmosis Aspergillosis Oral candidiasis Cryptococcus

200-400 mg lid for 2 wk to 3 mo

200-400 mg po once a day 2% cream topically qd or

bid

Special Clinical Implications GI distress is common and may be severe enough to warrant discontinuation of drug. May be abrogated if given with food Discontinue immediately if skin reaction is apparent-severe StevensJohnson syndrome may occur Monitor hepatic transaminases for hepatic toxicity Dose reduction may be necessary with renal insufficiency Enhances anticoagulant effects of warfarin Y site incompatibility with amphotericin May prolong myelosuppression GI distress is common and may be severe enough to warrant discontinuation of drug, but drug needs acidic medium for absorption. Best absorption if given with tea, coffee, or fruit juice. Never give with antacids. Monitor hepatic transaminases for hepatic toxicity Possible hypersensitivity skin reactions may occur (less severe than with fluconazole). May require topical steroid, antihistamine cream, or discontinuation of drug Photophobia increases risk of sunburn-advise the patient to wear sunscreen Histamine receptor antagonists (e.g. , cimetidine) decrease absorption of drug Phenytoin enhances metabolism of ketoconazole, potentially requiring dose adjustments Enhances clinical effects of cyclosporine, warfarin Cardiovascular adverse effects (tachydysrhythmias, hypotension) if given rapid IV Monitor cholesterol and triglycerides for high lipids Monitor CBC-may cause marrow suppression Enhances anticoagulant effects of warfarin Causes increased phenytoin levels Premedicate with an antiemetic for gastrointestinal adverse effects with IV formulation Dilute IV formulation in at least 200 ml NS

Triazoles ltraconazole*

GI distress is common and may be severe enough to warrant discontinuation of drug. May be abrogated if given with food Monitor for hypersensitivity skin reaction and treat symptomatically with steroid or antihistamine creams Monitor hepatic transaminases for hepatic toxicity

Monitor for potentially dangerous adverse effects-hypertension , hypokalemia Enhances anticoagulant effects of warfarin, antidiabetic effects of oral hypoglycemic agents If on digoxin, monitor digoxin levels and for dysrhythmias related to toxicity Anti metabolites 5-Fluorocytosine (Flucytosine)

Cryptococcosis Candidiasis (some forms)

PO: 50-150 mg/kg/d given qid IV: 150 mg/kg/d given qid

Monitor for neurotoxicities-drowsiness, headache, confusion, d izziness Monitor hepatic transaminases for hepatic toxicity Dose reduction with renal insufficiency GI distress is common and may be severe enough to warrant discontinuation of drug. Food interferes with absorption; may not be given with food or antacids May prolong myelosuppression, monitor CBC. Dose can be adjusted for leukopenia, anemia, or thrombocytopenia Store in light-resistant containers Activity decreased if g iven with cytosine arabinoside (ara-C)

Enhances antifungal penetration of steroid component of fungal cell wall Used primarily to enhance Flucytosine in treatment of aspergillosis or cryptococcus and resistant trichomonas

IV or PO: 600 mg qd with amphotericin and 5-fluorocytosine or with itraconazole

Monitor hepatic transaminases for hepatic toxicity Decreases c linical effects of phenytoin, theophylline, narcotics, and glucocorticoids May cause red-orange discoloration or urine, tears, sweat, and sputum Food interferes with absorption; may not be given with food or antacids IV or PO: 600 mg qd with amphotericin and 5-fluorocytosine or with itraconazole

Antifungal Enhancers

Rifampin

Note: There are a number of azoles (e.g., voriconazole) and liposomal formulations (e.g ., liposomal nystatin/nyotran) currently under investigation and not yet commercially available. They are therefore not included in this table. * This drug does not adequately cross blood-brain barrier and is not used when meningitis is suspected. GI = gastrointestinal; BMT = bone marrow transplant; CBC = complete blood count; NS = normal saline. Data from references 2, 5, 6, 8, 13, 17, 23, 34, 39, 59, 61 , 69, and 85.

