Fungal Infections

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139 Fungal Infections

Medical advances continue to improve the prognosis of patients with cancer and other immunodeficiencies. In the past 50 years, the field of transplantation has greatly impacted the management of patients with cancer, renal, cardiac, and liver diseases. Moreover, advances in neonatology continue to increase the survival of premature infants. Undoubtedly these advances have benefited society greatly, but they have also fueled the emergence of systemic mycoses. Candida species first appeared as significant nosocomial pathogens approximately 30 years ago.1 For 2 decades, infections due to these pathogens increased dramatically. With the establishment of the National Healthcare Safety Network (NHSN) in 2005, several Centers for Disease Control and Prevention (CDC) surveillance systems, including the Nosocomial Infections Surveillance System (NNIS), were phased out. The NHSN provides broader surveillance data of healthcare-associated infections than the NNIS, thus the results of the two systems are not exactly comparable. Although the surveillance methods have changed, the trends have not. NHSN pathogen distribution data for 2006-2007 were comparable to that of the NNIS reports from 1986-1999.2

Fungal infections among critically ill patients are primarily due to Candida spp. However, infections caused by other opportunistic fungal pathogens including Aspergillus, Fusarium, Cryptococcus neoformans, and agents of zygomycosis also occur in select critically ill populations (e.g., solid-organ transplant [SOT], hematopoietic stem cell recipients, and acquired immunodeficiency syndrome [AIDS] patients). Moreover, primary or endemic mycosis caused by Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides immitis can cause severe disseminated infection in immunocompetent or compromised hosts.

Fungal infections are generally more prevalent in ICUs than on the general medical wards.3 The importance of effective preventive measures against systemic mycosis is widely appreciated in critically ill oncology patients or hematopoietic stem cell transplant (HSCT) recipients. As our understanding of these infections in the general intensive care unit (ICU) setting continues to improve, so too does the ability to institute appropriate preventive measures. In the past decade, the development of agents possessing either a different mode or broader spectrum of activity, less toxicity, or a reduced propensity to interact with other drugs has increased the number of available systemic antifungal agents. Consequently, clinicians can now tailor antifungal therapy to specific patients. Moreover, our understanding of antifungal pharmacodynamics is developing, and methods to measure antifungal susceptibility are improving.

image Fungal Infections in the Critically Ill

Candida Infections in the ICU

Epidemiology

Candida albicans remains the fourth most common pathogen of healthcare-associated infections, and only coagulase-negative staphylococci, Staphylococcus aureus, and enterococci are more common.2 Candida spp. have consistently caused a substantial disease burden for at least the past decade. ICUs have a higher incidence of Candida bloodstream infections (BSIs) than medical and surgical wards.3 Although prior data had suggested the frequency of Candida BSIs among ICU patients in the United States had declined, estimates from national secondary databases and population-based studies suggest the disease burden may be shifting from the ICU to the general hospital population.1

C. albicans remains the most common invasive Candida spp. worldwide.4 However, decreasing trends in the isolation of this species over time have been observed in the ICU and non-ICU setting.4,5 An increased prevalence of C. albicans and Candida parapsilosis among neonatal ICU patients and an increasing prevalence of Candida glabrata infections among adults has been widely appreciated.1,4,5 C. albicans is responsible for approximately 45% of episodes of candidemia.6 The incidence of infection due to a particular Candida sp. varies considerably by the clinical service on which the patient is hospitalized. However, in general, C. albicans is the primary fungal pathogen in the ICU setting and is followed by C. glabrata, C. parapsilosis, Candida tropicalis, Candida krusei, and other Candida spp. (i.e., Candida guilliermondii, Candida lusitaniae, etc.).6 This rank order varies little across infection site, but it may vary with age.1,46 Surveillance data have noted that candidemia in neonatal ICUs is predominantly due to C. albicans and C. parapsilosis and rarely due to C. glabrata or other Candida spp.1,46 Surveillance studies have demonstrated that BSI due to C. albicans occurs less frequently with increasing age.1,46 In contrast, C. glabrata is rarely isolated among infants and children but is more frequently found with increasing patient age.1,46

C. albicans is part of the normal flora of the gastrointestinal tract. Infections including BSIs caused by most Candida spp., particularly C. albicans, arise endogenously from the gastrointestinal mucosa, skin, and urinary tract.7 Invasive Candida infections occur when alteration of endogenous flora leads to overgrowth of yeast which, in the presence compromised skin or gastrointestinal mucosa integrity, translocates from its commensal environment to the bloodstream.7 Candida spp., including C. albicans, may be transmitted exogenously in ICU settings.8,9 Exogenous transmission of non-albicans Candida spp. through indirect contact with the ICU environment occurs commonly.8 For example, C. parapsilosis is an exogenous pathogen known for its ability to form biofilms on catheters and inert devices. C. parapsilosis persists in the nosocomial environment.10 Moreover, it is spread throughout the hospital through hand carriage by healthcare workers.10 Therefore, colonization with this pathogen is not a prerequisite for infection.10

Mortality

Candida BSIs are often difficult to detect. Symptomatically, BSIs due to Candida spp. are indistinguishable from BSIs of bacterial etiology. Candida spp. are cleared from the blood very efficiently by several organs, particularly the liver, and blood cultures yield positive results in only 50% of patients with hematogenously disseminated candidiasis. However, the ability of automated blood culture systems to recover Candida spp. has continued to improve. For example, in a simulated candidemia study, Candida spp. were isolated in 74% (479/648) of blood culture bottles.11 However, isolation rates were highest in aerobic blood and mycology culture bottles (98% [211/216] and 97% [210/216], respectively) but lowest in anaerobic culture bottles (27% [58/216]).11 The ability to detect growth improved as inoculum size increased.11 Although the time to detect growth varied with Candida spp., most species were detected within 24 to 48 hours. Growth was detected faster in aerobic and mycology culture bottles than in anaerobic bottles. These data and other studies demonstrated the improved ability of current technology to detect simulated or clinical candidemia due to most common and uncommon Candida pathogens in aerobic cultures.11,12

Even with improved ability to recover Candida spp. from the blood, Candida BSIs carry a relatively poor prognosis. Candida spp. isolated from the blood have consistently been identified as an independent predictor of mortality.1315 The overall attributable mortality of nosocomial BSIs among critically ill patients is 35%.16 This mortality rate for nosocomial BSIs in the ICU setting is comparable to the mortality rate associated with BSIs due to Candida spp. Historically, the estimated crude mortality rate associated with Candida BSIs hospital-wide and in the ICU setting has ranged from 35% to 69%, while the estimated attributable mortality has been 38%.14,17

Recent estimates suggest that the attributable mortality due to candidemia and other forms of invasive candidiasis ranges from 10% to approximately 50%.1 Moreover, data demonstrate that despite the advent of potent and safer anti-Candida antifungal therapy, the risk mortality associated with candidemia has essentially remained unchanged for at least 2 decades.19,20 Inadequate treatment may be a reason why mortality has not improved despite the availability of potent and safe antifungal therapy. Inadequate therapy resulting from delays in administration, treatment with an agent to which the organism is resistant, inadequate dosing or treatment duration, or failure to recognize and treat candidemia all contribute to the mortality associated with Candida BSI.2127 In particular, it is increasingly clear that delaying initiation of adequate antifungal therapy even 12 to 48 hours is independently associated with mortality in candidemia patients.22,23,26,28,29

Candidemia produces significant morbidity and adds as much as a month to the length of hospital stay.1,7 Given the severity of illness associated with this infection, the added length of stay utilizes significant healthcare resources. Considering the incidence of candidemia in the United States alone, it is not surprising that the estimated annual healthcare costs associated with this infection easily exceed $1 billion.20