(,,) (,,)

C1I

w w en

Table 6

Amphotericin Type

Pharmacologic Structure

Amphotericin B (Fungizone)

Amphotericin B lipid complex (Abelcet [ABLC]}

Amphotericin is complexed with two lipids in a 1 : 1 drug:lipid molar ratio in a lipid ribbon

Administration

AMPHOTERICIN B FORMULATIONS Cost* (70-80 kg person)

Indications

0.25- 1.25 mg/kg/d given over 2- 6 h

$20/d

All invasive fungi

5 mg/kg/d given over 2 hat a rate of 2.5 mg/ kg/h

$280- $320/d

Aspergillosis in patients who are refractory or intolerant of conventional amphotericin

Comments Dose-related renal toxicity increases as dose exceeds 1 mg/kg/d . Can be abrogated with prehydration and posthydration with salt-containing fluid lnfusional toxicities of fever, chills are common (35% - 60%) and can be abrogated with acetaminophen , diphenhydramine and meperidine , or morphine Hypertension or hypotension can occur Renal excretion of electrolytes common - monitor for hypokalemia, hypocalcemia, and hypomagnesemia Stable up to 24 h when refrigerated Test dose 1 mg IV given over 15- 30 min to monitor for hypersensitivity Plasma concentration lower than conventional amphotericin Tissue concentration (liver and lungs) higher than conventional amphotericin No premedication for infusional toxicities recommended Stable up to 48 h if refrigerated

Liposomal amphotericin B (Ambisome [L-AmB])

Lyophilized formulation of amphotericin incorporated into unilamellar liposomes at a molar ratio of 10: 5.4; smallest diameter of all liposomal forms

3-5 mg/kg/d over 1-2 h

$628-$785/d

Amphotericin B cholesteryl sulfate (Amphotec [ABCO])

Colloidal dispersion with 1 : 1 molar structure in a disclike structure

3-4 to 6 mg/kg/d over 3-6 h for a rate of 1 mg/kg/h

$210-$320/d

Empiric therapy for presumed fungal infection in febrile, neutropenic patients Treatment of aspergillosis, candida, or cryptococcus refractory to conventional amphotericin or patients intolerant of conventional amphotericin Treatment of visceral leishmaniasis Aspergillosis

Plasma concentration higher than conventional amphotericin Liver concentration similar to conventional amphotericin, but lung concentration lower Premedication for infusion toxicities not always necessary. Observe for reactions, then determine need Stable for only 6 h after dilution

Plasma concentration lower than conventional amphotericin Liver concentration higher than conventional amphotericin, but lung concentration lower Premedication recommended for infusional toxicities Stable for 24 h when refrigerated

Note: Lipid formulations have less antifungal activity and therefore need higher doses than usual amphotericin B (i.e., ABLC, 5 mg/kg/d; ABCD, 3-6 mg/kg/d). 39 • Cost estimations based upon advertised market price. Data from references 23, 32, 39, 46, 67, 84, 85, 87, and 90.

(,,) (,,)

""

338

SHELTON

ability to deliver higher doses of amphotericin safely over a short period suggests a potential benefit in treating the notoriously refractory invasive aspergillus infection even without other documented indications.46· 87 Nurses administering lipid amphotericin formulations should understand the clinical differences in these agents and the implications for care, which may include administration

of premedications and monitoring of blood cholesterol and hepatic transaminases.67 Several newer antifungal agents are in development. The newest triazole, voriconazole, demonstrates less resistance emergence than older agents and greater effectiveness against aspergillus infection. 61 • 85 Another antifungal antimetabolite, called nyotran, is also in development. 17

SUMMARY Opportunistic fungal infections are increasingly common in acute care and now represent 10% to 15% of all nosocomial infections. 20• 22 · 31 Few references and clinical resources are readily available for nurses in planning care for these patients (as opposed to bacterial diseases, which are better known). Nurses must recognize patients at high risk for fungal infections and develop more detailed assessment plans that include orifice and breath sound assessments. They also must be familiar with antifungal therapies and the specialized nursing care required to administer them safely and with the best bioavailability.

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Address reprint requests to Brenda K. Shelton, MS , RN, CCRN, AOCN 2702 Chippewa Court Finksburg, MD 21048 e-mail: [email protected]