Risk Factors

Among critically ill patients, risk factors for Candida infections are well described.30,31 Broad-spectrum antimicrobial use, colonization, indwelling vascular catheters, and hemodialysis have been consistently identified as independent risk factors for Candida BSIs.14 In most ICU settings, many of these risk factors are commonly present and unavoidable. The ICU itself provides an ideal environment for transmission of Candida spp. among patients, thus it is not surprising that prolonged ICU stay has been identified as an independent risk factor.32 A study using validated risk factors in a simulated ICU population demonstrated that in the presence of multiple risk factors, the probability of infection increases exponentially.32 For example, in a hypothetical critical care unit, if a patient had prior exposure to 4 antibiotic classes, the calculated risk of candidemia for that patient would range from 5% to 35%, depending on the overall baseline candidemia rate in the ICU, varying between 1% and 5%. However, if that same hypothetical patient subsequently had Candida spp. cultured from another (non-bloodstream) anatomic site, the calculated risk would increase substantially to 40% to 80%.32 Given how common many of the risk factors (such as indwelling catheters, antibiotics, immunosuppressants, and TPN) are in the ICU, these data illustrate the need to accurately predict or identify patients who truly are at risk so that therapy can be instituted as early as possible.

The risk factors for non–C. albicans and C. albicans BSIs are similar, and the probability of a patient having either infection cannot be differentiated based on clinical characteristics alone.30,31 Several studies have developed prediction rules to stratify patients at increased risk for developing invasive infections with either C. albicans or non-albicans Candida spp. in hopes of providing guidance for clinical decision making to prevent candidemia in the ICU. These prediction rules are based upon retrospective studies and assess the combination of ICU length of stay, prior Candida colonization, and other host risks.3336 While these systems demonstrate risk stratification is possible, they are somewhat complicated to apply, and some have questioned the practicality of certain components of individual prediction rules.31,37 Using the database from a large prospective multicenter Spanish study in which fungal colonization was assessed weekly along with other potential risk factors, León and colleagues developed the “Candida Score” based upon four independent risk factors: multifocal Candida spp. colonization, surgery upon ICU admission, severe sepsis, and total parenteral nutrition (TPN). The score, obtained by adding the statistical weight of each risk factor, has a cutoff value of 2.5, providing a sensitivity of 81% and specificity of 74% for identifying patients with current or future candidal infection. Patients with a score greater than 2.5 were more than 7 times as likely to have proven infection as patients with a Candida Score up to 2.5.35 A prospective multicenter observational study demonstrated that a Candida Score ≥3 discriminated between colonization and invasive candidiasis in non-neutropenic ICU patients colonized with Candida spp., with a minimum length of ICU stay of 7 days.37 These data lend credence to the idea of using the Candida Score for guiding the start of empirical antifungal therapy in the ICU. However, even though the Candida Score is promising, the clinical utility of such prediction rules in establishing the benefit of targeted antifungal prophylaxis remains to be established in prospective studies.38

Opportunistic Fungal Infections in Immunocompromised Critically Ill Patients

Invasive Aspergillosis in Critically Ill Patients with Hematologic Malignancies

In contrast to Candida spp., the burden of infection due to Aspergillus spp. is small.1 National hospital discharge data from the 1990s through 2003 reveal that there are approximately 10,000 aspergillosis-related hospitalizations annually in the United States.1 Nonetheless, Aspergillus spp. cause infection in critically ill populations immunocompromised by burns, cytotoxic chemotherapy, prolonged corticosteroid therapy, malignancy, leukemia, SOT or HSCT, and other congenital or acquired immunodeficiencies. Aspergillus spp. are ubiquitous environmental molds. While several hundred species of Aspergillus have been described, relatively few are known to cause disease in humans. Most Aspergillus infections are acquired exogenously via inhalation. In the absence of an effective immune response, airborne conidia invade sinus or lung vasculature. Although the lung is the most common site of invasive aspergillosis, Aspergillus spp. also demonstrate tropism for cutaneous, central nervous system (CNS), and cardiac vasculature.

The incidence of invasive aspergillosis in immunocompromised patients varies among specific populations.39 Among patients with hematologic malignancies, those with acute myelogenous leukemia have the highest incidence of invasive aspergillosis. For more than a decade the incidence of invasive aspergillosis in this population remained stable (5%-6%).40 However, advances in diagnosis (i.e., galactomannan assay, high-resolution computed tomography [CT] scan) have improved the ability to confirm cases that would previously been labeled as “suspected” invasive aspergillosis, and thus the incidence of this infection in patients with leukemia has risen significantly (12.7%).40 Like patients with leukemia, patients undergoing HSCT are at high risk for invasive aspergillosis. The incidence of invasive aspergillosis varies depending on transplant type but not type of conditioning regimen (myeloablative versus non-myeloablative).39 The incidence is higher among allogeneic HSCT recipients than among autologous HSCT recipients.39 In the HSCT population, whether the incidence of invasive aspergillosis is truly increasing or decreasing is difficult to ascertain, because the rate of autopsy continues to decline.41 The incidence of invasive aspergillosis among SOT is highest among lung transplant recipients and lowest among renal transplant recipients.39 Patients receiving HSCT or SOT can develop invasive aspergillosis shortly (within 40 days) after transplantation, but typically it occurs late post HSCT (>40-100 days) or SOT (>90 days).4245

In patients with acute leukemia or in HSCT recipients, prolonged neutropenia after cytotoxic chemotherapy or HSCT is the primary risk for early invasive aspergillosis. Risk factors associated with invasive aspergillosis in HSCT and SOT recipients vary with time after the transplant. However, in general, risks early in the transplant process are related to transplant related factors (underlying disease, neutropenia, type of transplant), biological factors (hyperglycemia, iron overload), and extrinsic factors (excluding spores from the environment, air filtration). In contrast, risks for invasive aspergillosis occurring later in the transplant process include transplant complications (acute GVHD (grade ≥ 3) and high-dose corticosteroid therapy.43

Lesions associated with invasive pulmonary aspergillosis evolve over a period of weeks. CT findings, especially the “halo sign,” are strongly suggestive of invasive aspergillosis and infection from other angioinvasive fungi in immunocompromised patients. Moreover, this finding is associated with significantly improved response and survival if antifungal therapy is initiated shortly upon detection of this sign of infection.46 The combination of radiologic and clinical data may help in the differential diagnosis of fungal disease.

Recent diagnostic efforts have focused on detecting non–culture-based serum markers (e.g., galactomannan test, 1,3-β-D-glucan, polymerase chain reaction [PCR]). Galactomannan is a cell wall constituent of Aspergillus spp. that can be detected in the serum during invasive infection. The test is specific for invasive aspergillosis and is commercially available as a sandwich enzyme immunoassay (ELISA) that detects circulating galactomannan. The values from this test have been shown to strongly correlate with the clinical outcome of patients with invasive aspergillosis.4749 Because 1,3-β-D-glucan is a cell-wall component of many fungal pathogens, it can be detected by colorimetric detection assays. Although the test is highly sensitive, the presence of 1,3-β-D-glucan in the serum is not specific for any fungi. Using both of these non–culture-based serum markers may improve the ability to diagnose invasive aspergillosis in high-risk populations and could lead to earlier diagnosis or improved monitoring of the success of antifungal therapy.50,51 The combination of radiologic, serologic, and clinical data may ultimately improve the diagnosis of invasive aspergillosis and speed up initiation of appropriate antifungal therapy.

Miscellaneous Pathogens in Critically Ill Patients with Hematologic Malignancies

Candida and Aspergillus spp. are the primary fungal pathogens in critically ill patients with hematologic malignancies. However, other pathogens such as Fusarium spp., Pseudallescheria spp., and the zygomycetes are increasing in frequency.7 Each of these less common organisms has characteristic clinical characteristics or tissue tropism. In addition, they are often less susceptible than Aspergillus spp. to systemic antifungal agents. Consequently, infections due to these pathogens are associated with high mortality. Of these, the zygomycetes (which cause mucormycosis) are the most common among critically ill patients, particularly in a surgical ICU. These angioinvasive pathogens are acquired through inhalation and produce a necrotic infection. Rhinocerebral and paranasal infections are common manifestations of zygomycetes. Common risks are diabetic ketoacidosis, immunosuppression, organ transplantation, skin damage, and a prolonged ICU stay. Data suggest that exposure to voriconazole prophylaxis to prevent invasive aspergillosis in certain immunosuppressed populations (i.e., HSCT recipients) may be a risk factor for zygomycosis.52

Cryptococcosis, Histoplasmosis, Blastomycosis, and Coccidioidomycosis in Critically Ill Patients

Cryptococcus neoformans, Histoplasma capsulatum var. capsulatum, Blastomyces dermatitidis, and Coccidioides immitis are not common pathogens in the ICU setting. These organisms can cause infection in patients with intact immune function. However, with the exception of B. dermatitidis, severe infections due to these pathogens are more common among critically ill immunocompromised populations, particularly those with AIDS and SOT recipients. Cryptococcosis is the third most common invasive fungal infection among SOT recipients.7

C. neoformans is a ubiquitous encapsulated yeast isolated from diverse environmental sources (i.e., soil, trees and plant material, and droppings from pigeons). This pathogen is primarily acquired by inhalation. In the lung, the organism elicits a cell-mediated response involving neutrophils, monocytes, and macrophages. The cryptococcal polysaccharide capsule, an important virulence factor, facilitates laboratory identification and recognition by host cell-mediated immune response and possesses immunosuppressive properties. The advent of AIDS significantly altered the incidence of cryptococcosis. Before the AIDS epidemic, cryptococcosis was an uncommon disease in the United States, but since then, the majority of cases have been associated with HIV infection. The prevalence of cryptococcosis in HIV in the United States has declined with the widespread use of fluconazole and highly active antiretroviral therapy to treat HIV infection. Cryptococcosis still produces significant acute mortality, but overall long-term outcomes have improved dramatically in the past 2 decades.53 Mortality among HIV-infected patients and SOT recipients is similar and is estimated to be approximately 15% to 20%.5355

Among critically ill immunosuppressed populations, cryptococcal infections typically involve the CNS. However, non-HIV cases may have only extra-CNS (i.e., skin, soft tissue, or osteoarticular) manifestations. The onset of this infection may be acute or gradual, and patients often present with nonspecific complaints. When the disease manifests as subacute meningitis or meningoencephalitis, classic meningeal findings such as photophobia or nuchal rigidity may be absent.

In cases of cryptococcal meningitis, characteristic cerebrospinal fluid (CSF) findings may be present; however, CSF leukocyte count can be low, and CSF protein and glucose values may be normal. Therefore, CSF analysis for cryptococcal antigen and culture of the organism are required to diagnose cryptococcal meningitis. Detection of the organism by India ink stain is highly specific but associated with low sensitivity (=50%). Determination of serum cryptococcal antigen using latex agglutination is a highly sensitive (≈99%) and specific test, and therefore it is an important component of the diagnosis of cryptococcal disease. In patients with cryptococcal meningitis, particularly those with AIDS, the serum cryptococcal antigen is usually positive, and usually titers are very high (i.e., >1 : 2048). Detection of antigen in the CSF strongly suggests infection, but in HIV-infected patients, false-negative results can occur in up to 10%, even in the presence of positive cultures. The definitive diagnosis of cryptococcal infection requires a positive culture for C. neoformans.

Histoplasmosis (caused by H. capsulatum var. capsulatum), blastomycosis (B. dermatitidis), and coccidioidomycosis (C. immitis) are the major endemic mycoses found in North America. Infections by these pathogens are reported primarily in distinct geographic areas, but owing to population mobility, they can be reported throughout the United States. H. capsulatum is endemically distributed primarily in the Mississippi and Ohio River valleys, B. dermatitidis is found primarily in the south central United States, the Mississippi and Ohio River valleys, and in certain regions of Illinois and Wisconsin. C. immitis is found primarily in the arid southwest regions of the United States. Infection with all these pathogens is acquired via inhalation. Overall, hospitalization is required in an estimated 4.6 and 28.7 cases per million children and adults, respectively.56 Nationwide, endemic mycoses require substantial healthcare resources to manage and produce significant crude mortality rates in children and adults (5% and 7%, respectively).56 The severity of histoplasmosis depends on host immune function and the extent of exposure, particularly in the immunocompetent host. Hematogenous dissemination from the lungs occurs in all infected patients, but in immunocompetent hosts, it is controlled by the reticular endothelial system. However, among elderly hosts or those with cell-mediated immune disorders (e.g., HIV infection), progressive disseminated infection readily occurs. After inhalation, B. dermatitidis can disseminate from the lungs to other organs as the yeast form. The primary pneumonia is often undetected and resolves without sequelae. Endogenous reactivation in the lungs, skin, or bones is often the first sign of infection.

C. immitis requires the inhalation of only a few arthroconidia to produce primary coccidioidomycosis. Like the other endemic mycoses, in the majority of patients, primary coccidioidomycosis typically manifests as an asymptomatic pulmonary disease. However, it can also manifest as an acute respiratory illness, chronic progressive pneumonia, pulmonary nodules and cavities, extrapulmonary nonmeningeal disease, and meningitis.57

Among critically ill patients, histoplasmosis manifests as either chronic pulmonary histoplasmosis or progressive disseminated (extrapulmonary) histoplasmosis. Chronic or cavitary pulmonary histoplasmosis occurs in middle-aged and elderly patients with underlying lung disease that compromises the ability of nonspecific host defenses to effectively clear the organism.

Progressive disseminated histoplasmosis occurs in healthy or critically ill immunocompromised hosts, but it is more common and severe in the latter population (i.e., patients with malignancies or HIV infection). The infection can disseminate to a variety of organs including the reticuloendothelial system, oropharyngeal and gastrointestinal mucosa, skin, adrenal glands, and kidneys.

Clinical manifestations of blastomycosis can mimic many other diseases, such as TB and cancer, but typically occurs as an asymptomatic infection, acute or chronic pneumonia, or disseminated (extrapulmonary) disease.58 Extrapulmonary blastomycosis typically afflicts the skin, bones, and genitourinary system.58 Cutaneous lesions are the most common skin manifestations of this disease.58 Extrapulmonary (disseminated) coccidioidomycosis afflicts 1% to 5% of all patients infected with C. immitis, and is deadly if not treated properly. Even with appropriate treatment chronic infection is common.57

image Systemic Antifungal Agents

Amphotericin B Formulations

Amphotericin B Deoxycholate

Amphotericin B deoxycholate (AmB-d), a polyene antifungal agent, disrupts biological membranes, thereby increasing their permeability. AmB-d also stimulates the release of cytokines, which causes arteriolar vasoconstriction in the renal vasculature.59

Overview of Toxicity

AmB-d infusion-related reactions, including hypotension, fever, rigors, and chills, occur in approximately 70% of patients.61 These reactions occur early in therapy and often subside with time. Pretreatment regimens consisting of diphenhydramine, acetaminophen, meperidine, and hydrocortisone may be used to prevent infusion-related reactions. The efficacy of these regimens is unclear, so their routine use is discouraged until the reactions occur, after which pretreatment regimens should be employed with subsequent dosing.61 Although common and noxious, infusion-related reactions rarely cause early termination of AmB-d therapy or interfere with the use of other medications.

AmB-d also produces dose-related toxicities, including nephrotoxicity, azotemia, renal tubular acidosis, electrolyte imbalance, cardiac arrhythmias, and anemia.59 AmB-d–induced nephrotoxicity is the most common dose-related toxicity.62 In the ICU this toxicity often limits the use of AmB-d or interferes with the ability to use other medicines. Saline hydration before dosing can reduce the incidence of AmB-d–induced nephrotoxicity, but in the ICU setting, the utility of saline hydration may be limited by fluid restriction employed to manage the fluid status of critically ill patients.

Lipid Amphotericin B Formulations

Amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), and liposomal amphotericin B (LAmB) are lipid AmB formulations that in many centers have supplanted the use of AmB-d. They all retain the activity of AmB-d but have significantly less associated nephrotoxicity than the parent drug.62

Toxicity Comparisons of Lipid Amphotericin B Formulations

Compared with AmB-d, the lipid formulations have significantly less associated nephrotoxicity.62 The formulations differ in the incidence of infusion-related reactions and other adverse events associated with AmB-d infusion.64,65 These reactions typically do not result in early termination of therapy.64,66 Observational safety comparisons between ABLC and LAmB suggest the two formulations have a similar nephrotoxicity profile, but prospective comparative data suggest LAmB may be somewhat less nephrotoxic than ABLC.62,67 There are few data comparing the safety of lipid AmB formulations to the triazole antifungal agents in critically ill patients. Given the safety of triazoles, it is unlikely the lipid AmB formulations will prove to be any safer.

Azole Antifungal Agents

Fluconazole, Itraconazole, Voriconazole, Posaconazole

The systemic azoles exert a fungistatic effect by dose-dependent inhibition of cytochrome P450 (CYP)-dependent 14α-demethylase, the enzyme necessary for the conversion of lanosterol to ergosterol, leading to the depletion of ergosterol, the essential sterol of the fungal cell wall, an event that ultimately compromises cell wall integrity. The degree of inhibition varies among the different azole agents, which accounts for differences in spectrum of activity.

Pharmacology and Pharmacokinetics

The triazoles differ subtly in chemical properties, which form the basis of the pharmacokinetic differences between the agents and the propensity of this class to interact with other medications. Such properties can limit the use of these agents, particularly itraconazole and posaconazole in the ICU setting. For example, the lack of an intravenous (IV) formulation often precludes the use of posaconazole and itraconazole in critically ill patients.

Several studies have examined fluconazole pharmacokinetics in critically ill patients.6870 In surgical ICU patients, fluconazole clearance correlates with creatinine clearance (CrCl), and its volume of distribution correlates with body weight.69 In addition, fluconazole volume of distribution is greater in this population than in healthy volunteers.69 The fluconazole half-life is markedly prolonged in surgical ICU patients.69 In patients with severe renal dysfunction (CrCl <30 mL/min), some recommend dosage reductions of 50%,69 but such reductions should be made cautiously and take into account the infecting pathogen in patients receiving fluconazole via enteral feeding tubes.69 Data suggest that the systemic availability of fluconazole is relatively unaffected by administration via enteral feeding tubes. However, serum concentrations obtained with standard doses administered via an enteral feeding tube may not be adequate to treat C. glabrata infections.68 Moreover, in critically ill abdominal trauma patients with and without abdominal wall closure, IV fluconazole may be warranted because the bioavailability of enterally dosed fluconazole in these patients is highly variable.70

Itraconazole is a highly lipophilic weak base and practically insoluble in water. It is available as a capsule and as an oral solution formulated in hydroxypropyl-β-cyclodextrin (HP-βCD). The IV solution was removed from the U.S. market in 2008; however, this dosage form may be available in other countries. Slow and erratic absorption of the capsule form precludes its use in critically ill ICU patients. HP-βCD enhances itraconazole solubility and improves its oral systemic availability. HP-βCD is poorly absorbed from the gastrointestinal tract, stimulates gastrointestinal secretion and propulsion, and causes diarrhea.

Under fasting conditions in healthy adults, itraconazole is rapidly absorbed from the oral solution, and compared to the capsule there is less interpatient and intrapatient variability in serum concentrations.71 After IV administration, renal elimination of itraconazole is negligible, but HP-βCD is renally eliminated (80%-90%). IV itraconazole was contraindicated in cases of significant renal impairment (CrCl ≤ 30 mL/min) because of concerns over the renal accumulation of HP-βCD.

Voriconazole is a derivative of fluconazole with limited aqueous solubility and improved antifungal activity. It is available in IV and oral formulations. IV voriconazole contains sulfobutyl ether β-cyclodextrin (SBECD) as a solubilizing agent. There are few data on how critically ill patients handle voriconazole. In healthy volunteers, voriconazole exhibits good oral availability and wide tissue distribution, with hepatic metabolism and renal excretion of metabolites.72 In patients with moderate to severe renal function, SBECD accumulates, and it is recommended that oral dosing be used in patients with a CrCl less than 50 mL/min.73 Oral dosing in critically ill patients is often not possible, therefore how SBECD is handled in critically patients on dialysis has been examined. A small study observed accumulation of SBECD in three patients during hemodialysis. No toxicity due to accumulation of SBECD was observed, and the accumulated dose values were lower but comparable with those used in previous toxicity studies with animals.73 Nonetheless, if possible, use of IV voriconazole in patients on hemodialysis should be avoided. Data demonstrate that voriconazole achieves adequate CSF concentrations.72

Posaconazole is available as oral suspension and exhibits linear pharmacokinetics with dosages between 50 and 800 mg/d. However, absorption is saturated at doses exceeding 800 mg/d.74 Posaconazole absorption is influenced by gastric pH and is optimal under acidic conditions.75

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